sash-ka/mdpi_arguments_relation

1arg_1	round_1	ann_1	arg_2	round_2	ann_2	annotation_name	is_attacks
2In order to address your feedback fully, we felt it necessary to split Figure 7. This has enabled us to accommodate the additional representative flow cytometric histograms displaying CD14 and CD68 expression changes. The data contained in the original Figure 7 is now split between Figure 7 (deals with CD14 and CD68 only) and Figure 8 (deals with CD11b and CD36). Changes highlighted in yellow on the resubmission.	2	1	The figures should be improved in quality so the work would take on another aspect. Figure 7b is not very credible, when U937 become macrogphages adhere to the plate and assume the morphology of a macrophage. the figure is not clear and not well visible. The authors should also show the flow cytometers panels related to cd68 and cd14. This figure does not convince me very much.	1	2	antiox11040683_perova	1
3Fig 7b. We have removed the Giemsa images and replaced with phase contrast images to better show cell morphology under our light microscope. We also include representative flow cytometric overlayed histograms, which display CD14 and CD68 expression changes between our Vector control and WT / CXXS BCAT1 cells. Included on these histograms is the mean fold MFI change (ratio).	2	1	The figures should be improved in quality so the work would take on another aspect. Figure 7b is not very credible, when U937 become macrogphages adhere to the plate and assume the morphology of a macrophage. the figure is not clear and not well visible. The authors should also show the flow cytometers panels related to cd68 and cd14. This figure does not convince me very much.	1	2	antiox11040683_perova	1
4Fig S4B. This is fully compensated. The black population illustrates the isotype control for the FITC and PE conjugated antibodies. These isotype controls were used to set the negative thresholds, as indicated by the quadrants on the plot. The red population shows positive binding of anti-CD36 and anti-CD11b to the U937 cells (gated on the previous plot S4A, FSC/SSC). The curve in the plot is not due to a compensation issue, it is demonstrating the up-regulation of CD36, which is followed by up-regulation of CD11b.	2	1	Small comment, the supplementary Fig. S4B would need some compensation work....this would be better to correct before final approval for publication ( up to editor).	1	2	antiox11040683_perova	1
5Fig 4d. This is going in the correct direction. The DCFDA histogram data presented to the right is based on the viable homogeneous U937 cell gated population, which was determined by forward scatter (FSC) and side scatter profile (SSC) in the left hand plot. Debris in the bottom left of this FSC/SSC plot includes dead cells, which are eliminated and not considered for DCFDA analysis.	2	1	Also the gating strategy on Fig. 4d ( is going in right direction), what I am missing here is the exclusion of dead cells?	1	2	antiox11040683_perova	1
6We have included a section dedicated to addressing this in the discussion section, along with supporting references. This additional narrative is added at line 645-660 and highlighted in yellow on the resubmission.	2	1	The data presented by the authors are robust and interesting but are based on a single AML cell line, which is not a bonafide AML cell line (derived from the pleural effusion of a 37-year-old, White, male patient with histiocytic lymphoma, according to ATCC). Thus, authors should discuss limitations in interpreting their findings.	1	2	antiox11040683_perova	1
7We have included what we have written below for your convenience: “The U937 cell line was originally isolated from the pleural effusion of a patient with histiocytic lymphoma [42]. Early characterisation studies showed that U937 cells differed from typical lymphoblastoid cell lines [42]. Because of their pro-monocytic phenotype, many regard the U937 cell line to be representative of an AML subtype M5, under the French-American-British (FAB) classification system [43–46]. This pro-monocytic phenotype and cytochemistry, has accounted for the wide use of U937 cells as a model to study AML, including ROS mediated monocyte to macrophage transition [32,49,50]. We identified U937 cells as having a relatively low basal expression of BCAT1 compared other myeloid cell lines [49], which would allow an effective comparison between BCAT1 overexpressing cells to the vector control. Taken together, the U937 cell line presented as a good cellular model to study the putative antioxidant effect of the BCAT1 CXXC motif in myeloid differentiation, which is a defining feature of AML [50]. However, our study is limited to a single FAB subtype model. Future work could extend our analysis and examine the antioxidant capacity of the BCAT1 CXXC motif in other FAB subtype models, for example HL60 (AML, M2) and NB4 (AML M3 aka APL) [45].”	2	1	The data presented by the authors are robust and interesting but are based on a single AML cell line, which is not a bonafide AML cell line (derived from the pleural effusion of a 37-year-old, White, male patient with histiocytic lymphoma, according to ATCC). Thus, authors should discuss limitations in interpreting their findings.	1	2	antiox11040683_perova	1
8The authors have now addressed all my major initial comments.	3	2	Fig 7b. We have removed the Giemsa images and replaced with phase contrast images to better show cell morphology under our light microscope. We also include representative flow cytometric overlayed histograms, which display CD14 and CD68 expression changes between our Vector control and WT / CXXS BCAT1 cells. Included on these histograms is the mean fold MFI change (ratio).	2	1	antiox11040683_perova	1
9"We agree that transient analysis is important in designing a robot joint. The following sentence has been added at the end of Conclusions: ""For future work we will develop variable stiffness techniques of this joint, and explore its application in a robot arm considering both kinetostatic and transient behaviors"""	2	1	Transient analysis followed by reliability experiments/analysis/modeling of the proposed structure would be interesting and critical in aspect of joint application contrains. In my opoinion is should be added or explained in context of scheduled follow-up activities.	1	2	app12052642_makarova	1
10The mentioned reference is focused on an analytical method for modeling large deflections in compliant mechanisms, while this work presents a method of enhancing the tensile strength of lamina emergent joints by using double-layer materials.	2	1	The article being evaluated is an extension of the above cited reference, and the authors would be well advised as to summarize this article, in part, and to delineate what has changed as of 2019, i.e. put this in a paragraph and to explain the subsequent evolution since 2019.	1	2	app12052642_makarova	1
11"As to the second comment, Ref. [34] has been new added in the reference list and the following sentence has been added at the end of the second paragraph of Introduction: ""Ref. [34] made a robot using double-layer LEMs, which is driven by magnetic force. This paper further discussed how to adjust the motion by changing different parameters of the mechanism""."	2	1	Secondly what is missing in the article is in terms of application a clear delineation as to what benefits robotics accrue by the developments summarized in this article .	1	2	app12052642_makarova	1
12We have rewritten the conclusions and abstract, and added additional keywords.	2	1	Keywords are not sufficient after the abstract.	1	2	app12052642_makarova	1
13"The following sentences have been added in the first paragraph of Introduction to mention the base paper and the related work (more references have been added): ""Finding suitable compliant joints [7] can be a key step in designing LEMs. Jacobsen et al. [8] first proposed the design concept of utilizing torsional deflection to obtain out-of-plane motions from planar structures, leading to a new group of compliant joints for LEMs called Lamina Emergent Torsional (LET) joints""."	2	1	Recent references are to be added as well as it has to be cited, majority of them are old references.	1	2	app12052642_makarova	1
14The references have been reformatted according to standard journal format.	2	1	References are not written in the standard journal format.	1	2	app12052642_makarova	1
15We have added more relevant references in this version.	2	1	Work relevant to the research topic is not incorporated, i.e., the work done by other researchers / authors in this field are not incorporated.	1	2	app12052642_makarova	1
16The contribution of this work with respect to the relevant work is further described in Introduction (as marked in the manuscript).	2	1	Please add more details regarding paper’s novelty, it is not very clear what are the novelties of this paper.	1	2	app12052642_makarova	1
17The theoretical part has been extended in the modeling section (page 3).	2	1	Please add more details of how the theory from the first sections is applied in the results section and better detail the theoretical part, in this version the theoretical part is almost inexistent.	1	2	app12052642_makarova	1
18The modeling section (page 3) has been extended to make it clear how the parameters were obtained.	2	1	Please detail how the parameters were obtained. -	1	2	app12052642_makarova	1
19The recommended and other relevant references have been added.	2	1	The state of the art it is very poor regarding representative papers, maybe the author could add the following publications:	1	2	app12052642_makarova	1
20Subsection 3.2 has been rewritten to add more details regarding the obtained results.	2	1	Please add more details regarding the obtained results.	1	2	app12052642_makarova	1
21The following sentence has been added at the end of first paragraph of Conclusions to clarify disadvantage of DL-LET: “The DL-LET joint is vulnerable to delamination of the two layers.”	2	1	Add the both the advantages and the disadvantages of the proposed method.	1	2	app12052642_makarova	1
22We agree with the referee that in any open system as we have here , information will leak out and a corresponding backaction on the wavefunction cannot be avoided. However, by operating with ultra-cold quantum particles far of any internal resonance, the coherence time can be pretty long. This was shown with BEC’S trapped in cavities (see e.g. Ref 9). The effect of localization via cavity transmission can be reduced by working at higher cavity photon numbers. Ultimately the interplay between measurement induced localization and coherence spreading by unitary evolution could be one of the most interesting points in setting up such an experiment. One should study a transition from classical to quantum behavior depending on the degree of observation of the system.	2	1	It remains unclear how the quantum regime (with coherent spatial delocalization and interference of probability amplitudes of different paths) could possibly be reached in a real experiment, as spontaneous scattering of photons (of the cavity light or of the side pumper) into free space would localize the atomic wavefuction into one lattice site and thus decohere any spatial delocalization.	1	2	atoms3030433_makarova	1
23Axes added.	2	1	For a quick orientation it would be helpful to indicate the x-axis	1	2	atoms3030433_makarova	1
24We have reformulated to avoid confusion and unsubstantiated claims: “The mechanism is reminiscent of the one exploited in the creation of artificial potentials in optical lattices~\cite{Struck2012Tunable} applied here to the classical regime”	2	1	"In Section I the authors write: ""The mechanism is similar to the ones exploited in the creation of artificial potentials in optical lattices [17]"". This statement is a bit misleading since [17] uses coherent (quantum-mechanical) tunnelling with complex tunnel amplitudes, whereas the present manuscript deals with classical trajectories and classical jump probabilities."	1	2	atoms3030433_makarova	1
25We have rephrased: “In this sense, this work is a stepping stones towards a proposal for implementing a quantum random walk mirroring progress already achieved with photons…”.	2	1	"This is similar to previous works on implementation of the quantum random walk with photons [18], atoms in optical lattices [19], ions in traps [20] or on a one-dimensional lattice of superconducting qubits [21]"": This statement is also misleading, because the cited references have reached the coherent quantum walk regime, while the present manuscript only hypothesizes about an (unspecified) possibility to enter the quantum regime."	1	2	atoms3030433_makarova	1
26We have added a clarifying statement in the beginning of section 2: “We consider an effective one-dimensional model”.	2	1	In Section II it should be clearly stated that this is a one-dimensional model, transverse forces or motion are not considered.	1	2	atoms3030433_makarova	1
27The referee is correct; in the convention that we specify the negative detuning corresponds to the regime where motional instabilities are avoided and cavity cooling is possible. We included this in the figure caption.	2	1	"in Fig. 2: ""such that c < 0 corresponding to the stable regime of cavity QED with moving atoms"": what does this mean? The regime of cavity cooling?"	1	2	atoms3030433_makarova	1
28As we specify now in the beginning of section 3: “We treat $\eta_T$ as a free varying parameter. In the following we set $\kappa=1$ for numerical simulations and normalize the time in units of $\kappa^{-1}$”.	2	1	In Section III the numerical value of \kappa is not given (only in the caption of Fig. 3 it is mentioned that \kappa is set to unity).	1	2	atoms3030433_makarova	1
29As the referee correctly infers the random walk is merely an effect of the time modulation of the potential. The classical limit without time delayed action (characteristic of the cavity) will reproduce the kind of walk obtained in the LT limit where Fig. 3 and the analysis has been performed. The other regime where the transverse field kicks the particle out of the longitudinal trap is a cavity effect as the effective force (transverse) has a different modulation than the simple cosine of the free space transverse wave. However, for fine tuning of parameters and to insure stability of trajectories we have used the cavity cooling effect.	2	1	Does the special spatio-temporal shape of the potential, which is shown in Fig. 3, and which enables the effective random walk motion, originate in genuine cavity quantum effects, or could a similar potential be generated also in the classical (bad cavity) limit (g -> 0, \eta_L -> infinity and \kappa large), or for a classical standing wave laser beam interfering with a classical transverse running wave?	1	2	atoms3030433_makarova	1
30Yes, some momentum diffusion can be expected. In principle using a sufficiently narrow cavity and suitable operation parameters cavity cooling could be tuned to cancel such unwanted heating. However, this is connected to dissipative dynamics and will change the effective operating parameters of the system. In the bad cavity limited on the other hand, one can expect some “cavity heating” instead of cooling, but the rate of this heating should be slow enough to allow for many kicks before it gets relevant.	2	1	In describing the action of the optical potential as quasi-random potential kicks, is there some long-term heating effect (i.e. an increase of the average energy of the atom)? Does cavity cooling play a role to counteract this in the numerical simulations?Response Response We thank the referee for an extremely careful reading of the manuscript, his/her appreciation of it and for the very constructive criticism expressed in this report.	1	2	atoms3030433_makarova	1
31We have corrected the sign in the commutation relation.	2	1	In the paragraph following Eq. (2), please check the commutation relations between the raising (sigma^+) and lowering (sigma^-) operators and the Pauli matrix sigma^z. I suspect it should be [sigma^+,sigma^z] = - 2 sigma^+ and [sigma^-,sigma^z] = + 2 sigma^- .	1	2	atoms3030433_makarova	1
32We have added a proper reference as Ref. [23].	2	1	"A couple of lines below Eq. (4), the Authors write ""We proceed in a standard way to derive equations of motion for classical quantities."" I would suggest to provide a reference to guide the less experienced reader."	1	2	atoms3030433_makarova	1
33We have added the definition for \gamma in the text. Here we focus on a dispersive regime of weak atomic excitation, where the so called dipole force dominates the mechanical atom field interaction and spontaneous emission plays a negligible role. In this limit the mechanical forces can be derived from a deterministic (time dependent) optical potential (see refs. 7-9 for details). However, as the referee points out, in the nonlinear dynamical regime, the effects stemming from the inclusion of a random spontaneous emission could be amplified. A similar randomness is connected to cavity cooling in a regime of weak coherent intra-cavity fields. This certainly will have to be considered in a quantum treatment. In our simulation we got the “quasi random” dynamics from deterministic motion connected to details of the initial conditions without including random forces.	2	1	In the equations of motion for the atoms [Eqs. (6) and (7)] it is introduced the quantity gamma, which, I guess, is the atomic decay rate. Please, provide a definition of gamma. What is, if any, the role of gamma (spontaneous atomic decay rate) in the physical process under consideration? In the analytical results, derived in the adiabatic limit, gamma is eliminated and does not play any role. I wonder if one can draw any conclusion from the numerical simulations, where other regimes could have been explored.	1	2	atoms3030433_makarova	1
34Indeed all the above mentioned expressions were missing a factor of \kappa as the referee correctly observed.	2	1	"At the end of Section IV C. ""Optical forces"" the time independent value of the force is derived. Please, check this value. I'm afraid there is a factor k missing (simple dimensional analysis shows that something is wrong with it). The same argument (dimensional analysis) applies to Eqs. (24), (25) and (27). Please check again these expressions.”"	1	2	atoms3030433_makarova	1
35The analytical considerations fit very well with numerical results. Indeed, in this regime, we have performed the simulations by choosing parameters derived from analytical considerations. The R6 emergence of the jump regime is directly connected with the increase of the LT force to the value of the longitudinally-induced force but the fine tuning of the parameters is a bit tricky in order to insure that only jumps to neighbouring sites occur. Therefore we have restricted our presentation to the other regime where the jumps are strictly occurring owing to the transverse-longitudinal time modulation of the potential.	2	1	"In section VI E. ""Trapping by longitudinal pumping"", one can analytically estimate the threshold value for the transverse pumping. How does this analytical result compare with the numerical simulations?"	1	2	atoms3030433_makarova	1
36We have fixed this mistake.	2	1	Finally, some stylistic considerations: Please, be consistent with the choice of subscripts and superscripts: in the first column of page 2 the Pauli operator is denoted as sigma^z (superscript), whereas in the second column becomes sigma_z (subscript).	1	2	atoms3030433_makarova	1
37We changed the order of the figures and corrected the reference to the wrong figure.	2	1	Figure 4 is mentioned in the main text AFTER Fig. 5. It would be more logical to exchange their presentation order and, consequently, the figures numbering. Indeed, the same Authors already refer to the single trajectory plot as Fig. 4 (c) [see paragraph below Eq. (13)].	1	2	atoms3030433_makarova	1
38Comma has been introduced.	2	1	Page 4, first paragraph, the particle initial conditions are chosen in the interval [ - 0.1, 0.1] (in the text a comma is missing).	1	2	atoms3030433_makarova	1
39The b) has been eliminated.	2	1	"Page 5, first column, second paragraph ""... one can inspect Eq. (11) b) where the right-hand side ..."". Please, eliminate ""b)"" since it is simply Eq. (11). The same misprint appears at page 8 in the paragraph between Eqs. (32) and (33)."	1	2	atoms3030433_makarova	1
40Subscript has been introduced.	2	1	"Page 6, ""Optical forces"": there is a missing subscript L in the first force term at the end of the first paragraph, just before Eq. (21)."	1	2	atoms3030433_makarova	1
41We have restricted the analysis to 2 curves (full and dashed) and a thinner red dashed curve corresponding to the analytical solution in the lower plots. The visibility is clearly increased and the message stays the same.	2	1	Figure 8, Force correlation functions and numerical solutions of the variance: when printed in grey scale some lines are very faint (especially those in green and cyan). Try to use other colors and/or thicker lines.	1	2	atoms3030433_makarova	1
42If we understand correctly, the reviewer’s argument, i.e., a reduction in RNA when the cells were cultured in the presence of HSA may be due to the HSA’s RNA-hydrolyzing activity, requires that HSA contacts the RNA that will be hydrolyzed. This is not the case; HSA and the other fluids tested as inductors were added to the growth medium (LB) medium, and the cells were allowed to grow in these conditions for 5 h at 37ºC. After that, the cells were collected, and RNA was extracted. Since HSA does not reach the cytosol, at least not in an intact manner, hydrolysis seems not possible during cell growth. It could be argued that some RNA is hydrolyzed during extraction, but for this to be the case, one should assume that the cells were not well washed after being pelleted by centrifugation, which is not the case. Therefore, the RNA is intracellular at all moments during the experiment, and the HSA stays in the milieu. It is also worth mentioning that the presence of HSA in the growth medium produced a reduction only in some mRNA species. These results speak against an unspecific hydrolyzing effect. We also want to underscore that all RNA samples were checked after extraction. Agarose gels electrophoresis confirmed the integrity of RNA and lack of DNA contamination. The same cDNA amount for every condition was used to perform qRT-PCR assays.	2	1	It is known that HSA can bind RNA and DNA and has RNA hydrolyzing activity. In this way your experiment in par 2.2. may lead to not all RNA after incubation with such amount of albumin. That is why some of your effects may have other explanations. Have you done some control experiments? Maybe your effect is much higher or lower.	1	2	biomedicines10030600_perova	1
43Finally, the article provided by the reviewer describes HSA hydrolysis of extracellular, not intracellular, RNA.	2	1	https://www.sciencedirect.com/science/article/abs/pii/S0960894X08011086?via%3Dihub	1	2	biomedicines10030600_perova	1
44We agree that confirming that the effect of cefiderocol is bactericidal under the conditions tested is important. We have indeed carried out some experiments in the presence of human fluids. They actually show that adding these components to the growth medium does not modify the bactericidal nature of the action of the antibiotic. A follow-up project that will be submitted for publication in the near future extends the studies of the effects produced by human fluids, and their components will include the experiments demonstrating a bactericidal effect of cefiderocol. We would prefer to include those results in the upcoming publication.	2	1	It would be of great interest if for the key results the authors would also provide MBC and / or time-resolved kill-curves. I believe this kind of data would be of great relevance for assessing the clinical relevance of the observed effects.	1	2	biomedicines10030600_perova	1
45Thanks for pointing out the error in the range. Correction made in the text.	2	1	"Introduction Line 31 – ""(4-10 Hz) induced…"" this is not theta range; please correct."	1	2	brainsci11121640_makarova	1
46Reference added.	2	1	Line 32 – add the reference.	1	2	brainsci11121640_makarova	1
47No, we did not. We have added a statement in the study limitations to address the issue.	2	1	Methods Participants Did the authors take note of the menstrual cycle of the female participants?	1	2	brainsci11121640_makarova	1
48"The three left-handed participants exhibited rMT and aMt typical of young adults of their age (Right, n=16, mean rMT 42%, aMT, 32%, see below for Left). We did not perform bilateral testing, so we cannot comment on hemispheric differences in excitability. However, our own investigation on the matter showed that Left-handers had higher rMT on the right hemisphere and, in fact, those individuals exhibited comparable rMT on the left hemisphere to that of mixed and right-handed individuals ( See Figure 3 in Davidson & Tremblay 2013) Subject Left-handed rMT aMT KY13 56% 46% KY8 36% 34% KY19 54% 38% Davidson, T., and F. Tremblay. ""Hemispheric Differences in Corticospinal Excitability and in Transcallosal Inhibition in Relation to Degree of Handedness."" PloS One 8, no. 7 (2013): e70286."	2	1	Although the differences in handedness would not profoundly affect the overall results, can the author check if there were significant differences in stimulation intensity (AMT and RMT) in right and left-handed participants? Left-handed individuals often have a high threshold on the left motor cortex.	1	2	brainsci11121640_makarova	1
49The statement has been revised. We think it is important for readers to know that participants wore masks during testing because of the pandemic.	2	1	Line 89-90: edit this part.	1	2	brainsci11121640_makarova	1
50Yes, there are some differences given the difference in pulse configuration and coil output, However, rMT and aMT with the two stimulators were highly correlated at the individual level (r2=0.55).	2	1	Results Are there differences in stimulation intensities taken from the two devices (Magstim Rapid and BiStim2)?	1	2	brainsci11121640_makarova	1
51We have revised the statistical analysis given the Reviewer’s comment below. Thanks to the Reviewer, we found out that there was a duplicate value in the dataset for MEP amplitude (hence the issue with 20 subjects in Figure 3). The error has been corrected and the analysis re Note that the correction did not change the results or the conclusions. We now report for the ANOVA’s the F value and the partial eta squared to indicate the size of the intervention. Would it be interesting if the present data can give the same effect size (0.71) as those reported by Chung et al. (2016)? Indeed, it would be interesting. The size of the intervention for variations in MEP amplitude, as reflected in eta squared, is 0.19, which appears smaller than that reported by Chung et al. However, such an effect size could hardly be compared with the “standardized mean difference’ computed by Chung et al. The SMD is based on the assumption that differences in standard deviations among studies reflect differences in measurement scales and not real differences in variability among study participants (which is the case here)..	2	1	Can you report the F value and effect size?	1	2	brainsci11121640_makarova	1
52Please see above our reply regarding F values.	2	1	In line 209, the authors reported that “Of 21 participants, 19 (13 females) completed the protocol without any issues. Two female participants had to be excluded….”. However, looking at Figure 3, it is obvious that plotted data were from 20 participants. Can the author correct this discrepancy?	1	2	brainsci11121640_makarova	1
53"We agree it does seem arbitrary but this approach has been used by many other investigators (see Hinder et al or Perellon et al) to assess neuroplastic responses to rTMS. In this respect, the ±10% cutoff provides a reasonable criterion to classify responders given the variability of responses to rTMS interventions. Hinder, M. R., E. L. Goss, H. Fujiyama, A. J. Canty, M. I. Garry, J. Rodger, and J. J. Summers. ""Inter- and Intra-Individual Variability Following Intermittent Theta Burst Stimulation: Implications for Rehabilitation and Recovery."" Brain Stimulation 7, no. 3 (2014): 365-71. Perellon-Alfonso, R., M. Kralik, I. Pileckyte, M. Princic, J. Bon, C. Matzhold, et al. ""Similar Effect of Intermittent Theta Burst and Sham Stimulation on Corticospinal Excitability: A 5-Day Repeated Sessions Study."" European Journal of Neuroscience 48, no. 4 (2018): 1990-2000."	2	1	Is the cut-off plus or minus 10 standard for the responder and non-responders? Looking again at Figure 3, we can observe very high variability. In my opinion, plus or minus 10% is arbitrary.	1	2	brainsci11121640_makarova	1
54We have corrected the sentence to state that SICF is observed when two stimuli are given at or above threshold.	2	1	Discussion Line 402: in SIFC, one pulse is suprathreshold, and the other is subthreshold.	1	2	brainsci11121640_makarova	1
55We agree with the Reviewer that having a direct comparison with the 50 Hz protocol would have been ‘ideal’ but we have clearly stated the reasons as to why we did not perform such a comparison. First, our primary goal was to describe the effects of a modified 30 Hz iTBS protocol and not to test the relative efficacy of 30 vs 50 Hz bursts. Besides, as we have stated, there is already ample evidence of the effects of 50 Hz/5 Hz in the literature. Second, as we have explained in the limitations, our study was performed in the context of a worldwide pandemic. In this respect, we disagree with the reviewer. The pandemic has and continues to have a major impact on our research activities. Our lab is located in a geriatric hospital setting. For this reason, we had to follow very strict rules regarding who was coming on the premises and how long they would stay. We were allowed to recruit research participants only if they came for a short period and stayed in one room. A comparison between 30 and 50 Hz protocols would have meant having participants come twice (on different days), exposing them each time to risks for COVID. As for the benefits of the 30 Hz protocol, those are clearly stated in the discussion regarding the number of responders and the size of the facilitation.	2	1	Why did not compare to the sham stimulation group and 50 Hz/ 5 Hz standard iTBS protocol? I think COVID-19 is not reason. Do you think 30 Hz/6 Hz TBS protocol (intermittent mode) increased MEP amplitude as compared to 50 Hz/ 5 Hz standard iTBS? What are the benefits of 30 Hz/6 Hz TBS protocol (intermittent mode) in comparison with 50 Hz/ 5 Hz standard iTBS?	1	2	brainsci11121640_makarova	1
56We have added a sentence to clarify that participants were screened for health conditions.	2	1	Does the participants have a neurological disease or other diseases? Please write in the manuscript.	1	2	brainsci11121640_makarova	1
57We collected more MEPS at baseline to account that variations in excitability are often larger when participants received their first series of TMS pulses (even if they have received some stimuli before collecting data to experience the sensation). Thus, 20 MEPs were deemed adequate to get a reliable estimate of resting corticomotor excitability. Along with the same reasoning, we collected 15 MEPs post iTBS since participants were now more familiar with the sensation elicited by TMS pulse and saved time. As we have explained, we had constraints imposed on us by the local REB to limit the time participants were on-site. The fact that we use 130% rMT for the test intensity also reduced inter-trial variability to provide reliable estimates of corticospinal excitability.	2	1	The single-pulse TMS elicited 20 MEPs at baseline but at three specific time points after post-iTBS (i.e., 5-, 20- and 45-min) just elicited 15 MEPs respectively. Why did not also test 20, 25 or 30 MEPs?	1	2	brainsci11121640_makarova	1
58We have revised the sentence so that abbreviations are defined.	2	1	In line 125, MT needs to be defined.	1	2	brainsci11121640_makarova	1
59Correction made.	2	1	In line 145, full stop marked an error.	1	2	brainsci11121640_makarova	1
60done.	2	1	In line 28, please define rTMS.	1	2	brainsci11121640_makarova	1
61We have provided more explanations in the text as to how we used the MTAS software to estimate MT.	2	1	How do you test the aMT and rMT?	1	2	brainsci11121640_makarova	1
62We have added more details as to how the hotspot was determined?	2	1	Please give the detailed process. How do you get the hotspot?	1	2	brainsci11121640_makarova	1
63Corrections were made to check for extra spaces.	2	1	In lines 459 and 461, pay attention to the space between words.	1	2	brainsci11121640_makarova	1
64Correction done. The F value has been added.	4	1	In line 253, where is the F value?	3	2	brainsci11121640_makarova	1
65The coefficient of determination is for the regression analysis and indicates that Lat differences were significant predictors of MEP facilitation. However, as we explained in the text, when participants were sorted into two groups (early and late I-waves), the difference between the two was not significant according to the Mann-Whitney U test.	4	1	In line 282, the result showed r2 = 0.24, p = 0.03 but it is a difference in Fig. 5.	3	2	brainsci11121640_makarova	1
66Actually, we did, but it seems that the new figure legend with the correction was not properly inserted when the system reformated the document.	4	1	Although you state you defined the rMT in Fig. 1 you did not.	3	2	brainsci11121640_makarova	1
67Thanks for pointing out the error in the range. Correction made in the text.	2	1	"Line 31 – ""(4-10 Hz) induced…"" this is not theta range; please correct."	1	2	brainsci11121640_perova	1
68Reference added.	2	1	Line 32 – add the reference.	1	2	brainsci11121640_perova	1
69No, we did not. We have added a statement in the study limitations to address the issue.	2	1	Did the authors take note of the menstrual cycle of the female participants?	1	2	brainsci11121640_perova	1
70"The three left-handed participants exhibited rMT and aMt typical of young adults of their age (Right, n=16, mean rMT 42%, aMT, 32%, see below for Left). We did not perform bilateral testing, so we cannot comment on hemispheric differences in excitability. However, our own investigation on the matter showed that Left-handers had higher rMT on the right hemisphere and, in fact, those individuals exhibited comparable rMT on the left hemisphere to that of mixed and right-handed individuals ( See Figure 3 in Davidson & Tremblay 2013) Subject Left-handed rMT aMT KY13 56% 46% KY8 36% 34% KY19 54% 38% Davidson, T., and F. Tremblay. ""Hemispheric Differences in Corticospinal Excitability and in Transcallosal Inhibition in Relation to Degree of Handedness."" PloS One 8, no. 7 (2013): e70286."	2	1	Although the differences in handedness would not profoundly affect the overall results, can the author check if there were significant differences in stimulation intensity (AMT and RMT) in right and left-handed participants? Left-handed individuals often have a high threshold on the left motor cortex.	1	2	brainsci11121640_perova	1
71The statement has been revised. We think it is important for readers to know that participants wore masks during testing because of the pandemic.	2	1	Line 89-90: edit this part.	1	2	brainsci11121640_perova	1
72Yes, there are some differences given the difference in pulse configuration and coil output, However, rMT and aMT with the two stimulators were highly correlated at the individual level (r2=0.55).	2	1	Are there differences in stimulation intensities taken from the two devices (Magstim Rapid and BiStim2)?	1	2	brainsci11121640_perova	1
73We have revised the statistical analysis given the Reviewer’s comment below. Thanks to the Reviewer, we found out that there was a duplicate value in the dataset for MEP amplitude (hence the issue with 20 subjects in Figure 3). The error has been corrected and the analysis re Note that the correction did not change the results or the conclusions. We now report for the ANOVA’s the F value and the partial eta squared to indicate the size of the intervention.	2	1	Can you report the F value and effect size? Would it be interesting if the present data can give the same effect size (0.71) as those reported by Chung et al. (2016)?	1	2	brainsci11121640_perova	1
74Indeed, it would be interesting. The size of the intervention for variations in MEP amplitude, as reflected in eta squared, is 0.19, which appears smaller than that reported by Chung et al. However, such an effect size could hardly be compared with the “standardized mean difference’ computed by Chung et al. The SMD is based on the assumption that differences in standard deviations among studies reflect differences in measurement scales and not real differences in variability among study participants (which is the case here)..	2	1	Can you report the F value and effect size? Would it be interesting if the present data can give the same effect size (0.71) as those reported by Chung et al. (2016)?	1	2	brainsci11121640_perova	1
75Please see above our reply regarding F values.	2	1	In line 209, the authors reported that “Of 21 participants, 19 (13 females) completed the protocol without any issues. Two female participants had to be excluded….”. However, looking at Figure 3, it is obvious that plotted data were from 20 participants. Can the author correct this discrepancy?	1	2	brainsci11121640_perova	1
76"We agree it does seem arbitrary but this approach has been used by many other investigators (see Hinder et al or Perellon et al) to assess neuroplastic responses to rTMS. In this respect, the ±10% cutoff provides a reasonable criterion to classify responders given the variability of responses to rTMS interventions. Hinder, M. R., E. L. Goss, H. Fujiyama, A. J. Canty, M. I. Garry, J. Rodger, and J. J. Summers. ""Inter- and Intra-Individual Variability Following Intermittent Theta Burst Stimulation: Implications for Rehabilitation and Recovery."" Brain Stimulation 7, no. 3 (2014): 365-71. Perellon-Alfonso, R., M. Kralik, I. Pileckyte, M. Princic, J. Bon, C. Matzhold, et al. ""Similar Effect of Intermittent Theta Burst and Sham Stimulation on Corticospinal Excitability: A 5-Day Repeated Sessions Study."" European Journal of Neuroscience 48, no. 4 (2018): 1990-2000."	2	1	Is the cut-off plus or minus 10 standard for the responder and non-responders? Looking again at Figure 3, we can observe very high variability. In my opinion, plus or minus 10% is arbitrary.	1	2	brainsci11121640_perova	1
77We have corrected the sentence to state that SICF is observed when two stimuli are given at or above threshold.	2	1	Line 402: in SIFC, one pulse is suprathreshold, and the other is subthreshold.	1	2	brainsci11121640_perova	1
78We agree with the Reviewer that having a direct comparison with the 50 Hz protocol would have been ‘ideal’ but we have clearly stated the reasons as to why we did not perform such a comparison. First, our primary goal was to describe the effects of a modified 30 Hz iTBS protocol and not to test the relative efficacy of 30 vs 50 Hz bursts. Besides, as we have stated, there is already ample evidence of the effects of 50 Hz/5 Hz in the literature. Second, as we have explained in the limitations, our study was performed in the context of a worldwide pandemic. In this respect, we disagree with the reviewer. The pandemic has and continues to have a major impact on our research activities. Our lab is located in a geriatric hospital setting. For this reason, we had to follow very strict rules regarding who was coming on the premises and how long they would stay. We were allowed to recruit research participants only if they came for a short period and stayed in one room. A comparison between 30 and 50 Hz protocols would have meant having participants come twice (on different days), exposing them each time to risks for COVID. As for the benefits of the 30 Hz protocol, those are clearly stated in the discussion regarding the number of responders and the size of the facilitation.	2	1	Why did not compare to the sham stimulation group and 50 Hz/ 5 Hz standard iTBS protocol? I think COVID-19 is not reason. Do you think 30 Hz/6 Hz TBS protocol (intermittent mode) increased MEP amplitude as compared to 50 Hz/ 5 Hz standard iTBS? What are the benefits of 30 Hz/6 Hz TBS protocol (intermittent mode) in comparison with 50 Hz/ 5 Hz standard iTBS?	1	2	brainsci11121640_perova	1
79We have added a sentence to clarify that participants were screened for health conditions.	2	1	Does the participants have a neurological disease or other diseases? Please write in the manuscript.	1	2	brainsci11121640_perova	1
80We collected more MEPS at baseline to account that variations in excitability are often larger when participants received their first series of TMS pulses (even if they have received some stimuli before collecting data to experience the sensation). Thus, 20 MEPs were deemed adequate to get a reliable estimate of resting corticomotor excitability. Along with the same reasoning, we collected 15 MEPs post iTBS since participants were now more familiar with the sensation elicited by TMS pulse and saved time. As we have explained, we had constraints imposed on us by the local REB to limit the time participants were on-site. The fact that we use 130% rMT for the test intensity also reduced inter-trial variability to provide reliable estimates of corticospinal excitability.	2	1	The single-pulse TMS elicited 20 MEPs at baseline but at three specific time points after post-iTBS (i.e., 5-, 20- and 45-min) just elicited 15 MEPs respectively. Why did not also test 20, 25 or 30 MEPs?	1	2	brainsci11121640_perova	1
81We have revised the sentence so that abbreviations are defined.	2	1	In line 125, MT needs to be defined.	1	2	brainsci11121640_perova	1
82Correction made.	2	1	In line 145, full stop marked an error.	1	2	brainsci11121640_perova	1
83done.	2	1	In line 28, please define rTMS.	1	2	brainsci11121640_perova	1
84We have provided more explanations in the text as to how we used the MTAS software to estimate MT.	2	1	How do you test the aMT and rMT?	1	2	brainsci11121640_perova	1
85We have added more details as to how the hotspot was determined?	2	1	Please give the detailed process. How do you get the hotspot?	1	2	brainsci11121640_perova	1
86Corrections were made to check for extra spaces.	2	1	In lines 459 and 461, pay attention to the space between words.	1	2	brainsci11121640_perova	1
87Correction done. The F value has been added.	4	1	In line 253, where is the F value?	3	2	brainsci11121640_perova	1
88The coefficient of determination is for the regression analysis and indicates that Lat differences were significant predictors of MEP facilitation. However, as we explained in the text, when participants were sorted into two groups (early and late I-waves), the difference between the two was not significant according to the Mann-Whitney U test.	4	1	In line 282, the result showed r2 = 0.24, p = 0.03 but it is a difference in Fig. 5.	3	2	brainsci11121640_perova	1
89Actually, we did, but it seems that the new figure legend with the correction was not properly inserted when the system reformated the document.	4	1	Although you state you defined the rMT in Fig. 1 you did not.	3	2	brainsci11121640_perova	1
90The diesel generator equal to the rating of base load is kept as backup to avoid total black out situation of the system.	2	1	In the proposed system solar PV, wind generator and battery are the main generating system. As the proposed system is in isolated mode, how continuity of power supply be maintained?	1	2	en15031006_makarova	1
91According to your suggestion, we have improved the quality of Figures as can see Figure 1 and Figure2.	2	1	The quality of the figures needs to be improved.	1	2	en15031006_makarova	1
92According to your suggestion, we have modified the Equations 4, 9 and 12 in the revised version of the manuscript as fellows.	2	1	Equations 4, 9, and 12 include some corrections and need to be modified.	1	2	en15031006_makarova	1
93According to your suggestion the baseload is added in the result section as follows: In addition, to further validate the proposed system, the appliance schedule pattern for Monday is drawn in Figure 10 and Figure 9 represents the appliance weightage given by consumers for Monday. In addition, Figure 8 represents the power generated graph for the same day. The baseload is calculated as 1000 watts for each house to keep basic appliances turn ON uninterruptedly. As there are 5 houses in the community the total base power for the system is 5000 watts. The excess power is utilize to turn ON the schedulable appliances on Monday.	2	1	It could be better to include base load ratings in the results section (Fig: 10)	1	2	en15031006_makarova	1
94As Sizing of the grid system is not the main goal of the article, but as per your suggestion, it is briefly discuss in the subsections of Mathematical modelling of the Energy sources. Both solar and wind systems are designed for output power equal to the consumer’s load whose annual load curve peak is maximum out of all the consumer’s in the community. Battery storage systems have the capability to supply uninterrupted power equal to the base load of the system up to 6 hours. And diesel generator equal to the rating of system’s base load is kept as a backup to avoid total black out situation. The designed system is not the time-varying tariff, therefore the overall system is designed to treat each consumer of the community equally. In time-varying tariff based system, the sizing of the system is the main objective as to accommodate the wealthy consumers of the community.	2	1	Sizing of renewable energy sources and battery systems were not properly explored.	1	2	en15031006_makarova	1
95According to your suggestion the consumer comfortability is discussed from line 144-160. In this work, a DSM algorithm is proposed by using renewable resources PV and wind turbines for those houses that are located far away from the main city.	2	1	Please discuss how consumers’ comfortability is marinated in the proposed method.	1	2	en15031006_makarova	1
96According to your suggestion, in the revised version of the manuscript, the unnecessary use of subjective pronoun is removed and overall writing of the paper is improved.	2	1	Authors should avoid using the subjective pronoun “we” in academic works	1	2	en15031006_makarova	1
97Thank you for your comment. Due to the lack of real time datasets, we have used the publically available datasets for the verification of the proposed system.	2	1	In such a study an experimental case must be presented in a specified region.	1	2	en15031006_makarova	1
98Battery storage bank is included in the system to provide the baseload power in the time when renewable sources are not suffice to meet the baseload power demand. Diesel generators equal to the rating of base load is kept as backup to avoid total black out in worse conditions. Our objective is to schedule and shift the controllable appliances by estimating hourly power generation and considering consumer demand as a variable function. The appliances are prioritized based on their need and demand to achieve optimum energy utilization. The main contribution of this paper include: A demand side management algorithm is proposed to fulfil the energy gap between generation and consumer’s demand for standalone renewable energy system. K-mean clustering is used to make clusters of the data based on two factors: probability of turning ON a specific appliance at time t and priority number given by consumer to that specific appliance. Linear integer programming is used to schedule the appliances clusters based on the available power and state of charge of the battery system. According to your suggestion, the novelty of the proposed work has been made more clear and understandable for readers in the introduction section as follows: In this work, a DSM algorithm is proposed by using renewable resources PV and wind turbines for those houses that are located far away from the main city.	2	1	The authors should carefully distinguish the new contributions of their work from the new existing studies (DOI: 10.1016/j.est.2020.101221).	1	2	en15031006_makarova	1
99According to your suggestion, we have modified the literature review and included some latest references i.e., [22][29][30][32]. In addition, we organized the literature review in more comprehensive way.	2	1	A comprehensive deeper literature review is necessary to address the research issue, Also authors need to provide a literature survey in an organized way.	1	2	en15031006_makarova	1
100According to your suggestion, we have improved the Figures as can be seen in the revised version of the manuscript.	2	1	All the figures need to be improved.	1	2	en15031006_makarova	1
101The quoted literature has been adapted to the ACS Style Guide. For that, the authors used to software package Zotero.	2	1	The citations are not formatted according to the journal guidelines. Please revise.	1	2	healthcare10040723_makarova	1
102STD are included in the all tables were indicated: sum+STD has been added in the legend.	2	1	Include the full form of STD described in the results.	1	2	healthcare10040723_makarova	1
103In Table 3 (=) has been changed into (0). It was a typo, sorry.	2	1	Table 3 “Health apps and computer algorithms are for patients disturbing (=)…” should “(=)” be “(0)”?	1	2	healthcare10040723_makarova	1
104Line 252: 7/24 has been changed into 24/7.	2	1	Line 252, 24/7 is the commonly accepted form of 7/24.	1	2	healthcare10040723_makarova	1
105Line 267 and 268, the description of figure 1 “focused on senses” means that the diagnostic workup should be more focused on the physical examination (the doctor’s senses) rather than based on technical diagnostics. In the revised manuscript has been added in line 270 “and use their senses in physical examinations rather than rely on impersonal technical tools for the diagnostic work-up”.	2	1	Line 267 and 268, the description of figure 1 is not clear. Does “focused on senses” mean in-person patient-doctor interaction?	1	2	healthcare10040723_makarova	1
106In Line 266/267 the term “undermine” was wrong. It has been changed into “ease”. Thank you for the hint.	2	1	Table 4 data suggest Digital networks increase doctor nurse communication but Line 266 says it undermines the same. Can you clarify?	1	2	healthcare10040723_makarova	1
107Table 5: The students could rank their answer. 1 = don’t know, 2= false up to 7 = fully agree. The statistical calculation was done only for ranks 2 to 7, excluding the students, who could not or didn’t want to answer the question. The authors knew from the qualitative study part, that some students had no knowledge about AI. Therefor the “don’t know” option was included. In the first draft of the manuscript the legends contained a mistake, because the “fully agree” option had the highest number (7) but not 3. This has been changed in the revised manuscript.	2	1	Table 5, what does numbers 1 through 7 represent?	1	2	healthcare10040723_makarova	1
108Aspects of the organizational environment (e.g., creative problem solving) were identified in the qualitative component and statistically confirmed or rejected in the preceding quantitative study phase, which is exactly what the authors did in this study. Although our study integrates components of both strategies, the authors still think, that the sequential exploratory strategy describes our methods better than the convergent parallel design (see also: Curry et al Circ. Cardiovasc, Qual. Outcomes 2013, 6:119-123).	2	1	Clarity whether or not the study design was “exploratory mixed methods design” or mere a “convergent parallel design”	1	2	healthcare10040723_makarova	1
109The manuscript has been changed accordingly.	2	1	In the abstract, lines 23-27, I suggest to use the following expression or something like that. Around 38% of the students felt ill-prepared and could not answer AI-related questions because digitization in medicine and AI are not a formal part of the medical curriculum.	1	2	healthcare10040723_makarova	1
110The reviewer is right. The phase has been changed into the “analysis” of compounding factors.	2	1	Page 2, line 42, ‘the computation of compounding factors,’ I did not understand what it means. I suggest the authors to replace this with appropriate phrase.	1	2	healthcare10040723_makarova	1
111The authors followed the reviewer’s suggestions and re-wrote this para as follows: “The overall objective of this study was to investigate the today’s medical students attitudes towards AI and other digital working tools. We wanted to understand if age, gender, semester level and curriculum type influences their views. This study also assembled information on students’ understanding of AI algorithms and digital applications in health care and assessed their level of confidence in working alongside these tools after graduation in patient care. It is our belief that this information may possess the means to employ digital tools including AI into the curriculum of medical students efficiently, enhancing their confidence in using them and therefor to better equip our future physicians with sufficient knowledge.” On page 2, line 111, the phrase ‘to affirm or dismiss,’ does not make sense.	2	1	Also, the research questions lack describing the study setting.	1	2	healthcare10040723_makarova	1
112The phrase in question has been replaced by “to confirm”.	2	1	On page 2, line 111, the phrase ‘to affirm or dismiss,’ does not make sense. Replace this phrase with a more appropriate phrase.	1	2	healthcare10040723_makarova	1
113The authors choose 4 pre-clinical and 4 clinical students. The intention was - as outlined in the initial manuscript version - “… to understand how they perceive the subject of interest”. The wording has been specified, to clarify that in total 8 students tested the items but not 4 as the reviewer assumed. This number was considered sufficient a) to detect inconsistencies and b) to verify the correct meaning of the questions. AG and JE are two of the authors (first letter of the first and last name). In order to avoid any misunderstanding, this has been changed to “the authors” in the revised manuscript.	2	1	Second, what do ‘AG’ and ‘JE’ represent?	1	2	healthcare10040723_makarova	1
114Convenience sampling is defined as a method to collect data from a conveniently available pool of respondents. We used it, because it is the most commonly used sampling technique as it's incredibly prompt, uncomplicated, and economical.	2	1	Page 3, line 132, it says, Convenience sampling was used. I would ask, why did you use convenience sampling?	1	2	healthcare10040723_makarova	1
115The captation has been changed to “Characteristics of the study cohort.	2	1	Page 4, table 1, the caption and the table content do not match. Revise either of them.	1	2	healthcare10040723_makarova	1
116The sampling procedure was clearly described in the initial manuscript. For phase 1: “All participants of the first phase were students from from 1st to 6th year (undergraduate 1st to 2th year, graduate 3th to 6th year) from German Universities. The inclusion criteria were to actively study medicine and their agreement for their voluntarily participation. In the same way, the exclusion criteria were to have suspended their studies, as well as other exceptional situations. Prior to start, informed consent was obtained, which was followed by the collection of telephone numbers and email addresses. They were selected purposely and consecutively, in part by snowball until theoretical saturation was reached.” For phase 2: “For the second, quantitative study phase identical inclusion/exclusion criteria applied.” This referred to medical students of all semesters, excluding students from other faculties. “The online survey was sent to all medical faculties in Germany from which most forwarded the survey invitation by email to about 80 000 medical students to fulfill the principle of maximum diversity through convenience sampling method. Each contained an invitation letter and an information sheet.” Surely, sampling procedures in mixed method studies are phase depended different.	2	1	Also describe the final study sample for both.	1	2	healthcare10040723_makarova	1
117The statement has been changed into: “The focus on German educational system and the fact that only a small fraction of the total number of medical students filled out the online survey makes a generalization of the answers difficult”.	2	1	Page 12, line 389, the statement which says, ‘The non-probabilistic sampling makes a generalization of the answers difficult,’ is confusing. I suggest to re-write this sentence.	1	2	healthcare10040723_makarova	1
118The authors agree and the phase “so called” has been removed.	2	1	I suggest to remove the phrase ‘so called,’ that has been used in the conclusion section or any other section.	1	2	healthcare10040723_makarova	1
119The authors agree and this statement has been re-written in the revised manuscript version.	2	1	Page 13, lines 409-410, in the conclusion section, the statement which says, ‘This study also found significant differences between those groups indicating differences in subgroups of students from the quantitative survey.’ This is a confusing statement. Re-write this sentence clearly.	1	2	healthcare10040723_makarova	1
120The authors fully agree. Therefore, the conclusion paragraph has been split into the “Conclusion” paragraph, in which the study’s conclusions has been outlined, and into a the new para “Implications” where the usefulness of the integration of eHealth aspects (including AI) into the curriculum is discussed.	2	1	I suggest the authors to include a short section including the implications of the study after the conclusions.	1	2	healthcare10040723_makarova	1
121Thank you for this suggestion. While it would have been interesting to explore this further, our study focuses on retrospectively assessing and comparing disease progression within subgroups of patients receiving TOC. Patients not receiving TOC would have likely had a different presentation, progression and their follow-up would be slightly out of the scope of our observational retrospective study. When we compared patients who received TOC with the 86 severe patients who did not receive TOC (excluded from this analysis), the TOC group was far more severe, so there is no control group that could be matched. In addition, these patients did not have control CT scans.	2	1	The impact of Tocilizumab on radiological changes can not be adequately analyzed without a control group not receiving the drug.	1	2	jcm11051247_perova	1
122Following this suggestion, we have included in the analysis a calculation according to the FiO2. This has a cut-off which correlates to the oxygen flow cut-off.	2	1	The proposed timing of Tocilizumab administration based on oxygen flow rate is interesting but undoubtedly requires a more detailed statistical analysis to convince the readers.	1	2	jcm11051247_perova	1
123This is an interesting point. While knowledge of variants is of great importance from an epidemiologic point of view as they have different transmission rates and can cause diseases of different severity, the mechanism of the acute inflammatory response in severe infection seems to be similar regardless the strain. While we did not perform specific sequencing of the strain for every patient as this wouldn’t have been feasible, patients were included before the Delta variant emerged and we expect most of them to have had the initial D614G and UK B.1.1.7. Nonetheless, we have included a comment addressing this aspect in our limitations section to highlight this area of uncertainty.	2	1	If there are mutations or differences in viral strains during the course of the study, should differences in response to TOC and timing of administration depending on the strain be considered?	1	2	jcm11051247_perova	1
124We agree with the referee that the reasons for the exclusions were unclear and have rephrased accordingly. Addresed in text: „All those excluded were not administered TOC either because of contraindications or TOC supply gaps.” Point 3: 3.	2	1	86 cases are excluded from 187 cases, which is too many. What is the reason?	1	2	jcm11051247_perova	1
125We added the data using FiO2 ROC curve. The area under the curve for FiO2 ROC curve was smaller than the area under the curve for oxygen flow. In addition, the cut-off value for FiO2 corresponded to the cut-off for the oxygen flow rate, so the two groups in Table 3 would be similar.	2	1	When comparing different oxygen delivery methods, isn't it more appropriate to compare FiO2 rather than oxygen flow rate?	1	2	jcm11051247_perova	1
126We added this information also in Table 3. We analysed FiO2 (depending on the method of oxygen delivery - nasal canulae, HNF, MV), as you suggested and the cut-off value of FiO2 corresponded to the cut-off for the oxygen flow rate, so the two groups in Table 3 would be similar.	2	1	The median oxygen flow rate is shown to be 14 L/min, but FiO2 may vary depending on the method of oxygen delivery (nasal canulae, HNF, MV).	1	2	jcm11051247_perova	1
127Addressed in text and in Table 3.	2	1	The oxygen flow rate of 13 L/min measured by ROC as a cutoff value for TOC administration should be presented by FiO2.	1	2	jcm11051247_perova	1
128Thank you for pointing this out, we have changed Table 1 accordingly and we removed the imaging data, which as you mentioned, was the same as “before TOC” in Table 2.	2	1	In Table 2, about the change in CT findings in fatal and non-fatal patients before and after TOC administration, isn't it the same as the difference in imaging findings between patients who survive after severe illness and those who do not, regardless of TOC?	1	2	jcm11051247_perova	1
129Addressed, see previous comments and answers.	2	1	As mentioned above, the cutoff value is O2 13L/min, but the oxygen volume is difficult to interpret because FiO2 varies depending on the method of oxygen delivery.	1	2	jcm11051247_perova	1
130"Still, I disagree with the title of the paper, ""The impact of tocilizumab on radiological changes..."". Without the control group, this paper does not provide evidence that the radiological changes are indeed the result of TOC."	3	2	Thank you for this suggestion. While it would have been interesting to explore this further, our study focuses on retrospectively assessing and comparing disease progression within subgroups of patients receiving TOC. Patients not receiving TOC would have likely had a different presentation, progression and their follow-up would be slightly out of the scope of our observational retrospective study. When we compared patients who received TOC with the 86 severe patients who did not receive TOC (excluded from this analysis), the TOC group was far more severe, so there is no control group that could be matched. In addition, these patients did not have control CT scans.	2	1	jcm11051247_perova	1
131"Therefore I would suggest the authors to change the title of their paper. Something in line with ""Optimal timing of TOC administration"" would seem more appropriate."	3	2	Following this suggestion, we have included in the analysis a calculation according to the FiO2. This has a cut-off which correlates to the oxygen flow cut-off.	2	1	jcm11051247_perova	1
132The three references have been noticed with gratitude and included in the MS.	2	1	The place of RNA in LUCA (page 2): In search of features that are more conserved (carrying deep phylogenetic memory) than the sequence of genes, Wächtershäuser focuses on a paper of his in Systematic and Applied Microbiology (1998) that uses gene content and order of microbial genomes to make inferences about the last universal common ancestor (LUCA) of cellular life. He then mines the significance of some of the conserved chromosomal segments in light of some other evidence. The exercise is at places compelling, but forgets some recent, very global and exhaustive analyses that also use highly conserved biological features to reconstruct the makeup of LUCA (e.g., gene order, 3D molecular structure, molecular functions). See for example PubMed references PMID: 17370266, PMID: 21612591, and PMID: 17908824, which are in line with some conclusions derived from the alignment of Figure 1. The fact that these other analyses make use of hundreds of genomes to infer the ancient biochemistry of LUCA complements and strengthens the preliminary and fragmentary analysis of only 19 of them by the author, which also excludes eukaryotic genomes from the set (understandably, few sequenced genomes were available in 1998, and eukaryotes are in general “master rearrangers”).	1	2	life4041050_perova	1
133The 1998 paper leaves much to be desired. Its deficiencies reflect the excitement of the first hour. The state of the art at that time may be gleaned from an authoritative paper that came to the opposite conclusion: A.R. Mushegian and E.V. Koonin “Gene order is not conserved in bacterial evolution”. TIG 1996, 12, 289–290. The gene cluster table of 1998 was mainly retrieved from the annotations in published genomes and constructed manually with paper and pencil. The state of information technology at that time is reflcted by the fact that the table was folded an individually pasted by hand into each issue by the publisher.	2	1	Given my interest in the bioinformatics of gene content and order, I took the liberty of studying the brief Systematic & Applied Microbiology paper to check the validity of the “reconstruction” methods of Figure 1. The algorithmic implementation that is described is quite raw and does not extract important information that is embedded in the clusters of conserved gene segments. Important algorithms have been devised since the initial work of Sankoff in the sixties and seventies to do exactly that. I refer to the work of Pevzner, Tesler and Bourque as good examples, but also of Warnow. I also recommend visiting GRIMM (http://grimm.ucsd.edu/GRIMM/) and perhaps using the server to confirm or extract additional information from the alignments that are summarized in Figure 1. The Wächtershäuser algorithm makes use of conserved elements of gene content and order but discards information provided by the actual rearrangement operations that erase gene order history. The algorithm does not describe how gene homology was detected, how the limited set of genes was selected, and how the alignments were constructed (I imagine by hand). It is not clear if a guiding tree was used in the alignment (though this is mentioned in Line 65), since this is not made explicit in the 1998 publication. An alignment implies a tree but usually alignment algorithms are greedy and problematic and represent the most important limiting step of a phylogeny (the field is thus moving to the joint alignment and tree reconstruction). Therefore, I do not think the ancestors were properly reconstructed (the tracing of features in ancestor nodes of trees are not described, nor the actual trees). Regardless of all of these limitations, the tight conservation of certain segments is enough to show the existence of a core of ribosomal proteins that is universally present in cellular organisms. This in itself is valuable. Of course, a sample of 19 microbes may not be enough to encompass molecular diversity and the absence of Eukarya may also be problematic for any global evolutionary statement. In other words, the risks of sampling bias are clearly present and should be mentioned in the manuscript.	1	2	life4041050_perova	1
134The 1998 paper contemplated speculatively a combination of small-scale gene doubling (as evidenced by the immediate neighborhood of EF-Tu/EF-G) and of a large-scale gene cluster doubling (as evidenced by the spacing between secE/secY and rpoH-A/rpoD) with the hope of a future deeper understanding based on folding structures. Now the referee makes an exciting suggestion that may, if executed successfully, go some way to satisfy that hope.	2	1	The list of common genes in the alignment of Table 1 is enriched in small and large subunit ribosomal proteins that are the most ancient of the ribosomal set, according to the Caetano-Anolles theorem that is mentioned later in the manuscript. Interestingly, the most ancient of them are clustered toward the 5’ end of the genomic sequences that were aligned (S12, S17, S5, S4 and L2, L3 and L24). Could this imply a possible ancient segmental duplication? Also interesting is the placement of the most ancient ribosomal protein S12 between exactly two polymerase (beta and beta prime) and elongation factor (entry and translocation) genes (separated by single and much more derived ribosomal proteins). Could this be an ancient memory of the ribosome mediating translation and replication? A commentary would enhance the value of the section.	1	2	life4041050_perova	1
135The self-cleavage of RNA by 2'-OH is a chemical textbook fact. The 2'-OH group has the proper position and orientation for a nucleophilic attack on the phosphate bridge. The kinetics of the reaction is greatly favored by the 5-membered ring structure of the resulting cyclic phospho-bisester. The length of the RNA molecule is not relevant since each nucleophilic attack causes destruction of the chain. The effect should not be confused with the length-dependent “error catastrophe” of accumulating mutations of RNA. Incidentally, some anaerobic ribonucleotide reductases are ancient, while others (aerobic ones) are later inventions.	2	1	In terms of the genome organization of LUCA (Line 105), there are numerous arguments in favor of an RNA ancestral genome and the late unfolding of DNA as genetic repository (perhaps through viruses). I cannot understand how 2'-hydroxy groups could destabilize the molecule and lead to “intramolecular self-destruction” (Line 107). RNA has the wonderful property of folding in search of energetic and kinetic minima. These processes make use of a frustrated landscape, which is powerful in terms of its biological potential (stability, function, information). It is much more versatile than the rigid DNA alternative, which is enriched in the ‘information’ capacity. None of them have “self destruction” properties, which would have been weeded out by selection and self-organization very early in “chemical” evolution. In turn, everything about LUCA should be considered quite modern and far away from an initial FeS world. I refer to the work of Daniel Lundin and colleagues in Sweden about the rather late rise of some structures of the ribonuceotide reductase enzymes needed to built the DNA polymers. The Maurel theorem stands if one thinks of single genome molecules. But what if there were many short RNA genomes, as anticipated by Woese, each perhaps linked to different and ancient tRNA-like cofactors? As the author mentions, LUCA is contemporary to a rather complex biochemistry, with numerous structures harboring a multitude of active and allosteric sites in proteins, most of which drive central enzymatic functions.	1	2	life4041050_perova	1
136Genome rearrangements are certainly important during later evolution of the phyla. At the level of LUCA, i.e., prior to the splitting of the domains, it is not clear, if and to what extent rearrangements of the modern style occurred. In this regard we should bear in mind that the LUCA genome may have exhibited sense-antisense coding on both strands as suggested by Rodin and Carter. This position has been adopted and discussed in the present paper. Therefore, speculations concerning possible genome rearrangements may be a bridge too far.	2	1	In Line 114, the role of chromosomal rearrangement in evolution is not well described. What are the effects of genome rearrangements? Several scenarios are possible, including: (1) Genes remain linked R4 probably because it is more efficient to transcribe genes that produce interacting proteins (part of complexes) than those that are not; (2) Genes remain linked if they are of relatively recent origin (rearrangement has not had the change to split them apart); (3) Genes remain linked if they are part of functional groups historically united by genomic regions (encoding metabolic functions or rRNA? ); this includes genes sharing an operon structure for economy purposes in highly reduced organisms such as bacteria; (4) Genes remain linked because they originated when genomic rearrangements were not biochemically motivated and their sequence makeup was later refractory to rearrangement hotspots. There is a rich literature about rearrangement, hotspots and many processes related to these (including domain organization in proteins). Some discussion in this front could be clarifying.	1	2	life4041050_perova	1
137The present analysis comes to the conclusion that the sets of canonical amino acids and bases as well as the genetic triplet code were largely complete at the level of LUCA. The Wong coevolution theory of the genetic code has been discussed in detail. The literature comprises numerous proposals concerning the origin of translation and other aspects of the genetic machinery. A review of all these proposals and many others is beyond the scope of the present paper. The present paper is a research paper and not a review paper. It aims at a comprehensive account of early evolution from the origin of life all the way to LUCA. This puts a systematic constraint on literature selection. An effort (unfortunately fallible) has been made to include all those references that integrate with the main lines of the present account into a coherent account. Contributions by others that have the character of theoretical modules that fit well into this account have been termed “theorems” with names of the main authors attached. A reference to a paper on nucleotide biosynthesis phylogeny is now cited in Section 7.	2	1	In relation to comments of Line 188 onwards, Di Giulio, Caetano-Anolles and others have suggested that the genetic code started to unfold prior to LUCA but continue to do so once life diversified. The corollary, is that the complete canonical set of amino acids may have not been encoded in LUCA. In terms of metabolic and biochemical competency, there are numerous and interesting studies, which have not been cited (especially in origins and evolution of modern metabolism). This includes the coevolution theory of the genetic code, the coexistence of prebiotic chemistries with modern metabolic reactions (recently studied for nucleotide metabolism), and theories about the origin of translation.	1	2	life4041050_perova	1
138Based on the valuable criticism Section 2 has been extensively revised. Terminology has been clarified. This Section has a rather restricted purpose. It provides chemical arguments for the proposition that the pioneer organisms could only exist at high temperature and that the subsequent forms of life remained hyperthermophilic for a long time until much later an irreversible evolution generated organisms that required lower and lower temperatures. This conclusion places severe constraints on all aspects of the evolution of the genetic machinery. The fascinating topics of thermodynamics, energy dissipation and information are outside the scope of the paper.	2	1	Thermal course of evolution (Page 6): Why a focus on thermal energy? The framework should be on thermodynamics, energy dissipation and information, all of which are linked. What is thermally upward or downward adaptation? Is it conquering niches on Earth or a process involving molecular makeup? Vocabulary and definitions are murky, especially related to the links of environmental thermal fluctuations, energy of folding and stability of polymers. Subsection (1) must be rewritten to help the reader understand the ideas. Should all adaptations comply with maximizing energy R5 dissipation? How can this be reconciled with upward and downward trends? No references are provided despite the rich literature underscoring the controversial link between physics, information theory and biology. If the focus is conquering planetary niches, then perhaps reference the contrasting views and some of their proponents (deep sea versus surface; thermophilic versus mesophilic, etc.). Further elaboration of the Wolfenden theorem appears relevant and its connections to what is known about the origin and evolution of metabolism also of importance.	1	2	life4041050_perova	1
139The author expresses his gratitude for the two additional references, which have been included in the text.	2	1	Place of RNA in the origin and early evolution of translation/Pre-translational coding of peptides. The view that is presented in this crucial segment posits a pre-translational mechanism (side-by-side tRNA mediated coding) that very much resembles the ribosomal entropic system, which could be very advanced. What if the pre-translational coding was assembly line-like and mediated by the aminoacyl-tRNA synthetases themselves? See PMID: 23991065 for one such alternative and a related previous model (PMID: 22210458). This would also match commentary of a possible early origin of non-ribosomal peptide synthesis machinery compared to that of the ribosome.	1	2	life4041050_perova	1
140The statement has been clarified.	2	1	General overview. While the grand finale “Nothing in evolution makes sense except in the light of chemical predetermination” is impressive and summarizes the championing work of the author, chemical predetermination may apply to the very early stages of evolution and not to many of the stages described in the manuscript. How much chemical predetermination can there be with polymers as these explore a minute fraction of the space they make possible? In the enthalpic-entropic gradient that is proposed, there is also a gradient from “predetermination” to historical contingency. The boundaries of such a gradient is murky and the final statement may not apply to much of modern biochemistry, once proteins start to achieve stable complex structure and much earlier that the time of LUCA. In fact, the genome rearrangements that underlie Figure 1 are testament to the historical contingencies that were already at play in LUCA and not to chemical predetermination.	1	2	life4041050_perova	1
141In the introduction the term “or proteins” has been added after “RNA”	2	1	Title. The title does not encompass appropriately the wide subject matter covered by the manuscript. I suggest “The place of RNA in the origin and early evolution of life”.	1	2	life4041050_perova	1
142and the term “retrodict” has been defined.	2	1	Line 39. And what is the place of proteins in all that?	1	2	life4041050_perova	1
143The term “interpolate” has been clarified.	2	1	Line 39 and Section 1 “The place of RNA in LUCA”. The word retrodiction implies reconstruction of ancestors from extant information.	1	2	life4041050_perova	1
144The problem of mutational saturation is now included in the discussion of Figure 1.	2	1	Line 40. Interpolation of LUCA and competing theories of the origin of life. In my view, LUCA is not a theory of origin of life. It is a theory of origin of diversified cellular life.	1	2	life4041050_perova	1
145The term “multiply impaired” has been replaced by a clearer wording.	2	1	Line 52. Not only genes are gained and lost with time (Woese theorem), but also mutations accumulate to saturation in genes making homology statements difficult. This has been made explicit abundantly in the molecular evolutionary literature. A focus on gene content and order makes only sense if such homologies at gene level are preserved (if not there will be artifactual losses in the alignments).This should be highlighted in the text because it is relevant to the validity of the alignment of Figure 1, making its significance more important.	1	2	life4041050_perova	1
146LUCA is discussed only in Section 1.	2	1	Line 62: Change “multiply” to “multiple”.	1	2	life4041050_perova	1
147The protein cycle is discussed in a separate Section 4, which is concerned with the course of evolution before LUCA.	2	1	Line 406. “LUCA protein cycle”. Why bring LUCA to a link with the proposed “protein cycle”. LUCA is just the last of a chain of ancestor of diversified life. If the protein cycle requires a coupling of the enthalpic activation of amino acids and the entropic biosynthetic action of a primordial ribosome, then perhaps it is better to call it “ribocellular protein cycle”, since this coupling marks the start of modern cells, not necessarily “modern diversified cells” (i.e., LUCA).	1	2	life4041050_perova	1
148There are many relevant literature references. Among these there are specific proposals concerning a circumscribed problem that are included to fill a logical gap, as a theoretical module so to speak. These have been designated by the term “theorem” with the added name(s) of the main R7 author(s). This makes it clear that the account given is comprehensive in the sense that major independent contributions by other scientists integrate readily with the overall account given.	2	1	Please explain what do you mean with Kandler, Wolfenden etc. Theorem. Is a theorem Kandler’s theory or proposal?	1	2	life4041050_perova	1
149The relationship of His and Trp biosyntheses has been toned down.	2	1	Line 716: The biosyntheses of His and Trp are not so closely related. They only have in common that they use phosphoribosediphosphate as substrate and therefore share two related enzymes.	1	2	life4041050_perova	1
150Section 8 has been revised in order to address the issues involved in the last query.	2	1	In the iron sulfur world the surface metabolism prevents the diffusion of the fixed products into the ocean. But without compartmentation soluble intermediates would escape. Furthermore, the establishment of early bioenergetics based on electrochemical Na+ gradients would have been impossible.	1	2	life4041050_perova	1
151This review does not require any action on our part.	2	1	Very well presented, clear and graphically illustrated experimental findings that make a clear case for the model. Also a very thorough understanding of the limitations of the system are presented as well as proposals for even more complex instabilties that may underpin lifelike events. Overall a beautifully written, wonderfully presented, paper with clear concepts, methods and proposals that significantly contribute to original knowledge in the field.	1	2	life5010181_makarova	1
152Here, the reviewer did not like our use of the particular words “novelty” and “innovation”. o Use of the word novelty − Instances of “chemical novelty” in the manuscript replaced by “emergent chemical behaviour”. − On Page 8, after Equation 8, we removed sentence: The emergence of bistability will serve as a proxy for the emergence of other chemical novelties in the vesicle reactor model. Replaced whole paragraph, to read: In particular, in these initial stages, we will focus on the emergence of bistability in the vesicle reactor model—a dynamical feature deducible directly from the number and stability of the fixed points present (i.e., two asymptotically stable points separated by an unstable saddle point). We also expect that more complicated dynamical regimes could also be present in the model, like multi-stability or global phase space features such as limit cycles giving rise to sustained oscillations. However, investigation of these regimes will be deferred to later work: for the time being, the “emergent chemical behavior” referred to in the title will be restricted to bistability. We think this is a clearer explanation, and also uses the word “regime” suggested by the reviewer. o Use of the word innovation We kept the 2 occurrences of the word “innovation” in the abstract and the introduction. An innovation is defined as a “new method, idea or product” in the dictionary. We use the word to refer to new emergent chemical behaviour that the whole vesicle system exhibits (e.g., expanded steady states), which did not exist before. We think the use of this word is acceptable.	2	1	The authors write: “In these initial stages, the emergence of bistability will serve as a proxy for the emergence of other chemical novelties in the vesicle reactor model.” The authors probably means that the existence of more than one stable regime could consent regime changes, but this situation do not indicates how these changes appear: in the article, the change is stimulated by means of a deliberated injection of chemical substances from outside. So, I think that the appearance of novelties requires a different order of considerations, whereas the bistability plays possibly the role of novelties amplification and consolidation (in particular conditions). The same observation can be done for the word “innovation”, used on the abstract and at Line 45. In order to avoid misunderstandings, I think that the authors should avoid these expressions, ad use the words “regime change”, or similar concepts.	1	2	life5010181_makarova	1
153we added a new footnote, to explain our standing on this issue: Reference 36: In this work, concentrations outside the vesicle are set as system parameters. However, we make no commitment to the type of environment the vesicle is embedded in or how these concentrations are maintained. Our purpose is simply to show that bistability can exist in the model for certain sets of outside concentrations. Exploration of the model in explicit environments is deferred to future work.	2	1	Note 4 presents a very important issue: why the inner chemical environment is different from the external one, if the running chemical reactions are the same? The presence of particular features of the vesicle interior or of entrapped catalysts seem a too easy and ad hoc hypothesis. A useful reference proposing an explanation of this symmetry breaking (without requiring different conditions in internal and external environments) could be “R. Serra, M. Villani Mechanism for the formation of density gradients through semipermeable membranes Physical Review E 87, 2013”.	1	2	life5010181_makarova	1
154Reference 11 has been added after Equation 10, to point the reader to where to find information about phi limits was first discussed. Repeating this information here would complicate the paper. The lines Phi = 2^(1/3) and 4^(1/3) in Figure 1d have now been explained.	2	1	How the authors derive the range [0.9, 101/3] for the so called “reduced surface” index? In Figure 1d, Lines 21/3 and 41/3 have some particular meanings, or are plotted mainly to ease the figure comprehension? Could the authors add some indications about the derivation of these upper limits?	1	2	life5010181_makarova	1
155It is difficult to make a direct and meaningful comparison like this. Without a container, the reaction system has less parameters, and thus the sampled parameter space is smaller. The aim in the paper, was to simply show that encapsulating a Schlogl model which was bistable in bulk condition, seemed to destroy this bistability.	2	1	The authors write (case 1): “of the 5000 parameter set tested under constant surface area, 82% (4098) gave a single fixed point, 321 15.7% (785) gave two fixed points, and 2.3% (117) no fixed points.” How this statistics compare with a similar one, performed on a similar chemical situation without container? Could the authors add the results of the same within a not confined environment?	1	2	life5010181_makarova	1
156The minor issues were fixed.	2	1	Adamala, K.; Szostak, J. ompetition betweenmodel protocells driven by an encapsulated catalyst. Nat. Chem. 2013, 5, 495–501. → “ompetition” should be: “Competition”.	1	2	life5010181_makarova	1
157This immunoquantitation method used is described in detail in the reference given (Brown et al. 2008). The reviewer is directed in particular to the Supplementary Methods section. To allow readers to get a better understanding of the method in this manuscript we have revised this part of the Experimental Section, adding extra text to increase clarity concerning the method.	2	1	I don’t understand how they calculated the protein molar ratios. In the methodology section we learn that they extracted the crude proteins and then performed western analyses using specific antibodies, followed by image analyses. I don’t understand how they converted the western data to read the amount of specific proteins, in fmol, in the various organisms as shown in Figure 2; and used for the calculations in the rest of the paper. (Why are the units provided again in Line 220?). Please provide the reader with the methodology used for the quantification.	1	2	life5010403_perova	1
158Since submitting the manuscript, we have accumulated a set of 84 parallel measurements of steady state oxygen evolution and the functional content of PSII measured using flash yields (with a solid state optode) and simultaneous FRR chlorophyll fluorescence induction curves, from which we can extract e- PSII-1 s-1, for both Synechococcus and Prochlorococcus cultures. Consistent with the long literature history of such measurements (ex. Suggett et al. 2004, 2009), we observe a good correlation between the two measures of electron transport per PSII. Plotting the FRR estimate of e- PSII-1 s-1 versus the O2 evolution/PSII content estimate of e- PSII-1 s-1 gives a slope of 1.26 and an R2 of 0.58. We have added this information to the Materials and Methods to support our use of FRR estimates of electron transport per PSII. Furthermore, our estimates of ETRmax from FRR induction curves are independently validated by the close correlation between ETRmax and 1/tau, shown in Figure 4A, since 1/tau is derived from the rate constant for the decay of fluorescence after induction, and thus does not depend (computationally) upon our estimator for ETRmax.	2	1	PSII activity is derived from fluorescence measurement, as ETR. I am missing calibration with real measurements of PSII activity such as O2 evolution. You have got to show it for each organism you are examining otherwise it is worthless. There are many reports in the literature showing dramatic decline in fluorescence but hardly any change in O2 evolution.	1	2	life5010403_perova	1
159This has been addressed with the addition of text in the abstract, introduction and discussion specifying that the cultures were grown under low light conditions.	2	1	The cells were grown under a relatively low light intensity and thus the data presented here only apply to these conditions. Please make sure the reader is aware of it.	1	2	life5010403_perova	1
160We have removed the word “nondiazotrophic” as we agree that it is not relevant to the discussion.	2	1	Line 19 – I am not sure why stating the cyanobacteria are nondiazatrophic is relevant?	1	2	life5010403_perova	1
161We mean that they numerically dominate and we have clarified this in the introduction.	2	1	Line 46 – (and throughout) be clear if you mean numerically dominate or dominate production – they are not always the same thing.	1	2	life5010403_perova	1
162We have clarified this statement in the text. We refer to the nitrogen cost in the form of allocation to protein per pigment bound.	2	1	Introduction paragraph 2 – I am unsure we know that physbobilisomes require more resource than pcb proteins – this depends on the ratio of antenna to reaction centre? Please include references if R3 this has been shown. Also, not all Pcb proteins are constitutively expressed (e.g., see Bibby et al. Nature 2003).	1	2	life5010403_perova	1
163We are referring to the number of RUBISCO active sites measured by immunoquantitation. We are not referring to measured RUBISCO activity. We use this expression to be clear that we are referring to RbcL subunits rather than oligomeric RUBISCO. We have added a parenthetic phrase to make this more clear.	2	1	Line 250 – This is estimated number of RUBISCO active sites – or is there evidence all the RUBSCIO you quantify is active?	1	2	life5010403_perova	1
164We thank the reviewer for drawing this study to our attention. We have added a paragraph to the discussion to compare and contrast the Sukenik work with that presented here. The Sukenik data support a strong positive correlation between 1/tau and the RUBISCO to PSU ratio over a series of growth irradiances. While we also see a strong positive correlation between 1/tau and RUBISCO to PSII our results differ as the molar ratios of the components of the PSU differ significantly between the strains analyzed in the current work. This allows us to pinpoint the relationship of PSII to RUBISCO rather than other subunits of the PSU as the determinant of electron transport rate.	2	1	Figure 4 – The crunch of this paper is Figure 4e which show the Rubisco:PSII ratio is correlated to ETR. While I’m convinced in the presented data only three data-points are shown – I’m most convinced in that this same relationship is presented in in “Aquatic Photosynthesis (edition 2) Figure 7.9 – Falkowski” based on work of Sukenik (1986?). A greater discussion should be given in the text to how these datasets compare and what is significantly new in this dataset? References 35 and 36 are discussed in relation to the potential control of cytb6f on limiting electron transfer from PSII but more should be made of Falkowski’s observations which support this data.	1	2	life5010403_perova	1
165We have added text to the end of the discussion to address this comment and the relevant reference has been added. Thank you for this suggestion.	2	1	Line 308 – The data presented is used to support potential cyclic electron flow around PSI – however other alternative terminal electron sinks could also be up-regulated – these concepts are discussed in a recent review by Milligan and Behrenfeld annual review 2013 – the implications of this should be discussed unless the authors can show specifically enhanced flow around PSI.	1	2	life5010403_perova	1
166We have added a supplemental figure (Supplemental Figure #2) to show this calibrations curve. As all experiments presented here were performed under iron replete conditions, no iron starvation was performed.	4	1	“In line 178 onward we read about the calibration curve. Please presnt it in the paper. Once you apply stress such as iron starvation you should recalibrate.” R4 Response:	3	2	life5010403_perova	1
167We have added a supplemental figure (Supplemental Figure #1) that shows the method applied with a sample blot, calibration curve and data analysis. This work required dozens of blots, each with its own standard curve, so it would not be practical to show all of the standard curves for each determination.	4	1	“Please present the calibration curves for the protein levels.” Response:	3	2	life5010403_perova	1
168Multi-alignment of concatenated protein (or DNA) segments is a genome-scale, but not whole-genome approach. Its applicability depends on the scope of the phylogenetic study. When dealing with not-too-distantly related species it may yield more or less useful result. However, in a study covering many phyla it is very difficult, if not impossible, to collect a common set of conserved proteins. Moreover, the concatenation method can never lead to very convincing conclusion, as give or take a few proteins may change the result. The phylogenomics people have noticed this problem, see, e.g., O. Jeffroy, H. Brinkman, F. Delsuc, H. Philippe (2008) Phylogenomics: the beginning of incongruence? Trends in Genetics, 22(4): 225–231. An example from the Bacteria domain is the relationship of the closely related Shigella and Escherichia coli strains. Concatenation of different number of genes led to different way of mixing-up of the two groups, but CVTree gave unambiguous separation of the strains as different species in the same genus Escherichia, see: G.-H. Zuo, Z. Xu, B.L. Hao (2013) Shigella strains are not clones of Escherichia coli but sister species in the genus Escherichia. Genomics Proteomics Bioinformatics, 11: 61–65. In order to carry out multi-alignment of concatenated sequences, a postdoc or well-trained PhD student equipped with the corresponding software is required. In contrast, with genome sequencing becoming a common practice in many labs it costs no additional work for a bench-microbiologist to get phylogenetic and taxonomic information by using a convenient and publically available tool such as the CVTree web serve. Well, we would be glad to see comparison of CVTree phylogeny with multi-alignment of concatenated proteins if anyone finds a way to do it for so many diverse phyla, but we do not consider it as a doable job.	2	1	I would like to see a comparison with at least one regular alignment/treeing method, based on the same genomes the authors used, and not just a visual topological comparison with other published trees.	1	2	life5010949_perova	1
169These points were discussed in the “Material and Method” section added at the suggestion of Reviewer 2. The following was copied from the manuscript: “Traditionally a newly generated phylogenetic tree is subject to statistical re-sampling tests such as bootstrap and jackknife. CVTree does not use sequence alignment. Consequently, there is no way to recognize informative or non-informative sites. Instead we take all the protein products encoded in a genome as a sampling pool for carrying out bootstrap or jackknife tests (citing our 2004 paper). Although it was very time-consuming, CVTrees did have well passed these tests (citing our 2010 paper). However, successfully passing statistical re-sampling tests only tells about the stability and self-consistency of the tree with respect to small variations of the input data. It is by far not a proof of objective correctness of the tree. Direct comparison of all branchings in a tree with an independent taxonomy at all ranks would provide such a proof, The 16S rRNA phylogeny cannot be verified by the Bergey's taxonomy, as the latter follows the former. However, agreement of branchings in CVTree with the Bergey's taxonomy would provide much stronger support to the tree as compared to statistical tests. This is the strategy we adopt for the CVTree approach.” “There are two aspects of a phylogenetic tree: the branching order (topology) and the branch lengths. Branching order is related to classification and branch length to evolution time. Calibration of branch lengths is always associated with the assumption that mutation rate R3 remains more or less a constant across all species represented in a tree, an assumption that cannot hold true in a large-scale phylogenetic study like the present one. Therefore, branching order in trees is of primary concern, whereas calibration of branch lengths makes less sense. Accordingly, all figures in this paper only show the branching scheme without indication of branch lengths and bootstrap values”.	2	1	As far as I can see, statistical support on the branches is missing, so I have no way of assessing if this branching order is valid. Bootstrapping or jackknifing are by no means the final word on the significance of branches, however an explanation as to how the user should assess the significance of braches would be good, i.e., branch length.	1	2	life5010949_perova	1
170Yes, this is an apparent discrepancy of CVTree from 16S (and 23S) analysis for the given set of 179 archaeal genomes. However, in an on-going study of ours (not published yet) using a much larger data set this violation no longer shows up; both Korarchaeota and Crenarchaeota restore their phylum status. Taking into account the fact that both Korarchaeota and Thermofilaceae are represented by single species for the time being, their placement certainly requires further study with broader sampling of genomes.	2	1	The fact that Thermofilum is placed outside Crenarchaeota in Figures 3 and 4 is a little disturbing. I haven’t come across such a placement in other phylogenetic analyses of Archaea, for example in Brochier-Armanet et al 2008 Nat Rev Microb, or Rinke et al. 2013 Nature. I believe this needs to better explained in the manuscript, rather than just saying “this fact is noted”.	1	2	life5010949_perova	1
171Highly degenerated genomes of many symbiont organisms tend to move around, in particular, to the baseline of a tree and thus distorts the overall structure of the tree. Therefore, it is better not to mix them with free-living organisms in a study. We rephrased the corresponding paragraph in the manuscript: “The nanosized archaean symbiont Nanoarchaeum equitans has a highly reduced genome (490,885 bp). It is the only described representative of a newly proposed phylum Nanoarchaeota and it cuts into the otherwise monophyletic phylum Euryarchaeota. We note that the monophyly of Euryarchaeota was also violated by Nanoarchaeum in some 16S rRNA trees, see, e.g., Figure 4 in a 2009 microbial survey as well as (c) and (d) in our Figure 3. It has been known that tiny genomes of endosymbiont microbes often tend to move towards baseline of a tree and distort the overall picture. In fact, we have suggested skipping such tiny genomes when studying bacterial phylogeny, see, e.g., (citing our 2010 paper) and a note in the home page of the CVTree Web Server. In the present case we may at most say that Nanoarchaeota probably makes a separate phylum, but its cutting into Euryarchaeota might be a side effect due to the tiny size of the highly reduced genome”.	2	1	I am also not very convinced with the placement of Nanoarchaeota. It seems like this phylum is moving around with the addition of new sequence data (for example in Rinke et al. Figure 2 tree, they are on an entirely different branch than Euryarchaeota). Though the authors also rightfully point out that the reduced genome size may have something to do with this placement.	1	2	life5010949_perova	1
172Yes, there was certain disturbing effect of the tiny and lonely Nanoarchaeum genome, yet the Halobacteria is a very specific clade, forming a tightly connected group and moving around as a whole, mainly due to the biased acidity of their constituent amino acids. We anticipate that the relative placement of Halobacteria with respect to other groups may stabilize when more genomes are used to construct a tree.	2	1	The placement of Halobacteria (due to interfering Nanoarchaeota, I presume) is also a little disturbing. I would recommend that the authors provide a discussion of this. Especially with regards to other archaeal trees. For instance, in the tree of Armanet et al 2011 that the authors also refer to, the placement of Halobacteria with respect to Nanoarchaeota is very different.	1	2	life5010949_perova	1
173We have A new “Material and Method” section has been added. Such issues as statistical resampling tests (bootstrap and jackknife), calibration of branch length, the meaning and choice of the peptide length K, etc. , were discussed in the new section. Figures 1 and 2 were combined to a new Figure 1; Figures 3 and 4 were combined to become a new Figure 2. Figure captions were made more detailed. The whole text was checked for language flaws and many places were rephrased.	2	1	In summary, I find the piece interesting, but parts of the discussion are rather weak, therefore I am suggesting a major revision. Another reason for major revision is the style that the manuscript is written. I am not a native speaker, but given that I had to read sentences several times, I suspect the manuscript can benefit from an English language check.	1	2	life5010949_perova	1
174We thank the Reviewer for the detailed comments/suggestions given in the previous report and the suggestion of doing spelling-check this time. We have gone through the final manuscript carefully once more.	4	1	I found the revised version of this manuscript quite good, and I thank the authors for responding thoroughly to all my comments.	3	2	life5010949_perova	1
175A “Material and Method” section has been added where the CVTree algorithm, the interactive tree-viewer, statistical resampling tests (bootstrap, jackknife), calibration of branch lengths, etc., were discussed in slightly more detail.	2	1	I would really appreciate a “Methods” part where the CVTree is explained shortly, and the tree-viewer is explained with more detail. The absence of branch lengths and bootstraps should be discussed here. Other technical aspects of the paper (e.g., sequence dataset), parameters, criteria ... all could be well organized in this part.	1	2	life5010949_perova	1
176Yes, 16S rRNA phylogeny is quite stable and it almost defines the present taxonomy. We have given due credit for this. In general, CVTree does not challenge 16S rRNA analysis but complement it.	2	1	Archaeal phylogeny has already been studied in detail, with 16S and other marker genes, and with genomic approaches too. Some of the undersigning authors had already published on this before, although with smaller input datasets. Therefore, the fact that 16S topology is quite stable and comparable with other approaches is already known.	1	2	life5010949_perova	1
177A robust phylogenetic tree comes with a fixed branching order of leaves. One looks at the leaf names and their taxonomic lineage and tries to map the latter to the branches. To this end we added the following paragraphs in the “Material and Method” section. “There are two aspects of a phylogenetic tree: the branching order (topology) and the branch lengths. Branching order is related to classification and branch length to evolution time. Calibration of branch lengths is always associated with the assumption that mutation rate remains more or less a constant across all species represented in a tree, an assumption that cannot hold true in a large-scale phylogenetic study like the present one. Accordingly, all figures in this paper only show the branching scheme without indication of branch lengths and bootstrap values.” “Branching order in a tree by itself does not bring about taxonomic ranks, e,g, class or order.	2	1	Taxonomists have traditionally circumscribed the high taxa (specially orders and classes) with great subjectivity, i.e., without well accepted criteria. In terms of phylogenetic trees one premise has always been clear, a taxon must be monophyletic. This principle has been used in the present work to reconsider the status of some high taxa. However, authors do not explain objective criteria to properly interpret the rank of the clades, which impedes making a profound evaluation of the archaeal classification. Therefore, although authors have strong tools and dataset, they just achieved a small revision of the high taxa which is, indeed, quite biased by the underlying 16S guidelines.	1	2	life5010949_perova	1
178We have reorganized the manuscript mainly by adding a new “Material and Method” section where discussions on branch length, statistical resampling, meaning and choice of K, etc., were given. The original Figure 1 was deleted with some related points explained in the text accompanying the original Figure 2. All figure captions have been rewritten for clarity.	2	1	I have noted some lack of scientific rigor according to: many wrong taxonomic names and typos, scarce figure legends, few comments about the missing branch lengths or bootstraps (! ), redundancy in text and figures and fragments which are really difficult to understand. Authors should pay attention to language, explanations and text organization.	1	2	life5010949_perova	1
179A few more sentences were added in the “Conclusion” regarding the power and achievement of the 16S rRNA analysis.	2	1	Authors shouldn't forget (particularly in conclusion) that the resolution power of 16S for high ranks (genus and above) is currently well accepted. And the number of non-redundant 16S entries available is much much larger than that of archaeal genomes. 16s data offer a much comprehensive view of the archaeal diversity, including deep branches.	1	2	life5010949_perova	1
180We tried to rephrase the paragraph by changing, deleting, or adding a few words as follows: “In this paper we study Archaea phylogeny across many phyla. This is in contrast with phylogeny of species in a narrow range of taxa, e.g., that of vertebrates (a subphylum) or human versus close relatives (a few genera). Accordingly, the phylogeny should be compared with taxonomy at large, or, as Cavalier-Smith (citing cavalier-smith 2002) put it, with “megaclassificaton” of prokaryotes. Although in taxonomy the description of a newly discovered organism necessarily starts from the lower ranks, higher rank assignments are often incomplete or lacking. At present the ranks above class are not covered by the Bacteriological Code. The number of plausible microbial phyla may reach hundreds and archaeal ones are among the less studied. According to the 16S rRNA analysis, the major archaeal classes and their subordinate orders have been more or less delineated. Therefore, in order to carry out the aforementioned cross verification we make emphasis on higher ranks such as phyla, classes, and orders. A study using 179 Archaea genomes should provide a framework for further study of lower ranks.” Part 3.1	2	1	L40 “Since at present (…) are not covered (...)” is a weak reason for choosing high ranks. I recommend to shortly summarize why high ranks are so important, and why do you choose order as the lowest considered rank.	1	2	life5010949_perova	1
181Branching order in a tree is directly related to taxonomy, while branch lengths have more to do with evolution. For large-scale phylogenetic study across many phyla the former is more important than the calibration of branch lengths. The latter is based on the assumption that mutation rate is more or less constant. This assumption cannot hold when dealing with many phyla.	2	1	The figure legends require more rigorous explanation. Would be interesting to remember that the branch lengths are not taken into account, or were omitted.	1	2	life5010949_perova	1
182This is done in the newly added “Material and Method” section.	2	1	In Line 80—authors write some explanations to understand the tree figures. I would suggest to put this text before the first tree figure.	1	2	life5010949_perova	1
183The original Figure 1 was deleted and a few words added to the legend of the original Figure 2, now the new Figure 1.	2	1	Figure 1 is a bit redundant. A short comment about the inclusion of that particular sequence into the Thermoplasmatales can be added into the legend of Figure 2.	1	2	life5010949_perova	1
184Judging by the cluster labeled as Euryarchaeote{0+3} in Figure 2 Methanomassiliicoccus was not reclassified into Thermoplasmataceae but to an yet un-specified class.	2	1	However, the reclassification of Methanomassiliicoccus into Thermoplasmataceae needs more explanation. To be objective, authors should address the following question, why in the same family and not in another new family?	1	2	life5010949_perova	1
185The sentence has been moved to the legend of Fig. 1 and slightly rephrased.	2	1	L106–107: maybe a bit inappropriate on that position. I would suggest to add a comment on the figure legend instead.	1	2	life5010949_perova	1
186Done.	2	1	L109–118: Summarize and move to introduction. Those sentences are of general importance for the topic and not specific to part 3.2.	1	2	life5010949_perova	1
187the K issue is discussed in the newly added “Material and Method” section; so scattered mentioning of K has been deleted from the rest of text.	2	1	L119–123: if the K issue is relevant to understand the text then please add a proper explanation. If not, then keep it simple and avoid entering into the K issue (L122–123, L132, L135, L139, 183, and also remove this K = 6 from Figure 3.)	1	2	life5010949_perova	1
188Done in the caption of Figure 2.	2	1	Add more explanations in legend of Figure3.	1	2	life5010949_perova	1
189We have rewritten the paragraph as: “The new phylum Korarchaeota violates the monophyly of the phylum Crenarchaeota by drawing to itself the family Thermofilaceae. However, in an on-going study of ours (not published yet) using a much larger data set, this violation no longer shows up; both R8 Korarchaeota and Crenarchaeota restore their phylum status. Taking into account the fact that both Korarchaeota and Thermofilaceae are represented by single species for the time being, their placement certainly requires further study with broader sampling of genomes.”	2	1	L143: Sounds clearer if you avoid mixing class and phylum, for example: “The placement of phylum Korarchaeota, as a closest neighbor of family Thermofilaceae, violates the monophyly of phylum Crenarchaeota.” Response:	1	2	life5010949_perova	1
190From the original Figures 3 and 4 only one has been kept and the legend rewritten. In fact, the whole paragraph changed to: “The newly proposed phylum Thaumarchaeota appears to be non-monophyletic as an outlying strain Candidatus Caldiarchaeum subterranum was assigned to this phylum according to the NCBI taxonomy. The NCBI assignment might reflect its position in some phylogenetic tree based on concatenated proteins, e.g., Figure 2 in […]. However, in the original paper reporting the discovery of this strain […] and in recent 16S rRNA studies, e.g., […], Candidatus Caldiarchaeum subterranum was proposed to make a new phylum Aigarchaeota. CVTrees support the introduction of this new phylum. A lineage modification of Candidatus Caldiarchaeum subterranum from Thaumarchaeota to Aigarchaeota would lead to a monophyletic Thaumarchaeota{7}.”	2	1	L146: No need to explain the 6+2 if it is properly explained in the figure legend. Figure 3 is redundant. I would recommend to avoid presenting different versions of the same tree; just the final tree is OK (use final/valid labels) and all important explanations in the text or legend. Perhaps the whole reasoning in Lines 142–180 is not so relevant for the current objective of comparing CVT, LTP, Bergeys? Or, perhaps, define this objective more clearly.	1	2	life5010949_perova	1
191The problem of taxonomic placement of Aciduliprofundum is a good example to demonstrate how one extract information from CVTrees. In the Reysenbach et al. Nature 2006 paper it was taken as the first cultivated member of the DHEV2 (deep-sea hydrothermal euryarchaeate 2) clade based on a maximum-likelihood 16S rRNA tree. Unfortunately, all other 13 members of this clade were represented by 16S rRNA sequences only and no genome data are available so far. The NCBI taxonomy gave an incomplete lineage: Archaea; Euryrchaeota; unclassified Euryarchaeota; missing taxonomic assignment at the rank class and below. In order to make use of CVTree we must touch on the K-issue a little more. The alignment-free comparison of genomes in CVTree is implemented by counting the number of K-peptides in the protein products encoded in a genome followed by subtraction of a random background caused by neutral mutations. The peptide length K looks like a parameter, but it is actually not a parameter. Using a longer K emphasizes species-specificity, while a shorter K takes into account more common features with neighboring species. However, we never adjust K: a fixed K is used for all genomes to construct a tree, but one may construct a series of trees for K = 3, 4, 5, 6, 7, 8, … We have shown repeatedly that R9 K = 5 and 6 lead to best results in the sense of agreement with taxonomy, so usually only a K = 6 tree is given in publications. Let us look at a subtree, i.e., part of a tree, containing the organisms of interest. If the branching order in all trees built for different Ks turns out to be same, it would be a strong support to the branching order. In most cases the branching order varies with K: K = 3 and 4 make sense, K = 5 and 6 yield the best, K = 7 and 8 become slightly worse, etc. For too big a K, even if the closest strains remain grouped together the whole tree may tend to become a star-tree, i.e., every small clade stands in its own and their mutual placements become less meaningful. Therefore, inspection of trees for a range of K-values provides an additional dimension to evaluate the results. For Aciduprofumdum we have a stable pair (<C>Thermococci{18}, <G>Aciduprofumdum{2}) at K=3, 5, 6, 7. At K = 4 we have (<C>Thermococci{18}, (<G>Staphylothermus{2}, <G>Aciduprofundum{2})) In all these cases Thermoplasmata stands farther away from the above pair. However, at K = 8 and 9, when the overall tree picture has been largely distorted, Aciduliprofundum does stand closer to Thermaplasmata. Putting together all the above results we tend to consider the pair (<C>Thermococci{18}, <G>Aciduliprofundum{2}) as reflecting a more probable relation. Confined to the available data for the time being one may assign <G>Aciduliprofundum to <C>Thermococci, e.g., to denote the pair as <C>Thermococci{20}=(<F>Thermococcaceae{18}, <G>Aciduliprofundum{2}) leaving its family unclassified or assign it to a new family. Without further phenotypic and chemotaxonomic evidence it is better not to introduce new taxon names if the present naming scheme is capable to accommodate the leaves without conflict. This was why we wrote “this modification would hold as long as no new facts challenge it”. Anyway, taxonomy has always been a work in progress. One has to be prepared for modifications when new data appear. To make a long story short, we have rewritten the paragraph as: “The Candidatus genus Aciduliprofundum is considered a member of the DHEV2 (deap-sea hydrothermal vent euryarchaeotic 2) phylogenetic cluster. No taxonomic information was given in the original papers [55,56]. The NCBI Taxonomy did not provide definite lineage information for this taxon at the class, order, and family ranks. According to [55] the whole DHEV2 cluster was located close to Thermoplamatales in a maximum-likelihood analysis of 16S rRNA sequences. A similar placement was seen in [54] where a Bayesian tree of the archaeal domain based on concatenation of 57 ribosomal proteins put a lonely Aciduliprofundum next to Thermoplasmata. However, in CVTrees, constructed for all K-values from 3 to 9, Aciduliprofundum juxstaposes with the class Thermococci{18}. An observation in [56] that this organism shares a rare lipid structure with a few species from Thermococcales may hint on its possible association with the latter. If we temporarily presume a lineage <C>Thermococci<O>Unclassified<F>Unclassified<G>Aciduliprofundum… R10 one might have a monophyletic class <C>Thermococci{20}. Since none of the 13 DHEV2 members listed in [55] has a sequenced genome so far, CVTree cannot tell the placement of the DHEV2 cluster as a whole for the time being. It remains an open problem as whether DHEV2 is close to Thermoplasmata or to Thermococci, or a new class is needed to accommodate DHEV2.”	2	1	L156–166. If I understood right, there was good support for Candidatus Aciduliprofundum as part of a clade called DHEV2, which is a sister clade of Thermoplasmatales. However in the present work the authors intend here to reclassify Aciduliprofundum into family Thermococcaceae of Thermococcales. This needs further explanation. Since the new affiliation is quite in disagreement with previous observations, and this is not properly justified in the results/discussion, the final statement “this modification would hold as long as no new facts challenge it” seems unacceptable. In addition, why should Aciduliprofundum be regarded as member of Thermococcaceae and not as another distinct family?	1	2	life5010949_perova	1
192No, we did not mean it.	2	1	L163: If I’m right the current observation actually does not support the previous work done by Brochier-Armanet.	1	2	life5010949_perova	1
193We should first explain how these inappropriate names appeared. We have insisted to use the directory name at the NCBI FTP site as genome name. However, in November 2013 NCBI announced that they would not release genomes of different strains of the same species as before. In a period thereafter NCBI sometimes put several genomes in a directory and we had to extract the data and to assign a name from the “Source” line of the GenBank file. This caused some confusion. For example, as of February 27, 2015, a directory name at NCBI remained “archaeon_Mx1201_uid196597” and we had to change it to: Candidatus_Methanomethylophilus_alvus_Mx1201_uid196597 Now all “wrong names” as pointed out by the Reviewer no longer appear in figures. In the text we tried to refer to their names as complete as possible.	2	1	L167–173: The names are wrongly written (please check the original submission). Authors have to explain with more clarity, why is this clade of rank class. If that is the case, is it a single-order class? A single family order?	1	2	life5010949_perova	1
194The genome name at NCBI FTP site is “halophilic_archaeon_DL31_uid72619”. The uid number was dropped when mentioned in the text. We put it back and capitalized the first letter to “Halophilic”, still an illegal genus name.	2	1	L174–180: I don’t understand the reasoning along this paragraph. In addition “haolphiic_archaeon_DL31” is not well written, please be careful when copying names from other source. Also, a similar question about the objectiveness for detecting high taxa: why not to create new family?	1	2	life5010949_perova	1
195It is Figure 2 in the revised manuscript. We discussed it at some length.	2	1	Figure 4: the reclassifications must be clearly justified in the text.	1	2	life5010949_perova	1
196No, organism cannot be published. Thanks for correcting our mistake.	2	1	L191: organisms can't be validly published, but their names.	1	2	life5010949_perova	1
197The latter can be assigned only after comparison with a reference taxonomy which is not a rigid framework but a modifiable system. Though a dissimilarity measure figures in the CVTree algorithm, it is not realistic to delineate taxa by using this measure at least for the time being. Even if defined in the future, it must be lineage-dependent. For example, it cannot be expected that the same degree of dissimilarity may be used to delineate classes in all phyla. In addition, monophyly is a guiding principle in comparing branching order with taxonomy. Here monophyly must be understood in a pragmatic way restricted to the given set of input data and the reference taxonomy. If all genomes from a taxon appear exclusively in a tree branch, the branch is said to be monophyletic.” R6 One cannot tell the rank of a node/leaf in a tree by simply looking at it. A reference taxonomy is alwys needed. We put the following in the “Material and Method” section to explain it: “Branching order in a tree by itself does not bring about taxonomic ranks, e,g, class or order.	2	1	L221–222: Sure, but authors do not provide explanations about how do they know that a clade in a tree is a family, an order, a class, etc. There is a lack of criteria to reclassify the leaves.	1	2	life5010949_perova	1
198The phrase “3063 identical nucleotide positions” was copied from the caption of Figure 4 of the cited Nunoura et al. 2011 paper without much thinking. We simply deleted it.	2	1	L224: I don’t understand “3063 identical nucleotide positions”. Why identical?	1	2	life5010949_perova	1
199The whole paragraph has been rewritten as: “The nanosized archaean symbiont Nanoarchaeum equitans has a highly reduced genome (490,885 bp [44]). We note that the monophyly of Euryarchaeota was also violated by Nanoarchaeum in some 16S rRNA trees, see, e.g., Figure 4 in a 2009 paper [61] as well as (c) and (d) in our Figure 4. In fact, we have suggested skipping such tiny genomes when studying bacterial phylogeny, see, e.g., [29] and a note in the home page of the CVTree Web Server [21]. In the present case we may at most say that Nanoarchaeota probably makes a separate phylum, but its cutting into Euryarchaeota might be a side effect due to the tiny size of the highly reduced genome.” Conclusion	2	1	L239–244: hard to read, please rephrase.	1	2	life5010949_perova	1
200As a method CVTree is independent of 16S rRNA analysis. First, it uses protein products in a genome instead of RNA segments in the genome. Second, it does not do sequence alignment. CVTree generates stable trees but cannot tell which branch corresponds to what taxon. Only after comparison with the existing classification and nomenclature one would be able to make connections with taxonomy. In this sense it does depend on 16S rRNA taxonomy. Anyway, CVTree does not challenge 16S rRNA analysis but makes it more convincing in most cases. The revealed discrepancies call for further study.	2	1	I disagree that CVTree approach is independent of 16S, because authors are using the current accepted classification (which is mainly 16S-based) to validate the observed clades.	1	2	life5010949_perova	1
201In fact, genomic approaches are more effective at species level and below due to their high resolution power. At high ranks CVTree may be more effective in the sense that it does not require additional work. Suffice it to put genomes in CVTree web server and the branches come out, then compare them with a reference taxonomy.	2	1	Why at higher ranks, genomic approaches are more effective? That needs more explanation. And authors should also consider the large benefits of 16S data availability, specially at high ranks (genus and above) where the 16S has good resolution.	1	2	life5010949_perova	1
202Even “herenow” does not seem to be an correct English word; we changed it to “so far”.	2	1	L208: erenow → herenow	1	2	life5010949_perova	1
203We changed “is in contrast with” to “is distinct from” and added a phrase “focusing on taxonomy of higher ranks” at the end of a sentence. Now the sentences read: “This is distinct from phylogeny of species in a narrow range of taxa, e.g., that of vertebrates (a subphylum) or human versus close relatives (a few genera). Accordingly, the phylogeny should be compared with taxonomy at large, or, as Cavalier-Smith \cite{cavalier-smith2002} put it,with “megaclassificaton” of prokaryotes, focusing on taxonomy of higher ranks.” -	4	1	L35-38: I don’t get well the sentences which start from “This is in contrast ... ”. Please can you specify a bit more?	3	2	life5010949_perova	1
204done	4	1	L45: should provide → provides	3	2	life5010949_perova	1
205Moved to the conclusion section and the first word “Though” replaced by “In addition, since”	4	1	L47–49: move to conclusions?	3	2	life5010949_perova	1
206The whole paragraph has been deleted. This paragraph was added to the revised manuscript because one of the Reviewers asked “Does CVTree still require input genome data to be annotated to gene features, i.e., protein or CDS?” Well, this question reminds us that for many so-called “Permanent Draft” genomes it may be worthwhile returning to our early practice of using whole genome nucleotide sequences without distinguishing coding and non-coding segments. Although it did not lead to better results as compared with using translated protein products, but it is doable on un-annotated contigs. We will try this later.	4	1	L81–85: I think this paragraph is interrupting a bit the text flow. I suggest deletion.	3	2	life5010949_perova	1
207We have deleted all what appeared within the curly brackets and kept only “monophyletic Thaumarchaeota” as suggested. In fact, we could not tell how these words appeared there; there was none in our draft manuscript.	4	1	L244–245: I think the text within {} deviates the attention. I suggest delete that part, ending sentence with “monophyletic Thaumarchaeota” is also ok.	3	2	life5010949_perova	1
208To the best of our knowledge, rare earth doped yttrium iron garnet is still the main material used for magneto-optical devices. They include bismuth doped YIG, bismuth, terbium doped YIG and cerium doped YIG. Other materials such as Wely semimatels are still under theoretical study[1]. We have added comments to these materials in the manuscript. Revisions: Page 1, line 21, added “At present, rare earth doped yttrium iron garnet (RIG) is the most widely used magneto-optical material in integrated MO devices.” Point 2: How will the temperature dependence of the Faraday rotation hysteresis loops of Dy:CeYIG thin films change when moving to another wavelength range?	2	1	1) It is not indicated in the introduction whether any alternative to thin films of yttrium iron garnet is currently being considered for use as magneto-optical resonators.	1	2	ma15051691_perova	1
209Absoultly there is also temperature dependence of the Faraday rotation when shift to other wavelengths. However, the transparency window of this material is in the 1550 nm wavelength range. When moving to shorter wavelengths, the absorption of this material increases sharply, making them less practical for photonic device applications.	2	1	Is there any dependence on the wavelength? 2) How will the temperature dependence of the Faraday rotation hysteresis loops of Dy:CeYIG thin films change when moving to another wavelength range?	1	2	ma15051691_perova	1
210previously reported that the compensation temperature of DyIG is Tcomp = 225 K [2,3], which could decrease the Faraday rotation angle of Dy:CeIG in this work at the temperature below 300 K. Therefore, a higher Faraday rotation may be related to the increase of the saturation magnetization of this material in this temperature range. Revisions:Page 5, line 170-173, added “The increase of the Faraday rotation below 40 ℃ is possibly due to the increase of the magnetization of this material at this temperature range, considering a compensation temperature of 225 K in Dy3Fe5O12 [19,20].”. References: Okamura, Y.; Minami, S.; Kato, Y.; Fujishiro, Y.; Kaneko, Y.; Ikeda, J.; Muramoto, J.; Kaneko, R.; Ueda, K.; Kocsis, V.; et al. Giant magneto-optical responses in magnetic Weyl semimetal Co3Sn2S2. Nat Commun 2020, 11, 4619, doi:10.1038/s41467-020-18470-0. Sayetat, F. Huge magnetostriction in Tb3Fe5O12, Dy3Fe5O12, Ho3Fe5O12, Er3Fe5O12 garnets. Journal of magnetism and magnetic materials 1986, 58, 334-346.	2	1	How can one explain the increase in the value of the Faraday rotation angle in the range of 30-40 degrees for Dy:CeYIG (Fig. 3f), which is absent for Ce:YIG (Fig. 3f)? 3) How can one explain the increase in the value of the Faraday rotation angle in the range of 30-40 degrees for Dy:CeYIG (Fig. 3f), which is absent for Ce:YIG (Fig. 3f)?	1	2	ma15051691_perova	1
211We have updated the references and revised this in the context. Revisions: Page 1, line 21, revised to “for silicon integrated photonic circuits (PICs) [1-3].”. Page 1, line 24, revised to “including optical isolators [4-6]”. Page 1, line 41, revised to “which results in reduced bandwidth and isolation ratio [13].”. Page 1, line 45, revised to “in a temperature range of 20-60 ℃ [10].”. Page 5, line 148, revised to “measure the temperature stability of Dy:CeIG and Ce:YIG films[11].”.	2	1	"Reference source not found"" appears. Please check with the editor if this can be fixed. 1) For several references, the text ""Error!"	1	2	ma15051691_perova	1
212We have revised this in the context. Revisions: Page 3, line 98, revised to “where is the Faraday rotation angle of MO films at room temperature. is the NRPS at room temperature.” Point 3: Line 111.	2	1	2) In equation (2) and the following line, there are inconcistencies in the use of capital letters for the Faraday rotation angles.	1	2	ma15051691_perova	1
213Thanks for correcting this. “X-ray diffraction spectra” has been revised into “X-ray diffraction patterns”. Revisions: Page 3, line 109, revised to “X-ray diffraction patterns”.	2	1	"""X-ray diffraction patterns"", not ""spectra"". 3) Line 111."	1	2	ma15051691_perova	1
214Thanks for the commerts. The saturation magnetization of rare-earth doped YIG affects the Faraday rotation angle. Sayetat et al. and Ostorero et al. previously reported that the compensation temperature of DyIG is Tcomp = 225 K [1,2], which could decrease the Faraday rotation angle of Dy:CeIG in this work at the temperature below 300 K. Therefore, a higher Faraday rotation may be related to the increase of the saturation magnetization of this material in this temperature range. Revisions: Page 5, line 170-173, added “The increase of the Faraday rotation below 40 ℃ is possibly due to the increase of the magnetization of this material at this temperature range, considering a compensation temperature of 225 K in Dy3Fe5O12 [19,20].”.	2	1	While the Faraday rotation angle appears to decrease more or less linearly with temperature in the Ce:YIG film (as far as can be inferred from the non-linear horizontal scale), the decrease is not taking place at the same rate in the Dy:Ce:YIG film. What causes this different behavior? 4) Figures 2 (c) and (d).	1	2	ma15051691_perova	1
215Ostorero, J.; Escorne, M.; Pecheron‐Guegan, A.; Soulette, F.; Le Gall, H. Dy3Fe5O12 garnet thin films grown from sputtering of metallic targets. Journal of Applied Physics 1994, 75, 6103-6105. Page 6, revised the horizontal scale of Figure 3 (c) and updated Figure 3 (c). References: Sayetat, F. Huge magnetostriction in Tb3Fe5O12, Dy3Fe5O12, Ho3Fe5O12, Er3Fe5O12 Journal of magnetism and magnetic materials 1986, 58, 334-346.	2	1	5) Figures 3 (a) and (b): It could be good to use the same horizontal scale for a clearer comparison.	1	2	ma15051691_perova	1
216Thank you for your comment, we have tried to make the abstract less fragmented -Theoretical framework: it is very updated.	2	1	Abstract: it is not conventional. It is very “fragmented”. Try to elaborate it again.	1	2	nu14122489_makarova	1
217Thanks for your comments, we have found a more updated reference (reference 18), cited in lines 96-98 to explain more the importance of HRQoL.	2	1	Theoretical framework: it is very updated. To be prudent, try to update some references if you find.	1	2	nu14122489_makarova	1
218Line 501-503 We have added that we used a large sample size and that this was powerful enough to detect significant differences within sub-groups. We have also added a further description of our ability to capture results in a snapshot of time. I hope this clarifies this aspect.	2	1	Methods. This paper is based on cross sectional method. Can you justify it in depth? This study includes a size of 1139 adolescents.	1	2	nu14122489_makarova	1
219Thank you for your comment, the updated figures and tables are now at the end of the paper.	2	1	Results. In Results, the separations of text and Figures and Tables is strange (when a paper does it, the trend is to include it at the end of all the paper). I recommend you to alternate them (text, Figures and Tables in Results). Nevertheless, results are well elaborated.	1	2	nu14122489_makarova	1
220Thank you for your comment, we are glad that you think so	2	1	Conclusion and discussion: They are well elaborated.	1	2	nu14122489_makarova	1
221Thank you for your comments about the instruments and the associated domains. We have updated these and aimed to explain them in more detail and with more clarity, sections 2.5, 2.6 and 2.7 lines 193-196, 215-225, 236-244.	2	1	(1) The level of reporting of the core assessment instruments and their items, dimensions and subdomains needs to be enhanced.	1	2	nu14122489_makarova	1
222These issues have been addressed. The tables and figures are more clear and more detailed. We have provided are reasoning for the choices of statistical methods.	2	1	(2) There is a need to revising the reporting of the results and information in the tables along with the statistical methodology used with interval data and group comparison research.	1	2	nu14122489_makarova	1
223Thank you for this concern. We have aimed to explain that the KS-10 takes items from the longer KS versions but does not measure for each dimension as it is a general score. However, you have made a great point that some associations may be lost on the specific dimensions, we have tried to explain this reasoning such the burden of participation is lower to complete the KS-10 version lines 493-494 . We wanted to use the general score so that results can be compared with other studies and in other countries, which is one of the advantages of KS-10. Thank you for the insight, this has made us reflect on the KS-10 from the longer versions more.	2	1	(3) The focus on only the global mean score for the wellness KQ-10 measure rather than the 5 dimensions. Diet is only expected to influence 2 of these 5 dimensions.	1	2	nu14122489_makarova	1
224We have now recognised the impact and importance of income to a greater depth and are thankful for your comments on this matter. It is a shame that we cannot say anything about income in this article as this was not measured, only parental education, however this has been suggested for future studies lines 535-537 .	2	1	(4) The lack of recognition that income and cost of living rather than education of parents is also a likely reason for the findings.	1	2	nu14122489_makarova	1
225We have now made a recommendation to investigate this in more depth and to compare diet quality between school time and home time. It is important to assess if the lunches are the same across students of different SES, some insight on this is given in lines 522 and 534 and that an issue could be the diet quality provided at home as school lunches may even-out diet-related inequalities. Thank you for the recommendation as this is an important aspect of adolescents’ diet.	2	1	(5) The lack of recommendations associated with the Swedish free lunch program to assist the diets of students in low SES families to have more fruit and vegetables Comments as the paper was reviewed.	1	2	nu14122489_makarova	1
226Thank you for your comments on this matter, we have edited this and hope it makes more sense now and that it does not make that assumption any longer, see lines 48-50.	2	1	Better to say: Adolescents often do not consume a high-quality diet, concurrently their self- 13 reported mental health problems are increasing.	1	2	nu14122489_makarova	1
227We understand your concern, there are a lot of abbreviations, the abbreviations have been re-written in each section to help follow the flow, and we have now added an abbreviation and key word table before the introduction to provide additional help for readers, thank you for this comment lines 37-45.	2	1	Line 90 need to put in the full name Health Related Quality of Life (HRQoL). You have so many abbreviations confusing to follow in places. The authors may know what these are, but many reader will not. To assist the reader’s comprehension, explain the instruments more as you develop the paper.	1	2	nu14122489_makarova	1
228Thank you for your great comment, we want the dimensions to be clear for the readers and this is an important observation. We have now edited how the SHEIA and RADDS variables are explained as well as the KS-10, sections 2.5 and 2.6 and we hope they are clearer to understand lines 193-196, 215-225, 236-244.	2	1	The important issue is in the method section the reader needs understand the dimensions and sub-dimension that make up within each survey. Unless these are included the reader can not fully understand the study.	1	2	nu14122489_makarova	1
229Thank you for your comments, it is important to mention status and the term SES-F has now been incorporated. We have also now used the term parental education and in section 2.7 we have mentioned that this was used as a proxy for SES, lines 257-258. This is to make it clearer that we only had access to parental education and no other SES-Fs and we hope that this is clearer now, we have used parental education instead of SES in lines 21, 111-114 and 149-150. We have also emphasised the importance of parental income, lines 419-428, 503-506, 533-537 and 550-555.	2	1	The term is usually SES social economic status so it should be SES- F if it is social economic status – factors. Given you are using education of parents as the status measure of SES the term status is important in this paper and should not be dropped.	1	2	nu14122489_makarova	1
230Thank you, we agree that income as well as education plays a role in healthy food choices. However, the results in the article we are referring to looked at parental education, not income. As we did not have access to data in parental income, we were not able to include that variable in our paper	2	1	It is more that education it is also income re line 106-107 “It is proposed that parents with more educational experience are more likely to make healthier food choices for their family” . Miss the point It also assumes that parents with more educational experience are more likely to have higher incomes and so are more likely to make and avoid healthier food choices for their family	1	2	nu14122489_makarova	1
231Although a higher education might lead to a higher income we unfortunately do not have the data to look at that but as previously mentioned we have now stressed the importance of parental income, lines 419-428, 503-506, 533-537 and 550-555, thank you for pointing this out.	2	1	It also assumes that parents with more educational experience are more likely to have higher incomes and so are more likely to make and avoid healthier food choices for their family.	1	2	nu14122489_makarova	1
232Thank you for your comment, income is most certainly important and we have now emphasised its importance in lines 419-428, 503-506, 533-537 and 550-555. We also have mentioned that parental education is being used as a proxy for SES lines 257-258 but we cannot infer anything about income as this was not measured, only parental education, not overall SES.	2	1	If income is not important than the paper should be the on home education level and home diet not home SES and home diet.	1	2	nu14122489_makarova	1
233Thank you for suggesting that we reference these two papers, Darmon and Drewnoski was very insightful and most certainly useful for this article, and we now make it clearer that education is a factor of SES and a proxy for income. Lines 419-428 offer an insight into income and affluence, however we have elaborated more on income in future perspectives 533-537 and in the conclusion, lines 550-555 as it may, as you say, play a significant role in these associations.	2	1	The issues raised in the well quoted Darmon and Drewnowski paper need to be considered more.	1	2	nu14122489_makarova	1
234Thank you for your comment, we want to make the definition of this index as clear as possible and we have edited this in section 2.5.1 and included the sub-components, lines 193-196. We have also cited that reference in both sections 2.5.1 and 2.5.2 so that readers can find a more detailed description. We have also edited section 2.5.2, lines 215-225 so that the RADDS index is also easier to understand and have mentioned some of the sub-components.	2	1	The Swedish Healthy Eating Index for Adolescents 2015 (SHEIA15) is not well explained in this paper. The following paper did a better job of reporting it Moraeus L, Lindroos AK, Warensjö Lemming E, Mattisson I. Diet diversity score and healthy eating index in relation to diet quality and socio-demographic factors: results from a cross-sectional national dietary survey of Swedish adolescents. Public Health Nutr. 2020 Jul;23(10):1754-1765. doi: See their Table 5.	1	2	nu14122489_makarova	1
235Thanks for your observation, we have now tried to describe the KS-10 with more details, and to make it clearer, section 2.6, 236-244.	2	1	See how these researchers have described the KIDSCREEN-10 . Bouwmans, C., van der Kolk, A., Oppe, M., Schawo, S., Stolk, E., van Agthoven, M., ... & van Roijen, L. (2014). Validity and responsiveness of the EQ-5D and the KIDSCREEN-10 in children with ADHD. The European Journal of Health Economics, 15(9), 967-977.	1	2	nu14122489_makarova	1
236We are very pleased that you found this interesting!	2	1	In terms of results the flowchart was interesting.	1	2	nu14122489_makarova	1
237Thank you for this comment, the figure may have been minimised and red meat and poultry are now visible which may not have been before, apologies for this, also we have mentioned some of the sub-components in lines 215-225. Also the figures and tables became distorted when the manuscript was uploaded, we have fixed this.	2	1	I am a not European reviewer and so found the RADDS a rather restricted list without some meat.	1	2	nu14122489_makarova	1
238Thank you for your comment. However, we think chi-squared is the appropriate statistical test as we are only comparing the proportions of distribution between categorical variables, we are not comparing the means between more than two groups which is what ANOVA is used for. We have not used chi square to assess analysis of variance, we have now made it clearer that frequency distribution is being assessed in the statistical methods section In terms of gender and education: the mean, standard deviation, df and sig t or F test need to be reported in the tables.	2	1	Why was the Pearson's chi-squared test used (table 1) for analysis of variance? For while gender and in this study education are categorical (group) the data being evaluated is continuous and interval data and so an ANOVA or MANOVA by group is the method of analysis of variance. (Tabachnick, B.G., Fidell, L. S., & Ullman, J.B. (2007). Using multivariate statistics (5th ed.). Pearson.)	1	2	nu14122489_makarova	1
239Thanks for this comment, we have incorporated t and df scores, see tables 1 and 4.	2	1	In terms of gender and education: the mean, standard deviation, df and sig t or F test need to be reported in the tables.	1	2	nu14122489_makarova	1
240This has been put in the appendix, table A1, page 18, thanks for the suggestion The regression analyses “p” value is reported, but the beta values and significance must also be reported.	2	1	Similarly, a correlation matrix is typically reported as it the foundation of regression analyses and so it needs to be reported to understanding the interaction between three main tests variables being investigated in this study.	1	2	nu14122489_makarova	1
241Great that you mentioned the beta values, the coefficients in the tables are in fact unstandardised beta coefficient values, this has been made clearer in the tables. The tables have diet (ind variable) on the left and the dependent variable KS-10 is on the top to indicate that interaction, then this is stratified by gender. I hope this makes more sense now.	2	1	The regression analyses “p” value is reported, but the beta values and significance must also be reported. The regressing table needs reworked, as it is the influence of diet the independent variable on wellbeing KO-10, the dependent variable. If the focus is on gender typically both a boy and a girl regression model is reported.	1	2	nu14122489_makarova	1
242We had a problem with uploading the figures and they became distorted, thank you for your comments, we have fixed this and incorporated t and df values.	2	1	Table 5 is interesting but the setting out is poor and so the columns do not align with headings, particularly the wellness KQ -10 information. Again, an ANOVA “ t” value and df as well as the p value have to be reported. In table 5 only one p value is reported, but what it is measuring is unclear, as there are a number of interactions occurring. Should be reporting total, then girls, and then boys as there look to be interaction effects.	1	2	nu14122489_makarova	1
243We appreciate your concern regarding the KS-10 item domains. The reason we chose to use the general item value is that it is less burdensome than the longer versions and it is best practice to use the general score and not to directly try to analyse for each dimension. We are not sure that it is a fact that diet can not influence parent relations or social relations, if diet can help to improve quality of life then this may improve how an adolescent feels and their emotions which ultimately may have an influence on relations to others. However, we realise that we may miss out other findings and have mentioned this as a limitation, lines 496-497 and we appreciate your views on this matter. We have also incorporated more information about KS-10 reliability in measuring HRQoL, 236-244This is also a cross sectional study and so only associations can be established not causations.	2	1	Because the KQ-10 is a composite tests there is the likelihood to be some interaction with the sub-domains. Focusing only on the global KQ-10 scores is hiding the subdomain differences to diet. Diet is not expected to have any influence of parent relations, social relations or peers but your study may find an influence on psychological well-being and even school environment. This is the core of your study: does diet have an influence on psychological wellbeing? Remember the KQ-10 is made up of five subdomains (psychological well-being, autonomy and parent relation, social support and peers, and school environment) The fact is diet is no expected to change 3 of these KQ-3 subdomains and only one or two KQ-10 dimensions. Use all five of the KO-10 dimensions as your outcome measure not the Mean average global KQ-10 score. You may have a more important study if you do that, with a different finding to what you have just using the composite total.	1	2	nu14122489_makarova	1
244Great comments, we have elaborated more on income, lines 419-428, 503-506, 533-537 and 550-555. We have also included a detailed section about the significance of school lunches and education in Sweden across different SES groups lines 528-532. In Sweden the school lunch is of rather high diet quality, reaching many of the national dietary recommendations and is provided free of charge regardless of income or SES. However, it would be insightful to a complete a deeper analysis investigating the differences of school quality across differing socio-demographic areas. Nonetheless, the problem related to diet quality may lie in the food provided at home as financial constraints are most likely to be of more significance, lines 528-534.	2	1	The conclusion is sound given the findings but the lack of reference to income is an issue as educational status of parents is often a “de-facto” measure for income. It maybe, it is the cost of living associated with fresh fruit and vegetables that is the real issue. Given the findings the researchers could be arguing that a review may be needed with the Swedish school lunch program and increase the level of fruit and vegetables in the students' diet, particularly for students in lower SES locations. Schools may be making the lunches to a budget rather than to a healthy diet criteria which is more expensive. Different sub-populations even in the same school may need different mix of foods. A public education program could also be encouraged about health eating.	1	2	nu14122489_makarova	1
245The definition of glaucomatous visual field loss was elaborated in the corresponding reference. However, we agree that we were very brief in explaining glaucomatous visual field loss in the manuscript. Therefore we made the following changes to elaborate: In lines 89-98, we changed: “iOAG was defined as glaucomatous visual field loss in at least one eye with reproducibility of the defect, independent of IOP” To: “All participants underwent visual field testing using the Humphrey Field Analyzer (HFA; Carl Zeiss Meditec, Jena, Germany). A second supra-threshold test was performed when a visual field defect appeared to be present. Details have been described elsewhere. [1] If the second supra-threshold test showed at least one overlapping abnormality in the same hemifield, Goldmann kinetic perimetry (RS-I-1 and RS-I-3; Haag-Streit) or full-threshold HFA (all other cohort visits) was performed on both eyes. If abnormalities were consecutive and reproducible, thus present on the Goldmann or full-threshold test and on both supra-threshold tests, visual field loss was considered to be present. Defects had to be in a consistent hemifield and a least one depressed test point had to have exactly the same location on all fields.” In lines 98-100, we changed: “All other possible causes of visual field loss were excluded.” To: “Glaucoma specialists examined fundus photographs, ophthalmic examination reports, medical histories, and MRI scans of the brain to exclude all other possible causes of visual field loss. Discrepancies were resolved by consensus.” In lines 103-104, we added: “For IOP, three measurements were taken from each eye, of which the median value was recorded. [2] For iOAG cases, we used IOP measurements of the affected eye. If both eyes were affected or unaffected, a random eye was selected. IOP was not included in the definition of iOAG.” Was glaucoma also defined by an objective finding, such as the optic disc finding or imaging of the optic disc?	2	1	What was the definition of visual field loss that defined glaucoma?	1	2	nu14122490_perova	1
246OCT images were taken with SD-OCT (Topcon Corp., Tokyo, Japan) since 2007. This means that OCT images are not available for the first four visits of RS-I, and the first two visits of RS-II. Additionally, only part of the images are focused on the disc and even less are reliably segmented. Fundus images were available and were used rather to exclude other cases of visual field loss in participants that showed visual field defects than to observe optic disc abnormalities.	2	1	Was glaucoma also defined by an objective finding, such as the optic disc finding or imaging of the optic disc?	1	2	nu14122490_perova	1
247Thank you for this comment. We understand that it might be useful to present the number of treated glaucoma cases in our baseline characteristics table. Unfortunately, detailed information on prior treatment/surgery for glaucoma is limited (only present for RS-I), and therefore we did not include this variable as covariate in our models. It is thus possible that incident glaucoma cases have received treatment for glaucoma in between two research visits. However, since all participants were (confirmed by examination) free of OAG at baseline, treatment for glaucoma could not have been longer than maximum of one follow-up visit. Although not having this data is a limitation of this study, we do not think it is an important confounding factor, since we do not expect that glaucoma treatment would influence one’s diet. More importantly, dietary information was collected at baseline, with all participants free of OAG. Therefore, if glaucoma presence or glaucoma treatment would have an effect on dietary intake, this would not be applicable in our study. We have added a short sentence explaining this in lines 312-316 of the manuscript.	2	1	Were the incident cases of glaucoma or controls being treated in any case prior to their diagnoses?	1	2	nu14122490_perova	1
248We agree that, although our findings confirm earlier reported associations between dietary nitrate intake and OAG, intervention studies are necessary to investigate and confirm the association between dietary nitrate intake and iOAG. Therefore, we will change all references to “protective (effect)” to “association/associated with”.	2	1	"The authors should avoid making statements such as ""nitrate is protective"" since what they have found is a statistical association."	1	2	nu14122490_perova	1
249Thank you for this suggestion. Although the evidence for the association between ischemia--reperfusion and glaucoma pathogenesis might be scarce, this is only one possible pathway that is addressed in explaining the inverse association between dietary nitrate intake and glaucoma incidence. Nevertheless, we will adjust the manuscript (lines: 271-288) so that this statement is less strong and the focus is more on (a combination with) other pathways, rather than this pathway alone.	2	1	There is very little association between ischemia--reperfusion and glaucoma pathogenesis hence the statements on page nine are irrelevant.	1	2	nu14122490_perova	1
250We agree that the baseline dates of all three cohorts (RS-I, 1991-1993; RS-II, 2000-2001; RS-III, 2006-2008) are already quite some years ago and that dietary patterns in general have changed over time. However, since dietary recommendations are not standard of care for glaucoma patients, we believe that this would likely lead to non-differential misclassification (that causes a bias towards the null hypothesis), since we would expect that glaucoma cases would change their diet similarly to our control population and vice versa. We thus feel that this study and its findings are still highly relevant today since nutrition has become ever more important in medical sciences. Ophthalmology is one of the disciplines which has gained enormous insights from these recent developments. However, to date, no nutritional recommendations have been made for glaucoma patients and research into the association between nutrition (on each level, e.g. diets, food groups, nutrients) and glaucoma is scarce. If associated, this may support diet recommendations in patients that show first signs of developing glaucoma and/or people at-risk for glaucoma as well, impacting millions of people worldwide. Especially since diet changes into a vegetarian of vegan diet are becoming more popular, we think that understanding the potential beneficial effects of these changes, thus the effects of vegetables and their nutrients, is more important than ever. We do agree that these findings should be replicated or validated in another (preferably, an intervention study) study before dietary nitrate intake should be considered as an important public health implication. To address your question about the change of dietary patterns over time more thoroughly: Dinnisen et al. [6] recently published an article in Nutrients where they described changes in dietary intakes of Dutch adults between 2007-2010 and 2012-2016, and evaluated these changes by age, gender, and education. They demonstrated that there was no significant increase in vegetable intake for Dutch adults aged 19–69 years between 2007–2010 (n = 2106; DNFCS 2007–2010) and 2012–2016 (n = 1540; DNFCS 2007–2010) for the total population. There was also no difference when they compared the change in vegetable intake over time per sex or per age category (51-69 years being closest to the baseline age used in our study). Only in the group with the highest educational level, the mean consumption of vegetables increased over time. However, since there was no significant difference in education level in our study between cases and controls (Table 1), we assume that changes in vegetable intake would be similar between both groups, leading to non-differential misclassification. Moreover, we adjusted for education level in our additional model. Regarding dietary nitrate intake from non-vegetable sources, this article states that the intake of red or processed meat decreased over time. This was applicable to both males and females and seen for all age groups. Again, we would expect that this decrease is similar for glaucoma cases and controls. Another Dutch study [7], starting in 1986 (which is more close to the first visit of RS-I) stated that “Another potential limitation that should be considered is whether the food frequency questionnaire at baseline was a reliable estimate of past and future diet. The stability of dietary habits over time was evaluated from five annually repeated questionnaire administrations in independent random samples of the cohort. The mean intakes barely changed and the correlation between two measurements decreased only slightly over an increasing time interval. It was concluded that the single food frequency questionnaire measurement characterizes dietary habits for a period of at least 5 to 10 years.” [8] Nevertheless, since both studies are not directly translatable to the Rotterdam Study, we have assessed the association between the dietary nitrate intake and iOAG over cumulative follow-up periods to provide insight into the stability of the found estimates over time. Please see our comment regarding your next suggestion for more details.	2	1	If I am calculating correctly it has been over 20 years since the incident cases average followup occurred, that is 10-20 years after the start of a study in 1991. How much might the diet of persons in this population have changed since then? Thus, is this study still relevant to today? 30 years ago eating more vegetables was not the vogue it is today.	1	2	nu14122490_perova	1
251We agree that the lack of follow-up food questionnaires is a major limitation of this study. Please find an additional supplementary figure (Figure S1; original Figure S1 has now become Figure S2) below and in the supplements of the manuscript, to show that we assessed the association between the dietary nitrate intake and iOAG over cumulative follow-up periods (x-axis) to provide insight into possible reversed causality. The persistence of the association over time implies that reverse causality is unlikely. The effect of (baseline) dietary nitrate intake on glaucoma appears to be relatively stable over time. We therefore consider our results reliable, although we agree limitations are present and these findings should be interpreted with caution. In addition to the new supplementary figure, we have added information about this analysis to the methods (lines 152-153), results (209-211), and discussion (296-298).	2	1	This study would have been that much stronger if a follow-up food questionnaire had been administered. The long space between the questionnaire and the incidence of glaucoma (only mentioned at the last part of the limitations) is quite a major limitation.	1	2	nu14122490_perova	1
252Thank you very much for assessing the covariates included in these analyses so thoroughly. Unfortunately, family history of glaucoma was only available for a subset of the first cohort, and not for the second and third cohort. Therefore, we were unable to include this variable as a covariate, as this would severely limit our power (528 participants of 1038 participants; 133 glaucoma cases and 389 controls). As cup-to-disc ratio is highly correlated with glaucoma diagnosis, we feel that cup-to-disc ratio should not be included in the model. Moreover, cup-to-disc ratio is not associated with dietary nitrate intake, and therefore cannot be considered as confounding factor. By including cup-to-disc ratio into the model, we would adjust the association between dietary nitrate intake and glaucoma by “glaucoma presence” and thus diminish any existing association. To meet your comment/suggestion, we have added baseline spherical equivalent (proxy for myopia, excluding aphakic or pseudophakic participants) to model 3. As you can see in the results below (original results visualized in Figure 2 in the manuscript), adjusting additionally for SE did not change the results of the continuous nitrate intake analyses and did only marginally change the results of the quintile analyses, leading to a more significant finding for Q5 as compared to Q1. Because both analyses are similar, and since myopia is associated with education level, we chose to keep the original model 3 in the manuscript, adjusting for education level, but without adjustment for SE. To address your question, in lines 318-323, we will change: “Finally, although the analyses were adjusted for several confounders, residual confounding cannot completely be excluded.” To: “Although the analyses were adjusted for multiple confounders, we were unable to adjust for other possible confounders such as family history of glaucoma due to a lack of data. We did consider the risk factor myopia, for which we adjusted by including education level into model 3. We also included spherical equivalent into the model (data not shown), but this did not change the results. Lastly, residual confounding cannot completely be excluded.” Original model 3: model 1 additionally adjusted for education level and smoking status.	2	1	Past studies of the Rotterdam population mention several other risk factors which were not taken into account in this study including myopia, cup-to-disc ratio, and family history of glaucoma, as well as other features such as exfoliation. How big is the nitrate association compared to these?	1	2	nu14122490_perova	1
253In the introduction section we have suggested that dietary nitrate might have both IOP-dependent, or blood pressure dependent, and IOP-independent effects that could affect glaucoma risk. Unfortunately, we were only able to assess the effect of dietary nitrate intake on IOP and blood pressure. In the most ideal situation, we would have assessed the effect of dietary nitrate intake on retinal nerve fiber layer (RNFL) thickness. Unfortunately, due to limitations as described above, we were not able to do so. Since we found no significant effects of dietary nitrate intake on IOP and blood pressure, we suggest that IOP-independent effects of dietary nitrate intake might influence glaucoma risk. This should be further investigated in future studies.	2	1	Overall the finding seems to be an association without a rationale since in effect of nitric oxide presumably related to past nitrate intake would, by their own discussion, change eye pressure or blood pressure yet neither variable was associated with the incident glaucoma.	1	2	nu14122490_perova	1
254We would like to thank the reviewer for this interesting comment. In the Rotterdam Study we indeed find an inverse association between BMI and OAG incidence (Table 1). When we divide the participants in three categories based on their BMI (BMI < 18.5, BMI 18.5-24.9, or BMI >= 24.9), the difference between cases and controls is still (borderline) significant (p=0.054), with more people being overweight (68.7%) in the control group than in the glaucoma group (59.3%). The finding that BMI is inversely associated with OAG is in line with previous studies. Lin et al. [1] found that lower BMI was associated with increased odds of OAG, especially in younger females. Ramdas et al. found similar results, with an association between obesity and a lower risk of developing OAG, although only present in women. [2] In line with these findings, underweight was associated with increased risk of primary OAG in diabetes patients. [3] Moreover, in a group of patients in which visual field loss progressed despite treatment with eye drops, lower BMI was associated with progression of visual field loss in normal-tension glaucoma patients. [4] One possible explanation for this is that cerebrospinal fluid pressure (CSFP) has a positive, linear relationship with BMI. [5] As reduced CSFP may be a risk factor for primary OAG, individuals with lower BMI may have an increased risk for developing primary OAG. [6] Again, a higher BMI may be protective. We acknowledge that BMI is an important confounder in our study, as BMI is associated with both our outcome (OAG) and exposure (diet). We have therefore included BMI as covariate in our main model. Adding or removing BMI from the multivariate model (model 1) did not change the results, as can be seen in the table below. That the association did not change after adjustment for BMI suggests that the association between dietary nitrate intake and OAG cannot be explained by BMI, although residual confounding may persist. To account for a possible effect of BMI on the association between dietary nitrate intake and OAG, we performed additional matching. We returned to the original dataset and matched cases and controls based on age (3-years range) and sex, as done previously, and additionally for BMI (2 kg/m2 range). Please see below for the “new” baseline characteristics table. Once the participants have been matched on age, sex and BMI, you can see that none of the covariates included in the models are significant between iOAG cases and controls. Cases only have a significantly higher IOP, which is expected, and somewhat shorter follow-up (not surprising, since they are excluded one they are diagnosed with iOAG). Diastolic blood pressure, BMI, and the dietary nitrate intakes are no longer different in the univariate analyses between cases and controls. We have created two supplementary tables (Table S4 and Table S5), to show that the associations found between dietary nitrate intake and iOAG or IOP, were largely similar in the analyses where we matched on BMI additionally, as compared to including BMI as covariate into model 1. Only the association between dietary nitrate intake from non-vegetable food sources and iOAG is no longer significant, but the change in effect estimates was minimal and they remained far below 1 (Table S4). For the analyses of IOP, the association between dietary nitrate intake from non-vegetable food sources goes from borderline significant to significant (Table S5). Table S4. Multivariable adjusted odds ratio (95% confidence interval) of open-angle glaucoma by nitrate intake ORa per 1 unit increase in nitrate intakec P-value Total dietary nitrate intake (per 10 mg/day) Model 1a 0.95 (0.91-0.98) .002 Model 1b 0.96 (0.92-0.99) .03 Vegetable dietary nitrate intake (per 10 mg/day) Model 1a 0.95 (0.91-0.98) .004 Model 1b 0.96 (0.92-0.99) .03 Nitrate intake from non-vegetable food sources (per 10 mg/day) Model 1a 0.63 (0.41-0.96) .03 Model 1b 0.76 (0.49-1.17) .22 a Model 1: adjusted for body mass index, total energy intake, diet quality, physical activity, and follow-up time. Analysis performed in participants matched on age and sex. b Model 1: adjusted for total energy intake, diet quality, physical activity, and follow-up time. Analysis performed in participants matched on age, sex and BMI. c Odds Ratios (95%CI) for open-angle glaucoma by total dietary nitrate intake, nitrate intake from vegetables, and nitrate intake from non-vegetable food sources (as continuous variables) analyzed using conditional logistic regression. Table S5. Multivariable adjusted beta (95% confidence interval) of intraocular pressure by nitrate intake Betaa per 1 unit increase in nitrate intakec P-value Total dietary nitrate intake (per 10 mg/day) Model 1a 0.02 (-0.02-0.06) .35 Model 1b 0.00 (-0.06-0.05) .89 Vegetable dietary nitrate intake (per 10 mg/day) Model 1a 0.02 (-0.02-0.06) .29 Model 1b 0.00 (-0.05-0.05) .97 Nitrate intake from non-vegetable food sources (per 10 mg/day) Model 1a -0.45 (-0.96-0.06) .09 Model 1b -0.67 (-1.30- -0.05) .04 a Model 1: adjusted for body mass index, total energy intake, diet quality, physical activity, and follow-up time. Analysis performed in participants matched on age and sex. b Model 1: adjusted for total energy intake, diet quality, physical activity, and follow-up time, Analysis performed in participants matched on age, sex and BMI. c Betas (95%CI) for intraocular pressure by total dietary nitrate intake, nitrate intake from vegetables, and nitrate intake from non-vegetable food sources (as continuous variables) analyzed using linear regression. By displaying these results, we hope to have shown that the associations described in the original manuscript are most likely true associations and explained by dietary nitrate intake rather than age, sex, or BMI. Although an association between glaucoma and cardiovascular disease has been described in the literature [7-9], we believe this is more linked to their shared pathology, impaired auto regulatory capacity of glaucomatous eyes and arterial stiffness of CVD [7], or even genetics [10], than mediated by BMI. Apart from the two additional supplementary figures, we have added some information regarding this comment in lines 301-304 of the manuscript.	2	1	I would only like to ask about one fact that I find intriguing. The authors have found that participants without OAG had a significantly higher BMI than those with OAG. Their mean BMI was found to be 27.1 kg/m2 which is considered overweight. Lower risk of OAG would be related to a higher total dietary nitrate intake. “Previous research has shown that a higher dietary nitrate intake was associated with significantly wider retinal arterioles. [46] Widening of retinal arteriolar caliber is not only associated with lower risk of cardiovascular and cerebrovascular diseases [47,48], but also with lower risk of glaucoma”. On the other hand, “compared with individuals with a normal BMI (defined as a BMI of 18.5 to 24.9), lifetime risks for incident CVD [cardiovascular disease] were higher in middle-aged adults in the overweight and obese groups” Khan SS, Ning H, Wilkins JT, et al. Association of Body Mass Index With Lifetime Risk of Cardiovascular Disease and Compression of Morbidity. JAMA Cardiol. 2018;3(4):280–287. doi:10.1001/jamacardio.2018.0022 I wonder if the authors could comment on this in the Discussion.	1	2	nu14122490_perova	1
255I added a table listing the baseline characteristics, including BMI and smoking status, of subjects.	2	1	Please add a table with patients' baseline characteristics, including BMI and smoking status.	1	2	s22072682_perova	1
256Since this study focuses on AT search, detailed estimation of sample size is not performed. I added in data analysis section.	2	1	Did authors estimate sample size? Please add in data analysis section	1	2	s22072682_perova	1
257Project identification code is H29-4. I added in 2.1.subjects and 6.patents.	2	1	Please add ethics protocol approval number	1	2	s22072682_perova	1
258My manuscript is checked by an English proofreader. I will attach an English proofreading certificate.	2	1	I found some minor English errors throughout the paper. Please have a re-check.	1	2	s22072682_perova	1
259I described the paper's aim.	2	1	I suggest presenting the paper's aim as the last idea in the introduction to make the manuscript easier to read.	1	2	s22072682_perova	1
260I redraw Figures1-2 and described them as an adaptation of the original publication.	2	1	Given the poor quality of the images (Fig 1 and 2), it might be better to redraw them and describe them as an adaptation of the original publication.	1	2	s22072682_perova	1
261I described baseline load of the participants.	2	1	The methods do not specify how the baseline load of the participants was determined.	1	2	s22072682_perova	1
262I revised Fig3.	2	1	"In figure 3, the indication of the test time appears in the reverse direction. Time ""0"" should be at the start."	1	2	s22072682_perova	1
263I deleted Fig5,8,11.	2	1	I recommend deleting graphs 5, 8, and 11 because graphs 7, 10, and 13 show the same information together with lines obtained by analyzing the structural change of the time series.	1	2	s22072682_perova	1
264Authors addressed all my requests and suggestions to my fullest satisfaction.			The figures should be improved in quality so the work would take on another aspect. Figure 7b is not very credible, when U937 become macrogphages adhere to the plate and assume the morphology of a macrophage. the figure is not clear and not well visible. The authors should also show the flow cytometers panels related to cd68 and cd14. This figure does not convince me very much.	1	2	antiox11040683_perova	0
265The manuscript is well written, the results support the hypotheses.			The figures should be improved in quality so the work would take on another aspect. Figure 7b is not very credible, when U937 become macrogphages adhere to the plate and assume the morphology of a macrophage. the figure is not clear and not well visible. The authors should also show the flow cytometers panels related to cd68 and cd14. This figure does not convince me very much.	1	2	antiox11040683_perova	0
266Author Response Thank you again for taking time to review our manuscript and provide valuable constructive feedback, which has improved the quality of our work submitted.			Small comment, the supplementary Fig. S4B would need some compensation work....this would be better to correct before final approval for publication ( up to editor).	1	2	antiox11040683_perova	0
267The Authors showed the role of the BCAT1 CXXC motif in AML and to understand how this may influence cellular redox processes.			Also the gating strategy on Fig. 4d ( is going in right direction), what I am missing here is the exclusion of dead cells?	1	2	antiox11040683_perova	0
268Author Response Thank you again for taking time to review our manuscript and provide valuable constructive feedback.			The data presented by the authors are robust and interesting but are based on a single AML cell line, which is not a bonafide AML cell line (derived from the pleural effusion of a 37-year-old, White, male patient with histiocytic lymphoma, according to ATCC). Thus, authors should discuss limitations in interpreting their findings.	1	2	antiox11040683_perova	0
269Author Response Thank you again for taking time to review our manuscript and provide valuable constructive feedback.			The data presented by the authors are robust and interesting but are based on a single AML cell line, which is not a bonafide AML cell line (derived from the pleural effusion of a 37-year-old, White, male patient with histiocytic lymphoma, according to ATCC). Thus, authors should discuss limitations in interpreting their findings.	1	2	antiox11040683_perova	0
270The Authors showed the role of the BCAT1 CXXC motif in AML and to understand how this may influence cellular redox processes.			Fig 7b. We have removed the Giemsa images and replaced with phase contrast images to better show cell morphology under our light microscope. We also include representative flow cytometric overlayed histograms, which display CD14 and CD68 expression changes between our Vector control and WT / CXXS BCAT1 cells. Included on these histograms is the mean fold MFI change (ratio).	2	1	antiox11040683_perova	0
271The current paper proposes a novel lamina emergent torsional (LET) joint named double-laminated lamina emergent torsional joint (DL-LET) joint which utilizes a layer of flexible H18 aluminum foil to increase the tensile stiffness of LET joint.			Transient analysis followed by reliability experiments/analysis/modeling of the proposed structure would be interesting and critical in aspect of joint application contrains. In my opoinion is should be added or explained in context of scheduled follow-up activities.	1	2	app12052642_makarova	0
272Author Response Thanks for your encouragement and suggestion.			The article being evaluated is an extension of the above cited reference, and the authors would be well advised as to summarize this article, in part, and to delineate what has changed as of 2019, i.e. put this in a paragraph and to explain the subsequent evolution since 2019.	1	2	app12052642_makarova	0
273Following the reported physical experiments (Fig.			Secondly what is missing in the article is in terms of application a clear delineation as to what benefits robotics accrue by the developments summarized in this article .	1	2	app12052642_makarova	0
274In conclusion the paper deserves to be acceped as contribution in Applied Science journal.			Keywords are not sufficient after the abstract.	1	2	app12052642_makarova	0
275"A theoretical model is derived for the DL-LET joint and verified by FEA and experimental results."""			Recent references are to be added as well as it has to be cited, majority of them are old references.	1	2	app12052642_makarova	0
276Chen, G.; Ma, F.; Hao, G.; Zhu, W. Modeling large deflections of initially curved beams in compliant mechanisms using 277 chained Beam-Constraint-Model, ASME J. Mech.			References are not written in the standard journal format.	1	2	app12052642_makarova	0
277Chen, G.; Ma, F.; Hao, G.; Zhu, W. Modeling large deflections of initially curved beams in compliant mechanisms using 277 chained Beam-Constraint-Model, ASME J. Mech.			Work relevant to the research topic is not incorporated, i.e., the work done by other researchers / authors in this field are not incorporated.	1	2	app12052642_makarova	0
278"A theoretical model is derived for the DL-LET joint and verified by FEA and experimental results."""			Please add more details regarding paper’s novelty, it is not very clear what are the novelties of this paper.	1	2	app12052642_makarova	0
279In the proposed manuscript only the advantages are presented.			Please add more details of how the theory from the first sections is applied in the results section and better detail the theoretical part, in this version the theoretical part is almost inexistent.	1	2	app12052642_makarova	0
280373-387-11, 2021. o Event-Triggered Adaptive Fuzzy Control for Stochastic Nonlinear Systems with Unmeasured States and Unknown Backlash-Like Hysteresis, IEEE Transactions on Fuzzy Systems, doi 10.1109/TFUZZ.2020.2973950, pp. 1–19, 2020.			Please detail how the parameters were obtained. -	1	2	app12052642_makarova	0
281As compared to Ref. [19] which focuses on concepts and demonstrations, this work mainly focuses on analytical modeling of one design concept and provides finite element and experimental validations.			The state of the art it is very poor regarding representative papers, maybe the author could add the following publications:	1	2	app12052642_makarova	0
282The current paper proposes a novel lamina emergent torsional (LET) joint named double-laminated lamina emergent torsional joint (DL-LET) joint which utilizes a layer of flexible H18 aluminum foil to increase the tensile stiffness of LET joint.			Please add more details regarding the obtained results.	1	2	app12052642_makarova	0
283In the proposed manuscript only the advantages are presented.			Add the both the advantages and the disadvantages of the proposed method.	1	2	app12052642_makarova	0
284I wonder if one can draw any conclusion from the numerical simulations, where other regimes could have been explored.”			It remains unclear how the quantum regime (with coherent spatial delocalization and interference of probability amplitudes of different paths) could possibly be reached in a real experiment, as spontaneous scattering of photons (of the cavity light or of the side pumper) into free space would localize the atomic wavefuction into one lattice site and thus decohere any spatial delocalization.	1	2	atoms3030433_makarova	0
285The same argument (dimensional analysis) applies to Eqs.			For a quick orientation it would be helpful to indicate the x-axis	1	2	atoms3030433_makarova	0
286"Please, eliminate ""b)"" since it is simply Eq."			"In Section I the authors write: ""The mechanism is similar to the ones exploited in the creation of artificial potentials in optical lattices [17]"". This statement is a bit misleading since [17] uses coherent (quantum-mechanical) tunnelling with complex tunnel amplitudes, whereas the present manuscript deals with classical trajectories and classical jump probabilities."	1	2	atoms3030433_makarova	0
287“However, I have a few comments and suggestions to improve the overall quality and readability of the paper.			"This is similar to previous works on implementation of the quantum random walk with photons [18], atoms in optical lattices [19], ions in traps [20] or on a one-dimensional lattice of superconducting qubits [21]"": This statement is also misleading, because the cited references have reached the coherent quantum walk regime, while the present manuscript only hypothesizes about an (unspecified) possibility to enter the quantum regime."	1	2	atoms3030433_makarova	0
288The idea is clever and original and lends itself to further extensions: for instance, to simulate a kicked rotor, by means of a frequency comb drive, or towards hybrid optomechanics, when the two-level atom is replaced by a doped nano-sphere.			In Section II it should be clearly stated that this is a one-dimensional model, transverse forces or motion are not considered.	1	2	atoms3030433_makarova	0
289The consequence is a sign change in the effective potential that induces the atom to perform an erratic motion, hopping between neighbouring lattice sites.			"in Fig. 2: ""such that c < 0 corresponding to the stable regime of cavity QED with moving atoms"": what does this mean? The regime of cavity cooling?"	1	2	atoms3030433_makarova	0
290Indeed, the analysis here is restricted to the classical regime for both the field and atomic variables.			In Section III the numerical value of \kappa is not given (only in the caption of Fig. 3 it is mentioned that \kappa is set to unity).	1	2	atoms3030433_makarova	0
291"Please, eliminate ""b)"" since it is simply Eq."			Does the special spatio-temporal shape of the potential, which is shown in Fig. 3, and which enables the effective random walk motion, originate in genuine cavity quantum effects, or could a similar potential be generated also in the classical (bad cavity) limit (g -> 0, \eta_L -> infinity and \kappa large), or for a classical standing wave laser beam interfering with a classical transverse running wave?	1	2	atoms3030433_makarova	0
292I would suggest to provide a reference to guide the less experienced reader.”			In describing the action of the optical potential as quasi-random potential kicks, is there some long-term heating effect (i.e. an increase of the average energy of the atom)? Does cavity cooling play a role to counteract this in the numerical simulations?Response Response We thank the referee for an extremely careful reading of the manuscript, his/her appreciation of it and for the very constructive criticism expressed in this report.	1	2	atoms3030433_makarova	0
293In the analytical results, derived in the adiabatic limit, gamma is eliminated and does not play any role.			In the paragraph following Eq. (2), please check the commutation relations between the raising (sigma^+) and lowering (sigma^-) operators and the Pauli matrix sigma^z. I suspect it should be [sigma^+,sigma^z] = - 2 sigma^+ and [sigma^-,sigma^z] = + 2 sigma^- .	1	2	atoms3030433_makarova	0
294Try to use other colors and/or thicker lines.”			"A couple of lines below Eq. (4), the Authors write ""We proceed in a standard way to derive equations of motion for classical quantities."" I would suggest to provide a reference to guide the less experienced reader."	1	2	atoms3030433_makarova	0
295In the analytical results, derived in the adiabatic limit, gamma is eliminated and does not play any role.			In the equations of motion for the atoms [Eqs. (6) and (7)] it is introduced the quantity gamma, which, I guess, is the atomic decay rate. Please, provide a definition of gamma. What is, if any, the role of gamma (spontaneous atomic decay rate) in the physical process under consideration? In the analytical results, derived in the adiabatic limit, gamma is eliminated and does not play any role. I wonder if one can draw any conclusion from the numerical simulations, where other regimes could have been explored.	1	2	atoms3030433_makarova	0
296"(4), the Authors write ""We proceed in a standard way to derive equations of motion for classical quantities."""			"At the end of Section IV C. ""Optical forces"" the time independent value of the force is derived. Please, check this value. I'm afraid there is a factor k missing (simple dimensional analysis shows that something is wrong with it). The same argument (dimensional analysis) applies to Eqs. (24), (25) and (27). Please check again these expressions.”"	1	2	atoms3030433_makarova	0
297Indeed, the same Authors already refer to the single trajectory plot as Fig.			"In section VI E. ""Trapping by longitudinal pumping"", one can analytically estimate the threshold value for the transverse pumping. How does this analytical result compare with the numerical simulations?"	1	2	atoms3030433_makarova	0
298Reviewer 2: Report and Author Response The manuscript reports a theoretical study of the dynamics of an atom inside a time-dependent optical potential, generated in a two-color pumped cavity.			Finally, some stylistic considerations: Please, be consistent with the choice of subscripts and superscripts: in the first column of page 2 the Pauli operator is denoted as sigma^z (superscript), whereas in the second column becomes sigma_z (subscript).	1	2	atoms3030433_makarova	0
299The idea is clever and original and lends itself to further extensions: for instance, to simulate a kicked rotor, by means of a frequency comb drive, or towards hybrid optomechanics, when the two-level atom is replaced by a doped nano-sphere.			Figure 4 is mentioned in the main text AFTER Fig. 5. It would be more logical to exchange their presentation order and, consequently, the figures numbering. Indeed, the same Authors already refer to the single trajectory plot as Fig. 4 (c) [see paragraph below Eq. (13)].	1	2	atoms3030433_makarova	0
300How does this analytical result compare with the numerical simulations?”			Page 4, first paragraph, the particle initial conditions are chosen in the interval [ - 0.1, 0.1] (in the text a comma is missing).	1	2	atoms3030433_makarova	0
301However, the Authors outline possible generalizations to the quantum regime in the concluding section.			"Page 5, first column, second paragraph ""... one can inspect Eq. (11) b) where the right-hand side ..."". Please, eliminate ""b)"" since it is simply Eq. (11). The same misprint appears at page 8 in the paragraph between Eqs. (32) and (33)."	1	2	atoms3030433_makarova	0
302How does this analytical result compare with the numerical simulations?”			"Page 6, ""Optical forces"": there is a missing subscript L in the first force term at the end of the first paragraph, just before Eq. (21)."	1	2	atoms3030433_makarova	0
303In the analytical results, derived in the adiabatic limit, gamma is eliminated and does not play any role.			Figure 8, Force correlation functions and numerical solutions of the variance: when printed in grey scale some lines are very faint (especially those in green and cyan). Try to use other colors and/or thicker lines.	1	2	atoms3030433_makarova	0
304The authors extensively study the effects of human serum, human serum albumin, or human pleural fluid on Cefiderocol sensitivity of a panel of A. baumanii strains.			It is known that HSA can bind RNA and DNA and has RNA hydrolyzing activity. In this way your experiment in par 2.2. may lead to not all RNA after incubation with such amount of albumin. That is why some of your effects may have other explanations. Have you done some control experiments? Maybe your effect is much higher or lower.	1	2	biomedicines10030600_perova	0
305The authors extensively study the effects of human serum, human serum albumin, or human pleural fluid on Cefiderocol sensitivity of a panel of A. baumanii strains.			https://www.sciencedirect.com/science/article/abs/pii/S0960894X08011086?via%3Dihub	1	2	biomedicines10030600_perova	0
306"The authors presented the paper ""Human Serum Proteins and Susceptibility of Acinetobacter baumannii to Cefiderocol: role of iron transport""."			It would be of great interest if for the key results the authors would also provide MBC and / or time-resolved kill-curves. I believe this kind of data would be of great relevance for assessing the clinical relevance of the observed effects.	1	2	biomedicines10030600_perova	0
307Two female participants had to be excluded….”.			"Introduction Line 31 – ""(4-10 Hz) induced…"" this is not theta range; please correct."	1	2	brainsci11121640_makarova	0
308Although we would assume that the figure on the left is always the letter “A” and the one on the right is “B”, for the sake of clarification, kindly add a letter legend on the figures.			Line 32 – add the reference.	1	2	brainsci11121640_makarova	0
309(2012) would lead to lasting MEP facilitation.			Methods Participants Did the authors take note of the menstrual cycle of the female participants?	1	2	brainsci11121640_makarova	0
310The coefficient of determination is for the regression analysis and indicates that Lat differences were significant predictors of MEP facilitation.			Although the differences in handedness would not profoundly affect the overall results, can the author check if there were significant differences in stimulation intensity (AMT and RMT) in right and left-handed participants? Left-handed individuals often have a high threshold on the left motor cortex.	1	2	brainsci11121640_makarova	0
311Although you state you defined the rMT in Fig. 1 you did not.			Line 89-90: edit this part.	1	2	brainsci11121640_makarova	0
312The present study entitled “Facilitation of motor evoked potentials in response to a modified 30 Hz intermittent theta-burst stimulation protocol in healthy adults” investigated the effectiveness of intermittent 30 Hz/6 Hz TBS in inducing lasting facilitation of MEPs.			Results Are there differences in stimulation intensities taken from the two devices (Magstim Rapid and BiStim2)?	1	2	brainsci11121640_makarova	0
313What are the benefits of 30 Hz/6 Hz TBS protocol (intermittent mode) in comparison with 50 Hz/ 5 Hz standard iTBS?			Can you report the F value and effect size?	1	2	brainsci11121640_makarova	0
314Discussion Line 402: in SIFC, one pulse is suprathreshold, and the other is subthreshold.			In line 209, the authors reported that “Of 21 participants, 19 (13 females) completed the protocol without any issues. Two female participants had to be excluded….”. However, looking at Figure 3, it is obvious that plotted data were from 20 participants. Can the author correct this discrepancy?	1	2	brainsci11121640_makarova	0
315Although you state you defined the rMT in Fig. 1 you did not.			Is the cut-off plus or minus 10 standard for the responder and non-responders? Looking again at Figure 3, we can observe very high variability. In my opinion, plus or minus 10% is arbitrary.	1	2	brainsci11121640_makarova	0
316However, looking at Figure 3, it is obvious that plotted data were from 20 participants.			Discussion Line 402: in SIFC, one pulse is suprathreshold, and the other is subthreshold.	1	2	brainsci11121640_makarova	0
317Although the differences in handedness would not profoundly affect the overall results, can the author check if there were significant differences in stimulation intensity (AMT and RMT) in right and left-handed participants?			Why did not compare to the sham stimulation group and 50 Hz/ 5 Hz standard iTBS protocol? I think COVID-19 is not reason. Do you think 30 Hz/6 Hz TBS protocol (intermittent mode) increased MEP amplitude as compared to 50 Hz/ 5 Hz standard iTBS? What are the benefits of 30 Hz/6 Hz TBS protocol (intermittent mode) in comparison with 50 Hz/ 5 Hz standard iTBS?	1	2	brainsci11121640_makarova	0
318Discussion Line 402: in SIFC, one pulse is suprathreshold, and the other is subthreshold.			Does the participants have a neurological disease or other diseases? Please write in the manuscript.	1	2	brainsci11121640_makarova	0
319Although you state you defined the rMT in Fig. 1 you did not.			The single-pulse TMS elicited 20 MEPs at baseline but at three specific time points after post-iTBS (i.e., 5-, 20- and 45-min) just elicited 15 MEPs respectively. Why did not also test 20, 25 or 30 MEPs?	1	2	brainsci11121640_makarova	0
320"Introduction Line 31 – ""(4-10 Hz) induced…"" this is not theta range; please correct."			In line 125, MT needs to be defined.	1	2	brainsci11121640_makarova	0
321Looking again at Figure 3, we can observe very high variability.			In line 145, full stop marked an error.	1	2	brainsci11121640_makarova	0
322Although the differences in handedness would not profoundly affect the overall results, can the author check if there were significant differences in stimulation intensity (AMT and RMT) in right and left-handed participants?			In line 28, please define rTMS.	1	2	brainsci11121640_makarova	0
323The single-pulse TMS elicited 20 MEPs at baseline but at three specific time points after post-iTBS (i.e., 5-, 20- and 45-min) just elicited 15 MEPs respectively.			How do you test the aMT and rMT?	1	2	brainsci11121640_makarova	0
324Is the cut-off plus or minus 10 standard for the responder and non-responders?			Please give the detailed process. How do you get the hotspot?	1	2	brainsci11121640_makarova	0
325The coefficient of determination is for the regression analysis and indicates that Lat differences were significant predictors of MEP facilitation.			In lines 459 and 461, pay attention to the space between words.	1	2	brainsci11121640_makarova	0
326Some questions please need authors to answer.			In line 253, where is the F value?	3	2	brainsci11121640_makarova	0
327In line 209, the authors reported that “Of 21 participants, 19 (13 females) completed the protocol without any issues.			In line 282, the result showed r2 = 0.24, p = 0.03 but it is a difference in Fig. 5.	3	2	brainsci11121640_makarova	0
328I only have minor comments and questions that the author should answer to improve the manuscript.			Although you state you defined the rMT in Fig. 1 you did not.	3	2	brainsci11121640_makarova	0
329The single-pulse TMS elicited 20 MEPs at baseline but at three specific time points after post-iTBS (i.e., 5-, 20- and 45-min) just elicited 15 MEPs respectively.			"Line 31 – ""(4-10 Hz) induced…"" this is not theta range; please correct."	1	2	brainsci11121640_perova	0
330However, looking at Figure 3, it is obvious that plotted data were from 20 participants.			Line 32 – add the reference.	1	2	brainsci11121640_perova	0
331Two female participants had to be excluded….”.			Did the authors take note of the menstrual cycle of the female participants?	1	2	brainsci11121640_perova	0
332Why did not compare to the sham stimulation group and 50 Hz/ 5 Hz standard iTBS protocol?			Although the differences in handedness would not profoundly affect the overall results, can the author check if there were significant differences in stimulation intensity (AMT and RMT) in right and left-handed participants? Left-handed individuals often have a high threshold on the left motor cortex.	1	2	brainsci11121640_perova	0
333Do you think 30 Hz/6 Hz TBS protocol (intermittent mode) increased MEP amplitude as compared to 50 Hz/ 5 Hz standard iTBS?			Line 89-90: edit this part.	1	2	brainsci11121640_perova	0
334"Introduction Line 31 – ""(4-10 Hz) induced…"" this is not theta range; please correct."			Are there differences in stimulation intensities taken from the two devices (Magstim Rapid and BiStim2)?	1	2	brainsci11121640_perova	0
335(2012) would lead to lasting MEP facilitation.			Can you report the F value and effect size? Would it be interesting if the present data can give the same effect size (0.71) as those reported by Chung et al. (2016)?	1	2	brainsci11121640_perova	0
336"In line 119, the capital ""a"" changes lower case."			Can you report the F value and effect size? Would it be interesting if the present data can give the same effect size (0.71) as those reported by Chung et al. (2016)?	1	2	brainsci11121640_perova	0
337However, looking at Figure 3, it is obvious that plotted data were from 20 participants.			In line 209, the authors reported that “Of 21 participants, 19 (13 females) completed the protocol without any issues. Two female participants had to be excluded….”. However, looking at Figure 3, it is obvious that plotted data were from 20 participants. Can the author correct this discrepancy?	1	2	brainsci11121640_perova	0
338Methods Participants Did the authors take note of the menstrual cycle of the female participants?			Is the cut-off plus or minus 10 standard for the responder and non-responders? Looking again at Figure 3, we can observe very high variability. In my opinion, plus or minus 10% is arbitrary.	1	2	brainsci11121640_perova	0
339Is the cut-off plus or minus 10 standard for the responder and non-responders?			Line 402: in SIFC, one pulse is suprathreshold, and the other is subthreshold.	1	2	brainsci11121640_perova	0
340What are the benefits of 30 Hz/6 Hz TBS protocol (intermittent mode) in comparison with 50 Hz/ 5 Hz standard iTBS?			Why did not compare to the sham stimulation group and 50 Hz/ 5 Hz standard iTBS protocol? I think COVID-19 is not reason. Do you think 30 Hz/6 Hz TBS protocol (intermittent mode) increased MEP amplitude as compared to 50 Hz/ 5 Hz standard iTBS? What are the benefits of 30 Hz/6 Hz TBS protocol (intermittent mode) in comparison with 50 Hz/ 5 Hz standard iTBS?	1	2	brainsci11121640_perova	0
341(2012) would lead to lasting MEP facilitation.			Does the participants have a neurological disease or other diseases? Please write in the manuscript.	1	2	brainsci11121640_perova	0
342In line 209, the authors reported that “Of 21 participants, 19 (13 females) completed the protocol without any issues.			The single-pulse TMS elicited 20 MEPs at baseline but at three specific time points after post-iTBS (i.e., 5-, 20- and 45-min) just elicited 15 MEPs respectively. Why did not also test 20, 25 or 30 MEPs?	1	2	brainsci11121640_perova	0
343Left-handed individuals often have a high threshold on the left motor cortex.			In line 125, MT needs to be defined.	1	2	brainsci11121640_perova	0
344In my opinion, the major potential issues were already discussed in the limitation sections.			In line 145, full stop marked an error.	1	2	brainsci11121640_perova	0
345In line 209, the authors reported that “Of 21 participants, 19 (13 females) completed the protocol without any issues.			In line 28, please define rTMS.	1	2	brainsci11121640_perova	0
346Actually, we did, but it seems that the new figure legend with the correction was not properly inserted when the system reformated the document.			How do you test the aMT and rMT?	1	2	brainsci11121640_perova	0
347The coefficient of determination is for the regression analysis and indicates that Lat differences were significant predictors of MEP facilitation.			Please give the detailed process. How do you get the hotspot?	1	2	brainsci11121640_perova	0
348In line 282, the result showed r2 = 0.24, p = 0.03 but it is a difference in Fig. 5.			In lines 459 and 461, pay attention to the space between words.	1	2	brainsci11121640_perova	0
349The present study entitled “Facilitation of motor evoked potentials in response to a modified 30 Hz intermittent theta-burst stimulation protocol in healthy adults” investigated the effectiveness of intermittent 30 Hz/6 Hz TBS in inducing lasting facilitation of MEPs.			In line 253, where is the F value?	3	2	brainsci11121640_perova	0
350Although we would assume that the figure on the left is always the letter “A” and the one on the right is “B”, for the sake of clarification, kindly add a letter legend on the figures.			In line 282, the result showed r2 = 0.24, p = 0.03 but it is a difference in Fig. 5.	3	2	brainsci11121640_perova	0
351The present study entitled “Facilitation of motor evoked potentials in response to a modified 30 Hz intermittent theta-burst stimulation protocol in healthy adults” investigated the effectiveness of intermittent 30 Hz/6 Hz TBS in inducing lasting facilitation of MEPs.			Although you state you defined the rMT in Fig. 1 you did not.	3	2	brainsci11121640_perova	0
352Point 5: It could be better to include base load ratings in the results section (Fig: 10) Response 5:			In the proposed system solar PV, wind generator and battery are the main generating system. As the proposed system is in isolated mode, how continuity of power supply be maintained?	1	2	en15031006_makarova	0
353As the proposed system is in isolated mode, how continuity of power supply be maintained?			The quality of the figures needs to be improved.	1	2	en15031006_makarova	0
354As the proposed system is in isolated mode, how continuity of power supply be maintained?			Equations 4, 9, and 12 include some corrections and need to be modified.	1	2	en15031006_makarova	0
355As the proposed system is in isolated mode, how continuity of power supply be maintained?			It could be better to include base load ratings in the results section (Fig: 10)	1	2	en15031006_makarova	0
356The appliances are prioritized based on their need and demand to achieve optimum energy utilization.			Sizing of renewable energy sources and battery systems were not properly explored.	1	2	en15031006_makarova	0
357Point 5: It could be better to include base load ratings in the results section (Fig: 10) Response 5:			Please discuss how consumers’ comfortability is marinated in the proposed method.	1	2	en15031006_makarova	0
358Point 5: All the figures need to be improved.			Authors should avoid using the subjective pronoun “we” in academic works	1	2	en15031006_makarova	0
359Author Response Please see the attachment Author Response File: Author Response.docx			In such a study an experimental case must be presented in a specified region.	1	2	en15031006_makarova	0
360Point 4: Equations 4, 9, and 12 include some corrections and need to be modified.			The authors should carefully distinguish the new contributions of their work from the new existing studies (DOI: 10.1016/j.est.2020.101221).	1	2	en15031006_makarova	0
361Point 2: In the proposed system solar PV, wind generator and battery are the main generating system.			A comprehensive deeper literature review is necessary to address the research issue, Also authors need to provide a literature survey in an organized way.	1	2	en15031006_makarova	0
362- The authors should carefully distinguish the new contributions of their work from the new existing studies.for example: DOI: 10.1016/j.est.2020.101221 A comprehensive deeper literature review is necessary to address the research issue.			All the figures need to be improved.	1	2	en15031006_makarova	0
363In the convergent parallel strategy, quantitative and qualitative data collection occurred concurrently.			The citations are not formatted according to the journal guidelines. Please revise.	1	2	healthcare10040723_makarova	0
364Author Response See the point-by-point response in the attached Word file.			Include the full form of STD described in the results.	1	2	healthcare10040723_makarova	0
3651 Review comments Title: Medical students' perceptions towards digitization and artificial intelligence: A mixed methods study Thank you for the opportunity to review this manuscript.			Table 3 “Health apps and computer algorithms are for patients disturbing (=)…” should “(=)” be “(0)”?	1	2	healthcare10040723_makarova	0
366The aim of the study as reported in the manuscript was to explore attitudes of 2020 medical students’ generation towards various aspects of eHealth technologies with the focus on AI using an exploratory sequential mixed method analysis.			Line 252, 24/7 is the commonly accepted form of 7/24.	1	2	healthcare10040723_makarova	0
367Author Response See the point-by-point response in the attached Word file.			Line 267 and 268, the description of figure 1 is not clear. Does “focused on senses” mean in-person patient-doctor interaction?	1	2	healthcare10040723_makarova	0
368In an exploratory sequential mixed-methods design, the researcher emphasizes the qualitative data (QUAL) more than the quantitative data (quan).			Table 4 data suggest Digital networks increase doctor nurse communication but Line 266 says it undermines the same. Can you clarify?	1	2	healthcare10040723_makarova	0
369In an exploratory sequential mixed-methods design, the researcher emphasizes the qualitative data (QUAL) more than the quantitative data (quan).			Table 5, what does numbers 1 through 7 represent?	1	2	healthcare10040723_makarova	0
3701 Review comments Title: Medical students' perceptions towards digitization and artificial intelligence: A mixed methods study Thank you for the opportunity to review this manuscript.			Clarity whether or not the study design was “exploratory mixed methods design” or mere a “convergent parallel design”	1	2	healthcare10040723_makarova	0
371The fundamental issue that needs clarity is whether or not the study design was ‘exploratory mixed methods design’ or ‘convergent parallel design.’ As far as exploratory mixed methods design is concerned, the researcher begins with qualitative data and then collects quantitative information.			In the abstract, lines 23-27, I suggest to use the following expression or something like that. Around 38% of the students felt ill-prepared and could not answer AI-related questions because digitization in medicine and AI are not a formal part of the medical curriculum.	1	2	healthcare10040723_makarova	0
372First, why did you use only 4 students for pilot testing?			Page 2, line 42, ‘the computation of compounding factors,’ I did not understand what it means. I suggest the authors to replace this with appropriate phrase.	1	2	healthcare10040723_makarova	0
373For example, the first sentence should describe the general aim or the overall objective of the study in a more general term.			Also, the research questions lack describing the study setting.	1	2	healthcare10040723_makarova	0
374Importantly, the study has pointed out the lack of in-depth awareness about digital health technologies in students and highlighted the need for education of the same.			On page 2, line 111, the phrase ‘to affirm or dismiss,’ does not make sense. Replace this phrase with a more appropriate phrase.	1	2	healthcare10040723_makarova	0
375In this regard, your study fits with the exploratory nature.			Second, what do ‘AG’ and ‘JE’ represent?	1	2	healthcare10040723_makarova	0
376I suggest to re-write the aims and study questions more clearly.			Page 3, line 132, it says, Convenience sampling was used. I would ask, why did you use convenience sampling?	1	2	healthcare10040723_makarova	0
377Replace this phrase with a more appropriate phrase.			Page 4, table 1, the caption and the table content do not match. Revise either of them.	1	2	healthcare10040723_makarova	0
378Importantly, the study has pointed out the lack of in-depth awareness about digital health technologies in students and highlighted the need for education of the same.			Also describe the final study sample for both.	1	2	healthcare10040723_makarova	0
379The aim of the study as reported in the manuscript was to explore attitudes of 2020 medical students’ generation towards various aspects of eHealth technologies with the focus on AI using an exploratory sequential mixed method analysis.			Page 12, line 389, the statement which says, ‘The non-probabilistic sampling makes a generalization of the answers difficult,’ is confusing. I suggest to re-write this sentence.	1	2	healthcare10040723_makarova	0
380I suggest to remove the phrase ‘so called,’ that has been used in the conclusion section or any other section.			I suggest to remove the phrase ‘so called,’ that has been used in the conclusion section or any other section.	1	2	healthcare10040723_makarova	0
381Page 12, line 389, the statement which says, ‘The non-probabilistic sampling makes a generalization of the answers difficult,’ is confusing.			Page 13, lines 409-410, in the conclusion section, the statement which says, ‘This study also found significant differences between those groups indicating differences in subgroups of students from the quantitative survey.’ This is a confusing statement. Re-write this sentence clearly.	1	2	healthcare10040723_makarova	0
382I suggest the authors to include a short section including the implications of the study after the conclusions.			I suggest the authors to include a short section including the implications of the study after the conclusions.	1	2	healthcare10040723_makarova	0
383Comparative radiologic changes before and after TOC administration In Table 2, about the change in CT findings in fatal and non-fatal patients before and after TOC administration, isn't it the same as the difference in imaging findings between patients who survive after severe illness and those who do not, regardless of TOC?			The impact of Tocilizumab on radiological changes can not be adequately analyzed without a control group not receiving the drug.	1	2	jcm11051247_perova	0
384Point 2: The proposed timing of Tocilizumab administration based on oxygen flow rate is interesting but undoubtedly requires a more detailed statistical analysis to convince the readers.			The proposed timing of Tocilizumab administration based on oxygen flow rate is interesting but undoubtedly requires a more detailed statistical analysis to convince the readers.	1	2	jcm11051247_perova	0
385Results The median oxygen flow rate is shown to be 14 L/min, but FiO2 may vary depending on the method of oxygen delivery (nasal canulae, HNF, MV).			If there are mutations or differences in viral strains during the course of the study, should differences in response to TOC and timing of administration depending on the strain be considered?	1	2	jcm11051247_perova	0
386Results 2 The oxygen flow rate of 13 L/min measured by ROC as a cutoff value for TOC administration should be presented by FiO2.			86 cases are excluded from 187 cases, which is too many. What is the reason?	1	2	jcm11051247_perova	0
387Author Response Please see the attachment Author Response File: Author Response.pdf			When comparing different oxygen delivery methods, isn't it more appropriate to compare FiO2 rather than oxygen flow rate?	1	2	jcm11051247_perova	0
388Author Response Please see the attachment Author Response File: Author Response.pdf			The median oxygen flow rate is shown to be 14 L/min, but FiO2 may vary depending on the method of oxygen delivery (nasal canulae, HNF, MV).	1	2	jcm11051247_perova	0
389Study design and population If there are mutations or differences in viral strains during the course of the study, should differences in response to TOC and timing of administration depending on the strain be considered?			The oxygen flow rate of 13 L/min measured by ROC as a cutoff value for TOC administration should be presented by FiO2.	1	2	jcm11051247_perova	0
390Comparative radiologic changes before and after TOC administration In Table 2, about the change in CT findings in fatal and non-fatal patients before and after TOC administration, isn't it the same as the difference in imaging findings between patients who survive after severe illness and those who do not, regardless of TOC?			In Table 2, about the change in CT findings in fatal and non-fatal patients before and after TOC administration, isn't it the same as the difference in imaging findings between patients who survive after severe illness and those who do not, regardless of TOC?	1	2	jcm11051247_perova	0
391Comparative radiologic changes before and after TOC administration			As mentioned above, the cutoff value is O2 13L/min, but the oxygen volume is difficult to interpret because FiO2 varies depending on the method of oxygen delivery.	1	2	jcm11051247_perova	0
392The authors adequately addressed my concerns.			Thank you for this suggestion. While it would have been interesting to explore this further, our study focuses on retrospectively assessing and comparing disease progression within subgroups of patients receiving TOC. Patients not receiving TOC would have likely had a different presentation, progression and their follow-up would be slightly out of the scope of our observational retrospective study. When we compared patients who received TOC with the 86 severe patients who did not receive TOC (excluded from this analysis), the TOC group was far more severe, so there is no control group that could be matched. In addition, these patients did not have control CT scans.	2	1	jcm11051247_perova	0
393Results 2 The oxygen flow rate of 13 L/min measured by ROC as a cutoff value for TOC administration should be presented by FiO2.			Following this suggestion, we have included in the analysis a calculation according to the FiO2. This has a cut-off which correlates to the oxygen flow cut-off.	2	1	jcm11051247_perova	0
394Theories on the origin of life or on other aspects of early evolution, such as cellularization, serve merely as starting points.			The place of RNA in LUCA (page 2): In search of features that are more conserved (carrying deep phylogenetic memory) than the sequence of genes, Wächtershäuser focuses on a paper of his in Systematic and Applied Microbiology (1998) that uses gene content and order of microbial genomes to make inferences about the last universal common ancestor (LUCA) of cellular life. He then mines the significance of some of the conserved chromosomal segments in light of some other evidence. The exercise is at places compelling, but forgets some recent, very global and exhaustive analyses that also use highly conserved biological features to reconstruct the makeup of LUCA (e.g., gene order, 3D molecular structure, molecular functions). See for example PubMed references PMID: 17370266, PMID: 21612591, and PMID: 17908824, which are in line with some conclusions derived from the alignment of Figure 1. The fact that these other analyses make use of hundreds of genomes to infer the ancient biochemistry of LUCA complements and strengthens the preliminary and fragmentary analysis of only 19 of them by the author, which also excludes eukaryotic genomes from the set (understandably, few sequenced genomes were available in 1998, and eukaryotes are in general “master rearrangers”).	1	2	life4041050_perova	0
395Second Round of Evaluation Round 2: Most commentary has been addressed and new changes have improved the exposition.			Given my interest in the bioinformatics of gene content and order, I took the liberty of studying the brief Systematic & Applied Microbiology paper to check the validity of the “reconstruction” methods of Figure 1. The algorithmic implementation that is described is quite raw and does not extract important information that is embedded in the clusters of conserved gene segments. Important algorithms have been devised since the initial work of Sankoff in the sixties and seventies to do exactly that. I refer to the work of Pevzner, Tesler and Bourque as good examples, but also of Warnow. I also recommend visiting GRIMM (http://grimm.ucsd.edu/GRIMM/) and perhaps using the server to confirm or extract additional information from the alignments that are summarized in Figure 1. The Wächtershäuser algorithm makes use of conserved elements of gene content and order but discards information provided by the actual rearrangement operations that erase gene order history. The algorithm does not describe how gene homology was detected, how the limited set of genes was selected, and how the alignments were constructed (I imagine by hand). It is not clear if a guiding tree was used in the alignment (though this is mentioned in Line 65), since this is not made explicit in the 1998 publication. An alignment implies a tree but usually alignment algorithms are greedy and problematic and represent the most important limiting step of a phylogeny (the field is thus moving to the joint alignment and tree reconstruction). Therefore, I do not think the ancestors were properly reconstructed (the tracing of features in ancestor nodes of trees are not described, nor the actual trees). Regardless of all of these limitations, the tight conservation of certain segments is enough to show the existence of a core of ribosomal proteins that is universally present in cellular organisms. This in itself is valuable. Of course, a sample of 19 microbes may not be enough to encompass molecular diversity and the absence of Eukarya may also be problematic for any global evolutionary statement. In other words, the risks of sampling bias are clearly present and should be mentioned in the manuscript.	1	2	life4041050_perova	0
396I have only a few comments, which might improve the manuscript.			The list of common genes in the alignment of Table 1 is enriched in small and large subunit ribosomal proteins that are the most ancient of the ribosomal set, according to the Caetano-Anolles theorem that is mentioned later in the manuscript. Interestingly, the most ancient of them are clustered toward the 5’ end of the genomic sequences that were aligned (S12, S17, S5, S4 and L2, L3 and L24). Could this imply a possible ancient segmental duplication? Also interesting is the placement of the most ancient ribosomal protein S12 between exactly two polymerase (beta and beta prime) and elongation factor (entry and translocation) genes (separated by single and much more derived ribosomal proteins). Could this be an ancient memory of the ribosome mediating translation and replication? A commentary would enhance the value of the section.	1	2	life4041050_perova	0
397Therefore, my comments will be slanted by my own expertise and will only serve the author as a partial devil’s advocate effort General commentary Section 1.			In terms of the genome organization of LUCA (Line 105), there are numerous arguments in favor of an RNA ancestral genome and the late unfolding of DNA as genetic repository (perhaps through viruses). I cannot understand how 2'-hydroxy groups could destabilize the molecule and lead to “intramolecular self-destruction” (Line 107). RNA has the wonderful property of folding in search of energetic and kinetic minima. These processes make use of a frustrated landscape, which is powerful in terms of its biological potential (stability, function, information). It is much more versatile than the rigid DNA alternative, which is enriched in the ‘information’ capacity. None of them have “self destruction” properties, which would have been weeded out by selection and self-organization very early in “chemical” evolution. In turn, everything about LUCA should be considered quite modern and far away from an initial FeS world. I refer to the work of Daniel Lundin and colleagues in Sweden about the rather late rise of some structures of the ribonuceotide reductase enzymes needed to built the DNA polymers. The Maurel theorem stands if one thinks of single genome molecules. But what if there were many short RNA genomes, as anticipated by Woese, each perhaps linked to different and ancient tRNA-like cofactors? As the author mentions, LUCA is contemporary to a rather complex biochemistry, with numerous structures harboring a multitude of active and allosteric sites in proteins, most of which drive central enzymatic functions.	1	2	life4041050_perova	0
398Round 1: and Author Response The manuscript comprises an exciting account on the origin of life with emphasis on the emergence and function of RNA.			In Line 114, the role of chromosomal rearrangement in evolution is not well described. What are the effects of genome rearrangements? Several scenarios are possible, including: (1) Genes remain linked R4 probably because it is more efficient to transcribe genes that produce interacting proteins (part of complexes) than those that are not; (2) Genes remain linked if they are of relatively recent origin (rearrangement has not had the change to split them apart); (3) Genes remain linked if they are part of functional groups historically united by genomic regions (encoding metabolic functions or rRNA? ); this includes genes sharing an operon structure for economy purposes in highly reduced organisms such as bacteria; (4) Genes remain linked because they originated when genomic rearrangements were not biochemically motivated and their sequence makeup was later refractory to rearrangement hotspots. There is a rich literature about rearrangement, hotspots and many processes related to these (including domain organization in proteins). Some discussion in this front could be clarifying.	1	2	life4041050_perova	0
399Theories on the origin of life or on other aspects of early evolution, such as cellularization, serve merely as starting points.			In relation to comments of Line 188 onwards, Di Giulio, Caetano-Anolles and others have suggested that the genetic code started to unfold prior to LUCA but continue to do so once life diversified. The corollary, is that the complete canonical set of amino acids may have not been encoded in LUCA. In terms of metabolic and biochemical competency, there are numerous and interesting studies, which have not been cited (especially in origins and evolution of modern metabolism). This includes the coevolution theory of the genetic code, the coexistence of prebiotic chemistries with modern metabolic reactions (recently studied for nucleotide metabolism), and theories about the origin of translation.	1	2	life4041050_perova	0
400He reviews some of his previous work and presents an alternative to the dominant ‘Ancient RNA world’ hypothesis.			Thermal course of evolution (Page 6): Why a focus on thermal energy? The framework should be on thermodynamics, energy dissipation and information, all of which are linked. What is thermally upward or downward adaptation? Is it conquering niches on Earth or a process involving molecular makeup? Vocabulary and definitions are murky, especially related to the links of environmental thermal fluctuations, energy of folding and stability of polymers. Subsection (1) must be rewritten to help the reader understand the ideas. Should all adaptations comply with maximizing energy R5 dissipation? How can this be reconciled with upward and downward trends? No references are provided despite the rich literature underscoring the controversial link between physics, information theory and biology. If the focus is conquering planetary niches, then perhaps reference the contrasting views and some of their proponents (deep sea versus surface; thermophilic versus mesophilic, etc.). Further elaboration of the Wolfenden theorem appears relevant and its connections to what is known about the origin and evolution of metabolism also of importance.	1	2	life4041050_perova	0
401In light of recent research developments and argumentation (some of it reviewed), his views should be considered a welcome addition to the many ideas that populate the “origin of life” field of inquiry that counter the dominant paradigm.			Place of RNA in the origin and early evolution of translation/Pre-translational coding of peptides. The view that is presented in this crucial segment posits a pre-translational mechanism (side-by-side tRNA mediated coding) that very much resembles the ribosomal entropic system, which could be very advanced. What if the pre-translational coding was assembly line-like and mediated by the aminoacyl-tRNA synthetases themselves? See PMID: 23991065 for one such alternative and a related previous model (PMID: 22210458). This would also match commentary of a possible early origin of non-ribosomal peptide synthesis machinery compared to that of the ribosome.	1	2	life4041050_perova	0
402Response The author prefers the present title, because the paper is concerned with the origin of the genetic machinery.			General overview. While the grand finale “Nothing in evolution makes sense except in the light of chemical predetermination” is impressive and summarizes the championing work of the author, chemical predetermination may apply to the very early stages of evolution and not to many of the stages described in the manuscript. How much chemical predetermination can there be with polymers as these explore a minute fraction of the space they make possible? In the enthalpic-entropic gradient that is proposed, there is also a gradient from “predetermination” to historical contingency. The boundaries of such a gradient is murky and the final statement may not apply to much of modern biochemistry, once proteins start to achieve stable complex structure and much earlier that the time of LUCA. In fact, the genome rearrangements that underlie Figure 1 are testament to the historical contingencies that were already at play in LUCA and not to chemical predetermination.	1	2	life4041050_perova	0
403Theories on the origin of life or on other aspects of early evolution, such as cellularization, serve merely as starting points.			Title. The title does not encompass appropriately the wide subject matter covered by the manuscript. I suggest “The place of RNA in the origin and early evolution of life”.	1	2	life4041050_perova	0
404The article demonstrates that the iron-sulfur surface metabolism theory at high temperatures has a much better explanatory power than the RNA World theory.			Line 39. And what is the place of proteins in all that?	1	2	life4041050_perova	0
405In light of recent research developments and argumentation (some of it reviewed), his views should be considered a welcome addition to the many ideas that populate the “origin of life” field of inquiry that counter the dominant paradigm.			Line 39 and Section 1 “The place of RNA in LUCA”. The word retrodiction implies reconstruction of ancestors from extant information.	1	2	life4041050_perova	0
406I must note that a careful evaluation of all facets requires expertise in a multitude of disciplines (from prebiotic chemistry and structural biology to evolutionary bioinformatics and biochemistry) and considerable time, none of which I possess.			Line 40. Interpolation of LUCA and competing theories of the origin of life. In my view, LUCA is not a theory of origin of life. It is a theory of origin of diversified cellular life.	1	2	life4041050_perova	0
407I have only a few comments, which might improve the manuscript.			Line 52. Not only genes are gained and lost with time (Woese theorem), but also mutations accumulate to saturation in genes making homology statements difficult. This has been made explicit abundantly in the molecular evolutionary literature. A focus on gene content and order makes only sense if such homologies at gene level are preserved (if not there will be artifactual losses in the alignments).This should be highlighted in the text because it is relevant to the validity of the alignment of Figure 1, making its significance more important.	1	2	life4041050_perova	0
408Therefore, my comments will be slanted by my own expertise and will only serve the author as a partial devil’s advocate effort General commentary Section 1.			Line 62: Change “multiply” to “multiple”.	1	2	life4041050_perova	0
409He reviews some of his previous work and presents an alternative to the dominant ‘Ancient RNA world’ hypothesis.			Line 406. “LUCA protein cycle”. Why bring LUCA to a link with the proposed “protein cycle”. LUCA is just the last of a chain of ancestor of diversified life. If the protein cycle requires a coupling of the enthalpic activation of amino acids and the entropic biosynthetic action of a primordial ribosome, then perhaps it is better to call it “ribocellular protein cycle”, since this coupling marks the start of modern cells, not necessarily “modern diversified cells” (i.e., LUCA).	1	2	life4041050_perova	0
410The article demonstrates that the iron-sulfur surface metabolism theory at high temperatures has a much better explanatory power than the RNA World theory.			Please explain what do you mean with Kandler, Wolfenden etc. Theorem. Is a theorem Kandler’s theory or proposal?	1	2	life4041050_perova	0
411Second Round of Evaluation Round 2: Most commentary has been addressed and new changes have improved the exposition.			Line 716: The biosyntheses of His and Trp are not so closely related. They only have in common that they use phosphoribosediphosphate as substrate and therefore share two related enzymes.	1	2	life4041050_perova	0
412Theories on the origin of life or on other aspects of early evolution, such as cellularization, serve merely as starting points.			In the iron sulfur world the surface metabolism prevents the diffusion of the fixed products into the ocean. But without compartmentation soluble intermediates would escape. Furthermore, the establishment of early bioenergetics based on electrochemical Na+ gradients would have been impossible.	1	2	life4041050_perova	0
413Produces a dynamic model for chemical evolution rather than traditional deterministic, static, systems that requires centralised information to direct evolution, such as a constant gradient.			Very well presented, clear and graphically illustrated experimental findings that make a clear case for the model. Also a very thorough understanding of the limitations of the system are presented as well as proposals for even more complex instabilties that may underpin lifelike events. Overall a beautifully written, wonderfully presented, paper with clear concepts, methods and proposals that significantly contribute to original knowledge in the field.	1	2	life5010181_makarova	0
414Round 1: and Author Response The article “Emergent Chemical Behaviour in Variable-Volume Protocells” focuses on the consequences that a changing volume may have on a set of reactions encapsulated within a semipermeable vesicle; in particular, this kind of compartment can degenerate existing bistable reactions, or promote emergent bistability from very simple reactions, which are not bistable in bulk conditions.			The authors write: “In these initial stages, the emergence of bistability will serve as a proxy for the emergence of other chemical novelties in the vesicle reactor model.” The authors probably means that the existence of more than one stable regime could consent regime changes, but this situation do not indicates how these changes appear: in the article, the change is stimulated by means of a deliberated injection of chemical substances from outside. So, I think that the appearance of novelties requires a different order of considerations, whereas the bistability plays possibly the role of novelties amplification and consolidation (in particular conditions). The same observation can be done for the word “innovation”, used on the abstract and at Line 45. In order to avoid misunderstandings, I think that the authors should avoid these expressions, ad use the words “regime change”, or similar concepts.	1	2	life5010181_makarova	0
415The mathematical methods used to deal with the problem are based on approximations and require the support of a huge number of simulations; on the other side, the approximations themselves constitute an interesting feature of the article and allow interesting discussions on the involved physical situations.			Note 4 presents a very important issue: why the inner chemical environment is different from the external one, if the running chemical reactions are the same? The presence of particular features of the vesicle interior or of entrapped catalysts seem a too easy and ad hoc hypothesis. A useful reference proposing an explanation of this symmetry breaking (without requiring different conditions in internal and external environments) could be “R. Serra, M. Villani Mechanism for the formation of density gradients through semipermeable membranes Physical Review E 87, 2013”.	1	2	life5010181_makarova	0
416As the authors acknowledge, the article is the first step toward a more complete understanding of an interesting class of possible chemo-physical phenomena.			How the authors derive the range [0.9, 101/3] for the so called “reduced surface” index? In Figure 1d, Lines 21/3 and 41/3 have some particular meanings, or are plotted mainly to ease the figure comprehension? Could the authors add some indications about the derivation of these upper limits?	1	2	life5010181_makarova	0
417The authors discuss these issues by means of differential equations and simulations.			The authors write (case 1): “of the 5000 parameter set tested under constant surface area, 82% (4098) gave a single fixed point, 321 15.7% (785) gave two fixed points, and 2.3% (117) no fixed points.” How this statistics compare with a similar one, performed on a similar chemical situation without container? Could the authors add the results of the same within a not confined environment?	1	2	life5010181_makarova	0
418As the authors acknowledge, the article is the first step toward a more complete understanding of an interesting class of possible chemo-physical phenomena.			Adamala, K.; Szostak, J. ompetition betweenmodel protocells driven by an encapsulated catalyst. Nat. Chem. 2013, 5, 495–501. → “ompetition” should be: “Competition”.	1	2	life5010181_makarova	0
419Round 1: and Author Response The authors present a dataset where they have characterised the relative abundance of components of the photosynthetic electron transfer chain and related this to the measured rate of electron transfer from PSII.			I don’t understand how they calculated the protein molar ratios. In the methodology section we learn that they extracted the crude proteins and then performed western analyses using specific antibodies, followed by image analyses. I don’t understand how they converted the western data to read the amount of specific proteins, in fmol, in the various organisms as shown in Figure 2; and used for the calculations in the rest of the paper. (Why are the units provided again in Line 220?). Please provide the reader with the methodology used for the quantification.	1	2	life5010403_perova	0
420Second Round of Evaluation Round 2: and Author Response			PSII activity is derived from fluorescence measurement, as ETR. I am missing calibration with real measurements of PSII activity such as O2 evolution. You have got to show it for each organism you are examining otherwise it is worthless. There are many reports in the literature showing dramatic decline in fluorescence but hardly any change in O2 evolution.	1	2	life5010403_perova	0
421provides us with estimates of the concentrations of various proteins representing the PSII, PSI, cytb6 and Rubisco in there different cyanobacteria.			The cells were grown under a relatively low light intensity and thus the data presented here only apply to these conditions. Please make sure the reader is aware of it.	1	2	life5010403_perova	0
422The data presented is robust and worthy of publication but should be discussed more critically with regard to published literature (outlined below) I suggest some minor suggestions that should be incorporated before publications.			Line 19 – I am not sure why stating the cyanobacteria are nondiazatrophic is relevant?	1	2	life5010403_perova	0
423The data presented is robust and worthy of publication but should be discussed more critically with regard to published literature (outlined below) I suggest some minor suggestions that should be incorporated before publications.			Line 46 – (and throughout) be clear if you mean numerically dominate or dominate production – they are not always the same thing.	1	2	life5010403_perova	0
424Second Round of Evaluation Round 2: and Author Response			Introduction paragraph 2 – I am unsure we know that physbobilisomes require more resource than pcb proteins – this depends on the ratio of antenna to reaction centre? Please include references if R3 this has been shown. Also, not all Pcb proteins are constitutively expressed (e.g., see Bibby et al. Nature 2003).	1	2	life5010403_perova	0
425provides us with estimates of the concentrations of various proteins representing the PSII, PSI, cytb6 and Rubisco in there different cyanobacteria.			Line 250 – This is estimated number of RUBISCO active sites – or is there evidence all the RUBSCIO you quantify is active?	1	2	life5010403_perova	0
426The data presented is robust and worthy of publication but should be discussed more critically with regard to published literature (outlined below) I suggest some minor suggestions that should be incorporated before publications.			Figure 4 – The crunch of this paper is Figure 4e which show the Rubisco:PSII ratio is correlated to ETR. While I’m convinced in the presented data only three data-points are shown – I’m most convinced in that this same relationship is presented in in “Aquatic Photosynthesis (edition 2) Figure 7.9 – Falkowski” based on work of Sukenik (1986?). A greater discussion should be given in the text to how these datasets compare and what is significantly new in this dataset? References 35 and 36 are discussed in relation to the potential control of cytb6f on limiting electron transfer from PSII but more should be made of Falkowski’s observations which support this data.	1	2	life5010403_perova	0
427The approach and methods are robust and the ability to quantify components of the photosynthetic electron transfer chain is powerful.			Line 308 – The data presented is used to support potential cyclic electron flow around PSI – however other alternative terminal electron sinks could also be up-regulated – these concepts are discussed in a recent review by Milligan and Behrenfeld annual review 2013 – the implications of this should be discussed unless the authors can show specifically enhanced flow around PSI.	1	2	life5010403_perova	0
428The data are interesting and worth publishing but… (1)			“In line 178 onward we read about the calibration curve. Please presnt it in the paper. Once you apply stress such as iron starvation you should recalibrate.” R4 Response:	3	2	life5010403_perova	0
429provides us with estimates of the concentrations of various proteins representing the PSII, PSI, cytb6 and Rubisco in there different cyanobacteria.			“Please present the calibration curves for the protein levels.” Response:	3	2	life5010403_perova	0
430If all genomes from a taxon appear exclusively in a tree branch, the branch is said to be monophyletic.”			I would like to see a comparison with at least one regular alignment/treeing method, based on the same genomes the authors used, and not just a visual topological comparison with other published trees.	1	2	life5010949_perova	0
431Even if defined in the future, it must be lineage-dependent.			As far as I can see, statistical support on the branches is missing, so I have no way of assessing if this branching order is valid. Bootstrapping or jackknifing are by no means the final word on the significance of branches, however an explanation as to how the user should assess the significance of braches would be good, i.e., branch length.	1	2	life5010949_perova	0
432R13 Round 2: and Author Response Authors have substantially improved the article, including language corrections, and have provided extensive clarifications to all initial criticisms.			The fact that Thermofilum is placed outside Crenarchaeota in Figures 3 and 4 is a little disturbing. I haven’t come across such a placement in other phylogenetic analyses of Archaea, for example in Brochier-Armanet et al 2008 Nat Rev Microb, or Rinke et al. 2013 Nature. I believe this needs to better explained in the manuscript, rather than just saying “this fact is noted”.	1	2	life5010949_perova	0
433Besides, would be desirable that authors provide more objective criteria for high taxa circumscription based on their methodology.			I am also not very convinced with the placement of Nanoarchaeota. It seems like this phylum is moving around with the addition of new sequence data (for example in Rinke et al. Figure 2 tree, they are on an entirely different branch than Euryarchaeota). Though the authors also rightfully point out that the reduced genome size may have something to do with this placement.	1	2	life5010949_perova	0
434About 180 archaeal genomes were used to calculate a new tree topology using CVTree.			The placement of Halobacteria (due to interfering Nanoarchaeota, I presume) is also a little disturbing. I would recommend that the authors provide a discussion of this. Especially with regards to other archaeal trees. For instance, in the tree of Armanet et al 2011 that the authors also refer to, the placement of Halobacteria with respect to Nanoarchaeota is very different.	1	2	life5010949_perova	0
435Authors should define well their objectives, also make sure that the conclusions are novel (which ones are novel, which are supportive to previous published work, etc.			In summary, I find the piece interesting, but parts of the discussion are rather weak, therefore I am suggesting a major revision. Another reason for major revision is the style that the manuscript is written. I am not a native speaker, but given that I had to read sentences several times, I suspect the manuscript can benefit from an English language check.	1	2	life5010949_perova	0
436The tree was compared with several 16S rRNA trees reported in the literature, and the differences were minor.			I found the revised version of this manuscript quite good, and I thank the authors for responding thoroughly to all my comments.	3	2	life5010949_perova	0
437However, I am personally not convinced that whole genomes bring additional advantages, or if we are better off by just using a conserved set of proteins.			I would really appreciate a “Methods” part where the CVTree is explained shortly, and the tree-viewer is explained with more detail. The absence of branch lengths and bootstraps should be discussed here. Other technical aspects of the paper (e.g., sequence dataset), parameters, criteria ... all could be well organized in this part.	1	2	life5010949_perova	0
438About 180 archaeal genomes were used to calculate a new tree topology using CVTree.			Archaeal phylogeny has already been studied in detail, with 16S and other marker genes, and with genomic approaches too. Some of the undersigning authors had already published on this before, although with smaller input datasets. Therefore, the fact that 16S topology is quite stable and comparable with other approaches is already known.	1	2	life5010949_perova	0
439Authors emend classification of some strains.			Taxonomists have traditionally circumscribed the high taxa (specially orders and classes) with great subjectivity, i.e., without well accepted criteria. In terms of phylogenetic trees one premise has always been clear, a taxon must be monophyletic. This principle has been used in the present work to reconsider the status of some high taxa. However, authors do not explain objective criteria to properly interpret the rank of the clades, which impedes making a profound evaluation of the archaeal classification. Therefore, although authors have strong tools and dataset, they just achieved a small revision of the high taxa which is, indeed, quite biased by the underlying 16S guidelines.	1	2	life5010949_perova	0
440Authors should define well their objectives, also make sure that the conclusions are novel (which ones are novel, which are supportive to previous published work, etc.			I have noted some lack of scientific rigor according to: many wrong taxonomic names and typos, scarce figure legends, few comments about the missing branch lengths or bootstraps (! ), redundancy in text and figures and fragments which are really difficult to understand. Authors should pay attention to language, explanations and text organization.	1	2	life5010949_perova	0
441Authors present a new interactive tree-visualization tool which enables direct validation of taxonomic groups according to their monophyly.			Authors shouldn't forget (particularly in conclusion) that the resolution power of 16S for high ranks (genus and above) is currently well accepted. And the number of non-redundant 16S entries available is much much larger than that of archaeal genomes. 16s data offer a much comprehensive view of the archaeal diversity, including deep branches.	1	2	life5010949_perova	0
442About 180 archaeal genomes were used to calculate a new tree topology using CVTree.			L40 “Since at present (…) are not covered (...)” is a weak reason for choosing high ranks. I recommend to shortly summarize why high ranks are so important, and why do you choose order as the lowest considered rank.	1	2	life5010949_perova	0
443Besides, would be desirable that authors provide more objective criteria for high taxa circumscription based on their methodology.			The figure legends require more rigorous explanation. Would be interesting to remember that the branch lengths are not taken into account, or were omitted.	1	2	life5010949_perova	0
444It has been known that tiny genomes of endosymbiont microbes often tend to move towards baseline of a tree and distort the overall picture.			In Line 80—authors write some explanations to understand the tree figures. I would suggest to put this text before the first tree figure.	1	2	life5010949_perova	0
445Even if defined in the future, it must be lineage-dependent.			Figure 1 is a bit redundant. A short comment about the inclusion of that particular sequence into the Thermoplasmatales can be added into the legend of Figure 2.	1	2	life5010949_perova	0
446Besides, would be desirable that authors provide more objective criteria for high taxa circumscription based on their methodology.			However, the reclassification of Methanomassiliicoccus into Thermoplasmataceae needs more explanation. To be objective, authors should address the following question, why in the same family and not in another new family?	1	2	life5010949_perova	0
447I recommend acceptance for publication in Life Sciences journal.			L106–107: maybe a bit inappropriate on that position. I would suggest to add a comment on the figure legend instead.	1	2	life5010949_perova	0
448Authors should define well their objectives, also make sure that the conclusions are novel (which ones are novel, which are supportive to previous published work, etc.			L109–118: Summarize and move to introduction. Those sentences are of general importance for the topic and not specific to part 3.2.	1	2	life5010949_perova	0
449— Done Second Round of Evaluation Round 2: and Author Response			L119–123: if the K issue is relevant to understand the text then please add a proper explanation. If not, then keep it simple and avoid entering into the K issue (L122–123, L132, L135, L139, 183, and also remove this K = 6 from Figure 3.)	1	2	life5010949_perova	0
450Though a dissimilarity measure figures in the CVTree algorithm, it is not realistic to delineate taxa by using this measure at least for the time being.			Add more explanations in legend of Figure3.	1	2	life5010949_perova	0
451Though a dissimilarity measure figures in the CVTree algorithm, it is not realistic to delineate taxa by using this measure at least for the time being.			L143: Sounds clearer if you avoid mixing class and phylum, for example: “The placement of phylum Korarchaeota, as a closest neighbor of family Thermofilaceae, violates the monophyly of phylum Crenarchaeota.” Response:	1	2	life5010949_perova	0
452However, I am personally not convinced that whole genomes bring additional advantages, or if we are better off by just using a conserved set of proteins.			L146: No need to explain the 6+2 if it is properly explained in the figure legend. Figure 3 is redundant. I would recommend to avoid presenting different versions of the same tree; just the final tree is OK (use final/valid labels) and all important explanations in the text or legend. Perhaps the whole reasoning in Lines 142–180 is not so relevant for the current objective of comparing CVT, LTP, Bergeys? Or, perhaps, define this objective more clearly.	1	2	life5010949_perova	0
453Therefore, branching order in trees is of primary concern, whereas calibration of branch lengths makes less sense.			L156–166. If I understood right, there was good support for Candidatus Aciduliprofundum as part of a clade called DHEV2, which is a sister clade of Thermoplasmatales. However in the present work the authors intend here to reclassify Aciduliprofundum into family Thermococcaceae of Thermococcales. This needs further explanation. Since the new affiliation is quite in disagreement with previous observations, and this is not properly justified in the results/discussion, the final statement “this modification would hold as long as no new facts challenge it” seems unacceptable. In addition, why should Aciduliprofundum be regarded as member of Thermococcaceae and not as another distinct family?	1	2	life5010949_perova	0
454Authors present a new interactive tree-visualization tool which enables direct validation of taxonomic groups according to their monophyly.			L163: If I’m right the current observation actually does not support the previous work done by Brochier-Armanet.	1	2	life5010949_perova	0
455Authors present a new interactive tree-visualization tool which enables direct validation of taxonomic groups according to their monophyly.			L167–173: The names are wrongly written (please check the original submission). Authors have to explain with more clarity, why is this clade of rank class. If that is the case, is it a single-order class? A single family order?	1	2	life5010949_perova	0
456Results also provide additional support to recently proposed archaeal phyla and halobacterial orders.			L174–180: I don’t understand the reasoning along this paragraph. In addition “haolphiic_archaeon_DL31” is not well written, please be careful when copying names from other source. Also, a similar question about the objectiveness for detecting high taxa: why not to create new family?	1	2	life5010949_perova	0
457Besides, would be desirable that authors provide more objective criteria for high taxa circumscription based on their methodology.			Figure 4: the reclassifications must be clearly justified in the text.	1	2	life5010949_perova	0
458R13 Round 2: and Author Response Authors have substantially improved the article, including language corrections, and have provided extensive clarifications to all initial criticisms.			L191: organisms can't be validly published, but their names.	1	2	life5010949_perova	0
459Authors emend classification of some strains.			L221–222: Sure, but authors do not provide explanations about how do they know that a clade in a tree is a family, an order, a class, etc. There is a lack of criteria to reclassify the leaves.	1	2	life5010949_perova	0
460Even if defined in the future, it must be lineage-dependent.			L224: I don’t understand “3063 identical nucleotide positions”. Why identical?	1	2	life5010949_perova	0
461present a comparative analysis of the taxonomic classification of the Archaea domain.			L239–244: hard to read, please rephrase.	1	2	life5010949_perova	0
462If all genomes from a taxon appear exclusively in a tree branch, the branch is said to be monophyletic.”			I disagree that CVTree approach is independent of 16S, because authors are using the current accepted classification (which is mainly 16S-based) to validate the observed clades.	1	2	life5010949_perova	0
463General Comments The topic is relevant for microbial taxonomy.			Why at higher ranks, genomic approaches are more effective? That needs more explanation. And authors should also consider the large benefits of 16S data availability, specially at high ranks (genus and above) where the 16S has good resolution.	1	2	life5010949_perova	0
464Perhaps an additional discussion point would be the advantages of using CVtree approach with regular concatenated proteins.			L208: erenow → herenow	1	2	life5010949_perova	0
465Leaving that opinion aside, I think the alignment-free methodology is interesting, however			L35-38: I don’t get well the sentences which start from “This is in contrast ... ”. Please can you specify a bit more?	3	2	life5010949_perova	0
466General Comments The topic is relevant for microbial taxonomy.			L45: should provide → provides	3	2	life5010949_perova	0
467Evaluation I found major concerns along this manuscript, and suggest a substantial revision.			L47–49: move to conclusions?	3	2	life5010949_perova	0
468Results also provide additional support to recently proposed archaeal phyla and halobacterial orders.			L81–85: I think this paragraph is interrupting a bit the text flow. I suggest deletion.	3	2	life5010949_perova	0
469For example, it cannot be expected that the same degree of dissimilarity may be used to delineate classes in all phyla.			L244–245: I think the text within {} deviates the attention. I suggest delete that part, ending sentence with “monophyletic Thaumarchaeota” is also ok.	3	2	life5010949_perova	0
470Response: Thanks for your recognition of our work.			1) It is not indicated in the introduction whether any alternative to thin films of yttrium iron garnet is currently being considered for use as magneto-optical resonators.	1	2	ma15051691_perova	0
471It will be of interest to a wide range of researchers involved in magneto-optical resonators.			Is there any dependence on the wavelength? 2) How will the temperature dependence of the Faraday rotation hysteresis loops of Dy:CeYIG thin films change when moving to another wavelength range?	1	2	ma15051691_perova	0
472"Author Response Reviewer #1 (Comments to the Author): The article ""Dysprosium substituted Ce:YIG thin films for temperature in-2 sensitive integrated optical isolator applications contains the results"" presents a temperature stable magneto-optical material Dy2Ce1Fe5O12 for silicon integrated nonreciprocal photonic device applications."			How can one explain the increase in the value of the Faraday rotation angle in the range of 30-40 degrees for Dy:CeYIG (Fig. 3f), which is absent for Ce:YIG (Fig. 3f)? 3) How can one explain the increase in the value of the Faraday rotation angle in the range of 30-40 degrees for Dy:CeYIG (Fig. 3f), which is absent for Ce:YIG (Fig. 3f)?	1	2	ma15051691_perova	0
473Ostorero, J.; Escorne, M.; Pecheron‐Guegan, A.; Soulette, F.; Le Gall, H. Dy3Fe5O12 garnet thin films grown from sputtering of metallic targets.			"Reference source not found"" appears. Please check with the editor if this can be fixed. 1) For several references, the text ""Error!"	1	2	ma15051691_perova	0
474demonstrate a temperature stable magneto-optical material Dy2Ce1Fe5O12 for silicon integrated nonreciprocal photonic device applications.			2) In equation (2) and the following line, there are inconcistencies in the use of capital letters for the Faraday rotation angles.	1	2	ma15051691_perova	0
475There are several questions about the content of the article.			"""X-ray diffraction patterns"", not ""spectra"". 3) Line 111."	1	2	ma15051691_perova	0
476Response: Thanks for your recognition of our work.			While the Faraday rotation angle appears to decrease more or less linearly with temperature in the Ce:YIG film (as far as can be inferred from the non-linear horizontal scale), the decrease is not taking place at the same rate in the Dy:Ce:YIG film. What causes this different behavior? 4) Figures 2 (c) and (d).	1	2	ma15051691_perova	0
477It will be of interest to a wide range of researchers involved in magneto-optical resonators.			5) Figures 3 (a) and (b): It could be good to use the same horizontal scale for a clearer comparison.	1	2	ma15051691_perova	0
478Given you are using education of parents as the status measure of SES the term status is important in this paper and should not be dropped.			Abstract: it is not conventional. It is very “fragmented”. Try to elaborate it again.	1	2	nu14122489_makarova	0
479Given the findings the researchers could be arguing that a review may be needed with the Swedish school lunch program and increase the level of fruit and vegetables in the students' diet, particularly for students in lower SES locations.			Theoretical framework: it is very updated. To be prudent, try to update some references if you find.	1	2	nu14122489_makarova	0
480To assist the reader’s comprehension, explain the instruments more as you develop the paper.			Methods. This paper is based on cross sectional method. Can you justify it in depth? This study includes a size of 1139 adolescents.	1	2	nu14122489_makarova	0
481There is much about this paper that is of value, but it does need relooking at, particularly in the results reporting to do the research and the data justice.			Results. In Results, the separations of text and Figures and Tables is strange (when a paper does it, the trend is to include it at the end of all the paper). I recommend you to alternate them (text, Figures and Tables in Results). Nevertheless, results are well elaborated.	1	2	nu14122489_makarova	0
482The European Journal of Health Economics, 15(9), 967-977.			Conclusion and discussion: They are well elaborated.	1	2	nu14122489_makarova	0
483In Results, the separations of text and Figures and Tables is strange (when a paper does it, the trend is to include it at the end of all the paper).			(1) The level of reporting of the core assessment instruments and their items, dimensions and subdomains needs to be enhanced.	1	2	nu14122489_makarova	0
4842020 Jul;23(10):1754-1765. doi: See their Table 5.			(2) There is a need to revising the reporting of the results and information in the tables along with the statistical methodology used with interval data and group comparison research.	1	2	nu14122489_makarova	0
485It needs minor revision in places but the results need more attention.			(3) The focus on only the global mean score for the wellness KQ-10 measure rather than the 5 dimensions. Diet is only expected to influence 2 of these 5 dimensions.	1	2	nu14122489_makarova	0
486If the focus is on gender typically both a boy and a girl regression model is reported.			(4) The lack of recognition that income and cost of living rather than education of parents is also a likely reason for the findings.	1	2	nu14122489_makarova	0
487If the focus is on gender typically both a boy and a girl regression model is reported.			(5) The lack of recommendations associated with the Swedish free lunch program to assist the diets of students in low SES families to have more fruit and vegetables Comments as the paper was reviewed.	1	2	nu14122489_makarova	0
488Why was the Pearson's chi-squared test used (table 1) for analysis of variance?			Better to say: Adolescents often do not consume a high-quality diet, concurrently their self- 13 reported mental health problems are increasing.	1	2	nu14122489_makarova	0
489In Results, the separations of text and Figures and Tables is strange (when a paper does it, the trend is to include it at the end of all the paper).			Line 90 need to put in the full name Health Related Quality of Life (HRQoL). You have so many abbreviations confusing to follow in places. The authors may know what these are, but many reader will not. To assist the reader’s comprehension, explain the instruments more as you develop the paper.	1	2	nu14122489_makarova	0
490Why was the Pearson's chi-squared test used (table 1) for analysis of variance?			The important issue is in the method section the reader needs understand the dimensions and sub-dimension that make up within each survey. Unless these are included the reader can not fully understand the study.	1	2	nu14122489_makarova	0
491There is much about this paper that is of value, but it does need relooking at, particularly in the results reporting to do the research and the data justice.			The term is usually SES social economic status so it should be SES- F if it is social economic status – factors. Given you are using education of parents as the status measure of SES the term status is important in this paper and should not be dropped.	1	2	nu14122489_makarova	0
492Unless these are included the reader can not fully understand the study.			It is more that education it is also income re line 106-107 “It is proposed that parents with more educational experience are more likely to make healthier food choices for their family” . Miss the point It also assumes that parents with more educational experience are more likely to have higher incomes and so are more likely to make and avoid healthier food choices for their family	1	2	nu14122489_makarova	0
493Why was the Pearson's chi-squared test used (table 1) for analysis of variance?			It also assumes that parents with more educational experience are more likely to have higher incomes and so are more likely to make and avoid healthier food choices for their family.	1	2	nu14122489_makarova	0
494The issues raised in the well quoted Darmon and Drewnowski paper need to be considered more.			If income is not important than the paper should be the on home education level and home diet not home SES and home diet.	1	2	nu14122489_makarova	0
495Diet is not expected to have any influence of parent relations, social relations or peers but your study may find an influence on psychological well-being and even school environment.			The issues raised in the well quoted Darmon and Drewnowski paper need to be considered more.	1	2	nu14122489_makarova	0
4962020 Jul;23(10):1754-1765. doi: See their Table 5.			The Swedish Healthy Eating Index for Adolescents 2015 (SHEIA15) is not well explained in this paper. The following paper did a better job of reporting it Moraeus L, Lindroos AK, Warensjö Lemming E, Mattisson I. Diet diversity score and healthy eating index in relation to diet quality and socio-demographic factors: results from a cross-sectional national dietary survey of Swedish adolescents. Public Health Nutr. 2020 Jul;23(10):1754-1765. doi: See their Table 5.	1	2	nu14122489_makarova	0
497The American journal of clinical nutrition, 87(5), 1107-1117.			See how these researchers have described the KIDSCREEN-10 . Bouwmans, C., van der Kolk, A., Oppe, M., Schawo, S., Stolk, E., van Agthoven, M., ... & van Roijen, L. (2014). Validity and responsiveness of the EQ-5D and the KIDSCREEN-10 in children with ADHD. The European Journal of Health Economics, 15(9), 967-977.	1	2	nu14122489_makarova	0
498(Tabachnick, B.G., Fidell, L. S., & Ullman, J.B. (2007).			In terms of results the flowchart was interesting.	1	2	nu14122489_makarova	0
499The American journal of clinical nutrition, 87(5), 1107-1117.			I am a not European reviewer and so found the RADDS a rather restricted list without some meat.	1	2	nu14122489_makarova	0
500In table 5 only one p value is reported, but what it is measuring is unclear, as there are a number of interactions occurring.			Why was the Pearson's chi-squared test used (table 1) for analysis of variance? For while gender and in this study education are categorical (group) the data being evaluated is continuous and interval data and so an ANOVA or MANOVA by group is the method of analysis of variance. (Tabachnick, B.G., Fidell, L. S., & Ullman, J.B. (2007). Using multivariate statistics (5th ed.). Pearson.)	1	2	nu14122489_makarova	0
501The American journal of clinical nutrition, 87(5), 1107-1117.			In terms of gender and education: the mean, standard deviation, df and sig t or F test need to be reported in the tables.	1	2	nu14122489_makarova	0
502The basic information is not there in the paper: “KIDSCREEN-10 (KS-10) is derived from the KIDSCREEN-27, and provides a single index of global QoL using ten items related to physical well-being, psychological well-being, autonomy and parent relation, social support and peers, and school environment” See how these researchers have described the KIDSCREEN-10 .			Similarly, a correlation matrix is typically reported as it the foundation of regression analyses and so it needs to be reported to understanding the interaction between three main tests variables being investigated in this study.	1	2	nu14122489_makarova	0
503If the focus is on gender typically both a boy and a girl regression model is reported.			The regression analyses “p” value is reported, but the beta values and significance must also be reported. The regressing table needs reworked, as it is the influence of diet the independent variable on wellbeing KO-10, the dependent variable. If the focus is on gender typically both a boy and a girl regression model is reported.	1	2	nu14122489_makarova	0
504The lack of recognition that income and cost of living rather than education of parents is also a likely reason for the findings.			Table 5 is interesting but the setting out is poor and so the columns do not align with headings, particularly the wellness KQ -10 information. Again, an ANOVA “ t” value and df as well as the p value have to be reported. In table 5 only one p value is reported, but what it is measuring is unclear, as there are a number of interactions occurring. Should be reporting total, then girls, and then boys as there look to be interaction effects.	1	2	nu14122489_makarova	0
505The basic information is not there in the paper: “KIDSCREEN-10 (KS-10) is derived from the KIDSCREEN-27, and provides a single index of global QoL using ten items related to physical well-being, psychological well-being, autonomy and parent relation, social support and peers, and school environment” See how these researchers have described the KIDSCREEN-10 .			Because the KQ-10 is a composite tests there is the likelihood to be some interaction with the sub-domains. Focusing only on the global KQ-10 scores is hiding the subdomain differences to diet. Diet is not expected to have any influence of parent relations, social relations or peers but your study may find an influence on psychological well-being and even school environment. This is the core of your study: does diet have an influence on psychological wellbeing? Remember the KQ-10 is made up of five subdomains (psychological well-being, autonomy and parent relation, social support and peers, and school environment) The fact is diet is no expected to change 3 of these KQ-3 subdomains and only one or two KQ-10 dimensions. Use all five of the KO-10 dimensions as your outcome measure not the Mean average global KQ-10 score. You may have a more important study if you do that, with a different finding to what you have just using the composite total.	1	2	nu14122489_makarova	0
506I am a not European reviewer and so found the RADDS a rather restricted list without some meat.			The conclusion is sound given the findings but the lack of reference to income is an issue as educational status of parents is often a “de-facto” measure for income. It maybe, it is the cost of living associated with fresh fruit and vegetables that is the real issue. Given the findings the researchers could be arguing that a review may be needed with the Swedish school lunch program and increase the level of fruit and vegetables in the students' diet, particularly for students in lower SES locations. Schools may be making the lunches to a budget rather than to a healthy diet criteria which is more expensive. Different sub-populations even in the same school may need different mix of foods. A public education program could also be encouraged about health eating.	1	2	nu14122489_makarova	0
507The results and conclusions of this study are important.			What was the definition of visual field loss that defined glaucoma?	1	2	nu14122490_perova	0
508Marshall, H.; Mullany, S.; Qassim, A.; Siggs, O.; Hassall, M.; Ridge, B.; Nguyen, T.; Awadalla, M.; Andrew, N.H.; Healey, P.R., et al.			Was glaucoma also defined by an objective finding, such as the optic disc finding or imaging of the optic disc?	1	2	nu14122490_perova	0
509The study has been well planned and performed.			Were the incident cases of glaucoma or controls being treated in any case prior to their diagnoses?	1	2	nu14122490_perova	0
510Medicine 2020, 99, e19285, doi:10.1097/md.0000000000019285.			"The authors should avoid making statements such as ""nitrate is protective"" since what they have found is a statistical association."	1	2	nu14122490_perova	0
511There is very little association between ischemia--reperfusion and glaucoma pathogenesis hence the statements on page nine are irrelevant.			There is very little association between ischemia--reperfusion and glaucoma pathogenesis hence the statements on page nine are irrelevant.	1	2	nu14122490_perova	0
512"""As we did not observe an association between dietary nitrate intake and IOP, nitrate may protect against glaucoma via other, IOP-independent, mechanisms."""			If I am calculating correctly it has been over 20 years since the incident cases average followup occurred, that is 10-20 years after the start of a study in 1991. How much might the diet of persons in this population have changed since then? Thus, is this study still relevant to today? 30 years ago eating more vegetables was not the vogue it is today.	1	2	nu14122490_perova	0
513Cha, S.; Gu, B.; Sagong, M.; Son, J.; Kim, M. Association between glaucoma and cardiovascular disease risk in Korean population based study.			This study would have been that much stronger if a follow-up food questionnaire had been administered. The long space between the questionnaire and the incidence of glaucoma (only mentioned at the last part of the limitations) is quite a major limitation.	1	2	nu14122490_perova	0
514The authors have found that participants without OAG had a significantly higher BMI than those with OAG.			Past studies of the Rotterdam population mention several other risk factors which were not taken into account in this study including myopia, cup-to-disc ratio, and family history of glaucoma, as well as other features such as exfoliation. How big is the nitrate association compared to these?	1	2	nu14122490_perova	0
515Invest Ophthalmol Vis Sci 2000, 41, 3309-3321.			Overall the finding seems to be an association without a rationale since in effect of nitric oxide presumably related to past nitrate intake would, by their own discussion, change eye pressure or blood pressure yet neither variable was associated with the incident glaucoma.	1	2	nu14122490_perova	0
516"""
517Reviewer_1	Author	1	4	0	2	As we did not observe an association between dietary nitrate intake and IOP, nitrate may protect against glaucoma via other, IOP-independent, mechanisms.
518					0	"""			I would only like to ask about one fact that I find intriguing. The authors have found that participants without OAG had a significantly higher BMI than those with OAG. Their mean BMI was found to be 27.1 kg/m2 which is considered overweight. Lower risk of OAG would be related to a higher total dietary nitrate intake. “Previous research has shown that a higher dietary nitrate intake was associated with significantly wider retinal arterioles. [46] Widening of retinal arteriolar caliber is not only associated with lower risk of cardiovascular and cerebrovascular diseases [47,48], but also with lower risk of glaucoma”. On the other hand, “compared with individuals with a normal BMI (defined as a BMI of 18.5 to 24.9), lifetime risks for incident CVD [cardiovascular disease] were higher in middle-aged adults in the overweight and obese groups” Khan SS, Ning H, Wilkins JT, et al. Association of Body Mass Index With Lifetime Risk of Cardiovascular Disease and Compression of Morbidity. JAMA Cardiol. 2018;3(4):280–287. doi:10.1001/jamacardio.2018.0022 I wonder if the authors could comment on this in the Discussion.	1	2	nu14122490_perova	0
5191 Response to Reviewer 1 Comments Comments 1 Please add a table with patients' baseline characteristics, including BMI and smoking status.			Please add a table with patients' baseline characteristics, including BMI and smoking status.	1	2	s22072682_perova	0
520Comments 2 - Given the poor quality of the images (Fig 1 and 2), it might be better to redraw them and describe them as an adaptation of the original publication.			Did authors estimate sample size? Please add in data analysis section	1	2	s22072682_perova	0
521Comments 5 - I recommend deleting graphs 5, 8, and 11 because graphs 7, 10, and 13 show the same information together with lines obtained by analyzing the structural change of the time series.			Please add ethics protocol approval number	1	2	s22072682_perova	0
522Response 3 I described baseline load of the participants in 2.2.			I found some minor English errors throughout the paper. Please have a re-check.	1	2	s22072682_perova	0
5231 Response to Reviewer 2 Comments Comments 1 -The paper's aim should be the same in the abstract and the introduction.			I suggest presenting the paper's aim as the last idea in the introduction to make the manuscript easier to read.	1	2	s22072682_perova	0
524- I suggest presenting the paper's aim as the last idea in the introduction to make the manuscript easier to read.			Given the poor quality of the images (Fig 1 and 2), it might be better to redraw them and describe them as an adaptation of the original publication.	1	2	s22072682_perova	0
525Comments 4 I found some minor English errors throughout the paper.			The methods do not specify how the baseline load of the participants was determined.	1	2	s22072682_perova	0
526Response 2 I redrew Figures 1 and 2 and described them as an adaptation of the original publication.			"In figure 3, the indication of the test time appears in the reverse direction. Time ""0"" should be at the start."	1	2	s22072682_perova	0
527However, I would like to make a few comments.			I recommend deleting graphs 5, 8, and 11 because graphs 7, 10, and 13 show the same information together with lines obtained by analyzing the structural change of the time series.	1	2	s22072682_perova	0
528In order to address your feedback fully, we felt it necessary to split Figure 7. This has enabled us to accommodate the additional representative flow cytometric histograms displaying CD14 and CD68 expression changes. The data contained in the original Figure 7 is now split between Figure 7 (deals with CD14 and CD68 only) and Figure 8 (deals with CD11b and CD36). Changes highlighted in yellow on the resubmission.	2	1	The manuscript is well written, the results support the hypotheses.			antiox11040683_perova	0
529Fig 7b. We have removed the Giemsa images and replaced with phase contrast images to better show cell morphology under our light microscope. We also include representative flow cytometric overlayed histograms, which display CD14 and CD68 expression changes between our Vector control and WT / CXXS BCAT1 cells. Included on these histograms is the mean fold MFI change (ratio).	2	1	The manuscript is well written, the results support the hypotheses.			antiox11040683_perova	0
530Fig S4B. This is fully compensated. The black population illustrates the isotype control for the FITC and PE conjugated antibodies. These isotype controls were used to set the negative thresholds, as indicated by the quadrants on the plot. The red population shows positive binding of anti-CD36 and anti-CD11b to the U937 cells (gated on the previous plot S4A, FSC/SSC). The curve in the plot is not due to a compensation issue, it is demonstrating the up-regulation of CD36, which is followed by up-regulation of CD11b.	2	1	We agree with your comments and have addressed these to the best of our ability in the revised manuscript.			antiox11040683_perova	0
531Fig 4d. This is going in the correct direction. The DCFDA histogram data presented to the right is based on the viable homogeneous U937 cell gated population, which was determined by forward scatter (FSC) and side scatter profile (SSC) in the left hand plot. Debris in the bottom left of this FSC/SSC plot includes dead cells, which are eliminated and not considered for DCFDA analysis.	2	1	Author Response Thank you for taking time to review are work and for giving us the opportunity to comment on the use of U937 cells as a limitation for the work presented.			antiox11040683_perova	0
532We have included a section dedicated to addressing this in the discussion section, along with supporting references. This additional narrative is added at line 645-660 and highlighted in yellow on the resubmission.	2	1	Authors addressed all my requests and suggestions to my fullest satisfaction.			antiox11040683_perova	0
533We have included what we have written below for your convenience: “The U937 cell line was originally isolated from the pleural effusion of a patient with histiocytic lymphoma [42]. Early characterisation studies showed that U937 cells differed from typical lymphoblastoid cell lines [42]. Because of their pro-monocytic phenotype, many regard the U937 cell line to be representative of an AML subtype M5, under the French-American-British (FAB) classification system [43–46]. This pro-monocytic phenotype and cytochemistry, has accounted for the wide use of U937 cells as a model to study AML, including ROS mediated monocyte to macrophage transition [32,49,50]. We identified U937 cells as having a relatively low basal expression of BCAT1 compared other myeloid cell lines [49], which would allow an effective comparison between BCAT1 overexpressing cells to the vector control. Taken together, the U937 cell line presented as a good cellular model to study the putative antioxidant effect of the BCAT1 CXXC motif in myeloid differentiation, which is a defining feature of AML [50]. However, our study is limited to a single FAB subtype model. Future work could extend our analysis and examine the antioxidant capacity of the BCAT1 CXXC motif in other FAB subtype models, for example HL60 (AML, M2) and NB4 (AML M3 aka APL) [45].”	2	1	Author Response Thank you for taking time to review are work and for giving us the opportunity to comment on the use of U937 cells as a limitation for the work presented.			antiox11040683_perova	0
534The authors have now addressed all my major initial comments.	3	2	We agree with your comments and have addressed these to the best of our ability in the revised manuscript.			antiox11040683_perova	0
535"We agree that transient analysis is important in designing a robot joint. The following sentence has been added at the end of Conclusions: ""For future work we will develop variable stiffness techniques of this joint, and explore its application in a robot arm considering both kinetostatic and transient behaviors"""	2	1	However, the transient analysis requires relevant parameters of the robot arm be determined besides the parameters of the joint.			app12052642_makarova	0
536The mentioned reference is focused on an analytical method for modeling large deflections in compliant mechanisms, while this work presents a method of enhancing the tensile strength of lamina emergent joints by using double-layer materials.	2	1	Author Response Thanks a lot for your encouragement and suggestion.			app12052642_makarova	0
537"As to the second comment, Ref. [34] has been new added in the reference list and the following sentence has been added at the end of the second paragraph of Introduction: ""Ref. [34] made a robot using double-layer LEMs, which is driven by magnetic force. This paper further discussed how to adjust the motion by changing different parameters of the mechanism""."	2	1	"A theoretical model is derived for the DL-LET joint and verified by FEA and experimental results."""			app12052642_makarova	0
538We have rewritten the conclusions and abstract, and added additional keywords.	2	1	10 + description) steady state inverstigation is acceptable.			app12052642_makarova	0
539"The following sentences have been added in the first paragraph of Introduction to mention the base paper and the related work (more references have been added): ""Finding suitable compliant joints [7] can be a key step in designing LEMs. Jacobsen et al. [8] first proposed the design concept of utilizing torsional deflection to obtain out-of-plane motions from planar structures, leading to a new group of compliant joints for LEMs called Lamina Emergent Torsional (LET) joints""."	2	1	Author Response Thanks for your encouragement and suggestion.			app12052642_makarova	0
540The references have been reformatted according to standard journal format.	2	1	"A theoretical model is derived for the DL-LET joint and verified by FEA and experimental results."""			app12052642_makarova	0
541We have added more relevant references in this version.	2	1	Author Response We thanks the reviewer for the encouragement and valuable comments.			app12052642_makarova	0
542The contribution of this work with respect to the relevant work is further described in Introduction (as marked in the manuscript).	2	1	However, the transient analysis requires relevant parameters of the robot arm be determined besides the parameters of the joint.			app12052642_makarova	0
543The theoretical part has been extended in the modeling section (page 3).	2	1	The current paper proposes a novel lamina emergent torsional (LET) joint named double-laminated lamina emergent torsional joint (DL-LET) joint which utilizes a layer of flexible H18 aluminum foil to increase the tensile stiffness of LET joint.			app12052642_makarova	0
544The modeling section (page 3) has been extended to make it clear how the parameters were obtained.	2	1	[19], this paper proposed a DL-LET joint by fixing a layer of flexible H18 aluminum foil a LET joint.			app12052642_makarova	0
545The recommended and other relevant references have been added.	2	1	Author Response We thanks the reviewer for the encouragement and valuable comments.			app12052642_makarova	0
546Subsection 3.2 has been rewritten to add more details regarding the obtained results.	2	1	What new capacities and abilities so created by this evolutionary jump Aside from that the article is solidly researched and is useful as a source of technology development			app12052642_makarova	0
547The following sentence has been added at the end of first paragraph of Conclusions to clarify disadvantage of DL-LET: “The DL-LET joint is vulnerable to delamination of the two layers.”	2	1	In the proposed manuscript only the advantages are presented.			app12052642_makarova	0
548We agree with the referee that in any open system as we have here , information will leak out and a corresponding backaction on the wavefunction cannot be avoided. However, by operating with ultra-cold quantum particles far of any internal resonance, the coherence time can be pretty long. This was shown with BEC’S trapped in cavities (see e.g. Ref 9). The effect of localization via cavity transmission can be reduced by working at higher cavity photon numbers. Ultimately the interplay between measurement induced localization and coherence spreading by unitary evolution could be one of the most interesting points in setting up such an experiment. One should study a transition from classical to quantum behavior depending on the degree of observation of the system.	2	1	Try to use other colors and/or thicker lines.”			atoms3030433_makarova	0
549Axes added.	2	1	"“In section VI E. ""Trapping by longitudinal pumping"", one can analytically estimate the threshold value for the transverse pumping."			atoms3030433_makarova	0
550We have reformulated to avoid confusion and unsubstantiated claims: “The mechanism is reminiscent of the one exploited in the creation of artificial potentials in optical lattices~\cite{Struck2012Tunable} applied here to the classical regime”	2	1	The idea is clever and original and lends itself to further extensions: for instance, to simulate a kicked rotor, by means of a frequency comb drive, or towards hybrid optomechanics, when the two-level atom is replaced by a doped nano-sphere.			atoms3030433_makarova	0
551We have rephrased: “In this sense, this work is a stepping stones towards a proposal for implementing a quantum random walk mirroring progress already achieved with photons…”.	2	1	Analytic approximations of the effective trapping forces give some insight into the origin of the special form of the optical potential and delineate the regimes in which random walks are expected to occur.The proposal of this somewhat unconventional random-walk regime in cavity-QED is interesting and deserves publication.			atoms3030433_makarova	0
552We have added a clarifying statement in the beginning of section 2: “We consider an effective one-dimensional model”.	2	1	“Figure 8, Force correlation functions and numerical solutions of the variance: when printed in grey scale some lines are very faint (especially those in green and cyan).			atoms3030433_makarova	0
553The referee is correct; in the convention that we specify the negative detuning corresponds to the regime where motional instabilities are avoided and cavity cooling is possible. We included this in the figure caption.	2	1	"“Page 6, ""Optical forces"": there is a missing subscript L in the first force term at the end of the first paragraph, just before Eq."			atoms3030433_makarova	0
554As we specify now in the beginning of section 3: “We treat $\eta_T$ as a free varying parameter. In the following we set $\kappa=1$ for numerical simulations and normalize the time in units of $\kappa^{-1}$”.	2	1	Therefore, the manuscript is worthy of publication.			atoms3030433_makarova	0
555As the referee correctly infers the random walk is merely an effect of the time modulation of the potential. The classical limit without time delayed action (characteristic of the cavity) will reproduce the kind of walk obtained in the LT limit where Fig. 3 and the analysis has been performed. The other regime where the transverse field kicks the particle out of the longitudinal trap is a cavity effect as the effective force (transverse) has a different modulation than the simple cosine of the free space transverse wave. However, for fine tuning of parameters and to insure stability of trajectories we have used the cavity cooling effect.	2	1	(2), please check the commutation relations between the raising (sigma^+) and lowering (sigma^-) operators and the Pauli matrix sigma^z.			atoms3030433_makarova	0
556Yes, some momentum diffusion can be expected. In principle using a sufficiently narrow cavity and suitable operation parameters cavity cooling could be tuned to cancel such unwanted heating. However, this is connected to dissipative dynamics and will change the effective operating parameters of the system. In the bad cavity limited on the other hand, one can expect some “cavity heating” instead of cooling, but the rate of this heating should be slow enough to allow for many kicks before it gets relevant.	2	1	In particular, a force term contains a time modulation at the beat note between the two frequencies of the pump fields.			atoms3030433_makarova	0
557We have corrected the sign in the commutation relation.	2	1	"(4), the Authors write ""We proceed in a standard way to derive equations of motion for classical quantities."""			atoms3030433_makarova	0
558We have added a proper reference as Ref. [23].	2	1	Numerical simulations predict quasi-random jumps to neighbouring lattice sites at regular time intervals leading to diffusive motion over long times.			atoms3030433_makarova	0
559We have added the definition for \gamma in the text. Here we focus on a dispersive regime of weak atomic excitation, where the so called dipole force dominates the mechanical atom field interaction and spontaneous emission plays a negligible role. In this limit the mechanical forces can be derived from a deterministic (time dependent) optical potential (see refs. 7-9 for details). However, as the referee points out, in the nonlinear dynamical regime, the effects stemming from the inclusion of a random spontaneous emission could be amplified. A similar randomness is connected to cavity cooling in a regime of weak coherent intra-cavity fields. This certainly will have to be considered in a quantum treatment. In our simulation we got the “quasi random” dynamics from deterministic motion connected to details of the initial conditions without including random forces.	2	1	R5 Response We thank the referee for an extremely careful reading of the manuscript, his/her appreciation of it and for the very constructive criticism expressed in this report.			atoms3030433_makarova	0
560Indeed all the above mentioned expressions were missing a factor of \kappa as the referee correctly observed.	2	1	In particular, a force term contains a time modulation at the beat note between the two frequencies of the pump fields.			atoms3030433_makarova	0
561The analytical considerations fit very well with numerical results. Indeed, in this regime, we have performed the simulations by choosing parameters derived from analytical considerations. The R6 emergence of the jump regime is directly connected with the increase of the LT force to the value of the longitudinally-induced force but the fine tuning of the parameters is a bit tricky in order to insure that only jumps to neighbouring sites occur. Therefore we have restricted our presentation to the other regime where the jumps are strictly occurring owing to the transverse-longitudinal time modulation of the potential.	2	1	"“Page 6, ""Optical forces"": there is a missing subscript L in the first force term at the end of the first paragraph, just before Eq."			atoms3030433_makarova	0
562We have fixed this mistake.	2	1	R4 However, I have a few comments and suggestions to improve the overall quality and readability of the paper.			atoms3030433_makarova	0
563We changed the order of the figures and corrected the reference to the wrong figure.	2	1	I'm afraid there is a factor k missing (simple dimensional analysis shows that something is wrong with it).			atoms3030433_makarova	0
564Comma has been introduced.	2	1	"“Page 6, ""Optical forces"": there is a missing subscript L in the first force term at the end of the first paragraph, just before Eq."			atoms3030433_makarova	0
565The b) has been eliminated.	2	1	“Finally, some stylistic considerations: Please, be consistent with the choice of subscripts and superscripts: in the first column of page 2 the Pauli operator is denoted as sigma^z (superscript), whereas in the second column becomes sigma_z (subscript).”			atoms3030433_makarova	0
566Subscript has been introduced.	2	1	I'm afraid there is a factor k missing (simple dimensional analysis shows that something is wrong with it).			atoms3030433_makarova	0
567We have restricted the analysis to 2 curves (full and dashed) and a thinner red dashed curve corresponding to the analytical solution in the lower plots. The visibility is clearly increased and the message stays the same.	2	1	The idea is clever and original and lends itself to further extensions: for instance, to simulate a kicked rotor, by means of a frequency comb drive, or towards hybrid optomechanics, when the two-level atom is replaced by a doped nano-sphere.			atoms3030433_makarova	0
568If we understand correctly, the reviewer’s argument, i.e., a reduction in RNA when the cells were cultured in the presence of HSA may be due to the HSA’s RNA-hydrolyzing activity, requires that HSA contacts the RNA that will be hydrolyzed. This is not the case; HSA and the other fluids tested as inductors were added to the growth medium (LB) medium, and the cells were allowed to grow in these conditions for 5 h at 37ºC. After that, the cells were collected, and RNA was extracted. Since HSA does not reach the cytosol, at least not in an intact manner, hydrolysis seems not possible during cell growth. It could be argued that some RNA is hydrolyzed during extraction, but for this to be the case, one should assume that the cells were not well washed after being pelleted by centrifugation, which is not the case. Therefore, the RNA is intracellular at all moments during the experiment, and the HSA stays in the milieu. It is also worth mentioning that the presence of HSA in the growth medium produced a reduction only in some mRNA species. These results speak against an unspecific hydrolyzing effect. We also want to underscore that all RNA samples were checked after extraction. Agarose gels electrophoresis confirmed the integrity of RNA and lack of DNA contamination. The same cDNA amount for every condition was used to perform qRT-PCR assays.	2	1	Author Response Author’s Response: We appreciated the reviewers’ comment.			biomedicines10030600_perova	0
569Finally, the article provided by the reviewer describes HSA hydrolysis of extracellular, not intracellular, RNA.	2	1	Author Response Author’s Response: We appreciate the reviewers’ comment and the suggestion.			biomedicines10030600_perova	0
570We agree that confirming that the effect of cefiderocol is bactericidal under the conditions tested is important. We have indeed carried out some experiments in the presence of human fluids. They actually show that adding these components to the growth medium does not modify the bactericidal nature of the action of the antibiotic. A follow-up project that will be submitted for publication in the near future extends the studies of the effects produced by human fluids, and their components will include the experiments demonstrating a bactericidal effect of cefiderocol. We would prefer to include those results in the upcoming publication.	2	1	Author Response Author’s Response: We appreciated the reviewers’ comment.			biomedicines10030600_perova	0
571Thanks for pointing out the error in the range. Correction made in the text.	2	1	In line 282, the result showed r2 = 0.24, p = 0.03 but it is a difference in Fig. 5.			brainsci11121640_makarova	0
572Reference added.	2	1	"In line 119, the capital ""a"" changes lower case."			brainsci11121640_makarova	0
573No, we did not. We have added a statement in the study limitations to address the issue.	2	1	The present study entitled “Facilitation of motor evoked potentials in response to a modified 30 Hz intermittent theta-burst stimulation protocol in healthy adults” investigated the effectiveness of intermittent 30 Hz/6 Hz TBS in inducing lasting facilitation of MEPs.			brainsci11121640_makarova	0
574"The three left-handed participants exhibited rMT and aMt typical of young adults of their age (Right, n=16, mean rMT 42%, aMT, 32%, see below for Left). We did not perform bilateral testing, so we cannot comment on hemispheric differences in excitability. However, our own investigation on the matter showed that Left-handers had higher rMT on the right hemisphere and, in fact, those individuals exhibited comparable rMT on the left hemisphere to that of mixed and right-handed individuals ( See Figure 3 in Davidson & Tremblay 2013) Subject Left-handed rMT aMT KY13 56% 46% KY8 36% 34% KY19 54% 38% Davidson, T., and F. Tremblay. ""Hemispheric Differences in Corticospinal Excitability and in Transcallosal Inhibition in Relation to Degree of Handedness."" PloS One 8, no. 7 (2013): e70286."	2	1	Although you state you defined the rMT in Fig. 1 you did not.			brainsci11121640_makarova	0
575The statement has been revised. We think it is important for readers to know that participants wore masks during testing because of the pandemic.	2	1	Why did not compare to the sham stimulation group and 50 Hz/ 5 Hz standard iTBS protocol?			brainsci11121640_makarova	0
576Yes, there are some differences given the difference in pulse configuration and coil output, However, rMT and aMT with the two stimulators were highly correlated at the individual level (r2=0.55).	2	1	Although the differences in handedness would not profoundly affect the overall results, can the author check if there were significant differences in stimulation intensity (AMT and RMT) in right and left-handed participants?			brainsci11121640_makarova	0
577We have revised the statistical analysis given the Reviewer’s comment below. Thanks to the Reviewer, we found out that there was a duplicate value in the dataset for MEP amplitude (hence the issue with 20 subjects in Figure 3). The error has been corrected and the analysis re Note that the correction did not change the results or the conclusions. We now report for the ANOVA’s the F value and the partial eta squared to indicate the size of the intervention. Would it be interesting if the present data can give the same effect size (0.71) as those reported by Chung et al. (2016)? Indeed, it would be interesting. The size of the intervention for variations in MEP amplitude, as reflected in eta squared, is 0.19, which appears smaller than that reported by Chung et al. However, such an effect size could hardly be compared with the “standardized mean difference’ computed by Chung et al. The SMD is based on the assumption that differences in standard deviations among studies reflect differences in measurement scales and not real differences in variability among study participants (which is the case here)..	2	1	(2012) would lead to lasting MEP facilitation.			brainsci11121640_makarova	0
578Please see above our reply regarding F values.	2	1	The authors reported that the modified iTBS protocol facilitated MEPs for up to 45 min post-stimulation and that small latency differences were predictive of the facilitatory effect on corticospinal excitability.			brainsci11121640_makarova	0
579"We agree it does seem arbitrary but this approach has been used by many other investigators (see Hinder et al or Perellon et al) to assess neuroplastic responses to rTMS. In this respect, the ±10% cutoff provides a reasonable criterion to classify responders given the variability of responses to rTMS interventions. Hinder, M. R., E. L. Goss, H. Fujiyama, A. J. Canty, M. I. Garry, J. Rodger, and J. J. Summers. ""Inter- and Intra-Individual Variability Following Intermittent Theta Burst Stimulation: Implications for Rehabilitation and Recovery."" Brain Stimulation 7, no. 3 (2014): 365-71. Perellon-Alfonso, R., M. Kralik, I. Pileckyte, M. Princic, J. Bon, C. Matzhold, et al. ""Similar Effect of Intermittent Theta Burst and Sham Stimulation on Corticospinal Excitability: A 5-Day Repeated Sessions Study."" European Journal of Neuroscience 48, no. 4 (2018): 1990-2000."	2	1	Although you state you defined the rMT in Fig. 1 you did not.			brainsci11121640_makarova	0
580We have corrected the sentence to state that SICF is observed when two stimuli are given at or above threshold.	2	1	Discussion Line 402: in SIFC, one pulse is suprathreshold, and the other is subthreshold.			brainsci11121640_makarova	0
581We agree with the Reviewer that having a direct comparison with the 50 Hz protocol would have been ‘ideal’ but we have clearly stated the reasons as to why we did not perform such a comparison. First, our primary goal was to describe the effects of a modified 30 Hz iTBS protocol and not to test the relative efficacy of 30 vs 50 Hz bursts. Besides, as we have stated, there is already ample evidence of the effects of 50 Hz/5 Hz in the literature. Second, as we have explained in the limitations, our study was performed in the context of a worldwide pandemic. In this respect, we disagree with the reviewer. The pandemic has and continues to have a major impact on our research activities. Our lab is located in a geriatric hospital setting. For this reason, we had to follow very strict rules regarding who was coming on the premises and how long they would stay. We were allowed to recruit research participants only if they came for a short period and stayed in one room. A comparison between 30 and 50 Hz protocols would have meant having participants come twice (on different days), exposing them each time to risks for COVID. As for the benefits of the 30 Hz protocol, those are clearly stated in the discussion regarding the number of responders and the size of the facilitation.	2	1	In my opinion, the major potential issues were already discussed in the limitation sections.			brainsci11121640_makarova	0
582We have added a sentence to clarify that participants were screened for health conditions.	2	1	Does the participants have a neurological disease or other diseases?			brainsci11121640_makarova	0
583We collected more MEPS at baseline to account that variations in excitability are often larger when participants received their first series of TMS pulses (even if they have received some stimuli before collecting data to experience the sensation). Thus, 20 MEPs were deemed adequate to get a reliable estimate of resting corticomotor excitability. Along with the same reasoning, we collected 15 MEPs post iTBS since participants were now more familiar with the sensation elicited by TMS pulse and saved time. As we have explained, we had constraints imposed on us by the local REB to limit the time participants were on-site. The fact that we use 130% rMT for the test intensity also reduced inter-trial variability to provide reliable estimates of corticospinal excitability.	2	1	Please do not define aMT the second time in line 134.			brainsci11121640_makarova	0
584We have revised the sentence so that abbreviations are defined.	2	1	Discussion Line 402: in SIFC, one pulse is suprathreshold, and the other is subthreshold.			brainsci11121640_makarova	0
585Correction made.	2	1	The present study entitled “Facilitation of motor evoked potentials in response to a modified 30 Hz intermittent theta-burst stimulation protocol in healthy adults” investigated the effectiveness of intermittent 30 Hz/6 Hz TBS in inducing lasting facilitation of MEPs.			brainsci11121640_makarova	0
586done.	2	1	Is the cut-off plus or minus 10 standard for the responder and non-responders?			brainsci11121640_makarova	0
587We have provided more explanations in the text as to how we used the MTAS software to estimate MT.	2	1	The present study entitled “Facilitation of motor evoked potentials in response to a modified 30 Hz intermittent theta-burst stimulation protocol in healthy adults” investigated the effectiveness of intermittent 30 Hz/6 Hz TBS in inducing lasting facilitation of MEPs.			brainsci11121640_makarova	0
588We have added more details as to how the hotspot was determined?	2	1	Some questions please need authors to answer.			brainsci11121640_makarova	0
589Corrections were made to check for extra spaces.	2	1	In my opinion, plus or minus 10% is arbitrary.			brainsci11121640_makarova	0
590Correction done. The F value has been added.	4	1	"In line 119, the capital ""a"" changes lower case."			brainsci11121640_makarova	0
591The coefficient of determination is for the regression analysis and indicates that Lat differences were significant predictors of MEP facilitation. However, as we explained in the text, when participants were sorted into two groups (early and late I-waves), the difference between the two was not significant according to the Mann-Whitney U test.	4	1	(2012) would lead to lasting MEP facilitation.			brainsci11121640_makarova	0
592Actually, we did, but it seems that the new figure legend with the correction was not properly inserted when the system reformated the document.	4	1	Although the differences in handedness would not profoundly affect the overall results, can the author check if there were significant differences in stimulation intensity (AMT and RMT) in right and left-handed participants?			brainsci11121640_makarova	0
593Thanks for pointing out the error in the range. Correction made in the text.	2	1	I only have minor comments and questions that the author should answer to improve the manuscript.			brainsci11121640_perova	0
594Reference added.	2	1	What are the benefits of 30 Hz/6 Hz TBS protocol (intermittent mode) in comparison with 50 Hz/ 5 Hz standard iTBS?			brainsci11121640_perova	0
595No, we did not. We have added a statement in the study limitations to address the issue.	2	1	I only have minor comments and questions that the author should answer to improve the manuscript.			brainsci11121640_perova	0
596"The three left-handed participants exhibited rMT and aMt typical of young adults of their age (Right, n=16, mean rMT 42%, aMT, 32%, see below for Left). We did not perform bilateral testing, so we cannot comment on hemispheric differences in excitability. However, our own investigation on the matter showed that Left-handers had higher rMT on the right hemisphere and, in fact, those individuals exhibited comparable rMT on the left hemisphere to that of mixed and right-handed individuals ( See Figure 3 in Davidson & Tremblay 2013) Subject Left-handed rMT aMT KY13 56% 46% KY8 36% 34% KY19 54% 38% Davidson, T., and F. Tremblay. ""Hemispheric Differences in Corticospinal Excitability and in Transcallosal Inhibition in Relation to Degree of Handedness."" PloS One 8, no. 7 (2013): e70286."	2	1	However, as we explained in the text, when participants were sorted into two groups (early and late I-waves), the difference between the two was not significant according to the Mann-Whitney U test.			brainsci11121640_perova	0
597The statement has been revised. We think it is important for readers to know that participants wore masks during testing because of the pandemic.	2	1	Two female participants had to be excluded….”.			brainsci11121640_perova	0
598Yes, there are some differences given the difference in pulse configuration and coil output, However, rMT and aMT with the two stimulators were highly correlated at the individual level (r2=0.55).	2	1	Although we would assume that the figure on the left is always the letter “A” and the one on the right is “B”, for the sake of clarification, kindly add a letter legend on the figures.			brainsci11121640_perova	0
599We have revised the statistical analysis given the Reviewer’s comment below. Thanks to the Reviewer, we found out that there was a duplicate value in the dataset for MEP amplitude (hence the issue with 20 subjects in Figure 3). The error has been corrected and the analysis re Note that the correction did not change the results or the conclusions. We now report for the ANOVA’s the F value and the partial eta squared to indicate the size of the intervention.	2	1	Does the participants have a neurological disease or other diseases?			brainsci11121640_perova	0
600Indeed, it would be interesting. The size of the intervention for variations in MEP amplitude, as reflected in eta squared, is 0.19, which appears smaller than that reported by Chung et al. However, such an effect size could hardly be compared with the “standardized mean difference’ computed by Chung et al. The SMD is based on the assumption that differences in standard deviations among studies reflect differences in measurement scales and not real differences in variability among study participants (which is the case here)..	2	1	Some questions please need authors to answer.			brainsci11121640_perova	0
601Please see above our reply regarding F values.	2	1	The coefficient of determination is for the regression analysis and indicates that Lat differences were significant predictors of MEP facilitation.			brainsci11121640_perova	0
602"We agree it does seem arbitrary but this approach has been used by many other investigators (see Hinder et al or Perellon et al) to assess neuroplastic responses to rTMS. In this respect, the ±10% cutoff provides a reasonable criterion to classify responders given the variability of responses to rTMS interventions. Hinder, M. R., E. L. Goss, H. Fujiyama, A. J. Canty, M. I. Garry, J. Rodger, and J. J. Summers. ""Inter- and Intra-Individual Variability Following Intermittent Theta Burst Stimulation: Implications for Rehabilitation and Recovery."" Brain Stimulation 7, no. 3 (2014): 365-71. Perellon-Alfonso, R., M. Kralik, I. Pileckyte, M. Princic, J. Bon, C. Matzhold, et al. ""Similar Effect of Intermittent Theta Burst and Sham Stimulation on Corticospinal Excitability: A 5-Day Repeated Sessions Study."" European Journal of Neuroscience 48, no. 4 (2018): 1990-2000."	2	1	(2012) would lead to lasting MEP facilitation.			brainsci11121640_perova	0
603We have corrected the sentence to state that SICF is observed when two stimuli are given at or above threshold.	2	1	Looking again at Figure 3, we can observe very high variability.			brainsci11121640_perova	0
604We agree with the Reviewer that having a direct comparison with the 50 Hz protocol would have been ‘ideal’ but we have clearly stated the reasons as to why we did not perform such a comparison. First, our primary goal was to describe the effects of a modified 30 Hz iTBS protocol and not to test the relative efficacy of 30 vs 50 Hz bursts. Besides, as we have stated, there is already ample evidence of the effects of 50 Hz/5 Hz in the literature. Second, as we have explained in the limitations, our study was performed in the context of a worldwide pandemic. In this respect, we disagree with the reviewer. The pandemic has and continues to have a major impact on our research activities. Our lab is located in a geriatric hospital setting. For this reason, we had to follow very strict rules regarding who was coming on the premises and how long they would stay. We were allowed to recruit research participants only if they came for a short period and stayed in one room. A comparison between 30 and 50 Hz protocols would have meant having participants come twice (on different days), exposing them each time to risks for COVID. As for the benefits of the 30 Hz protocol, those are clearly stated in the discussion regarding the number of responders and the size of the facilitation.	2	1	Left-handed individuals often have a high threshold on the left motor cortex.			brainsci11121640_perova	0
605We have added a sentence to clarify that participants were screened for health conditions.	2	1	Please do not define aMT the second time in line 134.			brainsci11121640_perova	0
606We collected more MEPS at baseline to account that variations in excitability are often larger when participants received their first series of TMS pulses (even if they have received some stimuli before collecting data to experience the sensation). Thus, 20 MEPs were deemed adequate to get a reliable estimate of resting corticomotor excitability. Along with the same reasoning, we collected 15 MEPs post iTBS since participants were now more familiar with the sensation elicited by TMS pulse and saved time. As we have explained, we had constraints imposed on us by the local REB to limit the time participants were on-site. The fact that we use 130% rMT for the test intensity also reduced inter-trial variability to provide reliable estimates of corticospinal excitability.	2	1	Does the participants have a neurological disease or other diseases?			brainsci11121640_perova	0
607We have revised the sentence so that abbreviations are defined.	2	1	"Introduction Line 31 – ""(4-10 Hz) induced…"" this is not theta range; please correct."			brainsci11121640_perova	0
608Correction made.	2	1	What are the benefits of 30 Hz/6 Hz TBS protocol (intermittent mode) in comparison with 50 Hz/ 5 Hz standard iTBS?			brainsci11121640_perova	0
609done.	2	1	Would it be interesting if the present data can give the same effect size (0.71) as those reported by Chung et al. (2016)?			brainsci11121640_perova	0
610We have provided more explanations in the text as to how we used the MTAS software to estimate MT.	2	1	Actually, we did, but it seems that the new figure legend with the correction was not properly inserted when the system reformated the document.			brainsci11121640_perova	0
611We have added more details as to how the hotspot was determined?	2	1	In my opinion, the major potential issues were already discussed in the limitation sections.			brainsci11121640_perova	0
612Corrections were made to check for extra spaces.	2	1	Although the differences in handedness would not profoundly affect the overall results, can the author check if there were significant differences in stimulation intensity (AMT and RMT) in right and left-handed participants?			brainsci11121640_perova	0
613Correction done. The F value has been added.	4	1	The present study entitled “Facilitation of motor evoked potentials in response to a modified 30 Hz intermittent theta-burst stimulation protocol in healthy adults” investigated the effectiveness of intermittent 30 Hz/6 Hz TBS in inducing lasting facilitation of MEPs.			brainsci11121640_perova	0
614The coefficient of determination is for the regression analysis and indicates that Lat differences were significant predictors of MEP facilitation. However, as we explained in the text, when participants were sorted into two groups (early and late I-waves), the difference between the two was not significant according to the Mann-Whitney U test.	4	1	However, as we explained in the text, when participants were sorted into two groups (early and late I-waves), the difference between the two was not significant according to the Mann-Whitney U test.			brainsci11121640_perova	0
615Actually, we did, but it seems that the new figure legend with the correction was not properly inserted when the system reformated the document.	4	1	Although we would assume that the figure on the left is always the letter “A” and the one on the right is “B”, for the sake of clarification, kindly add a letter legend on the figures.			brainsci11121640_perova	0
616The diesel generator equal to the rating of base load is kept as backup to avoid total black out situation of the system.	2	1	The appliances are prioritized based on their need and demand to achieve optimum energy utilization.			en15031006_makarova	0
617According to your suggestion, we have improved the quality of Figures as can see Figure 1 and Figure2.	2	1	Battery storage bank is included in the system to provide the baseload power in the time when renewable sources are not suffice to meet the baseload power demand.			en15031006_makarova	0
618According to your suggestion, we have modified the Equations 4, 9 and 12 in the revised version of the manuscript as fellows.	2	1	Author Response Please see the attachment Author Response File: Author Response.docx			en15031006_makarova	0
619According to your suggestion the baseload is added in the result section as follows: In addition, to further validate the proposed system, the appliance schedule pattern for Monday is drawn in Figure 10 and Figure 9 represents the appliance weightage given by consumers for Monday. In addition, Figure 8 represents the power generated graph for the same day. The baseload is calculated as 1000 watts for each house to keep basic appliances turn ON uninterruptedly. As there are 5 houses in the community the total base power for the system is 5000 watts. The excess power is utilize to turn ON the schedulable appliances on Monday.	2	1	- The authors should carefully distinguish the new contributions of their work from the new existing studies.for example: DOI: 10.1016/j.est.2020.101221 A comprehensive deeper literature review is necessary to address the research issue.			en15031006_makarova	0
620As Sizing of the grid system is not the main goal of the article, but as per your suggestion, it is briefly discuss in the subsections of Mathematical modelling of the Energy sources. Both solar and wind systems are designed for output power equal to the consumer’s load whose annual load curve peak is maximum out of all the consumer’s in the community. Battery storage systems have the capability to supply uninterrupted power equal to the base load of the system up to 6 hours. And diesel generator equal to the rating of system’s base load is kept as a backup to avoid total black out situation. The designed system is not the time-varying tariff, therefore the overall system is designed to treat each consumer of the community equally. In time-varying tariff based system, the sizing of the system is the main objective as to accommodate the wealthy consumers of the community.	2	1	As the proposed system is in isolated mode, how continuity of power supply be maintained?			en15031006_makarova	0
621According to your suggestion the consumer comfortability is discussed from line 144-160. In this work, a DSM algorithm is proposed by using renewable resources PV and wind turbines for those houses that are located far away from the main city.	2	1	Response to Reviewer 1 Comments Point 1: More recent related work should be referred.			en15031006_makarova	0
622According to your suggestion, in the revised version of the manuscript, the unnecessary use of subjective pronoun is removed and overall writing of the paper is improved.	2	1	The proposed load scheduling algorithm is developed with the help of Kmean clustering and linear integer programming.			en15031006_makarova	0
623Thank you for your comment. Due to the lack of real time datasets, we have used the publically available datasets for the verification of the proposed system.	2	1	Point 2: In such a study an experimental case must be presented in a specified region Response 2: Thank you for your comment.			en15031006_makarova	0
624Battery storage bank is included in the system to provide the baseload power in the time when renewable sources are not suffice to meet the baseload power demand. Diesel generators equal to the rating of base load is kept as backup to avoid total black out in worse conditions. Our objective is to schedule and shift the controllable appliances by estimating hourly power generation and considering consumer demand as a variable function. The appliances are prioritized based on their need and demand to achieve optimum energy utilization. The main contribution of this paper include: A demand side management algorithm is proposed to fulfil the energy gap between generation and consumer’s demand for standalone renewable energy system. K-mean clustering is used to make clusters of the data based on two factors: probability of turning ON a specific appliance at time t and priority number given by consumer to that specific appliance. Linear integer programming is used to schedule the appliances clusters based on the available power and state of charge of the battery system. According to your suggestion, the novelty of the proposed work has been made more clear and understandable for readers in the introduction section as follows: In this work, a DSM algorithm is proposed by using renewable resources PV and wind turbines for those houses that are located far away from the main city.	2	1	Battery storage bank is included in the system to provide the baseload power in the time when renewable sources are not suffice to meet the baseload power demand.			en15031006_makarova	0
625According to your suggestion, we have modified the literature review and included some latest references i.e., [22][29][30][32]. In addition, we organized the literature review in more comprehensive way.	2	1	The proposed load scheduling algorithm is developed with the help of Kmean clustering and linear integer programming.			en15031006_makarova	0
626According to your suggestion, we have improved the Figures as can be seen in the revised version of the manuscript.	2	1	K-mean clustering is used to make clusters of the data based on two factors: probability of turning ON a specific appliance at time t and priority number given by consumer to that specific appliance.			en15031006_makarova	0
627The quoted literature has been adapted to the ACS Style Guide. For that, the authors used to software package Zotero.	2	1	Author Response See the point-by-point response in the attached Word file.			healthcare10040723_makarova	0
628STD are included in the all tables were indicated: sum+STD has been added in the legend.	2	1	Replace this phrase with a more appropriate phrase.			healthcare10040723_makarova	0
629In Table 3 (=) has been changed into (0). It was a typo, sorry.	2	1	In the convergent parallel strategy, quantitative and qualitative data collection occurred concurrently.			healthcare10040723_makarova	0
630Line 252: 7/24 has been changed into 24/7.	2	1	As I have seen a complementary role of the qualitative and quantitative pieces is apparent instead of the qualitative piece informing the quantitative pieces.			healthcare10040723_makarova	0
631Line 267 and 268, the description of figure 1 “focused on senses” means that the diagnostic workup should be more focused on the physical examination (the doctor’s senses) rather than based on technical diagnostics. In the revised manuscript has been added in line 270 “and use their senses in physical examinations rather than rely on impersonal technical tools for the diagnostic work-up”.	2	1	Replace this phrase with a more appropriate phrase.			healthcare10040723_makarova	0
632In Line 266/267 the term “undermine” was wrong. It has been changed into “ease”. Thank you for the hint.	2	1	In the methods section, clearly describe the sampling procedure for the quantitative and qualitative study parts separately.			healthcare10040723_makarova	0
633Table 5: The students could rank their answer. 1 = don’t know, 2= false up to 7 = fully agree. The statistical calculation was done only for ranks 2 to 7, excluding the students, who could not or didn’t want to answer the question. The authors knew from the qualitative study part, that some students had no knowledge about AI. Therefor the “don’t know” option was included. In the first draft of the manuscript the legends contained a mistake, because the “fully agree” option had the highest number (7) but not 3. This has been changed in the revised manuscript.	2	1	Page 3, line 132, it says, Convenience sampling was used.			healthcare10040723_makarova	0
634Aspects of the organizational environment (e.g., creative problem solving) were identified in the qualitative component and statistically confirmed or rejected in the preceding quantitative study phase, which is exactly what the authors did in this study. Although our study integrates components of both strategies, the authors still think, that the sequential exploratory strategy describes our methods better than the convergent parallel design (see also: Curry et al Circ. Cardiovasc, Qual. Outcomes 2013, 6:119-123).	2	1	I am suggesting this because the logic of quantitative sampling and qualitative sampling are different.			healthcare10040723_makarova	0
635The manuscript has been changed accordingly.	2	1	Page 2, line 42, ‘the computation of compounding factors,’ I did not understand what it means.			healthcare10040723_makarova	0
636The reviewer is right. The phase has been changed into the “analysis” of compounding factors.	2	1	I hope these suggestions are of use to the authors.			healthcare10040723_makarova	0
637The authors followed the reviewer’s suggestions and re-wrote this para as follows: “The overall objective of this study was to investigate the today’s medical students attitudes towards AI and other digital working tools. We wanted to understand if age, gender, semester level and curriculum type influences their views. This study also assembled information on students’ understanding of AI algorithms and digital applications in health care and assessed their level of confidence in working alongside these tools after graduation in patient care. It is our belief that this information may possess the means to employ digital tools including AI into the curriculum of medical students efficiently, enhancing their confidence in using them and therefor to better equip our future physicians with sufficient knowledge.” On page 2, line 111, the phrase ‘to affirm or dismiss,’ does not make sense.	2	1	‘The items were then tested through a pilot study consisting of a 117 group of 4 pre- and clinical students, mediated by AG and JE’			healthcare10040723_makarova	0
638The phrase in question has been replaced by “to confirm”.	2	1	From the explanation in the study design and the presentation of your results, it sounds to me as if the mixed-methods nature of this study fits more with the convergent parallel design.			healthcare10040723_makarova	0
639The authors choose 4 pre-clinical and 4 clinical students. The intention was - as outlined in the initial manuscript version - “… to understand how they perceive the subject of interest”. The wording has been specified, to clarify that in total 8 students tested the items but not 4 as the reviewer assumed. This number was considered sufficient a) to detect inconsistencies and b) to verify the correct meaning of the questions. AG and JE are two of the authors (first letter of the first and last name). In order to avoid any misunderstanding, this has been changed to “the authors” in the revised manuscript.	2	1	I am suggesting this because the logic of quantitative sampling and qualitative sampling are different.			healthcare10040723_makarova	0
640Convenience sampling is defined as a method to collect data from a conveniently available pool of respondents. We used it, because it is the most commonly used sampling technique as it's incredibly prompt, uncomplicated, and economical.	2	1	As I have seen a complementary role of the qualitative and quantitative pieces is apparent instead of the qualitative piece informing the quantitative pieces.			healthcare10040723_makarova	0
641The captation has been changed to “Characteristics of the study cohort.	2	1	Page 2, line 42, ‘the computation of compounding factors,’ I did not understand what it means.			healthcare10040723_makarova	0
642The sampling procedure was clearly described in the initial manuscript. For phase 1: “All participants of the first phase were students from from 1st to 6th year (undergraduate 1st to 2th year, graduate 3th to 6th year) from German Universities. The inclusion criteria were to actively study medicine and their agreement for their voluntarily participation. In the same way, the exclusion criteria were to have suspended their studies, as well as other exceptional situations. Prior to start, informed consent was obtained, which was followed by the collection of telephone numbers and email addresses. They were selected purposely and consecutively, in part by snowball until theoretical saturation was reached.” For phase 2: “For the second, quantitative study phase identical inclusion/exclusion criteria applied.” This referred to medical students of all semesters, excluding students from other faculties. “The online survey was sent to all medical faculties in Germany from which most forwarded the survey invitation by email to about 80 000 medical students to fulfill the principle of maximum diversity through convenience sampling method. Each contained an invitation letter and an information sheet.” Surely, sampling procedures in mixed method studies are phase depended different.	2	1	I hope these suggestions are of use to the authors.			healthcare10040723_makarova	0
643The statement has been changed into: “The focus on German educational system and the fact that only a small fraction of the total number of medical students filled out the online survey makes a generalization of the answers difficult”.	2	1	In this sense, the first (quantitative) phase informs the next, but the reviewer is right, that both phases are interlinked.			healthcare10040723_makarova	0
644The authors agree and the phase “so called” has been removed.	2	1	For example, the description of the study design says the following.			healthcare10040723_makarova	0
645The authors agree and this statement has been re-written in the revised manuscript version.	2	1	Based on the qualitative study part, the questions for the qualitative study were formulated when students’ attitudes were expressed frequently.			healthcare10040723_makarova	0
646The authors fully agree. Therefore, the conclusion paragraph has been split into the “Conclusion” paragraph, in which the study’s conclusions has been outlined, and into a the new para “Implications” where the usefulness of the integration of eHealth aspects (including AI) into the curriculum is discussed.	2	1	Designing and Conducting Mixed Methods Research.			healthcare10040723_makarova	0
647Thank you for this suggestion. While it would have been interesting to explore this further, our study focuses on retrospectively assessing and comparing disease progression within subgroups of patients receiving TOC. Patients not receiving TOC would have likely had a different presentation, progression and their follow-up would be slightly out of the scope of our observational retrospective study. When we compared patients who received TOC with the 86 severe patients who did not receive TOC (excluded from this analysis), the TOC group was far more severe, so there is no control group that could be matched. In addition, these patients did not have control CT scans.	2	1	Timing of TOC administration according to the oxygen flow rates As mentioned above, the cutoff value is O2 13L/min, but the oxygen volume is difficult to interpret because FiO2 varies depending on the method of oxygen delivery.			jcm11051247_perova	0
648Following this suggestion, we have included in the analysis a calculation according to the FiO2. This has a cut-off which correlates to the oxygen flow cut-off.	2	1	Results 2 The oxygen flow rate of 13 L/min measured by ROC as a cutoff value for TOC administration should be presented by FiO2.			jcm11051247_perova	0
649This is an interesting point. While knowledge of variants is of great importance from an epidemiologic point of view as they have different transmission rates and can cause diseases of different severity, the mechanism of the acute inflammatory response in severe infection seems to be similar regardless the strain. While we did not perform specific sequencing of the strain for every patient as this wouldn’t have been feasible, patients were included before the Delta variant emerged and we expect most of them to have had the initial D614G and UK B.1.1.7. Nonetheless, we have included a comment addressing this aspect in our limitations section to highlight this area of uncertainty.	2	1	The impact of Tocilizumab on radiological changes can not be adequately analyzed without a control group not receiving the drug.			jcm11051247_perova	0
650We agree with the referee that the reasons for the exclusions were unclear and have rephrased accordingly. Addresed in text: „All those excluded were not administered TOC either because of contraindications or TOC supply gaps.” Point 3: 3.	2	1	Study design and population If there are mutations or differences in viral strains during the course of the study, should differences in response to TOC and timing of administration depending on the strain be considered?			jcm11051247_perova	0
651We added the data using FiO2 ROC curve. The area under the curve for FiO2 ROC curve was smaller than the area under the curve for oxygen flow. In addition, the cut-off value for FiO2 corresponded to the cut-off for the oxygen flow rate, so the two groups in Table 3 would be similar.	2	1	Results 2 The oxygen flow rate of 13 L/min measured by ROC as a cutoff value for TOC administration should be presented by FiO2.			jcm11051247_perova	0
652We added this information also in Table 3. We analysed FiO2 (depending on the method of oxygen delivery - nasal canulae, HNF, MV), as you suggested and the cut-off value of FiO2 corresponded to the cut-off for the oxygen flow rate, so the two groups in Table 3 would be similar.	2	1	The impact of Tocilizumab on radiological changes can not be adequately analyzed without a control group not receiving the drug.			jcm11051247_perova	0
653Addressed in text and in Table 3.	2	1	Author Response Please see the attachment Author Response File: Author Response.pdf			jcm11051247_perova	0
654Thank you for pointing this out, we have changed Table 1 accordingly and we removed the imaging data, which as you mentioned, was the same as “before TOC” in Table 2.	2	1	Point 2: The proposed timing of Tocilizumab administration based on oxygen flow rate is interesting but undoubtedly requires a more detailed statistical analysis to convince the readers.			jcm11051247_perova	0
655Addressed, see previous comments and answers.	2	1	Thank you for improving this paper, especially regarding the timing of TOC administration.			jcm11051247_perova	0
656"Still, I disagree with the title of the paper, ""The impact of tocilizumab on radiological changes..."". Without the control group, this paper does not provide evidence that the radiological changes are indeed the result of TOC."	3	2	Results The median oxygen flow rate is shown to be 14 L/min, but FiO2 may vary depending on the method of oxygen delivery (nasal canulae, HNF, MV).			jcm11051247_perova	0
657"Therefore I would suggest the authors to change the title of their paper. Something in line with ""Optimal timing of TOC administration"" would seem more appropriate."	3	2	Point 2: The proposed timing of Tocilizumab administration based on oxygen flow rate is interesting but undoubtedly requires a more detailed statistical analysis to convince the readers.			jcm11051247_perova	0
658The three references have been noticed with gratitude and included in the MS.	2	1	He reviews some of his previous work and presents an alternative to the dominant ‘Ancient RNA world’ hypothesis.			life4041050_perova	0
659The 1998 paper leaves much to be desired. Its deficiencies reflect the excitement of the first hour. The state of the art at that time may be gleaned from an authoritative paper that came to the opposite conclusion: A.R. Mushegian and E.V. Koonin “Gene order is not conserved in bacterial evolution”. TIG 1996, 12, 289–290. The gene cluster table of 1998 was mainly retrieved from the annotations in published genomes and constructed manually with paper and pencil. The state of information technology at that time is reflcted by the fact that the table was folded an individually pasted by hand into each issue by the publisher.	2	1	I have only a few comments, which might improve the manuscript.			life4041050_perova	0
660The 1998 paper contemplated speculatively a combination of small-scale gene doubling (as evidenced by the immediate neighborhood of EF-Tu/EF-G) and of a large-scale gene cluster doubling (as evidenced by the spacing between secE/secY and rpoH-A/rpoD) with the hope of a future deeper understanding based on folding structures. Now the referee makes an exciting suggestion that may, if executed successfully, go some way to satisfy that hope.	2	1	Therefore, my comments will be slanted by my own expertise and will only serve the author as a partial devil’s advocate effort General commentary Section 1.			life4041050_perova	0
661The self-cleavage of RNA by 2'-OH is a chemical textbook fact. The 2'-OH group has the proper position and orientation for a nucleophilic attack on the phosphate bridge. The kinetics of the reaction is greatly favored by the 5-membered ring structure of the resulting cyclic phospho-bisester. The length of the RNA molecule is not relevant since each nucleophilic attack causes destruction of the chain. The effect should not be confused with the length-dependent “error catastrophe” of accumulating mutations of RNA. Incidentally, some anaerobic ribonucleotide reductases are ancient, while others (aerobic ones) are later inventions.	2	1	Therefore, my comments will be slanted by my own expertise and will only serve the author as a partial devil’s advocate effort General commentary Section 1.			life4041050_perova	0
662Genome rearrangements are certainly important during later evolution of the phyla. At the level of LUCA, i.e., prior to the splitting of the domains, it is not clear, if and to what extent rearrangements of the modern style occurred. In this regard we should bear in mind that the LUCA genome may have exhibited sense-antisense coding on both strands as suggested by Rodin and Carter. This position has been adopted and discussed in the present paper. Therefore, speculations concerning possible genome rearrangements may be a bridge too far.	2	1	I have however a number of quibbles that if addressed could increase the accuracy, value and impact of the manuscript.			life4041050_perova	0
663The present analysis comes to the conclusion that the sets of canonical amino acids and bases as well as the genetic triplet code were largely complete at the level of LUCA. The Wong coevolution theory of the genetic code has been discussed in detail. The literature comprises numerous proposals concerning the origin of translation and other aspects of the genetic machinery. A review of all these proposals and many others is beyond the scope of the present paper. The present paper is a research paper and not a review paper. It aims at a comprehensive account of early evolution from the origin of life all the way to LUCA. This puts a systematic constraint on literature selection. An effort (unfortunately fallible) has been made to include all those references that integrate with the main lines of the present account into a coherent account. Contributions by others that have the character of theoretical modules that fit well into this account have been termed “theorems” with names of the main authors attached. A reference to a paper on nucleotide biosynthesis phylogeny is now cited in Section 7.	2	1	In light of recent research developments and argumentation (some of it reviewed), his views should be considered a welcome addition to the many ideas that populate the “origin of life” field of inquiry that counter the dominant paradigm.			life4041050_perova	0
664Based on the valuable criticism Section 2 has been extensively revised. Terminology has been clarified. This Section has a rather restricted purpose. It provides chemical arguments for the proposition that the pioneer organisms could only exist at high temperature and that the subsequent forms of life remained hyperthermophilic for a long time until much later an irreversible evolution generated organisms that required lower and lower temperatures. This conclusion places severe constraints on all aspects of the evolution of the genetic machinery. The fascinating topics of thermodynamics, energy dissipation and information are outside the scope of the paper.	2	1	I have however a number of quibbles that if addressed could increase the accuracy, value and impact of the manuscript.			life4041050_perova	0
665The author expresses his gratitude for the two additional references, which have been included in the text.	2	1	Theories on the origin of life or on other aspects of early evolution, such as cellularization, serve merely as starting points.			life4041050_perova	0
666The statement has been clarified.	2	1	The manuscript represents a nice piece of work with many exciting ideas for further exploration.			life4041050_perova	0
667In the introduction the term “or proteins” has been added after “RNA”	2	1	I have however a number of quibbles that if addressed could increase the accuracy, value and impact of the manuscript.			life4041050_perova	0
668and the term “retrodict” has been defined.	2	1	I have only a few comments, which might improve the manuscript.			life4041050_perova	0
669The term “interpolate” has been clarified.	2	1	He reviews some of his previous work and presents an alternative to the dominant ‘Ancient RNA world’ hypothesis.			life4041050_perova	0
670The problem of mutational saturation is now included in the discussion of Figure 1.	2	1	The article demonstrates that the iron-sulfur surface metabolism theory at high temperatures has a much better explanatory power than the RNA World theory.			life4041050_perova	0
671The term “multiply impaired” has been replaced by a clearer wording.	2	1	I must note that a careful evaluation of all facets requires expertise in a multitude of disciplines (from prebiotic chemistry and structural biology to evolutionary bioinformatics and biochemistry) and considerable time, none of which I possess.			life4041050_perova	0
672LUCA is discussed only in Section 1.	2	1	The manuscript represents a nice piece of work with many exciting ideas for further exploration.			life4041050_perova	0
673The protein cycle is discussed in a separate Section 4, which is concerned with the course of evolution before LUCA.	2	1	In light of recent research developments and argumentation (some of it reviewed), his views should be considered a welcome addition to the many ideas that populate the “origin of life” field of inquiry that counter the dominant paradigm.			life4041050_perova	0
674There are many relevant literature references. Among these there are specific proposals concerning a circumscribed problem that are included to fill a logical gap, as a theoretical module so to speak. These have been designated by the term “theorem” with the added name(s) of the main R7 author(s). This makes it clear that the account given is comprehensive in the sense that major independent contributions by other scientists integrate readily with the overall account given.	2	1	He reviews some of his previous work and presents an alternative to the dominant ‘Ancient RNA world’ hypothesis.			life4041050_perova	0
675The relationship of His and Trp biosyntheses has been toned down.	2	1	I have however a number of quibbles that if addressed could increase the accuracy, value and impact of the manuscript.			life4041050_perova	0
676Section 8 has been revised in order to address the issues involved in the last query.	2	1	Second Round of Evaluation Round 2: Most commentary has been addressed and new changes have improved the exposition.			life4041050_perova	0
677This review does not require any action on our part.	2	1	The authors discuss these issues by means of differential equations and simulations.			life5010181_makarova	0
678Here, the reviewer did not like our use of the particular words “novelty” and “innovation”. o Use of the word novelty − Instances of “chemical novelty” in the manuscript replaced by “emergent chemical behaviour”. − On Page 8, after Equation 8, we removed sentence: The emergence of bistability will serve as a proxy for the emergence of other chemical novelties in the vesicle reactor model. Replaced whole paragraph, to read: In particular, in these initial stages, we will focus on the emergence of bistability in the vesicle reactor model—a dynamical feature deducible directly from the number and stability of the fixed points present (i.e., two asymptotically stable points separated by an unstable saddle point). We also expect that more complicated dynamical regimes could also be present in the model, like multi-stability or global phase space features such as limit cycles giving rise to sustained oscillations. However, investigation of these regimes will be deferred to later work: for the time being, the “emergent chemical behavior” referred to in the title will be restricted to bistability. We think this is a clearer explanation, and also uses the word “regime” suggested by the reviewer. o Use of the word innovation We kept the 2 occurrences of the word “innovation” in the abstract and the introduction. An innovation is defined as a “new method, idea or product” in the dictionary. We use the word to refer to new emergent chemical behaviour that the whole vesicle system exhibits (e.g., expanded steady states), which did not exist before. We think the use of this word is acceptable.	2	1	The authors discuss these issues by means of differential equations and simulations.			life5010181_makarova	0
679we added a new footnote, to explain our standing on this issue: Reference 36: In this work, concentrations outside the vesicle are set as system parameters. However, we make no commitment to the type of environment the vesicle is embedded in or how these concentrations are maintained. Our purpose is simply to show that bistability can exist in the model for certain sets of outside concentrations. Exploration of the model in explicit environments is deferred to future work.	2	1	The authors discuss these issues by means of differential equations and simulations.			life5010181_makarova	0
680Reference 11 has been added after Equation 10, to point the reader to where to find information about phi limits was first discussed. Repeating this information here would complicate the paper. The lines Phi = 2^(1/3) and 4^(1/3) in Figure 1d have now been explained.	2	1	Produces a dynamic model for chemical evolution rather than traditional deterministic, static, systems that requires centralised information to direct evolution, such as a constant gradient.			life5010181_makarova	0
681It is difficult to make a direct and meaningful comparison like this. Without a container, the reaction system has less parameters, and thus the sampled parameter space is smaller. The aim in the paper, was to simply show that encapsulating a Schlogl model which was bistable in bulk condition, seemed to destroy this bistability.	2	1	Produces a dynamic model for chemical evolution rather than traditional deterministic, static, systems that requires centralised information to direct evolution, such as a constant gradient.			life5010181_makarova	0
682The minor issues were fixed.	2	1	Produces a dynamic model for chemical evolution rather than traditional deterministic, static, systems that requires centralised information to direct evolution, such as a constant gradient.			life5010181_makarova	0
683This immunoquantitation method used is described in detail in the reference given (Brown et al. 2008). The reviewer is directed in particular to the Supplementary Methods section. To allow readers to get a better understanding of the method in this manuscript we have revised this part of the Experimental Section, adding extra text to increase clarity concerning the method.	2	1	This is done for a number of globally significance marine microbes of Syn and Pro lineage.			life5010403_perova	0
684Since submitting the manuscript, we have accumulated a set of 84 parallel measurements of steady state oxygen evolution and the functional content of PSII measured using flash yields (with a solid state optode) and simultaneous FRR chlorophyll fluorescence induction curves, from which we can extract e- PSII-1 s-1, for both Synechococcus and Prochlorococcus cultures. Consistent with the long literature history of such measurements (ex. Suggett et al. 2004, 2009), we observe a good correlation between the two measures of electron transport per PSII. Plotting the FRR estimate of e- PSII-1 s-1 versus the O2 evolution/PSII content estimate of e- PSII-1 s-1 gives a slope of 1.26 and an R2 of 0.58. We have added this information to the Materials and Methods to support our use of FRR estimates of electron transport per PSII. Furthermore, our estimates of ETRmax from FRR induction curves are independently validated by the close correlation between ETRmax and 1/tau, shown in Figure 4A, since 1/tau is derived from the rate constant for the decay of fluorescence after induction, and thus does not depend (computationally) upon our estimator for ETRmax.	2	1	Round 1: and Author Response The authors present a dataset where they have characterised the relative abundance of components of the photosynthetic electron transfer chain and related this to the measured rate of electron transfer from PSII.			life5010403_perova	0
685This has been addressed with the addition of text in the abstract, introduction and discussion specifying that the cultures were grown under low light conditions.	2	1	The approach and methods are robust and the ability to quantify components of the photosynthetic electron transfer chain is powerful.			life5010403_perova	0
686We have removed the word “nondiazotrophic” as we agree that it is not relevant to the discussion.	2	1	Round 1: and Author Response The authors present a dataset where they have characterised the relative abundance of components of the photosynthetic electron transfer chain and related this to the measured rate of electron transfer from PSII.			life5010403_perova	0
687We mean that they numerically dominate and we have clarified this in the introduction.	2	1	The approach and methods are robust and the ability to quantify components of the photosynthetic electron transfer chain is powerful.			life5010403_perova	0
688We have clarified this statement in the text. We refer to the nitrogen cost in the form of allocation to protein per pigment bound.	2	1	Second Round of Evaluation Round 2: and Author Response			life5010403_perova	0
689We are referring to the number of RUBISCO active sites measured by immunoquantitation. We are not referring to measured RUBISCO activity. We use this expression to be clear that we are referring to RbcL subunits rather than oligomeric RUBISCO. We have added a parenthetic phrase to make this more clear.	2	1	The data presented is robust and worthy of publication but should be discussed more critically with regard to published literature (outlined below) I suggest some minor suggestions that should be incorporated before publications.			life5010403_perova	0
690We thank the reviewer for drawing this study to our attention. We have added a paragraph to the discussion to compare and contrast the Sukenik work with that presented here. The Sukenik data support a strong positive correlation between 1/tau and the RUBISCO to PSU ratio over a series of growth irradiances. While we also see a strong positive correlation between 1/tau and RUBISCO to PSII our results differ as the molar ratios of the components of the PSU differ significantly between the strains analyzed in the current work. This allows us to pinpoint the relationship of PSII to RUBISCO rather than other subunits of the PSU as the determinant of electron transport rate.	2	1	The approach and methods are robust and the ability to quantify components of the photosynthetic electron transfer chain is powerful.			life5010403_perova	0
691We have added text to the end of the discussion to address this comment and the relevant reference has been added. Thank you for this suggestion.	2	1	This is done for a number of globally significance marine microbes of Syn and Pro lineage.			life5010403_perova	0
692We have added a supplemental figure (Supplemental Figure #2) to show this calibrations curve. As all experiments presented here were performed under iron replete conditions, no iron starvation was performed.	4	1	The data presented is robust and worthy of publication but should be discussed more critically with regard to published literature (outlined below) I suggest some minor suggestions that should be incorporated before publications.			life5010403_perova	0
693We have added a supplemental figure (Supplemental Figure #1) that shows the method applied with a sample blot, calibration curve and data analysis. This work required dozens of blots, each with its own standard curve, so it would not be practical to show all of the standard curves for each determination.	4	1	The data presented is robust and worthy of publication but should be discussed more critically with regard to published literature (outlined below) I suggest some minor suggestions that should be incorporated before publications.			life5010403_perova	0
694Multi-alignment of concatenated protein (or DNA) segments is a genome-scale, but not whole-genome approach. Its applicability depends on the scope of the phylogenetic study. When dealing with not-too-distantly related species it may yield more or less useful result. However, in a study covering many phyla it is very difficult, if not impossible, to collect a common set of conserved proteins. Moreover, the concatenation method can never lead to very convincing conclusion, as give or take a few proteins may change the result. The phylogenomics people have noticed this problem, see, e.g., O. Jeffroy, H. Brinkman, F. Delsuc, H. Philippe (2008) Phylogenomics: the beginning of incongruence? Trends in Genetics, 22(4): 225–231. An example from the Bacteria domain is the relationship of the closely related Shigella and Escherichia coli strains. Concatenation of different number of genes led to different way of mixing-up of the two groups, but CVTree gave unambiguous separation of the strains as different species in the same genus Escherichia, see: G.-H. Zuo, Z. Xu, B.L. Hao (2013) Shigella strains are not clones of Escherichia coli but sister species in the genus Escherichia. Genomics Proteomics Bioinformatics, 11: 61–65. In order to carry out multi-alignment of concatenated sequences, a postdoc or well-trained PhD student equipped with the corresponding software is required. In contrast, with genome sequencing becoming a common practice in many labs it costs no additional work for a bench-microbiologist to get phylogenetic and taxonomic information by using a convenient and publically available tool such as the CVTree web serve. Well, we would be glad to see comparison of CVTree phylogeny with multi-alignment of concatenated proteins if anyone finds a way to do it for so many diverse phyla, but we do not consider it as a doable job.	2	1	Even if defined in the future, it must be lineage-dependent.			life5010949_perova	0
695These points were discussed in the “Material and Method” section added at the suggestion of Reviewer 2. The following was copied from the manuscript: “Traditionally a newly generated phylogenetic tree is subject to statistical re-sampling tests such as bootstrap and jackknife. CVTree does not use sequence alignment. Consequently, there is no way to recognize informative or non-informative sites. Instead we take all the protein products encoded in a genome as a sampling pool for carrying out bootstrap or jackknife tests (citing our 2004 paper). Although it was very time-consuming, CVTrees did have well passed these tests (citing our 2010 paper). However, successfully passing statistical re-sampling tests only tells about the stability and self-consistency of the tree with respect to small variations of the input data. It is by far not a proof of objective correctness of the tree. Direct comparison of all branchings in a tree with an independent taxonomy at all ranks would provide such a proof, The 16S rRNA phylogeny cannot be verified by the Bergey's taxonomy, as the latter follows the former. However, agreement of branchings in CVTree with the Bergey's taxonomy would provide much stronger support to the tree as compared to statistical tests. This is the strategy we adopt for the CVTree approach.” “There are two aspects of a phylogenetic tree: the branching order (topology) and the branch lengths. Branching order is related to classification and branch length to evolution time. Calibration of branch lengths is always associated with the assumption that mutation rate R3 remains more or less a constant across all species represented in a tree, an assumption that cannot hold true in a large-scale phylogenetic study like the present one. Therefore, branching order in trees is of primary concern, whereas calibration of branch lengths makes less sense. Accordingly, all figures in this paper only show the branching scheme without indication of branch lengths and bootstrap values”.	2	1	R13 Round 2: and Author Response Authors have substantially improved the article, including language corrections, and have provided extensive clarifications to all initial criticisms.			life5010949_perova	0
696Yes, this is an apparent discrepancy of CVTree from 16S (and 23S) analysis for the given set of 179 archaeal genomes. However, in an on-going study of ours (not published yet) using a much larger data set this violation no longer shows up; both Korarchaeota and Crenarchaeota restore their phylum status. Taking into account the fact that both Korarchaeota and Thermofilaceae are represented by single species for the time being, their placement certainly requires further study with broader sampling of genomes.	2	1	Though a dissimilarity measure figures in the CVTree algorithm, it is not realistic to delineate taxa by using this measure at least for the time being.			life5010949_perova	0
697Highly degenerated genomes of many symbiont organisms tend to move around, in particular, to the baseline of a tree and thus distorts the overall structure of the tree. Therefore, it is better not to mix them with free-living organisms in a study. We rephrased the corresponding paragraph in the manuscript: “The nanosized archaean symbiont Nanoarchaeum equitans has a highly reduced genome (490,885 bp). It is the only described representative of a newly proposed phylum Nanoarchaeota and it cuts into the otherwise monophyletic phylum Euryarchaeota. We note that the monophyly of Euryarchaeota was also violated by Nanoarchaeum in some 16S rRNA trees, see, e.g., Figure 4 in a 2009 microbial survey as well as (c) and (d) in our Figure 3. It has been known that tiny genomes of endosymbiont microbes often tend to move towards baseline of a tree and distort the overall picture. In fact, we have suggested skipping such tiny genomes when studying bacterial phylogeny, see, e.g., (citing our 2010 paper) and a note in the home page of the CVTree Web Server. In the present case we may at most say that Nanoarchaeota probably makes a separate phylum, but its cutting into Euryarchaeota might be a side effect due to the tiny size of the highly reduced genome”.	2	1	— Done Second Round of Evaluation Round 2: and Author Response			life5010949_perova	0
698Yes, there was certain disturbing effect of the tiny and lonely Nanoarchaeum genome, yet the Halobacteria is a very specific clade, forming a tightly connected group and moving around as a whole, mainly due to the biased acidity of their constituent amino acids. We anticipate that the relative placement of Halobacteria with respect to other groups may stabilize when more genomes are used to construct a tree.	2	1	Though a dissimilarity measure figures in the CVTree algorithm, it is not realistic to delineate taxa by using this measure at least for the time being.			life5010949_perova	0
699We have A new “Material and Method” section has been added. Such issues as statistical resampling tests (bootstrap and jackknife), calibration of branch length, the meaning and choice of the peptide length K, etc. , were discussed in the new section. Figures 1 and 2 were combined to a new Figure 1; Figures 3 and 4 were combined to become a new Figure 2. Figure captions were made more detailed. The whole text was checked for language flaws and many places were rephrased.	2	1	For example, it cannot be expected that the same degree of dissimilarity may be used to delineate classes in all phyla.			life5010949_perova	0
700We thank the Reviewer for the detailed comments/suggestions given in the previous report and the suggestion of doing spelling-check this time. We have gone through the final manuscript carefully once more.	4	1	Therefore, branching order in trees is of primary concern, whereas calibration of branch lengths makes less sense.			life5010949_perova	0
701A “Material and Method” section has been added where the CVTree algorithm, the interactive tree-viewer, statistical resampling tests (bootstrap, jackknife), calibration of branch lengths, etc., were discussed in slightly more detail.	2	1	Besides, would be desirable that authors provide more objective criteria for high taxa circumscription based on their methodology.			life5010949_perova	0
702Yes, 16S rRNA phylogeny is quite stable and it almost defines the present taxonomy. We have given due credit for this. In general, CVTree does not challenge 16S rRNA analysis but complement it.	2	1	The idea to use whole genome data for archaeal phylogenies is interesting, as the 16S rRNA phylogenies can be poor in resolving relationships among archaeal lineage due to GC content bias in hyperthermophilic Archaea.			life5010949_perova	0
703A robust phylogenetic tree comes with a fixed branching order of leaves. One looks at the leaf names and their taxonomic lineage and tries to map the latter to the branches. To this end we added the following paragraphs in the “Material and Method” section. “There are two aspects of a phylogenetic tree: the branching order (topology) and the branch lengths. Branching order is related to classification and branch length to evolution time. Calibration of branch lengths is always associated with the assumption that mutation rate remains more or less a constant across all species represented in a tree, an assumption that cannot hold true in a large-scale phylogenetic study like the present one. Accordingly, all figures in this paper only show the branching scheme without indication of branch lengths and bootstrap values.” “Branching order in a tree by itself does not bring about taxonomic ranks, e,g, class or order.	2	1	Round 1: and Author Response Summary Zuo et al.			life5010949_perova	0
704We have reorganized the manuscript mainly by adding a new “Material and Method” section where discussions on branch length, statistical resampling, meaning and choice of K, etc., were given. The original Figure 1 was deleted with some related points explained in the text accompanying the original Figure 2. All figure captions have been rewritten for clarity.	2	1	The tree was compared with several 16S rRNA trees reported in the literature, and the differences were minor.			life5010949_perova	0
705A few more sentences were added in the “Conclusion” regarding the power and achievement of the 16S rRNA analysis.	2	1	Besides, would be desirable that authors provide more objective criteria for high taxa circumscription based on their methodology.			life5010949_perova	0
706We tried to rephrase the paragraph by changing, deleting, or adding a few words as follows: “In this paper we study Archaea phylogeny across many phyla. This is in contrast with phylogeny of species in a narrow range of taxa, e.g., that of vertebrates (a subphylum) or human versus close relatives (a few genera). Accordingly, the phylogeny should be compared with taxonomy at large, or, as Cavalier-Smith (citing cavalier-smith 2002) put it, with “megaclassificaton” of prokaryotes. Although in taxonomy the description of a newly discovered organism necessarily starts from the lower ranks, higher rank assignments are often incomplete or lacking. At present the ranks above class are not covered by the Bacteriological Code. The number of plausible microbial phyla may reach hundreds and archaeal ones are among the less studied. According to the 16S rRNA analysis, the major archaeal classes and their subordinate orders have been more or less delineated. Therefore, in order to carry out the aforementioned cross verification we make emphasis on higher ranks such as phyla, classes, and orders. A study using 179 Archaea genomes should provide a framework for further study of lower ranks.” Part 3.1	2	1	— Done Second Round of Evaluation Round 2: and Author Response			life5010949_perova	0
707Branching order in a tree is directly related to taxonomy, while branch lengths have more to do with evolution. For large-scale phylogenetic study across many phyla the former is more important than the calibration of branch lengths. The latter is based on the assumption that mutation rate is more or less constant. This assumption cannot hold when dealing with many phyla.	2	1	Authors should define well their objectives, also make sure that the conclusions are novel (which ones are novel, which are supportive to previous published work, etc.			life5010949_perova	0
708This is done in the newly added “Material and Method” section.	2	1	Though a dissimilarity measure figures in the CVTree algorithm, it is not realistic to delineate taxa by using this measure at least for the time being.			life5010949_perova	0
709The original Figure 1 was deleted and a few words added to the legend of the original Figure 2, now the new Figure 1.	2	1	— Done Second Round of Evaluation Round 2: and Author Response			life5010949_perova	0
710Judging by the cluster labeled as Euryarchaeote{0+3} in Figure 2 Methanomassiliicoccus was not reclassified into Thermoplasmataceae but to an yet un-specified class.	2	1	For example, it cannot be expected that the same degree of dissimilarity may be used to delineate classes in all phyla.			life5010949_perova	0
711The sentence has been moved to the legend of Fig. 1 and slightly rephrased.	2	1	Leaving that opinion aside, I think the alignment-free methodology is interesting, however			life5010949_perova	0
712Done.	2	1	Round 1: and Author Response Summary Zuo et al.			life5010949_perova	0
713the K issue is discussed in the newly added “Material and Method” section; so scattered mentioning of K has been deleted from the rest of text.	2	1	About 180 archaeal genomes were used to calculate a new tree topology using CVTree.			life5010949_perova	0
714Done in the caption of Figure 2.	2	1	are describing a comprehensive analysis of archaeal phylogeny with a genome-based alignment free method, and then comparing the findings to 16S rRNA based phylogenies.			life5010949_perova	0
715We have rewritten the paragraph as: “The new phylum Korarchaeota violates the monophyly of the phylum Crenarchaeota by drawing to itself the family Thermofilaceae. However, in an on-going study of ours (not published yet) using a much larger data set, this violation no longer shows up; both R8 Korarchaeota and Crenarchaeota restore their phylum status. Taking into account the fact that both Korarchaeota and Thermofilaceae are represented by single species for the time being, their placement certainly requires further study with broader sampling of genomes.”	2	1	are describing a comprehensive analysis of archaeal phylogeny with a genome-based alignment free method, and then comparing the findings to 16S rRNA based phylogenies.			life5010949_perova	0
716From the original Figures 3 and 4 only one has been kept and the legend rewritten. In fact, the whole paragraph changed to: “The newly proposed phylum Thaumarchaeota appears to be non-monophyletic as an outlying strain Candidatus Caldiarchaeum subterranum was assigned to this phylum according to the NCBI taxonomy. The NCBI assignment might reflect its position in some phylogenetic tree based on concatenated proteins, e.g., Figure 2 in […]. However, in the original paper reporting the discovery of this strain […] and in recent 16S rRNA studies, e.g., […], Candidatus Caldiarchaeum subterranum was proposed to make a new phylum Aigarchaeota. CVTrees support the introduction of this new phylum. A lineage modification of Candidatus Caldiarchaeum subterranum from Thaumarchaeota to Aigarchaeota would lead to a monophyletic Thaumarchaeota{7}.”	2	1	Though a dissimilarity measure figures in the CVTree algorithm, it is not realistic to delineate taxa by using this measure at least for the time being.			life5010949_perova	0
717The problem of taxonomic placement of Aciduliprofundum is a good example to demonstrate how one extract information from CVTrees. In the Reysenbach et al. Nature 2006 paper it was taken as the first cultivated member of the DHEV2 (deep-sea hydrothermal euryarchaeate 2) clade based on a maximum-likelihood 16S rRNA tree. Unfortunately, all other 13 members of this clade were represented by 16S rRNA sequences only and no genome data are available so far. The NCBI taxonomy gave an incomplete lineage: Archaea; Euryrchaeota; unclassified Euryarchaeota; missing taxonomic assignment at the rank class and below. In order to make use of CVTree we must touch on the K-issue a little more. The alignment-free comparison of genomes in CVTree is implemented by counting the number of K-peptides in the protein products encoded in a genome followed by subtraction of a random background caused by neutral mutations. The peptide length K looks like a parameter, but it is actually not a parameter. Using a longer K emphasizes species-specificity, while a shorter K takes into account more common features with neighboring species. However, we never adjust K: a fixed K is used for all genomes to construct a tree, but one may construct a series of trees for K = 3, 4, 5, 6, 7, 8, … We have shown repeatedly that R9 K = 5 and 6 lead to best results in the sense of agreement with taxonomy, so usually only a K = 6 tree is given in publications. Let us look at a subtree, i.e., part of a tree, containing the organisms of interest. If the branching order in all trees built for different Ks turns out to be same, it would be a strong support to the branching order. In most cases the branching order varies with K: K = 3 and 4 make sense, K = 5 and 6 yield the best, K = 7 and 8 become slightly worse, etc. For too big a K, even if the closest strains remain grouped together the whole tree may tend to become a star-tree, i.e., every small clade stands in its own and their mutual placements become less meaningful. Therefore, inspection of trees for a range of K-values provides an additional dimension to evaluate the results. For Aciduprofumdum we have a stable pair (<C>Thermococci{18}, <G>Aciduprofumdum{2}) at K=3, 5, 6, 7. At K = 4 we have (<C>Thermococci{18}, (<G>Staphylothermus{2}, <G>Aciduprofundum{2})) In all these cases Thermoplasmata stands farther away from the above pair. However, at K = 8 and 9, when the overall tree picture has been largely distorted, Aciduliprofundum does stand closer to Thermaplasmata. Putting together all the above results we tend to consider the pair (<C>Thermococci{18}, <G>Aciduliprofundum{2}) as reflecting a more probable relation. Confined to the available data for the time being one may assign <G>Aciduliprofundum to <C>Thermococci, e.g., to denote the pair as <C>Thermococci{20}=(<F>Thermococcaceae{18}, <G>Aciduliprofundum{2}) leaving its family unclassified or assign it to a new family. Without further phenotypic and chemotaxonomic evidence it is better not to introduce new taxon names if the present naming scheme is capable to accommodate the leaves without conflict. This was why we wrote “this modification would hold as long as no new facts challenge it”. Anyway, taxonomy has always been a work in progress. One has to be prepared for modifications when new data appear. To make a long story short, we have rewritten the paragraph as: “The Candidatus genus Aciduliprofundum is considered a member of the DHEV2 (deap-sea hydrothermal vent euryarchaeotic 2) phylogenetic cluster. No taxonomic information was given in the original papers [55,56]. The NCBI Taxonomy did not provide definite lineage information for this taxon at the class, order, and family ranks. According to [55] the whole DHEV2 cluster was located close to Thermoplamatales in a maximum-likelihood analysis of 16S rRNA sequences. A similar placement was seen in [54] where a Bayesian tree of the archaeal domain based on concatenation of 57 ribosomal proteins put a lonely Aciduliprofundum next to Thermoplasmata. However, in CVTrees, constructed for all K-values from 3 to 9, Aciduliprofundum juxstaposes with the class Thermococci{18}. An observation in [56] that this organism shares a rare lipid structure with a few species from Thermococcales may hint on its possible association with the latter. If we temporarily presume a lineage <C>Thermococci<O>Unclassified<F>Unclassified<G>Aciduliprofundum… R10 one might have a monophyletic class <C>Thermococci{20}. Since none of the 13 DHEV2 members listed in [55] has a sequenced genome so far, CVTree cannot tell the placement of the DHEV2 cluster as a whole for the time being. It remains an open problem as whether DHEV2 is close to Thermoplasmata or to Thermococci, or a new class is needed to accommodate DHEV2.”	2	1	Leaving that opinion aside, I think the alignment-free methodology is interesting, however			life5010949_perova	0
718No, we did not mean it.	2	1	The idea to use whole genome data for archaeal phylogenies is interesting, as the 16S rRNA phylogenies can be poor in resolving relationships among archaeal lineage due to GC content bias in hyperthermophilic Archaea.			life5010949_perova	0
719We should first explain how these inappropriate names appeared. We have insisted to use the directory name at the NCBI FTP site as genome name. However, in November 2013 NCBI announced that they would not release genomes of different strains of the same species as before. In a period thereafter NCBI sometimes put several genomes in a directory and we had to extract the data and to assign a name from the “Source” line of the GenBank file. This caused some confusion. For example, as of February 27, 2015, a directory name at NCBI remained “archaeon_Mx1201_uid196597” and we had to change it to: Candidatus_Methanomethylophilus_alvus_Mx1201_uid196597 Now all “wrong names” as pointed out by the Reviewer no longer appear in figures. In the text we tried to refer to their names as complete as possible.	2	1	Results also provide additional support to recently proposed archaeal phyla and halobacterial orders.			life5010949_perova	0
720The genome name at NCBI FTP site is “halophilic_archaeon_DL31_uid72619”. The uid number was dropped when mentioned in the text. We put it back and capitalized the first letter to “Halophilic”, still an illegal genus name.	2	1	The idea to use whole genome data for archaeal phylogenies is interesting, as the 16S rRNA phylogenies can be poor in resolving relationships among archaeal lineage due to GC content bias in hyperthermophilic Archaea.			life5010949_perova	0
721It is Figure 2 in the revised manuscript. We discussed it at some length.	2	1	Even if defined in the future, it must be lineage-dependent.			life5010949_perova	0
722No, organism cannot be published. Thanks for correcting our mistake.	2	1	Results also provide additional support to recently proposed archaeal phyla and halobacterial orders.			life5010949_perova	0
723The latter can be assigned only after comparison with a reference taxonomy which is not a rigid framework but a modifiable system. Though a dissimilarity measure figures in the CVTree algorithm, it is not realistic to delineate taxa by using this measure at least for the time being. Even if defined in the future, it must be lineage-dependent. For example, it cannot be expected that the same degree of dissimilarity may be used to delineate classes in all phyla. In addition, monophyly is a guiding principle in comparing branching order with taxonomy. Here monophyly must be understood in a pragmatic way restricted to the given set of input data and the reference taxonomy. If all genomes from a taxon appear exclusively in a tree branch, the branch is said to be monophyletic.” R6 One cannot tell the rank of a node/leaf in a tree by simply looking at it. A reference taxonomy is alwys needed. We put the following in the “Material and Method” section to explain it: “Branching order in a tree by itself does not bring about taxonomic ranks, e,g, class or order.	2	1	About 180 archaeal genomes were used to calculate a new tree topology using CVTree.			life5010949_perova	0
724The phrase “3063 identical nucleotide positions” was copied from the caption of Figure 4 of the cited Nunoura et al. 2011 paper without much thinking. We simply deleted it.	2	1	Therefore, branching order in trees is of primary concern, whereas calibration of branch lengths makes less sense.			life5010949_perova	0
725The whole paragraph has been rewritten as: “The nanosized archaean symbiont Nanoarchaeum equitans has a highly reduced genome (490,885 bp [44]). We note that the monophyly of Euryarchaeota was also violated by Nanoarchaeum in some 16S rRNA trees, see, e.g., Figure 4 in a 2009 paper [61] as well as (c) and (d) in our Figure 4. In fact, we have suggested skipping such tiny genomes when studying bacterial phylogeny, see, e.g., [29] and a note in the home page of the CVTree Web Server [21]. In the present case we may at most say that Nanoarchaeota probably makes a separate phylum, but its cutting into Euryarchaeota might be a side effect due to the tiny size of the highly reduced genome.” Conclusion	2	1	Even if defined in the future, it must be lineage-dependent.			life5010949_perova	0
726As a method CVTree is independent of 16S rRNA analysis. First, it uses protein products in a genome instead of RNA segments in the genome. Second, it does not do sequence alignment. CVTree generates stable trees but cannot tell which branch corresponds to what taxon. Only after comparison with the existing classification and nomenclature one would be able to make connections with taxonomy. In this sense it does depend on 16S rRNA taxonomy. Anyway, CVTree does not challenge 16S rRNA analysis but makes it more convincing in most cases. The revealed discrepancies call for further study.	2	1	are describing a comprehensive analysis of archaeal phylogeny with a genome-based alignment free method, and then comparing the findings to 16S rRNA based phylogenies.			life5010949_perova	0
727In fact, genomic approaches are more effective at species level and below due to their high resolution power. At high ranks CVTree may be more effective in the sense that it does not require additional work. Suffice it to put genomes in CVTree web server and the branches come out, then compare them with a reference taxonomy.	2	1	Perhaps an additional discussion point would be the advantages of using CVtree approach with regular concatenated proteins.			life5010949_perova	0
728Even “herenow” does not seem to be an correct English word; we changed it to “so far”.	2	1	About 180 archaeal genomes were used to calculate a new tree topology using CVTree.			life5010949_perova	0
729We changed “is in contrast with” to “is distinct from” and added a phrase “focusing on taxonomy of higher ranks” at the end of a sentence. Now the sentences read: “This is distinct from phylogeny of species in a narrow range of taxa, e.g., that of vertebrates (a subphylum) or human versus close relatives (a few genera). Accordingly, the phylogeny should be compared with taxonomy at large, or, as Cavalier-Smith \cite{cavalier-smith2002} put it,with “megaclassificaton” of prokaryotes, focusing on taxonomy of higher ranks.” -	4	1	Round 1: and Author Response Summary Zuo et al.			life5010949_perova	0
730done	4	1	Here monophyly must be understood in a pragmatic way restricted to the given set of input data and the reference taxonomy.			life5010949_perova	0
731Moved to the conclusion section and the first word “Though” replaced by “In addition, since”	4	1	However, I am personally not convinced that whole genomes bring additional advantages, or if we are better off by just using a conserved set of proteins.			life5010949_perova	0
732The whole paragraph has been deleted. This paragraph was added to the revised manuscript because one of the Reviewers asked “Does CVTree still require input genome data to be annotated to gene features, i.e., protein or CDS?” Well, this question reminds us that for many so-called “Permanent Draft” genomes it may be worthwhile returning to our early practice of using whole genome nucleotide sequences without distinguishing coding and non-coding segments. Although it did not lead to better results as compared with using translated protein products, but it is doable on un-annotated contigs. We will try this later.	4	1	In addition, monophyly is a guiding principle in comparing branching order with taxonomy.			life5010949_perova	0
733We have deleted all what appeared within the curly brackets and kept only “monophyletic Thaumarchaeota” as suggested. In fact, we could not tell how these words appeared there; there was none in our draft manuscript.	4	1	I recommend acceptance for publication in Life Sciences journal.			life5010949_perova	0
734To the best of our knowledge, rare earth doped yttrium iron garnet is still the main material used for magneto-optical devices. They include bismuth doped YIG, bismuth, terbium doped YIG and cerium doped YIG. Other materials such as Wely semimatels are still under theoretical study[1]. We have added comments to these materials in the manuscript. Revisions: Page 1, line 21, added “At present, rare earth doped yttrium iron garnet (RIG) is the most widely used magneto-optical material in integrated MO devices.” Point 2: How will the temperature dependence of the Faraday rotation hysteresis loops of Dy:CeYIG thin films change when moving to another wavelength range?	2	1	By replacing Y3+ ions with Dy3+ ions in Ce:YIG, authors demonstrate less than ±5% variation of the thin film Faraday rotation from the temperature of 25 ℃ to 70 ℃, compared to ~20% in Ce:YIG.			ma15051691_perova	0
735Absoultly there is also temperature dependence of the Faraday rotation when shift to other wavelengths. However, the transparency window of this material is in the 1550 nm wavelength range. When moving to shorter wavelengths, the absorption of this material increases sharply, making them less practical for photonic device applications.	2	1	demonstrate a temperature stable magneto-optical material Dy2Ce1Fe5O12 for silicon integrated nonreciprocal photonic device applications.			ma15051691_perova	0
736previously reported that the compensation temperature of DyIG is Tcomp = 225 K [2,3], which could decrease the Faraday rotation angle of Dy:CeIG in this work at the temperature below 300 K. Therefore, a higher Faraday rotation may be related to the increase of the saturation magnetization of this material in this temperature range. Revisions:Page 5, line 170-173, added “The increase of the Faraday rotation below 40 ℃ is possibly due to the increase of the magnetization of this material at this temperature range, considering a compensation temperature of 225 K in Dy3Fe5O12 [19,20].”. References: Okamura, Y.; Minami, S.; Kato, Y.; Fujishiro, Y.; Kaneko, Y.; Ikeda, J.; Muramoto, J.; Kaneko, R.; Ueda, K.; Kocsis, V.; et al. Giant magneto-optical responses in magnetic Weyl semimetal Co3Sn2S2. Nat Commun 2020, 11, 4619, doi:10.1038/s41467-020-18470-0. Sayetat, F. Huge magnetostriction in Tb3Fe5O12, Dy3Fe5O12, Ho3Fe5O12, Er3Fe5O12 garnets. Journal of magnetism and magnetic materials 1986, 58, 334-346.	2	1	While the Faraday rotation angle appears to decrease more or less linearly with temperature in the Ce:YIG film (as far as can be inferred from the non-linear horizontal scale), the decrease is not taking place at the same rate in the Dy:Ce:YIG film.			ma15051691_perova	0
737We have updated the references and revised this in the context. Revisions: Page 1, line 21, revised to “for silicon integrated photonic circuits (PICs) [1-3].”. Page 1, line 24, revised to “including optical isolators [4-6]”. Page 1, line 41, revised to “which results in reduced bandwidth and isolation ratio [13].”. Page 1, line 45, revised to “in a temperature range of 20-60 ℃ [10].”. Page 5, line 148, revised to “measure the temperature stability of Dy:CeIG and Ce:YIG films[11].”.	2	1	Please check with the editor if this can be fixed.			ma15051691_perova	0
738We have revised this in the context. Revisions: Page 3, line 98, revised to “where is the Faraday rotation angle of MO films at room temperature. is the NRPS at room temperature.” Point 3: Line 111.	2	1	Journal of Applied Physics 1994, 75, 6103-6105.			ma15051691_perova	0
739Thanks for correcting this. “X-ray diffraction spectra” has been revised into “X-ray diffraction patterns”. Revisions: Page 3, line 109, revised to “X-ray diffraction patterns”.	2	1	Please check with the editor if this can be fixed.			ma15051691_perova	0
740Thanks for the commerts. The saturation magnetization of rare-earth doped YIG affects the Faraday rotation angle. Sayetat et al. and Ostorero et al. previously reported that the compensation temperature of DyIG is Tcomp = 225 K [1,2], which could decrease the Faraday rotation angle of Dy:CeIG in this work at the temperature below 300 K. Therefore, a higher Faraday rotation may be related to the increase of the saturation magnetization of this material in this temperature range. Revisions: Page 5, line 170-173, added “The increase of the Faraday rotation below 40 ℃ is possibly due to the increase of the magnetization of this material at this temperature range, considering a compensation temperature of 225 K in Dy3Fe5O12 [19,20].”.	2	1	It is in general well written and the work deserves publication.			ma15051691_perova	0
741Ostorero, J.; Escorne, M.; Pecheron‐Guegan, A.; Soulette, F.; Le Gall, H. Dy3Fe5O12 garnet thin films grown from sputtering of metallic targets. Journal of Applied Physics 1994, 75, 6103-6105. Page 6, revised the horizontal scale of Figure 3 (c) and updated Figure 3 (c). References: Sayetat, F. Huge magnetostriction in Tb3Fe5O12, Dy3Fe5O12, Ho3Fe5O12, Er3Fe5O12 Journal of magnetism and magnetic materials 1986, 58, 334-346.	2	1	"The article ""Dysprosium substituted Ce:YIG thin films for temperature in-2 sensitive integrated optical isolator applications contains the results"" presents a temperature stable magneto-optical material Dy2Ce1Fe5O12 for silicon integrated nonreciprocal photonic device applications."			ma15051691_perova	0
742Thank you for your comment, we have tried to make the abstract less fragmented -Theoretical framework: it is very updated.	2	1	I recommend you to alternate them (text, Figures and Tables in Results).			nu14122489_makarova	0
743Thanks for your comments, we have found a more updated reference (reference 18), cited in lines 96-98 to explain more the importance of HRQoL.	2	1	This study includes a size of 1139 adolescents.			nu14122489_makarova	0
744Line 501-503 We have added that we used a large sample size and that this was powerful enough to detect significant differences within sub-groups. We have also added a further description of our ability to capture results in a snapshot of time. I hope this clarifies this aspect.	2	1	Validity and responsiveness of the EQ-5D and the KIDSCREEN-10 in children with ADHD.			nu14122489_makarova	0
745Thank you for your comment, the updated figures and tables are now at the end of the paper.	2	1	Validity and responsiveness of the EQ-5D and the KIDSCREEN-10 in children with ADHD.			nu14122489_makarova	0
746Thank you for your comment, we are glad that you think so	2	1	Diet diversity score and healthy eating index in relation to diet quality and socio-demographic factors: results from a cross-sectional national dietary survey of Swedish adolescents.			nu14122489_makarova	0
747Thank you for your comments about the instruments and the associated domains. We have updated these and aimed to explain them in more detail and with more clarity, sections 2.5, 2.6 and 2.7 lines 193-196, 215-225, 236-244.	2	1	The issues raised in the well quoted Darmon and Drewnowski paper need to be considered more.			nu14122489_makarova	0
748These issues have been addressed. The tables and figures are more clear and more detailed. We have provided are reasoning for the choices of statistical methods.	2	1	Remember the KQ-10 is made up of five subdomains (psychological well-being, autonomy and parent relation, social support and peers, and school environment) The fact is diet is no expected to change 3 of these KQ-3 subdomains and only one or two KQ-10 dimensions.			nu14122489_makarova	0
749Thank you for this concern. We have aimed to explain that the KS-10 takes items from the longer KS versions but does not measure for each dimension as it is a general score. However, you have made a great point that some associations may be lost on the specific dimensions, we have tried to explain this reasoning such the burden of participation is lower to complete the KS-10 version lines 493-494 . We wanted to use the general score so that results can be compared with other studies and in other countries, which is one of the advantages of KS-10. Thank you for the insight, this has made us reflect on the KS-10 from the longer versions more.	2	1	The important issue is in the method section the reader needs understand the dimensions and sub-dimension that make up within each survey.			nu14122489_makarova	0
750We have now recognised the impact and importance of income to a greater depth and are thankful for your comments on this matter. It is a shame that we cannot say anything about income in this article as this was not measured, only parental education, however this has been suggested for future studies lines 535-537 .	2	1	The term is usually SES social economic status so it should be SES- F if it is social economic status – factors.			nu14122489_makarova	0
751We have now made a recommendation to investigate this in more depth and to compare diet quality between school time and home time. It is important to assess if the lunches are the same across students of different SES, some insight on this is given in lines 522 and 534 and that an issue could be the diet quality provided at home as school lunches may even-out diet-related inequalities. Thank you for the recommendation as this is an important aspect of adolescents’ diet.	2	1	It maybe, it is the cost of living associated with fresh fruit and vegetables that is the real issue.			nu14122489_makarova	0
752Thank you for your comments on this matter, we have edited this and hope it makes more sense now and that it does not make that assumption any longer, see lines 48-50.	2	1	Validity and responsiveness of the EQ-5D and the KIDSCREEN-10 in children with ADHD.			nu14122489_makarova	0
753We understand your concern, there are a lot of abbreviations, the abbreviations have been re-written in each section to help follow the flow, and we have now added an abbreviation and key word table before the introduction to provide additional help for readers, thank you for this comment lines 37-45.	2	1	Reviewer 1: The proposal about “Investigation of the Associations between Diet quality and Health-Related Quality of Life in a Sample of Swedish Adolescents” is attractive.			nu14122489_makarova	0
754Thank you for your great comment, we want the dimensions to be clear for the readers and this is an important observation. We have now edited how the SHEIA and RADDS variables are explained as well as the KS-10, sections 2.5 and 2.6 and we hope they are clearer to understand lines 193-196, 215-225, 236-244.	2	1	Given the findings the researchers could be arguing that a review may be needed with the Swedish school lunch program and increase the level of fruit and vegetables in the students' diet, particularly for students in lower SES locations.			nu14122489_makarova	0
755Thank you for your comments, it is important to mention status and the term SES-F has now been incorporated. We have also now used the term parental education and in section 2.7 we have mentioned that this was used as a proxy for SES, lines 257-258. This is to make it clearer that we only had access to parental education and no other SES-Fs and we hope that this is clearer now, we have used parental education instead of SES in lines 21, 111-114 and 149-150. We have also emphasised the importance of parental income, lines 419-428, 503-506, 533-537 and 550-555.	2	1	There is much about this paper that is of value, but it does need relooking at, particularly in the results reporting to do the research and the data justice.			nu14122489_makarova	0
756Thank you, we agree that income as well as education plays a role in healthy food choices. However, the results in the article we are referring to looked at parental education, not income. As we did not have access to data in parental income, we were not able to include that variable in our paper	2	1	To assist the reader’s comprehension, explain the instruments more as you develop the paper.			nu14122489_makarova	0
757Although a higher education might lead to a higher income we unfortunately do not have the data to look at that but as previously mentioned we have now stressed the importance of parental income, lines 419-428, 503-506, 533-537 and 550-555, thank you for pointing this out.	2	1	Diet diversity score and healthy eating index in relation to diet quality and socio-demographic factors: results from a cross-sectional national dietary survey of Swedish adolescents.			nu14122489_makarova	0
758Thank you for your comment, income is most certainly important and we have now emphasised its importance in lines 419-428, 503-506, 533-537 and 550-555. We also have mentioned that parental education is being used as a proxy for SES lines 257-258 but we cannot infer anything about income as this was not measured, only parental education, not overall SES.	2	1	Diet is not expected to have any influence of parent relations, social relations or peers but your study may find an influence on psychological well-being and even school environment.			nu14122489_makarova	0
759Thank you for suggesting that we reference these two papers, Darmon and Drewnoski was very insightful and most certainly useful for this article, and we now make it clearer that education is a factor of SES and a proxy for income. Lines 419-428 offer an insight into income and affluence, however we have elaborated more on income in future perspectives 533-537 and in the conclusion, lines 550-555 as it may, as you say, play a significant role in these associations.	2	1	The European Journal of Health Economics, 15(9), 967-977.			nu14122489_makarova	0
760Thank you for your comment, we want to make the definition of this index as clear as possible and we have edited this in section 2.5.1 and included the sub-components, lines 193-196. We have also cited that reference in both sections 2.5.1 and 2.5.2 so that readers can find a more detailed description. We have also edited section 2.5.2, lines 215-225 so that the RADDS index is also easier to understand and have mentioned some of the sub-components.	2	1	The conclusion is sound given the findings but the lack of reference to income is an issue as educational status of parents is often a “de-facto” measure for income.			nu14122489_makarova	0
761Thanks for your observation, we have now tried to describe the KS-10 with more details, and to make it clearer, section 2.6, 236-244.	2	1	Schools may be making the lunches to a budget rather than to a healthy diet criteria which is more expensive.			nu14122489_makarova	0
762We are very pleased that you found this interesting!	2	1	2020 Jul;23(10):1754-1765. doi: See their Table 5.			nu14122489_makarova	0
763Thank you for this comment, the figure may have been minimised and red meat and poultry are now visible which may not have been before, apologies for this, also we have mentioned some of the sub-components in lines 215-225. Also the figures and tables became distorted when the manuscript was uploaded, we have fixed this.	2	1	The focus on only the global mean score for the wellness KQ-10 measure rather than the 5 dimensions.			nu14122489_makarova	0
764Thank you for your comment. However, we think chi-squared is the appropriate statistical test as we are only comparing the proportions of distribution between categorical variables, we are not comparing the means between more than two groups which is what ANOVA is used for. We have not used chi square to assess analysis of variance, we have now made it clearer that frequency distribution is being assessed in the statistical methods section In terms of gender and education: the mean, standard deviation, df and sig t or F test need to be reported in the tables.	2	1	It needs minor revision in places but the results need more attention.			nu14122489_makarova	0
765Thanks for this comment, we have incorporated t and df scores, see tables 1 and 4.	2	1	(Tabachnick, B.G., Fidell, L. S., & Ullman, J.B. (2007).			nu14122489_makarova	0
766This has been put in the appendix, table A1, page 18, thanks for the suggestion The regression analyses “p” value is reported, but the beta values and significance must also be reported.	2	1	This is the core of your study: does diet have an influence on psychological wellbeing?			nu14122489_makarova	0
767Great that you mentioned the beta values, the coefficients in the tables are in fact unstandardised beta coefficient values, this has been made clearer in the tables. The tables have diet (ind variable) on the left and the dependent variable KS-10 is on the top to indicate that interaction, then this is stratified by gender. I hope this makes more sense now.	2	1	For while gender and in this study education are categorical (group) the data being evaluated is continuous and interval data and so an ANOVA or MANOVA by group is the method of analysis of variance.			nu14122489_makarova	0
768We had a problem with uploading the figures and they became distorted, thank you for your comments, we have fixed this and incorporated t and df values.	2	1	Remember the KQ-10 is made up of five subdomains (psychological well-being, autonomy and parent relation, social support and peers, and school environment) The fact is diet is no expected to change 3 of these KQ-3 subdomains and only one or two KQ-10 dimensions.			nu14122489_makarova	0
769We appreciate your concern regarding the KS-10 item domains. The reason we chose to use the general item value is that it is less burdensome than the longer versions and it is best practice to use the general score and not to directly try to analyse for each dimension. We are not sure that it is a fact that diet can not influence parent relations or social relations, if diet can help to improve quality of life then this may improve how an adolescent feels and their emotions which ultimately may have an influence on relations to others. However, we realise that we may miss out other findings and have mentioned this as a limitation, lines 496-497 and we appreciate your views on this matter. We have also incorporated more information about KS-10 reliability in measuring HRQoL, 236-244This is also a cross sectional study and so only associations can be established not causations.	2	1	Given the findings the researchers could be arguing that a review may be needed with the Swedish school lunch program and increase the level of fruit and vegetables in the students' diet, particularly for students in lower SES locations.			nu14122489_makarova	0
770Great comments, we have elaborated more on income, lines 419-428, 503-506, 533-537 and 550-555. We have also included a detailed section about the significance of school lunches and education in Sweden across different SES groups lines 528-532. In Sweden the school lunch is of rather high diet quality, reaching many of the national dietary recommendations and is provided free of charge regardless of income or SES. However, it would be insightful to a complete a deeper analysis investigating the differences of school quality across differing socio-demographic areas. Nonetheless, the problem related to diet quality may lie in the food provided at home as financial constraints are most likely to be of more significance, lines 528-534.	2	1	Given you are using education of parents as the status measure of SES the term status is important in this paper and should not be dropped.			nu14122489_makarova	0
771The definition of glaucomatous visual field loss was elaborated in the corresponding reference. However, we agree that we were very brief in explaining glaucomatous visual field loss in the manuscript. Therefore we made the following changes to elaborate: In lines 89-98, we changed: “iOAG was defined as glaucomatous visual field loss in at least one eye with reproducibility of the defect, independent of IOP” To: “All participants underwent visual field testing using the Humphrey Field Analyzer (HFA; Carl Zeiss Meditec, Jena, Germany). A second supra-threshold test was performed when a visual field defect appeared to be present. Details have been described elsewhere. [1] If the second supra-threshold test showed at least one overlapping abnormality in the same hemifield, Goldmann kinetic perimetry (RS-I-1 and RS-I-3; Haag-Streit) or full-threshold HFA (all other cohort visits) was performed on both eyes. If abnormalities were consecutive and reproducible, thus present on the Goldmann or full-threshold test and on both supra-threshold tests, visual field loss was considered to be present. Defects had to be in a consistent hemifield and a least one depressed test point had to have exactly the same location on all fields.” In lines 98-100, we changed: “All other possible causes of visual field loss were excluded.” To: “Glaucoma specialists examined fundus photographs, ophthalmic examination reports, medical histories, and MRI scans of the brain to exclude all other possible causes of visual field loss. Discrepancies were resolved by consensus.” In lines 103-104, we added: “For IOP, three measurements were taken from each eye, of which the median value was recorded. [2] For iOAG cases, we used IOP measurements of the affected eye. If both eyes were affected or unaffected, a random eye was selected. IOP was not included in the definition of iOAG.” Was glaucoma also defined by an objective finding, such as the optic disc finding or imaging of the optic disc?	2	1	How big is the nitrate association compared to these?			nu14122490_perova	0
772OCT images were taken with SD-OCT (Topcon Corp., Tokyo, Japan) since 2007. This means that OCT images are not available for the first four visits of RS-I, and the first two visits of RS-II. Additionally, only part of the images are focused on the disc and even less are reliably segmented. Fundus images were available and were used rather to exclude other cases of visual field loss in participants that showed visual field defects than to observe optic disc abnormalities.	2	1	Cancer Epidemiol Biomarkers Prev 2005, 14, 483-490.			nu14122490_perova	0
773Thank you for this comment. We understand that it might be useful to present the number of treated glaucoma cases in our baseline characteristics table. Unfortunately, detailed information on prior treatment/surgery for glaucoma is limited (only present for RS-I), and therefore we did not include this variable as covariate in our models. It is thus possible that incident glaucoma cases have received treatment for glaucoma in between two research visits. However, since all participants were (confirmed by examination) free of OAG at baseline, treatment for glaucoma could not have been longer than maximum of one follow-up visit. Although not having this data is a limitation of this study, we do not think it is an important confounding factor, since we do not expect that glaucoma treatment would influence one’s diet. More importantly, dietary information was collected at baseline, with all participants free of OAG. Therefore, if glaucoma presence or glaucoma treatment would have an effect on dietary intake, this would not be applicable in our study. We have added a short sentence explaining this in lines 312-316 of the manuscript.	2	1	Chapter Material and Methods contain all necessary information.			nu14122490_perova	0
774We agree that, although our findings confirm earlier reported associations between dietary nitrate intake and OAG, intervention studies are necessary to investigate and confirm the association between dietary nitrate intake and iOAG. Therefore, we will change all references to “protective (effect)” to “association/associated with”.	2	1	"Reviewer #1 We would like to thank the reviewer for reviewing our manuscript entitled “Dietary nitrate intake is associated with decreased incidence of open-angle glaucoma: The Rotterdam Study"" (MS# nutrients-1760125)."			nu14122490_perova	0
775Thank you for this suggestion. Although the evidence for the association between ischemia--reperfusion and glaucoma pathogenesis might be scarce, this is only one possible pathway that is addressed in explaining the inverse association between dietary nitrate intake and glaucoma incidence. Nevertheless, we will adjust the manuscript (lines: 271-288) so that this statement is less strong and the focus is more on (a combination with) other pathways, rather than this pathway alone.	2	1	; Vingerling, J.R.; Jansonius, N.M. Heidelberg Retina Tomograph (HRT3) in population-based epidemiology: normative values and criteria for glaucomatous optic neuropathy.			nu14122490_perova	0
776We agree that the baseline dates of all three cohorts (RS-I, 1991-1993; RS-II, 2000-2001; RS-III, 2006-2008) are already quite some years ago and that dietary patterns in general have changed over time. However, since dietary recommendations are not standard of care for glaucoma patients, we believe that this would likely lead to non-differential misclassification (that causes a bias towards the null hypothesis), since we would expect that glaucoma cases would change their diet similarly to our control population and vice versa. We thus feel that this study and its findings are still highly relevant today since nutrition has become ever more important in medical sciences. Ophthalmology is one of the disciplines which has gained enormous insights from these recent developments. However, to date, no nutritional recommendations have been made for glaucoma patients and research into the association between nutrition (on each level, e.g. diets, food groups, nutrients) and glaucoma is scarce. If associated, this may support diet recommendations in patients that show first signs of developing glaucoma and/or people at-risk for glaucoma as well, impacting millions of people worldwide. Especially since diet changes into a vegetarian of vegan diet are becoming more popular, we think that understanding the potential beneficial effects of these changes, thus the effects of vegetables and their nutrients, is more important than ever. We do agree that these findings should be replicated or validated in another (preferably, an intervention study) study before dietary nitrate intake should be considered as an important public health implication. To address your question about the change of dietary patterns over time more thoroughly: Dinnisen et al. [6] recently published an article in Nutrients where they described changes in dietary intakes of Dutch adults between 2007-2010 and 2012-2016, and evaluated these changes by age, gender, and education. They demonstrated that there was no significant increase in vegetable intake for Dutch adults aged 19–69 years between 2007–2010 (n = 2106; DNFCS 2007–2010) and 2012–2016 (n = 1540; DNFCS 2007–2010) for the total population. There was also no difference when they compared the change in vegetable intake over time per sex or per age category (51-69 years being closest to the baseline age used in our study). Only in the group with the highest educational level, the mean consumption of vegetables increased over time. However, since there was no significant difference in education level in our study between cases and controls (Table 1), we assume that changes in vegetable intake would be similar between both groups, leading to non-differential misclassification. Moreover, we adjusted for education level in our additional model. Regarding dietary nitrate intake from non-vegetable sources, this article states that the intake of red or processed meat decreased over time. This was applicable to both males and females and seen for all age groups. Again, we would expect that this decrease is similar for glaucoma cases and controls. Another Dutch study [7], starting in 1986 (which is more close to the first visit of RS-I) stated that “Another potential limitation that should be considered is whether the food frequency questionnaire at baseline was a reliable estimate of past and future diet. The stability of dietary habits over time was evaluated from five annually repeated questionnaire administrations in independent random samples of the cohort. The mean intakes barely changed and the correlation between two measurements decreased only slightly over an increasing time interval. It was concluded that the single food frequency questionnaire measurement characterizes dietary habits for a period of at least 5 to 10 years.” [8] Nevertheless, since both studies are not directly translatable to the Rotterdam Study, we have assessed the association between the dietary nitrate intake and iOAG over cumulative follow-up periods to provide insight into the stability of the found estimates over time. Please see our comment regarding your next suggestion for more details.	2	1	; Hofman, A.; Vingerling, J.R.; Hitchings, R.A.; de Jong, P.T.			nu14122490_perova	0
777We agree that the lack of follow-up food questionnaires is a major limitation of this study. Please find an additional supplementary figure (Figure S1; original Figure S1 has now become Figure S2) below and in the supplements of the manuscript, to show that we assessed the association between the dietary nitrate intake and iOAG over cumulative follow-up periods (x-axis) to provide insight into possible reversed causality. The persistence of the association over time implies that reverse causality is unlikely. The effect of (baseline) dietary nitrate intake on glaucoma appears to be relatively stable over time. We therefore consider our results reliable, although we agree limitations are present and these findings should be interpreted with caution. In addition to the new supplementary figure, we have added information about this analysis to the methods (lines 152-153), results (209-211), and discussion (296-298).	2	1	Past studies of the Rotterdam population mention several other risk factors which were not taken into account in this study including myopia, cup-to-disc ratio, and family history of glaucoma, as well as other features such as exfoliation.			nu14122490_perova	0
778Thank you very much for assessing the covariates included in these analyses so thoroughly. Unfortunately, family history of glaucoma was only available for a subset of the first cohort, and not for the second and third cohort. Therefore, we were unable to include this variable as a covariate, as this would severely limit our power (528 participants of 1038 participants; 133 glaucoma cases and 389 controls). As cup-to-disc ratio is highly correlated with glaucoma diagnosis, we feel that cup-to-disc ratio should not be included in the model. Moreover, cup-to-disc ratio is not associated with dietary nitrate intake, and therefore cannot be considered as confounding factor. By including cup-to-disc ratio into the model, we would adjust the association between dietary nitrate intake and glaucoma by “glaucoma presence” and thus diminish any existing association. To meet your comment/suggestion, we have added baseline spherical equivalent (proxy for myopia, excluding aphakic or pseudophakic participants) to model 3. As you can see in the results below (original results visualized in Figure 2 in the manuscript), adjusting additionally for SE did not change the results of the continuous nitrate intake analyses and did only marginally change the results of the quintile analyses, leading to a more significant finding for Q5 as compared to Q1. Because both analyses are similar, and since myopia is associated with education level, we chose to keep the original model 3 in the manuscript, adjusting for education level, but without adjustment for SE. To address your question, in lines 318-323, we will change: “Finally, although the analyses were adjusted for several confounders, residual confounding cannot completely be excluded.” To: “Although the analyses were adjusted for multiple confounders, we were unable to adjust for other possible confounders such as family history of glaucoma due to a lack of data. We did consider the risk factor myopia, for which we adjusted by including education level into model 3. We also included spherical equivalent into the model (data not shown), but this did not change the results. Lastly, residual confounding cannot completely be excluded.” Original model 3: model 1 additionally adjusted for education level and smoking status.	2	1	"The authors should avoid making statements such as ""nitrate is protective"" since what they have found is a statistical association."			nu14122490_perova	0
779In the introduction section we have suggested that dietary nitrate might have both IOP-dependent, or blood pressure dependent, and IOP-independent effects that could affect glaucoma risk. Unfortunately, we were only able to assess the effect of dietary nitrate intake on IOP and blood pressure. In the most ideal situation, we would have assessed the effect of dietary nitrate intake on retinal nerve fiber layer (RNFL) thickness. Unfortunately, due to limitations as described above, we were not able to do so. Since we found no significant effects of dietary nitrate intake on IOP and blood pressure, we suggest that IOP-independent effects of dietary nitrate intake might influence glaucoma risk. This should be further investigated in future studies.	2	1	How big is the nitrate association compared to these?			nu14122490_perova	0
780We would like to thank the reviewer for this interesting comment. In the Rotterdam Study we indeed find an inverse association between BMI and OAG incidence (Table 1). When we divide the participants in three categories based on their BMI (BMI < 18.5, BMI 18.5-24.9, or BMI >= 24.9), the difference between cases and controls is still (borderline) significant (p=0.054), with more people being overweight (68.7%) in the control group than in the glaucoma group (59.3%). The finding that BMI is inversely associated with OAG is in line with previous studies. Lin et al. [1] found that lower BMI was associated with increased odds of OAG, especially in younger females. Ramdas et al. found similar results, with an association between obesity and a lower risk of developing OAG, although only present in women. [2] In line with these findings, underweight was associated with increased risk of primary OAG in diabetes patients. [3] Moreover, in a group of patients in which visual field loss progressed despite treatment with eye drops, lower BMI was associated with progression of visual field loss in normal-tension glaucoma patients. [4] One possible explanation for this is that cerebrospinal fluid pressure (CSFP) has a positive, linear relationship with BMI. [5] As reduced CSFP may be a risk factor for primary OAG, individuals with lower BMI may have an increased risk for developing primary OAG. [6] Again, a higher BMI may be protective. We acknowledge that BMI is an important confounder in our study, as BMI is associated with both our outcome (OAG) and exposure (diet). We have therefore included BMI as covariate in our main model. Adding or removing BMI from the multivariate model (model 1) did not change the results, as can be seen in the table below. That the association did not change after adjustment for BMI suggests that the association between dietary nitrate intake and OAG cannot be explained by BMI, although residual confounding may persist. To account for a possible effect of BMI on the association between dietary nitrate intake and OAG, we performed additional matching. We returned to the original dataset and matched cases and controls based on age (3-years range) and sex, as done previously, and additionally for BMI (2 kg/m2 range). Please see below for the “new” baseline characteristics table. Once the participants have been matched on age, sex and BMI, you can see that none of the covariates included in the models are significant between iOAG cases and controls. Cases only have a significantly higher IOP, which is expected, and somewhat shorter follow-up (not surprising, since they are excluded one they are diagnosed with iOAG). Diastolic blood pressure, BMI, and the dietary nitrate intakes are no longer different in the univariate analyses between cases and controls. We have created two supplementary tables (Table S4 and Table S5), to show that the associations found between dietary nitrate intake and iOAG or IOP, were largely similar in the analyses where we matched on BMI additionally, as compared to including BMI as covariate into model 1. Only the association between dietary nitrate intake from non-vegetable food sources and iOAG is no longer significant, but the change in effect estimates was minimal and they remained far below 1 (Table S4). For the analyses of IOP, the association between dietary nitrate intake from non-vegetable food sources goes from borderline significant to significant (Table S5). Table S4. Multivariable adjusted odds ratio (95% confidence interval) of open-angle glaucoma by nitrate intake ORa per 1 unit increase in nitrate intakec P-value Total dietary nitrate intake (per 10 mg/day) Model 1a 0.95 (0.91-0.98) .002 Model 1b 0.96 (0.92-0.99) .03 Vegetable dietary nitrate intake (per 10 mg/day) Model 1a 0.95 (0.91-0.98) .004 Model 1b 0.96 (0.92-0.99) .03 Nitrate intake from non-vegetable food sources (per 10 mg/day) Model 1a 0.63 (0.41-0.96) .03 Model 1b 0.76 (0.49-1.17) .22 a Model 1: adjusted for body mass index, total energy intake, diet quality, physical activity, and follow-up time. Analysis performed in participants matched on age and sex. b Model 1: adjusted for total energy intake, diet quality, physical activity, and follow-up time. Analysis performed in participants matched on age, sex and BMI. c Odds Ratios (95%CI) for open-angle glaucoma by total dietary nitrate intake, nitrate intake from vegetables, and nitrate intake from non-vegetable food sources (as continuous variables) analyzed using conditional logistic regression. Table S5. Multivariable adjusted beta (95% confidence interval) of intraocular pressure by nitrate intake Betaa per 1 unit increase in nitrate intakec P-value Total dietary nitrate intake (per 10 mg/day) Model 1a 0.02 (-0.02-0.06) .35 Model 1b 0.00 (-0.06-0.05) .89 Vegetable dietary nitrate intake (per 10 mg/day) Model 1a 0.02 (-0.02-0.06) .29 Model 1b 0.00 (-0.05-0.05) .97 Nitrate intake from non-vegetable food sources (per 10 mg/day) Model 1a -0.45 (-0.96-0.06) .09 Model 1b -0.67 (-1.30- -0.05) .04 a Model 1: adjusted for body mass index, total energy intake, diet quality, physical activity, and follow-up time. Analysis performed in participants matched on age and sex. b Model 1: adjusted for total energy intake, diet quality, physical activity, and follow-up time, Analysis performed in participants matched on age, sex and BMI. c Betas (95%CI) for intraocular pressure by total dietary nitrate intake, nitrate intake from vegetables, and nitrate intake from non-vegetable food sources (as continuous variables) analyzed using linear regression. By displaying these results, we hope to have shown that the associations described in the original manuscript are most likely true associations and explained by dietary nitrate intake rather than age, sex, or BMI. Although an association between glaucoma and cardiovascular disease has been described in the literature [7-9], we believe this is more linked to their shared pathology, impaired auto regulatory capacity of glaucomatous eyes and arterial stiffness of CVD [7], or even genetics [10], than mediated by BMI. Apart from the two additional supplementary figures, we have added some information regarding this comment in lines 301-304 of the manuscript.	2	1	Graefes Arch Clin Exp Ophthalmol 1994, 232, 141-144.			nu14122490_perova	0
781I added a table listing the baseline characteristics, including BMI and smoking status, of subjects.	2	1	"Dear Authors: I appreciate the possibility to review the paper entitled ""Exploration of an inflection point of ventilation parameters with anaerobic threshold using strucchange"" by the authors Aida et al."			s22072682_perova	0
782Since this study focuses on AT search, detailed estimation of sample size is not performed. I added in data analysis section.	2	1	1 Response to Reviewer 2 Comments Comments 1 -The paper's aim should be the same in the abstract and the introduction.			s22072682_perova	0
783Project identification code is H29-4. I added in 2.1.subjects and 6.patents.	2	1	In this paper, using a maximal exercise test on a cycle ergometer, it is proposed to determine the anaerobic threshold using the strucchange analysis of the time series and compare it with the V slope method and the respiratory and metabolic indexes proposed by Wasserman.			s22072682_perova	0
784My manuscript is checked by an English proofreader. I will attach an English proofreading certificate.	2	1	Comments 4 - In figure 3, the indication of the test time appears in the reverse direction.			s22072682_perova	0
785I described the paper's aim.	2	1	However, I would like to make a few comments.			s22072682_perova	0
786I redraw Figures1-2 and described them as an adaptation of the original publication.	2	1	However, I would like to make a few comments.			s22072682_perova	0
787I described baseline load of the participants.	2	1	1 Response to Reviewer 2 Comments Comments 1 -The paper's aim should be the same in the abstract and the introduction.			s22072682_perova	0
788I revised Fig3.	2	1	Response 2 I redrew Figures 1 and 2 and described them as an adaptation of the original publication.			s22072682_perova	0
789I deleted Fig5,8,11.	2	1	Comments 3 - The methods do not specify how the baseline load of the participants was determined.			s22072682_perova	0
790The manuscript is well written, the results support the hypotheses.			Author Response Thank you again for taking time to review our manuscript and provide valuable constructive feedback, which has improved the quality of our work submitted.			antiox11040683_perova	0
791Author Response Thank you again for taking time to review our manuscript and provide valuable constructive feedback.			The manuscript is well written, the results support the hypotheses.			antiox11040683_perova	0
792We agree with your comments and have addressed these to the best of our ability in the revised manuscript.			The Authors showed the role of the BCAT1 CXXC motif in AML and to understand how this may influence cellular redox processes.			antiox11040683_perova	0
793We agree with your comments and have addressed these to the best of our ability in the revised manuscript.			The Authors showed the role of the BCAT1 CXXC motif in AML and to understand how this may influence cellular redox processes.			antiox11040683_perova	0
794Authors addressed all my requests and suggestions to my fullest satisfaction.			Author Response Thank you again for taking time to review our manuscript and provide valuable constructive feedback.			antiox11040683_perova	0
795The manuscript is well written, the results support the hypotheses.			Author Response Thank you again for taking time to review our manuscript and provide valuable constructive feedback, which has improved the quality of our work submitted.			antiox11040683_perova	0
796Author Response Thank you again for taking time to review our manuscript and provide valuable constructive feedback, which has improved the quality of our work submitted.			Author Response Thank you again for taking time to review our manuscript and provide valuable constructive feedback, which has improved the quality of our work submitted.			antiox11040683_perova	0
797"The following sentence has been added at the end of Conclusion: ""For future work we will develop variable stiffness techniques of this joint, and explore its application in a robot arm considering both kinetostatic and transient behaviors."""			As compared to Ref. [19] which focuses on concepts and demonstrations, this work mainly focuses on analytical modeling of one design concept and provides finite element and experimental validations.			app12052642_makarova	0
798[19], this paper proposed a DL-LET joint by fixing a layer of flexible H18 aluminum foil a LET joint.			In conclusion the paper deserves to be acceped as contribution in Applied Science journal.			app12052642_makarova	0
799"A theoretical model is derived for the DL-LET joint and verified by FEA and experimental results."""			[19], this paper proposed a DL-LET joint by fixing a layer of flexible H18 aluminum foil a LET joint.			app12052642_makarova	0
800o Hybrid Data-Driven Fuzzy Active Disturbance Rejection Control for Tower Crane Systems, European Journal of Control, vol. 58, pp.			In conclusion the paper deserves to be acceped as contribution in Applied Science journal.			app12052642_makarova	0
801Author Response Thanks a lot for your encouragement and suggestion.			"At the beginning of the last paragraph of Introduction: ""In this work, based on the design concept of improving the tensile stiffness of LET joints in Ref."			app12052642_makarova	0
802Chen, G.; Ma, F.; Hao, G.; Zhu, W. Modeling large deflections of initially curved beams in compliant mechanisms using 277 chained Beam-Constraint-Model, ASME J. Mech.			o Hybrid Data-Driven Fuzzy Active Disturbance Rejection Control for Tower Crane Systems, European Journal of Control, vol. 58, pp.			app12052642_makarova	0
803Following the reported physical experiments (Fig.			Author Response Thanks for your encouragement and suggestion.			app12052642_makarova	0
804The flow of the paper or the organization of the paper has to be presented at the end of the introductory section.			Author Response Thanks a lot for your encouragement and suggestion.			app12052642_makarova	0
805However, the transient analysis requires relevant parameters of the robot arm be determined besides the parameters of the joint.			However, the transient analysis requires relevant parameters of the robot arm be determined besides the parameters of the joint.			app12052642_makarova	0
806Author Response Thanks a lot for your encouragement and suggestion.			In conclusion the paper deserves to be acceped as contribution in Applied Science journal.			app12052642_makarova	0
80710 + description) steady state inverstigation is acceptable.			What new capacities and abilities so created by this evolutionary jump Aside from that the article is solidly researched and is useful as a source of technology development			app12052642_makarova	0
808"At the beginning of the last paragraph of Introduction: ""In this work, based on the design concept of improving the tensile stiffness of LET joints in Ref."			10 + description) steady state inverstigation is acceptable.			app12052642_makarova	0
809Following the reported physical experiments (Fig.			As compared to Ref. [19] which focuses on concepts and demonstrations, this work mainly focuses on analytical modeling of one design concept and provides finite element and experimental validations.			app12052642_makarova	0
810“In the equations of motion for the atoms [Eqs.			Analytic approximations of the effective trapping forces give some insight into the origin of the special form of the optical potential and delineate the regimes in which random walks are expected to occur.The proposal of this somewhat unconventional random-walk regime in cavity-QED is interesting and deserves publication.			atoms3030433_makarova	0
811In this respect the Authors meet their goal to provide a possible quantum optical setting for the observation of a classical random walk.			The numerical and analytical analysis is thorough, and the manuscript is quite well written.			atoms3030433_makarova	0
812The numerical and analytical analysis is thorough, and the manuscript is quite well written.			"“Page 5, first column, second paragraph ""... one can inspect Eq."			atoms3030433_makarova	0
813The manuscript is generally well organized and clearly written.			What is, if any, the role of gamma (spontaneous atomic decay rate) in the physical process under consideration?			atoms3030433_makarova	0
814"“Page 5, first column, second paragraph ""... one can inspect Eq."			"(4), the Authors write ""We proceed in a standard way to derive equations of motion for classical quantities."""			atoms3030433_makarova	0
815"“Page 6, ""Optical forces"": there is a missing subscript L in the first force term at the end of the first paragraph, just before Eq."			However, the Authors outline possible generalizations to the quantum regime in the concluding section.			atoms3030433_makarova	0
816Numerical simulations predict quasi-random jumps to neighbouring lattice sites at regular time intervals leading to diffusive motion over long times.			The same argument (dimensional analysis) applies to Eqs.			atoms3030433_makarova	0
817Therefore, the manuscript is worthy of publication.			Indeed, the same Authors already refer to the single trajectory plot as Fig.			atoms3030433_makarova	0
818However, the Authors outline possible generalizations to the quantum regime in the concluding section.			The manuscript is generally well organized and clearly written.			atoms3030433_makarova	0
819The resulting trajectory closely resembles a random walk.			I would suggest to provide a reference to guide the less experienced reader.”			atoms3030433_makarova	0
820The manuscript is generally well organized and clearly written.			Analytic approximations of the effective trapping forces give some insight into the origin of the special form of the optical potential and delineate the regimes in which random walks are expected to occur.The proposal of this somewhat unconventional random-walk regime in cavity-QED is interesting and deserves publication.			atoms3030433_makarova	0
821The numerical and analytical analysis is thorough, and the manuscript is quite well written.			R4 However, I have a few comments and suggestions to improve the overall quality and readability of the paper.			atoms3030433_makarova	0
822"“At the end of Section IV C. ""Optical forces"" the time independent value of the force is derived."			The resulting trajectory closely resembles a random walk.			atoms3030433_makarova	0
823The simultaneous driving at two different frequencies gives rise to interference terms in the optical force acting on the particle.			"Please, eliminate ""b)"" since it is simply Eq."			atoms3030433_makarova	0
824However, the Authors outline possible generalizations to the quantum regime in the concluding section.			The resulting trajectory closely resembles a random walk.			atoms3030433_makarova	0
825“Figure 8, Force correlation functions and numerical solutions of the variance: when printed in grey scale some lines are very faint (especially those in green and cyan).			“Figure 4 is mentioned in the main text AFTER Fig.			atoms3030433_makarova	0
826I suspect it should be [sigma^+,sigma^z] = - 2 sigma^+ and [sigma^-,sigma^z] = + 2 sigma^- .”			“Page 4, first paragraph, the particle initial conditions are chosen in the interval [ - 0.1, 0.1] (in the text a comma is missing).”			atoms3030433_makarova	0
827I wonder if one can draw any conclusion from the numerical simulations, where other regimes could have been explored.”			I would suggest to provide a reference to guide the less experienced reader.”			atoms3030433_makarova	0
828“Page 4, first paragraph, the particle initial conditions are chosen in the interval [ - 0.1, 0.1] (in the text a comma is missing).”			"“Page 5, first column, second paragraph ""... one can inspect Eq."			atoms3030433_makarova	0
829I'm afraid there is a factor k missing (simple dimensional analysis shows that something is wrong with it).			"“In section VI E. ""Trapping by longitudinal pumping"", one can analytically estimate the threshold value for the transverse pumping."			atoms3030433_makarova	0
830"The authors presented the paper ""Human Serum Proteins and Susceptibility of Acinetobacter baumannii to Cefiderocol: role of iron transport""."			Author Response Author’s Response: We appreciate the reviewers’ comment and the suggestion.			biomedicines10030600_perova	0
831Author Response Author’s Response: We appreciated the reviewers’ comment.			The authors extensively study the effects of human serum, human serum albumin, or human pleural fluid on Cefiderocol sensitivity of a panel of A. baumanii strains.			biomedicines10030600_perova	0
832Author Response Author’s Response: We appreciated the reviewers’ comment.			Author Response Author’s Response: We appreciate the reviewers’ comment and the suggestion.			biomedicines10030600_perova	0
833However, as we explained in the text, when participants were sorted into two groups (early and late I-waves), the difference between the two was not significant according to the Mann-Whitney U test.			Please do not define aMT the second time in line 134.			brainsci11121640_makarova	0
834In my opinion, the major potential issues were already discussed in the limitation sections.			Line 145 - Edit the subheading Results Are there differences in stimulation intensities taken from the two devices (Magstim Rapid and BiStim2)?			brainsci11121640_makarova	0
835Looking again at Figure 3, we can observe very high variability.			Some questions please need authors to answer.			brainsci11121640_makarova	0
836Some questions please need authors to answer.			Would it be interesting if the present data can give the same effect size (0.71) as those reported by Chung et al. (2016)?			brainsci11121640_makarova	0
837The present study entitled “Facilitation of motor evoked potentials in response to a modified 30 Hz intermittent theta-burst stimulation protocol in healthy adults” investigated the effectiveness of intermittent 30 Hz/6 Hz TBS in inducing lasting facilitation of MEPs.			However, looking at Figure 3, it is obvious that plotted data were from 20 participants.			brainsci11121640_makarova	0
838The single-pulse TMS elicited 20 MEPs at baseline but at three specific time points after post-iTBS (i.e., 5-, 20- and 45-min) just elicited 15 MEPs respectively.			Discussion Line 402: in SIFC, one pulse is suprathreshold, and the other is subthreshold.			brainsci11121640_makarova	0
839I only have minor comments and questions that the author should answer to improve the manuscript.			Some questions please need authors to answer.			brainsci11121640_makarova	0
840Line 145 - Edit the subheading Results Are there differences in stimulation intensities taken from the two devices (Magstim Rapid and BiStim2)?			Please do not define aMT the second time in line 134.			brainsci11121640_makarova	0
841In my opinion, plus or minus 10% is arbitrary.			However, as we explained in the text, when participants were sorted into two groups (early and late I-waves), the difference between the two was not significant according to the Mann-Whitney U test.			brainsci11121640_makarova	0
842Do you think 30 Hz/6 Hz TBS protocol (intermittent mode) increased MEP amplitude as compared to 50 Hz/ 5 Hz standard iTBS?			I only have minor comments and questions that the author should answer to improve the manuscript.			brainsci11121640_makarova	0
843Although the differences in handedness would not profoundly affect the overall results, can the author check if there were significant differences in stimulation intensity (AMT and RMT) in right and left-handed participants?			Does the participants have a neurological disease or other diseases?			brainsci11121640_makarova	0
844Line 145 - Edit the subheading Results Are there differences in stimulation intensities taken from the two devices (Magstim Rapid and BiStim2)?			Actually, we did, but it seems that the new figure legend with the correction was not properly inserted when the system reformated the document.			brainsci11121640_makarova	0
845(2012) would lead to lasting MEP facilitation.			The present study entitled “Facilitation of motor evoked potentials in response to a modified 30 Hz intermittent theta-burst stimulation protocol in healthy adults” investigated the effectiveness of intermittent 30 Hz/6 Hz TBS in inducing lasting facilitation of MEPs.			brainsci11121640_makarova	0
846Although we would assume that the figure on the left is always the letter “A” and the one on the right is “B”, for the sake of clarification, kindly add a letter legend on the figures.			"In line 119, the capital ""a"" changes lower case."			brainsci11121640_makarova	0
847The coefficient of determination is for the regression analysis and indicates that Lat differences were significant predictors of MEP facilitation.			What are the benefits of 30 Hz/6 Hz TBS protocol (intermittent mode) in comparison with 50 Hz/ 5 Hz standard iTBS?			brainsci11121640_makarova	0
848Does the participants have a neurological disease or other diseases?			In line 209, the authors reported that “Of 21 participants, 19 (13 females) completed the protocol without any issues.			brainsci11121640_makarova	0
849Do you think 30 Hz/6 Hz TBS protocol (intermittent mode) increased MEP amplitude as compared to 50 Hz/ 5 Hz standard iTBS?			Is the cut-off plus or minus 10 standard for the responder and non-responders?			brainsci11121640_makarova	0
850However, looking at Figure 3, it is obvious that plotted data were from 20 participants.			Actually, we did, but it seems that the new figure legend with the correction was not properly inserted when the system reformated the document.			brainsci11121640_makarova	0
851In line 282, the result showed r2 = 0.24, p = 0.03 but it is a difference in Fig. 5.			Looking again at Figure 3, we can observe very high variability.			brainsci11121640_makarova	0
852Methods Participants Did the authors take note of the menstrual cycle of the female participants?			"Introduction Line 31 – ""(4-10 Hz) induced…"" this is not theta range; please correct."			brainsci11121640_makarova	0
853In my opinion, the major potential issues were already discussed in the limitation sections.			What are the benefits of 30 Hz/6 Hz TBS protocol (intermittent mode) in comparison with 50 Hz/ 5 Hz standard iTBS?			brainsci11121640_makarova	0
854Do you think 30 Hz/6 Hz TBS protocol (intermittent mode) increased MEP amplitude as compared to 50 Hz/ 5 Hz standard iTBS?			Would it be interesting if the present data can give the same effect size (0.71) as those reported by Chung et al. (2016)?			brainsci11121640_makarova	0
855This study investigated whether the modified 30 Hz/6 Hz TBS protocol (intermittent mode) proposed by Goldsworthy et al.			"In line 119, the capital ""a"" changes lower case."			brainsci11121640_perova	0
856Actually, we did, but it seems that the new figure legend with the correction was not properly inserted when the system reformated the document.			However, as we explained in the text, when participants were sorted into two groups (early and late I-waves), the difference between the two was not significant according to the Mann-Whitney U test.			brainsci11121640_perova	0
857The authors reported that the modified iTBS protocol facilitated MEPs for up to 45 min post-stimulation and that small latency differences were predictive of the facilitatory effect on corticospinal excitability.			Two female participants had to be excluded….”.			brainsci11121640_perova	0
858I only have minor comments and questions that the author should answer to improve the manuscript.			In line 282, the result showed r2 = 0.24, p = 0.03 but it is a difference in Fig. 5.			brainsci11121640_perova	0
859In my opinion, the major potential issues were already discussed in the limitation sections.			Why did not compare to the sham stimulation group and 50 Hz/ 5 Hz standard iTBS protocol?			brainsci11121640_perova	0
860What are the benefits of 30 Hz/6 Hz TBS protocol (intermittent mode) in comparison with 50 Hz/ 5 Hz standard iTBS?			Although you state you defined the rMT in Fig. 1 you did not.			brainsci11121640_perova	0
861Two female participants had to be excluded….”.			Although we would assume that the figure on the left is always the letter “A” and the one on the right is “B”, for the sake of clarification, kindly add a letter legend on the figures.			brainsci11121640_perova	0
862Although we would assume that the figure on the left is always the letter “A” and the one on the right is “B”, for the sake of clarification, kindly add a letter legend on the figures.			The coefficient of determination is for the regression analysis and indicates that Lat differences were significant predictors of MEP facilitation.			brainsci11121640_perova	0
863Some questions please need authors to answer.			However, as we explained in the text, when participants were sorted into two groups (early and late I-waves), the difference between the two was not significant according to the Mann-Whitney U test.			brainsci11121640_perova	0
864The present study entitled “Facilitation of motor evoked potentials in response to a modified 30 Hz intermittent theta-burst stimulation protocol in healthy adults” investigated the effectiveness of intermittent 30 Hz/6 Hz TBS in inducing lasting facilitation of MEPs.			"Introduction Line 31 – ""(4-10 Hz) induced…"" this is not theta range; please correct."			brainsci11121640_perova	0
865Although the differences in handedness would not profoundly affect the overall results, can the author check if there were significant differences in stimulation intensity (AMT and RMT) in right and left-handed participants?			Author Response Reply to Reviewer#1 Introduction			brainsci11121640_perova	0
866Actually, we did, but it seems that the new figure legend with the correction was not properly inserted when the system reformated the document.			(2012) would lead to lasting MEP facilitation.			brainsci11121640_perova	0
867In my opinion, plus or minus 10% is arbitrary.			The authors reported that the modified iTBS protocol facilitated MEPs for up to 45 min post-stimulation and that small latency differences were predictive of the facilitatory effect on corticospinal excitability.			brainsci11121640_perova	0
868Is the cut-off plus or minus 10 standard for the responder and non-responders?			Line 145 - Edit the subheading Results Are there differences in stimulation intensities taken from the two devices (Magstim Rapid and BiStim2)?			brainsci11121640_perova	0
869Actually, we did, but it seems that the new figure legend with the correction was not properly inserted when the system reformated the document.			In my opinion, the major potential issues were already discussed in the limitation sections.			brainsci11121640_perova	0
870Looking again at Figure 3, we can observe very high variability.			"Introduction Line 31 – ""(4-10 Hz) induced…"" this is not theta range; please correct."			brainsci11121640_perova	0
871"Introduction Line 31 – ""(4-10 Hz) induced…"" this is not theta range; please correct."			Does the participants have a neurological disease or other diseases?			brainsci11121640_perova	0
872However, as we explained in the text, when participants were sorted into two groups (early and late I-waves), the difference between the two was not significant according to the Mann-Whitney U test.			The authors reported that the modified iTBS protocol facilitated MEPs for up to 45 min post-stimulation and that small latency differences were predictive of the facilitatory effect on corticospinal excitability.			brainsci11121640_perova	0
873Although we would assume that the figure on the left is always the letter “A” and the one on the right is “B”, for the sake of clarification, kindly add a letter legend on the figures.			Discussion Line 402: in SIFC, one pulse is suprathreshold, and the other is subthreshold.			brainsci11121640_perova	0
874Actually, we did, but it seems that the new figure legend with the correction was not properly inserted when the system reformated the document.			In my opinion, plus or minus 10% is arbitrary.			brainsci11121640_perova	0
875In lines 459 and 461, pay attention to the space between words.			In line 282, the result showed r2 = 0.24, p = 0.03 but it is a difference in Fig. 5.			brainsci11121640_perova	0
876In line 209, the authors reported that “Of 21 participants, 19 (13 females) completed the protocol without any issues.			Author Response Reply to Reviewer#1 Introduction			brainsci11121640_perova	0
877The authors reported that the modified iTBS protocol facilitated MEPs for up to 45 min post-stimulation and that small latency differences were predictive of the facilitatory effect on corticospinal excitability.			"In line 119, the capital ""a"" changes lower case."			brainsci11121640_perova	0
878Battery storage bank is included in the system to provide the baseload power in the time when renewable sources are not suffice to meet the baseload power demand.			Also, authors need to provide a literature survey in an organized way.-			en15031006_makarova	0
879Our objective is to schedule and shift the controllable appliances by estimating hourly power generation and considering consumer demand as a variable function.			Also, authors need to provide a literature survey in an organized way.-			en15031006_makarova	0
880The main contribution of this paper include: A demand side management algorithm is proposed to fulfil the energy gap between generation and consumer’s demand for standalone renewable energy system.			Point 5: It could be better to include base load ratings in the results section (Fig: 10) Response 5:			en15031006_makarova	0
881Author Response Please see the attachment Author Response File: Author Response.docx			Point 4: Equations 4, 9, and 12 include some corrections and need to be modified.			en15031006_makarova	0
882In this paper, a demand-side management system for a renewable-based isolated residential community is proposed.			Point 7: Please discuss how consumers’ comfortability is marinated in the proposed method.			en15031006_makarova	0
883Point 3: The quality of the figures needs to be improved.			Author Response Please see the attachment Author Response File: Author Response.docx			en15031006_makarova	0
884Linear integer programming is used to schedule the appliances based on the available power and state of charge of the battery system.			Point 6: Sizing of renewable energy sources and battery systems were not properly explored.			en15031006_makarova	0
885Point 3: The quality of the figures needs to be improved.			Point 2: In the proposed system solar PV, wind generator and battery are the main generating system.			en15031006_makarova	0
886Point 7: Please discuss how consumers’ comfortability is marinated in the proposed method.			Simulation results are presented to show the effectiveness of the proposed method.			en15031006_makarova	0
887Point 7: Please discuss how consumers’ comfortability is marinated in the proposed method.			In this paper, a demand-side management system for a renewable-based isolated residential community is proposed.			en15031006_makarova	0
888Also, authors need to provide a literature survey in an organized way.-			Point 7: Please discuss how consumers’ comfortability is marinated in the proposed method.			en15031006_makarova	0
889First, why did you use only 4 students for pilot testing?			Author Response See the point-by-point response in the attached Word file.			healthcare10040723_makarova	0
890In the abstract, lines 23-27, I suggest to use the following expression or something like that.			For example, the description of the study design says the following.			healthcare10040723_makarova	0
891However, in this manuscript, I have not seen elements of these characteristics in the paper.			Dear Authors, Here attached, please find my comments for the improvement of your paper.			healthcare10040723_makarova	0
892I am suggesting this because the logic of quantitative sampling and qualitative sampling are different.			In the convergent parallel strategy, quantitative and qualitative data collection occurred concurrently.			healthcare10040723_makarova	0
893Please, use male undergraduate students or undergraduate male students instead of ‘male and undergraduate students’ in the abstract or simply throughout the paper.			I think, the manuscript benefits from a minor language editing.			healthcare10040723_makarova	0
894I hope these suggestions are of use to the authors.			I suggest to re-write the aims and study questions more clearly.			healthcare10040723_makarova	0
895I suggest to re-write the aims and study questions more clearly.			Around 38% of the students felt ill-prepared and could not answer AI-related questions because digitization in medicine and AI are not a formal part of the medical curriculum.			healthcare10040723_makarova	0
896Phrases like ‘2020 medical students’ generation,’ and ‘their level on confidence,’ are confusing for the readers.			Also, the research questions lack describing the study setting.			healthcare10040723_makarova	0
897The paper is well written in terms of clarity of idea and the authors use of mixed-methods design was interesting.			I suggest the authors to include a short section including the implications of the study after the conclusions.			healthcare10040723_makarova	0
898The components are given equal weight, and the two datasets are analyzed and compared in parallel.			Please, give your readers more information that conveniences the exploratory nature.			healthcare10040723_makarova	0
899Also, the research questions are not clearly stated.			Replace this phrase with a more appropriate phrase.			healthcare10040723_makarova	0
900I suggest the authors to include a short section including the implications of the study after the conclusions.			Also, the research questions are not clearly stated.			healthcare10040723_makarova	0
901Page 12, line 389, the statement which says, ‘The non-probabilistic sampling makes a generalization of the answers difficult,’ is confusing.			In this regard, your study fits with the exploratory nature.			healthcare10040723_makarova	0
902Page 2, line 42, ‘the computation of compounding factors,’ I did not understand what it means.			Dear Authors, Here attached, please find my comments for the improvement of your paper.			healthcare10040723_makarova	0
903However, the reviewer suggested that the convergent parallel design might fit our methodology even better.			It needs the careful wording of the study participants.			healthcare10040723_makarova	0
904‘The items were then tested through a pilot study consisting of a 117 group of 4 pre- and clinical students, mediated by AG and JE’			I am suggesting this because the logic of quantitative sampling and qualitative sampling are different.			healthcare10040723_makarova	0
905The article presents a study of perception of AI and digitization healthcare which is achieved by qualitative and quantitative surveys.			The paper is well written in terms of clarity of idea and the authors use of mixed-methods design was interesting.			healthcare10040723_makarova	0
906This emphasis may reveal by presenting the overarching question as an open-ended question or discussing the qualitative results in more detail than the quantitative results.			However, the first sentence did not appear to serve this purpose.			healthcare10040723_makarova	0
907Importantly, the study has pointed out the lack of in-depth awareness about digital health technologies in students and highlighted the need for education of the same.			As suggested by the reviewer, the authors specified in the method section that we used an additive rather than a parallel integrative strategy.			healthcare10040723_makarova	0
908Please, give your readers more information that conveniences the exploratory nature.			First, why did you use only 4 students for pilot testing?			healthcare10040723_makarova	0
909Timing of TOC administration according to the oxygen flow rates			Timing of TOC administration according to the oxygen flow rates As mentioned above, the cutoff value is O2 13L/min, but the oxygen volume is difficult to interpret because FiO2 varies depending on the method of oxygen delivery.			jcm11051247_perova	0
910Results When comparing different oxygen delivery methods, isn't it more appropriate to compare FiO2 rather than oxygen flow rate?			Results When comparing different oxygen delivery methods, isn't it more appropriate to compare FiO2 rather than oxygen flow rate?			jcm11051247_perova	0
9111 Response to Reviewer 1 Comments Point 1: This study has a design flaw.			Timing of TOC administration according to the oxygen flow rates As mentioned above, the cutoff value is O2 13L/min, but the oxygen volume is difficult to interpret because FiO2 varies depending on the method of oxygen delivery.			jcm11051247_perova	0
912Author Response Please see the attachment Author Response File: Author Response.pdf			Author Response Please see the attachment Author Response File: Author Response.pdf			jcm11051247_perova	0
913Author Response Please see the attachment Author Response File: Author Response.pdf			Timing of TOC administration according to the oxygen flow rates As mentioned above, the cutoff value is O2 13L/min, but the oxygen volume is difficult to interpret because FiO2 varies depending on the method of oxygen delivery.			jcm11051247_perova	0
914Results When comparing different oxygen delivery methods, isn't it more appropriate to compare FiO2 rather than oxygen flow rate?			Point 2: The proposed timing of Tocilizumab administration based on oxygen flow rate is interesting but undoubtedly requires a more detailed statistical analysis to convince the readers.			jcm11051247_perova	0
915The authors adequately addressed my concerns.			Comparative radiologic changes before and after TOC administration In Table 2, about the change in CT findings in fatal and non-fatal patients before and after TOC administration, isn't it the same as the difference in imaging findings between patients who survive after severe illness and those who do not, regardless of TOC?			jcm11051247_perova	0
916Point 2: The proposed timing of Tocilizumab administration based on oxygen flow rate is interesting but undoubtedly requires a more detailed statistical analysis to convince the readers.			Timing of TOC administration according to the oxygen flow rates As mentioned above, the cutoff value is O2 13L/min, but the oxygen volume is difficult to interpret because FiO2 varies depending on the method of oxygen delivery.			jcm11051247_perova	0
917Study design and population If there are mutations or differences in viral strains during the course of the study, should differences in response to TOC and timing of administration depending on the strain be considered?			1 Response to Reviewer 2 Comments Point 1: 2.			jcm11051247_perova	0
918The authors adequately addressed my concerns.			1 Response to Reviewer 2 Comments Point 1: 2.			jcm11051247_perova	0
919The impact of Tocilizumab on radiological changes can not be adequately analyzed without a control group not receiving the drug.			Comparative radiologic changes before and after TOC administration			jcm11051247_perova	0
920Therefore, my comments will be slanted by my own expertise and will only serve the author as a partial devil’s advocate effort General commentary Section 1.			Second Round of Evaluation Round 2: Most commentary has been addressed and new changes have improved the exposition.			life4041050_perova	0
921Round 1: and Author Response The manuscript comprises an exciting account on the origin of life with emphasis on the emergence and function of RNA.			Second Round of Evaluation Round 2: Most commentary has been addressed and new changes have improved the exposition.			life4041050_perova	0
922He reviews some of his previous work and presents an alternative to the dominant ‘Ancient RNA world’ hypothesis.			The alternative views he previously generated are much expanded in this manuscript.			life4041050_perova	0
923Theories on the origin of life or on other aspects of early evolution, such as cellularization, serve merely as starting points.			The alternative views he previously generated are much expanded in this manuscript.			life4041050_perova	0
924The alternative views he previously generated are much expanded in this manuscript.			Theories on the origin of life or on other aspects of early evolution, such as cellularization, serve merely as starting points.			life4041050_perova	0
925He reviews some of his previous work and presents an alternative to the dominant ‘Ancient RNA world’ hypothesis.			The manuscript represents a nice piece of work with many exciting ideas for further exploration.			life4041050_perova	0
926Round 1: and Author Response The manuscript comprises an exciting account on the origin of life with emphasis on the emergence and function of RNA.			He reviews some of his previous work and presents an alternative to the dominant ‘Ancient RNA world’ hypothesis.			life4041050_perova	0
927The article demonstrates that the iron-sulfur surface metabolism theory at high temperatures has a much better explanatory power than the RNA World theory.			The article demonstrates that the iron-sulfur surface metabolism theory at high temperatures has a much better explanatory power than the RNA World theory.			life4041050_perova	0
928Round 1: and Author Response The manuscript comprises an exciting account on the origin of life with emphasis on the emergence and function of RNA.			I must note that a careful evaluation of all facets requires expertise in a multitude of disciplines (from prebiotic chemistry and structural biology to evolutionary bioinformatics and biochemistry) and considerable time, none of which I possess.			life4041050_perova	0
929Second Round of Evaluation Round 2: Most commentary has been addressed and new changes have improved the exposition.			The alternative views he previously generated are much expanded in this manuscript.			life4041050_perova	0
930He reviews some of his previous work and presents an alternative to the dominant ‘Ancient RNA world’ hypothesis.			I must note that a careful evaluation of all facets requires expertise in a multitude of disciplines (from prebiotic chemistry and structural biology to evolutionary bioinformatics and biochemistry) and considerable time, none of which I possess.			life4041050_perova	0
931Theories on the origin of life or on other aspects of early evolution, such as cellularization, serve merely as starting points.			Theories on the origin of life or on other aspects of early evolution, such as cellularization, serve merely as starting points.			life4041050_perova	0
932I have however a number of quibbles that if addressed could increase the accuracy, value and impact of the manuscript.			Response The author prefers the present title, because the paper is concerned with the origin of the genetic machinery.			life4041050_perova	0
933Response The author prefers the present title, because the paper is concerned with the origin of the genetic machinery.			In light of recent research developments and argumentation (some of it reviewed), his views should be considered a welcome addition to the many ideas that populate the “origin of life” field of inquiry that counter the dominant paradigm.			life4041050_perova	0
934Second Round of Evaluation Round 2: Most commentary has been addressed and new changes have improved the exposition.			I must note that a careful evaluation of all facets requires expertise in a multitude of disciplines (from prebiotic chemistry and structural biology to evolutionary bioinformatics and biochemistry) and considerable time, none of which I possess.			life4041050_perova	0
935Response The author prefers the present title, because the paper is concerned with the origin of the genetic machinery.			He reviews some of his previous work and presents an alternative to the dominant ‘Ancient RNA world’ hypothesis.			life4041050_perova	0
936Round 1: and Author Response The manuscript comprises an exciting account on the origin of life with emphasis on the emergence and function of RNA.			Theories on the origin of life or on other aspects of early evolution, such as cellularization, serve merely as starting points.			life4041050_perova	0
937Second Round of Evaluation Round 2: Most commentary has been addressed and new changes have improved the exposition.			In light of recent research developments and argumentation (some of it reviewed), his views should be considered a welcome addition to the many ideas that populate the “origin of life” field of inquiry that counter the dominant paradigm.			life4041050_perova	0
938Therefore, my comments will be slanted by my own expertise and will only serve the author as a partial devil’s advocate effort General commentary Section 1.			He reviews some of his previous work and presents an alternative to the dominant ‘Ancient RNA world’ hypothesis.			life4041050_perova	0
939The mathematical methods used to deal with the problem are based on approximations and require the support of a huge number of simulations; on the other side, the approximations themselves constitute an interesting feature of the article and allow interesting discussions on the involved physical situations.			Remarkably, even reaction systems that have no chemical species in common could become R2 indirectly coupled to each other through the volume they share, by means of a sort of osmotic coupling.			life5010181_makarova	0
940The authors discuss these issues by means of differential equations and simulations.			Remarkably, even reaction systems that have no chemical species in common could become R2 indirectly coupled to each other through the volume they share, by means of a sort of osmotic coupling.			life5010181_makarova	0
941Produces a dynamic model for chemical evolution rather than traditional deterministic, static, systems that requires centralised information to direct evolution, such as a constant gradient.			The mathematical methods used to deal with the problem are based on approximations and require the support of a huge number of simulations; on the other side, the approximations themselves constitute an interesting feature of the article and allow interesting discussions on the involved physical situations.			life5010181_makarova	0
942The authors discuss these issues by means of differential equations and simulations.			As the authors acknowledge, the article is the first step toward a more complete understanding of an interesting class of possible chemo-physical phenomena.			life5010181_makarova	0
943The authors discuss these issues by means of differential equations and simulations.			Produces a dynamic model for chemical evolution rather than traditional deterministic, static, systems that requires centralised information to direct evolution, such as a constant gradient.			life5010181_makarova	0
944As the authors acknowledge, the article is the first step toward a more complete understanding of an interesting class of possible chemo-physical phenomena.			The authors discuss these issues by means of differential equations and simulations.			life5010181_makarova	0
945Round 1: and Author Response The authors present a dataset where they have characterised the relative abundance of components of the photosynthetic electron transfer chain and related this to the measured rate of electron transfer from PSII.			Round 1: and Author Response The authors present a dataset where they have characterised the relative abundance of components of the photosynthetic electron transfer chain and related this to the measured rate of electron transfer from PSII.			life5010403_perova	0
946The approach and methods are robust and the ability to quantify components of the photosynthetic electron transfer chain is powerful.			provides us with estimates of the concentrations of various proteins representing the PSII, PSI, cytb6 and Rubisco in there different cyanobacteria.			life5010403_perova	0
947Round 1: and Author Response The authors present a dataset where they have characterised the relative abundance of components of the photosynthetic electron transfer chain and related this to the measured rate of electron transfer from PSII.			The approach and methods are robust and the ability to quantify components of the photosynthetic electron transfer chain is powerful.			life5010403_perova	0
948The data are interesting and worth publishing but… (1)			The data presented is robust and worthy of publication but should be discussed more critically with regard to published literature (outlined below) I suggest some minor suggestions that should be incorporated before publications.			life5010403_perova	0
949This is done for a number of globally significance marine microbes of Syn and Pro lineage.			The approach and methods are robust and the ability to quantify components of the photosynthetic electron transfer chain is powerful.			life5010403_perova	0
950The approach and methods are robust and the ability to quantify components of the photosynthetic electron transfer chain is powerful.			Round 1: and Author Response The authors present a dataset where they have characterised the relative abundance of components of the photosynthetic electron transfer chain and related this to the measured rate of electron transfer from PSII.			life5010403_perova	0
951The approach and methods are robust and the ability to quantify components of the photosynthetic electron transfer chain is powerful.			This is done for a number of globally significance marine microbes of Syn and Pro lineage.			life5010403_perova	0
952The approach and methods are robust and the ability to quantify components of the photosynthetic electron transfer chain is powerful.			Second Round of Evaluation Round 2: and Author Response			life5010403_perova	0
953The data are interesting and worth publishing but… (1)			provides us with estimates of the concentrations of various proteins representing the PSII, PSI, cytb6 and Rubisco in there different cyanobacteria.			life5010403_perova	0
954The data presented is robust and worthy of publication but should be discussed more critically with regard to published literature (outlined below) I suggest some minor suggestions that should be incorporated before publications.			The data are interesting and worth publishing but… (1)			life5010403_perova	0
955provides us with estimates of the concentrations of various proteins representing the PSII, PSI, cytb6 and Rubisco in there different cyanobacteria.			provides us with estimates of the concentrations of various proteins representing the PSII, PSI, cytb6 and Rubisco in there different cyanobacteria.			life5010403_perova	0
956General Comments The topic is relevant for microbial taxonomy.			— Done Second Round of Evaluation Round 2: and Author Response			life5010949_perova	0
957In addition, monophyly is a guiding principle in comparing branching order with taxonomy.			About 180 archaeal genomes were used to calculate a new tree topology using CVTree.			life5010949_perova	0
958However, I am personally not convinced that whole genomes bring additional advantages, or if we are better off by just using a conserved set of proteins.			Authors present a new interactive tree-visualization tool which enables direct validation of taxonomic groups according to their monophyly.			life5010949_perova	0
959For example, it cannot be expected that the same degree of dissimilarity may be used to delineate classes in all phyla.			Leaving that opinion aside, I think the alignment-free methodology is interesting, however			life5010949_perova	0
960Here monophyly must be understood in a pragmatic way restricted to the given set of input data and the reference taxonomy.			The idea to use whole genome data for archaeal phylogenies is interesting, as the 16S rRNA phylogenies can be poor in resolving relationships among archaeal lineage due to GC content bias in hyperthermophilic Archaea.			life5010949_perova	0
961Leaving that opinion aside, I think the alignment-free methodology is interesting, however			Authors present a new interactive tree-visualization tool which enables direct validation of taxonomic groups according to their monophyly.			life5010949_perova	0
962Evaluation I found major concerns along this manuscript, and suggest a substantial revision.			Besides, would be desirable that authors provide more objective criteria for high taxa circumscription based on their methodology.			life5010949_perova	0
963Though a dissimilarity measure figures in the CVTree algorithm, it is not realistic to delineate taxa by using this measure at least for the time being.			Besides, would be desirable that authors provide more objective criteria for high taxa circumscription based on their methodology.			life5010949_perova	0
964However, I am personally not convinced that whole genomes bring additional advantages, or if we are better off by just using a conserved set of proteins.			are describing a comprehensive analysis of archaeal phylogeny with a genome-based alignment free method, and then comparing the findings to 16S rRNA based phylogenies.			life5010949_perova	0
965About 180 archaeal genomes were used to calculate a new tree topology using CVTree.			This kind of research should be encouraged further because old taxonomic paradigms must be systematically reviewed based on new genomic data.			life5010949_perova	0
966Therefore, branching order in trees is of primary concern, whereas calibration of branch lengths makes less sense.			The tree was compared with several 16S rRNA trees reported in the literature, and the differences were minor.			life5010949_perova	0
967Evaluation I found major concerns along this manuscript, and suggest a substantial revision.			Evaluation I found major concerns along this manuscript, and suggest a substantial revision.			life5010949_perova	0
968Though a dissimilarity measure figures in the CVTree algorithm, it is not realistic to delineate taxa by using this measure at least for the time being.			present a comparative analysis of the taxonomic classification of the Archaea domain.			life5010949_perova	0
969Round 1: and Author Response Summary Zuo et al.			About 180 archaeal genomes were used to calculate a new tree topology using CVTree.			life5010949_perova	0
970are describing a comprehensive analysis of archaeal phylogeny with a genome-based alignment free method, and then comparing the findings to 16S rRNA based phylogenies.			Besides, would be desirable that authors provide more objective criteria for high taxa circumscription based on their methodology.			life5010949_perova	0
971General Comments The topic is relevant for microbial taxonomy.			Even if defined in the future, it must be lineage-dependent.			life5010949_perova	0
972— Done Second Round of Evaluation Round 2: and Author Response			— Done Second Round of Evaluation Round 2: and Author Response			life5010949_perova	0
973Here monophyly must be understood in a pragmatic way restricted to the given set of input data and the reference taxonomy.			If all genomes from a taxon appear exclusively in a tree branch, the branch is said to be monophyletic.”			life5010949_perova	0
974It is the only described representative of a newly proposed phylum Nanoarchaeota and it cuts into the otherwise monophyletic phylum Euryarchaeota.			Therefore, branching order in trees is of primary concern, whereas calibration of branch lengths makes less sense.			life5010949_perova	0
975Even if defined in the future, it must be lineage-dependent.			The latter can be assigned only after comparison with a reference taxonomy which is not a rigid framework but a modifiable system.			life5010949_perova	0
976Here monophyly must be understood in a pragmatic way restricted to the given set of input data and the reference taxonomy.			However, I am personally not convinced that whole genomes bring additional advantages, or if we are better off by just using a conserved set of proteins.			life5010949_perova	0
977Authors present a new interactive tree-visualization tool which enables direct validation of taxonomic groups according to their monophyly.			— Done Second Round of Evaluation Round 2: and Author Response			life5010949_perova	0
978Besides, would be desirable that authors provide more objective criteria for high taxa circumscription based on their methodology.			However, I am personally not convinced that whole genomes bring additional advantages, or if we are better off by just using a conserved set of proteins.			life5010949_perova	0
979I recommend acceptance for publication in Life Sciences journal.			Though a dissimilarity measure figures in the CVTree algorithm, it is not realistic to delineate taxa by using this measure at least for the time being.			life5010949_perova	0
980Results also provide additional support to recently proposed archaeal phyla and halobacterial orders.			It has been known that tiny genomes of endosymbiont microbes often tend to move towards baseline of a tree and distort the overall picture.			life5010949_perova	0
981Round 1: and Author Response Summary Zuo et al.			The idea to use whole genome data for archaeal phylogenies is interesting, as the 16S rRNA phylogenies can be poor in resolving relationships among archaeal lineage due to GC content bias in hyperthermophilic Archaea.			life5010949_perova	0
982I recommend acceptance for publication in Life Sciences journal.			The latter can be assigned only after comparison with a reference taxonomy which is not a rigid framework but a modifiable system.			life5010949_perova	0
983I recommend acceptance for publication in Life Sciences journal.			It is the only described representative of a newly proposed phylum Nanoarchaeota and it cuts into the otherwise monophyletic phylum Euryarchaeota.			life5010949_perova	0
984Therefore, branching order in trees is of primary concern, whereas calibration of branch lengths makes less sense.			Here monophyly must be understood in a pragmatic way restricted to the given set of input data and the reference taxonomy.			life5010949_perova	0
985This kind of research should be encouraged further because old taxonomic paradigms must be systematically reviewed based on new genomic data.			If all genomes from a taxon appear exclusively in a tree branch, the branch is said to be monophyletic.”			life5010949_perova	0
986Perhaps an additional discussion point would be the advantages of using CVtree approach with regular concatenated proteins.			Perhaps an additional discussion point would be the advantages of using CVtree approach with regular concatenated proteins.			life5010949_perova	0
987are describing a comprehensive analysis of archaeal phylogeny with a genome-based alignment free method, and then comparing the findings to 16S rRNA based phylogenies.			Leaving that opinion aside, I think the alignment-free methodology is interesting, however			life5010949_perova	0
988About 180 archaeal genomes were used to calculate a new tree topology using CVTree.			Round 1: and Author Response Summary Zuo et al.			life5010949_perova	0
989For example, it cannot be expected that the same degree of dissimilarity may be used to delineate classes in all phyla.			Perhaps an additional discussion point would be the advantages of using CVtree approach with regular concatenated proteins.			life5010949_perova	0
990I recommend acceptance for publication in Life Sciences journal.			The idea to use whole genome data for archaeal phylogenies is interesting, as the 16S rRNA phylogenies can be poor in resolving relationships among archaeal lineage due to GC content bias in hyperthermophilic Archaea.			life5010949_perova	0
991Even if defined in the future, it must be lineage-dependent.			Perhaps an additional discussion point would be the advantages of using CVtree approach with regular concatenated proteins.			life5010949_perova	0
992If all genomes from a taxon appear exclusively in a tree branch, the branch is said to be monophyletic.”			This kind of research should be encouraged further because old taxonomic paradigms must be systematically reviewed based on new genomic data.			life5010949_perova	0
993Therefore, branching order in trees is of primary concern, whereas calibration of branch lengths makes less sense.			I recommend acceptance for publication in Life Sciences journal.			life5010949_perova	0
994Perhaps an additional discussion point would be the advantages of using CVtree approach with regular concatenated proteins.			R13 Round 2: and Author Response Authors have substantially improved the article, including language corrections, and have provided extensive clarifications to all initial criticisms.			life5010949_perova	0
995The tree was compared with several 16S rRNA trees reported in the literature, and the differences were minor.			Even if defined in the future, it must be lineage-dependent.			life5010949_perova	0
996There are just a few issues that the authors should take into account for further improving their paper prior to acceptance:			This manuscript relates to the effect of dysprosium substitution in Ce:YIG thin films and in particular to the temperature dependance of their Faraday rotation.			ma15051691_perova	0
997Response: Thanks for your recognition of our work.			Author Response Reviewer #2 (Comments to the Author): This manuscript relates to the effect of dysprosium substitution in Ce:YIG thin films and in particular to the temperature dependance of their Faraday rotation.			ma15051691_perova	0
998The article contains many original results of undeniable practical significance.			While the Faraday rotation angle appears to decrease more or less linearly with temperature in the Ce:YIG film (as far as can be inferred from the non-linear horizontal scale), the decrease is not taking place at the same rate in the Dy:Ce:YIG film.			ma15051691_perova	0
999Point 2: In equation (2) and the following line, there are inconcistencies in the use of capital letters for the Faraday rotation angles.			It is shown that integrated MO isolators consist of Dy:CeIG thin films show better temperature stability compared to Ce:YIG based devices in the temperature range of 23 ℃ to 70 ℃.			ma15051691_perova	0
1000The article contains many original results of undeniable practical significance.			Ostorero, J.; Escorne, M.; Pecheron‐Guegan, A.; Soulette, F.; Le Gall, H. Dy3Fe5O12 garnet thin films grown from sputtering of metallic targets.			ma15051691_perova	0
1001Please check with the editor if this can be fixed.			demonstrate a temperature stable magneto-optical material Dy2Ce1Fe5O12 for silicon integrated nonreciprocal photonic device applications.			ma15051691_perova	0
1002Point 1: It is not indicated in the introduction whether any alternative to thin films of yttrium iron garnet is currently being considered for use as magneto-optical resonators.			It will be of interest to a wide range of researchers involved in magneto-optical resonators.			ma15051691_perova	0
1003demonstrate a temperature stable magneto-optical material Dy2Ce1Fe5O12 for silicon integrated nonreciprocal photonic device applications.			The saturation magnetization of rare-earth doped YIG affects the Faraday rotation angle. Sayetat et al. and Ostorero et al.			ma15051691_perova	0
1004Given the findings the researchers could be arguing that a review may be needed with the Swedish school lunch program and increase the level of fruit and vegetables in the students' diet, particularly for students in lower SES locations.			It is more that education it is also income re line 106-107 “It is proposed that parents with more educational experience are more likely to make healthier food choices for their family” .			nu14122489_makarova	0
1005Bouwmans, C., van der Kolk, A., Oppe, M., Schawo, S., Stolk, E., van Agthoven, M., ... & van Roijen, L. (2014).			Journal of nutritional science and vitaminology, 61(Supplement), S66-S68.			nu14122489_makarova	0
1006The American journal of clinical nutrition, 87(5), 1107-1117.			The following paper did a better job of reporting it Moraeus L, Lindroos AK, Warensjö Lemming E, Mattisson I.			nu14122489_makarova	0
1007In table 5 only one p value is reported, but what it is measuring is unclear, as there are a number of interactions occurring.			Unless these are included the reader can not fully understand the study.			nu14122489_makarova	0
1008Table 5 is interesting but the setting out is poor and so the columns do not align with headings, particularly the wellness KQ -10 information.			Should be reporting total, then girls, and then boys as there look to be interaction effects .			nu14122489_makarova	0
1009Focusing only on the global KQ-10 scores is hiding the subdomain differences to diet.			The authors may know what these are, but many reader will not.			nu14122489_makarova	0
1010It needs minor revision in places but the results need more attention.			The regressing table needs reworked, as it is the influence of diet the independent variable on wellbeing KO-10, the dependent variable.			nu14122489_makarova	0
1011There is a need to revising the reporting of the results and information in the tables along with the statistical methodology used with interval data and group comparison research.			The level of reporting of the core assessment instruments and their items, dimensions and subdomains needs to be enhanced.			nu14122489_makarova	0
1012Reviewer 2: Open Review Investigation of the Associations between Diet quality and Health-Related Quality of Life in a Sample of Swedish Adolescents Overall comments: supportive of the paper but have concerns about it for the following 5 reasons.			There is a need to revising the reporting of the results and information in the tables along with the statistical methodology used with interval data and group comparison research.			nu14122489_makarova	0
1013The lack of recommendations associated with the Swedish free lunch program to assist the diets of students in low SES families to have more fruit and vegetables			(Tabachnick, B.G., Fidell, L. S., & Ullman, J.B. (2007).			nu14122489_makarova	0
1014Investigation of the Associations between Diet quality and Health-Related Quality of Life in a Sample of Swedish Adolescents Overall comments: supportive of the paper but have concerns about it for the following 5 reasons.			It maybe, it is the cost of living associated with fresh fruit and vegetables that is the real issue.			nu14122489_makarova	0
1015If the focus is on gender typically both a boy and a girl regression model is reported.			You have so many abbreviations confusing to follow in places.			nu14122489_makarova	0
1016In table 5 only one p value is reported, but what it is measuring is unclear, as there are a number of interactions occurring.			The conclusion is sound given the findings but the lack of reference to income is an issue as educational status of parents is often a “de-facto” measure for income.			nu14122489_makarova	0
1017The conclusion is sound given the findings but the lack of reference to income is an issue as educational status of parents is often a “de-facto” measure for income.			The regressing table needs reworked, as it is the influence of diet the independent variable on wellbeing KO-10, the dependent variable.			nu14122489_makarova	0
1018The term is usually SES social economic status so it should be SES- F if it is social economic status – factors.			Unless these are included the reader can not fully understand the study.			nu14122489_makarova	0
1019Reviewer 2: Open Review Investigation of the Associations between Diet quality and Health-Related Quality of Life in a Sample of Swedish Adolescents Overall comments: supportive of the paper but have concerns about it for the following 5 reasons.			I am a not European reviewer and so found the RADDS a rather restricted list without some meat.			nu14122489_makarova	0
1020Different sub-populations even in the same school may need different mix of foods.			Line 90 need to put in the full name Health Related Quality of Life (HRQoL).			nu14122489_makarova	0
1021To improve, you need the next questions: -Abstract: it is not conventional.			This is the core of your study: does diet have an influence on psychological wellbeing?			nu14122489_makarova	0
1022I am a not European reviewer and so found the RADDS a rather restricted list without some meat.			Focusing only on the global KQ-10 scores is hiding the subdomain differences to diet.			nu14122489_makarova	0
1023There is much about this paper that is of value, but it does need relooking at, particularly in the results reporting to do the research and the data justice.			Diet diversity score and healthy eating index in relation to diet quality and socio-demographic factors: results from a cross-sectional national dietary survey of Swedish adolescents.			nu14122489_makarova	0
1024The focus on only the global mean score for the wellness KQ-10 measure rather than the 5 dimensions.			Diet is only expected to influence 2 of these 5 dimensions.			nu14122489_makarova	0
1025It is more that education it is also income re line 106-107 “It is proposed that parents with more educational experience are more likely to make healthier food choices for their family” .			Different sub-populations even in the same school may need different mix of foods.			nu14122489_makarova	0
1026The basic information is not there in the paper: “KIDSCREEN-10 (KS-10) is derived from the KIDSCREEN-27, and provides a single index of global QoL using ten items related to physical well-being, psychological well-being, autonomy and parent relation, social support and peers, and school environment” See how these researchers have described the KIDSCREEN-10 .			It is more that education it is also income re line 106-107 “It is proposed that parents with more educational experience are more likely to make healthier food choices for their family” .			nu14122489_makarova	0
1027It needs minor revision in places but the results need more attention.			The focus on only the global mean score for the wellness KQ-10 measure rather than the 5 dimensions.			nu14122489_makarova	0
1028The proposal about “Investigation of the Associations between Diet quality and Health-Related Quality of Life in a Sample of Swedish Adolescents” is attractive.			I recommend you to alternate them (text, Figures and Tables in Results).			nu14122489_makarova	0
1029There is much about this paper that is of value, but it does need relooking at, particularly in the results reporting to do the research and the data justice.			Remember the KQ-10 is made up of five subdomains (psychological well-being, autonomy and parent relation, social support and peers, and school environment) The fact is diet is no expected to change 3 of these KQ-3 subdomains and only one or two KQ-10 dimensions.			nu14122489_makarova	0
1030This study includes a size of 1139 adolescents.			It needs minor revision in places but the results need more attention.			nu14122489_makarova	0
1031It maybe, it is the cost of living associated with fresh fruit and vegetables that is the real issue.			Diet diversity score and healthy eating index in relation to diet quality and socio-demographic factors: results from a cross-sectional national dietary survey of Swedish adolescents.			nu14122489_makarova	0
1032Reviewer 1: The proposal about “Investigation of the Associations between Diet quality and Health-Related Quality of Life in a Sample of Swedish Adolescents” is attractive.			Diet diversity score and healthy eating index in relation to diet quality and socio-demographic factors: results from a cross-sectional national dietary survey of Swedish adolescents.			nu14122489_makarova	0
1033Cardiovascular Disease Predicts Structural and Functional Progression in Early Glaucoma.			Medicine 2020, 99, e19285, doi:10.1097/md.0000000000019285.			nu14122490_perova	0
1034Model 2: model 1 additionally adjusted for intraocular pressure.			The writing is of perfect quality and the results are clearly presented.			nu14122490_perova	0
1035"Reviewer #1 We would like to thank the reviewer for reviewing our manuscript entitled “Dietary nitrate intake is associated with decreased incidence of open-angle glaucoma: The Rotterdam Study"" (MS# nutrients-1760125)."			Cha, S.; Gu, B.; Sagong, M.; Son, J.; Kim, M. Association between glaucoma and cardiovascular disease risk in Korean population based study.			nu14122490_perova	0
1036; Hofman, A.; Vingerling, J.R.; Hitchings, R.A.; de Jong, P.T.			Na, K.-S.; Kim, J.-H.; Paik, J.-S.; Cho, W.-K.; Ha, M.; Park, Y.-G.; Yang, S.-W. Underweight increases the risk of primary open-angle glaucoma in diabetes patients: A Korean nationwide cohort study.			nu14122490_perova	0
1037Results from Two Cross-Sectional National Food Consumption Surveys.			Past studies of the Rotterdam population mention several other risk factors which were not taken into account in this study including myopia, cup-to-disc ratio, and family history of glaucoma, as well as other features such as exfoliation.			nu14122490_perova	0
1038; Vingerling, J.R.; Jansonius, N.M. Lifestyle and risk of developing open-angle glaucoma: the Rotterdam study.			"""
1039Reviewer_1	Author	1	4	0	2	As we did not observe an association between dietary nitrate intake and IOP, nitrate may protect against glaucoma via other, IOP-independent, mechanisms.
1040					0	"""			nu14122490_perova	0
1041Cerebrospinal fluid pressure decreases with older age.			Medicine 2020, 99, e19285, doi:10.1097/md.0000000000019285.			nu14122490_perova	0
1042Berdahl, J.P.; Fleischman, D.; Zaydlarova, J.; Stinnett, S.; Allingham, R.R.			Association of Body Mass Index With Lifetime Risk of Cardiovascular Disease and Compression of Morbidity.			nu14122490_perova	0
1043Multivariable-adjusted odds ratios with corresponding 95% confidence intervals (CIs) for incident open-angle glaucoma per 10 gram/day increase in total dietary nitrate intake (A), nitrate intake from vegetables (B), and nitrate intake from non-vegetable food sources (C), shown per cumulative follow-up interval.			Genetic Risk of Cardiovascular Disease Is Associated with Macular Ganglion Cell–Inner Plexiform Layer Thinning in an Early Glaucoma Cohort.			nu14122490_perova	0
1044What was the definition of visual field loss that defined glaucoma?			We would like to thank the reviewer for the positive feedback on our study design and our final manuscript.			nu14122490_perova	0
1045Comments 4 - In figure 3, the indication of the test time appears in the reverse direction.			1 Response to Reviewer 2 Comments Comments 1 -The paper's aim should be the same in the abstract and the introduction.			s22072682_perova	0
1046- I suggest presenting the paper's aim as the last idea in the introduction to make the manuscript easier to read.			Comments 2 - Given the poor quality of the images (Fig 1 and 2), it might be better to redraw them and describe them as an adaptation of the original publication.			s22072682_perova	0
10471 Response to Reviewer 2 Comments Comments 1 -The paper's aim should be the same in the abstract and the introduction.			1 Response to Reviewer 2 Comments Comments 1 -The paper's aim should be the same in the abstract and the introduction.			s22072682_perova	0
1048Subject BMI Smoking history A 23.2 Non-smoker B 19.8 Non-smoker C 19.5 Non-smoker D 19.7 Non-smoker E 21.5 Non-smoker F 22.8 Non-smoker G 20 Non-smoker H 24.9 Non-smoker I 18.2 Non-smoker J 21.8 Non-smoker K 18.7 Non-smoker L 21.4 Non-smoker M 21.4 Non-smoker N 18.2 Non-smoker O 18.5 Non-smoker P 19.8 Non-smoker Q 20.5 Non-smoker mean 21 - SD 1.9 - Comments 2 Did authors estimate sample size?			Comments 3 - The methods do not specify how the baseline load of the participants was determined.			s22072682_perova	0
1049- I suggest presenting the paper's aim as the last idea in the introduction to make the manuscript easier to read.			In this respect, I find the work interesting, well-structured, and with promising results.			s22072682_perova	0
1050Comments 3 Please add ethics protocol approval number.			Comments 4 - In figure 3, the indication of the test time appears in the reverse direction.			s22072682_perova	0
1051Response 3 I described baseline load of the participants in 2.2.			In this respect, I find the work interesting, well-structured, and with promising results.			s22072682_perova	0
1052Comments 4 - In figure 3, the indication of the test time appears in the reverse direction.			Subject BMI Smoking history A 23.2 Non-smoker B 19.8 Non-smoker C 19.5 Non-smoker D 19.7 Non-smoker E 21.5 Non-smoker F 22.8 Non-smoker G 20 Non-smoker H 24.9 Non-smoker I 18.2 Non-smoker J 21.8 Non-smoker K 18.7 Non-smoker L 21.4 Non-smoker M 21.4 Non-smoker N 18.2 Non-smoker O 18.5 Non-smoker P 19.8 Non-smoker Q 20.5 Non-smoker mean 21 - SD 1.9 - Comments 2 Did authors estimate sample size?			s22072682_perova	0
1053"Dear Authors: I appreciate the possibility to review the paper entitled ""Exploration of an inflection point of ventilation parameters with anaerobic threshold using strucchange"" by the authors Aida et al."			1 Response to Reviewer 1 Comments Comments 1 Please add a table with patients' baseline characteristics, including BMI and smoking status.			s22072682_perova	0
1054