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For the questions of “is the deletion burden observed really exceptional in a population sample of similar ancestry”, we agree with the reviewer’s comment. We did the analysis a couple of years ago, at that time, there is no CNV data from the 1000 genome for Mexicans, Colombians, Puerto Ricans and Peruvians, however, there is data for the admixed populations, thus we used this for this study. There might be some difficulty to do more analysis since our statistician and bioinformatics person left the department and we are in the process of hiring somebody for this role. At the same, we continue in recruiting more subjects with cervical cancers to further confirm our findings. Moreover, in the discussion, we have list this as one of the limitations in page 8 “2) there might be bias of the CNA identified in cervical cancer for the Mexican Americans since we used the 1000 Genome admixed populations, not Mexican Americans, thus, we current recruit more subjects with cervical cancer from the same population and plan to validate the findings in more samples;” 2)
| 2 | 1 |
is the deletion burden observed really exceptional in a population sample of similar ancestry? To answer this question, I would refer to the 1000 genomes data where there are Mexicans, Colombians, Puerto Ricans and Peruvians. There must be available CNV estimations for these ancestries. If you find good estimates then perhaps a statistical tests with those as your control group would be more believable.
| 1 | 2 |
medsci4030012_perova
| 1 |
For the question of “is the deletion burden observed similar to those for other cancers? Then again there must be estimates of deletion burden for different types of cancers from TCGA studies”, our response is that we did search of CNAs observed in other cancer based on TCGA studies, although there are limited studies, we addressed this issue in the discussion section (page 8) “…Using the TCGA data, a recent study identified nine regions of deletion that were unique to ER+ post menopause tumors in patients with breast cancer, including deletion in 7p22.3 where our newly identified deletion in cases only located and it contains known tumor suppressor gene”.
| 2 | 1 |
is the deletion burden observed similar to those for other cancers? Then again there must be estimates of deletion burden for different types of cancers from TCGA studies. Please cite those.
| 1 | 2 |
medsci4030012_perova
| 1 |
Now we added a sentence of “Moreover, the pathway analysis revealed endometrial cancer and estrogen signaling pathways associated with this cancer (P < 0.05) using the KEGG” in the abstract as the reviewer’s suggestion. In addition, in the introduction section, we added “We are aware of the limited number of cases and lack of control group. Thus future a large study with a control sample and more cases as methodological alternative is needed”. (Please see page 3) Minor comments: 1-
| 2 | 1 |
The only real statistical inference they show is on the pathway analysis yet no mention is made on the abstract. I suggest bringing this result up to the surface and making it more relevant even from the abstract. You can refer to it as methodological alternative, in the introduction, for the limited number of cases and lack of control group; issues that must be tackle in a larger study.
| 1 | 2 |
medsci4030012_perova
| 1 |
as the reviewer’s suggestion, we changed “Latino” to “Mexican American” in the text of the manuscript and table
| 2 | 1 |
I missed a definition of the sample's ancestry. In the title it refers to Mexican American but in the rest of the manuscript it is treated as a latino population. Note that there are differences in admixture in the latino population depending of their country of origin. Studies on the 1000 genomes show differences between Puerto Ricans, Colombians, Mexicans and Peruvians. Therefore, if the authors can state that their sample is essentially Mexican that would be more informative and precise. I would then limit the use of latino. However if the ancestry is only self reported as latino, then I would write latino in the title and mention the issue of genetic variability between latinos in the discussion.
| 1 | 2 |
medsci4030012_perova
| 1 |
now we change “Latino population” to “Mexican American” as the reviewer’s suggestion
| 2 | 1 |
Abstract Line 23: should read Latino Populations
| 1 | 2 |
medsci4030012_perova
| 1 |
thank you for the comments. We also realized this issue which is due to that the color green overlaps with the other colors, thus it cannot be distinguished, and we have tried different color combinations without help. Now we made changes of the figure and legend.
| 2 | 1 |
Figure 1: I cannot see the supposed deletions marked in green
| 1 | 2 |
medsci4030012_perova
| 1 |
thanks, we removed the % sign in table cells in Table 2b
| 2 | 1 |
Table 2b: Please remove the % sign in some of the table cells, for instance in Reference (Deletion, 10-100kb).
| 1 | 2 |
medsci4030012_perova
| 1 |
thank you, reviewer, this is a typo, we corrected it.
| 2 | 1 |
1) Line 34. The authors need to make clear about “pre-, cancer (91.3%) groups”. It is not clear if there is one or two groups but just one percentage.
| 1 | 2 |
medsci4030012_perova
| 1 |
yes, we added up to six key words now
| 2 | 1 |
2) Line 40. The authors may add up to 6 key words.
| 1 | 2 |
medsci4030012_perova
| 1 |
we made changes based on the reviewer’s suggestion, please see statistical method in page 5 and result in page 6
| 2 | 1 |
3) Lines 196-197. It is not clear which statistical method is used for the significant results in Table 2.Please give more details.
| 1 | 2 |
medsci4030012_perova
| 1 |
thanks, we provided definition for pre-cancer in materials, which include patients with CIN I, II, and III.
| 2 | 1 |
4) Line 199. The authors need to define “pre-cancer” in materials.
| 1 | 2 |
medsci4030012_perova
| 1 |
thanks, we added “…using statistical analyses described in the method section”
| 2 | 1 |
Please give more details. 6) Lines 214-216. It is not clear which statistical method is used for the significant results.
| 1 | 2 |
medsci4030012_perova
| 1 |
thanks, the reviewer. Now we removed redundancy statement.
| 2 | 1 |
7) Lines 238-242 are replicated in discussion lines 376-380. The authors may need to delete the part in lines 238-242.
| 1 | 2 |
medsci4030012_perova
| 1 |
We have attempted to improve the language and hope we have found all significant errors.
| 2 | 1 |
There are some errors in spelling, syntax, punctuation, usage of capital letters, consistency in language style in the manuscript that must be improved.
| 1 | 2 |
molecules26247651_makarova
| 1 |
The characterization of the compounds is provided together with the NMR spectra as Suppl. Mat. S21.
| 2 | 1 |
2. Full characterization of all synthesized compounds is required in the experimental section.
| 1 | 2 |
molecules26247651_makarova
| 1 |
Spectra have been included in Suppl. Mat. S21.
| 2 | 1 |
3. All the 1HNMR and 13CNMR must be attached as supplementary information.
| 1 | 2 |
molecules26247651_makarova
| 1 |
A new Scheme 1 has been produced with the recommended format. The molecular structures in Figures 1 and 3 have been modified accordingly.
| 2 | 1 |
4. Scheme 1 must be redrawn using ACS document 1996 and all structures cleaned up.
| 1 | 2 |
molecules26247651_makarova
| 1 |
The misalignment is a result of the editorial procedure. We have tried to improve the alignment.
| 2 | 1 |
5. The cell values do not align please correct them.
| 1 | 2 |
molecules26247651_makarova
| 1 |
Done.
| 2 | 1 |
6. Use 4 significant figures for the RNH values in table 2.
| 1 | 2 |
molecules26247651_makarova
| 1 |
We appreciate the suggestion. However, we do not think we have time to perform a proper analysis of XRD data, considering solid state effects, crystal packing, etc.
| 2 | 1 |
7. It would be added value if these NH···O hydrogen bonds were also investigated in the solid state using XRD analysis.
| 1 | 2 |
molecules26247651_makarova
| 1 |
In the submitted MSWord document the font was Times New Roman for text and reference numbers. Something has happened during the editorial procedure when changing to Palatino Linotype. Not all reference numbers were changed correctly. We have tried to find and correct the errors.
| 2 | 1 |
8. Check the font of the reference numbers in the text and correct RESPONSE:
| 1 | 2 |
molecules26247651_makarova
| 1 |
This concerns the experimental section, S21, in the Supplementary Material document. We have scrutinized the text and corrected the errors. We have also corrected two typos in the main manuscript.
| 4 | 1 |
Correct subscripts and superscripts in the experimental also check the spacings to be consistent.
| 3 | 2 |
molecules26247651_makarova
| 1 |
The background for the investigation is described in the Introduction section. As indicated by the Reviewer, the present study is an extension of our previous OH···O binding studies. We have for some time wished to investigate the corresponding NH···O systems. The NH···O type of linkage has the advantage that a wide range of compounds can be investigated; in general, systems of the type NH···O=C with an intervening double bond are not tautomeric, in contrast to the corresponding OH···O=C systems. We have added a remark on this aspect to the Introduction section. - The ‘delay’ of 10 years is due to technical and personal factors of no relevance to the reported results.
| 2 | 1 |
In this article, the authors describe the spectral characteristics of NH in the hydrogen bridge NH...O. It is a continuation of similar OH...O binding studies performed 10 years ago. The rationale for undertaking the research is a bit puzzling. I am curious what prompted the Authors to deal with N-H...O bonding in place of the earlier O-H...O. The explanation should be cleared.
| 1 | 2 |
molecules26247651_makarova
| 1 |
We are aware of the controversial nature of this result. We also expected a linear relationship similar to the one observed by Dudek. However, we have in this work extended the range of compounds to include species of types J, K, and L, apparently resulting in the observed non-linear relationship. The correlation in Fig. 2 involves only experimental values, most of them from the literature, and we have no reason to doubt their reliability. The exponential regression yields R2 = 0.975, SD = 34.3 cm–1, while the corresponding linear regression gives R2 = 0.837, SD = 93.3 cm–1. Hence, the indication of a non-linear correlation is evident. We have added the sentence "Probably the extension of the range of compounds to include species of the types J, K, and L has led to the non-linear correlation” to the first paragraph on page 13.
| 2 | 1 |
The authors should give the reason for the nonlinear v(NH) vs delta correlation as it was (according to Dudek) linear for OH-O.
| 1 | 2 |
molecules26247651_makarova
| 1 |
Our attention was drawn to Ref. [54] where Grimme et al. state that "The [DFT-D3] method has been assessed on standard benchmark sets for inter- and intramolecular noncovalent interactions". We thus found it relevant to try out B3LYP-D3 for the present study of "intramolecular noncovalent interactions". But the Reviewer finds that these calculations "make no sense here", so we have removed these results from the manuscript. The Reviewer suggests that we check the functional B3PW91 (in the Introduction we actually mention B3PW91 as one of the two functionals recommended by Scott and Radom). We have performed additional B3PW91/6-311++G(d,p) calculations on a series of seven compounds covering a wide range of NH stretching wavenumbers. The computed harmonic wavenumbers are essentially linearly related to those obtained with B3LYP (R2 = 0.9999, SD = 2.6 cm–1). We have added a remark on this result to the last paragraph of Section 3.2.
| 2 | 1 |
Performing calculations with the Grimme dispersion correction did not make sense here, as D3 is important for intermolecular interactions, especially stacking. Here, calculations are performed for isolated molecules. Rather, the author could check B3PW91 (it often performs better than B3LYP) or any newer suitable functional.
| 1 | 2 |
molecules26247651_makarova
| 1 |
Corrected!
| 2 | 1 |
183: should be SD = 34.3 cm-1
| 1 | 2 |
molecules26247651_makarova
| 1 |
The sentence with "are reasonable" has been removed.
| 2 | 1 |
186: "are reasonable": Taking into account that (i) this fit is rather unphysical (ii) moving the points by say 50 cm-1 one way or the other would also give rather good fit, this phrase is rather an empty cliche.
| 1 | 2 |
molecules26247651_makarova
| 1 |
The orientation of the axes was chosen according to the trend reported by Novak [56]: Decreasing NH stretching wavenumber corresponds to decreasing isotope ratio.
| 2 | 1 |
Figure 5: Why is the y-axis reversed?
| 1 | 2 |
molecules26247651_makarova
| 1 |
We have attempted to improve the language and hope we have found all significant errors.
| 2 | 1 |
1. There are some errors in spelling, syntax, punctuation, usage of capital letters, consistency in language style in the manuscript that must be improved.
| 1 | 2 |
molecules26247651_perova
| 1 |
The characterization of the compounds is provided together with the NMR spectra as Suppl. Mat. S21.
| 2 | 1 |
2. Full characterization of all synthesized compounds is required in the experimental section.
| 1 | 2 |
molecules26247651_perova
| 1 |
Spectra have been included in Suppl.
| 2 | 1 |
3. All the 1HNMR and 13CNMR must be attached as supplementary information.
| 1 | 2 |
molecules26247651_perova
| 1 |
A new Scheme 1 has been produced with the recommended format. The molecular structures in Figures 1 and 3 have been modified accordingly.
| 2 | 1 |
4. Scheme 1 must be redrawn using ACS document 1996 and all structures cleaned up.
| 1 | 2 |
molecules26247651_perova
| 1 |
The misalignment is a result of the editorial procedure. We have tried to improve the alignment.
| 2 | 1 |
5. The cell values do not align please correct them.
| 1 | 2 |
molecules26247651_perova
| 1 |
Done.
| 2 | 1 |
6. Use 4 significant figures for the RNH values in table 2.
| 1 | 2 |
molecules26247651_perova
| 1 |
We appreciate the suggestion. However, we do not think we have time to perform a proper analysis of XRD data, considering solid state effects, crystal packing, etc.
| 2 | 1 |
7. It would be added value if these NH···O hydrogen bonds were also investigated in the solid state using XRD analysis.
| 1 | 2 |
molecules26247651_perova
| 1 |
In the submitted MSWord document the font was Times New Roman for text and reference numbers. Something has happened during the editorial procedure when changing to Palatino Linotype. Not all reference numbers were changed correctly. We have tried to find and correct the errors.
| 2 | 1 |
8. Check the font of the reference numbers in the text and correct RESPONSE:
| 1 | 2 |
molecules26247651_perova
| 1 |
This concerns the experimental section, S21, in the Supplementary Material document. We have scrutinized the text and corrected the errors. We have also corrected two typos in the main manuscript.
| 4 | 1 |
Correct subscripts and superscripts in the experimental also check the spacings to be consistent.
| 3 | 2 |
molecules26247651_perova
| 1 |
We are aware of the controversial nature of this result. We also expected a linear relationship similar to the one observed by Dudek. However, we have in this work extended the range of compounds to include species of types J, K, and L, apparently resulting in the observed non-linear relationship. The correlation in Fig. 2 involves only experimental values, most of them from the literature, and we have no reason to doubt their reliability. The exponential regression yields R2 = 0.975, SD = 34.3 cm–1, while the corresponding linear regression gives R2 = 0.837, SD = 93.3 cm–1. Hence, the indication of a non-linear correlation is evident. We have added the sentence "Probably the extension of the range of compounds to include species of the types J, K, and L has led to the non-linear correlation” to the first paragraph on page 13.
| 2 | 1 |
1) The authors should give the reason for the nonlinear v(NH) vs delta correlation as it was (according to Dudek) linear for OH-O.
| 1 | 2 |
molecules26247651_perova
| 1 |
Our attention was drawn to Ref. [54] where Grimme et al. state that "The [DFT-D3] method has been assessed on standard benchmark sets for inter- and intramolecular noncovalent interactions". We thus found it relevant to try out B3LYP-D3 for the present study of "intramolecular noncovalent interactions". But the Reviewer finds that these calculations "make no sense here", so we have removed these results from the manuscript. The Reviewer suggests that we check the functional B3PW91 (in the Introduction we actually mention B3PW91 as one of the two functionals recommended by Scott and Radom). We have performed additional B3PW91/6-311++G(d,p) calculations on a series of seven compounds covering a wide range of NH stretching wavenumbers. The computed harmonic wavenumbers are essentially linearly related to those obtained with B3LYP (R2 = 0.9999, SD = 2.6 cm–1). We have added a remark on this result to the last paragraph of Section 3.2.
| 2 | 1 |
2) Performing calculations with the Grimme dispersion correction did not make sense here, as D3 is important for intermolecular interactions, especially stacking. Here, calculations are performed for isolated molecules. Rather, the author could check B3PW91 (it often performs better than B3LYP) or any newer suitable functional.
| 1 | 2 |
molecules26247651_perova
| 1 |
Corrected!
| 2 | 1 |
183: should be SD = 34.3 cm-1
| 1 | 2 |
molecules26247651_perova
| 1 |
The sentence with "are reasonable" has been removed.
| 2 | 1 |
186: "are reasonable": Taking into account that (i) this fit is rather unphysical (ii) moving the points by say 50 cm-1 one way or the other would also give rather good fit, this phrase is rather an empty cliche.
| 1 | 2 |
molecules26247651_perova
| 1 |
The orientation of the axes was chosen according to the trend reported by Novak [56]: Decreasing NH stretching wavenumber corresponds to decreasing isotope ratio.
| 2 | 1 |
Figure 5: Why is the y-axis reversed?
| 1 | 2 |
molecules26247651_perova
| 1 |
We appreciate the recommendation and comments. We corrected the above-mentioned correction as suggested by the reviewer and presented as follows, 1H NMR (400 MHz, DMSO-d6, ppm): δ 11.43 (s, 2H), 8.34 (m, 2H), 8.28 (m, 1H), 7.65 (d, 2H, J = 4.8 Hz), 7.61 (d, 2H, J = 3.2 Hz), 7.14 (t, 2H, J = 8.8 Hz), 2.51 (s, 6H). 13C NMR (100 MHz, DMSO-d6, ppm): 159.44 (C=O), 154.55 (Ar-C), 148.91 (Ar-C), 143.22 (-C=N-), 140.48 (Ar-C), 130.06 (Ar-C), 129.44 (Ar-C), 128.20 (Ar-C), 125.75 (Ar- C), 15.32 (-CH3).
| 2 | 1 |
The manuscript by Sharmin Akther Rupa et al, the manuscript has many serious concerns on the basis that it cannot be accepted in this journal. for example, 13C NMR must be 100 MHz not 400 MHz, value must be either ascending order or descending order (13C NMR (400 MHz, DMSO-d6, ppm): 1 above example showed the manuscript not written carefully.
| 1 | 2 |
molecules27051656_makarova
| 1 |
We appreciate the recommendation and agree with the reviewer that the computational and experimental results of antimicrobial activity differ to some extent in this part of the study and required further investigation to understand why such activity differs to the ligands by other means in the future. In this study, we successfully synthesized the novel ligands and studied its spectroscopy with other probable studies. Fortunately, we have found outstanding results during the chemo-sensor study and hopefully, we could be able to show the excellent usage of the ligands as a chemo-sensor in near future. Also, we are planning to do a fluorescence imaging study of protein-ligands.
| 2 | 1 |
Second one that is very important for this paper: The activity of L2 molecule against Bacillus Megaterium (PDB 4j6u) was significant with a binding energy of -8.8 kcal/mol and three hydrogen bond interactions, which reveals the antimicrobial activity of the molecule. Both compounds are biologically active, but their activity was moderate which did not support their efforts.
| 1 | 2 |
molecules27051656_makarova
| 1 |
We appreciate the comments of the reviewer and the following are the answers in response to the question for the kind consideration of the reviewer- Tyrosinase is a key enzyme in melanogenesis, which is essential for pigmentation. Dysfunction of tyrosinase may cause skin cancer. It is well-known that tyrosinase of Bacillus Megaterium bacteria is an attractive target for the development of antimicrobials or antibiotic adjuvants for the treatment of hyperpigmentation because of its similarity (33.5%) to the human enzyme [97-103]. That’s why, to investigate and compare the antimicrobial activity of the synthesized compounds with in vitro data, docking analysis of L1 and L2 against tyrosinase from Bacillus Megaterium was performed. Also, molecular docking with other proteins of B. Megaterium was conducted, but 46ju provided better binding affinity with the synthesized compounds. For this reason, we aim to study the structure of tyrosinase from the bacteria. Preliminary antimicrobial studies were carried out to validate the docking protocol. At present, we are doing the fluorescence activities of these ligands and L2 showed excellent fluorescent emission at λmax 520 nm. So, we hope that we will carry out ALA scan (Alanine scanning) based MD experiments and 100ns Molecular dynamics (MD) simulation guided protein-ligand stability in the future for our next study since within this shortest time, we are unable to do these experiments. The active binding site of tyrosinase was predicted by CASTp. We have included this in the manuscript as follows: Binding affinity of L1 and L2 The highest anti-bacterial activity (zone of inhibition 12 mm) of compound L2 was detected with tyrosinase from Bacillus Megaterium (PDB ID: 4j6u) bacteria compared to L1. The binding energies for L1 and L2 with Bacillus Megaterium were −7.7 and −8.8 kcal mol−1, respectively, which were calculated by AutoDock Vina. The interactions of the 4j6u with compounds L1 and L2 are shown in the Fig. Results of docking studies revealed that L1 and L2 formed bonds to the active site of tyrosinase and showed strong interactions with Tyr267A, Ala44A, and ALA44B of tyrosinase enzyme (PDB ID: 4j6u), which also supports the literature [101-103]. Thus, computational results are in good agreement with in vitro antibacterial behaviour of our compounds for novel antibacterial drug design.
| 2 | 1 |
4. The authors did not report any Tyrosinase enzyme inhibition assay, they are requested to justify Tyrosinase inhibition as the probable mechanism of action for these sets of ligands by providing suitable literature references.
| 1 | 2 |
molecules27051656_makarova
| 1 |
We are delighted and thankful for the recommendation of the reviewer.
| 4 | 1 |
In this present study wehave synthesized two tritopic dihydrazide based ligands bearing Pyrrole and Thiophene as end groupings and characterized successfully by FT-IR, 1H and 13C NMR and massspectrometry. Based on the DFT the calculations, a complete structural detail, vibrational, electrostatic potential, Mulliken population, HOMO-LUMO and thermodynamic analysis were also doneThis manuscript is suitable publication in Molecules.
| 3 | 2 |
molecules27051656_makarova
| 1 |
We are delighted and thankful for the recommendation.
| 2 | 1 |
The manuscript is well-written and must be accepted in its present form for publication in Molecules.
| 1 | 2 |
molecules27051656_makarova
| 1 |
We appreciate the recommendation and rewrite the abstract as follows, Polytopic organic ligands with hydrazone moiety are in the forefront of new drug research among many others due to their unique and versatile functionality and ease of strategic ligand design. Quantum chemical calculations of these polyfunctional ligands can be carried out in silico to determine the thermodynamic parameters. In this report two new tritopic dihydrazide ligands, N'2, N'6-bis[(1E)-1-(thiophen-2-yl) ethylidene] pyridine-2, 6-dicarbohydrazide (L1) and N'2, N'6-bis[(1E)-1-(1H-pyrrol-2-yl) ethylidene] pyridine-2, 6-dicarbohydrazide (L2) were successfully prepared by the condensation reaction of pyridine-2, 6-dicarboxylic hydrazide with 2-acetylthiophene and 2-acetylpyrrole. The FT-IR, 1H and 13C NMR as well as mass spectra of both L1 and L2 were recorded and analyzed. Quantum chemical calculations were performed at DFT/B3LYP/cc-pvdz/6-311+ G (d, p) level of theory to study the molecular geometry, vibrational frequencies, and thermodynamic properties including changes of ∆H, ∆S, and ∆G for both the ligands. The optimized vibrational frequency and (1H and 13C) NMR obtained by B3LYP/cc-pvdz/6-311 + G (d, p) showed good agreement with experimental FT-IR and NMR data. Frontier molecular orbital (FMO) calculations were also conducted to find the HOMO, LUMO, and HOMO–LUMO gaps of the two synthesized compounds. To investigate the biological activities of the ligands, L1 and L2 were tested in vitro bioassays against some Gram-negative and Gram-positive bacteria and the fungus strain. In addition, Molecular docking was used to study the molecular behavior of L1 and L2 against tyrosinase from Bacillus megaterium. The outcomes revealed that both L1 and L2 can suppress microbial growth of bacteria and fungi with variable potency. The antibacterial activity results demonstrated the compound L2 to be potentially effective against Bacillus Megaterium with inhibition zones of 12 mm while molecular docking study showed the binding energies for L1 and L2 to be −7.7 and −8.8 kcal mol−1 respectively with tyrosinase from Bacillus megaterium. -
| 2 | 1 |
The conclusion is missing.
| 1 | 2 |
molecules27051656_makarova
| 1 |
We appreciate the recommendation and corrected the font of the references.
| 2 | 1 |
Font of the reference is different from the text
| 1 | 2 |
molecules27051656_makarova
| 1 |
We appreciate the recommendation and corrected the section as below: Polytopic ligands containing hydrazide-hydrazone moiety (—CO—NHN=CH—) are important for new drug development [1-6]. Because, their polyfunctional nature offer multifarious synthetic ways to derivatize such organic molecules towards suitable and effective drug-receptor interaction. The derivatives of hydrazide-hydrazone moiety specially with heterocyclic system possess a range of biological activities namely, anti-microbial, anti-mycobacterial, antitubercular, anticonvulsant, anticholinesterase [1], antiplatelet, and more importantly antitumor [5,7]. Transition metal complexes derived from such type of ligands have been widely studied since they also demonstrate significant biological and pharmacological properties [8-11].
| 2 | 1 |
This sentence “Polytopic ligands containing hydrazide-hydrazone moiety (—CO—NHN=CH—) are important for new drug development” should be better connected to the next one to explain why they are important for new drug development
| 1 | 2 |
molecules27051656_makarova
| 1 |
We appreciate the recommendation and corrected the section as below: This Section is corrected as “In addition to that, the compounds were tested in vitro against Gram-negative and positive bacteria and two fungi. Molecular docking was used to study the molecular behavior of L1 and L2 against tyrosinase from Bacillus megaterium.’’
| 2 | 1 |
Replace “In addition to that, the compounds were tested in vitro bioassays against some Gram-negative and Gram-positive bacteria and the fungus strain showing specially promising results for L2. Molecular docking methodology was used to study molecular behavior of L1 and L2 with Bacillus Megaterium to identify their binding interactions” with “In addition to that, the compounds were tested in vitro against Gram-negative and positive bacteria and two fungi. Molecular docking was used to study the molecular behavior of L1 and L2 against tyrosinase from Bacillus megaterium. Response:
| 1 | 2 |
molecules27051656_makarova
| 1 |
We appreciate the recommendation and added the required references as below. We have these specimens of strains available in our lab to study. Therefore, we used. We also updated the standard ciprofloxacin and miconazole with Ceftriaxone and Amphotericin-B and corrected the reference the number of Salmonella Typhi (K-323130) bacteria. We are showing our sincere apology for such mistakes. The changes are added as follows,
| 2 | 1 |
Section 2.3.1. Reference for the used strains is required. Why are those specific strains used?
| 1 | 2 |
molecules27051656_makarova
| 1 |
4.9. We appreciate the recommendation, and corrected this information as shown below: 3.2.
| 2 | 1 |
Please change the info accordingly. ODB ID 4j6u is for tyrosinase from Bacillus megaterium, not the bacillus megatherium cristal structure.
| 1 | 2 |
molecules27051656_makarova
| 1 |
The binding site residues predicted by CASTp for tyrosinase were used for grid generation. Protein-ligand Docking 3.2.1. Ligand and Protein preparation: The structures of L1 and L2 have been fully optimized by using Gaussian 09 software at B3LYP/6-311G+ (d, p) level. The 3D crystal structure of tyrosinase from Bacillus Megaterium (PDB ID: 4j6u; resolution: 2.5Å, Chain A, B) was obtained in pdb format from online RCSB protein data bank (PDB) database. The structure was verified, and an energy minimization was performed with the Swiss-Pdb Viewer software packages (version 4.1.0) [44], since the crystal structure contains a variety of issues related to improper bond order, side chains geometry, and missing hydrogen atoms. Prior to docking, all the heteroatoms and water molecules were removed from the crystal structure using PyMol (version 1.3) software packages [45]. The active binding pocket of tyrosinase was predicted by CASTp—having the highest pocket area and volume are 95.432 Å2 and 137.877 Å3, respectively [46]. Both the structures of the proteins and ligands were saved in .pdbqt format by AutoDock Vina (version 1.1.2, May 11, 2011) for docking analysis [47]. 3.2.2. Molecular docking Analysis: The docking calculations were performed using default parameters and 8 docked conformations were generated for both compounds. The energy calculations were done by genetic algorithms. Nonpolar hydrogen atoms, Gasteiger partial charges, rotatable bonds, and grid box with dimensions 66.57 × 58.25 × 84.98 Å3 created on the tyrosinase with the aid of Auto Dock Tools 1.1.2 and spacing of 0.3750 Å. The docked conformation of the respective protein conformer with lowest binding free energy and root mean-square deviation value (RMSD) 0.0 Å was analyzed using PyMOL Molecular Graphics System (version 1.7.4) and Accelrys Discovery Studio 4.1 [49]. We appreciate the recommendation, and splitted the data into 2 more subheads as, 3.2.1. Ligand and Protein preparation and 3.2.2. Molecular docking analysis. Also, more information was added about the software used as shown below: 3.2.
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Section 3.2. and 4.9. The data at least should be split into 2 more subheads, one for the ligand and receptor preparation and the second for the docking analysis. Divide the data into those 2 subheads and add more about the software used to perform the docking and the parameters used (Grid box, extensiveness …) Response:
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molecules27051656_makarova
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2.1.3. Antimicrobial activity assay In vitro antimicrobial activity of synthesized ligands was evaluated by agar disc diffusion method [40]. Mueller Hinton Agar (MHA) media (HIMEDIA, India) was used as a control medium for testing against bacteria and Potato Dextrose Agar (PDA) media (HIMEDIA, India) was used for fungal strain. After preparation, the MHA and PDA medias were incubated for 24 h and contaminations were checked. After incubation, the test organism was inoculated using sterile cotton bar on media. The sample discs were put gently on pre-inoculated agar plates and aerobically incubated for 24 h at 37 °C for antibacterial and for 48 h at 26 °C for antifungal assay. Dimethyl sulfoxide (DMSO) was used as control. Each disc was loaded with 25 µL of sample solution in DMSO containing 300 µg of synthesized compounds. 10 µL of ceftriaxone and amphotericin-B solutions containing 50 µg each in DMSO were loaded per disc for antibacterial and antifungal assays as positive control, respectively. The diameter of the inhibition zones in mm circling the disc were measured. Two gram-positive Staphylococcus aureus (cars-2) and Bacillus Megaterium (BTCC-18), two gram-negative Escherichia coli (carsgn-2) and Salmonella Typhi (K-323130) bacteria, and two fungal strains Trichoderma harzianum (carsm-2) and Aspergillus niger (carsm-3) were used in this study. We appreciate the recommendation, and this section is updated by changing the standard ciprofloxacin and miconazole with Ceftriaxone and Amphotericin-B. Also, the sentences of second part (4.8) are deleted and added to 2.3.1 as suggested by the reviewer. Antimicrobial activity using agar disc diffusion method In vitro sensitivities of two gram-positive and two gram-negative bacteria including two fungal strains against the synthesized compounds were evaluated by agar disc diffusion method. The formation of diameter of inhibition zones in mm by the synthesized analogues are shown in Table 5. Compound L2 showed moderate activity against Bacillus Megaterium bacteria while L1 showed promising antifungal activity against Aspergillus niger fungal strains compared to standard Amphotericin-B. Diameter of inhibition zones (mm) of the synthesized compounds, Ceftriaxone and Amphotericin-B against tested bacterial and fungal strains.
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Section 4.8. There is no proper description of the results and no discussion in this part. Please revise - This sentence should be moved to the materials and methods or deleted from the section “Two gram-positive Staphylococcus aureus (cars-2) and Bacillus Megaterium (BTCC-18), two gram-negative Escherichia coli (carsgn-2) and Salmonella Typhi (JCM-1652) bacteria, and two fungal strains Trichoderma harzianum (carsm-2) and Aspergillus niger (carsm-3) were used in this study.”
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molecules27051656_makarova
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Molecular Docking Study Molecular docking is a powerful tool to investigate and provide a proper understanding for ligand receptor interactions in order to facilitate the design of potential drugs [93-96]. To investigate and compare the antimicrobial activity of the synthesized compounds, docking analysis of L1 and L2 against tyrosinase from Bacillus Megaterium were performed. It is well-known that tyrosinase of Bacillus Megaterium bacteria is an attractive target for the development of antimicrobials or antibiotic adjuvants for the treatment of hyperpigmentation because of its similarity (33.5%) to the human enzyme [97-100]. We appreciate the recommendation and updated the molecular docking study by adding more details and literature references as follows, 4.9.
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The molecular docking study is missing a control to properly analyse the results.
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molecules27051656_makarova
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We appreciate the recommendation and changed the conclusion as follows, Pyrrole and thiophene as organic molecules and their metal cluster derivatives have been recognized to present a wide range of biological activities in recent years. In this present study we have synthesized two tritopic dihydrazide based ligands bearing Pyrrole and Thiophene as end groupings and characterized successfully by FT-IR, 1H and 13C NMR and mass spectrometry. Based on the DFT the calculations, a complete structural detail, vibrational, electrostatic potential, Mulliken population, HOMO-LUMO and thermodynamic analysis were also done. The computed FT-IR analysis as well as the 1H and 13C NMR using B3LYP/CC-PVDZ/6-311+G(d, p) method agreed satisfactorily with the experimental results. We further evaluated the thermodynamic parameters ∆H, ∆S, and ∆G of the ligands. The geometry optimization revealed the planarity of L1 and L2 molecules. Further, it was seen from the HOMO-LUMO energy values that the chemical potentials were negative and the frontier orbital gap of the molecule under investigation was small, and hence, both compounds are reactive and polarizable. To further showcase the biological activity of the ligands against organic pathogens, the antimicrobial assay was performed and revealed significant inhibition of L2 against Bacillus Megaterium gram positive bacteria, and L1 against Escherichia coli, Aspergillus niger although in lesser extent. The moderate activity of L2 molecule against Bacillus Megaterium is substantiated by molecular docking study against tyrosinase from Bacillus megaterium and was found significant with a binding energy of -8.8 kcal/mol and three hydrogen bond interactions, which might suggest the antimicrobial activity of the molecule. Overall, L1 and L2 compounds have spurred significant interest for us from the synthetic, computational and biological point of view. We anticipate continued research regarding these classes of exciting organic ligands.
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Conclusion: Repeated abstract. The conclusion must remind the reader why the article was written in the first place and why it is important in the field. The conclusion should briefly give an insight into the obtained results and also the limitations.
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molecules27051656_makarova
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4.9.1. 6. In L1-4j6u, one conventional hydrogen bond (3.04 Å) of O-H----O-C observed between O-H of Tyr267A and O-C group of compounds L1. Pi-cation, pi-sulfur and amide-pi bonds were also noticed with LYS47A, PHE48A, ILE39A, ALA40A, GLY43B and ALA44B, respectively. Moreover, ALA44A, LYS47A, ALA44B, LYS47B, PRO52A, ALA40B and ILE139B were actively involved in the non-covalent interaction (hydrophobic pi-alkyl). L2-4j6u complex was stabilized by four NH….O hydrogen bonds and they were LYS47A (2.25 Å), GLY143B (3.04 Å), Tyr267A (3.07 Å) and PRO219B (2.91 Å) (Fig. 6). Like L1, L2 formed pi-cation and amide-pi bonds with LYS47A, ILE39A, GLY43B, where the distances were 3.73, 4.34, 3.54 Å. L2 also formed seven pi-alkyl bonds with ALA44A (5.19 Å), LYS47A (4.35 Å), ALA44B (3.95 Å), LYS47B (4.98 Å), PRO52A (5.04 Å), ALA40B (4.67 Å) and ILE139B (4.24 Å), respectively. We appreciate the recommendation and rewrote the Molecular Docking study as follows as suggested by the reviewer, 4.9. Molecular Docking Study Molecular docking is a powerful tool to investigate and provide a proper understanding of ligand-receptor interactions in order to facilitate the design of potential drugs [92-95]. To investigate and compare the antimicrobial activity of the synthesized compounds, docking analyses of L1 and L2 against tyrosinase from Bacillus Megaterium were performed. It is well-known that tyrosinase of Bacillus Megaterium bacteria is an attractive target for the development of antimicrobials or antibiotic adjuvants for the treatment of hyperpigmentation because of its similarity (33.5%) to the human enzyme [96-99]. The docking results were also compared with well-testified inhibitor arbutin [97]. Binding affinity of L1 and L2 The highest antibacterial activity (zone of inhibition 12 mm) of compound L2 was detected with tyrosinase from Bacillus Megaterium (PDB ID: 4j6u) bacteria compared to L1. The binding energies for L1 and L2 with Bacillus Megaterium were −7.7 and −8.8 kcal mol−1, respectively, whereas for arbutin-4j6u the value was -9.1 kcal mol-1 which were calculated by AutoDock Vina. The interactions of the 4j6u with compounds L1 and L2 are shown in Fig. It was observed that arbutin formed six conventional hydrogen bonds with 4j6u (Supplementary Fig. S11) by the following residues: ALA40A (one O-H----O-C hydrogen bond), Glu141A (four O-H----O-C hydrogen bond), and LYS47B (one O-H----O-C hydro-gen bond). Also several hydrophobic interactions were found with ILE139A, ILE39A, and ALA40A. Results of docking studies revealed that L1 and L2 formed bonds to the active site of tyrosinase and showed strong interactions with Tyr267A, Ala40A, Ala44A, ALA44B and Lys47B of tyrosinase enzyme (PDB ID: 4j6u), which are in close vicinity to the control arbutin and supports the literature [100-102].
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The molecular study needs a control molecule to compare the results of L1 and L2. how would we know that −7.7 and −8.8 are good scores or not. Either perform a quick analysis for a molecule known for its tyrosinase inhibition or compare with other studies control that used the same methods in your paper.For exemple in this study "https://doi.org/10.1016/j.bmc.2011.10.078" they used Arbutin to compare the results of their studied molecule.
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molecules27051656_makarova
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We appreciate the recommendation and corrected the style of the references as suggested by the reviewer.
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The references are in a weird format containing only the author's name, journal name and date. article title and other data are missing. Reference style followed by the journalAuthor 1, A.B. ; Author 2, C.D. Title of the article. Abbreviated Journal Name Year, Volume, page range.
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molecules27051656_makarova
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We appreciate the recommendation and comments. We corrected the above-mentioned correction as suggested by the reviewer and presented as follows, 1H NMR (400 MHz, DMSO-d6, ppm): δ 11.43 (s, 2H), 8.34 (m, 2H), 8.28 (m, 1H), 7.65 (d, 2H, J = 4.8 Hz), 7.61 (d, 2H, J = 3.2 Hz), 7.14 (t, 2H, J = 8.8 Hz), 2.51 (s, 6H). 13C NMR (100 MHz, DMSO-d6, ppm): 159.44 (C=O), 154.55 (Ar-C), 148.91 (Ar-C), 143.22 (-C=N-), 140.48 (Ar-C), 130.06 (Ar-C), 129.44 (Ar-C), 128.20 (Ar-C), 125.75 (Ar- C), 15.32 (-CH3).
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The manuscript by Sharmin Akther Rupa et al, the manuscript has many serious concerns on the basis that it cannot be accepted in this journal. for example, 13C NMR must be 100 MHz not 400 MHz, value must be either ascending order or descending order (13C NMR (400 MHz, DMSO-d6, ppm): 1 above example showed the manuscript not written carefully.
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molecules27051656_perova
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We appreciate the recommendation and agree with the reviewer that the computational and experimental results of antimicrobial activity differ to some extent in this part of the study and required further investigation to understand why such activity differs to the ligands by other means in the future. In this study, we successfully synthesized the novel ligands and studied its spectroscopy with other probable studies. Fortunately, we have found outstanding results during the chemo-sensor study and hopefully, we could be able to show the excellent usage of the ligands as a chemo-sensor in near future. Also, we are planning to do a fluorescence imaging study of protein-ligands.
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Second one that is very important for this paper: The activity of L2 molecule against Bacillus Megaterium (PDB 4j6u) was significant with a binding energy of -8.8 kcal/mol and three hydrogen bond interactions, which reveals the antimicrobial activity of the molecule. Both compounds are biologically active, but their activity was moderate which did not support their efforts.
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molecules27051656_perova
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We appreciate the comments of the reviewer and the following are the answers in response to the question for the kind consideration of the reviewer- Tyrosinase is a key enzyme in melanogenesis, which is essential for pigmentation. Dysfunction of tyrosinase may cause skin cancer. It is well-known that tyrosinase of Bacillus Megaterium bacteria is an attractive target for the development of antimicrobials or antibiotic adjuvants for the treatment of hyperpigmentation because of its similarity (33.5%) to the human enzyme [97-103]. That’s why, to investigate and compare the antimicrobial activity of the synthesized compounds with in vitro data, docking analysis of L1 and L2 against tyrosinase from Bacillus Megaterium was performed. Also, molecular docking with other proteins of B. Megaterium was conducted, but 46ju provided better binding affinity with the synthesized compounds. For this reason, we aim to study the structure of tyrosinase from the bacteria. Preliminary antimicrobial studies were carried out to validate the docking protocol. At present, we are doing the fluorescence activities of these ligands and L2 showed excellent fluorescent emission at λmax 520 nm. So, we hope that we will carry out ALA scan (Alanine scanning) based MD experiments and 100ns Molecular dynamics (MD) simulation guided protein-ligand stability in the future for our next study since within this shortest time, we are unable to do these experiments. The active binding site of tyrosinase was predicted by CASTp. We have included this in the manuscript as follows: To investigate and compare the antimicrobial activity of the synthesized compounds, docking analysis of L1 and L2 against tyrosinase from Bacillus Megaterium were performed. It is well-known that tyrosinase of Bacillus Megaterium bacteria is an attractive target for the development of antimicrobials or antibiotic adjuvants for the treatment of hyperpigmentation because of its similarity (33.5%) to the human enzyme [97-100]. The binding energies for L1 and L2 with Bacillus Megaterium were −7.7 and −8.8 kcal mol−1, respectively, which were calculated by AutoDock Vina. The interactions of the 4j6u with compounds L1 and L2 are shown in the Fig. Results of docking studies revealed that L1 and L2 formed bonds to the active site of tyrosinase and showed strong interactions with Tyr267A, Ala44A, and ALA44B of tyrosinase enzyme (PDB ID: 4j6u), which also supports the literature [101-103]. Thus, computational results are in good agreement with in vitro antibacterial behaviour of our compounds for novel antibacterial drug design.
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4. 3. 2. Third one their binding study: 1. Why did the authors consider Tyrosinase from Bacillus megaterium N205A mutant pdb id 4j6u? As they did not report any enzyme specific inhibition related experiments. Docking is a preliminary experiment. How did the author validate the docking protocol? The authors are suggested using some decoy ligands and calculating the enrichment value in order to justify the docking protocol followed by ALA scan (Alanine scanning) based MD experiments. In addition, authors are suggested to report at list 100ns Molecular dynamics (MD) simulation guided protein-ligand stability report followed by either MM-GB or PB-SA based thermo data analysis. The pdb id 4j6u does not contain any bound ligand. How did the author select the binding site? If a few sets of amino acids were considered to define the binding site, then on what basis they select them? The authors did not report any Tyrosinase enzyme inhibition assay, they are requested to justify Tyrosinase inhibition as the probable mechanism of action for these sets of ligands by providing suitable literature references.
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molecules27051656_perova
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We are delighted and thankful for the recommendation.
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Abedin et al. explored "Synthesis of Novel Tritopic Hydrazone Ligands: Spectroscopy, Biological activity, DFT, and Molecular docking Studies". The manuscript is well-written and must be accepted in its present form for publication in Molecules.
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molecules27051656_perova
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We appreciate the recommendation and rewrite the abstract as follows, Polytopic organic ligands with hydrazone moiety are in the forefront of new drug research among many others due to their unique and versatile functionality and ease of strategic ligand design. Quantum chemical calculations of these polyfunctional ligands can be carried out in silico to determine the thermodynamic parameters. In this report two new tritopic dihydrazide ligands, N'2, N'6-bis[(1E)-1-(thiophen-2-yl) ethylidene] pyridine-2, 6-dicarbohydrazide (L1) and N'2, N'6-bis[(1E)-1-(1H-pyrrol-2-yl) ethylidene] pyridine-2, 6-dicarbohydrazide (L2) were successfully prepared by the condensation reaction of pyridine-2, 6-dicarboxylic hydrazide with 2-acetylthiophene and 2-acetylpyrrole. The FT-IR, 1H and 13C NMR as well as mass spectra of both L1 and L2 were recorded and analyzed. Quantum chemical calculations were performed at DFT/B3LYP/cc-pvdz/6-311+ G (d, p) level of theory to study the molecular geometry, vibrational frequencies, and thermodynamic properties including changes of ∆H, ∆S, and ∆G for both the ligands. The optimized vibrational frequency and (1H and 13C) NMR obtained by B3LYP/cc-pvdz/6-311 + G (d, p) showed good agreement with experimental FT-IR and NMR data. Frontier molecular orbital (FMO) calculations were also conducted to find the HOMO, LUMO, and HOMO–LUMO gaps of the two synthesized compounds. To investigate the biological activities of the ligands, L1 and L2 were tested in vitro bioassays against some Gram-negative and Gram-positive bacteria and the fungus strain. In addition, Molecular docking was used to study the molecular behavior of L1 and L2 against tyrosinase from Bacillus megaterium. The outcomes revealed that both L1 and L2 can suppress microbial growth of bacteria and fungi with variable potency. The antibacterial activity results demonstrated the compound L2 to be potentially effective against Bacillus Megaterium with inhibition zones of 12 mm while molecular docking study showed the binding energies for L1 and L2 to be −7.7 and −8.8 kcal mol−1 respectively with tyrosinase from Bacillus megaterium. -
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The conclusion is missing.
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molecules27051656_perova
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We appreciate the recommendation and corrected the font of the references.
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Font of the reference is different from the text
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molecules27051656_perova
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We appreciate the recommendation and corrected the section as below: Polytopic ligands containing hydrazide-hydrazone moiety (—CO—NHN=CH—) are important for new drug development [1-6]. Because, their polyfunctional nature offer multifarious synthetic ways to derivatize such organic molecules towards suitable and effective drug-receptor interaction. The derivatives of hydrazide-hydrazone moiety specially with heterocyclic system possess a range of biological activities namely, anti-microbial, anti-mycobacterial, antitubercular, anticonvulsant, anticholinesterase [1], antiplatelet, and more importantly antitumor [5,7]. Transition metal complexes derived from such type of ligands have been widely studied since they also demonstrate significant biological and pharmacological properties [8-11].
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This sentence “Polytopic ligands containing hydrazide-hydrazone moiety (—CO—NHN=CH—) are important for new drug development” should be better connected to the next one to explain why they are important for new drug development
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molecules27051656_perova
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We appreciate the recommendation and corrected the section as below: This Section is corrected as “In addition to that, the compounds were tested in vitro against Gram-negative and positive bacteria and two fungi. Molecular docking was used to study the molecular behavior of L1 and L2 against tyrosinase from Bacillus megaterium.’’ Section 2.3.1.
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Replace “In addition to that, the compounds were tested in vitro bioassays against some Gram-negative and Gram-positive bacteria and the fungus strain showing specially promising results for L2. Molecular docking methodology was used to study molecular behavior of L1 and L2 with Bacillus Megaterium to identify their binding interactions” with “In addition to that, the compounds were tested in vitro against Gram-negative and positive bacteria and two fungi. Molecular docking was used to study the molecular behavior of L1 and L2 against tyrosinase from Bacillus megaterium. Response:
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molecules27051656_perova
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We appreciate the recommendation and added the required references as below. We have these specimens of strains available in our lab to study. Therefore, we used. We also updated the standard ciprofloxacin and miconazole with Ceftriaxone and Amphotericin-B and corrected the reference the number of Salmonella Typhi (K-323130) bacteria. We are showing our sincere apology for such mistakes. The changes are added as follows, 2.1.3. Antimicrobial activity assay In vitro antimicrobial activity of synthesized ligands was evaluated by agar disc diffusion method [40]. Mueller Hinton Agar (MHA) media (HIMEDIA, India) was used as a control medium for testing against bacteria and Potato Dextrose Agar (PDA) media (HIMEDIA, India) was used for fungal strain. After preparation, the MHA and PDA medias were incubated for 24 h and contaminations were checked. After incubation, the test organism was inoculated using sterile cotton bar on media. The sample discs were put gently on pre-inoculated agar plates and aerobically incubated for 24 h at 37 °C for antibacterial and for 48 h at 26 °C for antifungal assay. Dimethyl sulfoxide (DMSO) was used as control. Each disc was loaded with 25 µL of sample solution in DMSO containing 300 µg of synthesized compounds. 10 µL of ceftriaxone and amphotericin-B solutions containing 50 µg each in DMSO were loaded per disc for antibacterial and antifungal assays as positive control, respectively. The diameter of the inhibition zones in mm circling the disc were measured. Two gram-positive Staphylococcus aureus (cars-2) and Bacillus Megaterium (BTCC-18), two gram-negative Escherichia coli (carsgn-2) and Salmonella Typhi (K-323130) bacteria, and two fungal strains Trichoderma harzianum (carsm-2) and Aspergillus niger (carsm-3) were used in this study.
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Reference for the used strains is required. Why are those specific strains used?
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molecules27051656_perova
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4.9. Molecular Docking Study Molecular docking is a powerful tool to investigate and provide a proper understanding for ligand receptor interactions in order to facilitate the design of potential drugs [93-96]. We appreciate the recommendation, and corrected this information as shown below: 3.2.
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Please change the info accordingly. ODB ID 4j6u is for tyrosinase from Bacillus megaterium, not the bacillus megatherium cristal structure.
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molecules27051656_perova
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The binding site residues predicted by CASTp for tyrosinase were used for grid generation. Protein-ligand Docking 3.2.1. Ligand and Protein preparation: The structures of L1 and L2 have been fully optimized by using Gaussian 09 software at B3LYP/6-311G+ (d, p) level. The 3D crystal structure of tyrosinase from Bacillus Megaterium (PDB ID: 4j6u; resolution: 2.5Å, Chain A, B) was obtained in pdb format from online RCSB protein data bank (PDB) database. The structure was verified, and an energy minimization was performed with the Swiss-Pdb Viewer software packages (version 4.1.0) [44], since the crystal structure contains a variety of issues related to improper bond order, side chains geometry, and missing hydrogen atoms. Prior to docking, all the heteroatoms and water molecules were removed from the crystal structure using PyMol (version 1.3) software packages [45]. The active binding pocket of tyrosinase was predicted by CASTp—having the highest pocket area and volume are 95.432 Å2 and 137.877 Å3, respectively [46]. Both the structures of the proteins and ligands were saved in .pdbqt format by AutoDock Vina (version 1.1.2, May 11, 2011) for docking analysis [47]. 3.2.2. Molecular docking Analysis: The docking calculations were performed using default parameters and 8 docked conformations were generated for both compounds. The energy calculations were done by genetic algorithms. Nonpolar hydrogen atoms, Gasteiger partial charges, rotatable bonds, and grid box with dimensions 66.57 × 58.25 × 84.98 Å3 created on the tyrosinase with the aid of Auto Dock Tools 1.1.2 and spacing of 0.3750 Å. The docked conformation of the respective protein conformer with lowest binding free energy and root mean-square deviation value (RMSD) 0.0 Å was analyzed using PyMOL Molecular Graphics System (version 1.7.4) and Accelrys Discovery Studio 4.1 [49]. We appreciate the recommendation, and splitted the data into 2 more subheads as, 3.2.1. Ligand and Protein preparation and 3.2.2. Molecular docking analysis. Also, more information was added about the software used as shown below: 3.2.
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The data at least should be split into 2 more subheads, one for the ligand and receptor preparation and the second for the docking analysis. Divide the data into those 2 subheads and add more about the software used to perform the docking and the parameters used (Grid box, extensiveness …) Response:
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molecules27051656_perova
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We appreciate the recommendation, and this section is updated by changing the standard ciprofloxacin and miconazole with Ceftriaxone and Amphotericin-B. Also, the sentences of second part (4.8) are deleted and added to 2.3.1 as suggested by the reviewer. 2.1.3. Antimicrobial activity assay In vitro antimicrobial activity of synthesized ligands was evaluated by agar disc diffusion method [40]. Mueller Hinton Agar (MHA) media (HIMEDIA, India) was used as a control medium for testing against bacteria and Potato Dextrose Agar (PDA) media (HIMEDIA, India) was used for fungal strain. After preparation, the MHA and PDA medias were incubated for 24 h and contaminations were checked. After incubation, the test organism was inoculated using sterile cotton bar on media. The sample discs were put gently on pre-inoculated agar plates and aerobically incubated for 24 h at 37 °C for antibacterial and for 48 h at 26 °C for antifungal assay. Dimethyl sulfoxide (DMSO) was used as control. Each disc was loaded with 25 µL of sample solution in DMSO containing 300 µg of synthesized compounds. 10 µL of ceftriaxone and amphotericin-B solutions containing 50 µg each in DMSO were loaded per disc for antibacterial and antifungal assays as positive control, respectively. The diameter of the inhibition zones in mm circling the disc were measured. Two gram-positive Staphylococcus aureus (cars-2) and Bacillus Megaterium (BTCC-18), two gram-negative Escherichia coli (carsgn-2) and Salmonella Typhi (K-323130) bacteria, and two fungal strains Trichoderma harzianum (carsm-2) and Aspergillus niger (carsm-3) were used in this study. 4.8. Antimicrobial activity using agar disc diffusion method In vitro sensitivities of two gram-positive and two gram-negative bacteria including two fungal strains against the synthesized compounds were evaluated by agar disc diffusion method. The formation of diameter of inhibition zones in mm by the synthesized analogues are shown in Table 5. Compound L2 showed moderate activity against Bacillus Megaterium bacteria while L1 showed promising antifungal activity against Aspergillus niger fungal strains compared to standard Amphotericin-B. Table 5. Diameter of inhibition zones (mm) of the synthesized compounds, Ceftriaxone and Amphotericin-B against tested bacterial and fungal strains.
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There is no proper description of the results and no discussion in this part.
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molecules27051656_perova
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We appreciate the recommendation and updated the molecular docking study by adding more details and literature references as follows, 4.9. Molecular Docking Study Molecular docking is a powerful tool to investigate and provide a proper understanding for ligand receptor interactions in order to facilitate the design of potential drugs [93-96]. To investigate and compare the antimicrobial activity of the synthesized compounds, docking analysis of L1 and L2 against tyrosinase from Bacillus Megaterium were performed. It is well-known that tyrosinase of Bacillus Megaterium bacteria is an attractive target for the development of antimicrobials or antibiotic adjuvants for the treatment of hyperpigmentation because of its similarity (33.5%) to the human enzyme [97-100].
| 2 | 1 |
This sentence should be moved to the materials and methods or deleted from the section “Two gram-positive Staphylococcus aureus (cars-2) and Bacillus Megaterium (BTCC-18), two gram-negative Escherichia coli (carsgn-2) and Salmonella Typhi (JCM-1652) bacteria, and two fungal strains Trichoderma harzianum (carsm-2) and Aspergillus niger (carsm-3) were used in this study.”
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molecules27051656_perova
| 1 |
In this present study we have synthesized two tritopic dihydrazide based ligands bearing Pyrrole and Thiophene as end groupings and characterized successfully by FT-IR, 1H and 13C NMR and mass spectrometry. Based on the DFT the calculations, a complete structural detail, vibrational, electrostatic potential, Mulliken population, HOMO-LUMO and thermodynamic analysis were also done. The computed FT-IR analysis as well as the 1H and 13C NMR using B3LYP/CC-PVDZ/6-311+G(d, p) method agreed satisfactorily with the experimental results. We further evaluated the thermodynamic parameters ∆H, ∆S, and ∆G of the ligands. The geometry optimization revealed the planarity of L1 and L2 molecules. Further, it was seen from the HOMO-LUMO energy values that the chemical potentials were negative and the frontier orbital gap of the molecule under investigation was small, and hence, both compounds are reactive and polarizable. To further showcase the biological activity of the ligands against organic pathogens, the antimicrobial assay was performed and revealed significant inhibition of L2 against Bacillus Megaterium gram positive bacteria, and L1 against Escherichia coli, Aspergillus niger although in lesser extent. The moderate activity of L2 molecule against Bacillus Megaterium is substantiated by molecular docking study against tyrosinase from Bacillus megaterium and was found significant with a binding energy of -8.8 kcal/mol and three hydrogen bond interactions, which might suggest the antimicrobial activity of the molecule. Overall, L1 and L2 compounds have spurred significant interest for us from the synthetic, computational and biological point of view. We anticipate continued research regarding these classes of exciting organic ligands. We appreciate the recommendation and changed the conclusion as follows, 9 Pyrrole and thiophene as organic molecules and their metal cluster derivatives have been recognized to present a wide range of biological activities in recent years.
| 2 | 1 |
The molecular docking study is missing a control to properly analyse the results.
| 1 | 2 |
molecules27051656_perova
| 1 |
4.9.1. Binding affinity of L1 and L2 The highest anti-bacterial activity (zone of inhibition 12 mm) of compound L2 was detected with tyrosinase from Bacillus Megaterium (PDB ID: 4j6u) bacteria compared to L1. 6. In L1-4j6u, one conventional hydrogen bond (3.04 Å) of O-H----O-C observed between O-H of Tyr267A and O-C group of compounds L1. Pi-cation, pi-sulfur and amide-pi bonds were also noticed with LYS47A, PHE48A, ILE39A, ALA40A, GLY43B and ALA44B, respectively. Moreover, ALA44A, LYS47A, ALA44B, LYS47B, PRO52A, ALA40B and ILE139B were actively involved in the non-covalent interaction (hydrophobic pi-alkyl). L2-4j6u complex was stabilized by four NH….O hydrogen bonds and they were LYS47A (2.25 Å), GLY143B (3.04 Å), Tyr267A (3.07 Å) and PRO219B (2.91 Å) (Fig. 6). Like L1, L2 formed pi-cation and amide-pi bonds with LYS47A, ILE39A, GLY43B, where the distances were 3.73, 4.34, 3.54 Å. L2 also formed seven pi-alkyl bonds with ALA44A (5.19 Å), LYS47A (4.35 Å), ALA44B (3.95 Å), LYS47B (4.98 Å), PRO52A (5.04 Å), ALA40B (4.67 Å) and ILE139B (4.24 Å), respectively. We appreciate the recommendation and rewrote the Molecular Docking study as follows as suggested by the reviewer, 4.9. Molecular Docking Study Molecular docking is a powerful tool to investigate and provide a proper understanding of ligand-receptor interactions in order to facilitate the design of potential drugs [92-95]. To investigate and compare the antimicrobial activity of the synthesized compounds, docking analyses of L1 and L2 against tyrosinase from Bacillus Megaterium were performed. It is well-known that tyrosinase of Bacillus Megaterium bacteria is an attractive target for the development of antimicrobials or antibiotic adjuvants for the treatment of hyperpigmentation because of its similarity (33.5%) to the human enzyme [96-99]. The docking results were also compared with well-testified inhibitor arbutin [97]. Binding affinity of L1 and L2 The highest antibacterial activity (zone of inhibition 12 mm) of compound L2 was detected with tyrosinase from Bacillus Megaterium (PDB ID: 4j6u) bacteria compared to L1. The binding energies for L1 and L2 with Bacillus Megaterium were −7.7 and −8.8 kcal mol−1, respectively, whereas for arbutin-4j6u the value was -9.1 kcal mol-1 which were calculated by AutoDock Vina. The interactions of the 4j6u with compounds L1 and L2 are shown in Fig. It was observed that arbutin formed six conventional hydrogen bonds with 4j6u (Supplementary Fig. S11) by the following residues: ALA40A (one O-H----O-C hydrogen bond), Glu141A (four O-H----O-C hydrogen bond), and LYS47B (one O-H----O-C hydro-gen bond). Also several hydrophobic interactions were found with ILE139A, ILE39A, and ALA40A. Results of docking studies revealed that L1 and L2 formed bonds to the active site of tyrosinase and showed strong interactions with Tyr267A, Ala40A, Ala44A, ALA44B and Lys47B of tyrosinase enzyme (PDB ID: 4j6u), which are in close vicinity to the control arbutin and supports the literature [100-102].
| 4 | 1 |
The molecular study needs a control molecule to compare the results of L1 and L2. how would we know that −7.7 and −8.8 are good scores or not. Either perform a quick analysis for a molecule known for its tyrosinase inhibition or compare with other studies control that used the same methods in your paper.For exemple in this study "https://doi.org/10.1016/j.bmc.2011.10.078" they used Arbutin to compare the results of their studied molecule.
| 3 | 2 |
molecules27051656_perova
| 1 |
We appreciate the recommendation and corrected the style of the references as suggested by the reviewer.
| 4 | 1 |
The references are in a weird format containing only the author's name, journal name and date. article title and other data are missing. Reference style followed by the journalAuthor 1, A.B. ; Author 2, C.D. Title of the article. Abbreviated Journal Name Year, Volume, page range.
| 3 | 2 |
molecules27051656_perova
| 1 |
We have changed the position of Figure 1 to line 182, and adjusted the arrangement of the figures in the article.
| 2 | 1 |
line. 57-58. It seems that Figure 1 should be placed in other section, namely Section 3.1. , where it is mentioned for the first time (line 176).
| 1 | 2 |
molecules27123843_makarova
| 1 |
We have removed the heading “2. Results” in the revised manuscript.
| 2 | 1 |
Line 59. "Remove ""2." "Results"""
| 1 | 2 |
molecules27123843_makarova
| 1 |
Thank you for your valuable opinion. NAA is an abbreviation for amino acid, and we have added the description of NAA in the section of “2.3 Construction of sensor array”.
| 2 | 1 |
line 148. What does NAA mean?
| 1 | 2 |
molecules27123843_makarova
| 1 |
We have made the appropriate changes in the text to make the sentences more concise and highlighted them in red (line 248).
| 2 | 1 |
line 251. "Write ""On TEM images "" instead of ""Transmission electrone microscopy can be observed..."""
| 1 | 2 |
molecules27123843_makarova
| 1 |
Thanks for the valuable comment. We have removed the word “that” in the revised manuscript.
| 2 | 1 |
line 284. "Remove the word ""that"""
| 1 | 2 |
molecules27123843_makarova
| 1 |
We have changed the position of Figure 1 to line 182, and adjusted the arrangement of the figures in the article.
| 2 | 1 |
line. 57-58. It seems that Figure 1 should be placed in other section, namely Section 3.1. , where it is mentioned for the first time (line 176).
| 1 | 2 |
molecules27123843_perova
| 1 |
We have removed the heading “2. Results” in the revised manuscript.
| 2 | 1 |
Line 59. "Remove ""2." "Results"""
| 1 | 2 |
molecules27123843_perova
| 1 |
Thank you for your valuable opinion. NAA is an abbreviation for amino acid, and we have added the description of NAA in the section of “2.3 Construction of sensor array”.
| 2 | 1 |
line 148. What does NAA mean?
| 1 | 2 |
molecules27123843_perova
| 1 |
We have made the appropriate changes in the text to make the sentences more concise and highlighted them in red (line 248).
| 2 | 1 |
line 251. "Write ""On TEM images "" instead of ""Transmission electrone microscopy can be observed..."""
| 1 | 2 |
molecules27123843_perova
| 1 |
Thanks for the valuable comment. We have removed the word “that” in the revised manuscript.
| 2 | 1 |
line 284. "Remove the word ""that"""
| 1 | 2 |
molecules27123843_perova
| 1 |
Our studies have shown that the effect of metal vapors on the color of the discharge plasma is much greater in the case of a pulsed breakdown in a nonuniform electric field. This made it possible to compare with the color of various discharges occurring in the upper atmosphere (Figure 1 in the text of the article). Even with well-studied discharges, it is very difficult to obtain such results. Thus, during an arc discharge, although there is a strong evaporation of the electrodes and the ejection of particles of various sizes, the voltage across the gap is low and the discharge in metal vapors outside the high-temperature arc channel is practically absent. Under these conditions, broadband Planck radiation from the arc channel plasma is observed. In a glow discharge, the sputtering of the electrodes has a low rate, and the emission spectra of the plasma of such discharges contain atomic and molecular transitions of the gases used. In the investigated mode, metal vapors are produced and excited by a pulsed discharge.
| 2 | 1 |
Of course, metal vapors, nano- and micro-particles can affect the characteristics of the discharge. This is known from numerous studies of simpler and more understandable plasma objects such as glow discharge and arc. Similar studies and comparisons with known experimental data could be carried out on these objects. In this connection, the use of high-voltage pulse discharges is not justified. The authors draw an analogy with the formation of sprites, then, in my opinion, the study would be more suitable for another journal related, for example, atmospheric research.
| 1 | 2 |
nano12040652_makarova
| 1 |
Plasma concentration discussions have been removed from the text because no such measurements have been made. The nature of the glow of the particles in Figure 3 corresponds to the glow of a micrometeorite that burns down in the Earth's atmosphere [13] and [http://galaxy.astron.kharkov.ua/statti/meteor.htm]. The brightness of the micrometeorite (the particle) glow increases towards the track’s end. This cannot be explained by an increase in the particle velocity, since the particle stops. This occurs after the voltage pulse action. We believe that an increase in the radiation intensity of the particle is due to its heating during deceleration on gas particles. The text of the article has been revised. Such inaccuracies are found throughout the text.
| 2 | 1 |
Lines 173-175 «Based on the brightness of the track glow, the plasma concentration at the particle surface increases with distance from the cathode.» Again, it is not clear how the plasma density on the particle surface can affect the brightness of the track glow.
| 1 | 2 |
nano12040652_makarova
| 1 |
The text of the article was finalized and the English was improved.
| 2 | 1 |
In this regard, I would recommend that the authors revise the article (taking into account their colossal authority in the scientific community and the possibility of conducting more thorough experimental research) and send the article to a more specialized journal.
| 1 | 2 |
nano12040652_makarova
| 1 |
The introduction of the manuscript and its text have been revised. In addition, new references have been added to the article. All changes in the text are highlighted in either yellow or red font. First of all, data describing the characteristics of the pulsed nanosecond discharge used were added and the influence of the electrode material was described in more detail. On the other hand, we should note that with a voltage pulse duration from ones to tens of nanoseconds, the experimental conditions differ significantly from the conditions of an electrostatic discharge and the creation of a foggy environment.
| 2 | 1 |
The introduction section could be improved. Some sentences are not well written or convey obvious ideas. Moreover, the aim of this work is to present an overview about the discharge behavior. The introduction would benefit from adding more content and detailed review overview to this research, such as particle lifting in electrostatic discharge , Turbulence effect, Mist-containing environment, Electrode materials.
| 1 | 2 |
nano12040652_makarova
| 1 |
The experimental system was described in more detail, and various modes of discharge ignition were analyzed.
| 2 | 1 |
Please describe better your experimental system, such as ignition energy.
| 1 | 2 |
nano12040652_makarova
| 1 |
In our preliminary studies, as well as in the papers of other authors, it was found that during pulsed discharges of short duration, the electrode material determines the composition of the vapors that evaporate from the electrodes and diffuse into the gap, including due to shock waves and turbulence. Since under these conditions diffuse discharges, at which the voltage across the gap remains high are formed, metal vapors are excited and ionized together with gas molecules in the discharge gap. This leads to the emission of radiation at various spectral transitions of metal atoms. Only a part of these transitions has a high radiation intensity in the region of interest to researchers. Also, to obtain a high intensity of radiation, transitions of atoms in metal vapors can be used, which are populated as a result of the efficient transfer of energy from excited gas molecules and atoms. Metals, the color of the emission of vapors of which, when excited in the plasma of nanosecond discharges, corresponds to the color of high-altitude atmospheric discharges, were chosen as the material of the electrodes.
| 2 | 1 |
The choice of the electrode material should be clearly explained in the present paper.
| 1 | 2 |
nano12040652_makarova
| 1 |
The color of the glow of the discharge plasma at electrodes made of various metals is associated with excitation certain energy levels of particles in the vapors of these metals. So, when using electrodes made of aluminum, steel and copper, we observed the glow of red, blue and green colors, respectively. The different colors of the discharge when changing the material of the electrodes are determined not by the spark or arc stages, but by bright spots on the electrodes, which are formed due to the explosive emission of electrons [Mesyats, G.A. Ecton mechanism of the vacuum arc cathode spot. IEEE transactions on plasma science, 1995, 23(6), pp. 879-883. (DOI: 10.1109/27.476469)]. These areas in the photographs have a bright white color (see, for example, the photographs in Figures 3, 6, 7). In spark or arc discharge, as well as in bright spots the electrodes are locally heated to a high temperature, which leads to the evaporation of the electrode material. High-temperature zones on the electrodes also supply micro- and nanoparticles into a discharge gap. However, emission of individual particles is determined by their temperature, it corresponds to the Planck radiation and is broadband. We note once again that in this work, to obtain metal vapors, as well as metal nano- and microparticles, a pulsed nanosecond discharge in a non-uniform electric field was used.
| 2 | 1 |
Please explain the mechanism of different color arcs produced by electrodes of different materials.
| 1 | 2 |
nano12040652_makarova
| 1 |
Several references was added.
| 2 | 1 |
The topic is timely and the results provided are interesting. However, most of the results provided consist in photographs of the discharges: while these are clear and descriptive, they provide a qualitative information only. A spectral analysis is given for one discharge only (discharge in air with a copper electrode): more quantitative results, such as a spectral analysis of the other discharges also, would be helpful for the comparison between the discharges produced in the lab and the ones observed in the atmosphere.
| 1 | 2 |
nano12040652_makarova
| 1 |
The main experiments were carried out with discharges in air, and the air pressure was chosen close to the pressures of high-altitude discharges. Other gases, such as argon, were chosen to better demonstrate the discoloration of the discharge.
| 2 | 1 |
A point that should be clarified is the choice of the gases used for the discharges. One would expect a comparison between discharges that happen in gas mixtures of similar composition. Is there any relationship between the specific choice of gases made by the authors and the composition of the atmosphere at the altitudes where the atmospheric discharges take place?
| 1 | 2 |
nano12040652_makarova
| 1 |
The manuscript has been revised. This judgment was removed from the text of the manuscript.
| 2 | 1 |
Page 5, line 168 The authors state: “An increase in the track brightness is apparently determined by an increase in the particle charge and size due to the evaporation of metal from the surface.” The sense of this sentence is not completely clear to me. Where does the evaporation of the metal take place? It it took place on the particle surface, it should produce a reduction of its size, rather than an increase.
| 1 | 2 |
nano12040652_makarova
| 1 |
Thanks for the advice. We plan to do this in our next work.
| 2 | 1 |
Page 6, line 218 The authors state: “Particles of metal and its compounds with oxygen and nitrogen with a size of 500 nm and less are nonuniformly distributed on the surface of the slide”. Some data should be provided to show the elemental composition of the particles.
| 1 | 2 |
nano12040652_makarova
| 1 |
Our studies have shown that the effect of metal vapors on the color of the discharge plasma is much greater in the case of a pulsed breakdown in a nonuniform electric field. This made it possible to compare with the color of various discharges occurring in the upper atmosphere (Figure 1 in the text of the article). Even with well-studied discharges, it is very difficult to obtain such results. Thus, during an arc discharge, although there is a strong evaporation of the electrodes and the ejection of particles of various sizes, the voltage across the gap is low and the discharge in metal vapors outside the high-temperature arc channel is practically absent. Under these conditions, broadband Planck radiation from the arc channel plasma is observed. In a glow discharge, the sputtering of the electrodes has a low rate, and the emission spectra of the plasma of such discharges contain atomic and molecular transitions of the gases used. In the investigated mode, metal vapors are produced and excited by a pulsed discharge.
| 2 | 1 |
Of course, metal vapors, nano- and micro-particles can affect the characteristics of the discharge. This is known from numerous studies of simpler and more understandable plasma objects such as glow discharge and arc. Similar studies and comparisons with known experimental data could be carried out on these objects. In this connection, the use of high-voltage pulse discharges is not justified. The authors draw an analogy with the formation of sprites, then, in my opinion, the study would be more suitable for another journal related, for example, atmospheric research.
| 1 | 2 |
nano12040652_perova
| 1 |
Plasma concentration discussions have been removed from the text because no such measurements have been made. The nature of the glow of the particles in Figure 3 corresponds to the glow of a micrometeorite that burns down in the Earth's atmosphere [13] and [http://galaxy.astron.kharkov.ua/statti/meteor.htm]. The brightness of the micrometeorite (the particle) glow increases towards the track’s end. This cannot be explained by an increase in the particle velocity, since the particle stops. This occurs after the voltage pulse action. We believe that an increase in the radiation intensity of the particle is due to its heating during deceleration on gas particles. The text of the article has been revised.
| 2 | 1 |
The article is more descriptive in nature, there is no explanation of physical laws, but which are misleading readers. For instance: Lines 168, 169 "An increase in the track brightness is apparently determined by an increase in the particle charge and size due to the evaporation of metal from the surface." One can agree with the influence of the particle size on the track size, but how can an increase in the particle charge affect the track glow? Lines 173-175 «Based on the brightness of the track glow, the plasma concentration at the particle surface increases with distance from the cathode.» Again, it is not clear how the plasma density on the particle surface can affect the brightness of the track glow. Such inaccuracies are found throughout the text.
| 1 | 2 |
nano12040652_perova
| 1 |
The text of the article was finalized and the English was improved.
| 2 | 1 |
In this regard, I would recommend that the authors revise the article (taking into account their colossal authority in the scientific community and the possibility of conducting more thorough experimental research) and send the article to a more specialized journal.
| 1 | 2 |
nano12040652_perova
| 1 |
The introduction of the manuscript and its text have been revised. In addition, new references have been added to the article. All changes in the text are highlighted in either yellow or red font. First of all, data describing the characteristics of the pulsed nanosecond discharge used were added and the influence of the electrode material was described in more detail. On the other hand, we should note that with a voltage pulse duration from ones to tens of nanoseconds, the experimental conditions differ significantly from the conditions of an electrostatic discharge and the creation of a foggy environment.
| 2 | 1 |
The introduction section could be improved. Some sentences are not well written or convey obvious ideas. Moreover, the aim of this work is to present an overview about the discharge behavior. The introduction would benefit from adding more content and detailed review overview to this research, such as particle lifting in electrostatic discharge , Turbulence effect, Mist-containing environment, Electrode materials.
| 1 | 2 |
nano12040652_perova
| 1 |
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