{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:06:13Z","timestamp":1789621573733,"version":"build-2803163510"},"reference-count":34,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014563","name":"Universitas Andalas","doi-asserted-by":"publisher","award":["340\/UN16.19\/PT.01.03\/PUJK\/2024"],"award-info":[{"award-number":["340\/UN16.19\/PT.01.03\/PUJK\/2024"]}],"id":[{"id":"10.13039\/501100014563","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>\n                    Background\n                    <ns3:italic>Paronema canescens<\/ns3:italic>\n                    Jack., commonly known as sungkai, is a medicinal plant native to Southeast Asia, particularly abundant in the forests of Sumatra and Borneo, Indonesia. Traditionally, sungkai has been used to treat various ailments, likely due to its rich content of bioactive secondary metabolites. This study aimed to isolate, characterize, and evaluate the immunostimulatory and anti-inflammatory potential of compounds from sungkai leaves based on in silico and in vivo analyses. Methods Apigenin was isolated from\n                    <ns3:italic>Paronema canescens<\/ns3:italic>\n                    leaves via ethanol extraction, liquid-liquid partitioning, and chromatographic purification, then characterized by UV-Vis, FT-IR, and NMR spectroscopy. Molecular docking was conducted using MOE software to assess apigenin\u2019s binding to granzyme B, perforin, and IFN-\u03b3, with levamisole as a reference. In vivo, 25 male mice were randomized into five groups and administered apigenin (1, 25, or 50 mg\/kg BW) intramuscularly for seven days, alongside COVID-19 vaccination. Granzyme B and IFN-\u03b3 serum levels were quantified using ELISA. Statistical analysis employed one-way ANOVA with Duncan\u2019s test (\n                    <ns3:italic>p<\/ns3:italic>\n                    &lt; 0.05). Results The\n                    <ns3:italic>in silico<\/ns3:italic>\n                    analysis demonstrated that apigenin exhibited favorable binding affinities and multiple stabilizing interactions with granzyme B, perforin, and interferon-\u03b3, supporting its potential role in enhancing cellular immune responses through direct molecular modulation of key cytotoxic effector proteins. To assess its immunostimulatory activity in vivo, apigenin was orally administered to mice (\n                    <ns3:italic>Mus musculus<\/ns3:italic>\n                    ) at doses of 1, 25, and 50 mg\/kg body weight. Mice were pre-induced with a COVID-19 vaccine to simulate immune system activation. Immunological responses were evaluated through the measurement of granzyme B, perforin, and interferon-\u03b3 expression levels. The results demonstrated that apigenin significantly increased the expression of all three markers in a dose-dependent manner. Conclusion Collectively, the chemical, computational, and biological data confirm that apigenin from sungkai leaves holds strong immunostimulant and selective anti-inflammatory potential, supporting its development as a natural immune booster or vaccine adjuvant.\n                  <\/ns3:p>","DOI":"10.12688\/f1000research.167153.1","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T10:50:08Z","timestamp":1754650208000},"page":"774","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Isolation of Apigenin from Sungkai (Peronema canescens) Leaves and Its Immunomodulatory Effects: An In Vivo Study on Granzyme B, Interferon-\u03b3, and Perforin Expression with Supporting In Silico Analysis"],"prefix":"10.12688","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0762-8447","authenticated-orcid":false,"given":"Dwisari","family":"Dillasamola","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufri","family":"Aldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najmiatul","family":"Fitria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biomechy","family":"Oktomalioputri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uce","family":"Lestari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risma","family":"Multia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"012071","DOI":"10.1088\/1755-1315\/886\/1\/012071","article-title":"Threats to the sustainability of biodiversity in Indonesia by the utilization of forest areas for national strategic projects: A normative review.","volume":"886","author":"M Maskun","year":"2021","journal-title":"IOP Conf. 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Pharmacol."},{"key":"ref34","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.15980341","author":"D Dillasamola","year":"2025","journal-title":"Zenodo."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/14-774\/v1\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/14-774\/v1\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/14-774\/v1\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T12:25:08Z","timestamp":1760531108000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/14-774\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,8]]},"references-count":34,"URL":"https:\/\/doi.org\/10.12688\/f1000research.167153.1","relation":{"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.184242.r411394","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.184242.r411397","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.184242.r411398","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.184242.r405596","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.184242.r411394","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.184242.r405596","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.184242.r411397","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.184242.r411398","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,8]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/14-774\/v1#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.184242.r405596, Dharmalingam Kirubakaran, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamilnadu, 16 Sep 2025, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/14-774\/v1#referee-response-405596","order":0,"name":"referee-response-405596","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Dwisari Dillasamola<\/b>; \n<i>Posted: 11 Oct 2025<\/i>; We sincerely thank the reviewer for the positive evaluation and constructive feedback. All suggested revisions have been carefully addressed to enhance the clarity, depth, and overall quality of the manuscript. Detailed responses to each comment are provided below.  \n<b>1. Revise grammar throughout the manuscript and correct all errors.<\/b> \n<b>Response:<\/b> We have thoroughly revised the manuscript for grammar, syntax, and language accuracy. All sections were edited for clarity and conciseness, with attention to tense consistency and technical phrasing. The final version has been proofread by a professional language editor.  \n<b>2. Strengthen and improve the Discussion section.<\/b> \n<b>Response:<\/b> The Discussion section has been comprehensively revised to enhance scientific interpretation.  We added detailed explanations on \n<b>apigenin\u2019s modulation of JNK\/ERK and NF-\u03baB signaling pathways<\/b>, as suggested. A new comparative discussion with other flavonoid immunomodulators (e.g., \n<b>quercetin and luteolin<\/b>) has been included to highlight mechanistic similarities and differences. The \n<b>biological relevance of modest (\u22485\u201320%) increases<\/b> in immune markers was elaborated using recent evidence. Several \n<b>recent references (2024\u20132025)<\/b> were added to support these updates (e.g., Allemailem et al., 2024; Kurek-G&oacute;recka et al., 2025; Mohammadkhanizadeh et al., 2025; Hsieh et al., 2024).  \n<b>3. Rewrite the Abstract for clarity and refine the Conclusion.<\/b> \n<b>Response:<\/b> Both the Abstract and Conclusion have been rewritten to improve clarity and logical flow.  The \n<b>Abstract<\/b> now emphasizes the novelty of isolating apigenin from \n<i>Peronema canescens<\/i> and integrates the \n<i>in silico\u2013in vivo<\/i> design, highlighting key quantitative findings (7\u201320% increases in immune markers). The \n<b>Conclusion<\/b> has been revised to indicate \n<b>potential immunostimulatory effects<\/b> rather than definitive claims, aligning with the study\u2019s preliminary scope. It now also suggests directions for \n<b>future research<\/b> (cytokine profiling, NK cell assays, pathway validation).  \n<b>4. Ensure all figures are of high quality and appropriately corrected.<\/b> \n<b>Response:<\/b> All figures have been re-rendered at high resolution (\u2265300 dpi), with standardized labeling and improved contrast. Figure legends were rewritten for accuracy and clarity. The corresponding raw image data were reviewed to confirm fidelity.","URL":"https:\/\/f1000research.com\/articles\/14-774\/v1#referee-comment-14760","order":1,"name":"referee-comment-14760","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.184242.r411398, Valentina Mittova, University Geomedi, Tbilisi, Tbilisi, 22 Sep 2025, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/14-774\/v1#referee-response-411398","order":2,"name":"referee-response-411398","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Dwisari Dillasamola<\/b>; \n<i>Posted: 11 Oct 2025<\/i>; We sincerely thank the reviewer for the positive evaluation and constructive feedback. All suggested revisions have been carefully addressed to enhance the clarity, depth, and overall quality of the manuscript. Detailed responses to each comment are provided below.  \n<i>Why was the COVID-19 vaccine chosen as an immunostimulator?<\/i> \n<b>Response:<\/b> We thank the reviewer for this insightful question. The COVID-19 vaccine was selected as an immunostimulatory model because it reliably induces a measurable cell-mediated immune response, particularly the activation of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, which are key producers of granzyme B, perforin, and interferon-\u03b3. This allowed us to evaluate whether apigenin could potentiate or modulate vaccine-induced immune activation under physiologically relevant conditions. Additionally, the vaccine model reflects a clinically relevant immune challenge, enabling translational insights into how apigenin might serve as a potential vaccine adjuvant or immune-supportive compound. These details have been clarified in the revised \n<i>Materials and Methods<\/i> section.  \n<i>Why was the control group, which received apigenin and was not vaccinated, not used in the experiments?<\/i> \n<b>Response:<\/b> We acknowledge this limitation and have discussed it in the revised \n<i>Discussion<\/i> (Study Limitations section). The initial design aimed to explore the immunomodulatory role of apigenin in the context of vaccine-induced immune activation, rather than its baseline effects. Hence, a non-vaccinated apigenin-only group was not included in this preliminary study.  I\n<i>n Fig. 9, signs like &quot;+&quot; and &quot;\u2013&quot; should be explained.<\/i> \n<b>Response:<\/b> We appreciate this observation.&nbsp; \u201c\u2013\u201d indicates the negative control group (NaCMC 0.5%). \u201c+\u201d indicates the positive control group (COVID-19 vaccine only).  \n<i>The conclusion section should be rephrased; the statement \u201capigenin significantly enhanced the expression of key immune effector molecules\u2014granzyme B, perforin, and interferon-\u03b3\u201d is not accurate, since it was revealed only in preliminary vaccinated mice.<\/i> \n<b>Response:<\/b> We fully agree with this important correction. The Conclusion section has been rewritten to reflect the preliminary and context-specific nature of our findings. The revised statement now reads: \u201cPreliminary in vivo assays in vaccinated mice indicated dose-dependent increases in the expression of these cytotoxic markers following apigenin administration. Although these findings suggest an immunostimulatory trend, they should be interpreted cautiously as indicative rather than conclusive evidence of efficacy.\u201d This phrasing avoids overstatement and accurately conveys the scope of the experimental findings.","URL":"https:\/\/f1000research.com\/articles\/14-774\/v1#referee-comment-14761","order":3,"name":"referee-comment-14761","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.184242.r411397, Bushra Hussain Shnawa, Soran University, Kurdistan, Kurdistan, 29 Sep 2025, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/14-774\/v1#referee-response-411397","order":4,"name":"referee-response-411397","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Dwisari Dillasamola<\/b>; \n<i>Posted: 11 Oct 2025<\/i>; We sincerely thank the reviewer for the positive evaluation and constructive feedback. All suggested revisions have been carefully addressed to enhance the clarity, depth, and overall quality of the manuscript. Detailed responses to each comment are provided below.  \n<i>What about the toxicity of apigenin, which is classified as a flavonoid, to determine its LD50?<\/i> \n<b>Response:<\/b> We appreciate this important observation. Experimental determination of apigenin\u2019s LD\u2085\u2080 was beyond the scope of this preliminary study; however, we have incorporated relevant toxicity data from recent literature. Previous reports indicate that apigenin has a high safety margin, with Acute oral toxicity studies revealing&nbsp;no mortality or signs of toxicity&nbsp;for the isolated apigenin at doses up to&nbsp;5000 mg\/kg&nbsp;in either mice or rats (El Shoubaky et al., 2016). This information has been added to the \n<i>Discussion<\/i> (Study Limitations section), and we have acknowledged the need for future in vivo toxicity and safety assessments under our specific experimental conditions.  \n<i>The authors didn't use another standard immunostimulatory material to compare with it. To determine the levels of the immune stimulation of apigenin in comparison with others.<\/i> \n<b>Response:<\/b> We acknowledge this limitation and thank the reviewer for the suggestion. In our \n<i>in silico<\/i> docking study, levamisole, a known immunostimulant, was used as a reference ligand for granzyme B, perforin, and IFN-\u03b3, providing a baseline for molecular interaction comparison. However, in the \n<i>in vivo<\/i> experiment, a reference immunostimulant was not included to focus the investigation on apigenin\u2019s independent effects. We have now clarified this rationale in the \n<i>Methods<\/i> and \n<i>Discussion<\/i> sections, and we note that future studies will incorporate both levamisole and plant-derived comparators (e.g., quercetin or luteolin) for quantitative benchmarking.  \n<i>Why did the authors select granzyme B, perforin, and interferon-\u03b3 (IFN-\u03b3)? No interleukin included.<\/i> \n<b>Response:<\/b> We thank the reviewer for this valuable question. Granzyme B, perforin, and IFN-\u03b3 were selected because they are key cytotoxic effector molecules directly associated with natural killer (NK) cell and CD8\u207a T-cell activity, which represent the innate and adaptive cellular immune arms of host defense. Our study aimed to determine whether apigenin could enhance cell-mediated immunity via these effectors. We agree that inclusion of interleukin markers (e.g., IL-2, IL-10, IL-12) would provide a broader immunological profile. This limitation has been explicitly acknowledged in the \n<i>Discussion<\/i> and \n<i>Conclusion<\/i>, with a note that future experiments will include cytokine profiling to assess Th1\/Th2 balance and helper T-cell responses.","URL":"https:\/\/f1000research.com\/articles\/14-774\/v1#referee-comment-14762","order":5,"name":"referee-comment-14762","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.184242.r411394, Pitchaporn Wanyo, Kalasin University, Kalasin, Kalasin, 07 Oct 2025, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/14-774\/v1#referee-response-411394","order":6,"name":"referee-response-411394","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Dwisari Dillasamola<\/b>; \n<i>Posted: 11 Oct 2025<\/i>; We sincerely thank the reviewer for the positive evaluation and constructive feedback. All suggested revisions have been carefully addressed to enhance the clarity, depth, and overall quality of the manuscript. Detailed responses to each comment are provided below.  \n<b>1. Abstract<\/b> \n<i>The Abstract should emphasize the novelty of isolating apigenin, integration of in silico\u2013in vivo design, and key quantitative findings.<\/i> \n<b>Response:<\/b> The Abstract has been fully rewritten to highlight the novel isolation of apigenin from \n<i>Peronema canescens<\/i>, the integration of \n<i>in silico<\/i> molecular docking and \n<i>in vivo<\/i> immunological assays, and to include key quantitative outcomes (7\u201320% increases in immune markers). The revised version now better reflects the study\u2019s originality, scope, and results.  \n<b>2. Introduction<\/b> \n<b>2.1 Clarify the research gap\u2014specifically, that apigenin\u2019s immunostimulatory role from <i>Peronema canescens<\/i> has not been previously demonstrated.<\/b> \n<b>Response:<\/b> This clarification has been incorporated. The Introduction now explicitly states that although \n<i>P. canescens<\/i> is traditionally recognized for medicinal properties, its apigenin component has never been scientifically confirmed to exhibit immunostimulatory effects, establishing the study\u2019s novelty. \n<b>2.2 Add recent (2023\u20132025) references about apigenin and flavonoid-based immunomodulators.<\/b> \n<b>Response:<\/b> We have added several recent references (2023\u20132025) to strengthen the contextual foundation, including:  Allemailem et al., \n<i>Biomed J<\/i>, 2024 Kurek-G&oacute;recka et al., \n<i>Pharm J (Basel)<\/i>, 2025 Mohammadkhanizadeh et al., \n<i>Brain Disord<\/i>, 2025 Naponelli et al., \n<i>Int J Mol Sci<\/i>, 2024 Hsieh et al., \n<i>J Cell Mol Med<\/i>, 2024  \n<b>2.3 Justify selection of granzyme B, perforin, and IFN-\u03b3 as immune markers representing cytotoxic activity.<\/b> \n<b>Response:<\/b> Justification has been added to the Introduction. These markers were chosen because they directly represent cytotoxic effector function of NK and CD8\u207a T cells, reflecting the cellular arm of immune activation. This rationale is now clearly stated in the text.  \n<b>3. Materials and Methods<\/b> \n<b>3.1 Reduce redundancy in brand and catalog details; focus on replicability.<\/b> \n<b>Response:<\/b> Redundant catalog and brand information have been condensed. Only essential details for reproducibility are retained. \n<b>3.2 Clarify animal randomization, blinding, and justification for sample size (n=5).<\/b> \n<b>Response:<\/b> Details regarding random allocation of animals, blinding during ELISA measurement, and justification of sample size (n=5) based on prior immunological pilot studies have been added. \n<b>3.3 Explain rationale for using COVID-19 vaccine as an immune activator in mice, and provide ethical justification.<\/b> \n<b>Response:<\/b> The use of the COVID-19 vaccine was intended to provide a controlled immune challenge mimicking a clinically relevant activation of CTL and NK cell responses. Ethical approval and humane treatment statements have been clarified and referenced to institutional guidelines. \n<b>3.4 Include an apigenin-only control group to assess independent effects.<\/b> \n<b>Response:<\/b> We acknowledge that an apigenin-only control group was not included in this preliminary study. This limitation has been explicitly discussed in the \n<i>Discussion<\/i> section, and future studies will incorporate apigenin-only and cytokine-profiling groups. \n<b>3.5 Mention toxicity or LD\u2085\u2080 data or cite prior literature confirming safety at tested doses.<\/b> \n<b>Response:<\/b> Toxicity&nbsp; information from previous studies have been cited (Allemailem et al., 2024; El Shoubaky et al., 2016), confirming the safety of the selected dose range. This addition is reflected in the revised Methods and Discussion. \n<b>3.6 Include effect sizes or confidence intervals for ANOVA results.<\/b> \n<b>Response:<\/b> We have added effect size (\u03b7&sup2;) and 95% confidence intervals for all ANOVA tests in the revised Results section to improve statistical transparency.  \n<b>4. Results<\/b> \n<b>Report RMSD, hydrogen bonds, and binding pocket residues in docking results.<\/b> \n<b>Response:<\/b> Docking results were expanded to include RMSD values, hydrogen bond, and binding pocket residues (Table 2) for granzyme B, perforin, and IFN-\u03b3. \n<b>Improve figure resolution, axis labeling, and statistical annotations.<\/b> \n<b>Response:<\/b> All figures were re-rendered at \u2265300 dpi. Figure legends were revised for clarity. \n<b>Discuss biological relevance of small increases (\u22485\u201320%) in immune markers.<\/b> \n<b>Response:<\/b> This aspect has been elaborated in the Discussion. We emphasized that even small increases in granzyme B, perforin, and IFN-\u03b3 can substantially enhance CTL and NK function, demonstrating the biological importance of such modest changes.  \n<b>5. Discussion<\/b> \n<b>5.1 Focus more on mechanism\u2014describe apigenin\u2019s modulation of JNK\/ERK or NF-\u03baB signaling pathways.<\/b> \n<b>Response:<\/b> The Discussion now provides a detailed mechanistic explanation of apigenin\u2019s modulation of MAPK (JNK\/ERK) and NF-\u03baB pathways, supported by recent references. \n<b>5.2 Discuss study limitations: lack of interleukin profiling, no apigenin-only control, and untested toxicity.<\/b> \n<b>Response:<\/b> The study limitations&nbsp;has been added explicitly addressing these three points, along with recommendations for future studies. \n<b>5.3 Compare results with other flavonoid immunomodulators (quercetin, luteolin).<\/b> \n<b>Response:<\/b> A comparative discussion with quercetin and luteolin has been added, emphasizing structural-functional relationships and mechanistic similarities\/differences (Oo et al., 2022; Kurek-G&oacute;recka et al., 2025). \n<b>5.4 Include recent references (2024\u20132025) to enhance depth.<\/b> \n<b>Response:<\/b> Recent studies (2024\u20132025) have been incorporated to strengthen discussion depth and update mechanistic perspectives.  \n<b>6. Conclusion<\/b> \n<b>6.1 Rephrase to indicate potential immunostimulatory effects rather than definitive proof.<\/b> \n<b>Response:<\/b> The Conclusion has been rewritten to use cautious and scientifically appropriate phrasing, stating that apigenin shows potential immunostimulatory activity rather than definitive proof. \n<b>6.2 Suggest future work: cytokine profiling (IL-2, IL-10), NK cell assays, or mechanistic pathway analysis.<\/b> \n<b>Response:<\/b> Future research directions now include cytokine profiling, NK-cell functional assays, and pathway validation (MAPK\/NF-\u03baB) to confirm mechanisms inferred from this study.","URL":"https:\/\/f1000research.com\/articles\/14-774\/v1#referee-comment-14763","order":7,"name":"referee-comment-14763","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author(s) declared that no grants were involved in supporting this work","order":8,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}