Physiology

Genetic variation of putative myokine signaling is dominated by biological sex and sex hormones

1. Leandro M Velez
2. Cassandra Van
3. Timothy Moore
4. Zhenqi Zhou
5. Casey Johnson
6. Andrea L Hevener
7. Marcus M Seldin

• Curated by eLife

  Evaluation Summary:

  This elegantly performed systems-genetics paper on the predicted human skeletal muscle secretome highlights the importance of sex and sex hormones in regulating myokine expression and predicted cross-tissue effects. Male and female mice lacking estrogen receptor α (Esr1) were used to understand how estrogen signalling affects myokine genes expression. The methods used and data presented in this manuscript can serve as an important resource for other researchers in the field.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

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Inhibition of the sodium-dependent HCO3- transporter SLC4A4, produces a cystic fibrosis-like airway disease phenotype

1. Vinciane Saint-Criq
2. Anita Guequén
3. Amber R Philp
4. Sandra Villanueva
5. Tábata Apablaza
6. Ignacio Fernández-Moncada
7. Agustín Mansilla
8. Livia Delpiano
9. Iván Ruminot
10. Cristian Carrasco
11. Michael A Gray
12. Carlos A Flores

• Curated by eLife

  Evaluation Summary:

  This paper is of interest to scientists and clinicians within the field of muco-obstructive diseases in the airways, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). It identifies the sodium-bicarbonate cotransporter SLC4A4 as a key component of the mechanism by which normal airways prevent the formation of sticky mucus and defend theirselves against bacterial and viral infections.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

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Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice

1. Priya Balasubramanian
2. Anne E Schaar
3. Grace E Gustafson
4. Alex B Smith
5. Porsha R Howell
6. Angela Greenman
7. Scott Baum
8. Ricki J Colman
9. Dudley W Lamming
10. Gary M Diffee
11. Rozalyn M Anderson

• Curated by eLife

  Evaluation Summary:

  In this manuscript, the authors provide promising results for the treatment of age-related sarcopenia with AdipoRon, a drug that targets the receptors for adiponectin. This is a well done study using an agonist (AdipoRon) involved in lipid and mitochondrial metabolism regulation to mitigate age related muscle loss in mice.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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Ca2+ inactivation of the mammalian ryanodine receptor type 1 in a lipidic environment revealed by cryo-EM

1. Ashok R Nayak
2. Montserrat Samsó

• Curated by eLife

  Evaluation Summary:

  Inactivation of ryanodine receptors (RyR1) is an important physiologic phenomenon disruption of which leads to skeletal muscle and heart diseases. By comparing cryoEM structures of RyR1 in closed, open, and inactivated states, this study provides structural insights into RyR1 calcium-dependent inactivation (CDI). The results rationalize how some disease-causing mutations in RyR1 eliminate CDI of the channel. The study will be of interest to ion channel structural biologists and physiologists studying skeletal muscle pathologies.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation

1. Charles E MacKay
2. Miranda Floen
3. M Dennis Leo
4. Raquibul Hasan
5. Tessa AC Garrud
6. Carlos Fernández-Peña
7. Purnima Singh
8. Kafait U Malik
9. Jonathan H Jaggar

• Curated by eLife

  Evaluation Summary:

  This study is potentially of high significance to a broad audience of scientists working on vascular reactivity and the role of ion channels in controlling endothelial cell signaling and vessel contractility. The study uses novel Endothelial cell specific knockout mice of Polycystin-1 and 2 (PC1 and PC2) proteins to show the requirement of PC1 and PC2 in flow-mediated vasodilation, how PC-1 and PC-2 interact and that their functions are interdependent. The findings from this study are novel and significant. The animal models used in this study are state of the art and the data overall are of high quality. However, additional data are needed to support the conclusions of the study. Further, additional controls and clarifications are required.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

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Distinct roles for two Caenorhabditis elegans acid-sensing ion channels in an ultradian clock

1. Eva Kaulich
2. Trae Carroll
3. Brian D Ackley
4. Yi-Quan Tang
5. Iris Hardege
6. Keith Nehrke
7. William R Schafer
8. Denise S Walker

• Curated by eLife

  Evaluation Summary:

  This study investigates the role of acid sensing channels in pH homeostasis required for normal rhythmic muscle contractions in the defecation cycle of C .elegans. It is of importance to scientists with interest in ASIC channel function, pH homeostasis and the cellular mechanisms underlying generation of ultradian rhythms.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)”

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The role of action potential changes in depolarization-induced failure of excitation contraction coupling in mouse skeletal muscle

1. Xueyong Wang
2. Murad Nawaz
3. Chris DuPont
4. Jessica H Myers
5. Steve RA Burke
6. Roger A Bannister
7. Brent D Foy
8. Andrew A Voss
9. Mark M Rich

• Curated by eLife

  Evaluation Summary:

  This addresses an important area of excitation contraction coupling failure of potential clinical translational importance. They report that progressive depolarization of the resting potential upon excitation contraction coupling results in a persistence of action potential generation in the face of a failure of Ca2+ release.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors

1. Alexis Ruiz
2. Sofia Benucci
3. Urs Duthaler
4. Christoph Bachmann
5. Martina Franchini
6. Faiza Noreen
7. Laura Pietrangelo
8. Feliciano Protasi
9. Susan Treves
10. Francesco Zorzato

• Curated by eLife

  Evaluation Summary:

  The paper describes improvement in muscle phenotype of a congenital myopathy mouse model by a combined treatment with pharmacological inhibitors of Class IIa histone deacetylases and DNA methylases. The paper demonstrates in principle that there are treatment avenues to pursue but their application could be limited as phenotypic rescue appears to be restricted to particular muscle fiber types.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

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High-intensity interval training remodels the proteome and acetylome of human skeletal muscle

1. Morten Hostrup
2. Anders Krogh Lemminger
3. Ben Stocks
4. Alba Gonzalez-Franquesa
5. Jeppe Kjærgaard Larsen
6. Julia Prats Quesada
7. Martin Thomassen
8. Brian Tate Weinert
9. Jens Bangsbo
10. Atul Shahaji Deshmukh

• Curated by eLife

  Evaluation Summary

  This paper will be of interest to readers in the fields of exercise physiology, muscle biology and energy metabolism. The authors provide a proteomic resource where changes in the skeletal muscle proteome and acetyl-proteome have been assessed following the increasingly popular exercise intervention of high intensity interval training (HIIT). The adaptive responses reported provide new insight into the metabolic, contractile and transcriptional changes in muscle, and may represent an excellent resource for stimulating future focussed molecular studies in the field.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit

1. Brogan Ashley
2. Claire Simner
3. Antigoni Manousopoulou
4. Carl Jenkinson
5. Felicity Hey
6. Jennifer M Frost
7. Faisal I Rezwan
8. Cory H White
9. Emma M Lofthouse
10. Emily Hyde
11. Laura DF Cooke
12. Sheila Barton
13. Pamela Mahon
14. Elizabeth M Curtis
15. Rebecca J Moon
16. Sarah R Crozier
17. Hazel M Inskip
18. Keith M Godfrey
19. John W Holloway
20. Cyrus Cooper
21. Kerry S Jones
22. Rohan M Lewis
23. Martin Hewison
24. Spiros DD Garbis
25. Miguel R Branco
26. Nicholas C Harvey
27. Jane K Cleal

• Curated by eLife

  Evaluation Summary:

  This manuscript uses primary placental units and villous explants to examine the placental metabolism of vitamin D and effects of vitamin D on placental gene expression. The studies demonstrate that the placenta actively transports 25D, such that the fetal levels are dependent on placental function rather than simple diffusion from the maternal circulation. Furthermore, they demonstrate actions of vitamin D on placental gene expression. This paper should be of interest to cell biologists and obstetricians/gynaecologists studying the role of the placenta in fetal growth and development.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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SOX4 facilitates PGR protein stability and FOXO1 expression conducive for human endometrial decidualization

1. Pinxiu Huang
2. Wenbo Deng
3. Haili Bao
4. Zhong Lin
5. Mengying Liu
6. Jinxiang Wu
7. Xiaobo Zhou
8. Manting Qiao
9. Yihua Yang
10. Han Cai
11. Faiza Rao
12. Jingsi Chen
13. Dunjin Chen
14. Jinhua Lu
15. Haibin Wang
16. Aiping Qin
17. Shuangbo Kong

• Curated by eLife

  Evaluation Summary:

  Huang et al have identified SOX4 as a key regulatory factor that controls prolactin and FOXO1 transcription factor which in turn regulate decidualization, an important process in embryo development. Further, they have identified that SOX4 also regulates progesterone receptor and dysregulated SOX4-progesterone and ubiquitin ligase HERC4can lead to embryo implantation failure thus explaining the molecular basis of recurrent implantation failure in humans. Overall the study is interesting and the data are very strong. Some concerns noted were the use of immortalized stromal cells, and incomplete nature of studies with human endometrial stroll cells from endometriosis patients, and lack of sufficient discussion in some parts of the text, and whether specific progesterone isofoms are involved downstream of SOX4.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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Neural basis for regulation of vasopressin secretion by anticipated disturbances in osmolality

1. Angela Kim
2. Joseph C Madara
3. Chen Wu
4. Mark L Andermann
5. Bradford B Lowell

• Curated by eLife

  Evaluation Summary:

  This study investigates the important question of how vasopressin neurons, which are critical for fluid balance, are rapidly activated or inhibited when mice begin to eat or drink. The study presents useful anatomic data on connectivity between these neurons and other structures and tests a broad range of possible inputs that could mediate these effects. The conclusions are largely supported by the data.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

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Genetically engineered mice for combinatorial cardiovascular optobiology

1. Frank K Lee
2. Jane C Lee
3. Bo Shui
4. Shaun Reining
5. Megan Jibilian
6. David M Small
7. Jason S Jones
8. Nathaniel H Allan-Rahill
9. Michael RE Lamont
10. Megan A Rizzo
11. Sendoa Tajada
12. Manuel F Navedo
13. Luis Fernando Santana
14. Nozomi Nishimura
15. Michael I Kotlikoff

• Curated by eLife

  Evaluation Summary:

  The manuscript by Lee and co-workers describes the development of 21 unique transgenic mouse lines that express optogenetic sensors and effectors in a cell lineage-specific fashion. The knock-in approach allows the sensors and effectors to be rapidly combined or moved to different backgrounds, such as genetic disease models. Such manipulations are often impractical when using a Cre-based system. This constitutes a vital advantage for many studies. The new mice described here will be very powerful tools to study physiology and alteration in disease models.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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Topography and motion of acid-sensing ion channel intracellular domains

1. Tyler Couch
2. Kyle D Berger
3. Dana L Kneisley
4. Tyler W McCullock
5. Paul Kammermeier
6. David M Maclean

• Curated by eLife

  Evaluation Summary:

  This is a rigorous and clearly written paper that provides quantitative data for the scope of intracellular signalling by ASIC channels. These channels are involved in pain signalling and other processes, and apparently can couple to intracellular pathways independent of ion flow. Here the authors measure the movements of the unstructured intracellular parts of ASIC using fluorescence spectroscopy coupled to functional measurements.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, #2, and #3 agreed to share their names with the authors.)

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Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability, and resistance to fibrinolysis

1. Helen R McPherson
2. Cedric Duval
3. Stephen R Baker
4. Matthew S Hindle
5. Lih T Cheah
6. Nathan L Asquith
7. Marco M Domingues
8. Victoria C Ridger
9. Simon DA Connell
10. Khalid M Naseem
11. Helen Philippou
12. Ramzi A Ajjan
13. Robert AS Ariëns

• Curated by eLife

  Evaluation Summary:

  This paper is of interest to a broad audience in the blood coagulation and fibrinolysis field. Previously undescribed roles in a range of blood clot properties are attributed to a region of the clotting protein fibrinogen, using state-of-the-art methodology. The data support the main conclusions of the paper, open new avenues of investigation for understanding clot properties, and have clinical implications.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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Modulation of fracture healing by the transient accumulation of senescent cells

1. Dominik Saul
2. David G Monroe
3. Jennifer L Rowsey
4. Robyn Laura Kosinsky
5. Stephanie J Vos
6. Madison L Doolittle
7. Joshua N Farr
8. Sundeep Khosla

• Curated by eLife

  Evaluation Summary:

  This is a well conducted study that examines the potential role of senescent cells in fracture healing. Furthermore, the authors have used senolytic agents to examine if targeting cellular senescence will have a significant impact on fracture healing phenotype. The manuscript is succinctly written, and the methods and results are well described. These data provide the first demonstration for a potential role for cellular senescence in regulating fracture healing. The authors’ conclusions are largely supported by the experimental data.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewers #1, #2, and #3 agreed to share their names with the authors.)

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P. falciparum K13 mutations present varying degrees of artemisinin resistance and reduced fitness in African parasites

1. Barbara H. Stokes
2. Kelly Rubiano
3. Satish K. Dhingra
4. Sachel Mok
5. Judith Straimer
6. Nina F. Gnädig
7. Jade R. Bath
8. Ioanna Deni
9. Kurt E. Ward
10. Josefine Striepen
11. Tomas Yeo
12. Leila S. Ross
13. Eric Legrand
14. Frédéric Ariey
15. Clark H. Cunningham
16. Issa M. Souleymane
17. Adama Gansané
18. Romaric Nzoumbou-Boko
19. Claudette Ndayikunda
20. Abdunoor M. Kabanywanyi
21. Aline Uwimana
22. Samuel J. Smith
23. Olimatou Kolley
24. Mathieu Ndounga
25. Marian Warsame
26. Rithea Leang
27. François Nosten
28. Timothy J.C. Anderson
29. Philip J. Rosenthal
30. Didier Ménard
31. David A. Fidock

• Curated by eLife

  Evaluation Summary:

  This study is of interest to the broad malaria research community and especially those who work on drug resistance. The authors provide a summary of their surveys of African and Southeast Asian Plasmodium falciparum parasites for the Kelch 13 gene, a marker of artemisinin resistance. The contribution of several K13 mutations to artemisinin resistance is investigated in different genetic backgrounds and confirms the lack of a barrier for the potential emergence of artemisinin resistance in African parasites. These findings are of prime importance in the context of public health perspective on managing the risk of resistance appearing in Africa.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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Multiple introductions of multidrug-resistant typhoid associated with acute infection and asymptomatic carriage, Kenya

1. Samuel Kariuki
2. Zoe A Dyson
3. Cecilia Mbae
4. Ronald Ngetich
5. Susan M Kavai
6. Celestine Wairimu
7. Stephen Anyona
8. Naomi Gitau
9. Robert Sanaya Onsare
10. Beatrice Ongandi
11. Sebastian Duchene
12. Mohamed Ali
13. John David Clemens
14. Kathryn E Holt
15. Gordon Dougan

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The anti-immune dengue subgenomic flaviviral RNA is found in vesicles in mosquito saliva and associated with increased infectivity

1. Shih-Chia Yeh
2. Wei-Lian Tan
3. Avisha Chowdhury
4. Vanessa Chuo
5. R. Manjunatha Kini
6. Julien Pompon
7. Mariano A. Garcia-Blanco

• Curated by eLife

  Evaluation Summary:

  Mosquito saliva can enhance transmission of arboviruses. Here, authors demonstrated that the anti-immune non-coding RNA from Dengue virus, known as the subgenomic flavivirus RNA (sfRNA), is secreted into mosquito saliva within the extracellular vesicles and can facilitate infection of the acceptor human cells when delivered together with infectious virus in mosquito saliva. The study potentially expands our understanding of flavivirus transmission.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics

1. Julia Stokes
2. Arielle Freed
3. Rebecca Bornstein
4. Kevin N Su
5. John Snell
6. Amanda Pan
7. Grace X Sun
8. Kyung Yeon Park
9. Sangwook Jung
10. Hailey Worstman
11. Brittany M Johnson
12. Philip G Morgan
13. Margaret M Sedensky
14. Simon C Johnson

• Curated by eLife

  Evaluation Summary:

  This manuscript reports that Volatile anesthetics VA induce a rapid depletion of circulating ß-HB and the induction of hypoglycemia by VA in neonates, but not in adults. The phenomenon is very interesting and robust, however it has already been described. Whats new here is that through a metabolomics analysis they demonstrate a role of ACC and CPT1 in this phenomenon.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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