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  1. Assessing drug safety by identifying the axis of arrhythmia in cardiomyocyte electrophysiology

    This article has 3 authors:
    1. Stewart Heitmann
    2. Jamie I Vandenberg
    3. Adam P Hill
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This compelling and novel mathematical method assesses drug pro-arrhythmic cardiotoxicity by examining the electrophysiology of untreated cardiac cells. It will be valuable for future drug safety design.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  2. Local Generation and Efficient Evaluation of Numerous Drug Combinations in a Single Sample

    This article has 2 authors:
    1. Vlad Elgart
    2. Joseph Loscalzo
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      In this manuscript, a method to test a large number of drug combinations in a single cell culture sample is presented. The strength of the evidence lies in their multiple experiments with different combinations of agents. The paper suggests that results from this application are feasible and the methodology could be applied in other laboratories to use drug combinations for defined outcomes.

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    This article has 5 evaluationsAppears in 2 listsLatest version Latest activity
  3. A generic binding pocket for small molecule I Ks activators at the extracellular inter-subunit interface of KCNQ1 and KCNE1 channel complexes

    This article has 9 authors:
    1. Magnus Chan
    2. Harutyun Sahakyan
    3. Jodene Eldstrom
    4. Daniel Sastre
    5. Yundi Wang
    6. Ying Dou
    7. Marc Pourrier
    8. Vitya Vardanyan
    9. David Fedida
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      By combining electrophysiological analysis of mutant channels and molecular dynamics simulations, this important study identifies a common binding site for two structurally distinct activators of KCNQ1-KCNE1 channels. The findings represent an important advance for the field, with convincing functional and computational data to support the claims. The work will be of interest to those studying the binding of small molecule drugs to membrane protein complexes.

    Reviewed by eLife

    This article has 10 evaluationsAppears in 2 listsLatest version Latest activity
  4. The generation of HepG2 transmitochondrial cybrids to reveal the role of mitochondrial genotype in idiosyncratic drug-induced liver injury: a translational in vitro study

    This article has 5 authors:
    1. Amy Louise Ball
    2. Carol Elizabeth Jolly
    3. Jonathan Lyon
    4. Ana Alfirevic
    5. Amy Chadwick
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This paper is of potential interest to scientists within the field of drug-induced liver injury. The concept of the study is interesting by generating mitochondrial genotype-specific liver cell lines to evaluate idiosyncratic hepatotoxicity. While the proof-of-concept is clearly presented, the current data do not yet allow to draw broad conclusions about the significance of the study in terms of drug effects.

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    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  5. Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics

    This article has 23 authors:
    1. Ziva Vuckovic
    2. Jinan Wang
    3. Vi Pham
    4. Jesse I. Mobbs
    5. Matthew J. Belousoff
    6. Apurba Bhattarai
    7. Wessel A.C. Burger
    8. Geoff Thompson
    9. Mahmuda Yeasmin
    10. Katie Leach
    11. Emma T. van der Westhuizen
    12. Elham Khajehali
    13. Yi-Lynn Liang
    14. Alisa Glukhova
    15. Denise Wootten
    16. Craig W. Lindsley
    17. Andrew B. Tobin
    18. Patrick M. Sexton
    19. Radostin Danev
    20. Celine Valant
    21. Yinglong Miao
    22. Arthur Christopoulos
    23. David M. Thal
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This fundamental study is important and carefully executed, providing important insights into the allosteric regulation of GPCRs with exceptional strength of evidence. This work will be of interest to a wide audience in drug discovery and receptor biology. The major strengths are the comprehensive structural and pharmacological characterization with only minor weaknesses, most notably a concern regarding the approach used to quantify efficacy.

    Reviewed by eLife

    This article has 5 evaluationsAppears in 2 listsLatest version Latest activity
  6. Population Dynamics of Immunological Synapse Formation Induced by Bispecific T-cell Engagers Predict Clinical Pharmacodynamics and Treatment Resistance

    This article has 6 authors:
    1. Can Liu
    2. Jiawei Zhou
    3. Stephan Kudlacek
    4. Timothy Qi
    5. Tyler Dunlap
    6. Yanguang Cao
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      The authors have developed a useful model for how proteins that mediate a connection between invariant components of the T cell antigen receptor and leukaemic cells antigens, called bispecific engagers (BiTEs), mediate immunological synapse formation and impact T cell search for tumour cells in vivo. The model was compared against the in vitro experiments and in vivo data following a solid approach. The developed framework could provide a direction for employing computational mechanistic models for evaluating various strategies for BiTE treatments.

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    This article has 5 evaluationsAppears in 2 listsLatest version Latest activity
  7. A mechanism of uncompetitive inhibition of the serotonin transporter

    This article has 10 authors:
    1. Shreyas Bhat
    2. Ali El-Kasaby
    3. Ameya Kasture
    4. Danila Boytsov
    5. Julian B. Reichelt
    6. Thomas Hummel
    7. Sonja Sucic
    8. Christian Pifl
    9. Michael Freissmuth
    10. Walter Sandtner
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This study presents the important finding of an unusual uncompetitive inhibitor (ECSI#6) of the serotonin transporter that removes the neurotransmitter serotonin from the synaptic cleft. Through careful and comprehensive analysis, the authors convincingly show that the molecule most likely binds to the inward-facing and K+-bound state and that it assists in folding and targeting the transporter. The work will be of interest to those engaged in biophysical analyses of the serotonin transporter, and colleagues developing pharmacological chaperoning strategies for transporters in general.

    Reviewed by eLife

    This article has 5 evaluationsAppears in 2 listsLatest version Latest activity
  8. Metformin protects trabecular meshwork against oxidative injury via activating integrin/ROCK signals

    This article has 5 authors:
    1. Lijuan Xu
    2. Xinyao Zhang
    3. Yin Zhao
    4. Yang Cao
    5. Yuanbo Liang
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This manuscript proposes that metformin protects against elevated intraocular pressure and oxidative injury by regulating cytoskeleton remodeling through the integrin/ROCK pathway, thus providing a new direction for further exploration toward the treatment of primary open-angle glaucoma as well as investigation of oxidative injury in multiple settings.

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  9. Modeling osteoporosis to design and optimize pharmacologic therapies comprising multiple drug types

    This article has 7 authors:
    1. David J. Jörg
    2. Doris H. Fürtinger
    3. Alhaji Cherif
    4. David A. Bushinsky
    5. Ariella Mermelstein
    6. Jochen G. Raimann
    7. Peter Kotanko
    This article has been curated by 1 group:
    • Curated by eLife

      Evaluation Summary:

      This paper will be of interest to the pharmacology community with interest in available drug treatments for osteoporosis and how to optimize these. The key findings of the paper are based on in silico results and indicate that combined drug treatments may be more efficient in treatment of osteoporosis. This could have a significant impact on clinical management of osteoporosis patients.

      (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.)

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  10. Mechanism of hyperproteinemia-induced blood cell homeostasis imbalance in an animal model

    This article has 10 authors:
    1. Guang Wang
    2. Yongfeng Wang
    3. Jianglan Li
    4. Ruji Peng
    5. Xinyin Liang
    6. Xuedong Chen
    7. Guihua Jiang
    8. Jinfang Shi
    9. Yanghu Si-ma
    10. Shiqing Xu
    This article has been curated by 1 group:
    • Curated by eLife

      Evaluation Summary:

      The authors present a manuscript addressing an important unmet need, specifically focused on understanding the effects of high protein on hematopoiesis. This information can be of interest to basic biologists and clinicians who specialize in the areas of various diseases associated with elevated protein concentration (e.g. infections, inflammation, multiple myeloma, renal failure, etc). This is in part what makes for the complexity in studying this entity as the consequences of such disparate diseases are difficult to parcel out as causes of which specific disease manifestations. Furthermore, the presented work is done in an invertebrate model without additional confirmation in other model systems. Taken together, the work, which is plentiful in experiments, provides an incomplete understanding of cause and effect, leading to overinterpretation of results and overstating of derived conclusions.

      (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.)

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  11. Robust and Efficient Assessment of Potency (REAP): A Quantitative Tool for Dose-response Curve Estimation

    This article has 9 authors:
    1. Shouhao Zhou
    2. Xinyi Liu
    3. Xinying Fang
    4. Vernon M. Chinchilli
    5. Michael Wang
    6. Hong-Gang Wang
    7. Nikolay V Dokholyan
    8. Chan Shen
    9. J Jack Lee
    This article has been curated by 1 group:
    • Curated by eLife

      Evaluation Summary:

      This article proposes methodology and accompanying software for robustly fitting dose-response curves where response is a number between 0 and 1. When response is transformed using the common logistic transformation, values close to 0 or 1 become large in magnitude, unduly influencing the fitted curve after back-transformation and introducing bias in the estimate of certain parameters. The proposed approach, called Robust and Efficient Assessment of Potency, is less perturbed by these extreme 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 agreed to share their name with the authors.)

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  12. A Single Multipurpose FSH–Blocking Therapeutic for Osteoporosis and Obesity

    This article has 43 authors:
    1. Sakshi Gera
    2. Tan-Chun Kuo
    3. Funda Korkmaz
    4. Damini Sant
    5. Victoria DeMambro
    6. Anisa Gumerova
    7. Kathayani Sudha
    8. Ashley Padilla
    9. Geoffrey Prevot
    10. Jazz Munitz
    11. Abraham Teunissen
    12. Mandy van Leent
    13. Tomas G.J.M. Post
    14. Jessica C. Fernandes
    15. Jessica Netto
    16. Farhath Sultana
    17. Eleanor Shelly
    18. Pushkar Kumar
    19. Liam Cullen
    20. Jiya Chatterjee
    21. Sari Miyashita
    22. Hasni Kannangara
    23. Megha Bhongade
    24. Kseniia Ievleva
    25. Valeriia Muradova
    26. Rogerio Batista
    27. Cemre Robinson
    28. Anne Macdonald
    29. Susan Babunovic
    30. Mansi Saxena
    31. Marcia Meseck
    32. John Caminis
    33. Jameel Iqbal
    34. Maria I. New
    35. Vitaly Ryu
    36. Se-Min Kim
    37. Jay J. Cao
    38. Neeha Zaidi
    39. Zahi Fayad
    40. Daria Lizneva
    41. Clifford J. Rosen
    42. Tony Yuen
    43. Mone Zaidi
    This article has been curated by 1 group:
    • Curated by eLife

      Evaluation Summary:

      The authors describe a comprehensive characterization of a new humanized FSH blocking antibody (MS-Hu6), which they have studied in-depth in terms of its efficacy on bone and fat tissues. They provide compelling data on mouse and monkey species with a complete evaluation of its pharmacokinetics and biodistribution and characterize its effect for the treatment of obesity and bone loss. It is an important contribution and will be useful to a general readership in endocrinology, bone and fat metabolism.

      (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.)

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  13. Effector membrane translocation biosensors reveal G protein and βarrestin coupling profiles of 100 therapeutically relevant GPCRs

    This article has 20 authors:
    1. Charlotte Avet
    2. Arturo Mancini
    3. Billy Breton
    4. Christian Le Gouill
    5. Alexander S. Hauser
    6. Claire Normand
    7. Hiroyuki Kobayashi
    8. Florence Gross
    9. Mireille Hogue
    10. Viktoriya Lukasheva
    11. Stéphane St-Onge
    12. Marilyn Carrier
    13. Madeleine Héroux
    14. Sandra Morissette
    15. Eric Fauman
    16. Jean-Philippe Fortin
    17. Stephan Schann
    18. Xavier Leroy
    19. David E. Gloriam
    20. Michel Bouvier
    This article has been curated by 1 group:
    • Curated by eLife

      Evaluation Summary:

      A challenge to understanding the physiology and therapeutic potential of G protein-coupled receptors (GPCRs) is to understand the range of their couplings to different G proteins. Avet et al developed of a novel set of biosensors to assess the coupling specificity of 100 therapeutically relevant G protein-coupled receptors (GPCRs) to various G protein isoforms and arrestins. The novel screen and results obtained with reference ligands will have broad use for researchers studying GPCRs, potentially impacting discovery of new physiological pathways, understanding adverse effects of currently marketed therapeutics, and discovery of novel, safer therapeutics.

      (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.)

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  14. Common coupling map advances GPCR-G protein selectivity

    This article has 7 authors:
    1. Alexander S. Hauser
    2. Charlotte Avet
    3. Claire Normand
    4. Arturo Mancini
    5. Asuka Inoue
    6. Michel Bouvier
    7. David E. Gloriam
    This article has been curated by 1 group:
    • Curated by eLife

      Evaluation Summary:

      This study is a meta-analysis of previously reported studies on G protein-coupled receptor (GPCR) coupling to G proteins. Three separate data sets that describe the coupling of members of the superfamily of non-sensory GPCRs (~200 genes) to the large family of G protein alpha subunits (~20 genes). The authors try to arrive at a consensus for receptor-G protein coupling from the three data sets, as well as identify and highlight differences or incongruencies. Compiling these vast data sets into a unified format will be extremely useful for investigators to understand receptor and effector relationships. The meta-analysis will help to deconvolute the complex physiology and pharmacology underlying hormone or drug actions acting on receptor superfamilies.

      (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.)

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  15. NBI-921352, a First-in-Class, Na V 1.6 Selective, Sodium Channel Inhibitor That Prevents Seizures in Scn8a Gain-of-Function Mice, and Wild-Type Mice and Rats

    This article has 50 authors:
    1. JP Johnson
    2. Thilo Focken
    3. Kuldip Khakh
    4. Parisa Karimi Tari
    5. Celine Dube
    6. Aaron Williams
    7. Jean-Christophe Andrez
    8. Girish Bankar
    9. David Bogucki
    10. Kristen Burford
    11. Elaine Chang
    12. Sultan Chowdhury
    13. Richard Dean
    14. Gina de Boer
    15. Shannon Decker
    16. Christoph Dehnhardt
    17. Mandy Feng
    18. Wei Gong
    19. Samuel J Goodchild
    20. Michael Grimwood
    21. Abid Hasan
    22. Angela Hussainkhel
    23. Qi Jia
    24. Stephanie Lee
    25. Jenny Li
    26. Sophia Lin
    27. Andrea Lindgren
    28. Verner Lofstrand
    29. Janette Mezeyova
    30. Rostam Namdari
    31. Karen Nelkenbrecher
    32. Noah Gregory Shuart
    33. Luis Sojo
    34. Shaoyi Sun
    35. Matthew Taron
    36. Matthew Waldbrook
    37. Diana Weeratunge
    38. Steven Wesolowski
    39. Michael Wilson
    40. Zhiwei Xie
    41. Rhena Yoo
    42. Clint Young
    43. Alla Zenova
    44. Wei Zhang
    45. Alison J Cutts
    46. Robin P Sherrington
    47. Simon N Pimstone
    48. Raymond Winquist
    49. Charles J Cohen
    50. James R Empfield
    This article has been curated by 1 group:
    • Curated by eLife

      Evaluation Summary:

      This exciting study reports on the characterization of a novel compound that preferentially targets Nav1.6 voltage-gated sodium channels and shows substantial activity against epilepsy associated SCN8A mutations and seizure activity in a variety of animal models. This compound and approach has significant promise to be translated into a therapeutic for individuals with treatment resistant epilepsy.

      (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.)

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  16. Fluorescence Activation Mechanism and Imaging of Drug Permeation with New Sensors for Smoking-Cessation Ligands

    This article has 19 authors:
    1. Aaron L. Nichols
    2. Zack Blumenfeld
    3. Chengcheng Fan
    4. Laura Luebbert
    5. Annet E. M. Blom
    6. Bruce N. Cohen
    7. Jonathan S. Marvin
    8. Philip M. Borden
    9. Charlene H. Kim
    10. Anand K. Muthusamy
    11. Amol V. Shivange
    12. Hailey J. Knox
    13. Hugo Rego Campello
    14. Jonathan H. Wang
    15. Dennis A. Dougherty
    16. Loren L. Looger
    17. Timothy Gallagher
    18. Douglas C. Rees
    19. Henry A. Lester
    This article has been curated by 1 group:
    • Curated by eLife

      Evaluation Summary:

      Nichols et al. developed and characterized the first fluorescent sensors for several nicotinic receptor partial agonists relevant to smoking cessation. It is potentially a major advance for the field. They leveraged crystallography to understand the mechanism by which the ligands enhance fluorescence, then characterized top sensors for sensitivity, selectivity, and kinetics, and their utility in plasma membrane and ER sensing in neurons and cell lines. The tools developed by this team will enable investigators to track nicotinic receptor partial agonists in different subcellular compartments with relatively fast time resolution.

      (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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    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  17. Remodeling of dermal adipose tissue alleviates cutaneous toxicity induced by anti-EGFR therapy

    This article has 8 authors:
    1. Leying Chen
    2. Qing You
    3. Min Liu
    4. Shuaihu Li
    5. Zhaoyu Wu
    6. Jiajun Hu
    7. Liangyong Xia
    8. Shiyi Zhang
    This article has been curated by 1 group:
    • Curated by eLife

      Evaluation Summary:

      This paper will be of interest to oncologists and dermatologists and has high clinical relevance. It reveals a novel mechanism of EGFR inhibitor-induced rash which be may closely related to atrophy of dermal white adipose tissue (dWAT). A series of experimental manipulations dissect the mechanism with a murine model, supporting the major claims of the paper.

      (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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    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  18. μ-Theraphotoxin-Pn3a inhibition of Ca V 3.3 channels reveals a novel isoform-selective drug binding site

    This article has 5 authors:
    1. Jeffrey R. McArthur
    2. Jierong Wen
    3. Andrew Hung
    4. Rocio K. Finol-Urdaneta
    5. David J. Adams
    This article has been curated by 1 group:
    • Curated by eLife

      Evaluation Summary:

      Low voltage-activated T-type calcium channels (CaV3.1-3.3) are important for several physiological processes. It is challenging to distinguish their specific physiological / pathophysiological roles as they share similar biophysical properties, expression profiles and there is a lack of subtype selective pharmacology. This study reports a spider toxin, Pn3a, which exhibits 100-fold selectivity for inhibiting CaV3.3 over CaV3.1 and CaV3.2 isoforms, and which therefore makes for an excellent reagent for the physiological study of CaV3.3.

      (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.)

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  19. Characterization of the Endogenous DAF-12 Ligand and Its Use as an Anthelmintic Agent in Strongyloides stercoralis

    This article has 11 authors:
    1. Zhu Wang
    2. Mi Cheong Cheong
    3. Jet Tsien
    4. Heping Deng
    5. Tian Qin
    6. Jonathan D. C. Stoltzfus
    7. Tegegn G. Jaleta
    8. Xinshe Li
    9. James B. Lok
    10. Steven A. Kliewer
    11. David J. Mangelsdorf
    This article has been curated by 1 group:
    • Curated by eLife

      Evaluation Summary:

      This work reveals the pathway by which an important human parasite synthesizes a nuclear hormone receptor ligand critical for progression through its life cycle and demonstrates the potential therapeutic implications of perturbing this pathway. The experiments are insightfully and expertly conceived, designed and executed, and the data support the conclusions. This manuscript will be of general interest to parasitologists, nematode biologists, and those studying transcriptional regulatory networks governed by ligand-gated nuclear receptors.

      (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 names with the authors.)

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    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  20. Covalent inhibition of endoplasmic reticulum chaperone GRP78 disconnects the transduction of ER stress signals to inflammation and lipid accumulation in diet-induced obese mice

    This article has 10 authors:
    1. Dan Luo
    2. Ni Fan
    3. Xiuying Zhang
    4. Fung Yin Ngo
    5. Jia Zhao
    6. Wei Zhao
    7. Min Huang
    8. Ding Li
    9. Yu Wang
    10. Jianhui Rong
    This article has been curated by 1 group:
    • Curated by eLife

      Evaluation Summary:

      This paper is of interest to a broad audience of cell biologists, pharmacologists and researchers who work in metabolic diseases. The work provides substantial new insights into the mechanism of action for a plant derived pentacyclic triterpene called celastrol elastrol, in effectively reducing the high fat diet induced tissue hypertrophy in mouse liver and adipose. A series of compelling experiments depict the site of covalent inhibition of the ER stress sensor GRP78 as essential for the beneficial effects in-vivo, supporting the main conclusions.

      (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.)

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity