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  1. Reversing protonation of weakly basic drugs greatly enhances intracellular diffusion and decreases lysosomal sequestration

    This article has 7 authors:
    1. Debabrata Dey
    2. Shir Marciano
    3. Anna Poryvai
    4. Ondřej Groborz
    5. Lucie Wohlrábová
    6. Tomás Slanina
    7. Gideon Schreiber
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This is a valuable study on the diffusion rates of drug molecules in human-derived cells, highlighting that their diffusion behavior depends on their charged state. It proposes that blocking drug protonation enhances diffusion and fractional recovery, suggesting improved intracellular availability of weakly basic drugs. The correlation between pKa and intracellular diffusion is well-supported, but the study would benefit from a more rigorous statistical treatment and a balanced comparison across different types of compounds. Despite these limitations, the findings are significant for drug design and understanding the biophysical behavior of small molecules in cells.

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  2. An Integrated Machine Learning Approach Delineates an Entropic Expansion Mechanism for the Binding of a Small Molecule to α -Synuclein

    This article has 3 authors:
    1. Sneha Menon
    2. Subinoy Adhikari
    3. Jagannath Mondal
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This study describes the application of machine learning and Markov state models to characterize the binding mechanism of alpha-Synuclein to the small molecule Fasudil. The results suggest that entropic expansion can explain such binding. However, the simulations and analyses in their present form are inadequate.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  3. Intracellular mechanical fingerprint reveals cell type specific mechanical tuning

    This article has 3 authors:
    1. Till M. Muenker
    2. Bart E. Vos
    3. Timo Betz
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      Münker and colleagues use an optical tweezer setup to apply oscillatory forces to endocytosed/phagocytosed glass beads over a wide frequency range (from ~1 to 1000 Hz) and probe cytoplasmic material properties at multiple time scales in six different cell types. Using statistical methods and principal component analysis, they find that the active and passive mechanical properties of cells can be described by 6 parameters (from power law fits) that allow characterizing the viscous and elastic nature of the cytoplasmic material as well as an effective active energy driven by cellular metabolism. Overall, this is very well done and important work, using convincing and state-of-the-art methods, albeit with some limitations related to the way the beads are internalized.

    Reviewed by eLife

    This article has 5 evaluationsAppears in 2 listsLatest version Latest activity
  4. iDEP-assisted isolation of insulin secretory vesicles

    This article has 7 authors:
    1. Mahta Barekatain
    2. Yameng Liu
    3. Zhongying Wang
    4. Vadim Cherezov
    5. Scott E. Fraser
    6. Kate L White
    7. Mark A. Hayes
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This paper presents a new method for separating organelles in an unbiased way. The method is applied to the separation of distinct subpopulations of insulin vesicles. There are concerns around whether the vesicles measured are in fact insulin vesicles and whether the observed changes in vesicle populations upon glucose stimulation are biologically meaningful, and thus it is difficult to assess at this stage how well the technique performs. This paper is likely to be of wide interest to cell biologists studying a variety of compartments, as well as to researchers in the beta cell field.

    Reviewed by eLife

    This article has 5 evaluationsAppears in 2 listsLatest version Latest activity
  5. Connecting Chromatin Structures to Gene Regulation Using Dynamic Polymer Simulations

    This article has 5 authors:
    1. Yi Fu
    2. Finnegan Clark
    3. Sofia Nomikou
    4. Aristotelis Tsirigos
    5. Timothee Lionnet
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This paper presents a valuable optimization algorithm for determining the spatio-temporal organization of chromatin. The algorithm identifies the polymer model that best fits population averaged Hi-C data and makes predictions about the spatio-temoral organization of specific genomic loci such as the oncogenic Myc locus. While the algorithm will be of value to biologists and physicists working in the field of genome organization, the provided methodological details and evidence are incomplete to fully substantiate the conclusions. In particular, the following would be beneficial: analysis of single-cell data, the inclusion of loci beyond Myc, testing the dependence of results on the chosen parameters, providing more details on CTCF occupancy at loop anchors, and better substantiating the claim about predictions of single-cell heterogeneity.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  6. Cell-cycle and Age-Related Modulations in Mouse Chromosome Stiffness

    This article has 5 authors:
    1. Ning Liu
    2. Wenan Qiang
    3. Philip Jordan
    4. John Marko
    5. Huanyu Qiao
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This valuable paper describes the stiffness of meiotic chromosomes in both oocytes and spermatocytes. The authors identify differences in stiffness between meiosis I and II chromosomes, as well as an age-dependent increase in stiffness in meiosis I (and meiosis II) chromosomes, results that are highly significant for the field of chromosome biology. The mechanisms underlying age-dependent changes in chromosome stiffness remain unclear, and the evidence to suggest that changes in stiffness are independent of cohesin, which is known to deteriorate with age, is incomplete.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  7. TMEM16 and TMEM63/OSCA proteins share a conserved potential to permeate ions and phospholipids

    This article has 6 authors:
    1. Augustus J. Lowry
    2. Pengfei Liang
    3. Y.C. Serena Wan
    4. Zhen-Ming Pei
    5. Huanghe Yang
    6. Yang Zhang
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This manuscript finds evidence for a latent capability in several members of the TMEM16 and OSCA/TMEM family of ion channels for lipid scramblase activity. The authors demonstrate that the introduction of lysine mutations in evolutionarily conserved areas of TM4 can confer constitutive ion conduction and scramblase activity. Although the significance and scope of the work are important, the strength of the evidence is incomplete and could be improved.

    Reviewed by eLife

    This article has 5 evaluationsAppears in 3 listsLatest version Latest activity
  8. The interplay between biomolecular assembly and phase separation

    This article has 4 authors:
    1. Giacomo Bartolucci
    2. Ivar S. Haugerud
    3. Thomas C.T. Michaels
    4. Christoph A. Weber
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      The authors present an important theoretical framework that describes the interplay between liquid-liquid phase separation and protein aggregation within a mean-field model. This work will be of high interest to the biophysics and molecular biology communities, as it will understand and analyse assembly within biomolecular condensates in cells or in-vitro. Major strengths of this convincing work are the consideration of aggregates with various dimensionality and the possibility for protein gelation. A relative weakness is the lack of intuitive interpretation of some of the results and the work could be more accessible to non-experts.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  9. CTFFIND5 provides improved insight into quality, tilt and thickness of TEM samples

    This article has 4 authors:
    1. Johannes Elferich
    2. Lingli Kong
    3. Ximena Zottig
    4. Nikolaus Grigorieff
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This valuable work presents the latest version of CTFFIND, which is the most popular software for determination of the contrast transfer function (CTF) in cryo-electron microscopy. CTFFIND5 estimates and considers acquisition geometry and sample thickness, which leads to improved CTF determination. The paper describes convincing evidence that CTFFIND5 finds better CTF parameters than previous methods, in particular for tilted samples (e.g. for cryo-electron tomography) or where thickness is an issue (e.g. cellular samples, or electron microscopy at low voltages).

    Reviewed by eLife

    This article has 4 evaluationsAppears in 3 listsLatest version Latest activity
  10. N-acetylation of α-synuclein enhances synaptic vesicle clustering mediated by α-synuclein and lysophosphatidylcholine

    This article has 12 authors:
    1. Chuchu Wang
    2. Chunyu Zhao
    3. Xiao Hu
    4. Jiali Qiang
    5. Zhenying Liu
    6. Jinge Gu
    7. Shengnan Zhang
    8. Dan Li
    9. Yaoyang Zhang
    10. Jacqueline Burré
    11. Jiajie Diao
    12. Cong Liu
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      In this useful study, the authors show that N-acetylation of synuclein increases clustering of synaptic vesicles in vitro and that this effect is mediated by enhanced interaction with lysophosphatidylcholine. While the evidence for enhanced clustering is largely solid, the biological significance remains unclear.

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  11. The mechanism of mammalian proton-coupled peptide transporters

    This article has 4 authors:
    1. Simon M Lichtinger
    2. Joanne L Parker
    3. Simon Newstead
    4. Philip C Biggin
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This study provides important insight into the mechanisms of proton-coupled oligopeptide transporters. It uses enhanced-sampling molecular dynamics (MD), backed by cell-based assays, revealing the importance of protonation of selected residues for PepT2 function. The simulation approaches are convincing, using long MD simulations, constant-pH MD and free energy calculations. Overall, the work has led to important findings that will appeal to structural biologists, biochemists, and biophysicists studying membrane transporters.

    Reviewed by eLife

    This article has 10 evaluationsAppears in 3 listsLatest version Latest activity
  12. The French flag problem revisited: Creating robust and tunable axial patterns without global signaling

    This article has 3 authors:
    1. Stephan Kremser
    2. Gabriel Vercelli
    3. Ulrich Gerland
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This important study uses cellular automata and evolution algorithms to offer an alternative to long-range signalling models of developmental patterning. The computational evidence that local rules suffice to produce a robust and global pattern is convincing. With some additional insights that connect the theoretical findings back to real biological examples, this work could be of interest to the broad community of developmental and systems biologists.

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  13. Fluid mechanics of luminal transport in actively contracting endoplasmic reticulum

    This article has 3 authors:
    1. Pyae Hein Htet
    2. Edward Avezov
    3. Eric Lauga
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This study explores the physical principles underlying fluid flow and luminal transport within the endoplasmic reticulum; its important contribution is to highlight the strong physical constraints imposed by viscous dissipation in nanoscopic tubular networks. In particular, the work presents convincing evidence that commonly discussed mechanisms such as tubular contraction are unlikely to be at the origin of the observed transport velocities. As this study is solely theoretical and concerned with order of magnitude estimates, its main conclusions await experimental validation. The work will be of relevance to cell biologists and physicists interested in organelle dynamics.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  14. Allosteric coupling asymmetry mediates paradoxical activation of BRAF by type II inhibitors

    This article has 10 authors:
    1. Damien M Rasmussen
    2. Manny M Semonis
    3. Joseph T Greene
    4. Joseph M Muretta
    5. Andrew R Thompson
    6. Silvia Toledo Ramos
    7. David D Thomas
    8. William CK Pomerantz
    9. Tanya S Freedman
    10. Nicholas M Levinson
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This elegant study presents important findings into how small molecules that were originally developed to inhibit the oncogenic kinase, BRAF, instead trigger activation of this kinase target. Compelling and comprehensive evidence supports a new allosteric model to explain the paradoxical activation. This rigorous work will be of great interest to biochemists, structural biologists, and those working on strategies to inhibit kinases in the context of human disease.

    Reviewed by eLife

    This article has 4 evaluationsAppears in 2 listsLatest version Latest activity
  15. Modulation of α -Synuclein Aggregation Amid Diverse Environmental Perturbation

    This article has 3 authors:
    1. Abdul Wasim
    2. Sneha Menon
    3. Jagannath Mondal
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This study provides important biophysical insights into the molecular mechanism underlying the association of alpha-synuclein chains, which is essential for understanding the pathogenesis of Parkinson's disease. The data analysis is solid, and the methodology can help investigate other molecular processes involving intrinsically disordered proteins. The benchmarking of the cgMD simulations should be improved to give the reader greater confidence in the conclusions presented.

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  16. Role of N343 glycosylation on the SARS-CoV-2 S RBD structure and co-receptor binding across variants of concern

    This article has 7 authors:
    1. Callum M Ives
    2. Linh Nguyen
    3. Carl A Fogarty
    4. Aoife M Harbison
    5. Yves Durocher
    6. John Klassen
    7. Elisa Fadda
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This study presents an important finding on the structural role of glycosylation at position N343 of the SARS-CoV-2 spike protein's receptor-binding domain in maintaining its stability, with implications across different variants of concern. The evidence supporting the claims of the authors is convincing, since appropriate and validated methodology in line with current state-of-the-art has been approached. The work will be of interest to evolutionary virologists.

    Reviewed by eLife

    This article has 9 evaluationsAppears in 2 listsLatest version Latest activity
  17. The Geometric Basis of Epithelial Convergent Extension

    This article has 5 authors:
    1. Fridtjof Brauns
    2. Nikolas H. Claussen
    3. Matthew F. Lefebvre
    4. Eric F. Wieschaus
    5. Boris I. Shraiman
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This is a very strong, well-written, and interesting paper analyzing in an original way how tension pattern dynamics can reveal the contribution of active versus passive intercalation during tissue elongation. The authors apply a new concept of isogonal tension decomposition to extract a global map of tissue mechanics that will be extremely valuable in the field of biomechanics. The model is convincing to explain the authors' data but could be strengthened further by analyzing data from mutant backgrounds that could serve as a test.

    Reviewed by eLife

    This article has 2 evaluationsAppears in 2 listsLatest version Latest activity
  18. Mitosis sets nuclear homeostasis of cancer cells under confinement

    This article has 6 authors:
    1. Malèke Mouelhi
    2. Alexis Saffon
    3. Morgane Roinard
    4. Hélène Delanoë-Ayari
    5. Sylvain Monnier
    6. Charlotte Rivière
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This important study describes the new observation that nuclear volume responds to confinement in a manner that requires transit through mitosis. The authors present solid evidence demonstrating that nuclear volume decreases upon nuclear envelope reformation under confinement in a manner that reestablishes a homeostatic state of nuclear envelope tension. Additional experimental support could provide a more complete case for the proposed underlying mechanisms governing this response. The work will be of broad interest to cell biologists and those interested in cell and organismal scaling.

    Reviewed by eLife

    This article has 5 evaluationsAppears in 2 listsLatest version Latest activity
  19. Dissecting Mechanisms of Ligand Binding and Conformational Changes in the Glutamine-Binding Protein

    This article has 17 authors:
    1. Zhongying Han
    2. Sabrina Panhans
    3. Sophie Brameyer
    4. Ecenaz Bilgen
    5. Marija Ram
    6. Anna Herr
    7. Alessandra Narducci
    8. Michael Isselstein
    9. Paul D. Harris
    10. Oliver Brix
    11. Kirsten Jung
    12. Don C. Lamb
    13. Eitan Lerner
    14. Douglas Griffith
    15. Thomas R. Weikl
    16. Niels Zijlstra
    17. Thorben Cordes
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This important study combines a range of biophysical techniques to carry out a series of compelling experiments to explore whether glutamine binding protein binds glutamine via an induced fit or a conformational selection process. The evidence supporting the major conclusion of the work is convincing, although it may not be generalized to other protein-ligand or protein-protein systems. The work will be of broad interest to biochemists and biophysicists.

    Reviewed by eLife

    This article has 3 evaluationsAppears in 2 listsLatest version Latest activity
  20. Mechanism of Dimer Selectivity and Binding Cooperativity of BRAF Inhibitors

    This article has 6 authors:
    1. Joseph Clayton
    2. Aarion Romany
    3. Evangelia Matenoglou
    4. Evripidis Gavathiotis
    5. Poulikos I. Poulikakos
    6. Jana Shen
    This article has been curated by 1 group:
    • Curated by eLife

      eLife assessment

      This important work illuminates the dynamics of BRAF in both its monomeric and dimeric forms, with or without inhibitors, combining traditional techniques and sophisticated computational analyses. The evidence presented is convincing and suggests a potential allosteric effect, though substantiating the exact mechanism will require further studies. The work has implications for understanding kinase signaling and the development of potential drug candidates. This study will be of interest to structural biologists, medicinal chemists, and pharmacologists.

    Reviewed by eLife

    This article has 8 evaluationsAppears in 2 listsLatest version Latest activity