eLife Assessment

This fundamental work demonstrates that compartmentalized cellular metabolism is a dominant input into cell size control in a variety of mammalian cell types and in Drosophila. The authors show that increased pyruvate import into the mitochondria in liver-like cells and in primary hepatocytes drives gluconeogenesis but reduces cellular amino acid production, suppressing protein synthesis. The evidence supporting the conclusions is compelling, with a variety of genetic and pharmacologic assays rigorously testing each step of the proposed mechanism. This work will be of interest to cell biologists, physiologists, and researchers interested in cell metabolism, and is significant because stem cells and many cancers exhibit metabolic rewiring of pyruvate metabolism.

eLife Assessment

This work is of fundamental significance and has a compelling level of evidence for the role of mutant p53 in regulation of tumorigenesis using an in vivo mouse model. The study is well-conducted and will be of interest to a broad audience including those interested in p53, transcription factors and cancer biology.

eLife Assessment

This manuscript provides potentially important findings examining in 2D and 3D models in MYC liver cancer cells changes in DNA repair genes and programs in response to hypoxia. The authors use convincing methodology in most cases, but there is some concern that the analysis is incomplete.

eLife Assessment

Overall, this fundamental study identified a novel role of NOLC1 in regulating p53 nuclear transcriptional activity and p53-mediated ferroptosis in gastric cancer. The evidence supporting the conclusions is solid, although some new evidence is needed to make it more robust. The work will be of broad interest to cancer biologists and oncologists.

eLife Assessment

This important work advances our understanding of how the SARS-CoV-2 Nsp16 protein is regulated by host E3 ligases to promote viral mRNA capping. However, support for the overall claims is incomplete as the authors need to demonstrate Nsp16 ubiquitination and the role of E3 ligases in a more biologically relevant context (ie. infection). This work will be of interest to those working in host-viral interactions and the role of the ubiquitin-proteasome system in viral replication.

eLife Assessment

In the field of early detection of disease and recurrence and monitoring of treatment efficacy by cfDNA analysis, this study presents a useful finding that HPV cfDNA level monitoring provides advantages over serum levels of squamous cell carcinoma antigen (SCC-Ag), specifically for HPV+ cervical cancer. The data were collected and analysed using solid and validated methodology but the sample number was limited.

eLife Assessment

This work presents a valuable self-supervised method for the segmentation of 3D cells in microscopy images, alongside an implementation as a Napari plugin and an annotated dataset. While the Napari plugin is readily applicable and promises to eliminate time consuming data labeling to speed up quantitative analysis, there is incomplete evidence to support the claim that the segmentation method generalizes to other light-sheet microscopy image datasets beyond the four specific ones used here.

eLife Assessment

This important study uses optogenetics in combination with single cell recordings to selectively activate sensory input channels within the olfactory bulb, providing direct evidence for activity-dependent and distance-independent enhancement of stimulus-evoked gamma oscillations via lateral interactions between input channels, most likely via granule cells. The article presents solid evidence to support the main conclusions.

eLife Assessment

The findings of this study are potentially valuable, offering insights into the neural representation of reversal probability in decision-making tasks, with potential implications for understanding flexible behavior in changing environments. The evidence presented is incomplete, with interesting comparisons between neural data and models, but the analyses do not yet provide clear evidence against line attractor dynamics for the accumulation of evidence of a reversal in this probabilistic reversal learning task.

eLife Assessment

This important work examines how microexons contribute to brain activity, structure, and behavior. The authors find that loss of microexon sequences generally has subtle impacts on these metrics in larval zebrafish, with few exceptions. The evidence is still partially incomplete and needs to be strengthened by key experiments or more precise data descriptions. Overall, this work will be of interest to neuroscientists and generate further studies of interest to the field.

eLife Assessment

This study demonstrates the potential role of 17α-estradiol in modulating neuronal gene expression in the aged hypothalamus of male rats, identifying key pathways and neuron subtypes affected by the drug. While the findings are useful and provide a foundation for future research, the strength of supporting evidence is incomplete due to the lack of female comparison, a young male control group, unclear link to 17α-estradiol lifespan extension in rats, and insufficient analysis of glial cells and cellular stress in CRH neurons.

eLife Assessment

This valuable study suggests that Naa10, an N-α-acetyltransferase with known mutations that disrupt neurodevelopment, acetylates Btbd3, which has been implicated in neurite outgrowth and obsessive-compulsive disorder, in a manner that regulates F-actin dynamics to facilitate neurite outgrowth. While the study provides promising insights and biochemical, co-immunoprecipitation, and proteomic data that enhance our understanding of protein N-acetylation in neuronal development, the evidence supporting larger claims is incomplete. Nonetheless, the implications of these findings are noteworthy, particularly regarding neurodevelopmental and psychiatric conditions tied to altered expression of Naa10 or Btbd3.

eLife Assessment

This study uncovers and characterizes a role for Pfdn5 in stabilizing axonal microtubules and synaptic morphology in the Drosophila peripheral nervous system. Although the mechanisms remain unresolved, the phenotypic characterization is an important contribution with solid evidence. The work also aims to address a potential interaction between Pfdn5/6 and Tau-mediated mechanisms of neurodegeneration; here, the evidence is partially incomplete.

eLife Assessment

This valuable study explores the role of spatial genome organization in oncogenic transformation, addressing an ambitious and significant topic. The authors have assembled comprehensive datasets from various subtypes of localized and lung-metastatic breast cancer cells, as well as from healthy and cancerous lung cells. They identified switching patterns in the 3D genome organization of lung-metastatic breast cancer cells, revealing a reconfiguration of genome architecture that resembles that of lung cells. If validated, this study could be critical for the field; however, at this stage, it is incomplete, as the main claims are only partially substantiated.

eLife Assessment

This study presents the state-dependent role of serotonin for the protein and sugar intake of Drosophila by expressing a dominant-negative serotonin transporter in subsets of serotoninergic neurons. This paper is valuable for neuroscientists working on neuromodulation and the effects of internal states such as hunger, however the characterization of behavioral and neuroanatomical data is incomplete.

eLife Assessment

This study reports important findings about the nature of feedback to primary visual cortex (V1) during object recognition. The state-of-the-art functional MRI evidence for the main claims is solid, although currently alternative explanations of the findings cannot be fully ruled out. The findings presented here are relevant to a number of scientific fields such as object recognition, categorisation and predictive coding.

eLife Assessment

This valuable study relating brain anatomy to reading ability in children studied longitudinally finds that a difference in sulcal anatomy is more predictive of reading ability than cognitive measures. The evidence that this anatomical difference is predictive and confers some benefit in the connectivity between brain areas is based on careful analyses and is solid. The findings would be of interest to researchers studying brain and cognitive development.

eLife Assessment

This valuable study combines evolution experiments with molecular and genetic techniques to study how a genetic lesion in MreB that causes rod-shape cells to become spherical, with concomitant deleterious fitness effects, can be rescued by natural selection. The results are convincing, although further improvement of the statistical analyses and figure presentation, and further clarification of the concrete contribution of the paper and how it relates to previous literature, would be welcome.

eLife Assessment

Gil Ávila et al. evaluated the aperiodic component in the medial prefrontal cortex using resting-state EEG recordings from 149 individuals with chronic pain and 115 healthy participants. The authors present compelling evidence that the aperiodic component of the EEG does not differentiate between those with chronic pain and healthy individuals. The study was well-designed and rigorously conducted, and the clear and conclusive results provide important insights that can guide future research in the field of pain neuroscience.

eLife Assessment

This important study enhances our understanding of the foraging behaviour of aerial insectivorous birds. Using solid methodology, the authors have collected extensive data on bird movements and prey availability, which in turn provide support for the main claim of the study. The work will be of broad interest to behavioural ecologists.

eLife Assessment

This important study describes two findings: first, that TEAD is subject to turnover by the ubiquitin-proteasome system involving RNF146 and Parylation, and second, the development of a pan-TEAD heterobifunctional degrader that is used to inhibit growth of a YAP-dependent cancer cell line and to characterize TEAD binding sites in the genome. Convincing evidence supports the development and specificity of the degrader. This article will be of relevance to cancer biologists and scientists interested in proteostasis, cellular signaling, and post-translation modification of proteins.

eLife Assessment

This study presents a useful model of genetic drift by incorporating variance in reproductive success, claiming to address several paradoxes in molecular evolution. However, some of the claimed "paradoxes" seem to be overstatements, as previous literature has pointed out the limitations of the standard model and proposed more advanced models to address those limitations. While the proposed new model presented in this paper yields some intriguing theoretical predictions, the analysis and simulations presented are incomplete to support the authors' strong claims, and it is unclear how much the model helps explain empirical observations.

eLife Assessment

In this important study, the authors employed three types of theoretical/computational models (coarse-grained molecular dynamics, analytical theory and field-theoretical simulations) to analyze the impact of salt on protein liquid-liquid phase separation. These different models reinforce each other and together provide convincing evidence to explain distinct salt effects on ATP mediated phase separation of different variants of caprin1. The insights and general approach are broadly applicable to the analysis of protein phase separation. Still, modeling at the coarse-grained level misses key effects that have been revealed by all-atom simulations, including salt-backbone coordination and strengthening of pi-type interactions by salt.

eLife Assessment

This manuscript aims to identify the pacemaker cells in the lymphatic collecting vessels - the cells that initiate the autonomous action potentials and contractions needed to drive lymphatic pumping. Through the exemplary use of existing approaches (genetic deletions and cytosolic calcium detection in multiple cell types), the authors convincingly determine that lymphatic muscle cells are the origin of the action potential that triggers lymphatic contraction. The inclusion of scRNAseq and membrane potential data enhances a tremendous study. This fundamental discovery establishes a new standard for the field of lymphatic physiology.

eLife Assessment

This valuable study presents new observations on white matter organisation at the micron scale, using a combination of synchrotron imaging and diffusion MRI across two species. Notably, the authors provide solid evidence for the fasciculation of axons within major fibre bundles into laminar structures, though these structures are not consistently observed across modalities or species. The study will be of general interest to neuroanatomists and those interested in white matter imaging.

eLife Assessment

This valuable study extends the previous interesting work of this group to address the potentially different control of movement and posture. Through experiments in which stroke participants used a robotic manipulandum, the authors provide solid evidence supporting a lack of a relation between the resting force postural bias they measure (closely related to the flexor synergy in stroke) and kinematic deficits during movement. Based on these results, the authors propose a conceptual framework that differentially weights the two main descending pathways (corticospinal tract and reticulospinal tract) for neurologically intact and stroke patients. Discussing the potential impact of differences on muscle/spinal circuit state and their responses between holding a posture and movement, as well as the assumptions of their statistical comparisons, would further improve the paper.

eLife Assessment

This study provides important insights into the regulation of a retained intron in the mRNA coding for OGT, a process known to be regulated by the O-GlcNAc cycling system, and highlights the functional role of the splicing regulator SFSWAP. The evidence supporting the claims of the authors is convincing: the authors performed an elegant state-of-the-art CRISPR knockout strategy and sophisticated bioinformatic analysis to identify SFSWAP as a negative regulator of alternative splicing. The work will be of interest to researchers in the fields of splicing and glycobiology.

eLife Assessment

This study provides useful findings about the effects of heterozygosity for Trio variants linked to neurodevelopmental and psychiatric disorders in mice. However, the strength of the evidence is limited and incomplete mainly because the experimental flow is difficult to follow, raising concerns about the conclusions' robustness. Clearer connections between variables, such as sex, age, behavior, brain regions, and synaptic measures, and more methodological detail on breeding strategies, test timelines, electrophysiology, and analysis, are needed to support their claims.

eLife Assessment

This study investigates the fundamental role of polyunsaturated fatty acids (PUFAs) in membrane biology, using a unique model to perform a thorough genetic screen that highlights that PUFA synthesis defects cannot be compensated for by mutations in other pathways. While the data are solid and generally support the claims, additional experimental validation or more detailed descriptions of their results would strengthen the broader conclusions. This study will appeal to researchers in membrane biology, lipid metabolism, and C. elegans genetics.

eLife Assessment

This paper provides a valuable contribution to our understanding of how adenosine acts as a signal of nutrient insufficiency and extends this idea to suggest that adenosine is released by metabolically active cells in proportion to the activity of methylation events. Convincing data support this idea. The authors use metabolic tracing approaches to identify the biochemical pathways that contribute to the regulation of adenosine levels and the S-adenosylmethionine cycle in Drosophila larval hemocytes in response to wasp egg infection.

eLife Assessment

This valuable study investigates the neural basis of causal inference of illness, suggesting that it relies on semantic networks specific to living things in the absence of a generalized representation of causal inference across domains. However, the evidence remains incomplete due to some unjustified design and analysis choices. Moreover, the authors do not fully exploit the potential of multivariate fMRI analyses to rigorously test their main hypothesis.

eLife Assessment

The authors examine the effect of cell-free chromatin particles (cfChPs) derived from human serum or from dying human cells on mouse cells in culture and propose that these cfChPs can serve as vehicles for cell-to-cell active transfer of foreign genetic elements. The work presented in this paper is intriguing and potentially important, but it is incomplete. At this stage, the claim that horizontal gene transfer can occur via cfChPs would strongly benefit from additional evidence emerging from multiple independent approaches. The evolutionary interpretations associated with the concept of "predatory genome" are premature based on the strength of evidence.

eLife Assessment

Valencia et al. combine elegant in vitro biochemical experiments with functional assays in cardiomyocytes to determine which properties of the FHOD3 formin are essential for sarcomere assembly. Using separation-of-function mutants, they show that FHOD3's elongation activity, rather than its nucleation, capping, or bundling activities, is key to its sarcomeric function. This is an important finding; most of the data presented in the manuscript are convincing, with the exception of two experiments (presence of FHOD3 at the barbed end of actin filaments in the TIRF elongation assays and characterization of the GS-FH1 mutant phenotype) that would merit few additional controls.

eLife Assessment

This important study investigates the role of vasopressin in modulating same-sex affiliative relationships in the context of linear dominance hierarchies. It provides convincing evidence that vasopressin signaling is involved in modulating aspects of affiliative behavior, although the evidence that affiliative relationships specifically arise from the triadic interaction study design is incomplete. Nevertheless, its focus on broadening the types of social relationships and species studied in this area makes it of interest to both neuroendocrinologists and colleagues studying the evolution and mechanisms underlying social affiliation.

eLife Assessment

In their valuable study, Lee et al. explore a role for the Hippo signaling pathway, specifically wts-1/LATS and the downstream regulator yap, in age-dependent neurodegeneration and microtubule dynamics using C. elegans mechanosensory neurons as a model. The authors demonstrate that disruption of wts-1/LATS leads to age-associated morphological and functional neuronal abnormalities, linked to enhanced microtubule stabilization, and shows a genetic connection between yap and microtubule stability. Despite some mechanistic gaps, the study employs robust genetic and molecular approaches to reveal a convincing link between the Hippo pathway, microtubule dynamics, and neurodegeneration.

eLife Assessment

This important work advances our understanding of parabrachial CGRP threat function. The evidence supporting CGRP aversive outcome signaling is solid, while the evidence for cue signaling and fear behavior generation is incomplete. The work will be of interest to neuroscientists studying defensive behaviors.

for - mindfulness meditation research - 4 pillars of wellbeing - Youtube - Tukdam talk - An Overview Of CHM’s Work On “Well-Being And Tukdam” - Prof. Richard J. Davidson

summary - four pillars of wellbeing - 1 awareness - 2 connection - 3 insight (of the nature of self) - 4 purpose (intention)

eLife Assessment

This study presents a valuable advancement in antiviral research by applying SHAPE-Map to analyze the secondary structure of the Porcine Epidemic Diarrhoea Virus RNA genome in infected cells, identifying promising therapeutic targets within viral genomic RNA. The authors provide convincing evidence of potential antiviral targetable RNA regions through a wide array of data from different methods, supported by well-documented experimental design and data analysis, demonstrating how RNA structural probing can effectively discover RNA targets and enabling further discoveries in the field. The work will be of interest to researchers focused on RNA therapeutics and viral genome studies.

eLife Assessment

In this report, the authors present valuable findings identifying a novel worm-specific protein (sdg-1) that is induced upon loss of dsRNA import via SID-1, but is not required to mediate SID-1 RNA regulatory effects. The genetic and genomic approaches are well-executed and the revision contain generally solid support for the central findings of the work. These findings will be of interest to those working in the germline epigenetic inheritance field.

eLife Assessment

This is a valuable study regarding the role of gasdesmin D in experimental psoriasis. The study contains solid evidence for such a role, involving neutrophils, from murine models of skin inflammation, as well as correlative data of elevated gasdermin D expression in human psoriatic skin. The findings will be of interest to researchers trying to unravel pathways of skin inflammation.

eLife Assessment

This important work is a versatile new addition to the chemical protein modifications and bioconjugation toolbox in synthetic biology. The technology developed cleverly uses Connectase to irreversibly fuse proteins of interest together so they can be studied in their native context, with convincing data showing the technique works for various protein partners. This work will help multiple fields to explore multi-function constructs in basic synthetic biology. This work will also be of interest to those studying fusion oncoproteins commonly expressed in various human pathologies.

eLife Assessment

This study investigated mitochondrial dysfunction and the impairment of the ciliary Sonic Hedgehog signaling in Lowe syndrome (LS), a timely topic given the limited research in this area. The data from patient iPSC-derived neurons and a mouse model were collected using solid methods, but the evidence supporting key claims is incomplete, and some technical aspects fall short of expectations. Despite these limitations, the study provides a useful foundation for exploring the relationship between mitochondrial defects and primary cilia in neural development.

eLife Assessment

This valuable study proposes a theoretical model of clathrin coat formation based on membrane elasticity that seeks to determine whether this process occurs by increasing the area of a protein-coated patch with constant curvature, or by increasing the curvature of a protein-coated patch that forms in an initially flat conformation (so called constant curvature or constant area models). Identifying energetically favorable pathways and comparing the obtained shapes with experiments provides solid support to the constant-area pathway. This work will be of interest for biologists and biophysicists interested in membrane remodelling and endocytosis. It provides an innovative approach to tackle the question of constant curvature vs. constant area coat protein formation, although some of the model's assumption are only partially supported by experimental evidence.

eLife Assessment

This study provides valuable quantitative data and analysis that reveals variations in 'Dorsal' nuclear dynamics along the dorso-ventral axis in the early Drosophila embryo. The evidence that supports that these variations are due to Dorsal/Cactus interactions in dorsal nuclei is convincing, albeit incomplete to understand the biological implications of these findings for developmental patterning.

eLife Assessment

With compelling electrophysiological and behavioural evidence, this work establishes that the activity of insulin-producing cells (IPCs) depends on the nutritional state in Drosophila and that, like in mammals, there is also an incretin-like effect with IPCs responding to glucose feeding but not to glucose perfusion. Moreover, the authors demonstrate that DH44 neurons respond to glucose perfusion and, together with IPCs, modulate locomotor activity. This important study on the neuronal regulation of metabolic homeostasis will be of interest to both neuroscience and to medical research in diabetes.

eLife Assessment

The manuscript presents valuable findings of bone remodeling under chronic unpredictable mild stress (CUMS). This is an interesting work on mental stress on bone health and osteoporosis, and the authors offer solid evidence of decreased bone mass mediated by miR-335-3p/Fos signaling in osteoclasts that are involved in the induction of bone loss caused by CUMS. This revised version provided new data that improved the quality of the manuscript and addressed the reviewers' concerns.

eLife Assessment

This study presents an advance in efforts to use histone post-translational modification (PTM) data to model gene expression and predict epigenetic editing activity. Such models are broadly useful to the research community, especially ones that can model epigenetic editing activity, which is novel; additionally, the authors have nicely integrated datasets across cell types into their model. The work is mostly solid, but it would be strengthened by performing rigorous comparisons to existing methods that predict gene expression from PTM data and from additional model validation beyond dCas9-p300 based perturbations.

eLife Assessment

This valuable study presents a meta-analysis of the literature, confirming the relationship between the coupling of slow oscillations and fast spindles in memory formation, although the reported effects are weak and should be more clearly justified. Furthermore, while the evidence is convincing overall, the manuscript provides an incomplete description of the methods, which may challenge comprehension for readers unfamiliar with advanced statistical techniques. This study will be of interest to neuroscientists focusing on sleep and memory.

eLife Assessment

This manuscript describes a fundamental investigation of the functioning of Cas9 and in particular on how variant xCas9 expands DNA targeting ability by an increase-flexibility mechanism. The authors provide compelling evidence to support their mechanistic models and the relevance of flexibility and entropy in recognition. This work can be of interest to a broad community of structural biophysicists, computational biologists, chemists, and biochemists.

eLife Assessment

This study reports valuable findings that highlight the importance of data quality and data representation for ligand-based virtual screening experiments. The authors' claims are supported by solid evidence, although the conclusions have been inferred from only two datasets. The work would gain much impact if additional datasets were used. The main findings will be of interest to cheminformaticians and medicinal chemists working in QSAR modeling, and possibly in other areas related to machine learning.

eLife Assessment

This important study used an automated system to collect eggs laid over the course of multiple days by individual female Drosophila to successfully reveal a robust yet noisy circadian rhythm of egg-laying. Their results show that the neural control of this rhythm is entirely different from the one that controls locomotor activity rhythmicity. Preliminary connectome-based analyses provide evidence for connections between the relevant clock neurons and neurons involved in oviposition. The evidence provided is solid, although using an independent tool for targeted knockdown of clock genes and including the time series of representative individuals for all genotypes tested would help interpret the results.

eLife Assessment

This important study demonstrates the ability for high-throughput recording and categorization of unconstrained and stimulus-based behaviors across a very large population of marmosets (n = 120 animals across 36 family units). The authors implement an analytical approach to identify "outlier" behavior that could be key in the development of next-generation precision psychiatry. While the strength of evidence appears solid overall, many key methodological details are incomplete.

eLife Assessment

This useful work identifies a key role for Tachykinin-1 parasubthalamic neurons in avoidance learning. At present, the evidence for the conclusions regarding fiber photometry, viral transfection, reporting of behavioral outcomes, and pathway-specificity is incomplete. This work will be of interest to neuroscientists studying neural mechanisms for avoidance and aversion.

eLife Assessment

This study uses a large dataset from both recent isolates and genomes in databases to provide an important analysis of the population structure of the pathogen Salmonella gallinarum. The authors present convincing results regarding the regional adaptation and the evolutionary trajectory of the resistome and mobilome, even though some issues regarding the genomic analysis could be improved. This work will interest microbiologists and researchers working on genomics, evolution, and antimicrobial resistance.

eLife Assessment

This valuable study tackles the well-established overflow metabolism issue by applying a coarse-grained metabolic flux model to predict how individual cells execute various energy strategies, such as respiration versus fermentation. The model's population average is convincing enough to align with experimental observations on overflow metabolism. However, the theoretical framework's reliance on single-cell growth rate variability must be questioned because of insufficient correlation with fluxes and the absence of regulatory mechanisms, highlighting the need for single-cell experimental validation to substantiate the proposed model.

eLife Assessment

This important study explores the association between mother-child interactions and the development of children's social brain networks, specifically the theory of mind and social pain networks. The findings provide solid evidence for enhanced stimulus-evoked neural synchronization between child-caregiver dyads, while the evidence for the other variables is incomplete and could be strengthened with further analyses. The study effectively bridges brain development with children's behavior and parenting practices and would be of interest to broad research communities in social neuroscience and developmental psychology.

eLife Assessment

NeuroSCAN is an accessible and interactive tool for streamlined observation of neuronal morphology, membrane contact, and synaptic connectivity across developmental stages in the nematode C. elegans. This important tool relies on solid electron microscopy datasets. This resource will be of high interest to C. elegans researchers interested in nervous system wiring and circuit function.

eLife Assessment

This important study is of significant relevance to the fields of predictive processing, perception, and learning. The well-designed paradigm allows the authors to avoid several common confounds in investigating predictions, such as stimulus familiarity and adaptation. Using a state-of-the-art multivariate EEG approach, the authors test the opposing process theory and find evidence in support of it, but some elements - especially the interactions across block - have only incomplete support at present. This could be strengthened via further analyses and justification.

eLife Assessment

The findings are considered valuable and have theoretical implications for the interdisciplinary field of value-based social decision-making. Support for the main claims is incomplete and these should be supported by further analyses.

eLife Assessment

This study presents important findings on the activity of two compounds, BKC and IBC, isolated from Psoralea corylifolia, which act synergistically to inhibit cancer cell proliferation. Using a spectrum of methods, the authors characterized the mechanisms of action of both drugs, providing convincing evidence that BKC targets DNA polymerases and IBC selectively inhibits CHK2. The study opens the possibility of improving the effectiveness of the combination of BKC and other damaging agents with IBC in cancer treatment.

[Editors' note: this paper was reviewed by Review Commons.]

eLife Assessment

This valuable study uses AlphaFold2 to guide the structural modelling of different states of the human voltage-gated potassium channel KV11.1, a key pharmacological drug target. Follow-up molecular dynamics and drug-docking simulations, combined with experimental comparisons, offer convincing evidence supporting the models, showing that drugs bind more effectively to the inactivated state. The work shows potential for improving drug potency predictions in ion channel pharmacology, though its applicability to other systems remains uncertain.

eLife Assessment

This is an important technical method paper that details the development and quality assessment of a 3D MERFISH method to enable spatial transcriptomics of thick tissues, representing a major step forward in the technical capacity of the MERFISH. The evidence presented is convincing.

eLife Assessment

This paper advances an important new concept in psoriasis pathogenesis and implicates Sema4a as a homeostatic regulator that is highly epithelial-specific. The findings are convincing and lend support for the biology described here as a mechanism with therapeutic implications.

eLife Assessment

This paper presents the important discovery that lipid metabolic imbalance caused by Snail, an EMT-related transcription factor, contributes to the acquisition of chemoresistance in cancer cells. However, the incomplete support for the authors' claims is due to concerns about the causal relationship and lack of sufficient quantitative analysis. With strengthened evidence, this work would be of broad interest to researchers in the fields of cancer biology, lipid metabolism, and cell biology.

eLife Assessment

The authors use deep mutational scanning to assess the effect of all possible protein-coding variants in MC4R, a G protein-coupled receptor associated with obesity. They develop new, more precise approaches, enabling them to probe molecular phenotypes directly relevant to the development of drugs that target this receptor. In this important work, the authors provide convincing evidence that variants impact signaling through MC4R in different ways, that some defective variants are amenable to a corrector drug and that deep mutational scanning data could guide compound optimization.

eLife Assessment

This important study demonstrates the therapeutic potential of recombinant human PDGF-AB/BB proteins in reducing the senescent signatures of primary human intervertebral disc cells. The study represents a significant advance in the treatment of intervertebral disc degeneration and can be applied broadly to other degenerative musculoskeletal tissues through the suppression of senescence. Solid evidence, primarily based on transcriptomic analysis and direct protein measurements from relatively homogeneous cell populations, supports the therapeutic potential of PDGF, but more experimental details would be needed to make the evidence stronger.

eLife Assessment

In this manuscript, Yao et al. present solid evidence to show that MnMYL3 may serve as a receptor for NNV via macropinocytosis. This manuscript is valuable for understanding the molecular mechanisms of NNV cell entry. However, the manuscript will benefit from broader implications of these findings for cell entry of other viruses.

eLife Assessment

This important work develops a new protocol to experimentally perturb target genes across a quantitative range of expression levels in cell lines. The evidence supporting their new perturbation approach is compelling, and the computational analyses to better understand dosage response relationships between genes are convincing. The study will be of broad interest to scientists in the fields of functional genomics and biotechnology. However, the evidence supporting the conclusions can be further improved.

eLife Assessment

This study presents valuable data on the identification and function of a protein complex present at the Maurer's cleft organelles of Plasmodium falciparum-infected red blood cells. The evidence supporting the findings is solid, but would benefit from greater rigor in presentation and analysis.

eLife Assessment

Morphological characteristics and phenotypes of mutations in key developmental genes suggest that head, trunk, and tail development are regulated by discernible modules. Gdf11 signalling plays a crucial role in orchestrating the transition from trunk to tail tissues in vertebrate embryos. This important study presents convincing evidence that Tgfbr1 acts upstream of Isl1 (a pivotal effector of Gdf11 signalling) and regulates blood vessels, the lateral plate mesoderm, and the endoderm associated with the trunk-to-tail transition. Together with the previous studies, this work identifies a key signal that acts as the pivot of the trunk-to-tail transition.

for - summary - polycrisis - requires a shift in stories - from little self - to big self - from - Emergence Magazine - interview - An Ethics of Wild Mind - David Hinton

summary - polycrisis - requires a shift in stories - from little self - to big self - from - Emergence Magazine - interview - An Ethics of Wild Mind - David Hinton - We think of ourselves as this little bubble of obsessions and memories going on in our head detached from everything else - THAT'S THE WOUND! - That sounds and IS FELT as bleak, isn't it? - The scientific story of the cosmos is that there are countless solar systems in our universe, countless suns and planets over vast time scales - Our planet evolved life billions of years ago - Some of those life forms became multicellular animals, like us - Some of them developed eyes, nose, ears, skin and a brain and central nervous system - When we look out into the world, it is the cosmos distilled in us looking out at itself - Hence, we are intertwingled and woven into the fabric of everything - the cosmos in human form experiencing the cosmos itself - When we think about our extinction, it is also the cosmos thinking about extinction - When we feel ANYTHING, that's the cosmos feeling it - And WHEN WE DIE that is the cosmos in this human form dying to itself

eLife Assessment

This study provides a methodological report on a modified adaptive sampling approach, multiple walker supervised molecular dynamics (mwSuMD), and its application to G protein-coupled receptors (GPCRs), which are the most abundant membrane proteins and key targets for drugs. The mwSuMD approach assists in sampling complex binding processes, leading to useful findings for GPCR activity, although results may be considered incomplete, given the high RMSD values reported and lack of validation using experimental data. The manuscript also needs corrected descriptions of high-resolution PDB structures and better relation to existing computational literature.

eLife Assessment

This study describes a novel mechanism for how collagen fibrils are formed. The authors present compelling evidence that collagen-I fibrillogenesis relies on a functional endocytic system for recycling collagen-I, with circadian-regulated VPS33b and integrin-α11 being critical for fibril assembly. This is an important study for the understanding of the pathophysiology of collagen fibrillogenesis.

eLife Assessment

This valuable study discusses a hot topic in post-endoscopic retrograde cholangiopancreatography pancreatitis. The new score for predicting post-ERCP pancreatitis offers an idea about the risk of pancreatitis before the procedure. Although most scores depend on intraprocedural manoeuvres, such as the number of attempts to cannulate the papilla, this is a solid retrospective single-center study in one country. To be validated in the future, this score will need to be done in many countries and on large numbers of patients.

eLife Assessment

This important study provides one mechanism that can explain the rapid diversification of poison-antidote pairs in fission yeast: recombination between existing pairs. The evidence is largely solid, but the study can benefit from demonstrating that the novel poison-antidote constructed by the authors can serve as a meiotic driver. The work is of interest to colleagues studying genetic incompatibilities.

eLife Assessment

This important chronobiological study in mice suggests that light modulated activity of Cdk5 activity on the PKA-CaMK-CREB signaling pathway provides missing molecular mechanistic details to understand light-induced circadian clock phase delays during the early night, but not for phase advances in the morning. The authors provide convincing evidence bridging from behavioral to molecular/cellular experiments to neural activity imaging.

eLife Assessment

This study examined the role of the dorsal medial prefrontal cortex of mice in anticipating reward-value switch points in a two-armed bandit task. They demonstrate the dorsal medial prefrontal cortex is involved in task performance and use model-based methods to uncover the algorithmic processes affected by prefrontal cortex perturbations. If the claims were supported, this would be a valuable finding. Unfortunately, the reviewers recognised significant issues with the task design and analyses, making the evidence to support the role of the prefrontal cortex in anticipation of switches inadequate.

eLife Assessment

This valuable study presents a thorough analysis of protein abundance changes caused by amino acid substitutions, using structural context to improve predictive accuracy. By deriving substitution response matrices based on solvent accessibility, the authors demonstrate that simple structural features can predict abundance effects with accuracy comparable to complex methods such as free energy calculations. The strength of the evidence is solid, supported by robust experimental design and comprehensive analyses. This work is expected to be of interest to broad audiences as it offers practical tools for analyzing mutational effects and insights into the structural basis of proteostasis.

eLife Assessment

This manuscript describes work that is fundamental to our understanding of the mechanism of how stress regulates the noradrenergic system and the CRH system. Using a combination of ex vivo physiology and in vitro methods, the study provides compelling evidence as to the signaling mechanisms of how glucocorticoids impact adrenergic GPCRs in CRH cells via receptor trafficking. While the ex vivo work is specific to the hypothalamus, the mechanisms here could be extrapolated and investigated in other brain regions that may have similar signaling regulation.

eLife assessment

This study reports analysis of the formation of electrosensory ampullary organs in non-model organisms, the sterlet sturgeon. By using a combination of targeted gene knock-out and inhibition, the study provides overall convincing evidence for differential roles of BMP signaling in lateral-line development, with few aspects that could be improved. The study is particularly valuable for understanding the development of a still-mysterious sensory system, and for its evolutionary implications.

eLife Assessment

This valuable study investigates the neural noise hypothesis of developmental dyslexia using electroencephalography (EEG) and 7T magnetic resonance spectroscopy (MRS). Solid results were reported that indicate no evidence of an imbalance between excitatory and inhibitory (E/I) brain activity in adolescents and young adults with dyslexia compared to controls, thereby challenging the neural noise hypothesis. This research advances our understanding of the neural mechanisms underlying dyslexia and offers broader insights into the neural processes involved in reading development.

eLife Assessment

This is a useful analysis of STORM data that characterizes the clustering of active zones in retinogeniculate terminals across ages and in the absence of retinal waves. The design makes it possible to relate fixed time point structural data to a known outcome of activity-dependent remodeling. However, the evidence is incomplete, weakening the claims the authors make regarding how activity influences the clustering of these synapses.

eLife Assessment

This is a fundamental study that addresses the key question of how the tetraspanin Tspan12 functions biochemically as a co-receptor for Norrin to initiate β-catenin signaling. The strength of the work lies in the rigorous and compelling binding analyses involving various purified receptors, co-receptors, and ligands, as well as molecular modeling by AlphaFold that was subsequently validated by an extensive series of mutagenesis experiments. The study advances the field by providing a novel mechanism of co-receptor function and shedding new light on how signaling specificity is achieved in the complex Wnt/Norrin signaling system.

eLife Assessment

This important study provides insights and strategies for assessing laminar structure in vivo in the visual cortex of the macaque monkey with high-density linear electrode arrays. The paper provides convincing evidence demonstrating that signals in higher frequency bands, related to the discharge of action potentials, are of substantially better use for achieving well-resolved cortical layer identification than are signals in lower frequency bands typically associated with local field potentials and standard-practice Current Source Density (CSD) analyses. These findings are of interest to a wide range of neuroscientists making comparisons between cortical layers or recording with array electrodes.

eLife Assessment

This important study provides solid evidence for a non-genomic action of progesterone in Xenopus oocyte activation. The findings demonstrate that two non-genomic progesterone receptors, ABHD2 and mPRb, function as a novel progesterone-stimulated phospholipase A2. The findings will be of broad interest to reproductive endocrinologists and physiologists.

eLife Assessment

This work is of fundamental significance to the field of nervous system development as it advances our mechanistic understanding of axon guidance. The rigorous biochemical and genetic approaches are compelling, experiments are well-controlled, and the major claims are supported by convincing data. The study should be of general interest to the developmental neurobiology community.

eLife Assessment

The paper presents a new behavioral assay for Drosophila aggression and demonstrates that social experience influences fighting strategies, with group-housed males favoring high-intensity but low-frequency tussling over aggressive lunging observed in isolated males. This paper is valuable for researchers studying Drosophila social behaviors, while the characterization of behavioral and neuroanatomical data is incomplete.

eLife Assessment

This paper proposes a new source reconstruction method for electroencephalography (EEG) data and claims that it can provide far superior spatial resolution than existing approaches and even superior spatial resolution to fMRI. This primarily stems from abandoning the established quasi-static approximation to Maxwell's equations. If verified, the potential impact of the proposed method is very high indeed, but it is currently impossible to verify because the clarity of presentation and the evidence for the claims in the current version is inadequate.

eLife Assessment

This important study reveals that disrupting fatty acid metabolism in macrophages significantly restricts the growth of Mycobacterium tuberculosis, showing that impaired lipid processing triggers various antimicrobial responses. Whilst the approach is robust, utilizing CRISPR-Cas9 knockout of multiple genes involved in lipid metabolism which yielded some convincing data, there are aspects that require improvement such as the autophagy assay and redox measurements. This work highlights how host lipid metabolism affects the ability of tubercle bacilli to thrive intracellularly, pointing to potential new therapeutic targets.

eLife Assessment

This study uses electrophysiological recordings, causal manipulations of activity, and modeling to investigate how the maintenance of a spatial location in working memory affects the representation of visual information in area V4 of monkeys. The work is important not just for understanding how visual information is encoded, but also for determining precisely how prefrontal inputs to the sensory cortex sculpt the corresponding visual responses during working memory. The data provide solid evidence of direct communication between prefrontal circuits that store spatial information and V4, which, under the current experimental conditions, manifests mainly as changes in temporal activity patterns (beta oscillations and phase coding).

eLife Assessment

Masroor Ahmad Paddar and colleagues reveal noncanonical roles of ATG5 and membrane ATG8ylation in regulating retromer assembly and function. They identify ATG5's unique non-autophagic role and show that CASM partially contributes to these phenotypes. Although the mechanism by which ATG8ylation regulates the retromer remains unclear, the findings provide important insights with solid supporting evidence.

eLife Assessment

This important study uses reinforcement learning to study how turbulent odor stimuli should be processed to yield successful navigation. They find that there is an optimal memory length over which an agent should ignore blanks in the odor to discriminate whether the agent is still inside the plume or outside of it, complementing recent studies using RNNs and finite state controllers to identify optimal strategies for navigating a turbulent plume. While the overall strength of evidence is convincing, better justification for using Brownian motion as a recovery strategy and the addition of accompanying code for reproducibility would add to this strength.

eLife Assessment

This study presents valuable findings on the role of a well-studied signal transduction pathway, the Slit/Robo system, in the context of the assembly of the hematopoietic niche in the Drosophila embryo. The evidence supporting the claims of the authors is solid. The work will interest developmental biologists working on molecular mechanisms of tissue morphogenesis.

eLife Assessment

This study unveils important data describing cell states of olfactory ensheathing cells, and how these cell states may relate to repair after spinal cord injury. The framework used for characterizing these cells is solid, although the study would be strengthened by additional quantification of immunohistochemical data and by complementing expression data with functional outcomes. This work will be of interest to stem cell biologists and spinal cord injury researchers.

eLife Assessment

This important paper provides solid evidence for an alternative conceptualization of the functional role of the place and grid cell network in the medial temporal lobe for memory as opposed to spatial processing or navigation. The theory is extensive, tightly integrating data on various spatial cell types. It accounts for many experimental results and generates strong predictions for future studies that will be of interest to researchers in this field. The impact of the work would be strengthened if future experiments reveal that grid cells do indeed encode specific nonspatial features.

eLife Assessment

The authors studied the development of mesentery borders in the rice coral Montipora, a new experimental system, to complement existing data from the sea anemone Nematostella. They make a solid case that in Montipora, there is a sequence of Hox-Gbx genes whose staggered expression in the unsegmented larva is suggestive of their role in subdividing the gastric cavity into repeated units bordered by mesenteries, as in the sea anemone Nematostella. Pharmacological experiments also point to the involvement of the BMP pathway in this process, but additional experiments validating this are necessary. This is a valuable contribution to the field of cnidarian evolution, suggesting that BMP- and "Hox-Gbx code"-dependent patterning of the directive axis was ancestral for Anthozoa.

eLife Assessment

This manuscript develops a theoretical model of osmotic pressure adaptation in microbes by osmolyte production and wall synthesis. The prediction of a rapid increase in growth rate on osmotic shock is experimentally validated using fission yeast. By using phenomenological rules rather than detailed molecular mechanisms, the model can potentially apply to a wide range of microbes, providing important insights that would be of interest to the wider community studying the regulation of cell size and mechanics. However, because the core assumptions of the model have not been tested across a range of microbial organisms, the evidence for the universality of the model remains incomplete.

eLife Assessment

This potentially important study describes the progressive transformation of olfactory information across five different brain regions in the olfactory pathway. While the dataset could be of broad interest to olfactory researchers, the analysis is incomplete and would benefit from a reconsideration of the data sampling window, a more uniform analysis framework, and greater clarity of presentation.

Describes the neural dynamics associated with auditory stream segregation and the verbal transformation effect (examples of auditory multistable perception).

Importantly, multistable perception occurs across sensory modalities. Auditory and visual multistable perception may involve similar neural mechanisms.

Visual representation of how auditory stream segregation is triggered and perceived.

Bistable perception example: binocular rivalry (highly relevant).

Bistable apparent motion perception example: the spinning wheel illusion.

Bistable perception example: the Necker cube (most cited).

When sensory information about a perceived stimulus is ambiguous, the visual system forms multiple distinct interpretations of said stimulus. Multistable perception occurs when perception of the stimulus alternates between interpretations over time.

Multistable perception may arise from interactions between lower-order and higher order brain processes. Lower order brain processes are involved in basic mental functions such as attention and perception, whereas higher order brain processes are involved in complex mental functions such as reasoning and abstract thinking.

The review discusses how brain processes underlying different levels of visual processing (low-level sensory, intermediate extrastriate, and high level frontoparietal) interact with one another to produce visual multistable phenomena such as binocular rivalry.

eLife Assessment

In this useful study, the authors use published scRNA-seq data to highlight the importance of mast cells (MCs) in TB granulomas, reporting a comparative assessment of chymase- and tryptase-expressing MCs in the lungs of tuberculosis-infected individuals and non-human primates, with MC-deficient mice showing reduced lung bacterial burden and pathology during infection. Whilst the findings are helpful, the evidence to support conclusions is inconsistent across models and thus incomplete. Specifically, the data supporting a role for MCs in coordinating cytokine responses to modulate pathology, susceptibility to tuberculosis, and dissemination during infection are weak.

eLife Assessment

This interesting study explores whether tumor cells can manipulate their Hydra hosts, and includes important findings on the consequences for the fitness of the host Hydra. The evidence supporting these findings is convincing. The work will be of broad interest to many fields including development biology, evolutionary biology and tumor biology.

eLife Assessment

This important study provides proof of principle that C. elegans models can be used to accelerate the discovery of candidate treatments for human Mendelian diseases by detailed high-throughput phenotyping of strains harboring mutations in orthologs of human disease genes. The data are compelling and support an approach that enables the potential rapid repurposing of FDA-approved drugs to treat rare diseases for which there are currently no effective treatments. The work will be of interest to all geneticists.

eLife Assessment

Saijilafu et al. describe that MLCK and MLCP bidirectionally regulate NMII phosphorylation ultimately impinging on axonal growth during regeneration in the central and peripheral nervous systems. However, the evidence is in most cases incomplete, since some key controls are missing, some major claims are too broad to be supported by data and contrasting data on how MLCK and MLCP regulates NMII activity is not fully addressed or discussed. In sum, this knowledge is potentially useful for the field due to the relevance of identifying mechanisms that regulate axonal regeneration.

eLife Assessment

This study provides important new insights into the contributions of local DNA features to the complex molecular mechanisms and dynamics of copy number variation (CNV) formation during adaptive evolution. While limited to a single CNV of interest, the study is well-designed and carefully controlled, presenting compelling evidence that supports the conclusions. This work will be of general interest to those studying genome architecture and evolution from yeast biologists to cancer researchers.

eLife Assessment

This important work by Veneditto and colleagues developed a new modeling approach, called a mixture-of-agent hidden Markov model (MoA-HMM), in which choice behaviors are modeled as transitions between discrete states defined by different weighting of several reinforcement learning and decision strategies. The authors apply this approach to their previous data collected from rats performing the two-step task, and show that this method predicts fluctuations in neural and other behavioral data and provides better fits to the data than previous methods. The revision has greatly improved the manuscript, the evidence supporting the conclusions is convincing, and the method is of general interest to the field.

eLife Assessment

This is an important study that combines an array of genetic, cell biological, and genomic techniques to elucidate the role of the transcription factor Hamlet in reproductive development. It provides compelling evidence that Hamlet is a master regulator of cell fate and differentiation to reveal transcriptional targets that mediate epithelial tissue fusion. While the genetic and genomic analyses are convincing, the images that report the phenotypes are difficult to interpret for non-experts. This, and other identified issues, should be addressed.

eLife Assessment

This useful study investigates the role of frontotemporal regions in integrating linguistic and extra-linguistic information during communication, focusing on the inferior frontal gyrus and posterior middle temporal gyrus. It uses brain stimulation and electroencephalography to study speech-gesture integration. While the research question is interesting, the methods are insufficient for studying tightly-coupled brain regions over short timescales, leading to incomplete support for the claims due to conceptual and methodological limitations.

eLife Assessment

This important study will allow for a better understanding of anthelmintic drug resistance in nematodes, a growing concern for public health. The authors provide a detailed analysis of the role of UBR-1 and its underlying mechanism in ivermectin resistance using convincing behavioural and genetic experiments with C. elegans. What is not yet clear is how much of this study applies to parasitic nematodes, in which resistance has naturally emerged in different populations. The study will be of relevance to colleagues working on the evolution of drug resistance and to parasitologists in general.

eLife Assessment

This important study describes a first-in-human trial of autologous p63+ stem cells in patients with idiopathic pulmonary fibrosis, a lethal condition for which effective treatments are lacking. The authors provide convincing evidence that P63+ progenitor cell therapy can be safely delivered in patients with ILD. However, given that this is a Phase 1 study, conclusions regarding efficacy should not yet be made.

eLife Assessment

The paper introduces DeepTX, a valuable deep-learning framework linking stochastic, mechanistic modelling with single-cell RNA sequencing data to investigate transcriptional burst kinetics on a genome-wide scale. This tool has been employed by the authors to evaluate transcriptional changes under DNA-damaging treatments, with observations that are of value to the systems biology and bioinformatics communities. The evidence supporting these findings is solid, though some concerns remain regarding specific technical details. This methodological advancement holds potential for application in diverse contexts, such as linking mechanistic models of signalling pathways to transcriptional data.

eLife Assessment

This study addresses fundamental questions surrounding otitis media effusion in Down syndrome, identifying DYRK1A as a key gene involved in the condition. The findings are compelling, highlighting DYRK1A as a promising therapeutic target for addressing hearing loss in patients with Down syndrome.

eLife Assessment

This valuable study presents an interesting analysis of the role of the polyamine precursor putrescine in the pili-dependent surface motility of a laboratory strain of Escherichia coli. The genetic data convincingly shows this role, yet without putrescine measurements, the evidence remains incomplete. This work will be of interest to biomedical scientists studying uropathogenic bacteria, and those studying bacterial polyamine function.

eLife Assessment

This valuable study combines experiments and modelling to advance our understanding of the nonlinear nature of homeostatic structural plasticity and its interaction with synaptic scaling. The methodology and findings are solid, although additional work is needed to better link models with experiments and support some of the conclusions drawn. This study will be of interest to theoretical and experimental neuroscientists working in homeostatic plasticity.

eLife Assessment

The study is noteworthy for its effort to achieve a deeper understanding of PTH-1 Receptor signaling. The PTH-1 pathway underpins the control of calcium and phosphate metabolism throughout life in land-dwelling animals and it can be targeted to therapeutic benefit in patients with osteoporosis. We consider the significance of the findings in this paper to be valuable to the community of investigators working on PTH receptor signaling, with convincing evidence.