eLife Assessment

The landmark significance of this manuscript is based on the mechanistic description of purine metabolism by Lactobacillus plantarum, which helps to alleviate hyperuricemia, which is a phenotype that underlies multiple disease symptoms. The evidence provided for L. plantarum's involvement in reducing hyperuricemia was exceptional, combining microbiomics, whole genomics, in vitro bacterial culture, gene knock-outs, and metabolomics. Collectively, the study shows a clear link between the gut microbiota and hyperuricemia, providing a pathway for modification to help alleviate this condition.

eLife Assessment

This work 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 based on theoretical analysis that commonly discussed mechanisms such as tubular contraction are unlikely to be at the origin of the observed transport velocities. As such, it will be of relevance to cell biologists and physicists interested in organelle dynamics. As this study is solely theoretical and deals with order of magnitude estimates, its main conclusions await experimental validation.

eLife Assessment

The useful studies described here are broadly applicable to all antibody discovery subfields, even though they are not a significant improvement over published methods. The findings are incomplete with respect to the methodology, since details that are crucial in order to repeat the experiments are lacking (such as a timestamp). They also do not take into account multiple recent papers that have tested similar strategies. These studies will be of interest to a specialized audience working on generating antibodies to infectious agents.

eLife Assessment

This important study shows the effect of gut dysbiosis on the colonization of mycobacteria in the lung. The data with comprehensive analysis of gene expression profiles in the lung with dysbiotic mice is compelling and goes beyond the current state of the art. However, the mechanistic insight, where the lung epithelial cell line was used, and the experiments with Mtb infection are currently incomplete.

eLife Assessment

This valuable study investigated the appearance of ultrasonic vocalizations around 44 kHz that occurs in response to prolonged fear conditioning in male rats. Evidence in support of the conclusions is solid and may be of interest to some researchers also investigating distress-related ultrasonic vocalizations.

eLife Assessment

This is a potentially interesting study regarding the role of gasdesmin D in experimental psoriasis. The study contains useful data from murine models of skin inflammation, however the main claims (on neutrophil pyroptosis) are incompletely supported in its current form and require additional experimental support to justify the conclusions made.

eLife Assessment

This valuable study presents a machine learning model to recommend effective antimicrobial drugs from patients' samples analysed with mass spectrometry. The evidence supporting the claims of the authors is convincing. This work will be of interest to computational biologists, microbiologists, and clinicians.

eLife Assessment

This important work compares the strain properties of a-synuclein fibrils isolated from LBD and MSA patient samples with the resulting amplified fibrils following SAA. Using orthogonal biochemical and structural approaches to strengthen their analyses, the authors provide solid evidence that the SAA-amplified fibrils do not recapitulate the disease-relevant strains present in the patient samples. CryoEM would further strengthen this data but it is outside the scope of the work. This work should be considered in the widespread applications of SAA in synucleopathies and its potential limitations.

eLife Assessment

This study presents useful, yet preliminary, findings on the transcriptomic changes in cardiac lymphatic cells after myocardial infarction in mice. The conclusions of the authors remain uncertain as sample sizes for lymphatic endothelial cells are very low. The single-cell transcriptomic data were analyzed using solid advanced methodology and may be used as a starting point for future studies of the impact of lymphatic cells on heart disease.

eLife Assessment

The study by Tsai et al. employed multi-omics approaches, including transcriptomic, methylomic, and single-cell RNA-seq, and provided a solid and comprehensive analysis of the correlation between retrotransposable element (RTE) expression and biological aging in human blood. Their findings highlight the differential roles of RTE families, providing valuable insights for understanding the mechanisms of human aging.

eLife Assessment

This valuable study contributes to the understanding of phase separation in Dishevelled (DVL) proteins, by investigating the endogenous complexes of DVL2 using ultracentrifugation and contrasting them with DVL1 and DVL3 behaviour and the functional validation of the DVL2 intrinsically disordered regions mediating the protein condensate. The study includes a solid characterisation of several overexpression constructs, including in KO cells. However, investigations of the roles of the described DVL2 regions at the endogenous level remain to be carried out.

eLife Assessment

This work describes a highly complex automated algorithm for analyzing vascular imaging data from two-photon microscopy. This tool has the potential to be extremely valuable to the field and to fill gaps in knowledge of hemodynamic activity across a regional network. The biological application provided, however, has several problems that make many of the scientific claims in the paper incomplete.

eLife Assessment

This is a fundamental research study which identifies some of the molecular mechanisms underlying the energy costly process of memory consolidation. The strength of evidence is exceptional. The paper should be of broad interest because it establishes a clear mechanistic link between long-term memory processes and the energy-producing machinery in neurons.

eLife Assessment

This manuscript provides important new insight into the mechanisms underlying seasonal physiology, using medaka fish as a functional genetic model that naturally exhibits photoperiodic responses. The authors provide a range of data that implicate agrp1 in feeding regulation in response to photoperiod and reproductive status. This paper provides solid evidence connecting the effects of long and short photoperiods on the food intake of female medaka fish and egg production. It will be of relevance for biologists interested in understanding the molecular and cellular underpinnings of environmental effects on animal biology.

eLife Assessment

This study presents a valuable conceptual approach that cell lineage can be determined using methylation data. However, the evidence supporting the claims of the author is currently inadequate. If the author could carry out some additional experiments as well as explore alternative explanations for the current data, this approach could be of broad interest to neuroscientists and developmental biologists.

eLife Assessment

This paper undertakes a valuable theoretical treatment of the potential role of foraging-related concepts in several forms of intertemporal choice. While the computational evidence and methodologies employed are novel, some issues with clarity and generality result in incomplete support for the paper's claims.

eLife Assessment

SCARF1 is a scavenger membrane-bound receptor that binds modified versions of lipoproteins and has a significant role in maintaining lipid homeostasis. This useful study reports the crystal structure of SCARF1 and identifies putative binding sites for modified lipoproteins. Supported by a convincing set of experimental approaches, this study advances our knowledge of how scavenger receptors clear modified lipoproteins to maintain lipid homeostasis.

eLife Assessment

The article uses a cell-based model to investigate how mutations and cells spread throughout a tumour. The paper uses published data and the proposed model to understand how growth and death mechanisms lead to the observed data. This work provides an important insight into the early stages of tumour development. From the work provided here, the results are convincing, using a thorough analysis.

eLife Assessment

This important study advances our understanding of maladaptive innate immune training. The experimental evidence supporting the conclusions is convincing with only a few clarifications required. The work will be of high interest to both researchers in the trained immunity field and clinician scientists.

eLife Assessment

This useful manuscript shows a set of interesting data including the first cryo-EM structures of human PIEZO1 as well as structures of disease-related mutants in complex with the regulatory subunit MDFIC, which generate different inactivation phenotypes. The molecular basis of PIEZO channel inactivation is of great interest due to its association with several pathologies. This manuscript provides some structural insights that may help to ultimately build a molecular picture of PIEZO channel inactivation. While the structures are of use and clear conformational differences can be seen in the presence of the auxiliary subunit MDFIC, the strength of the evidence supporting the conclusions of the paper, especially the proposed role for pore lipids in inactivation, is incomplete and there is a lack of data to support them.

eLife Assessment

This valuable paper seeks to determine the role of endogenous CNS hemoglobin in protecting mitochondrial homeostasis in hypoxia. There is merit in the work, although it remains incomplete as there is a question as to the validity of the hypoxia model as relevant to CNS-specific ischemia/hypoxia that should be considered. In particular, a whole-body hypoxia model may liberate exosomes from other hypoxic organs, which should be addressed by the authors. Overall, this work has the potential to be of broad interest to the neuroscience and hypoxia communities.

eLife Assessment

This manuscript reports on the effects of a single dose of methamphetamine vs placebo on a probabilistic reversal learning task with different levels of noise, in a large group of young healthy volunteers. The paper is well written and the methods are rigorous. The findings are valuable and have theoretical or practical implications for a subfield. The strength of the evidence is solid, with the methods, data, and analyses broadly supporting the claims with only minor weaknesses.

eLife Assessment

This study presents a useful characterisation of the topographical organisation of the human pulvinar, an associative thalamic subregion crucial for visual perception and attention. The evidence supporting the conclusions is solid given the multimodal validation and replication across datasets, although even higher-resolution imaging data would have strengthened the study. The manuscript would also be strengthened by clarifying how the work extends previous assessments of thalamic connectivity and expanding the results with a more digested interpretation of the findings and validation of the segmentation quality. With these components strengthened, the work would be of interest to neuroscientists, neurologists, and neuropsychiatrists working on pulvinar functioning in health and disease.

ID (digest/hash) is calculated on the normalized data 3. Embed the ID

I like to think of this as a way to "normalize the data" or "standardize the data" - Data normalization is a common practice

Three steps said simply: 1. Normalize the data (put #'s where there ID will be) 2. Compute ID on the normalized data 3. Embed ID in data

An "Address" is a way to find something. or "Search" for something.

The "SA" of SAID means the ID is embedded within the data it is ID'ing

a SAID is an ID

eLife Assessment

This important study uncovers a surprising link between two self-cleaving RNAs that belong to the same structural family. The evidence supporting the main conclusions is convincing and based on extensive biochemical and bioinformatic analysis. This research will be of broad interest to RNA molecular biologists and biochemists.

eLife Assessment

This valuable study delineates the cellular contributions of BMP signaling in liver development and function. The findings are convincing, and the study employs state-of-the-art molecular, genetic, and cellular approaches to demonstrate that hepatic stellate cells play a central role in liver health by mediating cell-to-cell crosstalk via the production of specific BMP proteins. This study will be of interest to scientists interested in developmental biology and organ physiology.

eLife Assessment

This study offers important insights into the generation and maintenance of monosomic yeast lines and is, to our knowledge, the first to evaluate gene expression in yeast monosomies. The research introduces an innovative method to assess epistasis between genes on the same chromosome, providing solid evidence for positive epistatic interactions affecting fitness. Although the authors have substantially improved the methodology and interpretation during revision, questions regarding the interpretation of the transcriptome data have not been completely addressed.

eLife Assessment

In this valuable study, Huffer et al posit that non-cold sensing members of the TRPM subfamily of ion channels (e.g., TRPM2, TRPM4, TRPM5) contain a binding pocket for icilin that overlaps with the one found in the cold-activated TRPM8 channel. After examining a body of TRP channel cryo-EM structures to identify the conserved site, this study presents convincing electrophysiological evidence supporting the presence of an icilin binding pocket within TRPM4. This study shows that icilin has modulatory effects on the TRPM4 channel and will be of direct interest to those working in the TRP-channel field, but it also has implications for studies of somatosensation, taste, as well as pharmacological targeting of the TRPM subfamily.

eLife Assessment

This study demonstrates a novel role for SIRT4; a mitochondrial deacetylase, shown to translocate into nuclei where it regulates RNA alternative splicing by modulating U2AF2 and the gene expression of CCN2 in tubular cells in response to TGF-β. This fundamental work substantially advances our understanding of kidney fibrosis development and offers a potential therapeutic approach. The evidence supporting the conclusions of a SIRT4-U2AF2-CCN2 axis activated by TGF-β is compelling and adds a new layer of complexity to the pathogenesis of chronic kidney disease.

eLife Assessment

This study uses ex vivo live imaging of uteri post-mating to test the role of the sperm hook in the house mouse sperm in sperm movement that would be interesting to evolutionary biologists. The significance of the work is useful as live imaging can reveal information not seen in fixed images. The strength of evidence is incomplete as they cannot directly test the role of the sperm hook in facilitating movement along the uterine wall.

eLife Assessment

This useful manuscript presents an interesting multi-modal omics analysis of lung adenocarcinoma patients with distinct clinical clusters, mutation hotspots, and potential risk factors identified in cases linked to air pollution. The findings show potential for clinical and therapeutic impact. Some of the conclusions remain incomplete as they are based on correlative or suggestive findings, and would benefit from further functional investigation and validating approaches.

eLife Assessment

The study elucidates a detailed molecular mechanism of the initial stages of transport in the medically relevant Na+-coupled GABA neurotransmitter transporter GAT1 and thus generates important new insights into this protein family. In particular, it presents convincing evidence for the presence of a "staging binding site" that locally concentrates Na+ ions to increase transport activity, whilst solid evidence for how Na+ binding influences larger scale dynamics.

eLife Assessment

This study presents an important finding on durotaxis in various amoeboid cells that is independent of focal adhesions. The evidence supporting the authors' claims is compelling. The work will be of interest to cell biologists and biophysicists working on rigidity sensing, the cytoskeleton, and cell migration.

eLife Assessment

This important paper uses elegant models, including genetic knock outs, to demonstrate that FABP4 contributes to lipid accumulation in tumor-associated macrophages, which seems to increase breast cancer migration. While the work is of high interest, the strength of the evidence relating to some of the conclusions is incomplete and the paper would benefit from some refinement. The work will be of interest to those researchers trying to link metabolism, the immune system, and cancer.

eLife Assessment

This manuscript describes a valuable study of a new lipid-mediated regulation mechanism of adenylyl cyclases. The biochemical evidence provided is convincing, but more evidence for regulation by lipids under natural cellular processes would be interesting. This manuscript will be of interest to all scientists working on lipid regulation and adenylyl cyclases.

eLife Assessment

This important study reports the transcriptomic and proteomic landscape of the oviducts at four different preimplantation periods during natural fertilization, pseudopregnancy, and superovulation. The data presented convincingly supported the conclusion in general, although more analyses would strengthen the conclusions drawn. This work will interest reproductive biologists and clinicians practicing reproductive medicine.

eLife Assessment

The authors follow up on a prior paper in which they showed that beta1 adrenergic receptors contributed to the pathogenesis of cavernous malformations. In the prior work, they used morpholinos and drugs to show this. In this new advance, they now extend this using a genetic knockout of the receptor. While both reviewers agree that this is important for the CV field, there are concerns about the labeling of figures and sample sizes used to make their claims, so the evidence is currently incomplete.

eLife Assessment

In this important study, the authors used a zebrafish model and scRNAseq analysis to show that a subset of keratinocytes within melanoma microenvironment highly up-regulate Twist and undergo Epithelial-Mesenchymal Transition (EMT). Surprisingly, when overexpressing Twist in keratinocytes, the resulting alteration in keratinocytes is inhibitory for melanoma invasion in both zebrafish and human cell culture models. The results are supported by overall convincing experimental data that provide new insights into the interactions between melanoma cells and their environment.

eLife Assessment

This study corroborates recent findings from another group and provides valuable insights into the structure of the autophagy initiation complex, which includes ULK1, ATG13, and FIP200. The authors present solid evidence that supports their claims and addresses one of the key questions in autophagy initiation.

eLife Assessment

This work attempts to demonstrate an ATP-independent non-canonical role of proteasomal component PA28y in the promotion of oral squamous cell carcinoma growth, migration, and invasion. The evidence around the following two areas remains incomplete and would benefit from further experimental work: 1) the stabilisation of the complement C1q binding protein (C1QBp) by PA28y, and 2) the impact of the PA28y-C1QBp interaction on mitochondrial function.

eLife Assessment

This useful study by Gao et al identifies Hspa2 as a heterogeneous transcript in the early embryo and proposes a plausible mechanism showing interactions with Carm1. The authors propose that variability in HSPA2 levels among blastomeres at the 4-cell stage skews their relative contribution to the embryonic lineage. Given only 4 other heterogeneous transcripts/non-coding RNA have been proposed to act similarly at or before the 4-cell stage, this would be a key addition to our understanding of how the first cell fate decision is made. Whilst this is a solid study, in order to support its conclusions image analyses and quantifications would need to be better described, and the overexpression studies should be validated.

eLife Assessment

This important study investigates the function of a critical regulator of human early cardiac development. The convincing examination of GATA6 function is thorough and well-executed. The study will be of interest to scientists working on how the human heart acquires its identity.

eLife Assessment

This study presents useful quantitative insights into the prevalence of functionally clustered synaptic inputs on neuronal dendrites. The simple analytical calculations and computer simulations provide solid support for the main arguments. With improvements to the presentation and more realistic simulations (e.g. including the interaction between calcium and electric signals) the findings can lead to a more detailed understanding of how dendrites contribute to the computation of neuronal networks.

ronaldos history at real madrid

transfer to real madrid and his awards

ronaldos transfer to man united and achievements

Ronaldos early life and career

talks about ronaldo, some basic information and his achievements

eLife Assessment

This manuscript reports fundamental discoveries on how necrotic cells contribute to organ regeneration through apoptotic signaling. These findings would be of broad interest to those who study wound repair and tissue regeneration. The strength of the evidence is solid, but would be stronger with additional quantifications and controls.

eLife Assessment

This important study develops a high throughput version of expansion microscopy that can be performed in 96-well plates. The engineered technology is convincing and compatible with standard microplates and automated microscopes and thus will be of broad interest. The application to hiPCS-derived cardiomyocytes treated with doxorubicin provides a solid proof-of-concept demonstrating the potential for high-throughput analysis.

eLife Assessment

Transient receptor potential mucolipin 1 (TRPML1) functions as a lysosomal ion channel whose variants are associated with lysosomal storage disorder mucolipidosis type IV. This important report describes local and global structural changes driven by binding of regulatory phospholipids and by mutations that allosterically cause gain or loss of channel function. Most of the claims related to the allosteric regulation of TRPML1 are convincingly supported by two new cryo-EM structures which are evaluated within the context of previously reported TRPML1 structures, and a proposed allosteric gating mechanism is partially supported by functional electrophysiology results.

eLife Assessment

This valuable study describes an apparatus, workflow, and proof-of-concept data for a system to study social cooperation in marmosets, an increasingly popular primate model for neuroscience. The apparatus and methodology have clear and convincing advantages over conventional methods based on manual approaches. However, claims of faster social learning or of finer-grained behavioural analysis in this setup will require further corroboration.

eLife Assessment

This study introduces a useful extension to a recently proposed model of neural assembly activity. The extension was to add recurrent connections to the hidden units of the Restricted Boltzmann Machine. The authors show solid evidence that the new model outperforms their earlier model on both a simulated dataset and on whole-brain neural activity from zebrafish.

eLife Assessment

Using a large animal model, this study demonstrated valuable findings that R25CPTH(1-34), based on a mutation associated with isolated familial hypoparathyroidism, generated an anabolic osteointegration effect comparable to that of native PTH1-34. The translational aspect of this human-to-animal work, aimed at animal-to-human translation for therapeutic purposes, should be highlighted. The study design is simple and straightforward, and the methods used are solid. The authors have addressed all the questions in their revision.

eLife Assessment

This valuable study is a detailed investigation of how chromatin structure influences replication origin function in yeast ribosomal DNA, with a focus on the role of the histone deacetylase Sir2 and the chromatin remodeler Fun30. Convincing evidence shows that Sir2 does not affect origin licensing but rather affects local transcription and nucleosome positioning which correlates with increased origin firing. Overall, the evidence is solid and the model plausible. However, the methods employed do not rigorously establish a key aspect of the mechanism where initiation precisely occurs or rigorously exclude alternative models and the effect of Sir2 on transcription is not re-examined in the fun30 context.

eLife Assessment

This important study shows that soluble uric acid is an endogenous inhibitor of CD38, a regulator of inflammatory responses. The convincing evidence draws both on biochemical analyses and in vivo models. This work provides insights into NAD+ metabolism, with significant implications for inflammation and potential roles in metabolic diseases and aging.

eLife Assessment

This paper, on the role of calcium and integrin-binding protein 2 and 3 in the hair-cell in the mechano-electrical transduction (MET) apparatus, is a mix of confirmatory studies with new and potentially important data. Some parts, such as zebrafish studies, the modelling and simulations, are regarded as necessary and convincing. Other parts of the paper do not have the same novelty. Both Liang et al. (2021) and Wang et al. (2023) had previously demonstrated a role for CIB2/CIB3 in auditory and vestibular cells in mice. Moreover, there are also data in Riazuddin et al. (2012) paper that demonstrates the importance of CIB2 in zebrafish and Drosophila. Breaking the manuscript up to focus on specific aspects of the problem might alleviate the limitations of this multi-faceted study.

eLife Assessment

This valuable study reports an extensive analysis of the way a humoral immune response to parasitoid wasp is expressed and regulated, building on previous work from the authors on an anti-parasitoid effector lectin. The solid evidence uses two complementary approaches to show which innate immune pathways are involved in the regulation of the anti-parasitoid response. The evidence would be stronger if some analytical and related concerns can be addressed. The work will be of relevance to the community of investigators studying insect immune cells as well as researchers interested in host defense against parasitism.

eLife Assessment

This manuscript introduces a new low-cost and accessible method for assembling combinatorially complete microbial consortia using basic laboratory equipment, which is a valuable contribution to the field of microbial ecology and biotechnology. The evidence presented is convincing, demonstrating the method's effectiveness through empirical testing on both synthetic colorants and Pseudomonas aeruginosa strains.

eLife Assessment

This study provides important new insight into chemosensation by showing that odors activate taste sensory neurons in Drosophila to promote feeding behaviors. Using a convincing methodology, combining behavior analysis, electrophysiology, and calcium imaging, Kazama and colleagues have deepened our understanding of how this phenomenon modulates the feeding behavior, although in some cases additional controls would strengthen the conclusions. Here, the authors articulate a clear instance of a novel neural and behavioral mechanism for gustatory receptors in an olfactory response making this work relevant to researchers studying chemosensation, sensory biology, and insect behavior.

eLife Assessment

This work by Hill and colleagues offers valuable insights into the development of learning abilities involved in action control from toddlerhood to adulthood. Data across 4 experiments provide solid evidence that in a task involving noisy but continuous action, the ability to learn reward probability develops gradually and may be limited by spatial processing and probabilistic reward reasoning. Questions remain about whether the task truly measures motor learning or more generic cognitive capacities, and whether a proposed model of reinforcement-based motor learning adequately captures the data.

eLife Assessment

This study presents TopOMetry, an important novel dimensionality reduction method that addresses a signficant challenge in the analysis of single-cell RNA sequencing data. The authors provide convincing evidence of the method's utility across various tasks, including estimating intrinsic dimensionalities and identifying cell types. The work would benefit from more rigorous validation and a reorganization of the text.

eLife Assessment

This important study provides convincing evidence that emotional information in biological motion can induce different patterns of pupil responses, which could serve as a behavioral marker of an autistic trait. These results broaden our understanding of how emotional biological motion can automatically trigger physiological changes and reveal the potential of using emotional-modulated pupil response to facilitate the diagnosis of social cognitive disorders. The work will be of broad interest to cognitive neuroscience, psychology, affective neuroscience, and vision science.

eLife Assessment

This important study identifies a short amino acid sequence that, when fused in multimeric form to the amino termini of luminal ER proteins, initiates proteasomal degradation via the Hrd1 ER quality control ubiquitin ligase complex. The authors provide solid evidence that this sequence functions as a "degron" for ER proteins. Future work is required to obtain a more detailed view of the properties of this degron, the mechanisms underlying its recognition by ER-resident and cytoplasmic factors, and the in vivo relevance of the findings.

eLife Assessment

Brain inflammation is a hallmark of multiple sclerosis. Using novel spatial transcriptomics methods, the authors provide solid evidence for a gradient of immune genes and inflammatory markers from the meninges toward the adjacent brain parenchyma in a mouse model. This important study advances our understanding of the mechanisms of brain damage in this autoimmune disease.

eLife Assessment

Genetic analysis of complex traits in Drosophila provides a resource for exploring the relationship between genetic and phenotypic variation. The web tool DGRPool presented in this paper makes data and results from the Drosophila Genetic Reference Panel accessible that will enable downstream analyses of genetic association. The findings of this paper are considered to be important, with practical implications beyond a single subfield, supported by convincing evidence using appropriate and validated methodology in line with current state of the art.

Editors Assessment:

This Data Release paper presents the genome of the whippet breed of dog. Demonstrating a streamlined laboratory and bioinformatics workflows with PacBio HiFi long-read whole-genome sequencing that enables the generation of a high-quality reference genome within one week. The genome study being a collaboration between an academic biodiversity institute and a medical diagnostic company. The presented method of working and workflow providing examples that can be used for a wide range of future human and non-human genome projects. The final is 2.47 Gbp assembly being of high quality - with a contig N50 of 55 Mbp and a scaffold N50 of 65.7 Mbp. This reference being scaffolded into 39 chromosome-length scaffolds and the annotation resulting in 28,383 transcripts. The results also looked at the Myostatin gene which can be used for breeding purposes, as these heterozygous animals can have an advantage in dog races. The reviewers making the authors clarify this part a little better with additional results. Overall this study demonstrating how rapidly animal genome research can be carried out through close and streamlined time management and collaboration.

This evaluation refers to version 1 of the preprint

eLife Assessment

This important study shows that a splice variant of the kainate receptor Glu1-1a that inserts 15 amino acids in the extracellular N-terminal region substantially changes the channel's desensitization properties, the sensitivity to glutamate and kainate, and the effects of modulatory Neto proteins. In the revised paper the authors have clarified several points raised by reviewers but the structural portion of the study has not been improved and consequently, more data are needed to determine the molecular mechanism by which the insert changes the functional profile of the channel. Even so, these solid findings advance our understanding of splice variants among glutamate receptors and will be of interest to neuro- and cell-biologists and biophysicists in the field.

eLife Assessment

This study presents an important investigation of water coordination in a specific kinase family with a focus on the regulation of osmosensing protein kinases. X-ray crystallographic approaches combined with functional assays are used to address the hypothesis that bound water participates in the osmosensing mechanism as an allosteric kinase inhibitor. The evidence for changes in kinase conformation and space group of the crystal as a function of added low molecular weight polyethylene glycol is solid. The work will be of considerable interest to the kinase field as well as colleagues studying allosteric regulation of protein function.

eLife Assessment

This fundamental study uses a creative experimental system to directly test Ohno's hypothesis, which describes how and why new genes might evolve by duplication of existing ones. In agreement with existing criticism of Ohno's original idea, the authors present compelling evidence that having two gene copies does not speed up the evolution of a new function as posited by Ohno, but instead leads to the rapid inactivation of one of the copies through the accumulation of mostly deleterious mutations. These findings will be of broad interest to evolutionary biologists and geneticists.

eLife Assessment

In this valuable study, the authors investigate how inflammatory priming and exposure to irradiated Mycobacterium tuberculosis or the bacterial endotoxin LPS impact the metabolism of primary human airway macrophages and monocyte-derived macrophages. The work shows that metabolic plasticity is greater in monocyte-derived macrophages than alveolar macrophages, with solid experimental methods and overall evidence. The findings are relevant to the field of immunometabolism.

eLife Assessment

This study investigates the role of Caspar (Casp), an orthologue of human Fas-associated factor-1, in regulating the number of primordial germ cells that form during Drosophila embryogenesis. The findings are important in that they reveal an additional pathway that contributes to germ cell specification and maintenance. The evidence supporting the conclusions is solid, as the authors identify Casp and its binding partner Transitional endoplasmic reticulum 94 (TER94) as factors that influence germ cell numbers.

eLife Assessment

This important paper addresses the role of fluid flows in nutrient uptake by microorganisms propelled by the action of cilia or flagella. Using a range of mathematical models for the flows created by such appendages, the authors provide convincing evidence that the two strategies of swimming and sessile motion can be competitive. These results will have significant implications for our understanding of the evolution of multicellularity in its various forms.

eLife Assessment

This important study introduces a new cortical circuit model for predictive processing. Simulations effectively illustrate that, with appropriate synaptic plasticity, a canonical layer 2/3 cortical circuit - comprising two classes of interneurons providing subtractive and divisive inhibition - can generate uncertainty-modulated prediction errors by pyramidal neurons. The model is compelling; although it relies on many assumptions and has not yet been compared directly to data, the model does align with empirical observations and yields a range of testable predictions. The study is expected to be of great interest to those involved in cortical and predictive processing research.

eLife Assessment

Treatment of pseudomonas aeruginosa (PA) is challenging because of intrinsic and acquired antibiotic resistance to most antibiotic drug classes. Therefore, by using donor B cells in subjects with cystic fibrosis who undergo intermittent or chronic airway PA infections, the authors tried to isolate BCRs against PA virulence factors and examine their biological activities. The data are solid and isolated protective antibodies could be useful for protection against PA.

eLife Assessment

This valuable study addresses one way in which animals identify predator-associated cues and respond in a manner that reflects the imminence of the potential threat. The report shows that, in mice, fresh saliva from a natural predator (cat) elicits a greater defensive response compared to old cat saliva and implicates the vomeronasal organ and ventromedial hypothalamus as part of a circuit that underlies this process. The evidence supporting the main conclusions is solid. This study will be of interest to those interested in aversive behavior, its processes, and mechanisms.

eLife Assessment

This important work shows how a simple geophysical setting of gas flow over a narrow channel of water can create a physical environment that leads to the isothermal replication of nucleic acids. The work presents convincing evidence for an isothermal polymerase chain reaction in careful experiments involving evaporation and convective flows, complimented with fluid dynamics simulations. This work will be of interest to scientists working on the origin of life and more broadly, on nucleic acids and diagnostic applications.

eLife assessment

This important study demonstrates a mechanism underlying the sex-dependent regulation of the susceptibility to gut colonization by Methicillin-resistant Staphylococcus aureus (MRSA). The evidence supporting the conclusion is solid, but additional experiments would strengthen the findings. The work will interest biologists who are working on intestinal infection and immunity.

eLife assessment

This valuable manuscript investigated the role of glutamate signaling in the dorsomedial striatum of rats in a treadmill-based task and reported that it differs in goal-trackers compared to sign-trackers in a way that corresponds to differences in behaviour. The evidence supporting these claims is solid but could be further strengthened by adding more analyses and more detailed descriptions of current analyses. These findings will primarily be of interest to behavioural neuroscientists.

eLife assessment

This important study reports the formation of a new organelle, called giant unilocular vacuole (GUVac), in mammary epithelial cells through a macropinocytosis-like process. The evidence supporting conclusions is convincing, using state-of-the-art cell biology techniques. This work will be of interest to cell biologists and contribute to the understanding of cell survival mechanisms against anoikis.

eLife assessment

This work demonstrates an important regulatory role of the N-terminal disordered tail of small ubiquitin-like modifier (SUMO) proteins, which modulate the function of various proteins in eukaryotic cells. The authors present convincing evidence that the N-terminal tail of SUMO inhibits SUMO's interaction with downstream effector proteins and SUMOylation targets, and that this regulatory mechanism depends on the SUMO paralogue or the phosphorylation of the N-terminal tail. This discovery significantly advances the field by providing a possible explanation of how SUMO paralogues select their effectors and SUMOylation targets.

eLife assessment

This work aimed at deconstructing how sebaceous gland differentiation is controlled in adult skin. Using monoclonal antibodies designed to inhibit specific Notch ligands or receptors, the authors present convincing evidence that the Jag2/Notch1 signaling axis is a crucial regulator of sebocyte progenitor proliferation and sebocyte differentiation. The valuable findings presented here contribute to the growing evidence that Notch signaling is not only key during the development of the skin and its appendages but also regulates cell fate in adult homeostatic tissues. From a translational perspective, it is intriguing that the effect of Jag2 or Notch1 inhibition, which leads to the accumulation of proliferative stem/progenitor cells in the sebaceous gland and prevents sebocyte differentiation, is reversible.

eLife assessment

In this small study involving patients with a history of myocardial infarction, Fawaz et al. found no significant contribution of clonal hematopoiesis and mosaic loss of the Y chromosome to the incidence of myocardial infarction and atherosclerosis. Although the evidence provided by the study is incomplete due to its small sample size, the findings are valuable for guiding future larger studies that will further investigate this significant and controversial subject.

eLife assessment

This important study describes the discovery of a mechanism by which multiple species of bacteria synthesize and localize polar flagella via a novel protein, FipA, which interacts with FlhF. The authors use appropriate methodological approaches (biochemistry, molecular microbiology, quantitative microscopy, and bacterial genetics) to obtain and present convincing results and interpretations. This work will particularly interest those studying bacterial motility and bacterial cell biologists.

eLife assessment

This study presents an assessment of the effect of lactate dehydrogenase (LDH) inhibition on the activity of glycolysis and tricarboxylic acid cycle. The data were collected and analyzed using solid and validated methodology. This paper makes a useful contribution to the field as it considers a control analysis of LDH flux.

eLife assessment

In this valuable work, Lodhiya et al. provide evidence that excessive ATP underlies the killing of the model organism Mycobacterium smegmatis by two mechanistically-distinct antibiotics. Clarification of the role(s) of reactive oxygen species and ADP, as well as discrepancies with existing literature, would strengthen the model proposed. The data are generally solid as the authors deploy multiple, orthogonal readouts and methods for manipulating reactive oxygen species and ATP. The work will be of interest to those studying antibiotic mechanisms of action.

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, this score should be done in many countries and on large numbers of patients, nevertheless, this paper should interest gastrointestinal endoscopists.

eLife assessment

This important study combines multiple techniques to investigate how caspase activity regulates non-lethal caspase-dependent processes. Through a combination of various approaches, and the development of new techniques, the authors provide compelling evidence supporting the claim that Fas3G-overexpression promotes non-lethal caspase activation in olfactory receptor neurons.

eLife assessment

This valuable study combines electrophysiology experiments and modeling to investigate the encoding of dynamic patterns of polarized light by identified neurons of the bumblebee central complex. The scientific question and methodology are compelling. However, the evidence supporting the authors' conclusions is incomplete without more comprehensive statistical analyses.

In "AI Image Generators Often Give Racist and Sexist Results: Can They Be Fixed?" by Ananya, the article dives deeper into sources of racial and gender bias in AI images and how to confront the issues.

eLife assessment

This study makes an important effort to observe and quantify synaptic integration in a large and active network of cultured neurons, using simultaneous patch-clamp and large-scale extracellular recordings. They developed a method to distinguish excitatory and inhibitory contributions, show compelling evidence that the subthreshold activity of these neurons is dominated by few presynaptic neurons. They provide convincing statistics about connectivity and network dynamics.

eLife assessment

Using microscopy experiments and theoretical modelling, the authors present convincing evidence of cellular coordination in the gliding filamentous cyanobacterium Fluctiforma draycotensis. The results are important for the understanding of cyanobacterial motility and the underlying molecular and mechanical pathways of cellular coordination.

eLife assessment

The authors present a solid statistical framework for using sibling phenotype data to assess whether there is evidence for de-novo or rare variants causing extreme trait values. Their valuable method is promising and will be of interest to researchers studying complex trait genetics.

eLife assessment

This manuscript describes the mapping of natural DNA sequence variants that affect gene expression and its noise, as well as cell cycle timing, using as input single-cell RNA-sequencing of progeny from crosses between wild yeast strains. The method represents an important advance in the study of natural genetic variation. The findings, especially given the follow-up validation of the phenotypic impact of a mapped locus of major effect, provide convincing support for the rigor and utility of the method.

eLife assessment

This important study investigates neurobiological mechanisms underlying the maintenance of stable, functionally appropriate rhythmic motor patterns during changing environmental conditions - temperature in this study in the crab Cancer borealis stomatogastric central neural pattern generating circuits producing the rhythmic pyloric motor pattern, which is naturally subjected to temperature perturbations over a substantial range. The authors present compelling evidence that the neuronal hyperpolarization-activated inward current (Ih), known to contribute to rhythm control, plays a vital role in the ability of these circuits to appropriately adjust the frequency of rhythmic neural activity in a smooth monotonic fashion while maintaining the relative timing of different phases of the activity pattern that determines proper functional motor coordination transiently and persistently to temperature perturbations. This study will be of interest to neurobiologists studying rhythmic motor circuits and systems and their physiological adaptations.

eLife assessment

This important study highlights cell types preserving long-lived proteins and lays a foundation for identifying exceptionally long-lived proteins in the ovary. Convincing evidence describes helpful data about protein turnover and identifies long-lived macromolecules in oocytes and somatic cells during mouse ovarian aging. This work will be of interest to researchers working on aging and reproductive health.

eLife assessment

This potentially valuable study examines the role of IL17-producing Ly6G PMNs as a reservoir for Mycobacterium tuberculosis to evade host killing activated by BCG immunisation. The authors report that IL17-producing polymorphonuclear neutrophils harbour a significant bacterial load in both wild-type and IFNg-/- mice and that targeting IL17 and Cox2 improved disease outcomes whilst enhancing BCG efficacy. Although the authors suggest that targeting these pathways may improve disease outcomes in humans, the evidence as it stands is incomplete and requires additional experimentation for the study to realise its full impact.

eLife assessment

This useful study investigates the role of Complement 3a Receptor 1 (C3aR) in the pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) using mouse models with specific target deletions in various cell types. While the relevance of C3aR in inflammatory contexts has been established, the authors provide helpful but incomplete evidence that C3aR does not contribute significantly to MASLD pathogenesis in their models, a claim that would require additional experiments for support.

eLife assessment

This important study demonstrates that interferon beta stimulation induces WTAP transition from aggregates to liquid droplets, coordinating m6A modification of a subset of mRNAs that encode interferon-stimulated genes and restricting their expression. The evidence presented is solid, supported by microscopy, immunoprecipitations, m6A sequencing, and ChIP, to show that WTAP phosphorylation controls phase transition and its interaction with STAT1 and the methyltransferase complex.

eLife assessment

This valuable study confirms the association between the human leukocyte antigen (HLA)-II region and tuberculosis (TB) susceptibility in genetically admixed South African populations, specifically identifying a near-genome-wide significant association in the HLA-DPB1 gene, which originates from KhoeSan ancestry. Whilst some of the evidence supporting the association between the HLA-II region and TB susceptibility is solid, the analysis is incomplete and requires further work for the study to achieve its full value. The work will be of interest to those studying the genetic basis of tuberculosis susceptibility/infection resistance.

eLife assessment

This valuable study presents compelling evidence that a single member of the Ly49 gene family (Ly49a) provides sufficient inhibitory signaling to license NK cell activity when its H-2Dd ligand is present. There is also convincing evidence of the effect of Ly49a expression on in vitro killing and IFNgamma production. The use of the authors' system to investigate additional Ly49 receptors, such as Ly49c/i on the H2b background, could provide information on their relative contribution to NK cell licensing. Improvements to the presentation with respect to figure clarity and terminology would allow a better understanding of this complex system by non-experts.

eLife assessment

This paper reports the synthesis of covalent inhibitors bearing a unique fragment as a protected covalent warhead for irreversible binding to histidine in carbonic anhydrase (CA) enzymes. These findings are important due to the broad utility of the approach for covalent drug discovery applications and could have long-term impacts on related covalent targeting approaches. The data convincingly support the main conclusions of the paper.

eLife assessment

This study presents an important platform for mapping mutation effects onto higher-level protein structural information, addressing a significant gap in current research. While the work is ambitious and incorporates often-overlooked aspects of higher-order structure, the strength of the evidence supporting some results seems incomplete. The quaternary structure modeling appears to underestimate oligomeric proteins compared to previous studies, and the mutation analysis lacks crucial baseline information. Despite these limitations, the method has potential for broader applications and generalization to additional organisms, warranting further development and refinement.

eLife assessment

This study focuses on the role of a T-cell-specific receptor, ctla-4, in a new zebrafish model of IBD-like phenotype. Although implicated in IBD diseases, the function of ctla-4 has been hard to study in mice as the KO is lethal. Ctla-4 mutant zebrafish exhibited significant intestinal inflammation and dysbiosis, mirroring the pathology of inflammatory bowel disease (IBD) in mammals, providing a new valuable model to the field of IBD research. However, although many of the results are solid, the methods as provided are incomplete, without information on methods for many data panels.

eLife assessment

Leafhoppers coat their body surface with nanoparticles, called brochosomes, which are an evolutionary innovation in this insect clade. The important paper adds significant evidence for the biological role of these structures consisting of a reflection effect of UV light as a defense against predatory spiders. Convincing support is provided for a new functional aspect of brochosomes, elucidating the emergence of the underlying genes and the principles of self-assembly of these biological nanoparticles.

eLife assessment

This paper reports a novel mechanism of regulation of the heat shock response in plants that acts as a brake to prevent hyperactivation of the stress response. The findings are valuable to understand and potentially manipulate the plant's response to heat stress and the presented evidence is overall solid. However, in some cases, the data are either poorly presented or insufficient to support the primary claims.

eLife assessment

This important study reveals a novel mechanism by which hypoxia-ischemia damages the neonatal brain and how hypothermia protects from brain injury. The paper presents an interesting combination of state-of-the-art optical measurements, mitochondrial assays, and the use of various control experiments providing solid evidence for the derived conclusions. Reviewers caution that possible adverse effects of prolonged anesthesia, as well as pain and stress after a major surgical procedure might influence the outcomes and should be carefully considered. This work will be of interest to the fields of hypoxia and brain metabolism research.

eLife assessment

This important study provides a comprehensive assessment of mitochondrial function across age and sex in mice. The strength of evidence supporting this resource is compelling, given the exhaustive number of tissues profiled and in-depth analyses performed.

eLife assessment

This study offers a valuable description of the layer-and sublayer specific outputs of the somatosensory cortex based on compelling evidence obtained with modern tools for the analysis of brain connectivity, together with functional validation of the connectivity using optogenetic approaches in vivo. Beyond bridging together, in one dataset, the results of disparate studies, this effort brings new insights on layer specific outputs, and on differences between primary and secondary somatosensory areas. This study will be of interest to neuroanatomists and neurophysiologists.

eLife assessment

The authors presented a valuable bioinformatics pipeline for screening and identifying inhibitory receptors for potential drug targets. They provided solid evidence showing a sequential reduction in the search space through various screening tools and algorithms and demonstrated that this pipeline can be used to "rediscover" known targets. Further experimental validation on putative and unknown inhibitory receptors will strengthen the evidence reported in this work. This study will be of interest to bioinformaticians and computational biologists working on immune regulation, sequence screening, and target identification of immune checkpoint inhibitors.

eLife assessment

This important study investigates the intracellular localization patterns of G proteins involved in GPCR signaling, presenting compelling evidence for their preference for plasma and lysosomal membranes over endosomal, endoplasmic reticulum, and Golgi membranes. This discovery has significant implications for understanding GPCR action and signaling from intracellular locations. This research will interest cell biologists studying protein trafficking and pharmacologists exploring localized signaling phenomena.

eLife assessment

This paper presents a valuable automated method to track individual mammalian cells as they progress through the cell cycle using the FUCCI system. The authors have developed a technique for analyzing cells that grow in suspension and used their method to look at different tumor cell lines that grow in suspension and determine the effect of drugs that directly affect the cell cycle. They show solid evidence that the method can be applied to both adherent and non-adherent cell lines. This paper will be of interest to cell biologists investigating cell cycle effects.

eLife assessment

This study presents a valuable finding and developed ME3BP-7 as a novel microencapsulated formulation of 3BP, which specifically targets MCT1-overexpressing PDAC cells. It demonstrates its specificity and efficacy in vitro and in PDAC mouse models, with significant anti-tumor effects and improved serum stability. Overall, the evidence supporting the authors' claims is solid.

eLife assessment

This important study identifies a new class of small molecules that activate the integrated stress response via the kinase HRI. Solid evidence indicates that two of these compounds promote mitochondrial elongation. The findings would be strengthened if the mutant cells with reduced fusion activity of Mfn2 were analyzed for the rescue of mitochondrial functions.

eLife assessment

This important manuscript shows that axonal transport of Wnd is required for its normal degradation by the Hiw ubiquitin ligase pathway. In Hiw mutants, the Wnd protein accumulates in nerve terminals. In the absence of axonal transport, Wnd levels also rise and lead to excessive JNK signaling, disrupting neuronal function. These are interesting findings supported by convincing data. However, how Rab11 is involved in Golgi processing or axonal transport of Wnd is not resolved as it is clear that Rab11 is not travelling with Wnd to the axon.

eLife assessment

This study presents valuable findings from an observational dataset in a riverine ecosystem about the effects of genetic and species diversity, across multiple trophic levels, on ecosystem functions. However, the support for these findings is currently incomplete because raw data are not provided and there is insufficient information in the manuscript for readers to understand and assess the statistical analyses and conclusions. The work will be of broad interest to ecologists.

eLife assessment

This study provides direct evidence showing that Kv1.8 channels provide the basis for several potassium currents in the two types of sensory hair cells found in the mouse vestibular system. This is an important finding because the nature of the channels underpinning the unusual potassium conductance gK,L in type I hair cells has been under scrutiny for many years. The experimental evidence is compelling and the analysis is rigorous. The study will be of interest to cell and molecular biologists as well as vestibular and auditory neuroscientists.