eLife Assessment

The study introduces new tools for measuring the intracellular calcium concentration close to transmitter release sites, which may be relevant for synaptic vesicle fusion and replenishment. This approach yields important new information about the spatial and temporal profile of calcium concentrations near the site of entry at the plasma membrane. This experimental work is complemented by a coherent, open-source, computational model that successfully describes changes in calcium domains. Key gaps in the data presented mean that the evidence for the main conclusions is currently incomplete.

eLife Assessment

This study presents valuable findings on the increased prevalence of pain in women with polycystic ovary syndrome and its relationship to health outcomes. The evidence supporting the conclusions is compelling with a large number of patients and sound methodology, and can be used as a starting point for studies of etiology and mechanisms of pain in women with polycystic ovary syndrome and comorbidities. The work will be of interest to medical biologists working on polycystic ovary syndrome pathophysiology and clinicians.

eLife Assessment

This valuable study characterises the activity of motor units from two of the three anatomical subdivisions ("heads") of the triceps muscle while mice walked on a treadmill at various speeds. Although this is the most thorough characterisation of motor unit activity in walking mice to date, the evidence supporting some of the claims, especially pertaining to probabilistic recruitment of motor units, is incomplete. Further investigating whether the differences in motor unit recruitment across muscle heads go beyond their different mechanical functions would also strengthen the paper.

eLife Assessment

This important study identifies a novel role for Hes5+ astrocytes in modulating the activity of descending pain-inhibitory noradrenergic neurons from the locus coeruleus during stress-induced pain facilitation. The role of glia in modulating neurological circuits including pain is poorly understood, and in that light, the role of Hes5+ astrocytes in this circuit is a key finding with broader potential impacts. However, the impact of this work is limited by incomplete evidence, notably the fact that acute restraint stress is generally anti-nociceptive rather than pro-nociceptive, and a lack of specificity in defining this novel circuit.

eLife Assessment

This is a useful follow-up on previous work on the same LGI1-ADAM22 complex using cross-linking to stabilize a trimeric state that the authors had previously observed by SEC-MALS and small-angle X-ray scattering (the previous crystal structure was determined in a dimeric form). A strength of this solid work is that oligomeric states do not affect the critical interaction between LGI1 and ADAM23, so the previous conclusions are still valid. A weakness is that the physiological relevance of the trimeric assembly is unclear.

eLife Assessment

This paper presents the important finding that BNIP3/NIX, a mitophagy receptor, and its binding to ATG18 are required for mitophagy during muscle cell reorganization in Drosophila. Although the involvement of the BNIP3-ATG18/WIPI axis in mitophagy induction has been reported in mammalian cell culture systems, this study provides the first compelling evidence for this pathway in vivo in animals. The physiological significance of this BNIP3-dependent mitophagy will require further investigation.

eLife Assessment

This paper provides a compelling and rigorous quantitative analysis of the turnover and maintenance of CD4+ tissue-resident memory T cell clones, in the skin and the lamina propria. It provides a fundamental advance in our understanding of CD4 T cell regulation. Interestingly, in both tissues, maintenance involves an influx from progenitors on the time scale of months. The evidence that is based on fate mapping and mathematical inference is strong, although open questions on the interpretation of the Ki67-based fate mapping remain.

eLife Assessment

This study approaches an important topic providing insight into the neuronal circuitry that interconnects memory consolidation and sleep. The data were collected and analysed using a solid methodology, contributing new findings for neurobiologists working on how memories are stored and the roles of sleep. However, the data is incomplete to support the proposed role of the PAM-DPM circuits as the link between sleep state and long-term memory consolidation.

eLife Assessment

Lu and colleagues developed an important imaging protocol that combines expansion microscopy, light-sheet microscopy, and image segmentation for use with the planarian Schmidtea mediterranea, a powerful model system for regeneration. This represents a substantial improvement on current standards and enables more rapid data acquisition. The utility of this solid protocol is demonstrated by quantifying several aspects of this flatworm's neural anatomy and musculature during homeostasis and regeneration. This work will be of interest to researchers looking to implement more systematic approaches towards imaging and quantifying intact specimens.

eLife Assessment

This study makes the fundamental discovery of the first natural animal rhodopsin that uses a chloride ion instead of an amino acid side chain as a counterion. Using a combination of biochemical and spectroscopic experiments together with QM/MM simulations, the authors identify the spectral tuning mechanism in the dark state and in the photoproduct state. The methods are sound and the results are convincing. This work will be of interest to biologists working on visual proteins and it also raises new questions about how environmental factors might affect coral opsins.

eLife Assessment

This paper reports the analysis of coevolutionary patterns and dynamical information for identifying functionally relevant sites. These findings are considered important due to the broad utility of the unified framework and network analysis capable of revealing communities of key residues that go beyond the residue-pair concept. The data are solid and the results are clearly presented.

eLife Assessment

CellDetective is a useful software package for segmentation, tracking, and analysis of time‐lapse microscopy datasets, specifically designed to be accessible to researchers without coding expertise. The authors provide solid evidence of its capabilities through comprehensive validations and well‐executed comparisons across immunological assays. However, the current implementation is limited to 2D widefield imaging and presents technical challenges - including occasional crashes, restricted flexibility in defining multiple cell populations, and some interface issues that hinder the full user experience. Overall, this work will be of significant interest to the bioimaging community, especially those in immunology and cell biology, and promises to evolve into a more robust tool with further development.

eLife Assessment

This manuscript describes the characterization of the conformational dynamics of two chemokine receptors at the single-molecule level using FRET. The authors make a convincing case for attributing the distinct interaction and pharmacology of the two receptors to differences in their conformational energy landscape. These important findings will be of interest to scientists working on activation mechanisms of GPCRs and signal transduction.

eLife Assessment

This manuscript focuses on understanding if and how the glycosylation of SARS-CoV2 spike protein affects a putative allosteric network of interactions controlled by the binding of a fatty acid. The main conclusion is that glycans do not significantly affect the network of allosteric interactions. This valuable information - albeit mainly consisting of negative results - is based on convincing evidence. It will be of interest to scientists focusing on SARS CoV2 protein structure and dynamics.

eLife Assessment

In this manuscript, Abd El Hay and colleagues use an innovative behavioral assay and analysis method, together with standard calcium imaging experiments on cultured dorsal root ganglion (DRG) neurons, to evaluate the consequences of global knockout of TRPV1 and TRPM2, and overexpression of TRPV1, on warmth detection. Compelling evidence is provided for a role of TRPM2 channels in warmth avoidance behavior, but it remains unclear whether this involves channel activity in the periphery or in the brain. In contrast, TRPV1 is clearly implicated at the cellular level in warmth detection. These findings are important because there is substantial ongoing discussion regarding the contribution of TRP channels to different aspects of thermo-sensation.

eLife Assessment

This is an important study that generates an inventory of accessible genomic regions bound by a transcription factor ZFHX3 within the suprachiasmatic nucleus in the hypothalamus and details the impact of its depletion on daily rhythms in behavior and gene expression patterns. Analysis using circadian phase-estimation algorithms makes the argument that gene regulatory networks are at play and changes in gene expression of a few clock genes cannot account for the observed animal behaviour. While the transcriptome analysis is compelling, the data on the activity of the TF in rhythmic gene expression is solid, and interpretations that allow for direct and/or indirect roles have been incorporated.

eLife Assessment

This work presents a useful resource combining scRNA-seq and spatial transcriptomics studies to map mouse pre-clinical models of colorectal cancer, identifying distinct cellular programs and microenvironments that could enhance patient stratification and therapeutic approaches in colorectal cancer. While the novelty of the biological findings remains limited and incompletely supported by the evidence provided in the manuscript, the data were collected and analyzed using a validated methodology that will be of interest to the community in future studies.

eLife Assessment

This is an important study linking olfactory bulb activity not only to sniffing parameters but also to movement and place. The evidence for odor sampling is mostly solid, but the analysis supporting the potentially exciting result on the encoding of place is currently incomplete.

eLife Assessment

This valuable manuscript presents a potentially novel mechanism by which the phospholipid scramblase, PLSCR1, defends against influenza A virus infection. The paper was based on solid findings involving knockout and lung-specific over-expressing Plscr1 mice, airway tissue expression, and mechanistic studies to show Plscr1 enhances type III interferon-mediated viral clearance. The study is extensive and overall well performed.

eLife Assessment

This study investigates the conditions under which abstract knowledge transfers to new learning. It presents convincing evidence across a number of behavioral experiments that when explicit awareness of learned statistical structure is present, knowledge can transfer immediately, but that otherwise similar transfer requires sleep-dependent consolidation. The valuable results provide new constraints on theories of transfer learning and consolidation.

eLife Assessment

This important study demonstrates that screening by artificial intelligence can identify relevant novel compounds for interacting with KATP channels. The experimental work is compelling. The broader significance of this work relates to the possibility that KATP channel mutations linked to congenital hyperinsulinism may be effectively rescued to the cell surface with a drug, which could normalize insulin secretion or enhance the effectiveness of existing KATP channel activators such as diazoxide.

eLife Assessment

This valuable manuscript uses mathematical modeling to address the synchrony of the vertebrate segmentation clock with the developmental processes. The authors use convincing arguments to support the idea that this would allow the evolution of flexible body plans and a variable number of segments. This manuscript could be of interest to developmental biologists and systems biologists.

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

eLife Assessment

This useful study presents a comparative investigation of category selectivity in dogs and humans. The study compares brain representations of animate and inanimate objects, replicating and extending previous reports in this nascent field of dog FMRI. The methods and results seem to lack sufficient detail, appropriate controls, or statistical evidence, so at this stage of the review process, the strength of evidence is deemed incomplete.

eLife Assessment

This valuable study provides new insights into the synchronization of ripple oscillations in the hippocampus, both within and across hemispheres. Using carefully designed statistical methods, it presents convincing evidence that synchrony is significantly higher within a hemisphere than across. However, further controlling for potential confounds related to differences in animal behavior will help clarify whether this effect is influenced by memory processing. This study will be of interest to neuroscientists studying the hippocampus and memory.

eLife Assessment

In this important study, the authors employed state-of-the-art biochemistry, cryo-EM, and HDX mass spec approaches to study the formation of the binary Uba7-UBE2L6 and ternary UBA7-UBE2L6-ISG15 complexes. The results established mechanisms by which UBA7 and UBE2L6 form disulfide bonds, disrupting the ISG15 transfer cascade. While the biochemical and structural experiments are largely convincing, the mechanism under in vivo conditions remains unclear, due to the limited use of a single E2 enzyme. The authors need to repeat their experiments with a representative panel of human E2 enzymes.

eLife Assessment

In this important quantitative study of HIV-1 evolution in humans and rhesus macaques, selection coefficients are inferred at scale over the HIV genome. Selection coefficients are similar in humans and macaques, providing convincing evidence that these coefficients are representative of the fitness landscapes of these viruses within hosts. This work should be of interest to the community working on quantitative evolution and fitness landscape inference, and the finding that rapid fitness gains in the HIV population predict bNAb emergence has implications for HIV vaccine design.

eLife Assessment

The authors attempt to identify which patients with benign lesions will progress to cancer using a liquid biomarker. Although the study is valuable, the evidence provided for the liquid biopsy EV miRNA signature developed based on radiomics features is incomplete. This is because the data are derived from discrepant sample sets and the description of the clinical characteristics of the samples enrolled in the study needs to be improved.

eLife Assessment

This is a valuable study that explores the function of CCP5 in mouse ependymal cells. The methods, data, and analyses broadly support the claims. However, the study is incomplete as it stands. Minor weaknesses remain and the authors may wish to address them.

BANKSY offers a practical approach to spatial omics analysis by combining cell typing and tissue domain segmentation, which could aid researchers in mapping tissue organization and microenvironment interactions more efficiently. Its scalability for large datasets may streamline workflows in studies of development, disease, or tissue heterogeneity.

eLife Assessment

This study provides an important first look at the influence of vertical transmission in the establishment of the amphibian microbiome, with a specific focus on the potential role of parental care. Through a combination of cross-fostering experimental work, comparative analysis across species that show variable levels of care, and developmental time series, the authors provide convincing evidence that vertical transmission through care is possible, but incomplete evidence that it plays a significant role in shaping frog skin microbiomes in nature or across time. This work will be of interest to researchers studying the evolution of parental care and microbiomes in vertebrates.

eLife Assessment

The valuable findings in this study reveal an intricate pattern of memory expression following retrieval extinction at different intervals from retrieval-extinction to test. They document that immediately after extinction there is a nonselective impairment in memory, which leads to no impairment at a 6-hour interval. At a 24-hour interval, there is a selective impairment. The evidence supporting the claims is incomplete and there are inconsistencies in the analyses reported that obscure the interpretation.

eLife Assessment

This study provides a valuable structural analysis of the Sedoheptulose-1,7-Bisphosphatase (SBPase) from Chlamydomonas reinhardtii. The data presented are solid and based on X-ray structures of the CrSBPase in an oxidized and reduced state, the authors identify a disulfide bond in close proximity to the dimer interface. They show that the redox-state of the CrSBPase impacts its oligomeric state and might also influence the activity of the protein.

eLife Assessment

The study presents important findings on inositol-requiring enzyme (IRE1α) inhibition on diet-induced obesity (overnutrition) and insulin resistance where IRE1α inhibition enhances thermogenesis and reduces the metabolically active and M1-like macrophages in adipose tissue. The evidence supporting the conclusions is convincing. The work will be of interest to cell biologists and biochemists working in metabolism, insulin resistance and inflammation with a broad eLife readership.

eLife Assessment

This manuscript presents important findings on a bacterial effector involved in plant symbiotic signaling. The effector proteolytically targets a key receptor while its activity is counteracted by host-mediated phosphorylation, revealing a dynamic interplay that fine-tunes symbiotic interactions. The evidence supporting these claims is solid, and the findings have potential signaling implications beyond bacterial interactions with plants.

eLife Assessment

This study leverages an impressive and comprehensive longitudinal 16S rRNA gut microbiome dataset from baboons to provide important insight regarding the use of a microbiome-based clock to predict biological age. The evidence for age-associated microbiome features and environmental and social variables that impact microbiome aging is convincing. This study of microbiomes as markers of host age will fuel inquiries and studies and interest a broad range of researchers, especially those interested in alternatives to measuring biological aging.

eLife Assessment

This research is valuable as it investigates metabolic shuttling between photoreceptors and retinal pigment epithelium (RPE) using in vivo infusion techniques and mouse models. The authors find that the retina significantly relies on circulating glucose, with photoreceptors being the primary consumers of glucose, which is convincing. However, the study has incomplete evidence to support the claims that photoreceptors can use lactate as a fuel source, that lactate exported from photoreceptors is utilized by the RPE, and that lactate contributes to the TCA cycle in the RPE. These claims need substantial revision to include potential alternative explanations or perform key experiments.

eLife Assessment

This study presents an important contribution to the understanding of neural speech tracking, demonstrating how minimal background noise can enhance the neural tracking of the amplitude-onset envelope. The evidence, through a well-designed series of EEG experiments, is convincing. This work will be of interest to auditory scientists, particularly those investigating biological markers of speech processing.

eLife Assessment

Saijilafu et al. describe valuable findings suggesting that MLCK and MLCP bidirectionally regulate NMII phosphorylation ultimately impinging on axonal growth during regeneration in the central and peripheral nervous systems. Solid evidence is collected from culture and in vivo models, and through pharmacologic and genetic loss-of-function approaches. However, how MLCK and MLCP regulates NMII activity is not fully addressed or discussed. In sum, this knowledge is of potential interest for the field due to the relevance of identifying mechanistic details that regulate axonal regeneration

eLife Assessment

This useful study identifies new monoclonal antibodies produced by cystic fibrosis patients against the Pseudomonas aeruginosa type three secretion system. The evidence supporting the authors' claim is solid. However, in the current version of the manuscript, it is unclear what the benefits of the newly isolated antibodies are with respect to antibodies previously identified using a similar approach. The study will be of interest to those working on developing mAbs against Pseudomonas aeruginosa and also against other pathogens that harbor the T3SS.

eLife Assessment

In this valuable study, the authors show the physiological response and molecular pathway mediating the effect of quinofumelin, a developed fungicide with an unknown mechanism. The authors present convincing data suggesting the involvement of the uridine/uracil biosynthesis pathway, by combining in vivo microbiology characterization as well as in vitro biochemical binding results.

eLife Assessment

This valuable manuscript by Jia et al. investigates the role of cartilage intermediate layer protein (CILP) and moderate exercise in maintaining hyaline cartilage integrity following anterior cruciate ligament transection (ACLt) in rats. Solid data support the downregulation of CILP in human OA cartilage and its potential role in regulating Keap1/Nrf2 interaction and chondrocyte ferroptosis. However, the data supporting a role for CILP in exercise-mediated inhibition of hyaline cartilage fibrosis in early OA are incomplete.

eLife Assessment

This study describes a useful technique to improve imaging depth using confocal microscopy for imaging large, cleared samples. The work is supported by solid findings and will be of broad interest to many microscopical researchers in different fields who want a cost effective way to image deep into samples.

eLife Assessment

This important study reports a novel function of ATG14 in preventing pyroptosis and inflammation in oviduct cells, thus allowing smooth transport of the early embryo to the uterus and implantation. The data supporting the main conclusion are convincing. This work will be of interest to reproductive biologists and physicians practicing reproductive medicine.

eLife Assessment

This fundamental study provides a comprehensive analysis of the EmrE efflux pump and the role of the C-terminal domain in preventing uncoupled proton leak in the absence of substrate. The evidence supporting the conclusions is solid, although incomplete analyses limit some of the conclusions.

eLife Assessment

This valuable descriptive manuscript builds on prior research showing that the elimination of Origin Recognition Complex (ORC) subunits does not halt DNA replication. The authors obtain solid data using various methods to genetically remove one or two ORC subunits from specific tissues and still observe replication. The replication appears to be primarily endoreduplication, indicating that ORC-independent replication may promote genome reduplication without mitosis. The mechanism behind this ORC-independent replication remains to be elucidated. The study and mutants described herein lay the groundwork for future research to explore how cells compensate for the absence of ORC and to develop functional approaches to investigate this process. The reviewers suggested the observations could be supported by additional experiments. This work will be of interest to those studying genome duplication and replication.

eLife Assessment

This valuable study reports the critical role of two cyclin-dependent kinases, CDK8 and CDK19, in spermatogenesis. The data presented are generally supportive of the main conclusion and are considered solid. This work may be of interest to reproductive biologists and physicians working on male fertility.

eLife Assessment

This manuscript presents a detailed characterization of male and female wildtype and Ctrp10 knockout mice, and reveals that knockout mice develop female-specific obesity that is largely uncoupled from metabolic dysfunction. The data are convincing, and the work will be an important contribution to understanding how obesity is coupled to metabolic dysfunction, and how this can occur in a sex-specific manner.

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 supports 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 is an important study that describes the development of optical biosensors for various Rab GTPases and explores the contributions of Rab10 and Rab4 to structural and functional plasticity at hippocampal synapses during glutamate uncaging. The evidence supporting the conclusions of the paper is solid, and several improvements were noted by the reviewers upon revision, although some persisting inconsistencies would benefit from further clarification.

eLife Assessment

This study presents important findings on the role of pyramidal cells driving vasoconstriction in brain arteries through a COX-2/PGE2 pathway, with additional contributions from NPY (interneurons) and 20-HETE (astrocytes). Optogenetic stimulation of cortical pyramidal neurons induces vasoconstriction, potentially leading to oxygen and nutrient undersupply in regions with sustained activation - a mechanism potentially relevant under pathological conditions. The authors provide convincing evidence from brain slice experiments and some in vivo data from anesthetized animals, carefully discussing the strengths and limitations of both approaches.

eLife Assessment

This study presents a useful demonstration that a specific protein fragment may induce the loss of synapses in Alzheimer's disease. The evidence supporting the data is solid but only partially supports the conclusion and would benefit from additional discussion indicated by the literature from reviewer #1. The application of the findings is limited because blocking the formation of the protein fragment has not benefited patients in several clinical trials.

eLife Assessment

NAD deficiency perturbs embryonic development resulting in multiple congenital malformations, collectively termed Congenital NAD Deficiency Disorder (CNDD). The authors report fundamental findings demonstrating that extra-embryonic visceral yolk sac endoderm is critical for NAD de novo synthesis during early organogenesis and perturbations of this pathway may underlie CNDD. The authors combine gene expression with metabolic assays to provide solid evidence of an essential role of the extra-embryonic visceral yolk sac in both mouse and human embryos.

eLife Assessment

This manuscript addresses the role of alpha oscillations in sensory gain control. The authors use an attention-cuing task in an initial EEG study followed by a separate MEG replication study to demonstrate that whilst (occipital) alpha oscillations are increased when anticipating an auditory target, so is visual responsiveness as assessed with frequency tagging. The authors propose their results demonstrate a general vigilance effect on sensory processing and offer a re-interpretation of the inhibitory role of the alpha rhythm. While these results are valuable, the provided evidence is incomplete.

eLife Assessment

This study presents a valuable finding on the importance of the plasma metabolome in glaucoma risk prediction. The authors have used the UK Biobank data to interrogate the association between plasma metabolites and glaucoma. The evidence supporting the claims of the authors is solid and the work offers insights into the design of protective therapeutic strategies for glaucoma.

eLife Assessment

This important study examines the neuronal mechanisms underlying visual perception of integrated face and body cues. The innovative paradigm, which employs monkey avatars in combination with electrophysiological recordings from fMRI-defined brain areas, is a compelling approach. These results should be of wide interest to system and cognitive neuroscientists, psychologists, and behavioural biologists working on visual and social cognition.

eLife Assessment

This study presents SegPore, a valuable new method for processing direct RNA nanopore sequencing data, which improves the segmentation of raw signals into individual bases and boosts the accuracy of modified base detection. The evidence presented to benchmark SegPore is solid and the authors provide a fully documented implementation of the method. If updated to process newer RNA nanopore sequencing data types, SegPore will be of great interest to researchers studying RNA modifications.

eLife Assessment

The study is a valuable contribution to the question of evolutionary shifts in neuronal proliferation patterns and the timing of developmental progressions. The authors present convincing data which confirm the presence of type-II NB lineages in beetle with the same molecular characteristics as the Drosophila counterparts but differing in lineage size and number. The data lay the foundation for future analysis of the role and molecular characteristics of individual lineages and of whether differences in the identity, proliferation pattern and timing of developmental progression can be linked to differences in the development of functionality of the central complex.

eLife Assessment

This important study employs an optogenetics approach aimed at activating oncogene (KRASG12V) expression in a single somatic cell, with a focus on following the progression of activated cell to examine tumourigenesis probabilities under altered tissue environments. Although the description of the methodologies applied is incomplete, the authors propose a mechanism whereby reactivation of re-programming factors correlates with the increased likelihood of a mutant cell undergoing malignant transformation. This work will be of interest to developmental and cancer biologists, especially in relation to the genetic tools described.

eLife Assessment

This study makes the important finding that pleiotropy is positively associated with parallelism of evolutionary responses in gene expression. This finding, if true, runs counter to current expectations in the field. The analysis uses state-of-the art experimental evolution approach to study the genetic basis of adaptation of Drosophila simulans to a hot environment. Although the experimental results are convincing, the theoretical model is incomplete, due to several unusual assumptions. It remains to be seen whether the main conclusion can be replicated in other contexts.

eLife Assessment

This study provides important findings that during credit assignment, the lateral orbitofrontal cortex (lOFC) and hippocampus (HC) encode causal choice representations, while the frontopolar cortex (FPl) mediates HC -lOFC interactions when the causality needs to be maintained over longer distractions. This research offers compelling evidence and employs sophisticated multivariate pattern analysis. However, while the task design captures the delayed component, it lacks the full complexity and ambiguity of the credit assignment process observed in real-world scenarios. Moreover, the data indicated that other frontal regions beyond just lOFC were involved in delayed credit assignment. This work will be of interest to cognitive and computational neuroscientists who work on value-based decision-making and fronto-hippocampal circuits.

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. Although the authors have addressed some concerns, uncertainties regarding the PA28g-C1QBP direct interaction still exist. The overall findings of the manuscript are useful, but the validation evidence is incomplete.

eLife Assessment

This valuable study leverages innovative high-dimensional imaging strategies to interrogate pancreatic immune cell profiles and distributions throughout stages of type 1 diabetes (T1D). Despite a notable limitation in the number of donor samples analyzed, the authors identify a series of intriguing "immune signatures" and histopathological features that collectively constitute a solid foundation for future investigations into immunological processes underpinning the pathogenesis of T1D. Accordingly, the work will be of considerable interest to the community of T1D researchers and clinicians.

eLife Assessment

The authors demonstrate the valuable discovery that human CD29+/CD56+ myogenic progenitors can differentiate into tendon through the TGFβ pathway, addressing mouse and human interspecies differences in regard to the potential of muscle stem cells. The in vivo transplantation experiments provide convincing evidence for the conclusion, as human CD29+/CD56+ myogenic progenitors contribute to tendon regeneration, resulting in functional recovery in mouse model. The authors' approach can be used for the development of cell therapy for tendon-injured patients.

eLife Assessment

This study presents a useful theoretical model of molecular evolution of multi-copy gene systems by extending the classic Haldane model and applies the model to explain the surprisingly rapid evolution of rRNA genes. Although the conceptual model is intuitive and provides a new perspective for contextualizing this problem, the model presented does not adequately consider plausible biological constraints on the molecular and genetic processes. The lack of such constraints in the model, along with technical issues in the data analysis, provide incomplete support for the conclusion that the genetic variation patterns of rRNA genes in mouse is compatible with neutral evolution.

eLife Assessment

This study presents a useful model of genetic drift by incorporating variance in reproductive success, aiming to address several apparent paradoxes in molecular evolution. However, some of the apparent paradoxes only arise in the most basic version of standard models and have been reconciled in more advanced models. Nonetheless, this paper offers intuitive explanations for these apparent paradoxes, by adopting a new perspective and solid modeling and analysis. More broadly, the proposed model provides an alternative framework to address puzzling observations in molecular evolution, which will be of interest to evolutionary and population geneticists.

eLife Assessment

This important study presents a method to visualize the location of the cell types discovered through single-cell RNA sequencing. The data allowed the authors to build spatial tissue atlases of the fly head and body, and to identify the location of previously unknown cell types. The data are convincing and appropriate, and the authors validate the methodology in line with the current state-of-the-art.

eLife Assessment

In this valuable study, Seidel et al. identify and characterize a novel subset of hepatocellular carcinoma patient-derived xenograft models defined by active Jagged 1-Notch2 signaling and a distinctive progenitor-like gene expression profile. Within the limitations of the PDX system they used, their methods are state-of-the-art, their data are strong and believable, and their conclusions are convincing. However, the ability to identify HCC patients that might respond is limited, and the mechanistic assessment downstream of JAG1/NOTCH2 is relatively descriptive. Some additional clarifications and experiments would strengthen the paper.

eLife Assessment

The manuscript contains important findings regarding inflammatory macrophage subsets that have theoretical and/or practical applications beyond the field of rheumatology. The authors demonstrate with convincing evidence the effects of PGE2 on TNF signaling in a well-written manuscript that features methods, data, and analyses in line with current state-of-the-art technologies. This work will be of broad interest to immunologists and cell biologists.

eLife Assessment

This important study presents novel data on variation in sperm whale communication, contributing to a richer understanding of the social transmission of vocal styles across neighbouring clans. The evidence is solid but could have been further improved with clarification of the specialized metrics and terminology used, particularly for comparisons to other taxa. This research will be of interest for bioacoustics and animal communication specialists, particularly those working on social learning and culture.

eLife Assessment

This fundamental study highlights potential mechanisms underlying the sex-dependent bias in susceptibility to gut colonization by Methicillin-resistant Staphylococcus aureus (MRSA). The evidence supporting the conclusion is compelling. The work will interest biologists who study intestinal infection and immunity.

eLife Assessment

This important study identifies one way in which episodic heat exposure can result in negative changes in motivated and affective behaviors. This work positively expands the field of thermoregulation. The data were collected using a myriad of next-generation approaches, including extensive behavior testing, thermal monitoring, electrophysiology, circuit mapping, and manipulations. There is convincing evidence that neurons of the paraventricular thalamus change plastically over three weeks of episodic heat stimulation this affects behavioral outputs such as social interactions and anxiety-related behavior. Conclusions regarding the specificity of the POA-pPVT pathway compared to other inputs to the PVT in the control of observed effects would benefit from further validation. The study will be of interest to behavioral neuroscientists, climate/environmental biologists, and pre-clinical neuropsychiatrists.

eLife Assessment

The results from this study, which investigates the mechanisms necessary for initiating tissue invagination using a cellular Potts modelling approach, suggest that apical constriction is not sufficient to drive the process by itself. The study highlights how choices inherent to modelling - such as permitting straight or curved cell edges - may affect the outcome of simulations and, consequently, their biophysical interpretation. Despite incomplete evidence supporting their major claims due to a rather coarse-grained exploration of the model, this work is useful for biophysicists investigating complex tissue deformation through computational frameworks.

eLife Assessment

This important study combines single nucleus transcriptional profiling with spatial transcriptomics to identify and map heterogeneity among dopamine neurons in the mouse ventral midbrain. The compelling results separate dopamine neurons into three broad families that have unique (yet overlapping) spatial distribution within the ventral tegmental area and substantia nigra, and also identify population-specific changes in a LRRK2 mouse model of Parkinson's Disease. The creation of a public-facing app where the snRNA-seq data can be investigated by anyone is a major strength.

eLife Assessment

This important and unique study proposes a framework to understand and predict generalization in visual perceptual learning in humans based on form invariants. Using behavioral experiments in humans and by training deep networks, the authors offer evidence that the presence of stable invariants in a task leads to faster learning. However, this interpretation is promising but counter-intuitive and incomplete, since there could be possible other confounds such as differing attentional demands that lead to differing patterns of generalization. It can be strengthened through additional experiments and by rejecting alternate explanations.

eLife Assessment

This is a valuable paper that might contribute new insight into the role of GABA in semantic memory, which is a significant question in higher cognition. However, the empirical support for the main claims is incomplete. These results, once further strengthened and more appropriately discussed, will be of interest to broad readers of the neuroscience and cognitive neuroscience community.

eLife Assessment

This valuable study investigates the immune system's role in pre-eclampsia. The authors map the immune cell landscape of the human placenta and find an increase in macrophages and Th17 cells in patients with pre-eclampsia. Following mouse studies, the authors suggest that the IGF1-IGF1R pathway might play a role in how macrophages influence T cells, potentially driving the pathology of pre-eclampsia. There is convincing evidence in this study that will be of interest to immunologists and developmental biologists.

eLife Assessment

This study makes the important claims that people track, specifically, the elasticity of control (rather than the more general parameter of controllability) and that control elasticity is specifically impaired in certain types of psychopathology. These claims will have implications for the fields of computational psychiatry and computational cognitive neuroscience. However the evidence for the claim that people infer control elasticity is incomplete, given that it is not clear that the task allows the elasticity construct to be distinguished from more general learning processes, the chosen models aren't well justified, and it is unclear that the findings generalize to tasks that aren't biased to find overestimates of elasticity. Moreover, the claim about psychopathology relies on an invalid interpretation of CCA; a more straightforward analysis of the correlation between the model parameters and the psychopathology measures would provide stronger evidence.

eLife Assessment

This valuable retrospective analysis identified three independent components of glucose dynamics - "value," "variability," and "autocorrelation" - which may be used in predicting coronary plaque vulnerability. The study is solid and of interest to a wide range of investigators in the medical field who are interested in the role of glycemia on cardiometabolic health. However, the generalizability of the results needs further confirmation through experimental and prospective validation.

eLife Assessment

The authors have demonstrated the use of adenine base editors delivered via adeno-associated viruses to introduce edits in the mitochondrial genome. The manuscript describes the methodology well, and the conclusions are convincingly supported by the results. The valuable results highlight the potential of these base editors to model mtDNA variations in somatic tissues in animal models.

eLife Assessment

Shah and colleagues take advantage of the presence of maternal and somatic ribosomes in zebrafish and confirm their differential expression during development. The authors convincingly show that ribosomes previously found expressed during oogenesis are also expressed in primordial germ cells and that hybrid maternal and somatic ribosomes are formed during development. The question of ribosome heterogeneity, the expression and function of maternal versus somatically provided ribosomes are of broad interest and this fundamental work sets new directions for future functional studies of this interesting phenomenon.

eLife Assessment

The manuscript presents a useful analysis of the relationship between climate variables and malaria incidence, for local temperature and rainfall and the global climate driver of ENSO from 2008 to 2019 in a lowland region of East Africa, with wavelet analyses and linear regressions after time series decomposition. The paper is convincing albeit not novel in its application of wavelets to the analysis of this type of time series data for a vector-borne infection. It is less persuasive on what is learned about the role of climate variability (non-seasonal climate effects), and it is also unclear how the analysis informs climate change and malaria, and this motivation for the work is not warranted as it pertains to longer time scales than those considered. The work should be better placed in the context of what is known for malaria in East Africa and in different transmission settings.

eLife Assessment

This work derives a valuable general theory unifying theories of efficient information transmission in the brain with population homeostasis. The general theory provides an explanation for firing rate homeostasis at the level of neural clusters with firing rate heterogeneity within clusters. Applying this theory to the primary visual cortex, the authors present solid evidence that accounts for stimulus-specific and neuron-specific adaptation.

eLife Assessment

This fundamental study provides compelling evidence that TRPV4 plays a crucial role in mechanical sensing during cancer cell transition from non-invasive to invasive states, and offers novel insights into metastasis. By employing multiple experimental approaches, including pharmacological and genetic manipulation, as well as advanced imaging techniques, the authors demonstrate a strong correlation between TRPV4 dynamics, calcium homeostasis, and cell volume plasticity. The findings significantly enhance our understanding of mechanotransduction in cancer and present TRPV4 as a promising therapeutic target for inhibiting metastasis.

eLife Assessment

This important study explores the interplay between gene dosage and gene mutations in the evolution of antibiotic resistance. The authors provide compelling evidence connecting proteostasis with gene duplication during experimental evolution in a model system. This paper is likely to be of interest to researchers studying antibiotic resistance, proteostasis, and bacterial evolution.

eLife Assessment

This is an important study with solid evidence that multi-voxel fMRI activity patterns for threat-conditioned stimuli are altered by learning CS-US contingencies. The analyses are dense but mostly rigorous. The protocol is quite nuanced and complex, but the authors have done a fair job of explaining and presenting the results, and the results could be further improved by adjustment for multiple comparisons. The readability could be improved for an audience without highly-specialised knowledge of the field and the fMRI analytical approach.

eLife assessment

The study presents a useful computational analysis of how the ratio between excitatory and inhibitory neural numbers affects coding capacity. The authors show that increasing the proportion of inhibitory neurons (as observed in upper cortical layers compared to the input recipient layer 4) increases the dimensionality of neural activity and improves the encoding of time-varying stimuli. However, the evidence about the role of the inhibitory population in coding is incomplete because numerical results are neither supported by analytical mathematical results nor include controls for changes in firing thresholds or subtypes of inhibitory neurons.

eLife Assessment

This study presents a useful pipeline for de novo design of antimicrobial peptides active both against bacteria and viruses. The method is based on deep learning, using a GAN generator and a regression tasked to predict antimicrobial activity. The experimental evidence supporting the conclusions is solid, with 24 validated peptides, although some additional justifications of the computational strategy would be a plus. This work will be of interest to the community working on machine learning for biomedical applications and specifically on antimicrobial peptides.

eLife Assessment

This study is important, and the findings add substantially to the evidence base regarding CCR5 antagonist drugs for neuroprotection and stroke management. The authors adhered to the expected systematic review and meta-analysis standards, and the presented evidence is convincing.

eLife Assessment

This manuscript provides valuable mechanistic insight into NSCLC progression, both in terms of tumour metastasis and the development of chemoresistance. The authors draw upon a range of techniques and assays and the evidence shown is solid and has been strengthened by incorporation of suggestions by the two reviewers. The work presented will be of interest to cancer biologists and more broadly to those interested in NSCLC translational studies.

eLife Assessment

This valuable study addresses a central question in systems neuroscience (validation of active inference models of exploration) using a combination of behaviour, neuroimaging, and modelling. The data provided offers solid evidence that humans do perceive, choose and learn in a manner consistent with the essential ingredients of active inference, and that quantities that correlate with relevant parameters of this active inference scheme are encoded in different regions of the brain.

eLife Assessment

In this important study, Li and others identified cell membrane receptors for juvenile hormone (JH), a terpenoid hormone in insects that regulates their development and reproduction. While intracellular receptors for JH are well characterized, membrane receptors for JH have remained elusive for many years. The authors provide convincing evidence indicating that two receptor tyrosine kinases (RTKs), CAD96CA and FGFR1, modulate the genomic effects of JH by phosphorylating the intracellular receptors in the cotton bollworm, Helicoverpa armigera. Although differential functions of the two RTKs and potential effects of the other endogenous ligands of these RTKs on JH signaling remain unclear, this study lays a foundation for future studies.

eLife Assessment

In this valuable study, Li and others identified cell membrane receptors for juvenile hormone (JH), a terpenoid hormone in insects important for their development and reproduction. While intracellular receptors for JH have been well characterized, membrane receptors for JH remained elusive for many years. Although the authors provide solid evidence to indicate that the receptor tyrosine kinases they identified bind to JH in vitro and induce non-genomic responses in cultured cells, their loss-of-function phenotypes are not consistent with known JH functions, so additional work is required to define physiological roles of these receptors.

eLife Assessment

This is a fundamental body of work reporting anatomical, molecular, and functional mapping of the central complex in Drosophila. There were a few concerns of a minor nature, and all were addressed by the authors. The tools generated and the findings, which include characterization of neuromodulators used by different cells, will undoubtedly serve as a foundation for future studies of this brain region. The data are compelling and likely to have a major impact.

> for - addiction model - Marc Lewis - addiction diagram

> summary - Marc gives a good summary of everything - prefrontal cortex in control of judgment - striatum in charge of - attraction - desire - craving - midbrain - dopamine system - dopamine goes to the striatum and sets up localized feedback cycle so crave more - then the striatum becomes hyperactivated in the presence of cues - then you get that mechanism of now appeal - that narrowing of attraction to the immediate reward and - the loss of everything else - the other stuff falls off the radar - then the connection between - the prefrontal cortex and - the striatum starts to become compromised - resulting in ego fatigue - The prefrontal cortex simply becomes less effective at control

eLife Assessment

This important study challenges conventional life-history theory by demonstrating that reproductive-survival trade-offs are minimal in birds, except when reproductive effort is experimentally exaggerated. The evidence is solid, drawing from a meta-analysis of over 30 bird species, and effectively separates the effects of individual quality from reproductive costs. The findings will be of broad interest to evolutionary biologists and ecologists studying life-history trade-offs and reproductive strategies.

eLife Assessment

This important study presents a transcriptomic analysis of enterochromaffin cells in the intestine. The evidence supporting the authors' claims is solid, although the functional analysis is focused on the Piezo2-expressing subset in the colon. The work will be of interest to biologists working on intestinal mucosal biology.

eLife Assessment

This study combines mathematical models and experimental data to analyse the emergence of heterogeneity within clonal NK cell responses during antigen-specific cell expansion. Although it comprises different experimental data and tests different theoretical hypotheses, the main claims remain incomplete and would benefit from the consideration of several previous findings about clonal immune responses and corresponding mathematical approaches. The study presents valuable findings with the potential to provide key insights about NK cell development if proposed claims could be confirmed by additional analyses.

eLife Assessment

The study by Ma et al. provides fundamental findings and compelling evidence that Pyrotinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (PERSIST): A multicenter phase II trial. The findings enhance the understanding of HER2-positive breast cancer. The claims are fully supported by the types of experiments that were performed.

eLife Assessment

Through cellular, developmental, and physiological analysis, this valuable study identifies a gene that regulates the relative growth of roots and shoots under salt stress. The holistic approach taken provides convincing evidence that this member of a larger tandemly duplicated gene family together with an upstream regulator contributes to salt tolerance. The manuscript will be of interest to plant biologists studying mechanisms of abiotic stress tolerance and gene family evolution.

eLife Assessment

The study conducted by Fang et al. offers significant and fundamental insights, notably enhancing our understanding of angiogenesis. While some of the claims are supported by convincing experimental approaches, others lack sufficient validation. Additionally, there are instances where critical experimental controls appear to be absent.

eLife Assessment

This important study is an advancement towards the understanding of animal nervous system organization and evolution by providing an exceptional, high-quality and detailed description of the entire connectome of the 3-day larva of the marine annelid Platynereis dumerilii. It provides a wealth of data on cell type diversity and the modules that interconnect them. Its strength is the massive amount of high-quality data, although this is also partly a weakness as it can make the work difficult to read and digest scientifically. This work lays the foundations for studies on cell type diversity, segmental vs. intersegmental connectivity, and mushroom bodies, but will certainly also be of use to scientists interested in other nervous systems parts, their functions, and evolution.

eLife Assessment

This study presents an important methodological advance to improve the sensitivity of PCR for detecting Trypanosoma cruzi in blood, combining DNA fragmentation, deep sampling, and blood cell pellet analysis. The findings offer solid evidence of enhanced detection sensitivity and shed light on parasite load dynamics during chronic infection in mammalian reservoirs. The evidence is sound for macaques and the method shows promise in expanding detection limits, but there is some variability in the limits of detection and small sample size of human samples. This work will be of interest to parasitologists, epidemiologists, and clinicians using molecular diagnostics to monitor responses to etiological treatments for Chagas disease.

eLife Assessment

This important study suggests that the composition of the extracellular matrix in a mouse model of liver fibrosis changes depending on the cause of liver fibrosis. The data could be used as a foundation for future antifibrotic therapies. The strength of evidence is convincing with respect to the use of animal models and proteomic analysis. The study provides a helpful inventory of proteins up or down-regulated.

eLife Assessment

This valuable study suggests that capsaicin nanoparticle administration in rats activates the transcription factor Nrf2 by directly binding to its repressor, KEAP1, leading to the induction of cytoprotective genes and preventing alcohol-induced gastric damage, offering a potential avenue for treating alcoholism-related gastric disorders. Although improvements were made following the first revision, the evidence supporting capsaicin as an Nrf2 activator remains incomplete, as some methodological aspects still require revision and the interpretation of key data needs further clarification.

eLife Assessment

This fundamental study reports the effects of the psychedelic drug psilocin on iPSC-derived human cortical neurons, analyzing different aspects of structural and functional neuronal plasticity. The evidence is convincing, integrating a comprehensive characterization of 5-HT2A expression and its subcellular distribution upon treatment with psilocin at different time points. The study supports the value of using iPSC-derived human cortical neurons for testing the potentially translational effects of psilocin and other psychedelic-related compounds.

eLife Assessment

The authors aimed to quantify feral pig interactions in eastern Australia to inform disease transmission networks. They used GPS tracking data from 146 feral pigs across multiple locations to construct proximity-based social networks and analyze contact rates within and between pig social units. This fundamental study shows that targeting adult males in feral pig control programs could help global efforts to contain disease. The methods are compelling and the paper should be of interest to the fields of veterinary medicine, public health, and epidemiology.

eLife Assessment

This is an important study demonstrating that anosmia in Parkinson's disease patients is due to dysfunction in cholinergic neurons. This study provides compelling evidence, using scRNA sequencing, that cholinergic olfactory projection neurons (OPN) are consistently affected in five different fruit fly models of Parkinson's disease, exhibiting synaptic dysfunction before the onset of motor deficits. Comparisons with scRNA sequencing of patients' human brain samples reveals similar synaptic gene deregulation in cholinergic neurons of patients. This study points the possibility that targeting cholinergic neurons could be a potential avenue for early diagnosis and intervention in PD.

eLife Assessment

This study provides important findings on the nature of eye movement choices by human subjects. The study uses a novel approach and provides relatively clear and convincing results of the relationship between pupil size and saccade production. The results should be of interest to a broad audience interested in sensorimotor integration and sensory-guided decision-making.

eLife Assessment

This manuscript presents valuable findings showing that rapamycin directly activates the cool-sensing ion channel, TRPM8, acting through a different binding site than other small-molecule cooling agents such as menthol. The use of Ca2+-imaging, electrophysiology, and computational biology provides solid evidence to support the finding. The authors also present a novel NMR-based method to help identify details of the binding site interactions. In this revised version, some analysis and the presentation have been corrected and improved. Their findings provide insights into TRP channel pharmacology and may indicate previously unknown physiological effects or therapeutic mechanisms of the immunosuppressant, rapamycin.

eLife Assessment

This important study by Liu et al. presents a comprehensive structure-function analysis of the presynaptic protein UNC-13, leading to new insights into how its distinct domains control neurotransmitter release. The methods, data, and analyses are convincing, and the genetic and electrophysiological approaches support many of their conclusions. The work will be of interest to neuroscientists studying synaptic transmission, as it provides a foundation for future mechanistic studies of Munc13/UNC-13 family proteins.

eLife Assessment

This important study uses advanced computational methods to elucidate how environmental dielectric properties influence the interaction strengths of tyrosine and phenylalanine in biomolecular condensates. The evidence supporting the claims of the authors is solid, as the simulations are performed rigorously providing mechanistic insights into the origin of the differences between the two aromatic amino acids considered. This study will be of broad interest to researchers studying biomolecular phase separation.

eLife Assessment

This study presents important methodologies for repeated brain ultrasound localization microscopy (ULM) in awake mice and a set of results indicating that wakefulness reduces vascularity and blood flow velocity. The data supporting these findings are solid. This study is relevant for scientists investigating vascular physiology in the brain.

eLife Assessment

This valuable paper explores the idea that transient modulations of neural gain promote switches between distinct perceptual interpretations of ambiguous stimuli. The authors provide solid evidence for this idea by pupillometry (an indirect proxy of neuromodulatory activity), fMRI, neural network modeling, and dynamical systems analyses. The highly integrative nature of this approach is rare in the field.

eLife Assessment

This useful study aimed to examine the relationship of spatial frequency selectivity of single macaque inferotemporal (IT) neurons to category selectivity. Interesting findings in this report suggest a shift in preferred spatial frequency during the response, from low to high spatial frequencies. This agrees with a coarse-to-fine processing strategy, which is in line with multiple studies in the early visual cortex. Some of the findings were difficult to evaluate because the methods are incomplete. The conclusion that single-unit spatial frequency selectivity can predict object coding requires further evidence to confirm.

eLife Assessment

This important study identifies species- and sex-specific neuronal cell types and gene expression in the preoptic area (POA) to help understand the evolutionary divergence of social behaviors. The evidence from single-nucleus RNA sequencing and immunostaining is compelling and suggests that cellular differences in the POA may contribute to behavioral variations such as mating and parental care that are apparent in two closely related deer mouse species. These rich observations provide an entry point for future hypothesis-driven experiments to demonstrate a causal role for these populations in sex- or species-variable behaviors in vertebrates. These data will be a resource that is of value to behavioral neuroscientists.

eLife Assessment

This is a valuable study, tackling the long-standing issue of the difficulty in imaging the inferior olive and addressing the most relevant questions with a rigorous approach. The technological advance allowed the authors to generate solid experimental evidence with high-quality data. The results are presented clearly and the analyses are rigorous.