eLife assessment

This paper marks a fundamental advance in our understanding of prokaryotic Type IV restriction systems. The authors provide an encyclopedic overview of a hitherto uncharacterized branch of these systems, which they name CoCoNuTs, for coiled-coil nuclease tandems. They provide compelling evidence that these nucleases target RNA and are part of an echeloned defense response following viral infection. This article will be of great interest to scientists studying prokaryotic immunity mechanisms, as well as broadly to protein scientists engaged in the analysis, classification, and functional annotation of the proteome of life.

eLife assessment

This study presents a useful tool for predicting TCR specificity with compelling evidence for improvements over prior art. This work/tool will be broadly relevant to computational biologists and immunologists.

eLife assessment

This important study conducts genetic analyses utilizing zebrafish, mouse, and mouse embryonic stem cell models to elucidate the role of Rtf1, a component of the PAF1 complex, in early cardiac development. By combining marker gene expression analysis, single-cell transcriptomics, ChIP-seq, and chemical inhibition, the study provides convincing evidence that Rtf1-mediated RNAPII (Pol2) transcriptional pausing is required for early cardiac development and that attenuation of pause release by pharmacological inhibition of Cdk9, a component of the PTEF-b complex that regulates the transition between the pausing and elongation phases of transcription, can partially restore transcriptional pausing and cardiogenesis in zebrafish rtf1 mutants. The work will be of broad interest to developmental biologists.

eLife assessment

The current manuscript re-examines an established claim in the literature that human PANX-1 is regulated by Src kinase phosphorylation at two tyrosine residues, Y199 and Y309. This issue is important for our understanding of Pannexin channel regulation. The authors present an extensive series of experiments that fail to detect PANX-1 phosphorylation at these sites. Although the authors' approach is more rigorous than the previous studies, this work relies primarily on negative results that are not unambiguously definitive; the work nonetheless provides a compelling reason for the field to reexamine conclusions drawn in earlier studies.

eLife assessment

This valuable study describes the molecular mechanism of daptomycin insertion into bacterial membranes. The authors provide solid in vitro evidence for the early events of daptomycin interaction with phospholipid headgroups and stronger, specific interaction with phosphatidylglycerol. This work will be of interest to bacterial membrane biologists and biochemists working in the antimicrobial resistance field.

eLife assessment

The manuscript constitutes an important contribution to antimalarial drug discovery, employing diverse systems biology methodologies; with a focus on an improved M1 metalloprotease inhibitor, the study provides convincing evidence of the utility of chemoproteomics in elucidating the preferential targeting of PfA-M1. Additionally, metabolomic analysis effectively documents specific alterations in the final steps of hemoglobin breakdown. These findings underscore the potential of the developed methodology, not only in understanding PfA-M1 targeting but also in its broader applicability to diverse malarial proteins or pathways. Revisions are needed to further enhance overall clarity and detail the scope of these implications.

eLife assessment

This manuscript describes structures of HER4 homo- and HER4/HER2 hetero-dimer complexes using single particle cryo-EM. This important work describes convincingly new structural details of these complexes that expand our understanding of their function. This work will be of interest to researchers working on cell surface signalling and kinase activity.

eLife assessment

This interesting and important work shows that diacety, a volatile organic compound released by yeast in fermenting fruit, can act as a histone deacetylase (HDAC) inhibitor and trigger wide changes in gene expression, together with suppression neurotoxicity in a Drosophila model of Huntington's disease. While the effects on gene expression changes and degenerative phenotypes are convincingly shown, further studies are required to determine whether and how olfactory sensory neurons and odorant receptors mediate the effects of diacetyl described by the authors.

eLife assessment

This study presents a useful method for the extraction of behaviour-related activity from neural population recordings based on a specific deep learning architecture - a variational autoencoder. However, the evidence supporting the scientific claims resulting from the application of this method is incomplete as the results may stem, in part, from its properties. The main limitations are: (1) benchmarking against comparable methods is limited; and (2) some observations may be a byproduct of their method, and may not constitute new scientific observations.

eLife assessment

The study makes a valuable empirical contribution to our understanding of visual processing in primates and deep neural networks, with a specific focus on the concept of factorization. The analyses provide solid evidence that high factorization scores are correlated with neural predictivity, yet more evidence would be needed to show that neural responses show factorization. Consequently, while several aspects require further clarification, in its current form this work is interesting to systems neuroscientists studying vision and could inspire further research that ultimately may lead to better models of or a better understanding of the brain.

eLife assessment

This paper provides valuable insights into the neural substrates of human working memory. Through clever experimental design and rigorous analyses, the paper provides compelling evidence that the working memory representation of stimulus orientation is a reformatted version of the presented stimulus, reflecting the content that is of importance to the task. This work will be of broad interest to cognitive neuroscientists working on the neural bases of visual perception and memory.

eLife assessment

Based on analyses of retinae from genetically modified mice, and from wild-type ground squirrel and macaque employing microscopic imaging, electrophysiology, and pharmacological manipulations, this useful study on the role of Cav1.4 calcium channels in cone photoreceptor cells (i) shows that the expression of a Cav1.4 variant lacking calcium conductivity supports the development of cone synapses beyond what is observed in the complete absence of Cav1.4, and (ii) indicates that the cone pathway can partially operate even without calcium flux through Cav1.4 channels, thus preserving behavioral responses under bright light. The evidence for the function of Cav1.4 protein in synapse development is convincing, and in agreement with a closely related earlier study by the same authors on rod photoreceptors, but the evidential support for the notion of a homeostatic compensation of Cav1.4 loss by Cav3 is incomplete. As congenital Cav1.4 dysfunction can cause stationary night blindness, this work relates to a wide range of neuroscience topics, from synapse biology to neuro-ophthalmology.

eLife assessment

This paper provides a valuable method that uses a computational model to predict photoreceptor currents in mammalian photoreceptors. By inverting the model, visual stimuli can be constructed to produce desired photoreceptor current responses. The authors provide convincing evidence that this approach can disentangle the effects of photoreceptor nonlinearities including light adaptation from downstream nonlinear processing, thus facilitating future studies of the higher visual system.

eLife assessment

In this important work, authors show that brain activity thought to be a travelling wave may just be a series of sequentially activated sources at the neuron spiking level. They support this with convincing results from a turtle cortex preparation and relevant simulations. This work will be of interest to neuroscientists interested in understanding how cortical computations are made.

eLife assessment

This fundamental study advances our understanding of nitrogen metabolism by identifying a new type of guanidine-forming enzyme in eukaryotes. The key claims of the article are convincingly supported by the data, with meticulous biochemical, cellular, and in vivo studies on guanidine production. The work will stimulate interest in the cellular roles of homoarginine, and, more generally, in the biochemistry and metabolism of guanidine derivatives.

eLife assessment

This study presents a valuable finding on a new role of Foxp3+ regulatory T cells in sensory perception, which may have an impact on our understanding of somatosensory perception. The authors identified a previously unappreciated action of enkephalins released by immune cells in the resolution of pain and several upstream signals that can regulate the expression of the proenkephalin gene PENK in Foxp3+ Tregs. However, whereas the generation of transgenic mice with conditional deletion of PENK in Foxp3+ cells and PENK fate-mapping is novel and generates compelling data, they show an incomplete analysis of Tregs in the control and transgenic mice, proper tamoxifen controls nor the role of PENK+ skin T cells to further support their hypothesis. Nonetheless, the study would be of interest to the biologists working in the field of neuroimmunology and inflammation.

eLife assessment

In this important study, Lui and colleagues examine whether the locus coeruleus is involved in extinction of an appetitive conditioned response. Using a set of optogenetic approaches aimed at manipulating the activity of locus coeruleus cells, the authors provide solid evidence that these neurons regulate the extinction of conditioned responses. Overall this study further highlights the key role of noradrenaline in cognitive processes and will be of interest to those interested in associative learning, extinction, noradrenaline, associated brain systems and translational endpoints.

eLife assessment

The current manuscript presents a cryo-EM structure of a tripartite ATP-independent periplasmic (TRAP) transporter that contributes to Haemophilus influenzae virulence. Convincing biophysical and cryo-EM experiments yield a valuable molecular model, but the functional importance of some of the molecular features identified remains to be demonstrated.

eLife assessment

ROCO proteins are evolutionarily conserved GTPases characterized by the presence of a tandem "COR" domain, sometimes accompanied by a kinase domain as in the LRRK2 protein that is linked to neurodegeneration. Previously the authors have shown that two conformational nanobodies can be used to trap a ROCO protein CtRoco in a monomer-GTPyS-bound state. The high-resolution structural data here provides convincing insights into the active state conformation of CtRoco, an important initial advance towards a broader mechanistic understanding of these cryptic tandem-domain proteins.

eLife assessment

This valuable paper compares blood gene signature responses between small cohorts of individuals with mild and severe COVID-19 and claims that an early innate immune response mediated via NK cells leads to less severe infection, more rapid viral clearance, and Th1/2 differentiation. The evidence supporting the conclusions is solid based on the use of appropriate and comprehensive assays and analysis tools, but not definitive based on mismatched timing of samples between the two cohorts coupled with small cohort size.

eLife assessment

This valuable study demonstrates that there is significant variation in the susceptibility of isoniazid-resistant Mycobacterium tuberculosis clinical isolates to killing by rifampicin, in some cases at the same tolerance levels as bona fide resistant strains. The evidence provided is solid, with no clear genetic marker for increased tolerance, suggesting that there may be multiple routes to achieving this phenotype. The work will be of interest to infectious disease researchers.

eLife assessment

This valuable study demonstrates that the Chitinase 3-like protein 1 (Chi3l1) interacts with gut microbiota and protects animals from intestinal injury in laboratory colitis model. The evidence supporting the claims of the authors is considered incomplete. The inclusion of consistent in vivo and in vitro data would have strengthened the study. The work will be of interest to scientists studying crosstalk between gut microbiota and inflammatory diseases.

eLife assessment

This important study, using three bioactive compounds as a model, demonstrates that estimating the intake of food components based on food composition databases and self-reported dietary data is highly unreliable. The authors present convincing data showing the differences in the estimated quantile of intake of three bioactive compounds between biomarker and 24-hour dietary recall with food-composition database. The work will be of broad interest to the clinical nutrition research community.

eLife assessment

The findings in this study are useful and may have practical implications for predicting DLBCL risk subject to further validating the bioinformatics outcomes. We found the approach and data analysis solid. However, some concerns regarding the drug sensitivity prediction and the links between the selected genes for the risk scores have been raised that need to be addressed by further functional works.

eLife assessment

This valuable study correlates the size of various prefrontal brain regions in primate species with socioecological variables like foraging distance and population density. The evidence presented is solid but needs to be strengthened with additional analyses that demonstrate the robustness of their results. It is also unclear how this approach would work in other species that show variation in socioecological variables despite lacking clear anatomical markers to define brain areas.

eLife assessment

This valuable manuscript reports alterations in autophagy present in dopaminergic neurons differentiated from iPSCs in patients with WDR45 mutations. The authors identified compounds that improved the defects present in mutant cells by generating isogenic iPSC without the mutation and performing an automated drug screening. The methodological approaches are solid, but the claims still need to be completed: showing the effects of the identified compounds on iron-related alterations is crucial. The effects of these drugs in vivo would be a great addition to the study.

eLife assessment

Overall, the reviewers found the significance of the work valuable to the field of visual neuroscience, particularly given the large data set and strength of the method used that allowed for spatial analysis of neuronal responses in macaque V1. The evidence was deemed compelling, owing in part to the consistency of responses across animals and the fitness of modeling. Ways to improve the manuscript as outlined include an expanded discussion of similar prior literature and limitations of the method used to read out neuronal responses.

eLife assessment

These are valuable findings that support a link between low-dimensional brain network organisation, patterns of ongoing thought, and trait-level personality factors, making it relevant for researchers in the field of spontaneous cognition, personality, and neuropsychiatry. While this link is not entirely new, the paper brings to bear a rich dataset and a well-conducted study, to approach this question in a novel way. The evidence in support of the findings is convincing.

eLife assessment

This paper provides a valuable alternative explanation for the influence of environmental volatility on learning, attributing such effects to a mixture of strategies (MoS), rather than changes in the learning rate. The authors demonstrate that the MoS model provides a superior fit to previously published data, and suggest that atypical learning in individuals with anxiety and depression might reflect their use of a suboptimal strategy. While the approach should be of interest to researchers across decision sciences, the evidence is incomplete, limiting its potential impact.

eLife assessment

This manuscript is a fundamental contribution to the understanding of the role of intrinsically disordered proteins in circadian clocks and the potential involvement of phase separation mechanisms. The authors convincingly report on the structural and biochemical aspects and the molecular interactions of the intrinsically disordered protein FRQ. The paper will be of interest to scientists focusing on circadian clock regulation, liquid-liquid phase separation, and phosphorylation.

eLife assessment

This study highlights several important regulatory pathways that contribute to the control of entry into meiosis by turning down mitotic functions. Central to this regulation is the control of Swi4 level and activity, and convincing overexpression experiments identify downstream effectors of Swi4.

eLife assessment

This important and comprehensive study describes the development of a heterobifunctional degrader, which is used to provide insights into the mechanism of TEAD proteolysis, with potential implications for signaling pathways in cancer. While the methods are solid, the analyses and descriptions are still incomplete. With further molecular refinements, experimental controls, and a more cohesive and unified story, this article will be of interest to cancer biologists and scientists interested in proteostasis, cellular signaling, and post-translation modification of proteins.

eLife assessment

This important study expands our understanding of the role of two axon guidance factors in a specific axon guidance decision. The strength of the study is the convincing axonal labeling and quantification, which allows the authors to establish precise consequences of the loss of each guidance factor or receptor.

eLife assessment

This valuable study evaluates the effects of nifuroxazide on radiotherapy for the treatment of hepatocellular carcinoma. Solid evidence is provided to support the conclusion that nifuroxazide facilitates the downregulation of PD-L1 and may improve therapy outcomes when combined with radiotherapy, though the inclusion of additional cell lines and animal models would have strengthened the study. This work will be of interest to cancer biologists and those working in immuno-oncology.

eLife assessment

This paper presents H3-OPT, a deep learning method that effectively combines existing techniques for the prediction of antibody structure. This work is important because the method can aid in the design of antibodies, which are key tools in many research and industrial applications. The experiments for validation are convincing, but some further statistical evaluation would be helpful for the readers.

eLife assessment

This study delves into the complex role of STAT3 signaling and its interplay with TGF-beta and SMAD4 in KRAS mutant pancreatic cancer. The authors demonstrate that both the presence and absence of STAT3, relative to SMAD4, can lead to poor PDAC differentiation and that STAT3 mutations affect p53-null fibroblasts with KRASG12D and induce an EMT-like phenotype. By providing convincing evidence, the authors were able to derive important insights into KRAS mutant cancers.

eLife assessment

This manuscript presents a detailed characterization of male and female wild-type and CTRP10 knockout mice, revealing that knockout mice develop female-specific obesity that is largely uncoupled from metabolic dysfunction. The data are convincing, and the work is a valuable contribution to understanding how obesity is coupled to metabolic dysfunction, and how this can occur in a sex-specific manner.

eLife assessment

This study presents an important method and resource in cell lines and in mice for mass spectrometry-based identification of interactors of the proteasome, a multi-protein complex with a central role in protein turnover in almost all tissues and cell types. The method presented-including the experimental workflow and analysis pipeline, as well as the several lines of validation provided throughout, is convincing. Given the growing interest in protein aggregation and targeted protein degradation modalities, this work will be of interest to a broad spectrum of basic cell biologists and translational researchers.

eLife assessment

This useful study investigates the role of the centrosomal protein CEP44 in centriole duplication and mitotic spindle formation. While the analysis of CEP44 mitotic phosphorylation and spindle recruitment is solid, the characterization of CEP44's role at centrioles is incomplete and would benefit from additional controls and analyses. Since the work links CEP44 reduced expression to poor survival in breast cancer patients, it is of interest not only to cell biologists but also to cancer researchers.

eLife assessment

This is an important study on the damage-induced checkpoint maintenance and termination in budding yeast that provides convincing evidence for a role of the spindle assembly checkpoint and mitotic exit network in halting the cell cycle after prolonged arrest in response to irreparable DNA double strand breaks (DSBs). The study identifies particular components from both checkpoints that are specifically required for the establishment and/or the maintenance of a cell cycle block triggered by such DSBs. The authors propose an interesting model for how these different checkpoints intersect and crosstalk for timely resumption of cell cycling even without repairing DNA damage with theoretical and practical implications.

eLife assessment

This important study elucidates the function of the cohesin subunit SCC3 in impeding DNA repair between inter-sister chromatids in rice. The observation of sterility in the SCC3 weak mutant prompted an investigation of abnormal chromosome behavior during anaphase I through karyotype analysis. While the evidence presented is largely solid, the strength of support can be substantially improved in some aspects, leaving room for further investigation. This research contributes to our understanding of meiosis in rice and attracts cell biologists, reproductive biologists, and plant geneticists.

eLife assessment

This study focuses on nuclear pore complex dysfunction in a mouse model of Alzheimer's disease related Aβ pathology. The findings are useful in supporting the idea that nuclear cytoplasmic transport defects occur prior to plaque deposition in this disease model and may be caused by Alzheimer's disease pathology. However, the work suffers from overinterpretation of some of the data and remains incomplete in several respects; 1) molecular mechanisms that drive nuclear pore complex dysfunction are not explored, 2) evidence that time-dependent loss of the nuclear pore complex is linked to normal aging is lacking, and 3) a clear description of how the observations reported in this work fit into broader views in the field surrounding amyloid aggregation and accumulation in neurons and pathogenesis in neurons needs to be clarified.

eLife assessment

This manuscript describes a valuable study aimed at identifying the substrate specificity of two cell wall hydrolases LSS and LytM in S. aureus. The authors show that LytM has a novel function of cleaving D-Ala-Gly instead of only Gly-Gly by using synthetic substrates and convincing NMR-based real-time kinetics measurements. The biological relevance of the reported results will have to be investigated in future in vivo experiments.

eLife assessment

This is a valuable study on K187 acetylation of the nuclear protein, TIP60, required for its phase separation and function. The evidence supporting the primary conclusion is incomplete and warrants more scrutiny.

eLife assessment

This is a fundamental study describing a novel methylation event on EZH2 that regulates EZH2 protein stability and hematopoiesis. The methodologies are sound and the conclusions are largely supported by solid data. The work will be of interest to biomedical researchers in the field of cancer epigenetics.

eLife assessment

This important study adds to the growing body of evidence that neural responses fluctuate in time to alternatively represent one among multiple concurrent stimuli and that these fluctuations seize when objects fuse into one perceived object. The present study provides solid evidence from multiple brain areas and stimuli types to support this hypothesis. Overall, the study illustrates how the brain can use time dimension and synchrony to either parse or integrate stimuli into a coherent representation.

eLife assessment

This valuable paper addresses a notable problem, the cell biological control of biomineralization, with the sea urchin embryo as an experimental model. The paper provides evidence that ROCK and the cytoskeleton play a role in biomineralization, but the evidence is deemed currently incomplete, as there are concerns regarding the efficacy and specificity of the reagents used to perturb ROCK function. In addition, the data do not point to a plausible mechanism by which the actin cytoskeleton might regulate the biomineralization process.

eLife assessment

This is a fundamental work that significantly advances our understanding of the role of mossy cells in the dentate gyrus in Fragile X Syndrome. The carefully designed and executed extensive series of experiments provide compelling evidence that changes in their excitability occur due to up-regulation of Kv7 currents. The study unveils the underlying mechanisms of the disease, and therefore the work will be of interest to neuroscientists working on various aspects of Fragile X pathology. In addition, it also provides insights into how neuronal activity is balanced in networks through diverse cellular mechanisms.

eLife assessment

Drawing on a human population genomic data set, this valuable study seeks to show that potentially advantageous alleles are on average older than neutral alleles, invoking the action of balancing selection as the underlying explanation. Currently it is unfortunately unclear how robust the estimates of allele ages are, and the evidence for the authors' proposal is therefore at this stage incomplete. If confirmed, the conclusions would be of interest to population genomicists, especially those studying humans.

eLife assessment

This fundamental study explored the impact of migraine-related cortical spreading depression (CSD) on the firing of nerves innervating the coverings of the brain that are considered the putative source of migraine-related pain. Using convincing approaches they show that these responses are altered in response to mechanical deformation of the brain coverings. Given that migraine is characterized by worsening head pain in response to movement, the findings offer a potential mechanism that may explain this clinical phenomenon.

eLife assessment

This valuable paper examines gene expression differences between male and female individuals over the course of flower development in the dioecious angiosperm Trichosantes pilosa. Male-biased genes evolve faster than female-biased and unbiased genes, which is frequently observed in animals, but this is the first report of such a pattern in plants. In spite of the limited sample size, the evidence is mostly solid and the methods appropriate for a non-model organism. The resources produced will be used by researchers working in the Cucurbitaceae, and the results obtained advance our understanding of the mechanisms of plant sexual reproduction and its evolutionary implications: as such they will broadly appeal to evolutionary biologists and plant biologists.

eLife assessment

This study identifies two new transporters in the apicoplast, a non-photosynthetic organelle of apicomplexan parasites. While this is important work, it only partially reveals how essential these transporters are, as it does not address the metabolic function of the transporters for the parasite. Although the evidence is still incomplete, the results should be of interest to parasitologists and eukaryotic cell biologists.

eLife assessment

This study presents an important conceptual advance of how vitamin A and its derivatives contribute to atherosclerosis. There is solid evidence for the contributions of specialized populations of T cells in atherosclerosis resolution, including use of multiple in vivo models to validate the functional effects. A limitation is the insufficient analysis of lesions, but the manuscript has been improved from the original preprint version and the overarching conclusions have been refined.

eLife assessment

This important study combines state-of-the art proteomics and genetic manipulation of Chlamydia trachomatis to study the function of a chlamydial effector, Cdu1, with deubiquitination and acetylation activities. Solid evidence is provided to show that Cdu1 is able to protect itself and three other chlamydial effectors, which are involved in the control of chlamydial egress from host cells, from ubiquitin-mediated degradation, and that this depends on the acetylation activity of Cdu1, but not on its deubiquitination activity. This work will be of interest to microbiologists and cell biologists studying host cell-pathogen interactions.

eLife assessment

This important study advances our understanding of how different types of communication signals differentially affect mouse behaviors and amygdala cholinergic/dopaminergic neuromodulation. Researchers interested in the complex interaction between prior experience, sex, behavior, hormonal status, and neuromodulation should benefit from this study. Nevertheless, some of the statistical comparisons using baseline normalized data might result in inadequate statistical power at this stage, requiring additional analysis to support the conclusions fully. With a few analytical parts strengthened, this paper will be of interest to neuroscientists and ethologists.

eLife assessment

This study presents important new insights into how best to address common problems encountered in the statistical analysis of neural data, including those related to temporal autocorrelations and unknown variables. The authors show that certain approaches, including those using cross-validation and permutation tests, are better than others at controlling error rates, particularly false negatives. At present, the evidence presented is incomplete, including a lack of more rigorous theoretical justifications for the differences observed between the different approaches tested and a focus on p-values without considering effect sizes, but could be improved with substantial revisions that address these issues.

eLife assessment

The aim of this important study is to functionally characterize neuronal circuits underlying the escape behavior in Drosophila larvae. Upon detection of a noxious stimulus, larvae follow a series of stereotyped movements that include bending their body, rolling, and crawling away. This paper combines quantitative behavioral analyses, cell-type specific manipulations, optogenetics, calcium imaging, immunostaining, and connectomic analysis to provide convincing evidence of an inhibitory descending pathway that controls the switch from rolling to fast crawling behaviors of the larval escape response.

eLife assessment

This study presents a valuable finding on the influence of visual uncertainty and Bayesian cue combination on implicit motor adaptation in young healthy participants. The evidence supporting the claims of the authors is solid, although a better discussion of the link between the model variables and the outcomes of related behavioral experiments would strengthen the conclusions. The work will be of interest to researchers in sensory cue integration and motor learning.

eLife assessment

This study presents useful results on glutamine-rich motifs in relation to protein expression and alternative genetic codes. The solid data are based on bioinformatic approaches that are employed to systematically uncover sequence features associated with proteome-wide amino acid distribution and biological processes.

eLife assessment

The authors have greatly expanded their important hippocampome.org resource about rodent hippocampal cell types, their physiological properties, and their interactions. With version 2.0, they make a significant advance in providing a user-friendly means to make computer models of hippocampal circuits. The work is convincing, and there are only minor reservations that the figures may be too complex.

eLife assessment

This convincing study demonstrates a potentially important role for the factor Numb in skeletal muscle excitation-contraction coupling, since a Numb knockout reduced contractile force. The authors thus demonstrate a novel role for Numb in calcium release in skeletal muscle.

Modula and Oberon should have been codenames rather than independent projects.

eLife assessment

This important study reports jAspSnFR3, a biosensor that enables high spatiotemporal resolution of aspartate levels in living cells. To develop this sensor, the authors used a structurally guided amino acid substitution in a glutamate/aspartate periplasmic binding protein to switch its specificity towards aspartate. The in vitro and in cellulo functional characterization of the biosensor is convincing, but evidence of the sensor's effectiveness in detecting small perturbations of aspartate levels and information on its behavior in response to acute aspartate elevations in the cytosol are still lacking.

eLife assessment

This important study presents convincing evidence for the use of orangutan teeth as terrestrial proxies to reconstruct rainfall regimes, while exploring the potentially conflicting impact of breastfeeding signals. The findings will be of broad interest for those using and developing methods and tools to reconstruct environmental conditions in the historical and archaeological past.

eLife assessment

This study presents useful work comparing different techniques for monitoring insect species in agricultural settings, including a brand new one using optical sensors. That said, the data were analysed using an inadequately-described -- or potentially inadequate -- framework, and more careful thought must be given to the interpretation of the results before the new methodology can be used as a starting point for insect studies in agricultural fields and beyond.

eLife assessment

This valuable manuscript describes a genetic system in yeast used to find mutations in two distinct amino acid transporters that enable the cells to utilize additional amino acids as a nitrogen source. The study provides solid evidence in membrane proteins of a phenomenon that has been previously described in enzymes: that substrate specificity can be altered through the introduction of point mutations to either the ligand binding site or gating helices. This work establishes that amino acid transporters likely evolved specific functionality/specificity from an ancestral transporter that could transport most amino acids.

eLife assessment

By taking advantage of noise in gene expression, this important study introduces a new approach for detecting directed causal interactions between two genes without perturbing either. The main theoretical result is supported by a proof, although clearer statements are needed to ensure that there are no edge cases that can violate the theorem. Preliminary simulations and experiments on small circuits are presented, but the evidence remains incomplete because further investigations are needed to demonstrate the broad applicability and scalability of the method.

eLife assessment

This study presents important findings on long-lived proteins in the mouse ovary and oocytes. Convincing evidence using two-generation stable isotope-based metabolic labelling of mice in combination with mass spectrometry analysis describes a resource of enriched long-lived macromolecules in oocytes and somatic cells. Mitochondrial, cytoskeletal, and myosin proteins were identified as long-lived. While this is a unique resource with significant value in the understanding of female reproductive aging, the results would be strengthened if supported by an orthogonal validation and a more in-depth mechanistic explanation of the relationship between mitochondrial and cytoskeletal protein stability and aging.

eLife assessment

This important paper examined how attention affects temporal binding. Through a combination of careful experimental designs and computational modelling, this study provides solid evidence highlighting the role of attention in shaping temporal binding. Overall, the present findings will be of interest to cognitive scientists studying phenomena related to time perception, temporal binding, and spatial attention.

eLife assessment

In an important study that will be of interest to the mechanistic membrane transport community, the authors capture the first cryo-EM structure of the inward facing melbiose transporter MelB, a well-studied model transporter from the major facilitator (MFS) superfamily. Cryo-EM experiments and supporting biophysical experiments provide solid evidence for transporter conformational changes.

eLife assessment

This study presents a useful inventory of immune signatures that are correlated with cancer treatment-related pneumonitis. The data were collected and analysed using solid and validated methodology and can be used as a starting point for further functional studies.

eLife assessment

This useful manuscript focuses on understanding how an Eklf mutation confers anticancer and longevity advantages in vivo. The data demonstrate that Eklf (K74R) imparts such advantages in a background and age independent manner in both female and male mice, and that the benefits are transferable by bone marrow transplantation. Despite added data since a previous version, the paper unfortunately remains incomplete, as it is still unclear whether Eklf affects resistance to malignant progression/metastasis by modulating Pd1 or Pdl1, or by increasing NK cells. The authors provide evidence that supports in principle both mechanisms, and they do not resolve which mechanism is primarily involved.

eLife assessment

This study provides useful insights into inter- and intra-site B cell receptor repertoire heterogeneity, noting that B cell clones from the tumour interact more with their draining lymph node than with the blood and that there is less mutation/expansion/activation of B cell clones in tumours. Unfortunately, the main claims are incomplete and only partially supported. This work could be of interest to an audience including medical biologists/immunologists and computational biologists across cancer specialities.

eLife assessment

This paper provides an important assessment of competition dynamics allowing coexistence of the carnivore guild within a large national park. A solid dataset and multiple surveying techniques (camera traps and DNA metabarcoding) provide convincing evidence that spatial segregation represents the main strategy of coexistence, while species have a certain degree of temporal and dietary overlap. Altogether, the manuscript provides important information critical to the conservation and management agenda of the park.

eLife assessment

This important study identifies the gene mamo as a new regulator of pigmentation in the silkworm Bombyx mori, a function that was previously unsuspected based on extensive work on Drosophila where the mamo gene is involved in gamete production. The evidence supporting the role of Bm-nano in pigmentation is convincing, including high-resolution linkage mapping of two mutant strains, expression profiling, and reproduction of the mutant phenotypes with state-of-the-art RNAi and CRISPR knock-out assays. While the discussion about genetic changes being guided or accelerated by the environment is extremely speculative and has little relevance for the findings presented, the work will be of interest to evolutionary biologists and geneticists studying color patterns and evolution of gene networks.

eLife assessment

This study presents a valuable dissection on how functional HSCs are expanded in PVA cultures. The functional and multi-omic analyses provided are convincing, although the additional data and their analysis provided during revision could have been included in the test to assist readers and to strengthen the published manuscript. Nevertheless, the present work will be of value for stem cell biologists interested in HSC regulation.

eLife assessment

This study presents valuable findings on the mechanism of glucocorticoid-induced osteonecrosis of the femoral head. The data were collected and analyzed using solid, validated methodology and can be used as a starting point for functional studies of development of glucocorticoid-induced osteonecrosis. This paper would be of interest to cell biologists and biophysicists working on potential pharmacological treatments for glucocorticoid-induced osteonecrosis.

eLife assessment

This valuable paper explores the idea that transient modulations of neural gain promote switches between distinct perceptual interpretations of ambiguous stimuli. Evidence for this idea is provided by pupillometry (an indirect proxy of neuromodulatory activity), fMRI, neural network modeling, and dynamical systems analyses. While this integrative approach is intriguing, the data analysis, as well as computational modeling, are incomplete, especially for supporting the many causal statements in the paper.

eLife assessment

This important paper uses a genome-wide, massively parallel reporter assay to determine how CpG methylation affects regulatory sequences that control the expression of human genes. The authors provide compelling evidence that methylation not only influences baseline activity of regulatory sequences but also the magnitude of acute responses to environmental stimuli. The findings are of broad interest, and the extensive data set will likely become a key resource for the community.

eLife assessment

This study investigates the role of the bile acid receptor TGR5 in adult hematopoiesis of the mouse model. The findings are potentially useful because the loss of TGR5 leads to dysregulation of bone marrow adipose tissue (BMAT) that has emerging regulatory functions. However, the study is still incomplete because the mechanism of TGR5 is not clear, the stromal cells expressing TGR5 have not been well defined, and there is not strong evidence for the role of TGR5 in recovery from transplant stress.

eLife assessment

This study presents valuable information that demonstrates CCDC146 as a novel cause of male infertility that play key role in microtubule-associated structures. The evidence supporting the claims of the authors is solid using combination of human and mouse genetics, biochemical and imaging approaches. This paper would be of interest to cell and developmental biologists working on genes involved in spermatogenesis and male infertility.

eLife assessment

This important study advances our understanding of why diabetes is a risk factor for more severe Covid-19 disease. The authors offer solid evidence that cathepsin L is more active in diabetic individuals, that this higher activity is recapitulated at the cellular level in the presence of high glucose, and that high glucose leads to higher cathepsin L maturation. While not all aspects of the relationship between diabetes and cathepsin L (e.g., effects of metabolic acidosis) have been investigated, the work should be of interest to researchers in diabetes, virology, and immunology.

eLife assessment

This useful study uses a mouse model of pancreatic cancer to examine mitochondrial mass and structure in atrophying muscle along with aspects of mitochondrial metabolism in the same tissue. Most relevant are the solid transcriptomics and proteomics approaches to map out related changes in gene expression networks in muscle during cancer cachexia.

eLife assessment

This important study explores the physicochemical properties of SARS-CoV-2 N proteins with mutations that have been found in variants of concern but for which there is limited knowledge of their contribution to the biological activity of such variants. The evidence presented is solid; however, this study could be considerably improved by a more extensive analysis of LLPS in R203K/G204R and in the P31L mutants, as well as a more quantitative analysis of the LLPS droplets.

eLife assessment

The authors present evidence suggesting that MDA5 can substitute as a sensor for triphosphate RNA in a species that naturally lacks RIG-I. The key findings are potentially important for our understanding of the evolution of innate immune responses, but the evidence is incomplete, as additional biochemical and functional experiments are needed to unambiguously assign MDA5 as a bona fide sensor of triphosphate RNA in this model. This also leaves the title as overstating its case.

eLife assessment

This important study addresses the mechanisms by which mutations in the PURA protein, a regulator of gene transcription and mRNA transport and translation, cause the neurodevelopmental PURA syndrome. Based on convincing evidence from structural biology, molecular dynamics simulation, biochemical, and cell biological analyses, the authors show that the PURA structure is very dynamic, rendering it generally sensitive to structure-altering mutations that affect its folding, DNA-unwinding activity, RNA binding, dimerization, and partitioning into processing bodies. These findings are of substantial importance to cell biology, neurogenetics, and neurology alike, because they provide first insights into how very diverse PURA mutations can cause similar and penetrant molecular, cellular, and clinical defects.

eLife assessment

This important study investigates the molecular mechanisms underpinning how the tumor necrosis factor alpha-induced protein, TIPE, regulates aerobic glycolysis to promote tumor growth in melanoma. Data using multiple independent approaches provide new insights into the molecular mechanisms underpinning aerobic glycolysis, also known as the Warburg Effect, in melanoma cells. The claims of the authors are solid, although more in-depth metabolic assays as well as the inclusion of melanoma patient survival analysis in TIPE high and low tumors would strengthen the study. The work will be of interest to biomedical researchers working in cancer and metabolism.

eLife assessment

This study presents a cellular automaton model to study the dynamics of virus-induced signalling and innate host defense against viruses such as SARS-CoV-2 in epithelial tissue. The data presented are convincing and represent a valuable contribution that would be of interest to researchers studying the dynamics of viral propogation. The significance of the study might be further elevated with more details on the reduction of expression data to the model rules discussed.

eLife assessment

This study presents a valuable finding that a testis-enriched gene is essential for normal formation and function of the sperm flagellum, motility, and male fertility in mice. The data on phenotypic characterization are solid, but the evidence supporting the direct role of this protein in preventing RNP granule formation in the sperm flagellum appears insufficient. This work will be of interest to biomedical researchers who work on testicular biology and male fertility.

eLife assessment

This study provides a detailed evaluation of how HIV evades nascent immune pressure from people living with HIV followed nearly immediately after infection. There is convincing evidence that H173 mutations in the V2 loop was a key determinant of selection pressure and escape. These data are congruent with protection in the RV144 clinical trial, the only trial that showed protection from infection. Overall, this study is valuable to the field.

eLife assessment

In this valuable study, the authors investigate the transcriptional landscape of tuberculous meningitis, revealing key molecular differences contributed by HIV co-infection. Whilst some of the evidence presented is compelling, the bioinformatics analysis is limited to a descriptive narrative of gene-level functional annotations, which are somewhat basic and fail to define aspects of biology very precisely. Whilst the work will be of broad interest to the infectious disease community, validation of the data is critical for future utility.

eLife assessment

This current revision builds on observations in validated conditional double KO (cDKO) mice for LRRK1 and LRRK2 that will be useful for the field, given that LRRK2 is widely expressed in the brain and periphery, and many divergent phenotypes have been attributed previously to LRRK2 expression. The manuscript presents solid data demonstrating that it is the loss of LRRK1 and LRRK2 expression within the SNpc DA cells that is not well tolerated, as it was previously unclear from past work whether neurodegeneration in the LRRK double Knock Out (DKO) was cell autonomous or the result of loss of LRRK1/LRRK2 expression in other types of cells. Future studies may pursue the biochemical mechanisms underlying the reason for the apoptotic cells noted in this study, as here, the LRRK1/LRRK2 KO mice did not replicate the dramatic increase in the number of autophagic vacuoles previously noted in germline global LRRK1/LRRK2 KO mice.

eLife assessment

This important study presents interesting findings that suggest that the UPR and immune regulators can act as evaluators of nutritional quality in C. elegans. Convincing evidence expands our understanding both of physiological food evaluation systems and of the known roles of stress response pathways in organismal physiology. However, there is limited mechanistic exploration in the study, and in some cases, the effect size is small and statistical significance questionable.

eLife assessment

This valuable paper presents a thoroughly detailed methodology for mesoscale-imaging of extensive areas of the cortex, either from a top or lateral perspective, in behaving mice. While the examples of scientific results to be derived with this method are in the preliminary stages, they offer promising and stimulating insights. Overall, the method and results presented are convincing and will be of interest to neuroscientists focused on cortical processing in rodents.

eLife assessment

This study reports a valuable new mechanism through which the TGF-beta signaling pathway promotes contacts between oocytes and their surrounding somatic cells via regulating the number of transzonal projections (TZPs) in mice. The evidence supporting the major conclusions is solid, although further assessments of the physiological significance of SMAD4-dependent formation of transzonal projection networks would have strengthened the study. The work will be of interest to biomedical researchers who work on ovarian biology and female fertility.

eLife assessment

In this manuscript, the authors investigate the properties of prokaryotic NADPH oxidases (NOX) and discuss the implications for NOX regulation and function. The structure of the S. pneumoniae Nox protein is an important step forward in our understanding of procaryotic NOX enzymes and the characterization and interpretation are convincing. The results will be of interest to structural biologists as well as biochemists focusing on enzymatic functions.

eLife assessment

This paper presents an important finding: that Styxl2, a poorly characterized pseudo-phosphatase, plays a role in the sarcomere assembly by promoting the degradation of non-muscle myosins. The genetic evidence supporting the conclusions is compelling, although future work will be needed to elucidate the functional role and biochemical mechanism of autophagic degradation of non-muscle myosins. This work will be of interest to biologists studying muscle development, cell biology, and proteolysis.

eLife assessment

CCL2 is a chemokine known to have relevant immune cell chemoattractant properties, and it is believed to play a role in several chronic inflammatory diseases. The RNA-binding protein HuR controls the stability and translation of CCL2 mRNA. This paper presents solid evidence that a relatively common genetic variant tied to several disease phenotypes affects the interaction between the mRNA of CCL2 and the RNA-binding protein HuR. As CCL2 is believed to be relevant for leukocyte migration in various conditions, including chronic inflammation and cancer, this is an important finding that may be relevant to a broad audience.

eLife assessment

This study addresses how protein synthesis in activated lymphocytes keeps up with their rapid division, with important findings that are of significance to cell biologists and immunologists endeavouring to understand the 'economy' of the immune system. The work is supported by solid data. Because it proposes non-conventional mechanisms, the study sets the scene for further work in this area.

eLife assessment

The effect of Vitamin D supplementation in reducing asthma via anti-inflammatory mechanisms is a topic of wide interest, with somewhat conflicting published data. Here, bioinformatic approaches help to identify a role of VDR in inducing the expression of the key regulator Ikzf3, which possibly suppresses the IL-2/STAT5 axis, consequently blunting the Th2 response and mitigating allergic airway inflammation. These are important findings based on convincing evidence.

eLife assessment

This manuscript utilizes a Drosophila explant system and modeling to provide important insights into the mechanism of microtubule aster positioning. Although the intellectual framework of aster positioning has been worked out by the same authors in their previous work, this study provides additional solid evidence to solidify their model.

eLife assessment

This important report studies the recovery of genome-reduced bacterial cells in laboratory evolution experiments to understand how they regain their fitness. Through the analysis of gene expression and a series of tests, the authors discover distinct molecular changes in the evolved bacterial strains and propose that various mechanisms are employed to offset the effects of a reduced genome. While the findings have intriguing implications for understanding genome evolution, it is crucial to note that the evidence supporting these claims is incomplete due to insufficient experimental tests and statistical analysis.

eLife assessment

This important work by Hann et al. advances our understanding of the role of the survival motor neuron (SMN) protein in coordinating pathogenesis of the spinal muscular atrophy (SMA). The authors addressed many concerns raised by the reviewers, providing convincing evidence in terms of skeletal analyses not being able to satisfactorily elucidate SMN regulation of bone development.

eLife assessment

This important work combines DNA contact analysis and controlled genome rearrangements to investigate the processes that organize the E. coli chromosome, with a particular focus on how the SMC-related complex MukBEF is regulated. The evidence supporting the conclusions is compelling, with time-resolved experiments and analysis of mutant strains. The work will be of broad interest to chromosome biologists and bacterial cell biologists.

eLife assessment

This manuscript describes an important web resource for kinases connected to cytokines. The compelling information will be used by researchers across a number of fields including analysts, modelers, wet lab experimentalists and clinician-researchers, who are looking to improve our understanding of pathologies and means to correct them through modulating the immune response.

eLife assessment

This is a methodologically state-of-the-art systematic review and meta-analysis of studies that addressed the question of whether the administration of multiple antibiotics simultaneously prevents antibiotic resistance development in individuals. The findings are solid. Rather than providing a precise answer, the synthesis of studies eligible for analysis leads to the conclusion that "our analysis could not identify any benefit or harm of using a higher or a lower number of antibiotics regarding within-patient resistance development." This article is important as it articulates the existing knowledge gap, but also serves as an example to careful future use of the meta-analysis methodology, when existing data just don't allow conclusions.

eLife assessment

This very interesting study by Vuond and colleagues reports on the kinetics of viremia in a large set of individuals from Vietnam. In the large cohort, all 4 dengue serotypes are represented and the authors try to correlate viraemia measured at various days from illness onset with thrombocytopaenia and severe dengue, according to the WHO 2009 classification scheme. These are fundamental findings and provide compelling evidence of the importance of measuring viremia early in the phase of the disease. These data will help to inform the design of studies of antiviral drugs against dengue.

eLife assessment

This solid study investigates the transdifferentiation of chicken embryonic fibroblasts into muscle and fat cells in 3D to create whole-cut meat mimics. The study is important and provides a method to control muscle, fat, and collagen content within the 3D meat mimics and thus provides a new avenue for customized cultured meat production. Limitations of this study include the use of transgene for transdifferentiation and thus the creation of GMO food.

eLife assessment

The study provides useful data supporting prior findings that mitochondria in cultured cells maintain a temperature that is up to 15°C above the external temperature at which cultured cells are maintained. The evidence supporting the hypothesis is solid, although direct measures of temperature in isolated mitochondria or comparison with other cellular compartments would have strengthened the ability to interpret the relevance of the findings. Nevertheless, the bioenergetic implications of the work will be of interest to cell biologists, biochemists, and physiologists.

eLife assessment

The study provides valuable data supporting prior findings that mitochondria in cultured cells maintain a temperature that is up to 15°C above the external temperature at which cells are cultured. The evidence supporting the hypothesis is incomplete at this stage, and additional benchmarking of temperature probes and inclusion of outcome measures beyond mitochondrial temperature will strengthen the ability to interpret the relevance of the findings. Nevertheless, the bioenergetic implications of the work will be of interest to cell biologists, biochemists, and physiologists.

eLife assessment

This study presents the useful observation that repetitive Transcranial Magnetic Stimulation (rTMS) over the medial prefrontal cortex (mPFC) is associated with immediate dampening effects of conditioned responses and generalization of these responses to similar cues. Additionally, the effects were still present one week later, in the absence of any stimulation. However, the evidence supporting the claims of the authors is incomplete. The main outcome data (skin conductance response) have been normalized and standardized in suboptimal ways and, most critically, no comparisons are being made with the strength of conditioned responses during acquisition. If the observations hold, when based on within-subject comparisons, the work will be of interest to psychologists and neuroscientists working on interventions into aberrant emotional memories.

eLife assessment

Large populations of neurons are capable of entering pathological synchronous oscillations under a variety of conditions and work over many decades has found ways to disrupt such oscillations using stimulation in both open loop and closed loop configurations. This study adds useful results and methodology to this line of research, by providing solid evidence that delayed feedback control via electrical stimulation can, under certain conditions, terminate network level oscillations in cultured cortical neurons. The study provides analyses and simulation results that shed light on why some networks respond to such feedback control while others do not.

eLife assessment

This important study demonstrates that the transcription factor TEAD1 is required for the function of Yap/Taz in Schwann cells, with conditional mouse mutants having very similar dysmyelinated phenotypes. Convincing histological evidence is shown for the role of TEAD1 itself, leaving open the function of other TEAD proteins in this system. This study will nevertheless be of great interest to researchers in the field of peripheral nerve development.

eLife assessment

This study examines an interplay between synaptic mitochondria and glutamate receptor exocytosis in C. elegans. Collectively, the solid results support the idea that mitochondrial function influences receptor dynamics at postsynaptic sites. This is important because tight control of synaptic function likely integrates several mitochondrial functions: energy production, calcium buffering, and (here) reactive oxygen species signaling.

eLife assessment

This convincing manuscript represents a valuable advance in understanding the role of MCT1 – a transporter for lactate and other organic anions – in hepatocytes and hepatic stellate cells in the liver. The authors also generate exciting new tools to investigate hepatic stellate cell biology, and these may have much broader applications, but future studies are required to validate these new tools.

eLife assessment

This important study extends insights on NAFLD and NASH regarding the role of plasma lactate levels using mice haplo-insufficient for the gene encoding lactate transporter MCT-1. While the evidence is largely convincing and the work significantly advances our understanding of the roles of distinct hepatic cell types in steatosis, a number of issues require attention and would best be solved by further experimentation.

eLife assessment

Payne et al. present a novel model that predicts the sites and directions of plasticity within the vestibular cerebellum to explain the basis for learned adjustments to reflexive eye movements in monkeys. The work is solid; the model is well constrained by prior biological observations and makes an important prediction about the level of feedback available to the cerebellar cortex post-learning. Overall, a number of exciting and testable experiments will likely be motivated by this study.

eLife assessment