eLife Assessment

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

eLife Assessment

This study provides important computational insights into the dynamics of PROTAC-induced degradation complexes, offering a convincing demonstration that differences in degradation efficacy can be linked to linker properties. The analyses address reproducibility considerations comprehensively, reinforcing the study's conclusions. Overall, these findings are significant for advancing cancer treatments and will be of broad interest to both biochemists and biophysicists.

eLife Assessment

This study provides a valuable approach to image and analyze in vivo metabolic flux through glucose turnover kinetics in glioblastoma tumor microenvironments. The evidence for the method's validity is convincing, which establishes the dynamic Deuterium Metabolic Imaging technique as an effective tool enabling non-invasive exploration of various tumors.

eLife Assessment

Seminal plasma is a crucial component of semen that can affect sperm capacitation. However, the role of seminal plasma components, including fatty acids, in sperm function and fertility is poorly understood. In this important study, the authors provide a solid evidence of the testosterone-induced metabolic shift in the epithelial cells of seminal vesicle to support an fatty acid synthesis and also describe the potential effect of oleic acid on sperm motility.

eLife Assessment

This important study addresses the idea that defective lysosomal clearance might be causal to renal dysfunction in cystinosis. With mostly solid data, the authors observe that restoring expression of vATPase subunits and treatment with Astaxanthin ameliorate mitochondrial function in a model of renal epithelial cells, opening opportunities for translational application to humans.

eLife Assessment

This is an important and convincing study of the morphological properties of Purkinje cell dendrites and dendritic spines in adult humans and mice, and the anatomical determinants of multi-innervation by climbing fibers. The data will provide a helpful resource for the field of cerebellar computation.

eLife Assessment

Combining experiments in microfluidic devices and computer simulation, this study provides a valuable analysis of the relevant parameters that determine the motility of (multicellular) magnetotactic bacteria in sediment-like environments. Despite the limitations imposed by the specific experimental design of the pores, the study presents convincing evidence that there is an optimum in the biological parameters for motile life under such conditions.

eLife Assessment

This valuable study assesses epigenetic clocks across ancestries, including in the context of accelerated aging in Alzheimer's Disease patients. It provides convincing evidence for population differences in age estimation accuracy across a variety of epigenetic clocks, but the degree to which these differences reflect continuous variation in ancestry, and/or are confounded by environmental or power differences is not entirely clear; consequently, the evidence that reduced portability is rooted in genetics is incomplete. Given the accelerating use of epigenetic clocks across fields, this study is nevertheless likely to be of interest to researchers working on human genetic and epigenetic variation or who apply epigenetic clocks to diverse human populations.

eLife Assessment

Using several hundreds of samples and cutting-edge genomic methods, including BioNano, PacBio HiFi, and advanced bioinformatic pipelines, the authors identify six large chromosomal inversions segregating in over 100 species of Lake Malawi cichlids. This important study provides compelling evidence for the presence of these six inversions, their differential distribution among populations, and the association of chromosome 10 inversion with a sex-determination locus. This work also provides a starting point for further investigating the role of these inversions with respect to local adaptation, speciation, sex determination, hybridization, and incomplete lineage sorting in cichlids, which represent ~5% of the extant vertebrate species and are one of the most prominent examples of adaptive radiations.

eLife Assessment

This important work advances our understanding of intraflagellar transport, ciliogenesis, and ciliary-based signaling, by identifying the interactions of IFT172 with IFT-A components, ubiquitin-binding, and ubiquitination, mediated by IFT172 C-terminus and its role in ciliogenesis and ciliary signaling. The results of the structural analysis of the IFT172 C-terminus and the evidence for the interaction between IFT172 and IFT-A components are convincing. However, the analysis of ubiquitin-binding and ubiquitination mediated by IFT172 is incomplete.

eLife Assessment

This study presents an important finding that has identified 27 differentially methylated regions as a signature for non-invasive early cancer detection and predicting prognosis for colorectal cancer. The findings demonstrate promising clinical potential, particularly for improving cancer screening and patient monitoring. However, the evidence supporting the claims of the authors is incomplete due to a small sample size and some methodological concerns. The work will be of interest to researchers interested in cancer diagnosis or colorectal cancer monitoring.

eLife Assessment

This study presents a valuable and simplified classification system for predicting clinical outcomes in RPLS patients. The evidence supporting the claims of the authors is solid, although the elaboration of the marker selection process would have strengthened the study. The work will be of interest to scientists working in the field of retroperitoneal liposarcoma.

eLife Assessment

This work presents a valuable extension of qFit-ligand, a computational method for modeling conformational heterogeneity of ligands in X-ray crystallography and cryo-EM density maps. The evidence presented for improved capabilities through careful validation against the previous version, notably in expanding ligand sampling within the conformational space, is solid yet still incomplete. The enhanced methodology demonstrates practical utility for challenging applications, including macrocyclic compound modeling and crystallographic drug fragment screening.

eLife Assessment

This important study uses recently developed EEG analysis methods to investigate spatial distractor suppression in a combined visual search/working memory task. The reported results are compelling, although they are open to multiple interpretations. The study will be of interest to cognitive neuroscientists and psychologists working on visual attention and memory.

eLife Assessment

This study offers a valuable treatment of how the population of excitatory and inhibitory neurons integrates principles of energy efficiency in their coding strategies. The convincing analysis provides a comprehensive characterisation of the model, highlighting the structured connectivity between excitatory and inhibitory neurons. The role of the many free parameters are discussed and studied in depth.

eLife Assessment

This short manuscript uses mutation counts in phylogenies of millions of SARS-CoV-2 genomes to show that mutation rates systematically differ between regions that are paired or unpaired in the predicted RNA secondary structure of the viral genome. Such an effect of pairing state is not unexpected, but its systematic demonstration using millions of viral genomes is valuable and convincing.

eLife Assessment

This phenomenological study reported that cold exposure induced mRNA expression of genes related to lipid metabolism in the paraventricular nucleus of the hypothalamus (PVH). While the paper does not address cell-type specificity or the functional role of lipids in PVH, the findings might still serve as a useful basis for others to explore their relevance to brain responses to cold. In the revised manuscript, the authors made adequate editions, such as new immunostaining and immunoblotting of AGTL and HSL in the PVH, and pharmacological inhibition of lipid peroxidation and lipolysis. The authors also increased the sample size of some experiments and revised the text to limit their data interpretation. Thus, the reviewers considered that these studies are solid in conclusively describing how the PVH is reprogrammed at the level of gene expression by cold exposure.

eLife Assessment

This important study describes a first-in-human trial of autologous p63+ stem cells in patients with idiopathic pulmonary fibrosis, a lethal condition for which effective treatments are lacking. The authors provide convincing evidence that P63+ progenitor cell therapy can be safely delivered in patients with ILD, warranting movement to a Phase 2. However, given that this is a Phase 1 study with a small sample size, conclusions regarding efficacy should not yet be made.

eLife Assessment

The authors implement a valuable multi-tissue approach to dissect the physiologic consequences of JNK inhibition in parallel with dietary perturbation via sucrose. The conclusions of disrupted liver, muscle and adipose metabolism being central to these effects are solid, as they are supported by a combination of experimental dissection and network modeling approaches.

eLife Assessment

In their important manuscript, Costa et al. establish an in vitro model for dorsal root ganglion (DRG) axonal asymmetry, revealing that central and peripheral axon branches have distinct patterns of microtubule populations that are linked to their differential regenerative capacities. The authors employ creative tissue culture methods to demonstrate how these branches develop uniquely in vitro, offering a potential explanation for long-observed regeneration disparities. The convincing evidence provides a contribution to our understanding of the neuronal cytoskeleton and axonal regeneration.

eLife Assessment

This important study investigates the role of ATG6 in regulating NPR1, a key protein in the plant immune response. The authors present compelling evidence that ATG6 not only interacts with NPR1 in both the cytoplasm and nucleus but also enhances its stability and nuclear accumulation, leading to increased resistance to Pst DC3000/avrRps4 infection in Arabidopsis thaliana. The work incorporates a variety of approaches from molecular biology, confocal imaging, and biochemistry, which together strengthen the conclusions.

eLife Assessment

This important study investigates the signaling pathways regulating retinal regeneration. Convincing evidence shows that the sphingosine-1-phosphate (S1P) signaling pathway is inhibited following retinal injury. Small-molecule activators and inhibitors support a model in which S1P signaling must be inhibited to generate Müller glial progenitor cells-a key step in retinal regeneration. The presented results support the major conclusions. However, whether the drug treatments directly or indirectly affect the Müller cells remains unclear.

eLife Assessment

This study presents a valuable finding that synthetically lethal kinase genes FYN and KDM4 may play a role in drug resistance to kinase inhibitors in TNBC. The evidence supporting the claims of the authors is solid, although the exploration of the upstream mechanisms regulating KDM4A or the downstream pathways through which FYN upregulation confers drug resistance would have strengthened the study. The work will be of interest to medical biologists working in the field of breast cancer.

eLife Assessment

In this useful study, the authors tested a novel approach to eradicating HIV reservoirs by constructing a herpes simplex virus (HSV)-based therapeutic vaccine and evaluating efficacy in experimental infections of chronically SIV-infected, antiretroviral therapy (ART)-treated macaques. While mean viremia at rebound was lower in the HSV vaccine-treated group, the evidence presented appears to be incomplete, as the group size was small and the viral load at rebound was highly variable. This is a revised paper, but the support for the conclusions, particularly the effect of the HSV-vectored therapeutic vaccine on the SIV reservoir in the SIV-infected macaques, remains limited.

eLife Assessment

The results highlight an important physiological function of PGAM in the differentiation and suppressive activity of Treg cells by regulating serine synthesis. This role is proposed to intersect with glycolysis and one-carbon metabolism. Although the study's conclusion is supported by solid evidence from in-vitro cellular and in-vivo mouse models, there are some weaknesses and the reviewers suggested ways to improve the manuscript.

eLife Assessment

This valuable study uses single-molecule imaging for characterization of factors controlling the localization, mobility, and function of RNase E in E. coli, a key bacterial ribonuclease central for mRNA catabolism. While the supporting evidence for the differential roles of RNAse E's membrane targeting sequence and the C-terminal domain (CTD) is solid, the work could be further strengthened by clarifying some experimental discrepancies, restructuring the narration order, and exploring the generality of some observations and their physical basis, such as the membrane-RNase E interactions and the unstructured nature of the RNase E C-terminal domain. This interdisciplinary study will be of interest to cell biologists, microbiologists, biochemists, and biophysicists.

eLife Assessment

This important study reports single-nucleus multiomics-based profiling of transcriptome and chromatin accessibility of mouse XX and XY primordial germ cells (PGCs). The main conclusions of this study, which will be of interest to developmental and reproductive biologists, as well as andrologists, are supported by convincing data.

eLife Assessment

In this useful study, the authors tested a novel approach to eradicate the HIV reservoir by constructing a herpes simplex virus (HSV)-based therapeutic vaccine designed to reactivate HIV from latently infected cells and induce an immune response to kill such infected cells. Testing this approach with SIV in a primate model, the authors report that the SIV reservoir was reduced. However, the evidence presented appears to be incomplete because the animal group size was small and the SIV reservoir size highly variable.

eLife Assessment

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

eLife Assessment

By combining Synthetic Genetic Array (SGA) analysis with state-of-the-art imaging techniques, this study provides strong evidence that sphingolipid metabolism controls the maturation of Parkinson's disease-associated Synphilin-1 inclusion bodies (SY1 IBs) on the mitochondrial surface in a yeast model. The authors present compelling proof that perturbing the sphingolipid metabolic pathway leads to delayed SY1 IB maturation and enhanced SY1-triggered toxicity. Altogether, the authors show the important role of sphingolipid metabolism in the detoxification process of misfolded proteins by facilitating large IB formation on the mitochondrial outer membrane.

eLife Assessment

This important study presents an original and promising approach to combine convolutional neural networks of visual processing with evidence accumulation models of decision-making. While the methodological approach is technically sophisticated and the evidence is solid, there is still a gap between the model and the behavioral data. The study will be of interest to researchers working in the fields of machine learning and cognitive modeling.

eLife Assessment

The study presents a potentially valuable approach to genetically modify cells to produce extracellular matrices with altered compositions, termed cell-laid, engineered extracellular matrices (eECM). The evidence supporting the authors' conclusions regarding the utility of eECM for endogenous repair is solid, although there are some disagreements on the chondrogenicity of lyophilized constructs which was viewed as lacking robust evidence for endochondral ossification.

eLife Assessment

This important study provides solid evidence to support the anti-tumor potential of citalopram, originally an anti-depression drug, in hepatocellular carcinoma (HCC). In addition to their previous report on directly targeting tumor cells via glucose transporter 1 (GLUT1), they tried to uncover additional working mechanisms of citalopram in HCC treatment in the current study. The data here suggested that citalopram may regulate the phagocytotic function of TAM via C5aR1 or CD8+T cell function to suppress HCC growth in vivo.

eLife Assessment

Using a unique cerebellar disruption approach in non-human primates, this study provides valuable new insight into how cerebellar inputs to the motor cortex contribute to reaching. Evidence for many claims is solid, but several analyses - especially with respect to control at the end of the reaches - could be expanded or clarified. Additional details about the behavioral task and a clearer description about the limits of the disruption approach with respect to selectivity are also warranted.

eLife Assessment

This valuable short paper is an ingenious use of clinical patient data to address an issue in imaging neuroscience. The authors clarify the role of face-selectivity in human fusiform gyrus by measuring both BOLD fMRI and depth electrode recordings in the same individuals; furthermore, by comparing responses in different brain regions in the two patients, they suggested that the suppression of blood oxygenation is associated with a decrease in local neural activity. While the methods are compelling and provide a rare dataset of potentially general importance, the presentation of the data in its current form is incomplete.

eLife Assessment

This study shows that strip cropping -- planting different crops in strips on the same field -- enhances the taxonomic diversity of ground beetles relative to corresponding monocultures in multiple experiments with different crops in the Netherlands. While these findings are important for demonstrating the potential beneficial effects of this form of intercropping, the information presented is incomplete with regard to sampling design and data obtained.

eLife Assessment

This is a useful and potentially significant set of experiments. The authors found that cmk-1 and tax-6 act in separate habituation processes, primarily in AFD, and both serve to habituate the thermosensory reversal response. They found that cmk-1 primarily acts in AFD and tax-6 primarily acts in RIM (and FLP for naïve responses). While the study is significant, it is currently somewhat incomplete as key control experiments are needed in order to support the conclusions.

eLife Assessment

In this valuable manuscript, authors ablate cerebellar oligodendrocytes during postnatal development and show that synchrony of calcium transients in Purkinje neurons and behaviours are affected even at later stages. While the work is solid, it is incomplete in that the causal relationship between the two has not been sufficiently explored.

eLife Assessment

In this valuable study, ectopic expression and knockdown strategies were used to assess the effects of increasing and decreasing Cyclic di-AMP on the developmental cycle in Chlamydia. The authors convincingly demonstrate that overexpression of the dacA-ybbR operon results in increased production of c-di-AMP and early expression of the transitionary gene hctA and late gene omcB. Whilst these results are intriguing, the model currently proposed is over-simplified and likely incomplete.

eLife Assessment

The manuscript represents a fundamental advance in designing peptide inhibitors targeting Cdc20, a key activator and substrate-recognition subunit of the APC/C ubiquitin ligase. Supported by compelling biophysical and cellular evidence, the study lays a strong foundation for future developments in degron-based therapeutics. The unexpected findings regarding degradation efficiency highlight intriguing questions that merit further investigation. This work will interest researchers focused on peptide drug design targeting complex protein interactions.

eLife Assessment

This study presents a valuable finding on the alterations in the autophagic-lysosomal pathway in a Huntington's disease model. The evidence supporting the claims of the authors is solid. However, the observed changes in autophagy are moderate, the images were not fully represented by the quantification results, and some of the short forms used in the text are not clearly stated; these issues hinder further evaluation of the claims. The work will be of interest to neuroscientists working on HD.

eLife Assessment

This valuable study on Pseudomonas subverting host immunity identifies a new immune evasion strategy. There is solid evidence for the cleavage of VgrG2B by Caspase 11 and the generation of fragments that inhibit activity of the NLRP3 inflammasome. This work should be of interest to immunologists and microbiologists.

eLife Assessment

This study provides valuable insights into the lesser-known effects of the sodium-potassium pump on how nerve cells process signals, particularly in highly active cells like those of weakly electric fish. The authors use a detailed mathematical model to show how the pump can shift a cell's normal firing patterns and disrupt the coordination of signals when inputs change quickly. The computational methods used to establish the claims in this work are solid and can be used as a starting point for further studies, yet the conclusions would be strengthened with experimental evidence or testable predictions regarding some of the proposed mechanisms across different cell types.

eLife Assessment

This well-designed study provides important findings concerning the way the brain encodes prediction about self-generated sensory inputs. The authors report that neurons in auditory cortex respond to mismatches in locomotion-driven auditory feedback and that those responses can be enhanced by concurrent mismatches in visual inputs. While there remain alternative explanations for some of the data, these findings provide convincing support for the role of predictive processing in cortical function by indicating that sensorimotor prediction errors in one modality influence the computation of prediction errors in another modality.

eLife Assessment

Giamundo et al. present fundamental data with new insights into the role of Ezrin, a major membrane-actin linker that assembles signaling complexes, in the spatial regulation of EGF signaling mediators. The use of multiple state-of-the-art microscopy techniques, multiple cell lines and inhibitors, together with in vivo models convincingly supports the majority of their conclusions. The findings are helpful for understanding EGF/mTOR signal transduction and support a critical role for the scaffolding protein Ezrin in the upstream regulation of EGFR/AKT activity, TSC subcellular localization and mTORC1 signaling. These findings contribute substantially to understanding how endo-lysosomal signaling are regulated, alterations which are implicated in many human diseases.

eLife Assessment

This study builds on previous findings showing modular organisation of primate visual cortical areas by presenting important results about the cortical processing of colour, disparity and naturalistic textures in the human visual cortex at the spatial scale of cortical layers and columns using state-of-the-art high-resolution fMRI methods at ultra-high magnetic field strength (7 T). Solid evidence supports an interesting layer-specific informational connectivity analysis to infer information flow across early visual areas for processing disparity and color signals. While the question of how the modularity of representation relates to cortical hierarchical processing is interesting, the findings that texture does not map onto previously established columnar architecture in V2 is suggestive. The successful application of high-resolution fMRI methods to study the functional organization along cortical columns and layers is relevant to a broad readership interested in general neuroscience.

eLife Assessment

This valuable study investigated the role of PLECTIN, a cytoskeletal crosslinker protein, in hepatocellular carcinoma development and progression. Using a liver-specific Plectin knockout mouse model, the authors showed solid evidence that PLECTIN is critical for hepatocarcinogenesis, since inhibition of PLECTIN suppressed tumor formation in multiple models. They also show that PLECTIN is key for HCC invasion and metastasis. They show a correlation between PLECTIN inhibition and attenuated FAK, MAPK/ERK, and PI3K/AKT signaling.

eLife Assessment

This valuable study provides in-vivo evidence that CCR4 regulates the early inflammatory response during atherosclerotic plaque formation. The authors propose that altered T-cell response plays a role in this process, shedding light on mechanisms that may be of interest to medical biologists, biochemists, cell biologists, and immunologists. The work is currently considered incomplete pending textual changes and the inclusion of proper controls.

eLife Assessment

This important study investigates how signals from the nervous system can influence the response to different food sources. To demonstrate the role of specific neuronal and intestinal regulators in sensing food quality and modulating digestion, the authors present evidence through a combination of genetic screening, RNA-seq analysis, and functional studies. While the findings shed light on an adaptive strategy to integrate food perception with physiological responses, the evidence presented varies between convincing and incomplete, and additional experiments are needed to more fully support their central hypothesis.

eLife Assessment

This important study examines the effects of acute social stress on brain function, focusing on dynamic shifts in large-scale networks such as the salience and default mode networks. It highlights a robust association between stress-induced changes in salience network activation and stress reactivity in daily life, although evidence linking brain function changes following acute stress to real-life stress is incomplete. The findings are significant for stress biology research and could influence future studies on stress responses.

eLife Assessment

This study uses state-of-the-art methods to label endogenous dopamine receptors in a subset of Drosophila mushroom body neuronal types. The authors report that Dop1R1 and Dop2R receptors, which have opposing effects on intracellular cAMP, are present in axons termini of Kenyon cells, as well as those of two classes of dopaminergic neurons that innervate the mushroom body indicative of autocrine modulation by dopaminergic neurons. Additional experiments showing opposing effects of starvation on Dop1R1 and Dop2R levels in mushroom body neurons are consistent with a role for dopamine receptor levels increasing the efficiency of learned food-odour associations in starved flies. Supported by solid data, this is an important contribution to the field.

eLife Assessment

Wang et al. presented visual (dot) motion and/or the sound of a walking person and found solid evidence that EEG activity tracks the step rhythm, as well as the gait (2-step cycle) rhythm, with some demonstration that the gait rhythm is tracked superadditively (power for A+V condition is higher than the sum of the A-only and V-only condition). The valuable findings will be of wide interest to those examining biological motion perception and oscillatory processes more broadly.

eLife Assessment

These studies make a fundamental contribution to our understanding of axon-guidance mechanisms, focusing on the role of UNC-6/Netrin in the long-range growth and targeting of axons. Using state-of-the-art genetics and in vivo imaging, the authors provide compelling support for the finding that UNC-6/Netrin can act via both chemotaxis and haptotaxis. This work will be of interest to a wide variety of cell and developmental biologists and neuroscientists.

eLife Assessment

This important study offers convincing evidence that fmo-4 plays essential roles in established lifespan interventions and downstream of its paralog fmo-2. The work is of substantial benefit for our understanding of this enzyme family, underscoring their importance in longevity and stress resistance. The study also suggests a connection between fmo-4 and dysregulation of calcium signalling, with conclusions and interpretations based on solid genetic methodology and evidence.

eLife Assessment

This important study substantially advances our understanding of the circadian clock in Antarctic krill, a key species in the Southern Ocean ecosystem. Through logistically challenging shipboard experiments conducted across seasons, the authors provide compelling evidence for their conclusions. The study will be of broad interest to marine biologists and ecologists.

eLife Assessment

In this study, the authors present compelling data illustrating a potential mechanism for a hitherto not described form of extracellular vesicle biogenesis. Their model suggests that small extracellular vesicles are secreted from cells within larger vesicles, termed amphiectosomes, which subsequently rupture to release their smaller vesicle contents. This discovery represents an important advancement in the field.

eLife Assessment

This important study showing that sleep deprivation increases functional synapses while depleting silent synapses supports previous findings that excitatory signaling increases during wakefulness. This manuscript focuses in particular on AMPA/NMDA ratios. An interesting, although speculative, aspect of the manuscript is the inclusion of a model for the accumulation of sleep needs that is based upon the MEF2C transcription factor but also links to the sleep-regulating SIK3-HDAC4/5 pathway. The authors have clarified some questions raised in the previous review, rendering this a solid piece of work that poses questions for future studies.

eLife Assessment

This important study shows that a monoclonal antibody against the repetitive region of the circumsporozoite protein (CSP) of the Malaria-causing parasite P. berghei has neutralizing activity on parasite invasion and development. The authors present convincing in vivo data confirming previous in vitro work, that suggested the intracellular post -invasion effect for this antibody. The findings offer insights into the inhibitory action of this anti-CSP antibody, which could inform the development of more effective malaria vaccines and therapeutic antibodies."

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

eLife Assessment

This important study assessed the effects of food intake on sharp wave-ripples in the hippocampus of mice during subsequent sleep. Solid evidence supports the conclusion that sharp wave-ripples are enhanced by food consumption. This work will likely interest researchers studying multiple functions including memory, metabolism, and brain-body physiology.

eLife Assessment

This study presents fundamental insights into overcoming resistance in hormone receptor-positive breast cancer by demonstrating that sustained CDK4/6 inhibitor treatment, either alone or in combination with CDK2 inhibitors, significantly suppresses the growth of drug-resistant cancer cells. The findings are supported by compelling evidence from both in vitro cell line experiments and in vivo mouse models, highlighting the therapeutic potential of maintaining CDK4/6 inhibitors beyond disease progression. Additionally, the identification of cyclin E overexpression as a key driver of resistance offers a target that will be of value for future therapeutic strategies, potentially improving outcomes for patients with advanced breast cancer.

eLife Assessment

Gating of mechanosensitive channels has been explained by the force-from-lipids model in which mechanical coupling of the channel protein to the plasma membrane transfers force from membrane tension to open the channel. In this important manuscript, the authors provide evidence for this mechanism in two different mechanically gated channels. The experiments were carried out in the same membranes, but the evidence is incomplete without a clear explanation of the relationship between measured mechanical parameters and membrane interfacial tension.

eLife Assessment

This study develops useful tools for distinct optogenetic control of neuronal activity by red or blue light. The basic characterization of the activation of a red-shifted channelrhodopsin paired with a blue-light sensitive anion channel engineered to obtain desired inhibitory current kinetics is solid. However, evidence for their practical use under simultaneous multi-color or high frequency stimulation in cells are missing.

eLife Assessment

This study presents valuable findings on the relative cerebral blood volume of non-human primates that move us closer to uncovering the functional and architectonic principles that govern the interplay between neuronal and vascular networks. The evidence of areal variations is solid, but that of vessel counting and laminar analysis is incomplete. The lack of a direct comparison of their approach against better-established MRI-based methods for measuring hemodynamics and vascular structure weakens the evidence provided in the current paper version. The work will be of interest to NHP imaging scientists.

eLife Assessment

This important work addresses the relationship between the transdiagnostic compulsivity dimension and confidence as well as confidence-related behaviours like reminder setting. The relationship between confidence and compulsive disorders has recently received a lot of attention and has been considered to be a key cognitive change. The authors paired an elegant experimental design and pre-registration to give convincing evidence of the relationship between compulsivity, reminder setting, and confidence. In the revised version they thoroughly addressed the reviewers comments, in particular adding new analyses clarifying how their findings relate to prediction error based learning further strengthening the manuscript.

eLife Assessment

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

eLife Assessment

This study investigates the conditions under which abstract knowledge transfers to new learning. It presents solid 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

The study presents compelling evidence that the melanocortin system originating in the arcuate nucleus of the hypothalamus plays a crucial role in puberty onset, representing a significant advance in our understanding of reproductive biology. The research employs innovative approaches and benefits from the combined expertise of two respected laboratories, enhancing the robustness of the findings. Given the potential impact on human health and the strength of the evidence presented, this fundamental work will likely influence the field substantially and may inform future clinical applications.

eLife Assessment

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

eLife Assessment

This important study enhances our understanding of ephaptic interactions by utilizing earthworm recordings to refine a general model and use it to predict ephaptic influences across various synaptic configurations. The integration of experimental evidence, a robust mathematical framework and computer simulations convincingly demonstrate the effects of action potential propagation and collision properties on nearby membranes. The study will interest both computational neuroscientists and physiologists.

eLife Assessment

This study presents important findings on the early development of cardiac and respiratory interoceptive sensitivity based on an investigation of infants aged 3, 9 and 18 months and on extensive statistical analyses. The evidence supporting the conclusions are convincing although the research faced technical challenges that limited part of the findings interpretation. This study will be of significant interest to developmental psychologists and neuroscientists working on interoception and its influence on socio-cognitive development.

eLife Assessment

In flies defective for axonal transport of mitochondria, the authors report the upregulation of one subunit, the beta subunit, of the heterotrimeric eIF2 complex via mass spectroscopy proteome analysis. Neuronal overexpression of eIF2β phenocopied aspects of neuronal dysfunction observed when axonal transport of mitochondria was compromised. Conversely, lowering eIF2β expression suppressed aspects of neuronal dysfunction. While these are intriguing, potentially useful observations, several technical weaknesses limit the interpretation and mean the evidence supporting the current claims is incomplete.

eLife Assessment

The paper presents valuable computational findings on how growth feedback affects the performance of synthetic gene circuits designed for adaptive responses. By systematically analyzing over four hundred circuit topologies, the authors provide solid evidence for their conclusions on failure mechanisms and design features that enhance robustness against growth dynamics. While the study's significance and rigor are somewhat constrained by its reliance on previously published network topologies, these results are highly relevant for advancing the engineering of gene circuits in various applications.

eLife Assessment

This manuscript provides an important overview of potential resistance mutations within MET Receptor Tyrosine Kinase. The evidence supporting the findings is convincing - it should be pointed out that the approach is comparatively new for the application of protein kinases and the results are therefore of potentially great value. The results will be of value for clinicians facing drug resistance mutations, computational biologists who are training models of drug resistance mechanisms and biologists with an interest in cell signaling.

eLife Assessment

The study is important to show the role of MED26 in red cell formation. Linking transcription pausing with erythropoiesis is a key discovery. The data are solid although there are still spaces to improve. The in vivo data are limited by specificity concerns on their Cre model. Having RNA-seq, using more erythroid markers such as band3 and a4-integrin, and orthogonal validation with iPSC-erythropoiesis model will improve the study.

eLife Assessment

This auhors present findings on the role of the sirtuins SIRT1 and SIRT3 during Salmonella Typhimurium infection. This valuable study increases our understanding of the mechanisms used by this pathogen to interact with its host and may have implications for other intracellular pathogens. The reviewers disagreed on the strength of the evidence to support the claims. Although one reviewer found the strength of the evidence convincing, the other found that it was incomplete, and that the main claims are only partially supported, as can be seen from the public reviews.

eLife Assessment

This important study advances our understanding of the mechanisms controlling lipid flux and ion permeation in the TMEM16 and OSCA/TMEM63 family channels. The study provides compelling new evidence indicating that side chains along the TM4/6 interface play a key role in gating lipid and ion fluxes in these channels. The authors suggest that the transmembrane channel/scramblase family proteins may have originally functioned as scramblases but lost this capacity over evolution.

eLife Assessment

This valuable study proposes that protein secreted by colon cancer cells induces cells with Paneth-like properties that favor colon cancer metastasis. The evidence supporting the conclusions is strong but would benefit from more direct experiments to test the functional role of Paneth-like cells and to monitor metastasis from colon tumors. The work will be of interest to researchers studying colon cancer metastasis.

eLife Assessment

The ingenious design in this study achieved the observation of 3D cell spheroids from an additional lateral view and gained more comprehensive information than the traditional one angle of imaging. This extended the methods to investigate cell behaviors in the growth or migration of tumor organoids in a time-lapse manner and these extensions should be important to the field. The authors provide compelling evidence that the methods work as described.

eLife Assessment

This useful work reveals differential activity to food and shock outcomes in central amygdala GABAergic neurons. Evidence supports claims of unconditioned stimulus activity that changes with learning. Compelling evidence that the circular shift method rigorously identifies functional neuron types is also presented. However, the evidence regarding claims related to valence or salience signaling in these neurons is incomplete. This work will be of interest to neuroscientists studying sensory processing and learning in the amygdala.

eLife Assessment

This is a valuable report of a spatially-extended model to study the complex interactions between immune cells, fibroblasts, and cancer cells, providing insights into how fibroblast activation can influence tumor progression. The model opens up new possibilities for studying fibroblast-driven effects in diverse settings, which is crucial for understanding potential tumor microenvironment manipulations that could enhance immunotherapy efficacy. While the results presented are convincing and follow logically from the model's assumptions, some of these assumptions, as acknowledged by the authors, may oversimplify certain aspects in light of complex experimental findings, system geometry, and general principles of active matter research. Nonetheless, the authors provide justification for their work as a meaningful step towards more comprehensive modeling approaches.

eLife Assessment

In this manuscript, the authors describe the creation of a transgenic mouse expressing a reporter for Integrated Stress Response (ISR) activation in a CRE-dependent manner. Reliable tools for detecting ISR activation in situ are lacking, so this manuscript describes a potentially valuable tool that builds on and overcomes some of the limitations of a similar viral vector described by the authors in a previous publication. Solid evidence suggests that distinct populations of cells (ChAT) in the nervous system are marked by some level of ISR activation, and that the mouse could be most helpful as a screen for cell types in which the ISR is particularly active, although it would be difficult to draw conclusions from the reporter alone. Additional validations of the reporter activity in situ will further strengthen the manuscript.

eLife Assessment

This is an important study that reports the mechanism by which Ankle2 (LEM4 in humans) interacts with and recruits PP2A and the ER protein Vap33 to promote BAF dephosphorylation and mediate nuclear membrane reformation, using Drosophila as their model. Using Ankle2 mutants, they find that the ER protein Vap33 is key for the normal interphase localisation of Ankle2/LEM4 and also impacts on the function of Ankle2/LEM4 during mitosis. The conclusions on the subcellular localization of Ankle2 are drawn from overexpression of constructs. Overall, the authors use a variety of complementary techniques and provide convincing evidence to support the claims and advance our knowledge in the field of mitosis and nuclear envelope biology.

eLife Assessment

This study proposes a new model that could solve some long-standing puzzles about inversion polymorphisms in Drosophila melanogaster by invoking sexually antagonism and negative frequency-dependent selection. While the idea developed here is a valuable contribution to the field, the experiment only addresses one element of the hypothesis, so that the empirical evidence in support of the model remains incomplete.

eLife Assessment

This valuable work provides novel insights into the substrate binding mechanism of a tripartite ATP-independent periplasmic (TRAP) transporter, which may be helpful for the development of specific inhibitors. The structural analysis is convincing, but additional work will be required to establish the transport mechanism as well as well as binding sites for all ligands. This study will be of interest to the membrane transport and bacterial biochemistry communities.

eLife assessment

The article has important scientific merit in the field of cardiovascular research and other fields where the design and rigor of scientific experiments is key for translation of preclinical research to clinical studies. This study holds convincing evidence that sheds light on the lack of progress in this area over the past decade, despite a substantial body of existing research. Although there is a need to re-evaluate the statistical test used, the descriptive paper outcomes serves as a strong call to action for the wider scientific community.

eLife Assessment

This valuable work presents an interesting strategy to interfere with the HBV infectious cycle as it identifies two previously unexplored HBc-Ag binding pockets. The experimental data is compelling and opens the door to generating and testing novel anti-HBV therapies.

eLife Assessment

In this manuscript, the authors describe a new AlphaFold2 pipeline called PabFold that can represent a useful tool for identifying linear antibody epitopes (B-cell epitopes) for different antigens. This information can be used in the selection of different reagents in competitive ELISA assays which can save time and reduce costs. Because several questions about the work remain, the study is currently incomplete.

eLife Assessment

The objective of this important study is to assess the study design and rigor, enhance the quality of clinical research studies, and emphasize crucial design elements in basic science research. It specifically tackles the ongoing problem of experimental design deficiencies that obstruct the effective translation of research findings into clinical applications. This paper is particularly convincing as it highlights the lack of progress in addressing these issues over the past decade, despite a substantial body of existing research. It serves as a strong call to action for the broader scientific community to improve research practices.

eLife Assessment

This is a valuable 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 behaviour 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 solid, the data do not currently support the mechanism of activity of the TF in rhythmic gene expression.

eLife Assessment

This study answers an essential question about how migratory primordial germ cells mobilize based on their anterior or posterior location. Convincing data support the model that interactions of migrating mouse PGCs with their niches influences their proliferation, cytoskeletal regulation, epigenetic state and pluripotent state. Rigorous methodology and analysis of single-cell RNA sequencing of migratory primordial germ cells and surrounding somatic cells result in datasets which will be valuable to developmental biologists.

eLife Assessment

This useful manuscript provides a newly curated database (termed AACDB) of antibody-antigens structural information, alongside annotations that are either taken and from the PDB, or added de-novo. Sequences, structures, and annotations can be easily downloaded from the AACDB website, speeding up the development of structure-based algorithms and analysis pipelines to characterize antibody-antigen interactions. The methodology presented for this data curation is solid, although some key annotations are missing which would greatly improve the database.

eLife Assessment

Mackie and colleagues present a valuable comparison of lateralized gustation in two well-studied nematodes. The evidence they present that ASEL/R lateralization exists and is achieved by different means in P. pacificus compared to C. elegans is solid, but would be strengthened by the inclusion of calcium imaging data for C. elegans and additional verification of P. pacificus AFD neuron identity. This work will be of interest to evolutionary biologists, ecologists, and sensory neurobiologists interested in how small nervous systems make sense of the environment, and how evolution can take multiple paths to asymmetry within a neuron class.

eLife Assessment

This valuable paper describes the regulatory pathway of rRNA synthesis by Meioc-Piwil1 in germ cell differentiation in zebrafish. Using the molecular genetic and cytological approaches, the authors provide convincing evidence that Meioc antagonizes Piwil1, which downregulates the 45S pre-rRNA synthesis by heterochromatin formation for spermatocyte differentiation. The key results are solid and of use to researchers in the field of germ cell/meiosis as well as RNA biosynthesis and chromatin.

­eLife Assessment

The authors examine the role of Numb, a Notch inhibitor, in intestinal stem cell self-renewal in Drosophila during homeostasis and regeneration. This is an important study providing evidence of a Numb-mediated, back-up mechanism for intestinal stem cell maintenance. The strength of evidence is convincing as the authors present a carefully constructed series of experiments, robust genetics, large sample sizes, and appropriate statistical analyses.

eLife Assessment

This is a useful study that seeks to address the role of the TET family of DNA demethylation enzymes in pancreatic beta cell senescence in the context of type 2 diabetes (T2DM). Although the concepts are novel and of interest, the study presents incomplete evidence to fully support its main conclusions.

eLife Assessment

Building on earlier evidence that Topoisomerase 2 depletion can extend yeast lifespan, the authors present convincing data demonstrating that reduced Top2 levels confer significant longevity benefits in C. elegans and mice. They show that these benefits encompass not only extended survival but also improved healthspan and mitigation of aging phenotypes, supported by robust transcriptomic, epigenetic, and histological analyses. While the exact mechanistic underpinnings-such as the potential connection to classical aging pathways and the selective down-regulation of genes with active promoters-remain to be fully elucidated, the breadth of these important findings strongly indicates a conserved role for Top2 in aging regulation.

eLife Assessment

This study offers a valuable treatment of how the population of excitatory and inhibitory neurons integrates principles of energy efficiency in their coding strategies. The convincing analysis provides a comprehensive characterisation of the model, highlighting the structured connectivity between excitatory and inhibitory neurons. The role of the many free parameters are discussed and studied in depth.

eLife Assessment

This is a useful study depicting the ultrastructural features of layer 1 of the human temporal cortex, the authors assess various synaptic parameters, astrocytic coverage, and mitochondrial morphology. High-quality data were collected using a solid methodology, however, the analysis of the functional vesicle pools is incomplete, technical issues remaining related to the identification of astrocytic processes and the measurement of vesicle diameters, and reliance solely on electron microscopy limits the scope of the work to structural observation. The work will be of interest to neuroscientists and computational researchers investigating cortical and network function.

eLife Assessment

This valuable study uses high-field fMRI to test the hypothesized involvement of subcortical structures, particularly the striatum, in updating working memory. The study overcomes limitations of prior work by applying high-field imaging with a more precise definition of regions of interest in the brain. Thus, the empirical observations are of use to specialists interested in working memory gating or the reference back task specifically. The evidence is generally solid, but strong conclusions on dopaminergic contributions must await additional work using molecular imaging or related techniques.

eLife Assessment

This important study successfully applies an innovative chemogenetic tool to investigate cerebellar function to advance our understanding of the contributions of Purkinje cell populations to postural control in larval zebrafish. The evidence supporting the conclusions is convincing and supported by rigorous statistical analysis. The study highlights the power of combining genetically targeted perturbations with quantitative high-throughput behavioral analysis and original microscopy tools.

eLife Assessment

This important study provides convincing evidence that developing neurons in the neocortex regulate glial cell development. The data demonstrates that the transcription factor FOXG1 negatively regulates gliogenesis by controlling the expression of a member of the FGF ligand family and by suppressing the receptor for this ligand in developing neurons. This study leads to a new understanding of the cascade of events regulating the timing of glial development in the neocortex.

eLife Assessment

The work by Han and collaborators describes valuable findings on the role of Akkermansia muciniphila during ETEC infection. If confirmed, these findings will add to a growing list of beneficial properties of this organism. The strength of the evidence used to justify the conclusions in the manuscript is solid, as the analyses broadly support the claims with only minor weaknesses.

eLife Assessment

This study tested the specific hypothesis that age-related changes to hearing involve a partial loss of synapse connections between sensory cells in the ear and the nerve fibers that carry information about sounds to the brain, and that this interferes with the ability to discriminate rapid temporal fluctuations in sounds. Physiological, behavioral, and histological analyses provide a powerful combination to test this hypothesis in gerbils. Contrary to previous suggestions, it was found that chemically-induced isolated synaptopathy (at similar levels as observed in aged gerbils) did not result in worse performance on a behavioral task measuring sensitivity to fine-structure. Further, altered neural coding of rapid fluctuations produced no perceptual deficits in either these gerbils or in aged gerbils. These findings are important for understanding age-related changes to hearing; however, the evidence provided is incomplete due to problems in interpretation and the discussion of possible confounds and/or limitations of these data that currently limits mechanistic insight.

eLife Assessment

This valuable study shows that a very slow (infraslow) oscillation occurs in voltage recordings from the dentate gyrus of the adult mouse. The authors suggest that it is related to sleep stage and serotonin acting at one type of serotonin receptor in the dentate gyrus. The ideas are potentially significant because they suggest that this oscillation affects memory through serotonin receptors in the dentate gyrus. Solid evidence is provided to broadly support the main claims, although analytical weaknesses remain that could be improved by clarification of methods, analyses, and data shown in the figures.

eLife Assessment

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

eLife Assessment

This valuable study reports the induction of supernumerary inner hair cells in the mouse cochlea upon reducing the expression level of a tight-junction protein (claudin-9) at developmental stages. Although these ectopic hair cells are functional and persists through adulthood, the evidence supporting some of the claims is incomplete, particularly regarding the underlying mechanisms of cell differentiation and the potential of the approach for hair-cell regeneration. The work will be of interest to scientists working in the development and regeneration of hair cells in the inner ear.

eLife Assessment

What makes one member of the species behave differently from another? This is a core problem in behavioral neuroscience. This valuable study seeks an answer for the specific case of the fruit fly expressing preferences for one odor over another. By a combination of behavioral measurements, neurophysiology, and network modeling, the authors find solid evidence for at least one locus of individuality in the peripheral olfactory system.

eLife Assessment

The study evaluates the feasibility, safety, and tolerability of neoadjuvant radiotherapy followed by a CDK4/6 inhibitor (dalpiciclib) and hormonal therapy in treatment-naive patients with unilateral early-stage HR+/HER2- breast cancer. The findings are convincing, with a strong scientific rationale supported by integrated correlative studies. The trial is considered to be important as the outcomes could inform the design of larger, future studies. The strength of the conclusions should be tempered as the study included only a small cohort of patients (n=12) and was not adequately powered to definitively assess the efficacy or safety of this combinatorial treatment approach.

eLife Assessment

This valuable study uses zebrafish as a model to reveal a role for the cell cycle protein kinase CDK2 as a negative regulator of type I interferon signaling. The evidence supporting the authors' claims is convincing, including both in vivo and in vitro investigative approaches that corroborate a role for CDK2 in regulating TBK1 degradation. In this latest version, the authors included data addressing concerns raised by the reviewers at the first peer review round that strengthens the conclusions. This work will interest cell biologists, immunologists, and virologists.

eLife Assessment

In this important work, Lodhiya et al. provide evidence that excessive ATP underlies the killing of the model organism Mycobacterium smegmatis by two mechanistically-distinct antibiotics. The data are generally solid as the authors deploy multiple, orthogonal readouts and methods for manipulating reactive oxygen species and ATP. The work will be of interest to those studying antibiotic mechanisms of action.

eLife Assessment

This fundamental work extends our understanding of the role of TGFβ2 as a modulator of mechanosensing in the eye and identifies the TRPV4 ion channel as a common regulator of Trabecular Meshwork (TM) contractility and pathological OHT. The data and evidence are convincing, with some minor limitations. This work will clearly be of interest to researchers investigating the role of mechanosensors in the TM and may underpin future research into treatments that aim to lower intra ocular pressure. This work will additionally be of interest to the growing field of researchers investigating the regulation of force sensing via ion channels and their roles in health and disease, in particular the ion channel TRPV4.

eLife Assessment

The findings are important and intriguing, with theoretical or practical implications beyond a single subfield. The computational methods employed are clever and sophisticated and the strength of evidence is convincing. However, all three reviewers also highlight a lack of focus and clarity, as well as missing information about model comparison, fit statistics and group comparison of parameters from different models.

eLife Assessment

This valuable study tests a methodology for the discovery of new honey bee-repellent odorants via machine learning. The conclusions of the study are supported by solid evidence, with predicted compounds validated in the lab and the field. This work will be of interest to researchers in ecology, pest control and olfactory neuroscience.

eLife Assessment

This is a fundamental body of work reporting anatomical, molecular, and functional mapping of the central complex in Drosophila. 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. Overall, the data are compelling and likely to have a major impact.

eLife Assessment

This important study investigates how hummingbird hawkmoths integrate stimuli from across their visual field to guide flight behavior. Cue conflict experiments provide solid evidence for an integration hierarchy within the visual field: hawkmoths prioritize the avoidance of dorsal visual stimuli, potentially to avoid crashing into foliage, while they use ventrolateral optic flow to guide flight control. With a more systematic quantification of specific parameter combinations, this paper would be of broad interest to enthusiasts of visual neuroscience and ethology.

eLife Assessment

This important Research Advance presents convincing evidence on the neuroprotective effects of reserpine in a well-established model of retinitis pigmentosa (P23H-1). This study builds on previous work establishing reserpine as a neuroprotectant in models of Leber congenital amaurosis. Here authors show reserpine's disease gene-independent influence on photoreceptor survival and emphasizes the importance of considering biological sex in understanding inherited retinal degeneration and the impact of drug treatments on mutant retinas. The work will be of interest to vision researchers as well as a broad audience in translational research.