eLife assessment

This is an important paper as it is the first to use a reconstituted translation system to study competition among mRNAs for the initiation machinery. Understanding the principles of the biochemistry of mRNA competition for initiation factors cannot be achieved without such a system. The authors provide compelling evidence that Ded1 is required for efficient initiation in highly structured RNAs. A highly significant finding that validates the in vitro reconstituted system indeed recapitulates the effects of in-vivo perturbations of translation initiation.

eLife assessment

The study presents valuable findings on how the hypoxia response pathway senses and responds to changes in the homeostasis of the amino acid cysteine and other sulfur-containing molecules. By providing a compelling, rigorous genetic analysis of the pathway, the study adds to a growing body of literature showing that prolyl hydroxylation is not the only mechanism by which the hypoxia response pathway can act. Although the paper does not reveal new biochemical insight into the mechanism, it opens up new areas of investigation that will be of interest to cell biologists and biomedical researchers studying the many pathologies involving hypoxia and/or cysteine metabolism.

eLife assessment

This useful study aimed to examine the relationship of spatial frequency selectivity of single macaque inferotemporal (IT) neurons to category selectivity. There are some interesting findings in this report but some of these findings were difficult to evaluate because several critical details of the analysis are incomplete. The conclusion that single-unit spatial frequency selectivity can predict object coding needs further evidence to confirm.

eLife assessment

This fundamental study reveals the major role of calcium-binding proteins (CaBP1 and CaBP2) in sustained exocytosis from mouse inner hair cell ribbon synapses. Compelling data and analysis from CaBP1/2 double-knockout mice show enhanced calcium channel (CaV1.3) inactivation, slowed recovery from inactivation, and reduced synaptic vesicle exocytosis as assayed by membrane capacitance measurements, as well as greatly reduced in vivo spontaneous and sound-evoked spikes from the postsynaptic spiral ganglion neurons. Importantly, transgenic expression of CaBP2 led to the rescue of hearing capabilities. The continuous transmission of sound-evoked signals from auditory hair cells thus depends on the expression of both CaBP1 and CaBP2 and their suppression of CaV1.3 inactivation.

eLife assessment

Given a great need for novel human model systems to study small cell lung cancer (SCLC), the authors describe an important pre-clinical model with broad potential for the study of how genetic perturbations or drug treatments alter SCLC tumor growth, metastasis, and response to therapy. For the major finding, the authors provide convincing evidence that RB/TP53 suppression coupled with MYC overexpression in an ES cell-derived model system results in aggressive and metastatic SCLC. However, comparisons of the RB/TP53-suppressed, MYC overexpressing model with RB/TP53-suppressed cells in supporting the minor conclusion that MYC overexpression increases the neuroendocrine compartment are incomplete, and the impact of the work would have been increased with the inclusion of a broader set of genetic perturbations, such as over-expression of MYCL, to better model major SCLC phenotypes. The new model described will be of significant interest to researchers studying lung cancer.

eLife assessment

This study presents valuable insights into the potential role of a general transcription factor in MYCN-dependent regulation of transcription. The study presents solid evidence that TFIIIC and MYCN interact to control transcription. The methods, data, and analyses broadly support the claims with minor weaknesses, yet the logic can be improved, and several specific issues should be addressed. The paper would be of interest to molecular biologists working on MYCN-dependent regulation of gene expression.

eLife assessment

This important work substantially advances our understanding of osteoblast migration to the sites of bone formation and regeneration. The evidence supporting the conclusion is convincing, with rigorous in vitro assays for cellular and biochemical aspects and with appropriate in vivo models. The work will be of broad interest to developmental biologists and bone biologists.

eLife assessment

To investigate the evolutionary relationship between the RNAi pathway and innate immunity, this study uses biochemistry and structural biology to investigate the trimeric complex of Dicer-1, DRH-1 (a RIGI homologue), and RDE-4, which exists in C. elegans. The results described include rigorous kinetic analysis of the enzymatic activity of the complex and a moderate resolution cryo-EM structure. The results are convincing and valuable to the broader understanding of the evolution of antiviral defense.

eLife assessment

This valuable study shows that eliminating a large portion of the principal neurons in the mammalian olfactory bulb does not affect the initial establishment of the circuit but has an impact on its maintenance. The strength of the paper is that the anatomical changes induced by genetic ablation of neurons are clear-cut. There is a solid description of the structural and behavioral effects of ablating the majority of M/T neurons; however, the conclusions are incompletely supported by the findings.

eLife assessment

This paper describes valuable results from studies investigating circuits in the brain that underlie behavioral responses in fearful situations. The authors identified a role for a class of neurons that are sufficient to cause these stereotyped behaviors including freezing behaviors. These solid studies increase our understanding of brain pathways regulating these types of behaviors.

eLife assessment

This important work provides a robust yet simple protocol to isolate small extracellular vesicles from small volumes of plasma. The evidence supporting the conclusions is convincing, although a more thorough statistical comparison of the different techniques and technique combinations explored in the study would have been appreciated. The work will be of broad interest to cell biologists and biochemists.

eLife assessment

This useful study compares gene expression patterns among different autonomic ganglia and will be of interest to developmental neuroscientists and neurophysiologists. The study expands the database of genes expressed by subpopulations of autonomic neurons in ganglia, a key step in decoding their developmental origins and physiological functions. The evidence supporting the alternative view that the pelvic ganglionic neurons are actually modified sympathetic neurons is incomplete and may cause confusion, given the enrichment of cholinergic neurons, as well as the large number of molecular and functional differences known to be present between cranial and sacral neurons.

eLife assessment

This useful study compares gene expression patterns among different autonomic ganglia and will be of interest to developmental neuroscientists and neurophysiologists. The study expands the database of genes expressed by subpopulations of autonomic neurons in ganglia, a key step in decoding their developmental origins and physiological functions. The alternative view that the pelvic ganglionic neurons are actually modified sympathetic neurons is incompletely demonstrated given the large number of molecular and functional differences known to be present between cranial and sacral neurons.

eLife assessment

This study explores how Ebola virus evades human immune responses. The study reports a potential new mechanism wherein Ebola virus traps human IRF3, a key transcription factor involved in immune signaling, into virus-produced "inclusion bodies". The topic is important, the paper has many merits, and the biochemical assays are solid. However, the current data do not clearly explain the relationship between the VP35 protein and IRF3.

eLife assessment

This study presents a potentially valuable discovery which indicates that activation of the P2RX7 pathway by the small molecule HEI3090 can reduce lung fibrosis after its establishment by inflammatory damage. If confirmed, the study could clarify the role of specific immune networks in the establishment and progression of lung fibrosis. The presented data and analyses showing the efficacy of HEI3090 small molecule acting via the P2RX7 pathway in reducing lung fibrosis are solid. The studies also show that genetic deletion of P2RX7 itself can reduce the extent of fibrosis. P2RX7 can thus have distinct effects in various phases of the development of lung fibrosis. There is a need for additional definitive studies that specifically identify the discrete phases of when inflammasome activation via P2RX7 signaling can worsen fibrosis versus when the same signaling can be beneficial. It also needs to be established whether distinct immune cell populations mediate the detrimental and beneficial effects of P2RX7 activation in lung fibrosis.

eLife assessment

The authors develop a novel genetic strategy for specific and comprehensive labeling of axo-axonic cells, also referred to as Chandelier cells, in the mouse brain. The approach and analysis are rigorous such that the data convincingly support the key conclusions, including the expanded distribution of axo-axonic cells throughout the brain. This study provides valuable new information about the distribution of this neuronal cell type, as well as new tools for future studies. This work will be of broad interest to neuroscientists who work on the anatomical and functional organization of neural circuits.

eLife assessment

The manuscript addresses a fundamental question: are IDRs responsible for subnuclear clustering of transcription factors? A screen of 75 IDRs yielded convincing evidence that IDRs are rarely sufficient for subnuclear clustering, while the experimental design and data analysis provided limited evidence for the authors' claims regarding transcription factor clustering.

eLife assessment

This is an important paper that combines methods ranging from agronomy and plant breeding to Arabidopsis functional genetics, to argue that polymorphism in a single gene affects crop yield in pearl millet by affecting root cell elongation and drought stress resilience in a poorly studied crop. The overall argument is plausible but whether the solid evidence generated with Arabidopsis experiments can be extended to pearl millet itself is unclear.

eLife assessment

In this valuable contribution, the authors demonstrate that the infusion of NAD+ may prevent death and reduce disease severity from lethal experimental bacterial sepsis, possibly through inflammasome inhibition, without reducing bacterial load. They provide solid evidence for these protective effects of NAD+, though the precise mechanisms involved remain unclear and need further support and elucidation. The core findings may well have clinical implications but, in addition to mechanistic clarifications, contextualised interpretation as metabolic adaptation to sepsis would create wider interest.

eLife assessment

This detailed and well powered manuscript explores auditory perception of modulated noise in the presence of transcranial alternating-current stimulation (tACS) and shows valuable results suggesting that there are subject-specific effects when the phase of 2-Hz tACS varies relative to the phase of the noise modulation. The strength of the evidence is mixed. There is convincing evidence that tACS alters perception significantly in individuals; however, the effects are inconsistent across subjects and even across sessions, frustrating attempts to draw conclusions about the underlying mechanisms of the idiosyncratic effects. Despite these limitations, the paper will be of great interest to researchers interested in determining when and how tACS influences neural processes, especially those interested in neural entrainment and its relationship to perception.

eLife assessment

The study is an important advancement to the consideration of antimalarial drug resistance: the authors make use of both modelling results and supporting empirical evidence to demonstrate the role of malaria strain diversity in explaining biogeographic patterns of drug resistance. The theoretical methods and the corresponding results are compelling, with the novel model presented moving beyond existing models to incorporate malaria strain diversity and antigen-specific immunity. This work is likely to be interesting to malaria researchers and others working with antigenically diverse infectious diseases.

eLife assessment

This study presents a valuable method to visualize the location of the cell types discovered through single-cell RNA sequencing. The evidence supporting the claims is solid, but the inclusion of a larger number of samples would strengthen the study. It would also be helpful to have the methods explained in more detail. The work will be of interest to those seeking to identify new cell types from scRNA-seq and snRNA-seq data.

Certainly! Let's break down the provided code snippets:

1. What is it and why is it used?

In Mongoose, a schema is a blueprint for defining the structure of documents within a collection. When you define a schema, you can also attach methods to it. These methods become instance methods, meaning they are available on the individual documents (instances) created from that schema.

Instance methods are useful for encapsulating functionality related to a specific document or model instance. They allow you to define custom behavior that can be executed on a specific document. In the given example, the findSimilarTypes method is added to instances of the Animal model, making it easy to find other animals of the same type.

2. Syntax:

Using methods object directly in the schema options:

javascript const animalSchema = new Schema( { name: String, type: String }, { methods: { findSimilarTypes(cb) { return mongoose.model('Animal').find({ type: this.type }, cb); } } } );

Using methods object directly in the schema:

javascript animalSchema.methods.findSimilarTypes = function(cb) { return mongoose.model('Animal').find({ type: this.type }, cb); };

Using Schema.method() helper:

javascript animalSchema.method('findSimilarTypes', function(cb) { return mongoose.model('Animal').find({ type: this.type }, cb); });

3. Explanation in Simple Words with Examples:

Why it's Used:

Imagine you have a collection of animals in your database, and you want to find other animals of the same type. Instead of writing the same logic repeatedly, you can define a method that can be called on each animal instance to find similar types. This helps in keeping your code DRY (Don't Repeat Yourself) and makes it easier to maintain.

Example:

```javascript const mongoose = require('mongoose'); const { Schema } = mongoose;

// Define a schema with a custom instance method const animalSchema = new Schema({ name: String, type: String });

// Add a custom instance method to find similar types animalSchema.methods.findSimilarTypes = function(cb) { return mongoose.model('Animal').find({ type: this.type }, cb); };

// Create the Animal model using the schema const Animal = mongoose.model('Animal', animalSchema);

// Create an instance of Animal const dog = new Animal({ type: 'dog', name: 'Buddy' });

// Use the custom method to find similar types dog.findSimilarTypes((err, similarAnimals) => { console.log(similarAnimals); }); ```

In this example, findSimilarTypes is a custom instance method added to the Animal schema. When you create an instance of the Animal model (e.g., a dog), you can then call findSimilarTypes on that instance to find other animals with the same type. The method uses the this.type property, which refers to the type of the current animal instance. This allows you to easily reuse the logic for finding similar types across different instances of the Animal model.

Evaluation statement (10 January 2024)

Driggers et al. is an elegant study that reports the structure of an open KATP channel complex formed from the Q52R diabetes mutation of the pore-forming subunit Kir 6.2, the sulfonylurea receptor (SUR1), and long-chain phosphatidylinositol 4,5-bisphosphate (PIP2) – a key lipid that stabilizes the open state of the channel and regulates inhibition by intracellular ATP. The structure reveals one PIP2 site related to that seen in other Kir channels as well as a second unanticipated one where the lipid snuggles into the interface between Kir6.2 and a region of SUR1 previously implicated in promoting the open state of KATP. This important finding helps to explain how PIP2 exerts such a profound regulatory influence on KATP.

Biophysics Colab considers this to be a convincing study and recommends it to scientists working on KATP and other membrane proteins regulated by PIP2.

(This evaluation by Biophysics Colab refers to version 2 of this preprint, which has been revised in response to peer review of version 1.)

eLife assessment

This valuable manuscript follows up on previous findings from the same lab supporting the idea that deficits in learning due to enhanced synaptic plasticity are due to saturation effects. Convincing evidence is presented that behavioral learning deficits associated with enhanced synaptic plasticity in a transgenic mouse model can be rescued by manipulations designed to reverse the saturation of synaptic plasticity. In particular, the finding that a previously FDA-approved therapeutic can rescue learning could provide new insights for biologists, psychologists, and others studying learning and neurodevelopment.

eLife assessment

In this important study, Gaikwad and colleagues employed ribosome profiling in conjunction with standard biochemical approaches to investigate the role of eIF2A in translation initiation in yeast under optimal growth conditions or stress. The authors provide convincing data that eIF2A is not implicated in translation initiation in yeast, a finding that is anticipated to inspire future investigations to identify the cellular role(s) of eIF2A in yeast. Considering the broad scope of cellular functions attributed to eIF2A, this study should be of interest to a wide spectrum of biomedical researchers ranging from those studying mechanisms of translation regulation to virologists and cancer biologists.

eLife assessment

This fundamental study presents a method to restore muscle innervations in ALS mouse models using optogenetics. It is convincing that embryonic stem cell derived motor neurons can be transplanted into and applied to reinnervate the muscles in an ALS mouse model. The work will be of broad interest to researchers and medical biologists to develop new strategies for the treatment of neurodegenerative disorders resulting from denervated skeletal muscles.

eLife assessment

This is a valuable paper that might contribute new insight into the role of GABA in semantic memory, which is a significant question in higher cognition. However, the empirical support for the main claims is incomplete, with some results not fully coherent and robust – the paper would benefit from more rigorous analyses. These results, once strengthened, will be of interest to broad readers of the neuroscience and cognitive neuroscience community.

eLife assessment

This important study combines experiments with optogenetic actuation and theory to understand how signalling proteins control the switch between cell protrusion and retraction, two processes in single-cell migration. The authors examine the role of a guanine exchange factor (GEF) on the downstream effectors RhoA and Cdc42, which trigger retraction and protrusion, respectively. The experimental and theoretical evidence provides a convincing explanation for why and how a single signalling protein – here, a GEF of RhoA – can control both protrusion and retraction.

eLife assessment

In this valuable study, the authors characterize the role of splicing factor SRSF1 during spermatogenesis with a conditional knockout of Srsf1 in male germ cells. The phenotype and molecular role of SRSF1 in regulating alternative splicing in precursor spermatogonial stem cells in juvenile testes are convincingly supported. The paper also provides convincing evidence that the mRNA encoding Tial, a factor relevant to spermatogonial maintenance and male fertility, is alternatively spliced in testis and that this splicing is regulated by SRSF1. The work will be of interest to the fields of reproductive biology, stem cell biology, and alternative splicing.

eLife assessment

This work presents important findings for the field of Alzheimer's disease, especially for the electrophysiology subfield, by investigating the temporal evolution of different disease stages typically reported using M/EEG markers of resting-state brain activity. The evidence supporting the conclusions is convincing and the methodology as well as the descriptions of the processes are of high quality, although a separation of individuals who are biomarker positive versus negative would have strengthened the results and conclusions of the study.

eLife assessment

This study presents a useful set of tools to perform tissue clearing and labeling on large-scale formalin-fixed paraffin-embedded brain specimens. This has the potential for the use of archival pathology specimens in modern research. Whilst the evidence supporting the validity of the method is convincing, the method development and protocol description are still incomplete and would benefit from a more comprehensive analysis. This paper would be of interest to neuroscientists and pathologists.

eLife assessment

This valuable study by Jeong and Choi studied neural activity in the medial prefrontal cortex (mPFC) while rats performed a foraging paradigm in which they forage for rewards in the absence or presence of a threatening object (Lobsterbot). The authors conclude that the mPFC population activity switches between distinct functional modes conveying distinct task variables such as the distance to the reward location and types of threat-avoidance behaviors depending on the location of the animal. The reviewers appreciated the use of the naturalistic paradigm but thought that the evidence was incomplete as the authors could not exclude the possibility that there are separate populations of neurons encoding different task variables, and in addition, various confounding factors such as specific movements have not been dissociated from the activity encoding the above variables.

eLife assessment

This study reports important findings that intermediate states exist in epithelial-mesenchymal transition (EMT) during natural development and differentiation of mammalian neural crest cells, similar to recent reports in cancer. The authors convincingly determined that there were at least two paths to delamination and migration - one that occurs during S-phase of cell cycle and another during G2/M phase, and that the process of delamination is not restricted to cell fate. Finally, the authors showed that expression of Dlc1 may be used to identify cells in an intermediate state of EMT as well as their spatial location in the mouse embryo. The work will be of interest to developmental biologists, neurobiologists and cancer researchers.

eLife Assessment

This important study demonstrates the use of the mammalian Musashi-1 (MSI-1) RNA-binding protein as a tool for regulating gene expression in Escherichia coli. The authors provide convincing evidence that MSI-1 functions as an effective repressor of translation, and that MSI-1 can be allosterically controlled by oleic acid. This work establishes MSI-1 as a potential tool for synthetic biology applications, and the system developed here can be used for mechanistic studies of MSI-1.

eLife assessment

The authors used an appropriate micro-engineered experimental model of angiogenesis coupled to mathematical model to study the early steps of the angiogenic sprouting. To this end, the authors developed a convincing model to predict how VEGF activates Delta-Notch signaling. The work affords important new insight into the complex processes involved in the onset of angiogenesis.

eLife assessment

This valuable paper examines the Bithorax complex in several butterfly species, in which the complex is contiguous and not split, as it is in the well-studied fruit fly Drosophila. Based on genetic screens and genetic manipulations of a boundary element involved in segment-specific regulation of Ubx, the authors provide convincing evidence for their conclusions, which could be strengthened by additional data and analyses in the future. The data presented are relevant for those interested in the evolution and function of Hox genes and of gene regulation in general.

eLife assessment

This study presents an important tool for tracking the connectivity of neurons in mouse and potentially other mammals using a combined approach of barcoded rabies virus libraries and spatial transcriptomics. The data supporting the technique are convincing, the validation against known anatomical knowledge is rigorous, and the authors advance the techniques by combing them in vivo. Overall, this is a very good paper describing a technique for tracking neural circuits.

eLife assessment

This fundamental study advances our understanding of TRAIL-induced apoptosis by defining how Heparan triggers this pathway at the molecular level. The evidence supporting the conclusions is compelling, with rigorous binding assays, structural methods, and cellular studies. The work will be of broad interest to cell biologists and biochemists.

eLife assessment

This study provides continuous maps of human brain gene expression and explores their relationship with a large variety of microscopic and macroscopic aspects of brain organisation. The authors provide convincing evidence for a relationship between gene expression maps with various aspects of the anatomy of adult brains, during development, and in the case of mental disorders. The data and methods introduced can be an important tool for neuroimaging research.

eLife assessment

The manuscript describes the synergy among PI3Kbeta activators, providing compelling results concerning the mechanism of their activation. The particular strengths of the work arise to a great extend from the reconstitution system better mimicking the natural environment of the plasma membrane than previous setups have. The study will be a landmark contribution to the signaling field.

eLife assessment

This important study describes how PhoP regulates cyclic-AMP production in the human pathogen Mycobacterium tuberculosis. The authors provide convincing evidence that PhoP acts as a repressor of the cyclic-AMP-specific phosphodiesterase, Rv0805, which can degrade cyclic-AMP. The work requires substantive revision to clarify the presentation of the data, together with appending conclusions, and will be of interest to bacteriologists.

eLife assessment

This study offers important insights into the transcriptional regulatory networks driving female gametocyte maturation in rodent malaria parasites. The work is based on solid methodology and shows how two female-specific transcription factors, AP2-FG and PFG (aka Fd2), co-operate to up-regulate the expression of genes required for development after fertilization occurs in the mosquito midgut. This study will be of interest to scientists working on sexual differentiation and gene regulation in Plasmodium and other apicomplexan parasites.

eLife assessment

The authors have developed a compelling coarse-grained simulation approach for nucleosome-nucleosome interactions within a chromatin array. The data presented are solid and provide new insights that allow for predictions of how chromatin interactions might occur in vivo. The tools presented herein will be valuable for the chromosome biology field.

eLife assessment

This valuable paper builds on a method, previously conceptualized and validated, of genetic control for insect populations. The method, called pgSIT, uses integrated CRISPR-Cas9 based constructs to generate, in certain combinations of genotypes, mutations that cause both male sterility and female inviability. Release of such genotypes in sufficiently large numbers can lead to an inundation of a local insect population with sterile males and this can lead to localised population suppression, which represents an effective method of control for problematic insect populations. The data are convincing and will be of interest to anyone working on vector control strategies.

eLife assessment

This important study uses genomically-engineered glypican alleles (Dally and Dally-like) to determine the role of these proteins on the Dpp/BMP morphogen gradient in the wing disc of Drosophila melanogaster. The new glypican null and tagged add-back alleles, as well as a Dpp mutant that cannot bind heparin sulfate moieties in glypicans, provide solid results that support the model in which Dally but not Dally-like stabilizes Dpp on the cell surface by counteracting receptor-mediated Dpp internalization. This paper would be of interest to developmental biologists working on morphogens.

eLife assessment

The manuscript explores the interplay between cytoskeletal bactofilins and cell wall hydrolases in bacterial morphogenesis, utilizing a range of methodologies from bacteriological to biochemical. The study provides important insights into bactofilin polymers' control over peptidoglycan synthesis and the identification of LdmC, supported by a comprehensive array of genetic, bioinformatic, biochemical, and biophysical tools. These convincing findings propose a conserved module governing bacterial morphogenesis, emphasizing the direct association of cell wall remodeling enzymes with a dynamic cytoskeleton, akin to mechanisms observed in other cellular processes such as cell growth and division.

eLife assessment

This useful study presents findings regarding the impact of forest cover and fragmentation on the prevalence of malaria in non-human primates. The evidence supporting the claims of the authors is solid.

eLife assessment

This is a valuable contribution to our understanding of how some bacteria can transport sterols from the cytoplasm to the outer membrane. Though much remains to be tested and explored, the data and analyses presented here provide solid evidence for the genetic and physical interaction of BstA/B/C with bacterially-produced sterols. The manuscript will be of interest to scientists focusing on the characterization of novel bacterial proteins and those studying lipid transport and acquisition in bacterial pathogens.

eLife assessment

This important study advances our understanding of the machinery that couples DNA synthesis with the deposition of histone proteins onto newly synthesized DNA. A convincing array of experiments combines NMR, protein biochemistry, and in vivo analyses of Chromatin Assembly Factor-1 of fission yeast. The work is of interest to researchers in the field of chromosome/chromatin biology as well as epigenetics.

eLife assessment

This valuable study presents convincing evidence for an association between PARP-1 and H4K20me1 in transcriptional regulation, supported by biochemical and ChIP-seq analyses, but further validation and attempts to obtain mechanistic insights are warranted along with discussion of recent findings by others in this area.

eLife assessment

For decades it has been accepted that only the growth-arrested "stumpy" form of Trypanosoma brucei can infect the arthropod vector, the Tsetse fly, but this was recently challenged by a demonstration that - under artificial conditions that are known to enhance infectivity - the proliferative "slender" form can also establish Tsetse infections. The infectiousness of the two forms is a fundamental question in trypanosome biology and epidemiology, concerning both infection dynamics and parasite differentiation. The authors of the current study provide compelling evidence that without artificial enhancement, the "stumpy" form is indeed much more infective for Tsetse than the slender form; they suggest that this is probably also true in the wild. Since the authors of this paper did not themselves test the effect of enhancing conditions, the precise reason for the discrepancy in results between the two laboratories has not been demonstrated conclusively.

eLife assessment

The authors introduce a useful machine-learning model for predicting binding sites of diverse ligands, including DNA, RNA, peptides, proteins, ATP, HEM, and metal ions, on proteins. The method is freely accessible and user-friendly. The authors have conducted thorough benchmarking and ablation studies, providing solid evidence of the model's overall performance, but the comparisons to other methods are incomplete, due to the lack of consistency between training methods and data.

eLife assessment

In Drosophila melanogaster, the SOCE channel Orai is required for the development of flight promoting dopaminergic neurons. The Hasan laboratory has previously shown that disabling Orai function impairs Drosophila flight due to aberrant neuronal development at the pupal stage. In this fundamental study, Mitra et al show that SOCE drives a transcriptional feedback loop via the homeobox transcription factor, 'Trithorax-like' (Trl), and histone modifiers, Set2 and E(z), to regulate the expression of key genes required for the function of dopaminergic flight neurons, including the muscarinic acetylcholine receptor and the inositol 1,4,5-trisphosphate receptor. This solid study is carefully performed with validated methodology and most of the analyses are rigorous.

eLife assessment

This valuable study aims to identify pioneer transcription factors, which are defined as transcription factors that compete with nucleosomes for DNA binding. The authors provide methods for identifying pioneer transcription factors on a cell type basis, using nucleosome positioning and motif information across different cell lines. The evidence to support the claims is largely solid. This work will be of interest to computational and molecular biologists working on transcription factors.

eLife assessment

This study presents a valuable syngeneic zebrafish model for studying glioblastoma and will be of interest to neuro-oncologists and cancer biologists. Using a feasible in vivo model to study the tumour microenvironment, cell/cell interaction, and immunity, the data are compelling, although the study can benefit from the additional characterization of tumours, as well as non-tumour cells in the niche including microglia/macrophage population.

eLife assessment

The work described in this manuscript is timely and useful in that it builds on prior research investigating the neural basis of abstract and concrete concepts by examining how these concepts are processed for a naturalistic stimulus - movie watching. The authors provide incomplete evidence that the varying strength of the relationship between a word and a particular visual scene is associated with a change in the similarity between the brain regions active for concrete and abstract words. This work makes a contribution that will be of general interest within the field despite some limitations in how the authors chose to define context, highlighting both the inherent challenge of quantifying context in a multimodal stimulus and the need to move towards brain imaging paradigms that capture context better than isolated word or sentence paradigms do.

eLife assessment

The authors report that an interaction between the sodium-activated potassium channel Slack and Nav1.6 sensitizes Slack to inhibition by quinidine. This is an important finding because it contributes to our understanding of how the antiseizure drug quinidine affects epilepsy syndromes arising from mutations in the Slack-encoding gene KCNT1. The results are largely compelling and the work will likely spark interest in further examining the proposed channel-channel interaction in neuronal cell membranes.

eLife assessment

This potentially important study used single-cell whole-brain imaging of the immediate early gene Fos to identify the brain areas recruited by two anesthetics, ketamine and isoflurane. The utilization of a custom software package to align and analyze brain images for c-Fos positive cells stands out as an impressive component of the approach. The results suggest these anesthetics might induce anesthesia via different brain regions and pathways, and raw fos showed shared and distinct activation patterns after ketamine- v. isoflurane-based anesthesia. However, the support for the primary conclusions is incomplete owing largely to concerns with the data transformation. The results could also be influenced by differences in route of administration between the drugs. This paper may be of interest to preclinical and clinical scientists working with anesthetic and dissociative drugs.

eLife assessment

In this manuscript, the authors present a wealth of fMRI data at both 3T and 7T to identify a scene-selective region of the intraparietal gyrus ("PIGS") that appears to have some responsivity to characteristics of ego-motion. In a series of experiments, they delineate the anatomical location of PIGS and functionally differentiate it from nearby V6 and OPA. Evidence for these valuable findings is solid, but further (a) consideration of whether this region overlaps with others reported previously and (b) support for, or tempering of, the ego-motion claim may be warranted.

eLife assessment

This important study provides evidence supporting the idea that visual experience plays a role in shaping the patterns of functional connectivity between extrastriate visual cortex and prefrontal regions during development, by comparing neonates, blind and sighted adults. The evidence supporting the authors' claim is solid, although control analyses could strengthen the conclusions and possibly offer additional mechanistic insights. This study will be of significant interest to neuroscientists and neuroimaging researchers working on vision, plasticity, and development.

eLife assessment

Songbirds provide a tractable model system to study mechanisms of vocal production and sequencing, and past work showed that the lesions to LMAN, the output of a basal ganglia thalamocortical loop, reduced vocal variability, consistent with a role in motor exploration. In this important work, the authors examined how lesions to an understudied neighboring region, MMAN, part of a parallel basal ganglia loop, affect singing in Bengalese finches, whose songs exhibit complex sequential transitions. They provide convincing evidence that MMAN lesions cause increased sequential variability, showing that distinct frontal systems can have distinct functions for producing and sequencing song syllables.

eLife assessment

This study provides a valuable contribution to our understanding of causal inference in visual perception. The evidence provided through multiple well-designed psychophysical experiments is solid. However, the conclusions drawn on the implementation of causal inference in general are too broad to be properly supported by the current results given their narrow focus on visual launch events.

eLife assessment

This valuable study reports on the characteristics of premotor cortical population activity during the execution and observation of a moderately complex reaching and grasping task. By using new variants of well-established techniques to analyse neural population activity, the authors provide solid evidence that while the geometry of neural population activity changes between execution and observation, their dynamics are largely preserved. While these observations are novel and robust barring the need for additional controls, the authors should do additional work to define the functional implications of their findings.

eLife assessment

This study presents important findings about synaptic connectivity among subsets of unipolar brush cells (UBCs), a specialized interneuron primarily located in the vestibular lobules of the cerebellar cortex. The evidence supporting the claims are interesting and solid. The work will be of interest to cerebellar neuroscientists as well as those focussed on synaptic properties and mechanisms. Although several compelling pieces of data were presented, some in vivo work remains to be conducted in order to test if the hypothesis and predictions translate into the behaving animal and how it would impact the processing of feedback or feedforward activity that would be required to promote behavior.

eLife assessment

This study provides direct evidence showing that Kv1.8 channels underly several potassium currents in the two types of sensory hair cells found in the mouse vestibular system. This is an important finding because the nature of the channels underpinning the unusual potassium conductance gK,L in type I hair cells has been under scrutiny for many years. Although most of the experimental evidence is compelling and the analysis is rigorous, the evidence supporting some of the claims related to Kv1.4 channels is incomplete. The study will be of interest to cell and molecular biologists and auditory neuroscientists.

eLife assessment

This manuscript presents valuable findings on the identification of epigenetically mediated control for the recognition of dihydropyrimidine dehydrogenase (DPYD) gene expression that is linked with cancer treatment resistance using 5-fluorouracil. The evidence is compelling, supported by data from patient-derived specimens and direct assessment of 5-fluorouracil sensitivity, which provides confidence in the proposed mechanisms. The model is additionally supported by genome data from a population with high "compromised allele frequency". This work will interest those studying drug resistance in cancer therapy.

eLife assessment

This important study using engineered mouse models provides a first compelling demonstration of a pathogenic phenotype associated with lack of expression of p53AS, an isoform of the p53 protein with a different C-terminus as canonical p53. The work also offers correlative evidence that Ackr4, differentially expressed in this mouse model, may be a male-specific prognostic factor in a specific type of B-cell lymphomas. Direct functional evidence testing the links proposed would better support the major findings of the study.

eLife assessment

This study offers valuable insights into the remarkable resistance of tardigrades to ionizing radiation by showing that radiation treatment induces a suite of DNA repair proteins. They identify a strongly induced tardigrade-specific DNA-binding protein that can reduce the number of double-strand breaks in human cancer-derived cells. The evidence of upregulation of repair proteins is compelling and the case for a role of the newly identified protein in repair can be strengthened as genetic tools for tardigrades become better developed. The results will be of interest the fields of DNA repair and radiobiology as well as tardigrade biologists.

eLife assessment

This study provides a valuable theoretical exploration of non-enzymatic sustained replication of RNA systems, in the parabolic growth regime of the evolution of putative primordial replicators. It provides solid evidence that parabolic growth mitigates the error threshold catastrophe, thus demonstrating another way in which this regime contributes to the maintenance of genetic diversity, although the justification of modeling choices and of parameter values is sometimes incomplete. The findings shed light on relevant evolutionary regimes of primordial replicators, with potential applicability to our understanding of the origin of life.

eLife assessment

Based on a technological advance which couples onboard calcium imaging with in vivo electrophysiology in freely behaving mice, this important work presents data about the modulation of some long range brain activity correlations during social interactions. Solid evidence shows that neural activity across cerebellum and cingulate cortex is more correlated during social behaviors than during non-social epochs. This study is of interest for a broad range of neurophysiologists.

eLife assessment

This important manuscript focuses on the mechanisms by which food signals and food ingestion modulate animal foraging. The authors provide convincing support for the interesting idea that chemosensory and interoceptive signals converge on transcriptional regulation of the TGF-beta ligand DAF-7 in a single pair of C. elegans chemosensory neurons (ASJ) to regulate behavior. Their studies implicate a conserved signaling molecule, ALK, in this regulation, suggesting a conserved link between food cues and the neuroendocrine control of foraging behavior.

eLife assessment

This work advances on two Aso et al 2014 eLife papers to describe further resources that are valuable for the field. This paper identified and contributes additional MBON split-Gal4s, convincingly describing their anatomy, connectivity and function.

eLife assessment

This valuable study shows that auxin exposure perturbs feeding behavior, survival rates, lipid metabolism, and gene expression patterns in adult Drosophila flies. The results are solid with proper methods and data analyses, and the evidence broadly supports the conclusions with only minor weaknesses. This work is relevant for fly geneticists who are interested in using the auxin-inducible gene expression system for inducing target protein degradation acutely.

eLife assessment

This study provides important findings on the evolution and function of the X-linked miR-506 miRNA cluster. The evidence supporting the conclusions is convincing, including the generation and characterization of an impressive number of the miRNA deletion mutants. This work will be of interest to RNA biologists, evolution biologists and reproductive biologists.

eLife assessment

This study presents new data highlighting the importance of appropriate coenzyme A handling in the mitochondria for maintaining appropriate energy production capacity. Several findings regarding the role of a key metabolic enzyme in how skeletal muscle cells use different substrates for energy production are valuable and supported by solid evidence, but there are concerns whether the data support the conclusion that ACOT2 regulates mitochondrial matrix acyl-CoA levels in white skeletal muscle to facilitate fatty acid oxidation β-oxidation.

eLife assessment

This fundamental study provides a unique tool for assessing the range of phosphorylation in insulin reactions due to genetic variation and dietary influence through the utilization of genetically distinct mouse strains. The discoveries of this study hold substantial importance, as they shed light on the interplay between genetic attributes and environmental conditions in shaping the insulin-signaling network within skeletal muscle, a crucial regulator of metabolism. The supporting evidence presented is compelling, and the work is anticipated to captivate a wide audience within the metabolism discipline due to its extensive appeal and by providing inspiration for further hypothesis-driven research.

eLife assessment

This study presents a valuable and comprehensive mutagenesis map of the AAV2 rep gene, which will undoubtedly capture the interest of scientists working with adeno-associated viruses and those engaged in the field of gene therapy. The thorough characterization of massive rep variants across multiple AAV production systems bolsters the claims made in the study, highlighting its utility in enhancing our understanding of Rep protein function and advancing gene therapy applications. The evidence presented is convincing and establishes a strong foundation that will stimulate and inform future research in the field.

eLife assessment

The demonstration that the PARG dePARylation enzyme is required in S phase to remove polyADP-ribose (PAR) protein adducts that are generated in response to the presence of unligated Okazaki fragments is potentially valuable, but the evidence is incomplete, and identification of relevant PARylated PARG substrates in S-phase is needed to understand the role of PARP1-mediated PARylation and PARG-catalyzed dePARylation in S-phase progression.

eLife assessment

This manuscript presented convincing single-cell transcriptomic data of hematopoietic cells and immunocytes in zebrafish kidney marrow and showed that these cells have distinctive responses to viral infection. The findings in this study suggest that zebrafish kidney is a secondary lymphatic organ and hematopoietic stem cells in zebrafish may exhibit trained immunity. This represents a valuable discovery of the unique features of the fish immune system.

eLife assessment

This useful work provides insight into agonist binding to nicotinic acetylcholine receptors, which is the stimulus for channel activation that regulates muscle contraction at the neuromuscular junction. The authors use in silico methods to explore the transient conformational change from a low to high affinity agonist-bound conformation as occurs during channel opening, but for which structural information is lacking owing to its transient nature. The evidence supporting the main conclusion that ligands flip ~180 degrees in the binding site as it transitions from a low to high affinity bound conformation is incomplete because little support is available for the starting low affinity docked conformations, and the rather approximate methods for computing binding free energies differ significantly from experimental measures for two of the four tested ligands. Nonetheless, this work presents an intriguing possibility for the nature of a transient conformational change at the agonist binding site correlated with channel opening. If the ligand flip observed in these simulations can be reproduced or verified by other studies, then this work would stand as a significant advance in our knowledge of nicotinic receptor gating.

eLife assessment

This manuscript presents important findings that inform the genetic underpinnings of the model plant Arabidopsis' resistance to turnip mosaic virus (TuMV). The strength of the evidence in the manuscript is exceptional, with very large sample sizes, careful controls, multiple follow-up experiments, and broadening to the evolutionary context. The evidence provides robust support for each of the manuscript's conclusions and could pave the way for functional studies.

eLife assessment

This is an important study on the role of phenotypic aging in cancer risk. It presents results that show that Phenotypic Age Acceleration (PhenoAgeAccel) can predict cancer incidence of different types and could be used with genetic risk to facilitate the identification of cancer-susceptible individuals. This article presents solid results that would be of broad interest to the research community and clinicians.

eLife assessment

This manuscript shows that manipulating the expression of the histone acetyltransferase Gcn5 affects blood cell homeostasis in the Drosophila larval hematopoietic organ. The data suggest a link between autophagy and the mTOR pathway, as could be expected from the literature. The authors use several genetic manipulations as well as some chemical modulators to generate solid evidence supporting most of their conclusions, but some of the analyses are inadequate and would benefit from improvement.

eLife assessment

This important work describes the first high-resolution structure of HGSNAT, a lysosomal membrane protein required for the degradation of heparan sulfate (HS). Through careful structural analysis, this work proposes potential reasons why certain mutations in HGSNAT lead to lysosomal storage disorders and outlines the enzyme's catalytic mechanism. The experimental evidence presented provides incomplete support for the proposed molecular mechanism of the HS acetylation reaction and the impact of disease-causing mutations.

eLife assessment

This research advance article describes a valuable image analysis method to identify individual cells (neurons) within a ‎population of fluorescently labeled cells in the nematode C. elegans. The findings are solid and the method succeeds to identify cells with high precision. The method will be valuable to the C. elegans research community.

eLife assessment

This valuable study addresses the question of whether pupil size can serve as a sensitive physiological marker of information anticipation in human infants. The authors present solid experimental findings indicating that pupil size differs depending on the expected information content of a visual signal and that this effect might rapidly generalize to new visual information. The results could be further strengthened by additional eye movement processing and statistical analyses to rule out confounding effects of saccades and other artifacts as well as a stronger and more consistent rationale for excluding data.

eLife assessment

By leveraging optical coherence tomography this study provides important insight into the deformation of human fingertip ridges when contacting raised features such as edges and contours. The study provides solid evidence that such features tend to cause deformation and relative movement of what the authors term ridge flanks rather than bending of the ridges themselves. Clarification about the anatomical structures under study is needed to fully interpret the claims and the resulting implications for both skin mechanics as well as the neural coding of touch.

eLife assessment

This is an important study that leverages a human-chimpanzee tetraploid iPSC model to test whether cis-regulatory divergence between species tends to be cell type-specific. The evidence supporting the study's primary conclusions together provide convincing evidence for enrichment of species differences in gene regulation in cell type-specific genes and regulatory elements, motivating future work with larger sample sizes of cell lines. This work will be of broad interest in evolutionary and functional genomics.

eLife assessment

This work represents an important contribution to computational neuroscience by providing a parsimonious model for spiking-phase precession/procession in the hippocampus. The proposed model, which relies on firing-rate adaptation, is able to capture many distinct experimental observations about phase precession/procession, such as forward and backward sweeps, as well as constant cycling of sweeps across different arms of a T-maze. The convincing evidence presented in support of this work relies on classical analytical and computational techniques about continuous attractor networks.

eLife assessment

This important work reports on the transcriptomic analysis of leukocytes in the brain of adult zebrafish. A specific novel finding is the identification of dendritic cells distinct from microglia or macrophages; regional distribution of these subsets is described using transgenic lines and immunhistochemistry. The dependence of these subsets of specific transcription factors or receptors is addressed with mutants. This is a thorough and compelling analysis, of interest for scientists using the zebrafish models for neurology, immunology, and infectiology, as well as for those interested in the evolution of the brain and immune system.

eLife assessment

This fundamental work substantially advances our understanding of the molecular basis of long-term memory formation. The study identifies PKCδ as a major molecular player in long-term memory formation and describes its translocation to mitochondria to promote pyruvate metabolism, specifically after spaced training. The evidence supporting the conclusions is compelling and the work will be of broad interest to neuroscience and medicine.

eLife assessment

Shore et al. report important findings on the impact of a gain-of-function mutation (Y777H) in the Kcnt1 gene on ion currents and firing behavior in both excitatory and inhibitory neurons in the mouse cortex. The KCNT1 gene encodes a subunit of the Na+-activated K+ (KNa) channel, and the authors substantiate their claims with solid evidence from electrophysiological patch-clamp recordings of dissociated cortical neurons. Nevertheless, the majority of reviewers recommended additional studies to reinforce key findings, proposing the replication of experiments using a more physiologically intact preparation, such as an ex vivo slice.

eLife assessment

This important study presents the first comprehensive catalog of the large neurons that compute optic flow in any insect. The morphological reconstructions from volume electron microscopy of the large arbors of these neurons, the Lobula Plate Tangential Neurons, were followed by the examination of their spatial arrangement to estimate their individual receptive fields and predict their optimal motion sensitivity. This compelling, rigorous data set, which includes the synaptic connectivity of the neurons under study with major target neurons in the fly brain, establishes a foundation for future studies on visual processing on the basis of a known connectome plus genetic driver lines to manipulate its constituent neurons. It will be of interest beyond insect vision to those studying sensory processing and neural circuit function.

eLife assessment

This important study provides convincing evidence of artifactual calcium micro-waves during calcium imaging of populations of neurons in the hippocampus using methods that are common in the field. The evidence that this artifact occurs in the data is convincing; however, the evidence for the particular conditions under which the calcium waves occur is incomplete. The work raises awareness of these artifacts so that any research labs planning to do calcium imaging in the hippocampus can avoid them by using alternative strategies that the authors propose.

eLife assessment

This study presents a valuable confirmation of the roles of Dact1 and Dact2, two factors involved in Wnt signaling, during zebrafish gastrulation and craniofacial development. The limitation of the study is that its examination of genetic interactions with other Wnt factors does not conclusively distinguish primary from secondary effects for each factor. Addressing this weakness is essential for supporting claims on interactions between dact1/2 and any Wnt factors examined. The findings of a new potential target of dact1/2-mediated Wnt signaling are potentially of value; however, experimental evidence supporting the veracity of this finding is incomplete due to an apparent lack of reproducibility.

eLife assessment

Urofacial syndrome is a rare early-onset lower urinary tract disorder characterized by variants in HPSE2, the gene encoding heparanase-2. This valuable study demonstrates that AAV9-based gene therapy for urofacial syndrome is feasible and safe, at least over the time frame evaluated, with restoration of HPSE2 expression leading to re-establishment of evoked contraction and relaxation of bladder and outflow tract tissue, respectively, in organ bath studies. The evidence supporting these findings is solid, although the analysis would benefit from evaluation of additional replicates for several endpoints, quantitative assessment of HPSE2 expression, inclusion of in vivo analyses such as void spot assays or cystometry, more rigorous assessment of viral integration, and single-cell analysis of the urinary tract in mutants versus controls, all of which make the analysis of the data currently incomplete.

eLife assessment

P-glycoprotein is a major ABC-transporter that exports drugs used in chemotherpay and effects the pharmacokinetics of other drugs. Here the authors have determined cryo-EM structures of drug complexes in previously unforeseen outward-facing conformations. These convincing findings are mechanistically important and reveal potential regions to be exploited by rational-based drug design.

eLife assessment

This is an important follow-up study to a previous paper in which the authors reconstituted CO2 metabolism (autotrophy) in Escherichia coli. Here, the authors define a set of just three mutations that promote autotrophy, highlighting the malleability of E. coli metabolism. The authors make a convincing case that mutations in pgi are loss-of-function mutations that prevent metabolic efflux from the reductive pentose phosphate autocatalytic cycle, and their data suggest possible roles of mutations in two other genes - crp and rpoB. This research will be particularly interesting to synthetic biologists, systems biologists, and metabolic engineers aiming to develop synthetic autotrophic microorganisms.

eLife assessment

Efforts to increase the representation of women in academia have focussed on efforts to recruit more women and to reduce the attrition of women. This study - which is based on analyses of data on more than 250,000 tenured and tenure-track faculty from the period 2011-2020, and the predictions of counterfactual models - shows that hiring more women has a bigger impact than reducing attrition. The study is an important contribution to work on gender representation in academia, and while the evidence in support of the findings is solid, the description of the methods used is in need of improvement.

eLife assessment

This study defines a fundamental aspect of protein kinase signalling in the protist parasite Toxoplasma gondii that is required for acute and chronic infections. The authors provide compelling evidence for the role of SPARK/SPARKEL kinases in regulating cAMP/cGMP signalling, although evidence linking the loss of these kinases to changes in the phosphoproteome is incomplete. Overall, this study will be of great interest to those who study Toxoplasma and related apicomplexan parasites.

eLife assessment

This study presents a valuable finding on how lentiviral infection has driven the diversification of the HIV/SIV entry receptor CD4. Using a combination of molecular evolution approaches coupled with functional testing of extant and ancestral reconstructions of great ape CD4, the authors provide solid evidence to support the idea that endemic simian immunodeficiency virus infection in gorillas have selected for gorilla CD4 alleles that are more resistant to SIV infection. However, this conclusion would be supported more strongly with additional functional testing of other great ape CD4 relative to human and ancestral sequences. Additionally, given the difficulty in definitively proving drivers of selection, the current title of the study is considered an overstatement relative to the data presented.

eLife assessment

This study presents evidence that suggests that the coalescence of sister chromatids induced by global double-strand DNA breaks (DSBs) during late mitosis is mediated by cohesin SMC3. These findings are valuable for studying the mechanism of eukaryotic cells to repair DNA during late mitosis. Although the discrete DSB induction system in budding yeast is sound, the strength of evidence is incomplete and could be buttressed to better support the major claims and to represent a clear advance with respect to the authors' previous contributions to this field.

eLife assessment

This manuscript offers valuable information on the effect of two small molecule combinations (2C), CHIR99021 and A-485, during the reprogramming of mature cardiomyocytes into regenerative cardiac cells. This manuscript is incomplete, as the mechanistic insights derived from transcriptomic and genomic datasets are without experimental validation. This manuscript also needs additional experimental support to confirm the regenerative potential of 2C and improvements in the data analysis and presentation. Overall, this interesting work provides insights into the development of therapeutic targets for cardiac regeneration in infarcted hearts.

eLife assessment

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

eLife assessment

This study provides fundamental new knowledge into the role of reversible cysteine oxidation and reduction in protein kinase regulation. The data provide convincing evidence that intra-molecular disulfide bonds serve a repressive regulatory role in the Brain Selective Kinases (BRSK) 1 & 2; part of the as yet understudied 'dark kinome'. The findings will be of broad interest to biochemists, structural biologists, and those interested in the rationale design and development of next-generation kinase inhibitors.

eLife assessment

The authors use a powerful combination of phylogenetics, structure prediction, biochemistry, and mutagenesis to provide an understanding of the mechanism that provides target specificity of Drosophila HP1 homolog Rhino vs. HP1, with Rhino specifically binding to piRNA loci. The authors show that a single amino acid substitution in the chromodomain of Rhino allows binding of the zinc finger protein Kipferl, which directs the complex to a subset of heterochromatic regions that other HP1 homologs do not. The evidence supporting the conclusions is compelling, providing an impressive level of mechanistic understanding of how the specificity of the piRNA genome defense system is defined. Also, the study highlights how a single amino acid change can change the functionality of a protein, providing fundamental insight into protein evolution.

eLife assessment

Using genomic data from ancient and modern samples, this important study investigates the genomic history of cattle in Iberia, focusing on the admixture between domestic cattle and their wild ancestors, aurochs. The authors present solid evidence for interbreeding between domestic cattle and wild aurochs since the Neolithic period, although the extent, sex bias, and directionality of genetic flow over time remain highly unclear. The authors also show that the aurochs ancestry in cattle stabilized at ~20% since ~4000 years ago and continues into modern breeds, including the Lidia breed that is bred for aggressiveness and used in bullfighting. The work will be of interest to evolutionary biologists and quantitative geneticists who seek to understand the genomic history and genetic basis of trait variation of domesticated animals.

eLife assessment

This useful study, which is of potential interest to a broad readership as it systematically addresses off-target effects of a commonly used chemotherapy drug on bone and bone marrow cells, presents evidence that reducing systemic inflammation induced by doxorubicin limits to some extent bone loss. Unfortunately, the work does not inform sufficiently on the mechanisms of doxorubicin action on bone, although the demonstration of the effect of systemic inflammation on bone loss is convincing. While this finding is not new, additional genetic and pharmacologic experiments and a deeper analysis of the bone phenotype would improve our understanding of what the mechanisms involved in doxorubicin-induced bone loss are, and may substantiate the clinical relevance of targeting inflammation in order to limit the negative impact of chemotherapies on bone quality.

eLife assessment

This study follows the career trajectories of the winners of an early-career funding award in the United States, and finds that researchers with greater mobility, men, and those hired at well-funded institutions experience greater subsequent funding success. Using data on K99/R00 awards from the National Institutes of Health's grants management database, the authors provide compelling evidence documenting the inequalities that shape faculty funding opportunities and career pathways, and show that these inequalities disproportionately impact women and faculty working at particular institutions, including historically black colleges and universities. Overall, the article is an important addition to the literature examining inequality in biomedical research in the United States.

eLife assessment

This study examines the human voltage-gated chloride channel CLC-2. A combination of cryo-EM, electrophysiology, and computational analysis provides compelling support for a "ball and chain" mechanism of inactivation. This and other findings regarding the gating and inhibition mechanisms of the channel are of fundamental interest to ion channel physiologists.

eLife assessment

The paper addresses the mechanism of initiation of DNA replication in human cells by analyzing published data on the location of origins of DNA replication and the location of binding sites in the genome for ORC and MCM2-7 complexes. There are some useful analyses of existing data but there are concerns regarding the conclusion that there might be alternative mechanisms for determining the location of origins of DNA replication in human cells compared to the well known mechanism known from many eukaryotic systems, including yeast, Xenopus, C. elegans and Drosophila. The lack of overlap between binding sites for ORC1 and ORC2, which are known to form a complex in human cells, is a particular concern and points to the evidence for the accurate localization of their binding sites in the genome being incomplete.

eLife assessment

By developing a novel method for detecting genetic variants associated with germline mutation spectrum variation, this important study identifies a new "mutator" locus in a population of inbred mouse strains, although the causal gene(s) and allele(s) within this locus remain uncertain. The authors further demonstrate that this new mutator locus interacts epistatically with a previously identified mutator allele on C>A mutation rate, showcasing the complexity of the genetic basis underlying variation in mutation rate and spectrum. Evidence for major findings in this paper is convincing, and the new method has the potential to be applicable to a variety of experimental systems and natural populations.

eLife assessment:

This valuable manuscript by Go et al. provides an interesting account documenting the role of resident CD56(br) NK cells in driving interaction with DCs that attract CD8+ T cells to the pancreas cancer tumor microenvironment (TME). The work convincingly illustrates how irradiation combined with CCR5i and PD1 blockade leads to a reduction in pancreatic cancer growth that correlates with a reduction in Tregs and enhancement of NK and CD8 T cells in the TME. The correlation of NKC1 signature with survival in pancreatic cancer patients is indeed of broader interest regarding potential relevance to other types of cancer.

eLife assessment

This study discloses important physiological function for TMEM63 in regulating postnatal growth in mice. The data supporting the impaired body growth and skeletal phenotype as well as disrupted growth hormone/insulin-like growth factor-I (GH/IGF-I) signaling in TMEM63 knockout mice are compelling. However, to establish that alteration of hepatic GH/IGF-I signaling is the cause for observed growth and skeletal phenotype in TMEM63 knockout mice would need additional work.

eLife assessment

The authors' findings have theoretical or practical deep implications, which makes them important. The methods, data, and analyzes support the authors' arguments with only minor weaknesses, and overall they are solid. In vitro culture experiments could provide evidence to strengthen the evidence for the functional significance of Th1-mediated cytokines in the observed B cell responses.

eLife assessment

This important study advances the understanding of physiological mechanisms in deep-sea Planctomycetes bacteria, revealing unique characteristics such as the only known Phycisphaerae using a budding mode of division, extensive involvement in nitrate assimilation, and release phage particles without cell death. The study uses convincing evidence based on experiments using growth assays, phylogenetics, transcriptomics, and gene expression data. The work will be of interest to bacteriologists and microbiologists in general.

eLife assessment

This study presents a computational model to explore how neurostimulation could impact hippocampal theta oscillations. The computational model combines a detailed physiologically realistic hippocampus model and an abstract theta oscillator. The study could provide valuable predictions on pathological changes in this network. The modelling is based on convincing approaches that could be improved with experimental validation in future experiments.