eLife Assessment

This study presents useful albeit preliminary findings on transcriptome changes in cardiac lymphatic cells after myocardial infarction in mice. Despite revision, the conclusions of the authors remain uncertain as sample sizes in general are very low, and even sometimes too low to allow for valid statistical comparisons. Accordingly, there are concerns regarding statistical robustness, raised by both the editors and the reviewers. While the single-cell transcriptomic data were analyzed using solid advanced methodology, too few cells were included in the scRNA-seq data set and the spatial transcriptomics analyses. Thus, this study rather represents more a collection of preliminary transcriptomic data than a full scientific report that would definitively advance the field.

eLife Assessment

This important study presents a series of results aimed at uncovering the involvement of the endosomal sorting protein SNX4 in neurotransmitter release. While the evidence supporting the conclusions is solid, the molecular mechanisms remain unclear. This paper will be of interest to cell biologists and neurobiologists.

eLife Assessment

This manuscript provides fundamental studies to help us better understand the effects of mutations in the presenilin-1 (PSEN1) gene on proteolytic processing of the amyloid precursor protein (APP). The authors provide compelling evidence using mutations in PSEN to understand what drives alternative substrate turnover with conclusive data and rigorous analysis. This deep mechanistic study provides a framework towards the development of small molecule inhibitors to treat Alzheimer's disease.

eLife Assessment

This valuable study provides a novel method to detect sleep cycles based on variations in the slope of the power spectrum from electroencephalography signals. The method, dispensing with time-consuming and potentially subjective manual identification of sleep cycles, is supported by solid evidence and analyses. This study will be of interest to researchers and clinicians working on sleep and brain dynamics.

eLife Assessment

This important study investigates how working memory load influences the Stroop effect from a temporal dynamics perspective. Convincing evidence is provided that the working memory load influences the Stroop effect in the late-stage stimulus-response mapping instead of the early sensory stage. This study will be of interest to both neuroscientists and psychologists who work on cognitive control.

eLife Assessment

This study uses carefully designed experiments to generate a useful behavioural and neuroimaging dataset on visual cognition. The results provide solid evidence for the involvement of higher-order visual cortex in processing visual oddballs and asymmetry. However, the evidence provided for the very strong claims of homogeneity as a novel concept in vision science, separable from existing concepts such as target saliency, is incomplete. The authors and the reviewers do not agree on several points, which are explained in the reviews and author response.

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 demonstrates the effects of action potential propagation and collision properties on nearby membranes. The study will interest both computational neuroscientists and physiologists.

eLife Assessment

This paper represents a "classic" approach towards evaluating a novel taste stimulus in an animal model, including standard behavioral tests (some with nerve transections), taste nerve physiology and immunocytochemistry of the tongue. The stimulus being tested is ornithine, from a class of stimuli called "kokumi", which enhance other canonical tastes, increasing their hedonic attributes; the mechanism for ornithine detection is thought to be GPRC6A receptors expressed in taste cells. The authors showed evidence for this in an earlier paper with mice; this paper evaluates ornithine taste in a rat model. This work is valuable but incomplete.

eLife Assessment

This study proposes an important new approach to analyzing cell-count data that are often undersampled and cannot be correctly assessed with traditional statistical analyses. The presented case studies provide convincing evidence of the superiority of the proposed methodology to existing approaches, which could promote the use of Bayesian statistics among neuroscientists. However, the generalizability of the methodology to other data types is not fully evidenced.

eLife Assessment

This study utilizes an elegant approach to examine valence encoding of the mesolimbic dopamine system. The findings are valuable, demonstrating differential responses of dopamine to the same taste stimulus according to its valence (i.e., appetitive or aversive) and in alignment with distinct behavioral responses. The evidence supporting the claims is convincing, resulting from a well-controlled experimental design with minimal confounds and thorough reporting of the data.

eLife Assessment

In this paper, the authors use single-cell RNA sequencing to understand post-mitotic cone and rod developmental states and identify cone-specific features that contribute to retinoblastoma genesis. The work is important and the evidence is generally convincing. The findings of rod/cone fate determination at a very early stage are intriguing.

eLife Assessment

This important study addresses how DNA replication restarts in Escherichia coli in the absence of a functional replication initiator protein DnaA. The authors show that helicase DnaB loading at the replication origin oriC can be executed by PriC under sub-optimal initiation conditions. While the genetic and biochemical evidence is solid, there is so far no direct evidence for PriC acting at oriC in vivo.

eLife Assessment

This is a useful 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 solid and follow logically from the model's assumptions, some of these assumptions may require further validation, as they appear to oversimplify certain aspects in light of complex experimental findings, system geometry, and general principles of active matter research.

eLife Assessment

This study provides valuable advances in our understanding of how inputs from multiple sources can impact the physiology of motor neurons during the process of multisensory integration. Specifically, the authors show how streams of auditory and principally visual information modulate the physiology of Mauthner neurons in goldfish, thus allowing the different senses to influence escape behavior. Supporting evidence is generally convincing, although material reporting the direct control of behavior is less representative of the data.

eLife Assessment

This study provides an important advancement of knowledge by showing neural functional compensation in the brains of healthy older adults completing a fluid-intelligence task. Validated whole-brain voxel-wide analyses and multivariate Bayesian approaches provide compelling evidence that supports the claims of the authors. The work delivers methods for quantifying reserve and compensation in future studies and will be of interest to researchers in the field of the neuroscience of healthy aging.

eLife Assessment

This manuscript reports a detailed model of juvenile rat somatosensory cortex, consisting of 4.2 million morphologically and biophysically detailed neuron models, arranged in space and connected according to diverse experimental data - a valuable tool for the field. The construction of the model is based on a methodology with solid supporting evidence. It should be noted that, by necessity, such a large-scale model development involves many assumptions, interpolations, and decisions that could have compounding downstream effects on further analyses that may be difficult to disambiguate.

eLife Assessment

This work is potentially important and largely convincing given the state-of-the-art approaches used to unravel the mechanism underlying the release of Claudins via Rho-mediated activation of Matriptase during tight junction formation. However, there are a few concerns. Addressing the following two major concerns a) showing Matriptase is indeed activated and b) Matriptase inhibition does not interfere with keratinocyte specification, would significantly improve the strength of the evidence. In addition, including quantifications, missing methods, and improving the rigor of the analyses would be helpful.

eLife Assessment

The ingenious design in this study achieved the observation of 3D cell spheroids from 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 valuable to the field. The authors provide solid evidence that the methods work as described.

eLife Assessment

In this valuable study, the authors used an elegant genetic approach to delete EED at the post-neural crest induction stage. The usage of the single-cell RNA-seq analysis method is extremely suitable to determine changes in the cell type-specific gene expression during development. Results backed by solid evidence demonstrate that Eed is required for craniofacial osteoblast differentiation and mesenchymal proliferation after the induction of the neural crest.

eLife Assessment

This study introduces an important approach using selection linked integration (SLI) to generate Plasmodium falciparum lines expressing single, specific surface adhesins PfEMP1 variants, enabling precise study of PfEMP1 trafficking, receptor binding, and cytoadhesion. By moving the system to different parasite strains and introducing an advanced SLI2 system for additional genomic edits, this work provides compelling evidence for an innovative and rigorous platform to explore PfEMP1 biology and identify novel proteins essential for malaria pathogenesis including immune evasion.

eLife Assessment

This is a study that makes the important finding that pleiotropy is positively associated with parallelism of evolutionary responses in gene expression, while theory would predict the opposite. The analysis uses a state-of-the-art experimental evolution approach to study the genetic basis of adaptation of Drosophila simulans to a hot environment. The experimental data is relevant and its analysis is robust, however, this paper appears to conflate gene expression variation and its underlying causative variation, in both its data interpretation and theoretical framework. This leads to incomplete conclusions on the causal link between pleiotropy and genetic variation and their role during adaptation.

eLife Assessment

Liang et al. have conducted a small pilot study investigating the feasibility and tolerability of a regimen of neoadjuvant chemo-immunotherapy for non-small cell lung cancer; with lower cumulative dose of chemotherapy and with the immunotherapy delivered on D8 of each cycle. The clinical data are interesting and novel, and overall the findings of the study are valuable. However, the translational data and analyses are incomplete and do not support key claims in the title.

eLife Assessment

This valuable study is a detailed investigation of how chromatin structure influences replication origin function in yeast ribosomal DNA, with a focus on the role of the histone deacetylase Sir2 and the chromatin remodeler Fun30. The paper shows that Sir2 does not affect origin licensing but rather affects local transcription and nucleosome positioning which correlates with increased origin firing. Overall, the evidence is convincing and the model is plausible.

eLife Assessment

This paper aims to understand why prostate cancer with CDK12 loss does not respond to HRd-based therapeutics, such as PARP inhibitors. The work is felt to be fundamental given a thorough computational and genomic analysis, the generation of CDK12-adapted cell lines, and potential synthetic vulnerability to CDK13 loss with genetic knockdown or co-inhibition with a CDK12/13 inhibitor. The evidence is compelling given the authors' systematic testing of components of the CDK12/13 pathways in a number of prostate cancer models. Some weaknesses focused on the functional effect of the various mutations found at different CDK12 sites (loss vs. altered), more comprehensive characterization of CDK12 KO lines, and specificity of the CDK12/13 inhibitor and in vivo experimental schema.

eLife Assessment

This is an important study showing that age-related gut microbiota modulate uric acid metabolism through the NLRP3 inflammasome pathway and thereby regulate susceptibility to age-related gout. Several experimental approaches (mechanistic insights) and methods (data quality) remain incomplete. This paper should be of interest to researchers working on gout and microbiota.

eLife Assessment

The aim of this important study is to identify novel genes involved in sleep regulation and memory consolidation. It combines transcriptomic approaches following memory induction with measurements of sleep and memory to discover molecular pathways underlying these interlinked behaviors. The authors explore transcriptional changes in specific mushroom body neurons and suggest roles for two genes involved in RNA processing, Polr1F and Regnase-1, in the regulation of sleep and memory. Their findings offer convincing evidence that the expression of RNA processing genes is modulated during sleep-dependent memory, with Polr1F potentially contributing to increased sleep.

eLife Assessment

This is a fundamental study into human spinal neurulation, which substantially advances our understanding of human neural tube closure. Crucial unanswered questions in the field currently rely on model systems, not faithful to human development. The evidence provided is compelling, with a large number of specimens and the rigorous use of state-of-the-art methodology providing robustness. The work will be of broad interest to developmental biologists, embryologists, and medical professionals working on neural tube defects, and will act as a precious reference resource for future studies.

eLife Assessment

This article uncovers a new important role of STAMBPL1 in promoting angiogenesis in triple-negative breast cancer (TNBC) and elucidates the specific mechanisms by which it activates the GRHL3/HIF1α/VEGFA axis through interaction with FOXO1. The finding that STAMBPL1 mediates GRHL3 transcription through the interaction with FOXO1 is novel. These experimental results corroborate each other, forming a solid foundation of evidence that supports the main findings of the article.

eLife Assessment

This valuable study investigates the development of high-level visual responses in infants, finding that neural responses specific to faces are present by 4-6 months but not earlier. The study is methodologically convincing, using state-of-the-art experimental design and analysis approaches. The findings would be of broad interest to the cognitive neuroscience and developmental psychology research communities.

eLife Assessment

The authors provide convincing data that identify a novel, non-opioid biologic from human birth tissue products with anti-nociceptive properties in a preclinical mouse model of surgical pain. This important study highlights the potential use of naturally derived biologics from human birth tissues as safe and sustainable pain treatment options that do not possess the adverse side effects associated with opioids and synthetic pharmaceuticals. Whether these results will translate to the clinic remains to be seen, nevertheless, these preclinical findings are promising.

eLife Assessment

The work presented is important for our understanding of the development of the cardiac conduction system and its regulation by T-box transcription factors. The conclusions are supported by convincing data. Overall this is an excellent study that advances our understanding of cardiac biology and has implications beyond the immediate field of study.

eLife Assessment

Sanchez-Vasquez et al establish an innovative approach to induce aneuploidy in preimplantation embryos. This important study extends the author's previous publications evaluating the consequences of aneuploidy in the mammalian embryo. In this work, the authors investigate the developmental potential of aneuploid embryos and characterize changes in gene expression profiles under normoxic and hypoxic culture conditions. Using a solid methodology they identify sensitivity to Hif1alpha loss in aneuploid embryos, and in further convincing experiments they assess how levels of DNA damage and DNA repair are altered under hypoxic and normoxic conditions.

eLife Assessment

This study provides important findings in characterizing dopamine neuron heterogeneity in the ventral midbrain. The strength of evidence is strong for a convincing classification, but claims related to the effects of G2019S-LRRK2 expression were considered more preliminary. The creation of an snRNA-seq exploration tool for these datasets should interest groups interested in understanding dopamine neuron subclass dynamics in behavior and diseases.

eLife Assessment

This potentially valuable study investigates the interaction of two integral membrane proteins (Cdhr1a and Pcdh15b) and their roles in cone-rod dystrophy. Convincing evidence using loss-of-function mutants demonstrates that both proteins are required for cone maintenance and survival. There is insufficient evidence to support the subcellular localization and the proposed heterodimeric interaction of the two proteins from distinct subcellular compartments. The methodologies are unclear, and the statistical methods and analysis are improperly applied.

eLife Assessment

Using multiple techniques previously validated by the authors, this study identified INTS12, a component of the Integrator complex involved in 3' processing of small nuclear RNAs U1 and U2, as a factor promoting HIV-1 latency. The work is valuable, based on a sound strategy for screening targets to activate HIV latency and the deep mechanistic insights it provides on INTS12 repression of transcriptional elongation. While the work is solid, authors must address minor weaknesses, including assessing knockdown efficiency and validating the target by examining the impact on cell viability and latency-reversing activity in combination with LRAs other than AZD5582 & I-BET151.

Editors Assessment:

Due to them being found in the landlocked, isolated habitat of Lake Baikal makes the Baikal Seal (Pusa sibirica) unique among all pinnipeds as the only freshwater seal. This paper presents reference-based assemblies of six newly sequenced Baikal seal individuals, one individual of the ringed seal, as well as the first short-read data of the harbor seal and the Caspian seal . This data aiding the study of the genomic diversity of the Baikal seal and to contribute baseline data to the limited genomic data available for seals. Peer review extended the description of the used tools and parameters in the revised manuscript, and provided some more information on the methods..This newly generated sequencing data hopefully now helps to extend the phylogeny of the Phoca/Pusa group on genome-wide data and can also broaden the view into the genetic structure and diversity of the Baikal seal

This evaluation refers to version 1 of the preprint

Editors Assessment:

The article presents strategies for accelerating sequence alignment using multithreading and SIMD (Single Instruction, Multiple Data) techniques, and introduces a new algorithm called TSTA (Thread and SIMD-Based Trapezoidal Pairwise/Multiple Sequence-Alignment). The Technical Release write-up presenting a detailed description of TSTA's performance in pairwise sequence alignment (PSA) and multiple sequence alignment (MSA), and compares it with various existing alignment algorithms. Demonstrating the performance gains achieved by vectorized SIMD technology and the application of threading. Testing and debugging a few errors, and adding some more background detail, demonstrating it can achieve faster comparison speed. Demonstrating TSTA's efficacy in pairwise sequence alignment and multiple sequence alignment, particularly with long reads, and showcasing considerable speed enhancements compared to existing tools.

This evaluation refers to version 1 of the preprint

eLife Assessment

This is a convincing paper that addresses topics important in our understanding of how inflammatory markers are modulated in both obesity and type 2 diabetes and their effects on Wnt signaling mediators in human bone. There are changes in bone at the tissue level in these 2 common metabolic disorders that ultimately lead to compromised bone strength. These data will be critical to our understanding of the pathophysiology of skeletal fragility in obesity and diabetes.

eLife Assessment

This valuable study examines the effects of side-wall confinement on the chemotaxis of swimming bacteria in a shallow microfluidic channel. The authors present solid experimental evidence, combined with geometric analysis and numerical simulations of simplified models, showing that chemotaxis is enhanced when the distance between the side walls is comparable to the intrinsic radius of circular swimming near open surfaces. This study should be of interest to scientists specializing in bacteria-surface interactions.

Editors Assessment:

The crested gecko (Correlophus ciliatus), is a lizard species endemic to New Caledonia, and a potentially interesting model organism due to its unusual (for a gecko) inability to regenerate amputated tails. With that in mind here is presented a new reference genome for the species, assembled using PacBio Sequel II platform and Dovetail Omni-C libraries. Producing a genome with a total size of 1.65 Gb, 152 scaffolds, a L50 of 6, and N50 of 109 Mb. Peer review making sure more detail was added on data acquisition and processing to enhance reproducibility. In the end producing potentially useful data for studying the genetic mechanisms involved in loss of tail regeneration.

This evaluation refers to version 1 of the preprint

Editors Assessment:

This paper presents the SMARTER database, a collection of tools and scripts to gather, standardize, and share with the scientific community a comprehensive dataset of genomic data and metadata information on worldwide small ruminant populations. Which has come out of the EU multi-actor (12 country) H2020 project called SMARTER: SMAll RuminanTs breeding for Efficiency and Resilience. This bringing together genotypes for about 12,000 sheep and 6,000 goats, alongside phenotypic and geographic information. The paper providing insight into how the database was put together, presenting the code for the SMARTER—frontend, backend and API, alongside instructions for users. Peer review tested the platform and provided suggestions on improving the metadata. Demonstrating the project provides valuable information on sheep and goat populations around the world, that can be an essential tool for ruminant researchers. Enabling them to generate new insights and offer the possibility to store new genotypes and drive progress in the field.

This evaluation refers to version 1 of the preprint

Editors Assessment:

This paper presents NucBalancer, a R-pipeline and Shiny app designed for the optimal selection of barcode sequences for sample multiplexing in sequencing. Providing a user-friendly interface aiming to make this process accessible to both bioinformaticians and experimental researchers, enhancing its utility in adapting libraries prepared for one sequencing platform to be compatible with others. Important now with the introduction of additional sequencing platforms by Element Biosciences (AVITI System) and Ultima Genomics (UG100) increasing the diversity and capability of genomic research tools available. NucBalancer’s incorporation of dynamic parameters, including customizable red flag thresholds, allows for precise and practical barcode sequencing strategies. This adaptability is key in ensuring uniform nucleotide distribution, particularly in MGI sequencing and single-cell genomic studies, leading to more reliable and cost-effective sequencing outcomes across various experimental conditions. All the code is available under an open source license, and upon review the authors have also shared the code for the Shiny app.

This evaluation refers to version 1 of the preprint

论文提出了一种名为RepoUnderstander的新颖方法，该方法指导代理通过以下几个步骤来全面理解整个代码仓库：

• 构建代码仓库知识图谱：通过自上而下的方式将整个仓库的关键信息压缩成知识图谱，以降低仓库的复杂性。
• 基于蒙特卡洛树搜索的仓库探索策略：赋予代理理解整个仓库的能力，通过模拟多种路径并评估它们的奖励分数，逐步缩小搜索空间，引导代理关注最相关的区域。
• 信息利用与补丁生成：指导代理总结、分析和规划，然后操作工具动态获取信息并生成解决现实世界GitHub问题的补丁。

eLife Assessment

This manuscript offers a modeling platform in which horizontal gene transfer (HGT) is incorporated into the ecological dynamics of microbial communities. The investigation is valuable as it brings to the forefront a potentially significant process and highlights its implications. However, the investigation in its current form is incomplete because it is based on a narrow range of parameters and assumptions. As a result, the scope and relevance of the findings are not fully clear. A more in-depth description of model assumptions and the formulation structure and a more thorough analysis of the impact of different parameters would strengthen the manuscript. This work will be of interest to microbiologists as well as researchers in ecological and evolutionary biology.

eLife Assessment

This important study compares the cortical projections to primary motor and sensory areas originating from the ipsilateral and contralateral hemispheres. They find that, while there is substantial symmetry between the two hemispheres regarding the areas sending projections to these primary cortical areas, contra-hemispheric projections had more inputs from layer 6 neurons than ipsi-projecting ones. The evidence is convincing and most of the conclusions are supported by rigorous analyses.

eLife Assessment

This manuscript provides important structural insights into the recognition and degradation of the host tRNA methyltransferase TRMT1 by SARS-CoV-2 protease nsp5 (Mpro). The data provide compelling support for the main conclusions of the authors. These results will be of interest to researchers studying structures, substrate recognition and specificity of viral proteases and their action on cellular targets.

eLife Assessment

This study provides valuable insights into the cellular responses to complex aneuploidy in human preimplantation embryos. The evidence supporting the claims of the authors is now convincing after addressing previous concerns. This work will be of interest to embryologists, geneticists and scholars working on reproductive medicine by increasing our understanding of how human embryos respond to chromosomal abnormalities.

eLife Assessment

This work introduces an important new method for depleting ribosomal RNA from bacterial single-cell RNA sequencing libraries, demonstrating its applicability for studying heterogeneity in microbial biofilms. The findings provide convincing evidence for a distinct subpopulation of cells at the biofilm base that upregulates PdeI expression. Future studies exploring the functional relationship between PdeI and c-di-GMP levels, along with the roles of co-expressed genes within the same cluster, could further enhance the depth and impact of these conclusions.

eLife Assessment

This study presents important findings on the role of CXXC-finger protein 1 in regulatory T cell gene regulation and function. The evidence supporting the authors' claims is solid, with mostly state-of-the-art technology, although the inclusion of more mechanistic insights would have strengthened the study. The work will be of relevance to immunologists interested in regulatory T cell biology and autoimmunity.

eLife Assessment

This important manuscript provides an extensive and convincing analysis of the foetal and adult TCR repertoire in the mouse thymus. A potential implication of the work is that the earliest appearing T cells during ontogeny may have properties that are fundamentally distinct from those appearing later in life. The study will be of interest to immunologists concerned with T cell development and TCR repertoires.

eLife assessment

In this important study, the authors found, with the use of statistical methods, that compound heterozygous rare deletion variants affecting the kinase-domain of non-receptor tyrosine kinase TNK2/ACK1 and PTK6/BRK are associated with human systemic lupus erythematosus (SLE). The authors use a convincing mouse experimental model and human-induced pluripotent stem cell (hiPSC)-derived macrophages to clarify cause-effect relationships and the cellular basis of nephritis. With the identification of new SLE-related genes, this manuscript improves our understanding of human SLE pathogenesis.

eLife Assessment

This is an important work and it correlates capsid stability with mutations that promote heparan sulfate binding. The data is solid, but there is a need for further analysis and experiments to support the claims and to propose a more detailed mechanism that could explain how these mutations altered capsid stability.

eLife Assessment

This manuscript makes an important contribution to the understanding of protein-protein interaction (PPI) networks by challenging the widely held assumption that their degree distributions uniformly follow a power law. The authors present convincing evidence that biases in study design, such as data aggregation and selective research focus, may contribute to the appearance of power-law-like distributions. While the power law assumption has already been questioned in network biology, the methodological rigor and correction procedures introduced here are valuable for advancing our understanding of PPI network structure.

eLife Assessment

This study is important, with the potential to greatly impact future research on the evolution of chemical defense mechanisms in animals. The authors present compelling evidence for the presence of low quantities of alkaloids in amphibians previously thought to lack these toxins. They then integrate these findings with existing literature to propose a four-phase scenario for the evolution of chemical defense in alkaloid-containing poison frogs, emphasizing the role of passive accumulation mechanisms.

eLife Assessment

Utilizing transgenic lineage tracing techniques and tissue clearing-based advanced imaging and three-dimensional slices reconstruction, the authors comprehensively mapped the distribution atlas of NFATc1+ and PDGFR-α+ cells in dental and periodontal mesenchyme and tracked their in vivo fate trajectories. This important work extends our understanding of NFATc1+ and PDGFR-α+ cells in dental and periodontal mesenchyme homeostasis, and should provide impact on clinical application and investigation. The strength of this work is compelling in employing CRISPR/Cas9-mediated gene editing to generate two dual recombination systems, and mapped gNFATc1+ and PDGFR-α+cells residing in dental and periodontal mesenchyme, their capacity for progeny cell generation, and their inclusive, exclusive and hierarchical relations in homeostasis, generating a spatiotemporal atlas of these skeletal stem cell population.

eLife Assessment

This study presents an important new bioinformatics tool for normalizing gene copy number from metagenomic assemblies and applies it to gain functional insights into the loss of microbial diversity during conditions of stress. The inclusion of extensive computational validation makes this a compelling study that raises intriguing new hypotheses regarding the impact of disease states on the gut microbiome. This paper will likely be of broad interest to researchers studying the role of complex microbial communities in host health and disease.

eLife Assessment

This important paper shows that the acquisition and expression of Pavlovian conditioned responding are lawfully related to temporal characteristics of an animal's conditioning experience. It showcases a rigorous experimental design, several different approaches to data analysis, careful consideration of prior literature, and a thorough introduction. The evidence supporting the conclusions is strong and convincing. The paper will have a general appeal to those interested in the behavioral and neural analysis of Pavlovian conditioning.

eLife Assessment

This important study addresses how 3' splice site choice is modulated by the conserved spliceosome-associated protein Fyv6. The authors provide compelling evidence that Fyv6 functions to enable selection of 3' splice sites distal to a branch point and in doing so antagonizes more proximal, suboptimal 3' splice sites.

eLife Assessment

This study reports single-cell RNA sequencing results of lung adenocarcinoma, comparing 4 treatment-naive and 5 post-neoadjuvant chemotherapy tumor samples. Of interest is the delineation of two macrophage subtypes: Anti-mac cells (CD45+CD11b+CD86+) and Pro-mac cells (CD45+CD11b+ARG+), with the proportion of Pro-mac/pro-tumorigenic cells significantly increasing in LUAD tissues after neoadjuvant chemotherapy. In terms of significance, the findings might be useful. However issues remain after the revision with lengthy descriptive clustering type analysis, insufficient statistical support, and inefficient figure presentation. As it stands, the level of supportive evidence is inadequate.

eLife Assessment

This useful study examined the associations of a healthy lifestyle with comprehensive and organ-specific biological ages defined using common blood biomarkers and body measures. Its large sample size, longitudinal design, and robust statistical analysis provide solid support for the findings, which will be of interest to epidemiologists and clinicians.

eLife Assessment

This fundamental, clearly written, and timely manuscript links the timing of ART with the kinetics of total and intact proviral HIV DNA. The conclusions are interesting and novel, and the importance of the work is high because the focus is on African women and clade C virus, both of which are understudied in the HIV reservoir field. The strength of the evidence is compelling. Overall, this work will be of very high interest to scientists and clinicians in the HIV cure/persistence fields.

eLife Assessment

This important study shows that Toxoplasma gondii uses paracrine mechanisms, in addition to cell-intrinsic methods, to evade the host immune system, with MYR1 playing a key role in transporting effector molecules into host cells. The authors present convincing evidence that in vivo, MYR1-deficient parasites can be rescued by wild-type parasites, revealing a limitation in pooled CRISPR screens, where such paracrine effects may obscure the identification of key parasite pathways involved in immune evasion

eLife Assessment

This study presents a valuable finding on a potential signaling pathway responsible for the direct effects of nicotine on intestinal stem cell growth and tumorigenesis. The evidence supporting the claims of the authors is solid. This research will be of interest to medical biologists specializing in intestinal tumors.

eLife Assessment

This valuable study highlights how the diversity of the malaria parasite population diminishes following the initiation of effective control interventions but quickly rebounds as control wanes. The data presented is convincing and the work shows how genetic studies could be used to monitor changes in disease transmission.

eLife Assessment

This valuable study characterizes the molecular signatures and function of a type of enteric neuron (IPAN) in the mouse colon, identifying molecular markers (Cdh6 and Cdh8) for these cells. A battery of solid experimental findings suggest data from other species are likely translatable to mice, bridging the abundant literature from humans and other mammals into this experimentally tractable animal model, but the data establishing the role of Cdh6 in synapses among IPANs and in cell-cell contacts with non-neuronal cells is incomplete. This work will be of interest to scientists studying the motor control of the colon and more generally the enteric neuromuscular system.

eLife Assessment

This important study reports on a basis for neurabin-mediated specification of substrate choice by protein phosphatase-1. The data from the comprehensive approach using structural, biochemical, and computational methods are compelling, but the role of the crucial tryptophan residue in the recognition motif can be further tested to strengthen the main argument. This paper is broadly relevant to those investigating various cellular signaling cascades that entail phosphorylation as the main mechanism.

eLife Assessment

This solid paper reports on the use of artificial intelligence to assess bone marrow adipose tissue in the skull. The method employing MRI is novel and that approach allows for the identification of genetic loci that regulate this trait as well as others using data from the UK biobank. Overall this is an important contribution although the authors should consider several points: 1-validation of the T1-weighted MRI signal intensity; 2-further discussion of the sex differences; and 3-cross-trait linkage disequilibrium score regression (LDSC) for osteoporosis, Parkinson's disease, and cognitive function.

eLife Assessment

The authors use a multidisciplinary approach to provide a useful link between Beta-alanine and S. Typhimurium (STM) infection and virulence. The work shows how Beta-alanine synthesis mediates zinc homeostasis regulation, possibly contributing to virulence. However, the work is incomplete and requires additional data to firmly establish the connection between Beta-alanine synthesis and zinc homeostasis. Measuring the source and zinc content of STM in vivo and examining mechanisms in human clinical strains and other serovars would be essential.

eLife Assessment

This article reports a useful set of findings on how electrophysiological response properties of neurons correlate with their position in the brain. The evidence currently remains incomplete, with reviewers making specific suggestions for how clustering needs to be redone. The manuscript would also benefit from a more focused presentation of results and the removal of incorrect claims about recording biases.

eLife Assessment

This valuable study clarifies the mechanism by which the kinesin-10 motor protein, chromosome-associated kinesin, Kid (KIF22), enables chromosome movement during mitosis, demonstrating that human and Xenopus Kid proteins function as processive, homodimeric kinesins capable of processive microtubule plus-end motility. The convincing work highlights that Kid can recruit and transport duplex DNA along microtubules via its conserved C-terminal DNA binding domain, revising our understanding of chromokinesins' role in chromosome motility during mitosis. Although the data are robust, the manuscript would benefit from some editing for clarity.

eLife Assessment

This valuable study uses the analysis of connectomic and transcriptomic datasets to survey the anatomy and connectivity of neurosecretory cells in the Drosophila brain. While the connectivity analyses are convincing, the anatomical and functional data provided to verify cell type identity and paracrine signaling is incomplete. Once these aspects are improved, this study would be of interest to neuroscientists working on hormonal signaling in Drosophila and other animals.

eLife Assessment

The study describes a valuable new technology in the field of targeted protein degradation that allows identification of E3-ubiquitin ligases that target a protein of interest. The presented data are convincing, however, additional work will be needed to optimize for high-throughput evaluation. This technology will therefore serve the community in the initial stages of developing targeted protein degraders.

eLife Assessment

This important study identifies the "H-state" as a potential conformational marker distinguishing amyloidogenic from non-amyloidogenic light chains, addressing a critical problem in protein misfolding and amyloidosis. By combining advanced techniques such as small-angle X-ray scattering, molecular dynamics simulations, and H-D exchange mass spectrometry, the authors provide convincing evidence for their novel findings. However, incomplete experimental descriptions, limitations in SAXS data interpretation, and the way HDX MS data is presented affect the strength and generalizability of the conclusions. Strengthening these aspects would enhance the impact of this work for researchers in amyloidosis and protein misfolding.

eLife Assessment

The manuscript by Guo and colleagues reports valuable findings about the inhibitory activity of caffeic acid phenethyl ester (CAPE) against TcdB, a key toxin produced by Clostridioides difficile. C. difficile infections are a major public health concern, and this manuscript provides interesting data on toxin inhibition by CAPE, a potentially promising therapeutic alternative for this disease. The strength of the evidence to support the conclusions is solid, with some concerns about the moderate effects on the mouse infection model and direct binding assays of CAPE to the toxin.

eLife Assessment

This important study uses Mendelian Randomisation to show that early life phenotypes (i.e. onset of age at menarche and age at first birth) have an influence on a multitude of health outcomes later in life. The provided empirical evidence supporting the antagonistic pleiotropy theory is solid. However, some additional analyses and a more comprehensive discussion of the findings are needed to make the study stronger.

eLife Assessment

This basic research study presents useful data concerning the menstrual fluid composition and its potential for endometriosis biomarker research. However, despite solid bioinformatics analyses, the choice of markers used to separate or identify the different cell types needs to be justified and the results better discussed in relation to current knowledge of the pathophysiology of endometriosis.

eLife Assessment

This important work combines self-report, neural and physiology data to examine the efficacy and mechanisms of counter conditioning versus extinction in reducing re-emergence of conditioned threat responses and show that this appears to rely on the nucleus accumbens rather than the ventromedial prefrontal cortex. These findings are supported by convincing evidence, though some areas could benefit from added clarity and a few targeted refinements and justifications of analytical choices. Results will be of interest to researchers across multiple subfields, including neuroscientists, cognitive theory researchers, and clinicians, particularly those with an interest in clinical applications in trauma therapies.

eLife Assessment

This valuable study examines the activity and function of dorsomedial striatal neurons in the estimation of time. The authors examine striatal activity as a function of time as well as the impact of optogenetic striatal manipulation on the animal's ability to estimate a time interval, providing solid evidence for their claims. The study could be further strengthened with a more rigorous characterization of activity and a stronger connection between their proposed model and the experimental data. The work will be of interest to neuroscientists examining how striatum contributes to behavior.

eLife Assessment

This important study presents interesting results aimed at explaining the effects of a human mutation on the mitochondrial import protein TIMM50 on mitochondrial function and neuronal excitability. While the evidence supporting the conclusions is convincing, the mechanisms driving changes in the levels of certain proteins within and outside the mitochondria (such as certain ion channels) remain unexplained. This paper will be of interest to scientists in the mitochondria field.

eLife Assessment

This important study advances our understanding of how FGF13 variants confer seizure susceptibility. By acting in a set of inhibitory interneurons, FGF13 regulates synaptic transmission and excitability. The data presented here are convincing and combine cell type-specific knockouts and electrophysiology, complemented by histology/RNA studies. Collectively, this research will be of interest to a wide audience, particularly those involved in the study of epilepsy, inhibitory neurons, and ion channels.

eLife Assessment

This useful study reports how neuronal activity in the prefrontal cortex maps time intervals during which animals wait to reach a reward, with this mapping remaining consistent across days. While most claims are supported by solid evidence, the study could have benefitted from an improved experimental design to more clearly disambiguate correlations between neuronal patterns and not only time but also stereotypical behaviors and restraint from impulsive decisions. This study will be of particular interest to neuroscientists focused on decision-making and motor control.

eLife Assessment:

This study presents valuable findings that add to our understanding of cortical astrocytes, which respond to synaptic activity with calcium release in subcellular domains that can proceed to larger calcium waves. The proposed concept of a spatial "threshold" is based on solid evidence from in vivo and ex vivo imaging data and the use of mutant mice. Details of the specific threshold must be taken with caution and are necessarily incomplete, but may be supported by additional experiments with higher resolution in space and time in the future.

eLife Assessment

This important study addresses key assumptions underlying current models of the formation of value-based decisions. The authors provide convincing evidence that the subjective values human participants assign to items change across sequences of multiple decisions. They establish methods to detect these changes in frequently used behavioral task designs.

eLife Assessment

The study describes a useful tool for assessing microglia morphology in a variety of experimental conditions. The MorphoCellSorter provides a solid platform for ranking microglia to reflect their morphology continuum and may offer new insight into changes in morphology associated with injury or disease. While the study provides an alternative approach to existing methods for measuring microglia morphology, the functional significance of measured morphological changes remains unclear.

eLife Assessment

This well-written report uses functional neuroimaging in human observers to provide convincing evidence that activity in the early visual cortex is suppressed at locations that are frequently occupied by a task-irrelevant but salient item. This suppression appears to be general to any kind of stimulus, and also occurs in advance of any item actually appearing. The work in its present form will be valuable to those examining attention, perception, learning and prediction, but with a few additional analyses could more informatively rule out potential alternative hypotheses. Further discussion of the mechanistic implications could clarify further the broad extent of its significance.

eLife Assessment

This important work advances our understanding of CHMP5's role in regulating osteogenesis through its impact on cellular senescence. The evidence supporting the conclusion is mostly convincing, although including additional experiments and discussions would further strengthen the study. This paper holds potential interest for skeletal biologists who study the pathogenesis of age-associated skeletal disorders.

eLife Assessment

In this potentially valuable computational study, the authors conducted atomistic and coarse-grained simulations to probe the temperature-dependent phase behaviors of ELF3, a disordered component of the evening complex in plant. The results aim to highlight the role of polyQ tracts in modulating the temperature sensitivity. The level of evidence is considered incomplete, due to the lack of systematic calibration of the coarse-grained model and limited statistical uncertainty analysis, especially considering the relatively subtle nature of the differences due to temperature change.

eLife Assessment

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

eLife Assessment

This valuable study investigates the brain representations of Braille letters in blind participants and provides evidence using EEG and fMRI that the decoding of letter identity across the reading hand takes place in the visual cortex. The evidence supporting the claims of the authors is convincing and the work will be of interest to neuroscientists working on brain plasticity.

eLife Assessment

This study presents a useful finding on the ferroptosis-mediated tumor microenvironment (TME) in triple-negative breast cancer (TNBC) using public single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data. The evidence supporting the claims of the authors is somewhat incomplete and some data are rather questionable; the authors should clarify the relations between ferroptosis-related genes in immune cells and those genes applied in a risk factor analysis in tumor cells. Moreover, the authors should provide experimental validation for the risk score model based on ferroptosis-related genes. The work will be of interest to scientists or clinical scientists working in the field of breast cancer.

eLife Assessment

This fundamental study substantially advances our understanding of how habitat fragmentation and climate change jointly influence bird community thermophilization in a fragmented island system. The authors provide convincing evidence using appropriate and validated methodologies to examine how island area and isolation affect the colonization of warm-adapted species and the extinction of cold-adapted species. This study is of high interest to ecologists and conservation biologists, as it provides insight into how ecosystems and communities respond to climate change.

eLife Assessment

Leveraging state-of-the-art experimental and analytical approaches, this important study characterizes the recruitment and activation of large populations of human motor units during slow isometric contractions in two lower limb muscles. Evidence for the main claims is solid and advances our understanding of how humans generate and control voluntary force.

eLife Assessment

This study provides valuable advances in our understanding of how inputs from multiple sources can impact the physiology of motor neurons during the process of multisensory integration. Specifically, the authors show how streams of auditory and principally visual information modulate the physiology of Mauthner neurons in goldfish, thus allowing the different senses to influence escape behavior. Supporting evidence is generally convincing, although material reporting the direct control of behavior is less representative of the data.

eLife Assessment

This important study highlights the use of siderophores as antibacterials, and the authors also discuss the consequences and efficacy of 'siderophore therapy' in more complex communities/environments. The evidence supporting the overall hypotheses ranges is largely convincing. The work will be of broad interest to people working in the fields of evolutionary ecology, microbiology and medical sciences.

eLife Assessment

This work is an important contribution to the development of a biologically plausible theory of statistical modeling of spiking activity. The authors convincingly implemented the statistical inference of input likelihood in a simple neural circuit, demonstrating the relationship between synaptic homeostasis, neural representations, and computational accuracy. This work will be of interest to neuroscientists, both theoretical and experimental, who are exploring how statistical computation is implemented in neural networks.

eLife Assessment

This study provides important findings on the modulation of cortical neuronal responses to sensory stimuli by motor-driven predictive signals. The study is methodologically sound and well-designed. Solid evidence is presented for the conclusion that audiomotor mismatch responses are observed in the auditory cortex and that these are strongly modulated by crossmodal signals, though further investigation of the effects of running speed on audiomotor coupling and of sound offset effects on the observed responses would strengthen the interpretation of the results.

eLife Assessment

This study investigates the role of the Cadherin Flamingo (Fmi) in cell competition in developing tissues in Drosophila melanogaster. The findings are valuable in that they show that Fmi is required in winning cells in several competitive contexts. The evidence supporting the conclusions is solid, as the authors identify Fmi as a potential new regulator of cell competition, however, they don't delve into a mechanistic understanding of how this occurs.

eLife Assessment

This fundamental study advances substantially our understanding of sound encoding at synapses between single inner hair cells of the mouse cochlea and spiral ganglion neurons. Dual patch-clamp recordings-a technical tour-de force-and careful data analysis provide compelling evidence that the functional heterogeneity of these synapses contributes to the diversity of spontaneous and sound-evoked firing by the neurons. The work will be of broad interest to scientists in the field of auditory neuroscience.

eLife Assessment

This useful study employs AlphaFold2 to predict interactions among 20 nuage proteins, identifying five novel interaction candidates, three of which are validated experimentally through co-immunoprecipitation. Expanding the analysis to 430 oogenesis-related proteins and screening ~12,000 Drosophila proteins for interactions with Piwi, the study identifies 164 potential binding partners, demonstrating how computational predictions can streamline experimental validation. This study provides a solid basis for further investigations into eukaryotic protein interaction networks.

eLife Assessment

This study presents important findings on cold tolerance shared between hibernating and non-hibernating mammals, identifying a key molecule, GPX4, through multi-species genome-wide CRISPR screens. The evidence supporting these conclusions is compelling, combining multi-species CRISPR screening with rigorous pharmacological assays. This work will be of significant interest to biologists studying hibernation physiology and medical researchers interested in cold tolerance.

eLife Assessment

The presented evidence is compelling given a range of complementary and mutually supportive studies. Experiments are generally robustly conducted and well-presented, supporting the claims regarding miRNA mechanisms converging on EMC10 overexpression with 22q11 Del. This is an important study that works to establish a novel antisense oligonucleotide-based approach to treating 22q11.2 deletion syndrome; the findings are likely to advance therapeutic efforts. The authors provide evidence both in vitro in patient-derived iPSCs and in vivo in a 22q11 Del mouse supporting the knockdown (KD) of EMC10 as an effective strategy for the amelioration of neuronal and behavioral deficits.

eLife Assessment

This is an important study that aims to investigate the behavioral relevance of multisensory responses recorded in the auditory cortex. The experiments are elegant and well-designed, and are supported by appropriate analyses of the data. However, the evidence presented for learning-dependent encoding of visual information is incomplete and it is possible that the surprisingly short-latency increases in activity are actually motor-related signals. Demonstrating that they really are visual responses is necessary in order to draw definitive conclusions from this study.

eLife Assessment

This study addresses a significant question in sensory ethology and active sensing in particular. It links the production of a specific signal - electrosensory chirps - to various contexts and conditions to propose that chirps may also serve an active sensing role in addition to their more well-known role in communication. The evidence supporting the role for active sensing is strong. In particular, the evidence showing increased chirping in more cluttered environments and the relationship between chirping and movement are convincing. The study provides a lot of valuable data, and is likely to stimulate follow-up behavioral and physiological studies.

eLife Assessment

This work attempts to demonstrate an ATP-independent non-canonical role of proteasomal component PA28y in the promotion of oral squamous cell carcinoma growth, migration, and invasion. The evidence remains incomplete and the work would benefit from further experimental work. The authors have not adequately addressed the reviewers' comments.

eLife Assessment

This study provides valuable insights into our understanding of the development of the enteric nervous system. The authors use genetically engineered mice to study the behavior of stem cells in organizing the enteric nervous system and the secreted signals that regulate these cells. The study rests on a degree of incomplete evidence since the characterization of some of the mouse resources is not complete in the current version.

eLife Assessment

This fundamental study addresses the regulation of the MICAL-family of actin regulators by Rab GTPases, which play a key role in directing membrane trafficking within cells. The compelling evidence explains how Rab8 family members bind at two sites to allosterically regulate MICAL1, and relieve an auto-inhibited state unable to bind actin. This study lays the basis for further progress in understanding membrane trafficking and cytoskeleton dynamics in eukaryotic cells.

eLife Assessment

This study offers valuable insights into the molecular mechanisms by which Osx influences osteocyte function, particularly through its regulation of Cx43. However, the evidence supporting the authors' claims is incomplete, necessitating additional experimental data and further investigation to fully substantiate these findings. While this study presents a new perspective on the complex role of Osx in bone biology, it also raises significant questions about the intricacies of its regulatory network.

eLife Assessment

This work presents an important method for depleting ribosomal RNA from bacterial single-cell RNA sequencing libraries, enabling the study of cellular heterogeneity within microbial biofilms. The approach convincingly identifies a small subpopulation of cells at the biofilm's base with upregulated PdeI expression, offering invaluable insights into the biology of bacterial biofilms and the formation of persister cells. Further integrated analysis of gene interactions within these datasets could deepen our understanding of biofilm dynamics and resilience.

eLife Assessment

This work presents an important method for depleting ribosomal RNA from bacterial single-cell RNA sequencing libraries, enabling the study of cellular heterogeneity within microbial biofilms. The approach convincingly identifies a small subpopulation of cells at the biofilm's base with upregulated PdeI expression, offering invaluable insights into the biology of bacterial biofilms and the formation of persister cells. Further integrated analysis of gene interactions within these datasets could deepen our understanding of biofilm dynamics and resilience.

eLife Assessment

This study presents a useful theoretical model of molecular evolution and attempts to use it to resolve the paradox of rapid evolution of ribosomal RNA genes. While intuitive, the model's underlying issue is grouping many factors under "variance in reproductive success" without explicitly modeling the molecular processes. This limitation, along with insufficient consideration of technical challenges in alignment and variants calling, provides incomplete support for the authors' claim that the observed paradoxical patterns in rRNA genes can largely be explained by homogenizing processes, such as gene conversion, unequal crossover and replication slippage.

eLife Assessment

This is a valuable study on the diffusion rates of drug molecules in human-derived cells, presenting convincing data indicating that their diffusion behavior depends on their charged state. It proposes that blocking drug protonation enhances diffusion and fractional recovery, suggesting improved intracellular availability of weakly basic drugs. The findings are significant for drug design and understanding the biophysical behavior of small molecules in cells.

eLife Assessment

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

eLife Assessment

In this manuscript, Kaplan et al. study mesenchymal Meis2 in whisker formation and the links between whisker formation and sensory innervation. These useful findings analyze the impact of the conditional deletion of Meis2 using the Wnt1 driver on whisker development and their interaction with trigeminal nerves. The evidence supporting the conclusions is incomplete lacking mechanistic links to the phenotype described and detailed information on the methods used to analyze single-cell RNA sequencing data. The work will be of interest to developmental and skin biologists.

eLife assessment

The work introduces a valuable new method for depleting the ribosomal RNA from bacterial single-cell RNA sequencing libraries and shows that this method is applicable to studying the heterogeneity in microbial biofilms. The evidence for a small subpopulation of cells at the bottom of the biofilm which upregulates PdeI expression is solid. However, more investigation into the unresolved functional relationship between PdeI and c-di-GMP levels with the help of other genes co-expressed in the same cluster would have made the conclusions more significant.

eLife Assessment

The paper reports the important discovery that the mouse dorsal inferior colliculus, an auditory midbrain area, encodes sound location. The evidence supporting the claims is solid, being supported by both optical and electrophysiological recordings. The observations described should be of interest to auditory researchers studying the neural mechanisms of sound localization and the role of noise correlations in population coding.

eLife Assessment

This useful study investigates the impact of disrupting the interaction of RAS with the PI3K subunit p110α in macrophage function in vitro and inflammatory responses in vivo. Solid data overall supports a role for RAS-p110α signalling in regulating macrophage activity and so inflammation, however for many of the readouts presented the magnitude of the phenotype is not particularly pronounced. Further analysis would be required to substantiate the claims that RAS-p110α signalling plays a key role in macrophage function. Of note, the molecular mechanisms of how exactly p110α regulates the functions in macrophages have not yet been established.