eLife assessment

In this useful study, Holzinger et al. present compelling evidence that scorpionfish bactericidal/permeability-increasing protein (scoBPI) exhibits remarkable antibacterial activity against multi-drug resistant Pseudomonas aeruginosa. These findings open new avenues of research for identifying novel chemotherapies to treat Pseudomonas infections and have broader implications in developing chemotherapies against other drug-resistant Gram-negative bacterial infections. The work will be of interest to individuals investigating novel cystic fibrosis antimicrobials.

eLife assessment:

This important paper highlights the clonal organization of the dorsal telencephalon, a major region of the vertebrate brain, and analyzes the distinctive gene expression and chromatin accessibility present in each clonal using the adult teleost fish medaka. High-quality data were collected using convincing and solid methods and these were used to identify synaptic genes with a distinct chromatin landscape and expression in one of the regions of the dorsal pallium, with the goal of ascribing an evolutionary origin to these neurons.

eLife assessment

This paper is of potential interest to both the hippocampal and computational neuroscience fields because it provides a framework for understanding how adult-born granule cells in the hippocampus contribute to network processing. It contains novel interesting ideas, such as the analysis of input-output transformation by SRM models and the establishment of "greedy networks". However, not all major conclusions are sufficiently supported by the data. The paper demonstrates that mixed networks show better encoding performance than pure networks, but the differences are small and only visible with specific performance metrics. Intuitive explanations are not provided.

eLife assessment

In this study, the authors use high-speed and high-resolution imaging to investigate the role of the yeast syntaxin homolog Tlg2p in endocytic vesicle sorting. They obtain compelling data to show that the Tlg2p-residing compartment within the trans-Golgi network functions as an early/sorting compartment, where endocytic cargos are sorted to either the recycling pathway or the endo-lysosomal pathway. The authors also describe additional molecular details of this sorting process, and overall provide important insights into the mechanism of endocytic vesicle sorting in budding yeast.

eLife assessment

This valuable study shows that new, virulent genotypes of Xanthomonas oryze pv. oryzae, that are similar to strains present in east Asia, cause outbreaks of bacterial blight of rice in Tanzania. The authors' use of CRISPR-based gene editing on multiple pathogen targets in an elite African rice variety to create lines resistant to both endemic and emerging pathogen strains in Africa makes for a compelling contribution to meet this alarming development. The work describing the new strains of the pathogen is solid but could be stronger if there were genome sequence data for all strains examined and a clearer presentation of recent disease outbreaks and their severity.

eLife assessment

The findings in this study are important, as this brainstem region is implicated in a multitude of functions. The experimental procedures are difficult to implement and the preparation used and the skill required are impressive. The methods and data are solid, however, some analyses are incomplete, and the strength of evidence is also incomplete because the claims are only partially supported by the data. This work will interest those who study respiration, airway protection, and other oral behaviors.

eLife assessment

This manuscript explores the potential regulatory role of a previously unstudied phosphorylation site in the Src kinase SH3 domain. A mutant intended to mimic the phosphorylation of this site, Y90E, shows enhanced activity and transforming capacity, reduced mobility in the lipid bilayer, and a more open catalytic structure. In general, these findings are supported by compelling evidence. The paper will be of interest to biochemists and structural biologists studying new mechanisms that are capable of modulating the allosteric regulation of multi-domain protein kinases.

eLife assessment

Using chemogenetic manipulation, the authors induce or suppress activity in D1 spiny neurons in the dorsomedial striatum of mice. The results effectively demonstrate that excitation or inhibition of this class of neurons results in a consistent behavioral effect that is linked to an impact on local dynamics in thalamic regions that project to this part of the thalamus, as well as cortical regions that can be more readily defined as unimodal as identified by a classification approach. This work has clear relevance to the field of neuroimaging, getting at the broader hemodynamic signatures of direct pathway stimulation in the striatum, but requires critical revisions to justify their main conclusions.

Using chemogenetic manipulation, the authors induce or suppress activity in D1 spiny neurons in the dorsomedial striatum of mice. The results effectively demonstrate that excitation or inhibition of this class of neurons results in a consistent behavioral effect that is linked to an impact on local dynamics in thalamic regions that project to this part of the thalamus, as well as cortical regions that can be more readily defined as unimodal as identified by a classification approach. This work has clear relevance to the field of neuroimaging, getting at the broader hemodynamic signatures of direct pathway stimulation in the striatum, but requires critical revisions to justify their main conclusions.

eLife assessment

This paper reports a detailed functional analysis of the Rab1 effector Uso1, and it provides a fundamental advance in our understanding of how ER-derived vesicles deliver their cargo. The authors provide compelling evidence that the key function of Uso1 is promoting SNARE complex formation rather than tethering vesicles as generally assumed. These insights will be of interest to cell and structural biologists who study membrane traffic.

eLife assessment

This study makes an important effort to observe and quantify synaptic integration in a large and active network of cultured neurons, using simultaneous patch-clamp and large-scale extracellular recordings. They developed a method to distinguish excitatory and inhibitory contributions, showing compelling evidence that the subthreshold activity of these neurons is dominated by few presynaptic neurons. They provide basic statistics about connectivity and network dynamics, but their statistical analysis of the interplay between excitatory and inhibitory inputs is incomplete, mainly showing examples and averages, with little quantification of variability and therefore requiring additional analysis to better support their claims.

eLife assessment

This important study details an enrichment of the IL-6 signaling pathway in human tendinopathy, and applies transcriptional profiling to an advanced in vitro model to test IL-6 specific phenotypes in tendinopathy. Overall, the strength of evidence is solid yet incomplete, as transcriptomic measurements provide clarity, though functional studies including analysis of proliferation are needed to confirm these findings. This work will be of interest to stem cell biologists and immunologists.

eLife assessment

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

eLife assessment

This study is important as it examined the role of Perk (Protein kinase RNA-like endoplasmic reticulum kinase) and Atf4 (Activating Transcription Factor-4) in the integrated neurodegenerative and regenerative responses following the optic nerve injury. The evidence is convincing as the authors relied on both newly generated transcriptomic data and publicly available databases to support their research. While there are some limitations in data quality and interpretations, the study is likely to be of interest to researchers studying optic neuropathies and axonal regeneration.

eLife assessment

This is a very interesting and important study that convincingly demonstrates a descending pathway for the control of nociception in non-mammalian organisms.

eLife assessment

This important paper reports recent improvements and extensions to stdpopsim, a community-driven resource that is built on top of powerful software for performing simulations of population genomic data and provides a catalog of species with curated genomic parameters and demographic models. In addition to describing the new features and species in stdpopsim, the authors provide a set of practical guidelines for implementing realistic simulations. Overall, this convincing manuscript serves as an excellent overview of the utility, challenges, common pitfalls, and best practices of population genomic simulations. It will be of broad interest to population, evolutionary, and ecological geneticists studying humans, model organisms, or non-model organisms.

eLife assessment

This valuable paper informs on the role of type I PRMTs in programming muscle stem cell identification. The evidence presented is mostly solid, with some weaknesses in the evidence regarding the proposed mechanism. The paper will be of particular interest to those who study skeletal muscle satellite cell biology.

eLife assessment

The important study by Barreat and Katzourakis examines the evolutionary history of eukaryotic viruses (and related mobile elements) in the Bamfordvirae kingdom, and evaluates potential alternative scenarios regarding the origin of different lineages in this highly diverse kingdom. Through convincing phylogenetic analyses, the authors propose a new evolutionary model for the origin of this kingdom where their last common ancestor is inferred to have been an exogenous, non-virophage DNA virus with a small genome. This work advances our understanding of the deep evolutionary history of viruses, the interaction between viruses and the first eukaryotes, and the diversification of viral lineages.

eLife assessment

This paper describes an important new marine reptile specimen. A solid ostelogical description of the saurosphargid Prosaurosphargis yingzishanensis, the earliest known member of this group, combined with a large-scale phylogenetic analysis enhances our understanding of the affinities of a wide range of Triassic reptiles. As such the relevance of this paper goes far beyond the immediate importance of this remarkable fossil - it also sheds light on the position of several important Triassic groups, including Testudinata and Archosauromorpha.

eLife assessment

Vocalizations are controlled by neural circuits connecting the amygdala and periaqueductal gray. This study presents valuable measures of the neurons that suppress vocalization in appropriate contexts using a rich variety of behavioural, imaging, optogenetic, and tracing methodologies. The evidence supporting the claims of the authors is solid, although their results only hint at the mechanisms that could underlie the hierarchical control of vocalization. The work will be of interest to neurobiologists working on motor control and vocalization.

eLife assessment

This study presents valuable findings on the risk factors of avascular osteonecrosis in patients with Gaucher disease. The evidence supporting the claims of the authors is convincing. The work will interest clinicians who treat patients with inborn errors of metabolism.

eLife assessment

This study presents valuable findings regarding the functional diversification of flavodoxins from diatoms, a protein initially described as an Fe-sparing substitute for ferredoxin in Fe-poor open ocean environments. The evidence supporting the claims of the authors is solid, although the study could be strengthened by using a wider gradient of oxidative stress in the experiments and using Fe limitation methodology, which allows more certain differentiation between a low Fe and oxidative stress response.

eLife assessment

This valuable study combines population genetic theory and deep learning approaches to estimate the extent of assortative mating and sex bias in modern admixed populations in the Americas. The new approach provides solid evidence for their main conclusions that socially constructed hierarchies have influenced mating behaviors, though certain results would benefit from further consideration. This paper would be of interest to human population geneticists and social scientists, particularly those studying demographic processes.

eLife assessment

This compelling study brings together two earlier observations: that Ca2+ influx can trigger exosome release from multivesicular bodies, and that plasma membrane repair after wounding requires Ca2+ and involves Ca2+-binding annexin proteins. This important work takes these earlier findings in an interesting new direction by showing that exosome release from MVBs is also triggered by Ca2+ influx during plasma membrane wounding and requires the annexin isoform ANX6. The study suggests a few possible mechanisms (such as Ca2+-dependent tethering of MVBs to the plasma membrane by ANX6) and raises the interesting possibility that cell injury and repair may contribute to the release of exosomes into biological fluids.

eLife assessment

This manuscript reports an important finding that spermatogenic defects in Parl KO mice, a genetic model for Leigh syndrome, may result from mitochondrial defects leading to ferroptosis. The finding, if confirmed, would be of great significance because male germ cell ferroptosis has not been well characterized. However, the criteria for determining male germ cell ferroptosis were vague, and the supporting data were inadequate.

eLife assessment

This study presents important findings on the decision-making capacities of honey bees in controlled conditions. The evidence supporting the study is solid, however, the explanation of the methods, importance, and novelty of the study requires further clarification. With a deeper development of the relevance of this study, the reader will have a clear idea of how this study contributes to the field.

eLife assessment

This paper will be of broad interest to immunologists that study T cell responses and formation of the peripheral T cell compartment. Using elegant live imaging approaches, the authors provide convincing evidence in support of a revised model for how positive-selected thymocytes are called to the thymus medulla to interact with distinct antigen-presenting cells. The work makes an important contribution to the field by identifying previously unappreciated complexities related to cellular movement during T cell generation.

eLife assessment

This study presents valuable findings on how gender-neutral vaccination against human papillomavirus can help improve program resilience in the case of vaccination disruptions. The evidence supporting the claims of the authors is convincing, although the results are only applicable to India and other countries with a similar HPV context; researchers can adapt the model for their local context and use it as a starting point for future research.

eLife assessment

This paper reports on the role of RIF1 during early stages of zebrafish embryonic development, with the important finding that Rif1 seems to be required predominantly to establish the correct embryonic transcriptional program first, followed by a switch to a more replication-timing centered later function. The evidence is convincing, with the major strength being the elegant system and the possibility to also address the problem of the maternal pool of Rif1. A weakness is that the study remains descriptive and the presentation slightly disconnected, with limited mechanistic insight. The work will be of interest for researchers both in the transcription and the replication field, especially for scientists investigating the interplay between the two processes.

eLife assessment

This important study reports a novel mechanism linking DHODH inhibition-mediated pyrimidine nucleotide depletion to antigen presentation. Alternative means of inducing antigen presentation provide therapeutic opportunities to augment immune checkpoint blockade for cancer treatment. While the solid mechanistic data in vitro are compelling, in vivo assessments of the functional relevance of this mechanism are still incomplete.

eLife assessment

Gap junctions, formed from connexins, are important in cell communication, allowing ions and small molecules to move directly between cells. By determining the Cryo EM structure of the structure of connexin 43 in a putative closed state involving lipids, the study makes an important contribution to the development of a mechanistic model for connexin activation. The connexin 43 structure is solid and its presentation will appeal to the channel and membrane protein communities.

eLife assessment

This important study provides an unprecedented overview of the subcellular organization of proliferative blood stage malaria parasites. The localization of multiple parasite organelles is comprehensively probed using three-dimensional super-resolution microscopy throughout the entire intraerythrocytic development cycle. This work provides a compelling framework to investigate in future more deeply the unconventional cell biology of malaria-causing parasites.

eLife assessment

This valuable paper reports the development of SCA-seq, a nanopore-based multiOME mapping method for simultaneously measuring chromatin accessibility, genome 3D and CpG DNA methylation. The methods, data and analyses are solid and largely support the claims. This new tool to interrogate genome structure-function relationships will be of broad interest to geneticists and many others.

eLife assessment

The authors set out to study the development of high altitude polycythemia, which affects mice in a hypoxia chamber and humans staying at a hypoxic atmosphere at high altitude. The findings are useful both for initiating the discussion of the hypothesis that splenic red pulp macrophages, central to red cell survival, are impacted by hypoxia, and for providing some data that partially supports this hypothesis. However, the current data are inadequate to fully support the authors' conclusions.

eLife assessment

This important paper reports data on the cellular response to a single site-specific replication fork block in human MCF7 cells. Compelling evidence shows the efficacy of the bacterial Tus-Ter system to stall replication forks in human cells, with fork stalling leading to lasting ATR-dependent phosphorylation of histone H2AX but not of ATR itself and its downstream targets RPA and CHK1. The work will be of broad interest to students of DNA replication.

eLife assessment

This valuable study uses multiple large neuroimaging data sets acquired at different points through the lifespan to provide solid evidence that birthweight (BW) is associated with robust and persistent variations in cortical anatomy, but less-substantial influences on cortical change over time. These findings, supported by robust statistical methods, illustrate the long temporal reach of early developmental influences and carry relevance for how we conceptualize, study, and potentially modify such influences more generally. The paper will be of interest to people interested in brain development and aging.

eLife assessment

This valuable study revisits the effects of substitution model selection on phylogenetics by comparing reversible and non-reversible DNA substitution models. The authors provide evidence that 1) non time-reversible models sometimes perform better than general time-reversible models when inferring phylogenetic trees out of simulated viral genome sequence data sets, and that 2) non time-reversible models can fit the real data better than the reversible substitution models commonly used in phylogenetics, a finding consistent with previous work. However, the methods are incomplete in supporting the main conclusion of the manuscript, that is that non time-reversible models should be incorporated in the model selection process for these data sets.

eLife assessment

This important manuscript combines cryo-EM and a suite of compelling whole cell and proteoliposome transport assays to establish the mechanism and structure of the full-length human SLC26A6 chloride/bicarbonate exchangers, including the first partial view of the previously unresolved IVS region of an SLC26 STAS domain. In combination with prior studies on additional SLC26 paralogs, including the SLC26A9 paralog initially reported by the same group, the study provides broadly relevant insights into the mechanistic diversity of the SLC26 transporters. This study is of interest to the biophysics community and the field of membrane transport.

eLife assessment

This important study provides novel strategies to overcome certain limitations when investigating the metabolism of hematopoietic stem cells, mainly due to their low abundance. The study provides some solid evidence suggesting that hematopoietic stem cells mainly use glycolysis (rather than mitochondrial OXPHOS or TCA cycle) as their primary energy source, when proliferating in response to hematopoietic stress, as opposed to homeostasis. With the evidence further strengthened by more direct links between metabolic features and cell proliferation, and after consideration of alternative energy sources, this study would be of great interest to stem cell biologists.

eLife assessment

This important study uses CRISPRi to silence multiple effectors in the pathogen Legionella pneumophila. The paper provides a technique that will allow researchers to address functional redundancy amongst effectors, a problem that has persisted even after decades of study. The methodology used is convincing, and further improvement can lead to the identification of novel virulence factors.

eLife assessment

This important study unifies our current understanding of phosphate homeostasis and starvation responses in different eukaryotes, in which the nutrient messenger 1,5-InsP8 binds to one or several cellular SPX receptors, which in turn regulate very different, species-specific PHO pathway components. The evidence is compelling and supported by biochemical analyses, protein localization by fluorescence, and genetic approaches, but could still be strengthened by additional experiments. The work will be of interest to a broad community working on nutrient signalling in eukaryotes.

eLife assessment

This important study addresses both the native role of the Plasmodium falciparum protein PfFKBP35 and whether this protein is the target of FK506, an immunosuppressant with antiplasmodial activity. The genetic evidence for the essentiality of FKBP35 in parasite growth is compelling. However, the conclusion that the role of FKBP35 is to secure ribosome homeostasis and the claim that FK506 exerts its antimalarial activity independently of FKBP35 rely on incomplete evidence.

eLife assessment

The current manuscript investigates the energy landscape of the mammalian sugar porter GLUT5 using enhanced molecular dynamics simulations and biochemical assays. The approach generates important insights into the mechanism of GLUT5 conformational change, and into mechanistic diversity among the GLUT sugar porters more generally. The overall strategy is solid, but without an additional error analysis, the computational components remain incomplete. These findings will be of interest to the transporter and membrane biology communities.

eLife assessment

This useful study adapts methods from causal inference to develop analytical tools for determining the causal influence of single cells on downstream neurons. The simulation evidence is solid, suggesting that these causal methods produce better estimates under biologically-relevant confounds given enough data, although the practical application of the method and the biophysics it relies on is unclear. Nonetheless, this application of causal methods developed in econometrics and other fields could suggest new ways to think about largely observational datasets in neuroscience.

eLife assessment

Hyperpolarised-activated and Cyclic Nucleotide-gated (HCN) channels are the only mammalian channels to open under hyperpolarisation, being important for their roles in cardiac and neuronal cells. The authors of this study use atomistic simulations to enforce changing interaction distances that have been identified from a cryoEM structure and a homology model based on the hERG channel. The simulations suggest state-dependent interactions involving pore and voltage sensor helices, as well as with lipids, leading the authors to propose a domino-like mechanism of activation. These findings will be of considerable interest to the ion channel community.

eLife assessment

This is a comprehensive approach to understanding the genetic requirements of the VEGF family in the generation of brain capillary structure in zebrafish. The manuscript combines vascular brain/meningeal anatomy revealed with a variety of reporter lines, with mutants for Wnt/β-catenin signaling and angiogenic cues. In particular revealing genetic redundancy in VEGF receptor family in an essential function in vasculature development.

This paper is significant because it provides compelling evidence that features methods, data, and analyses more rigorous than the current state-of-the-art in analysis of brain vasculature development. The data derived from the reporter lines are convincing, and the germline mutations allow for solid visualization and quantification of results.

eLife assessment

This important 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

These valuable findings will be of interest for the study of dystroglycanopathies and in the general area of axon migration and synapse formation. This work provides solid conclusions about how a range of dystroglycan mutations alter CCK interneuron axonal targeting and synaptic connectivity in the forebrain, and seizure susceptibility.

eLife assessment

This work represents an important contribution to our understanding of how phenomena associated with the theta rhythm in the hippocampus could be generated even in the absence of theta. This convincing computational work provides a parsimonious continuous attractor network model of how hippocampal place cell networks can briefly sweep forward to represent future locations and then sweep back, even in animal species in which theta oscillations are only weakly (or not at all) present.

eLife assessment

The study expands our understanding of the neural circuitry downstream of the cerebellum by describing pathways between the deep cerebellar nuclei and the nucleus accumbens. The authors use a combination of in vivo electrophysiology, electrical and optogenetic stimulation, and both anterograde and retrograde tracing to demonstrate two functional neural pathways. The experiments convincingly support the claims. The finding extends previous investigations about the connections between these two brain areas, and are important for elucidating the role of the cerebellum in influencing functions supported by the nucleus accumbens, such as motivation and reward.

eLife assessment

This important work presents an interesting perspective for the generation and interpretation of phase precession in the hippocampal formation. Through numerical simulations and comparison to experiments, the study provides solid evidence for the role of the DG-CA3 loop in generating theta-time scale correlations and sequences, which would be reinforced through the clarification of the concepts introduced in the study, in particular the notion of intrinsic and extrinsic sequences. This study will be of interest for the hippocampus and neural coding fields.

eLife assessment

This important paper reveals how cells in adjacent tissues use the extracellular matrix to establish mechanical connections. Through a series of crisp genetic manipulations and quantitative image analyses, the authors provide compelling evidence to show how an essential adhesion between the uterus and the seam cells in the nematode C. elegans is formed. The assembly of type IV collagen triggers internalization of a cell surface receptor, which then signals from endocytic vesicles to strengthen the connection.

eLife assessment

This important study shows that lipid degradation is critical for spermatogenesis, with data supporting relevance of this finding across phyla. The authors contribute to a growing realization that lipid droplets have critical roles during differentiation and can influence cell fate, and use convincing methods to analyze the effects of loss of the lipase Brummer on germ line differentiation. This paper will be of interest to developmental and cell biologists working on gametogenesis.

eLife assessment

The important paper describes the structure of a single alpha helix in the large subunit of the Chromatin Assembly Factor 1 (CAF-1) that binds DNA. The single alpha-helix DNA interaction is novel and, combined with the CAF-1 Winged Helix Domain, is required for CAF-1 function in vivo for gene silencing and DNA damage response. The data are convincing, but there are additional analyses that may be considered.

eLife assessment

This study reports of a new signaling pathway in hippocampal neurons by which alpha-1 receptors for norepinephrine regulates Cav1.2 calcium channels; activation of alpha-1 receptors enhances a form of long-lasting synaptic plasticity that is dependent on L-type calcium channels. The experiments are comprehensive and well executed although additional data are warranted to compellingly support the main conclusions. The work has significance for the field of neuroscience in general and for cellular mechanisms of neuroregulation in particular.

eLife assessment

Modi et al. investigate the question of how learned information guides behavior. They combine optogenetic conditioning in Drosophila to spatially restrict the formation of olfactory memory traces in mushroom bodies (MBs), where olfactory memory traces are formed during pavlovian olfactory conditioning and follow up with behavioral studies and physiological analysis to examine how flies use these 'minimal memories' during learned olfactory discrimination. They discover that MBONs' responses predict behavioral outcomes, with odor responses showing physiological differences under conditions where broadly similar odorants must be discriminated. Thus, flies use olfactory memory templates flexibly to suit their behavioral needs. Modi et al. conclude that a hitherto unknown mechanism downstream of mushroom body output neurons creates these context-specific responses at the MBONs. Overall, the experiments provide convincing physiological evidence for a neural mechanism that underlies a contextual basis for the precision of memory recall, which constitutes a fundamentally important advance in our understanding of the neurobiology of memory retrieval, however, the authors need to more deeply consider caveats to their arguments, more deeply discuss differences and similarities with prior publications and bolster their data by including a few controls that are currently missing.

eLife assessment

The authors set out to characterize a function of Drosophila glia that form an expansion of myelin-like membranes that might facilitate rapid nerve conduction. A combination of Drosophila genetics, antibody staining, and electron microscopy is used to characterize this "myelin" and the role of glial wrapping in clustering of sodium/potassium channels at motor exit points. The results are valuable, as they would point to Drosophila as a new, genetically accessible model organism to study myelin evolution. While the results are interesting, the strength of the evidence provided is incomplete due to inadequate quantification of the data provided.

eLife assessment

This manuscript is of interest for the fields of ageing, mRNA translation and C. elegans biology, as it provides new insights into the regulation of lifespan by alternate mechanisms that modulate mRNA translation in selected environmental contexts. While overall the main conclusions are supported by the data and of interest, the work would be stronger with control experiments that more fully and more consistently support all the conclusions. Furthermore, data presentation and interpretation need some attention.

eLife assessment

The important work presented here provides findings that substantially advance our understanding of a major research question into how bicarbonate/CO2 signaling regulates cardiac mitochondrial energy supply. The methods, data, and analyses broadly support the claims with only minor weaknesses concerning the exact spatial location of the enzymes involved. The work will be of broad interest to cell biologists and biochemists interested in metabolic control.

eLife assessment

This study presents an important description on the dynamics of histone variant exchange controlling the organization of the chromatin state of the Arabidopsis genome, combining the analysis of histone variants, histone modification, and chromatin states. The evidence supporting the claims of the authors is compelling, but some of the main claims are only partially supported experimentally. This work will be of great interest to those in the field of epigenetics and chromatin biology.

eLife assessment

This valuable study investigates the environmental drivers behind termite construction, focusing, in particular, on pellet deposition behavior, with the conclusion that termites likely sense curvature indirectly through substrate evaporation. The findings reconcile discrepancies between previous studies through experimental and computational approaches. The strength of the evidence supporting the claims is solid, although many computational details are still missing, and the are concerns about the repeatability of the results across replicates, the dynamics of evaporation in their experiment, and the termites' ability to sense humidity.

eLife assessment

This paper describes a useful analysis tool for quantitative assessment of sarcomere structures in healthy and perturbed cardiomyocytes. The work is solid, and the methods, data and analyses broadly support the claims with only minor weaknesses. The tool will be of interest to biologists working on sarcomere structure, function and development.

eLife assessment

This useful manuscript challenges the utility of current paradigms for estimating brain-age with magnetic resonance imaging measures, but presents inadequate evidence to support the suggestion that an alternative approach focused on predicting cognition is more useful. The paper would benefit from a clearer explication of the methods and a more critical evaluation of the conceptual basis of the different models. This work will be of interest to researchers working on brain-age and related models.

eLife assessment

This study presents important findings that set a new standard for generating and maintaining monosomic yeast lines, and is the first, to our knowledge, to assess gene expression in yeast monosomies. The research offers an innovative approach to evaluate epistasis between genes on the same chromosome; however, the strength of evidence supporting the conclusions on positive epistasis for fitness is still incomplete due to the need for clarification for the exact calculation method of expected fitness without epistasis, as well as due to a lack of molecular mechanisms. Additionally, the interpretation of transcriptome results would benefit from a more comprehensive consideration of previous studies on genomic balance and the inclusion of further analyses and experiments.

eLife assessment

This valuable manuscript provides a single-cell RNA sequencing analysis of adult pig skin from different species and anatomical regions. The evidence supporting the conclusions is compelling, with identification molecular and cellular differences in pig skin, yet the analyses are incomplete in the analysis of regional- or species-based differences.

eLife assessment

This is an important study that defines cell type changes upon the expression of a mutant tau protein and put it into context of human postmortem tissue. Technically, the single cell mRNA sequencing data are convincing but the loss of neurons already at the earliest stages assessed in this model may rather suggest there are also elements of developmental toxicity.

eLife assessment

This fundamental study substantially advances our understanding of how aging and stress resilience across an organism is determined by identifying a new player in this process and uncovering its mode of action. The evidence is solid as the methods, data and analyses broadly support the claims with only minor weaknesses. The work will be of broad interest to the field of aging and protein homeostasis.

eLife assessment

Studies of prey behavior have the potential to provide insight into the chemical encoding of stress in the brain and the mechanisms by which this generates behavioral plasticity. In this important work, the authors identify a novel predation-evoked behavior in the nematode C. elegans and implicate dopamine in its implementation. While the support for some claims in the current paper is incomplete, this work provides an exciting foundation for future studies of behavioral plasticity in this powerful system.

eLife assessment

The toxin mycolactone is produced by mycobacterium ulcerans which is responsible for the Buruli ulcer. The authors performed a valuable study showing the effects of mycolactone on blood vessels integrity. This convincing data provide new therapeutic targets to accelerate healing of Buruli ulcers.

eLife assessment

This paper is of interest to neuroscientists studying the effects of sex hormones on neural and behavioral plasticity, and more specifically to researchers studying the neural mechanisms underlying birdsong plasticity. The experimental design is excellent, and the work provides a comprehensive resource for understanding the intersection between testosterone's influence on gene expression and behavior. However, the work also makes claims concerning cellular effects and gene regulatory mechanisms that extend beyond the data and under the current analyses are not rigorously supported.

eLife assessment

This study is an excellent example of how one can use high-throughput technologies to address animal evolution from a cell-type perspective. The authors present a beautiful analysis of single-nucleus RNA-seq data from three embryonic stages in a sea star; this is the first single-cell data from this large group of echinoderms and the first single-nucleus transcriptomic study in any echinoderm. The authors demonstrate the presence of unique as well as previously unnoticed homologous cell types between a sea star and a sea urchin, discovery very intriguing to echinoderm developmental biologists, which will also be of great interest to scientists in the broad fields of evolution and development.

eLife assessment

The findings of this study yield important new insights into the relationship between the number of close friends and mental health, cognition, and brain structure. Due to the large sample sizes, the evidence is solid but would have been improved if both of the analyzed datasets contained more closely matched measures. This work advances our understanding of how the friendship network relates to young adolescents' mental well-being and cognitive functioning and their underlying neural mechanisms.

eLife assessment

This potentially important work proposes a novel approach, based on co-evolution analysis, machine-learning protocols and molecular dynamics simulations, to predict structures and energetics of the main states of the alternating access cycle of a family of membrane transporters, the sugar porters. The approach is compelling, especially the application of co-evolution and Alphafold to generate highly accurate models in different conformational states of a given protein, but the work is currently incomplete due to shortcomings in the calculation of the energy landscape. With this aspect strengthened, the manuscript will be of interest to the transporter and computational modeling communities.

eLife assessment

This study presents useful structural and functional connectivity profiles of patients receiving deep brain stimulation in the posterior hypothalamus for severe and refractory aggressive behavior. The inclusion of data from multiple centers is compelling. However, the imaging analysis is incomplete and the interpretation of the findings is not solid.

eLife assessment

This study reports a joint experimental and computational investigation of the structural features of biomolecular condensates formed by a specific intrinsically disordered protein. The authors also adapt emerging rules to discuss and physico-chemical determinants of these structures of condensates. Specifically, the authors adapt the analysis of fractal structures, co-opted from the field of colloidal chemistry / physics, and generate important insights regarding the network-like organization of disordered proteins within in silico facsimiles of condensates. The usage of these analyses in the context of studying all atom models for multi-chain assemblies intended to mimic the internal organization of condensates is very interesting. The work is of relevance to cell biology and structural biology.

eLife assessment

The study of Thiery et al. details the heterogeneous expression of a very large number of genes presumably associated with cell fate decisions in the ectoderm at the neural plate border in early avian embryos. The authors mostly succeed in presenting their very complex strategy of data analysis in a clear way but the work is incomplete with some conceptual weaknesses in how the authors describe and interpret their results. By focusing on one of the earliest cell fate decisions in the ectoderm of a vertebrate embryo, this study will be valuable to a broad range of developmental biologists.

eLife assessment

This study presents a useful application of a prior model published by the authors to a new dataset. The results from this approach were interesting and solid but the conclusions that one can make from the application of the model to only one paper are limited in scope and would depend on further probing to know if the model itself has face validity as a model of ventral visual stream function.

eLife assessment

Protein and lipid homeostasis are important for maintaining cellular functions but their crosstalk remains largely unknown. This important manuscript deals with this interesting topic and applies the powerful unbiased tools of somatic cell genetics to discover evidence suggesting a link between sphingolipids/cholesterol ester metabolism and lysosomal protein aggregation. However, in our view the experimental evidence in support of the paper's stated conclusions remains incomplete and measures that (i) go beyond reliance on the ProteoStat stain as the sole metric for aggregation and proteostatic challenge, (ii) biochemically back up the results and provide plausible mechanistic insights into the connection of lysosomal lipid handling and protein aggregation are needed.

eLife assessment

This paper introduces the python software package Pynapple and a separate package of more advanced routines (Pynacollada) to the Neuroscience/Neural Engineering community. Pynapple provides a set of data objects and methods that have the potential to simplify data analysis for neural and behavioral data types. This represents a valuable contribution to the field. The evidence was judged to be incomplete due to the fact that key details were missing.

eLife assessment

This is an important paper that revises the canonical model of how olfactory sensory neurons choose which odor receptor to express. The data presented in the paper are convincing and the model proposed is provocative and likely to enable important future work.

eLife assessment

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

eLife assessment

This work presents an important methodological advance for single-molecule force spectroscopy of membrane proteins providing a new robust design of the linkage between a target single molecule and solid support. The data provide compelling evidence of the improved mechanical stability of the pulling system. Allowing more statistically reliable force measurements of biomolecules, this method may be broadly applicable in the field of single-molecule biophysics.

eLife assessment

The authors present an exciting idea about how to integrate morphogens into a gene regulatory network with the dynamics of morphogenesis and cell movement. It represents a novel methodology, but in its current form the hypotheses, data and relationships described do not provide a sufficiently compelling model to disentangle cause and effect or elucidate the impact of cell movements on differentiation dynamics the zebrafish mesoderm.

eLife assessment

This important work investigates how two distinct processes, morphological changes and synaptic plasticity, contribute to the final shape of neuronal dendrites and the spatial structure of their synaptic inputs. The modelling is solid and could be broadly applied to other similar questions. Some of the findings are a direct result of how the model is constructed, which limits the impact. The work will be of interest to neuroscientists studying dendritic development and connectivity at a single-cell level.

eLife assessment

This paper presents important findings on the hexametric structure of MCM8/9, which potentially explain its role as a DNA helicase in homologous recombination. Due to the lack of DNA in the complex and the invisibility of HROB the current data only provide an incomplete model of the function of the MCM8/9 complex. This work will be of interest to biologists studying DNA transactions.

eLife assessment

The authors present a useful analysis of different factors that are required for release of the lipid-linked morphogen Shh from cellular membranes. The evidence is currently still incomplete as experiments rely on over-expression of Shh in a single cell line and are sometimes of a correlative nature. The study confirms and extends previous findings and will be of interest to developmental biologists who work on Hedgehog signaling.

eLife assessment:

This study introduces a valuable paradigm in the filed of adipose biology field: blocking triglyceride storage in adipose tissue does not lead to lipodystrophy and impaired glucose homeostasis but instead improves metabolic health. The evidence supporting these claims are convincing, with the authors providing a comprehensive metabolic analysis. However, mechanistic studies, which are currently incomplete, would strengthen the study and its impact. Regardless, this study will be of high interest to those in the adipose tissue biology and metabolism fields.

eLife assessment

This study presents an important open-source resource for high-throughput behavioral screening. The protocols employ inexpensive, off the shelf hardware, and carry out real-time analysis of hundreds of behaving flies. Although these protocols were developed using Drosophila melanogaster, they could easily be applied to other model systems. The evidence in support of the conclusions is solid although more details on the algorithms used for phenotyping would be helpful in order to better assessing the overall robustness of the platform.

Within the pantheon of types of notes there are: - paraphrasing notes, which one can use to summarize ideas for later recall and review as well as to check one's own knowledge and understanding of what an author has said. - commentary notes, which take the text and create a commentary on them, often as part of having a conversation with the text. These can be seen historically in the Midrashim tradition of commenting on Torah.

[23:12 - 24:47]

separately also: - productivity notes - to do lists, reminders of work to be done, often within or as part of a larger complex project

eLife assessment

This valuable work provides new insights into history-dependent biases in human perceptual decision-making. It provides compelling behavioral and MEG evidence that humans adapt their history-dependent to the correlation structure of uncertain sensory environments. Further neural data analyses would strengthen some of the findings, and the studied bias would be more accurately framed as a stimulus- or outcome-history bias than a choice-history bias because tested subjects are biased not by their previous choice, but by the previous feedback (indicating the category of the previous stimulus).

eLife assessment

This study presents valuable findings on a cleaved form of METTL3 that may play an essential role in regulating the assembly of the METTL3-METTL14-WTAP complex. The evidence supporting the claims of the authors is solid, but the model and assays can be improved. The work will be of interest to biologists working on RNA epigenetics and cancer biology.

eLife assessment

This study provides potentially important, new information about the combination of information from the two eyes in humans. The data included frequency tagging of each eye's inputs and measures reflecting both cortical (EEG) and sub-cortical processes (pupillometry). Binocular combination is of potentially general interest because it provides -in essence- a case study of how the brain combines information from different sources and through different circuits. The strength of supporting evidence appears to be solid, showing that temporal modulations are combined differently than spatial modulations, with additional differences between subcortical and cortical pathways. However, the manuscript's clarity could be improved, including by adding more convincing motivations for the approaches used.

eLife assessment

This study offers new fundamental information on a role for the sodium/potassium pump in sleep regulation. Elegant methods were used to provide compelling evidence supporting the claim. The work will be of interest to sleep researchers in zebrafish as well as in other species.

eLife assessment

Yang et al. investigate whether distinct sources of conflict are represented in a common cognitive space. The study uses an interesting task that mixes two different sources of difficulty and reports that the brain appears to represent these sources as a mixture on a continuum, in the prefrontal areas involved in resolving task difficulty. While these results are useful, they overlap with previous findings, leave open several design and logical concerns, and rely on novel statistical analyses that may require further validation, so they are currently incomplete.

eLife assessment

This is an important study demonstrating that vitamin D-bound VDR both increases SIRT1 expression and directly interacts with SIRT1 to cause auto-deacetylation on Lys610, thereby regulating activation of SIRT1 catalytic activity. The data presented to support the presented conclusions are convincing, and the findings are particularly relevant to the actions of VDR on colorectal cancer.

eLife assessment

This study presents valuable findings on a potential positive feedback loop between ZEB2 and ACSL4 that regulates lipid metabolism and breast cancer metastasis. The evidence supporting the claims of the authors is solid, but more appropriate validation for ACSL4 interacting with ZEB2 would have strengthened the study. The work will be of particular interest to colleagues working on breast cancer.

eLife assessment

This important study uses calcium imaging in mice to advance our understanding of the effect of antipsychotic drugs on neural functioning. The evidence supporting the conclusions is solid, although the statistical testing of the data may be improved. This work will be of interest to neuroscientists working on visual processing and psychosis researchers.

eLife assessment

This study will be of interest and valuable to scientists of many different subareas in the study of eukaryotic extracellular vesicles. The authors' efforts to improve the way we analyze EVs are highly appreciated and their results are convincing: they not only used appropriate and validated methodologies in line with current state-of-the-art but also presented alternatives to improve these approaches.

eLife assessment

This valuable study reports a complete in vitro system where different steps and direct interactions between different components of MHCI maturation can be monitored, hence leading to a better mechanistic understanding of MHC I maturation. The evidence supporting the findings is currently incomplete and would benefit from clarification of some key issues. This work will be of interest to immunologists and biochemists.

Globin Gene Switching is a process of sequential activation and inactivation of globin genes during development. Here's how it works:

1. Transcription factors along with epigenetic elements such as DNA methyltransferases and demethylases interact with enhancers "upstream" of the β-globin gene cluster that contact globin gene promoters.
2. This process silences the embryonic and fetal genes.
3. Activation of fetal globin gene repressors during development allows expression of the adult genes.
4. Developmental factors such as RNA-binding factors and microRNAs also impact hemoglobin switching.

β-Globin Gene Switching:

1. An upstream super-enhancer called the β-globin locus control region (LCR) binds erythroid-specific and ubiquitous transcription factors.
2. The LCR interacts directly with globin gene promoters.
3. Transcription factors that silence and activate genes also interact with elements of the globin genes.
4. Competition among the β-like genes for the LCR and autonomous silencing of the embryonic and fetal globin genes depends on transcription factors.
5. Silencing, first of HBE and then of HBG2 and HBG1, favors the interaction of the LCR with HBB.
6. When HBG2 or HBG1 is upregulated by rare point mutations in their promoters, expression of the linked HBB is downregulated.
7. Deletions of the HBB promoter remove competition for the LCR, increasing the expression of HBG2, HBG1, and HBD.
8. The transcription factors BCL11A and ZBTB7A silence the HbF genes.
9. BCL11A binds to the HbF gene promoters, repressing them and silencing transcription; ZBTB7A binds upstream of BCL11A with similar repressive effects.
10. Mutations in these binding sites abolish the normal silencing of the HbF genes, leading to hereditary persistence of fetal hemoglobin (HPFH).
11. Disruption of the BCL11A regulatory elements or the binding sites for BCL11A by gene editing is a prime therapeutic target for HbF induction.

α-Globin Gene Switching:

1. A less complex switch takes place in the α-globin gene cluster.
2. A regulatory locus of four elements termed R1-R4 is present within introns of the gene NPRL3 that is upstream of HBA2.
3. A developmental switch from embryonic ζ- to adult α-globin gene expression occurs at about 6 weeks’ gestation.

Modulation of HbF Level:

1. Variations in three quantitative trait loci (QTL), BCL11A, MYB, and a locus linked to the HBB cluster, account for a major portion of HbF variation among normal individuals and patients with sickle cell anemia and β thalassemia.
2. BCL11A, a zinc finger protein that represses HbF genes, binds TGACCA motifs, the most important at position –115 in the promoter of each γ-globin gene.
3. ZBTB7A binds 85 nucleotides upstream of these BCL11A binding sites; its binding also represses γ-globin gene transcription.
4. When binding of either BCL11A or ZBTB7A is disrupted, silencing of HBG2 and HBG1 is abrogated.
5. The MYB gene is essential for hematopoiesis and erythroid differentiation.
6. MYB inhibits HbF expression directly by activation of KLF1 and other repressors and indirectly through alteration

Here are the major points summarizing the text on globin gene clusters and hemoglobin:

Globin Gene Clusters:

• Globin is encoded in two nonallelic gene clusters: β-globin gene cluster on chromosome 11 and α-globin gene cluster on chromosome 16.
• The β-globin gene cluster contains an embryonic ε-globin gene, two fetal γ-globin genes, a major adult β-globin gene, and a minor adult δ-globin gene.
• The α-globin gene cluster contains an embryonic ζ-globin gene and duplicated α-globin genes with identical proteins.
• Hemoglobin production begins with embryonic hemoglobins: Gower I, Gower II, Portland I, and Portland II.
• Fetal hemoglobin (HbF) production starts at 6-8 weeks of gestation, peaks during mid-gestation, and falls to <1% of total hemoglobin during the first 6 months of extrauterine life.
• Adult hemoglobin A (HbA) production follows a pattern reciprocal to that of HbF.
• Hemoglobin composition of normal adults is >95% HbA, ~1% HbF, and 2-3% HbA2.
• Hemoglobin is subject to posttranslational modifications, the most important being the nonenzymatic glycosylation of HbA forming the adduct HbA1c.

Hemoglobin Structure:

• All globin polypeptides have similar but not identical primary structures. α-Globins contain 141 amino acids, and β-like globins have 146 amino acids.
• The primary structure dictates the secondary structure of globin into α-helical sections joined by small nonhelical stretches.
• Each globin chain folds into a tertiary conformation known as the globin fold, where charged amino acid residues face the exterior of the molecules and uncharged residues face the hydrophobic interior.
• The iron-containing tetrapyrrole heme moiety is protected from oxidation and located between two of the helical segments; O2 loading and unloading occur when heme iron is in its reduced ferrous form.
• Globin gene mutations affecting critical heme-binding amino acid residues allow iron to be oxidized, forming methemoglobin, which has high O2 affinity and does not release O2 in tissues.
• Dimers of α- and non-α-globin chains reversibly assemble into tetramers, forming a quaternary structure.

Hemoglobin Function:

• Hemoglobin transports O2 from lungs to tissues and carbon dioxide (CO2) from tissues to lungs.
• Hemoglobin is a nitrate reductase that releases nitric oxide (NO) from nitrite to promote vasodilation.
• Oxygen binding is defined by the sigmoidal shape of the hemoglobin-O2 dissociation curve.
• The P50 is a point on this curve that indicates the partial pressure of O2 where hemoglobin is half saturated.
• The P50 is influenced by the binding of 2,3-bisphosphoglycerate, pH, and temperature.
• The conformation of hemoglobin fully saturated with O2 is known as the R or relaxed state; desaturated hemoglobin is in the T or tense state.
• Hemoglobin variants that decrease P50 are characterized by isolated erythrocytosis as compensation for hypoxia.
• Variants with increased P50 sometimes are accompanied by cyanosis and anemia as hemoglobin becomes unsaturated and O2 delivery is enhanced.
• Mutations of residues critical for heme binding, R-T transitions, or tetramer stability cause hemoglobinopathies characterized by hemolytic anemia

eLife assessment

This work aims to discover the mechanisms governing the switch between conventional DNA replication and telomeric end-replication that requires a specialized mechanism. Genetic and biochemical assays for protein modifications and interactions suggest an interplay between sumoylated PCNA and chromosome terminal capping proteins. The results address an important question that would have implications for several fields interested in genome stability questions. However, several claims, even some that form the basis of the proposed molecular models, are incompletely supported by the data.

eLife assessment

This study presents convincing evidence of the correlation between social tolerance and communicative complexity in a comparison of three macaque species. Notably, the authors use an innovative, detailed methodology for quantifying facial expressions during social interactions that provides a valuable framework for future comparative research in animal communication. These findings would be further strengthened with some conceptual clarity regarding the basis of the hypotheses being tested and the addition of an interobserver reliability test.

eLife assessment

This study provides valuable information on the biogenesis of eccDNAs during spermatogenesis, i.e., eccDNAs in spermatogenic cells are not derived from miotic recombination hotspots but represent oligonucleosomal DNA fragments from apoptotic male germ cells, whose ends are ligated through microhomology-mediated end-joining. The study is currently incomplete because the method of bioinformatics needs more details and data interpretation should take the amplification bias into consideration.

Sure, here's a summary of the causes of secretory diarrhea presented in the text:

Causes of secretory diarrhea:

1. Medications: Regular ingestion of drugs and toxins, including prescription and over-the-counter medications, may produce diarrhea. Stimulant laxatives and chronic ethanol consumption may also cause secretory-type diarrhea.

2. Bowel resection, mucosal disease, or enterocolic fistula: These conditions may result in secretory-type diarrhea because of inadequate surface for reabsorption of secreted fluids and electrolytes.

3. Partial bowel obstruction, ostomy stricture, or fecal impaction: These may paradoxically lead to increased fecal output due to fluid hypersecretion.

4. Hormones: Secretory diarrhea may be caused by hormones, including those released by metastatic gastrointestinal carcinoid tumors, gastrinomas, VIPomas, medullary carcinoma of the thyroid, and systemic mastocytosis.

5. Bacterial infections: Certain bacterial infections may occasionally persist and be associated with a secretory-type diarrhea.

6. Environmental toxins: Inadvertent ingestion of certain environmental toxins (e.g., arsenic) may lead to chronic rather than acute forms of diarrhea.

7. Idiopathic bile acid malabsorption (BAM): Reduced negative feedback regulation of bile acid synthesis in hepatocytes by fibroblast growth factor 19 (FGF-19) produced by ileal enterocytes results in a degree of bile-acid synthesis that exceeds the normal capacity for ileal reabsorption, producing BAD. An alternative cause of BAD is a genetic variation in the receptor proteins (β-klotho and fibroblast growth factor 4) on the hepatocyte that normally mediate the effect of FGF-19.

8. Colonic transit: Genetic variation in the bile acid receptor (TGR5) in the colon may result in accelerated colonic transit.

It's worth noting that some of these causes may overlap or occur in conjunction with each other.

Points:

The cornerstone of diagnosis in those suspected of severe acute infectious diarrhea is microbiologic analysis of the stool.

Workup includes cultures for bacterial and viral pathogens; direct inspection for ova and parasites; and immunoassays for certain bacterial toxins (C. difficile), viral antigens (rotavirus), and protozoal antigens (Giardia, E. histolytica).

Clinical and epidemiologic associations may assist in focusing the evaluation.

If a particular pathogen or set of possible pathogens is implicated, either the whole panel of routine studies may not be necessary or, in some instances, special cultures may be appropriate.

Molecular diagnosis of pathogens in stool can be made by identification of unique DNA sequences, and evolving microarray technologies have led to more rapid, sensitive, specific, and cost-effective diagnosis.

Persistent diarrhea is commonly due to Giardia, but additional causative organisms that should be considered include C. difficile, E. histolytica, Cryptosporidium, Campylobacter, and others.

Flexible sigmoidoscopy with biopsies and upper endoscopy with duodenal aspirates and biopsies may be indicated if stool studies are unrevealing.

Structural examination by sigmoidoscopy, colonoscopy, or abdominal computed tomography (CT) scanning may be appropriate in patients with uncharacterized persistent diarrhea to exclude IBD or as an initial approach in patients with suspected noninfectious acute diarrhea.

Fluid and electrolyte replacement are of central importance to all forms of acute diarrhea.

Oral sugar-electrolyte solutions (iso-osmolar sport drinks or designed formulations) should be instituted promptly with severe diarrhea to limit dehydration, which is the major cause of death.

Profoundly dehydrated patients, especially infants and the elderly, require IV rehydration.

In moderately severe nonfebrile and nonbloody diarrhea, antimotility and antisecretory agents such as loperamide can be useful adjuncts to control symptoms.

Such agents should be avoided with febrile dysentery, which may be prolonged by them, and should be used with caution with drugs that increase levels due to cardiotoxicity.

Bismuth subsalicylate may reduce symptoms of vomiting and diarrhea but should not be used to treat immunocompromised patients or those with renal impairment because of the risk of bismuth encephalopathy.

Judicious use of antibiotics is appropriate in selected instances of acute diarrhea and may reduce its severity and duration.

Many physicians treat moderately to severely ill patients with febrile dysentery empirically without diagnostic evaluation using a quinolone, such as ciprofloxacin (500 mg bid for 3–5 d).

Empirical treatment can also be considered for suspected giardiasis with metronidazole (250 mg qid for 7 d).

Selection of antibiotics and dosage regimens are otherwise dictated by specific pathogens, geographic patterns of resistance, and conditions found.

Newer agents such as nitazoxanide may be required for Giardia and Cryptosporidium infections because of resistance to first-line treatments.

Antibiotic coverage is indicated, whether or not a causative organism is discovered, in patients who are immunocompromised, have mechanical heart valves or recent vascular grafts, or are elderly.

Bismuth subsalicylate may reduce the frequency of traveler’s diarrhea.

Antibiotic prophylaxis is only indicated for certain patients traveling to high-risk countries in whom the likelihood or seriousness of acquired diarrhea would be especially high.

Use of ciprofloxacin, azithromycin, or rifaximin may reduce bacterial diarrhea in such travelers by 90%, though rifaximin is not suitable for invasive disease but rather as treatment for uncomplicated traveler’s

Sure, here are some additional sub points for each category of infectious agents:

1. Travelers:
2. Enterotoxigenic E. coli (ETEC) and enteroaggregative E. coli (EAEC)
3. Campylobacter
4. Shigella
5. Aeromonas
6. Norovirus
7. Coronavirus
8. Salmonella

9. Vibrio cholerae

10. Consumers of certain foods:

11. Salmonella (from chicken, eggs)
12. Campylobacter (from undercooked hamburger)
13. Shigella (from undercooked pork)
14. Enterohemorrhagic E. coli (EHEC) O157:H7 (from undercooked hamburger)
15. Bacillus cereus (from fried rice or other reheated food)
16. Staphylococcus aureus (from mayonnaise or creams)
17. Listeria monocytogenes (from fresh or frozen uncooked foods, mushrooms, or dairy products)

18. Vibrio species (from seafood, especially if raw)

19. Immunodeficient persons:

20. Mycobacterium species
21. Cytomegalovirus
22. Adenovirus
23. Herpes simplex virus
24. Cryptosporidium
25. Isospora belli
26. Microsporidia
27. Blastocystis hominis
28. Neisseria gonorrhoeae
29. Treponema pallidum

30. Chlamydia

31. Daycare attendees and their family members:

32. Shigella
33. Giardia
34. Cryptosporidium
35. Rotavirus
36. Adenovirus

37. Norovirus

38. Institutionalized persons:

39. Clostridioides difficile (C. difficile)
40. Norovirus
41. Rotavirus
42. Adenovirus
43. Salmonella
44. Shigella
45. Campylobacter
46. Vibrio cholerae

Additionally, some infectious agents may cause specific clinical features: - Small-bowel hypersecretion: preformed bacterial toxins, enterotoxin-producing bacteria, and enteroadherent pathogens (resulting in profuse, watery diarrhea) - Marked vomiting and minimal or no fever: preformed bacterial toxins and enterotoxin-producing bacteria - Abdominal cramping or bloating, higher fever: enteroadherent pathogens - High fever and abdominal pain: cytotoxin-producing and invasive microorganisms - Bloody diarrhea (dysentery): invasive bacteria and Entamoeba histolytica - Severe abdominal pain with tenderness mimicking acute appendicitis: Yersinia invades the terminal ileal and proximal colon mucosa

Here's a simplified list of causes of different types of gastrointestinal symptoms:

1. Heartburn: Opportunistic fungal or viral esophageal infections, GERD, hiatal hernia, peptic ulcer disease, and gastritis.

2. Odynophagia (painful swallowing): Opportunistic fungal or viral esophageal infections.

3. Upper abdominal pain: Biliary colic, pancreatic disease (chronic pancreatitis, malignancy), hepatocellular carcinoma, Ménétrier’s disease, infiltrative diseases (sarcoidosis, mastocytosis, eosinophilic gastroenteritis), mesenteric ischemia, thyroid and parathyroid disease, and abdominal wall strain.

4. Nausea and vomiting: Gastroparesis, viral or bacterial gastroenteritis, chemotherapy-induced nausea and vomiting, motion sickness, and vestibular disorders.

5. Gas, bloating, and discomfort: Intestinal lactase deficiency, intolerance of other carbohydrates (e.g., fructose, sorbitol), and small-intestinal bacterial overgrowth.

6. Dyspepsia (indigestion): Peptic ulcer disease, gastritis, GERD, celiac disease, nonceliac gluten sensitivity, pancreatic disease (chronic pancreatitis, malignancy), hepatocellular carcinoma, Ménétrier’s disease, infiltrative diseases (sarcoidosis, mastocytosis, eosinophilic gastroenteritis), mesenteric ischemia, thyroid and parathyroid disease, and abdominal wall strain.

7. Other causes of indigestion: Congestive heart failure and tuberculosis.

Sure, here are some variants and examples of the conditions mentioned in the text:

Intraperitoneal Disorders: - Ulcers: peptic ulcers, stress ulcers - Malignancy: stomach cancer, colon cancer - Benign or malignant tumors: intestinal tumors, colon polyps - Inflammatory diseases: Crohn's disease, ulcerative colitis - Superior mesenteric artery syndrome: Wilkie's syndrome - Median arcuate ligament syndrome: Dunbar syndrome - Biliary colic: gallstones, cholecystitis - Enteric infectious causes: norovirus gastroenteritis, bacterial food poisoning (e.g. Staphylococcus aureus, Bacillus cereus), cytomegalovirus enteritis

Gut sensorimotor dysfunction: - Gastroparesis: diabetic gastroparesis, idiopathic gastroparesis, postsurgical gastroparesis - Intestinal pseudoobstruction: Ogilvie's syndrome, chronic idiopathic intestinal pseudoobstruction, secondary pseudoobstruction (e.g. from scleroderma, amyloidosis, small-cell lung carcinoma) - Gastroesophageal reflux: GERD - Irritable bowel syndrome: IBS - Chronic constipation: functional constipation, slow-transit constipation

Other functional gastroduodenal disorders: - Chronic nausea vomiting syndrome: functional nausea vomiting disorder - Cyclic vomiting syndrome: CVS - Cannabinoid hyperemesis syndrome: CHS - Rumination syndrome: regurgitation disorder

Extraperitoneal Disorders: - Myocardial infarction: heart attack - Congestive heart failure: CHF - Postoperative emesis: postoperative nausea and vomiting (PONV) - Increased intracranial pressure: intracranial hypertension, pseudotumor cerebri - Anorexia nervosa: restrictive eating disorder - Bulimia nervosa: binge-eating disorder

Medications and Metabolic Disorders: - Analgesics: opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) - Antibiotics: macrolides, fluoroquinolones, tetracyclines - Cardiac antiarrhythmics: amiodarone - Antihypertensives: calcium channel blockers, ACE inhibitors, beta blockers - Oral hypoglycemics: sulfonylureas, meglitinides - Antidepressants: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) - Smoking cessation drugs: varenicline, nicotine replacement therapy (NRT) - Contraceptives: combined oral contraceptives (COCs), progestin-only contraceptives (POCs) - Cancer chemotherapy: cisplatin, carboplatin, paclitaxel, docetaxel, doxorubicin - Metabolic disorders: pregnancy (nausea of pregnancy, hyperemesis gravidarum), uremia, diabetic ketoacidosis, Addison's disease, hypoparathyroidism, hyperthyroidism, hypothyroidism - Circulating toxins: fulminant liver failure, enteric bacterial infections (e.g. Salmonella, Shigella, Escherichia coli), ethanol intoxication.

Start | |---Brainstem nuclei (including the nucleus tractus solitarius; dorsal vagal and phrenic nuclei; medullary nuclei regulating respiration; and nuclei that control pharyngeal, facial, and tongue movements) | |---Coordinate initiation of emesis | |---Neurokinin NK1 pathway | |---Serotonin 5-HT3 pathway | |---Endocannabinoid pathway | |---Vasopressin pathway | |---Activators of emesis | |---Emetic stimuli act at several sites | | | |---Unpleasant thoughts or smells (brain) | | | |---Motion sickness and inner ear disorders (labyrinthine pathways) | | | |---Gastric irritants and cytotoxic agents (gastroduodenal vagal afferent nerves) | | | |---Nongastric afferents (bowel obstruction and mesenteric ischemia) | | | |---Bloodborne stimuli (area postrema) | |---Neurotransmitters mediating vomiting are selective for different sites | |---Vestibular muscarinic M1 and histaminergic H1 receptors (labyrinthine disorders) | |---5-HT3 receptors (vagal afferent stimuli) | |---5-HT3, M1, H1, and dopamine D2 subtypes (area postrema) | |---NK1 receptors in the CNS (nausea and vomiting) | |---Cannabinoid CB1 pathways (cerebral cortex and brainstem) | |---Somatic and visceral muscles respond stereotypically during emesis | |---Inspiratory thoracic and abdominal wall muscles contract | |---Distally migrating gut contractions are abolished | |---Orally propagating spikes evoke retrograde contractions to facilitate expulsion of gut contents | |---Therapies for vomiting act on receptor-mediated pathways End

• Nausea: the sensation or feeling of an urge to vomit.
• Vomiting (emesis): the act of expelling the contents of the stomach through the mouth due to the contraction of the gastrointestinal and thoracoabdominal muscles.
• Regurgitation: the effortless movement of food or liquid from the stomach back into the mouth without the forceful contractions seen in vomiting.
• Rumination: the repeated regurgitation of food residue, which may be rechewed and reswallowed voluntarily.
• Indigestion: a collection of symptoms that includes nausea, vomiting, heartburn, regurgitation, and dyspepsia. Dyspepsia is a group of symptoms that originate in the gastroduodenal region and include postprandial fullness, early satiety, bloating, eructation, and anorexia. Epigastric burning or pain may also be present.
• Avoidant/restrictive food intake disorder: a condition in which individuals have difficulty consuming certain types of food or food in general, leading to weight loss or nutritional deficiencies. Nausea, vomiting, and dyspepsia have been associated with this disorder.

summary Oropharyngeal Dysphagia: - Poor bolus formation and control, drooling, and difficulty initiating swallowing are characteristic signs. - May result in premature spillage of food into the hypopharynx, aspiration into the trachea, or regurgitation into the nasal cavity. - Causes include neurologic, muscular, structural, iatrogenic, infectious, and metabolic factors, with iatrogenic, neurologic, and structural pathologies being the most common. - Iatrogenic causes include head and neck cancer treatments such as surgery and radiation. - Neurogenic dysphagia resulting from cerebrovascular accidents, Parkinson’s disease, and amyotrophic lateral sclerosis is a major cause of morbidity related to aspiration and malnutrition. - Asymmetry in the cortical representation of the pharynx provides an explanation for the dysphagia that occurs as a consequence of unilateral cortical cerebrovascular accidents. - Structural lesions causing dysphagia include Zenker’s diverticulum, cricopharyngeal bar, and neoplasia. - Rapid-sequence fluoroscopy is necessary to evaluate for functional abnormalities. - Adequate fluoroscopic examination requires that the patient be conscious and cooperative. - Timing and integrity of pharyngeal contraction and opening of the UES with a swallow are analyzed to assess both aspiration risk and the potential for swallow therapy. - Structural abnormalities of the oropharynx should be assessed by direct laryngoscopic examination.

Esophageal Dysphagia: - The adult esophagus measures 18-26 cm in length and is anatomically divided into the cervical esophagus and the thoracic esophagus. - Solid food dysphagia becomes common when the lumen is narrowed to <13 mm. - The most common structural causes of dysphagia are Schatzki’s rings, eosinophilic esophagitis, and peptic strictures. - Propulsive disorders leading to esophageal dysphagia result from abnormalities of peristalsis and/or deglutitive inhibition, potentially affecting the cervical or thoracic esophagus. - Rapid-sequence fluoroscopy is necessary to evaluate for functional abnormalities. - Adequate fluoroscopic examination requires that the patient be conscious and cooperative. - High-resolution manometry is used to measure pressure changes along the length of the esophagus during swallowing. - Structural abnormalities of the esophagus should be assessed by endoscopic examination.

Here's a table summarizing the information:

| Category | Oropharyngeal Dysphagia | Esophageal Dysphagia | | --- | --- | --- | | Signs and Symptoms | Poor bolus formation and control, drooling, difficulty initiating swallowing | Solid food dysphagia, potentially accompanied by altered esophageal sensation, reduced distensibility, or motor dysfunction | | Causes | Neurologic, muscular, structural, iatrogenic, infectious, metabolic | Structural causes include Schatzki’s rings, eosinophilic esophagitis, and peptic strictures; propulsive disorders due to abnormalities of peristalsis and/or deglutitive inhibition | | Iatrogenic Causes | Head and neck cancer treatments such as surgery and radiation | N/A | | Diagnosis | Rapid-sequence fluoroscopy, direct laryngoscopic examination | Rapid-sequence fluoroscopy, high-resolution manometry, endoscopic examination |

1. Iron is transported in the blood by the iron-transferrin complex.
2. The complex interacts with specific transferrin receptors on the surface of cells that express transferrin receptors, such as developing erythroblast cells.
3. The iron-bearing transferrin is internalized via clathrin-coated pits and transported to an acidic endosome.
4. Iron is released from the transferrin at the low pH of the endosome.
5. Iron is made available for heme synthesis.
6. The transferrin-receptor complex is recycled to the surface of the cell.
7. The bulk of the transferrin is released back into circulation, and the transferrin receptor re-anchors into the cell membrane.
8. Iron in excess of the amount needed for hemoglobin synthesis binds to a storage protein, apoferritin, forming ferritin.
9. Senescent red cells are recognized by the cells of the reticuloendothelial system and undergo phagocytosis.
10. Hemoglobin is broken down, and the iron is shuttled back to the surface of the RE cell.
11. Iron is presented to circulating transferrin via the iron export channel, ferroportin.
12. Iron is then available for reutilization for hemoglobin synthesis

eLife assessment

This work explores how centrosomes, which function as the primary microtubule organizing center in animal cells, regulate cell division by examining the process in cells in which centrosome formation has been inhibited. The carefully conducted experiments provide convincing support for the important observation that elongated, but successful, mitosis observed in cells lacking centrosomes is due to delays in cell cycle progression, though the reviewers highlight some caveats that merit further discussion.

eLife assessment

This important work provides evidence that artificial recurrent neural networks can be used to investigate neural mechanisms underlying reversible remapping of spatial representations. Authors perform convincing state of the art analyses showing how population activity preserves the encoding of spatial position despite remappings due to the tracking of an internal variable. This paper will be of interest to neuroscientists studying contextual computations, neural representation of space and links between artificial neural networks and the brain.

eLife assessment

This behavioral modeling study investigates how humans make decisions on the difficulty of perceptual categorization tasks. The study finds that such judgments are best described by an evidence-accumulation model that includes a dynamic comparison of difficulty-related evidence, which terminates when the difference in evidence between two tasks reaches a predetermined bound - a valuable finding for research in perceptual decision-making. The paper provides solid behavioral evidence for the proposed model, but reviewers noted some potential improvements in the model selection procedure and the relation of the optimal model of the task to the human data, and to the best-fitting model.

eLife assessment

This paper presents an important finding that Styxl2, a poorly characterized pseudo-phosphatase, plays a role in the sarcomere assembly by promoting autophagic degradation of non-muscle myosins. The evidence supporting the conclusions is convincing. This work will be of interest to biologists working on muscle development, cell biology, and proteolysis.

eLife assessment

This valuable work fills a gap in the mapping of gene expression patterns in the early embryo of C. elegans. The presented data are solid and provides a resource for future analysis. The manuscript can still be improved in order to strengthen some of the conclusions made.

eLife assessment

In this important study, the authors provide convincing evidence that current DNA-based microbial genomics for skin bacteria cannot always detect the source of sequenced DNA and whether it originated from viable or non-viable bacteria. Additionally, the authors demonstrated in humans and mice that most of the viable bacteria reside inside hair follicles rather than the surface of the skin per se. Overall, the work has significance beyond a single discipline and will be of interest to those studying microbiomes.

eLife assessment

This important study provides exciting first-time evidence linking palmitate-induced insulin resistance to ceramide accumulation within the mitochondrial compartment and subsequent depletion of CoQ, an essential component of mitochondrial respiration. Whereas the results and interpretations are generally solid, the mechanistic aspect of the work and conclusions put forth rely heavily on in vitro studies performed in cultured L6 myocytes, which are highly glycolytic and generally not viewed as a good model for studying muscle metabolism and insulin action. Nonetheless, the findings offer intriguing new insights into mechanisms that connect ceramides to both insulin resistance and mitochondrial dysfunction, and are likely to open new avenues of preclinical/clinical research with broad therapeutic implications.