eLife assessment

This important study aims to move beyond current experimental approaches in speech production by (1) investigating speech in the context of a fully interactive task and (2) employing advanced methodology to record intracranial brain activity. Together these allow for examination of the unfolding temporal dynamics of brain-behaviour relationships during interactive speech. While this approach makes the findings highly compelling, the data are currently deemed incomplete in that neural recordings were only analysed from the left hemisphere (due to insufficient clinical electrode implantation in the right), neglecting the contribution of the right hemisphere.

eLife assessment

This study presents a valuable finding relating to how the state of arousal is represented within the superior colliculus, a principal visuo-oculomotor structure. The main conclusion that the representation of arousal is segregated, and thus does not directly influence motor output, is incompletely supported by the evidence and the work would be improved if additional analyses were performed to rule out alternative explanations. The work will be of interest to sensory, motor, and cognitive neuroscientists.

eLife assessment

Sisigano et al. report findings about the role of sphingolipids using lipidomics with machine learning in paclitaxel-induced peripheral neuropathy and preliminary translation of the impact of SA1P in cultured neuronal cells. This study presents a valuable finding on the increased activity of two well-studied signal transduction pathways in a subtype of breast cancer. The significance is limited by incomplete evidence which can be addressed in larger clinical cohorts in the future and with more robust biological validation approaches.

eLife assessment

This study presents a valuable finding that pathways associated with ribosome biogenesis (RiBi) are activated during transition cell states and targeting ribosome biogenesis could be a viable approach to overcome EMT-related chemoresistance in BCs. The evidence supporting the claims of the authors is quite solid, although inclusion of additional experimental support that blocking of EMT/MET is necessary for the synergistic effect of standard chemotherapy together with RiBi blockage would have strengthened the study. The work will be of interest to scientists working on breast cancer.

eLife assessment

This fundamental study identifies the kinase DYRK1A as a novel component of the tuberous sclerosis complex (TSC) protein complex, which is central to cellular growth and cell size. The findings presented here have broad implications for how cell size and growth is regulated. The methodology and analysis are convincing and support the findings.

eLife assessment

This important computational study provides new insights into how neural dynamics may lead to time-evolving behavioral errors as observed in certain working-memory tasks. By combining ideas from efficient coding and attractor neural networks, the authors construct a two-module network model to capture the sensory-memory interactions and the distributed nature of working memory representations. They provide convincing evidence supporting that their two-module network, but not any of the alternative circuit structures they considered, can account for error patterns reported in orientation estimation tasks with delays.

eLife assessment

This important study defines signaling mechanisms in tendinopathy development, which is significant as there is a clear need to identify therapeutic targets to prevent or reverse tendon pathology. The evidence supporting the conclusions are compelling combining an existing human tendinopathy transcriptomics dataset with ex-vivo assembloid model, and an in vivo injury model using genetic reporter mice. This work will be of interest to developmental and stem cell biologists.

eLife assessment

Hou and colleagues describe the the use of a previously characterized FRET sensor for use in determining gamma secretase activity in the brain of living mice. In an approach that targeted the sensor to neurons, they observe patterns of fluorescent sensor readout suggesting clustered regions of secretase activity. These results once validated would be valuable in the field of Alzheimer's Disease research, yet further validation of the approach is required, as the current evidence provided is inadequate to support the conclusions.

eLife assessment

This important study develops a machine learning method to reveal hidden unknown functions and behaviors in gene regulatory networks by searching parameter space in an efficient way. Solid evidence is presented for the method, which should be of broad interest to anyone working in biology, as the ideas put forward by the authors extend beyond gene regulatory networks to reveal hidden functions in any complex system with many interacting parts.

eLife assessment

This important work unravels how female Drosophila can assess their social context via chemosensory cues and modulate the sperm storage process after copulation accordingly. A compelling set of rigorous experiments uncovers specific pheromones that influence the excitability of the female brain receptivity circuit and their propensity to discard inseminate from a mating. This insight into neuronal mechanisms of sexual behavior plasticity is of general interest to scientists working in the fields of animal behavior, neuroscience, evolution, and sexual selection, as well as insect chemosensation and reproduction.

eLife assessment

This important study by Lee and colleagues examined how neural representations are transformed between the olfactory tubercle (OT) and the ventral pallidum (VP) using single neuron calcium imaging in head-fixed mice trained in classical conditioning. They show that the dimensionality of neural responses is lower in the VP than in the OT and suggest that VP responses represent values in a more abstract form at the single neuron level while OT contains more odor information, potentially enhancing odor contrast. The results are overall convincing and this study provides insights into how odor information is transformed in the olfactory system.

eLife assessment

This important study shows that a splice variant of the kainate receptor Glu1-1a that inserts 15 amino acids in the extracellular N-terminal region substantially changes the channel's desensitization properties, the sensitivity to glutamate and kainate, and the effects of modulatory Neto proteins. In the revised paper the authors have clarified several points raised by reviewers but the structural portion of the study has not been improved and consequently, more data are needed to determine the molecular mechanism by which the insert changes the functional profile of the channel. Even so, these solid findings advance our understanding of splice variants among glutamate receptors and will be of interest to neuro- and cell-biologists and biophysicists in the field.

eLife assessment

This manuscript uses public datasets of myelodysplastic syndrome (MDS) patients to undertake a multi-omics analysis of clinical, genomic, and transcriptomic datasets. Useful findings are provided by way of interesting correlations of specific mutations with inflammation and differing clinical outcomes. The evidence is solid and interesting, and the manuscript is of substantive value to hematologists and clinical immunologists.

eLife assessment

This study attempts to resolve an apparent paradox of rapid evolutionary rates of multi-copy gene systems by using a theoretical model that integrates two classic population models. While the conceptual framework is intuitive and thus useful, the specific model is perplexing and difficult to penetrate for non-specialists. The data analysis of rRNA genes provides inadequate support for the conclusions due to a lack of consideration of technical challenges, mutation rate variation, and the relationship between molecular processes and model parameters.

eLife assessment

This important study reports a high-resolution cryoEM structure of the supercomplex between photosystem I (PSI) and fucoxanthin chlorophyll a/c-binding proteins (FCPs) from the model diatom Thalassiosira pseudonana CCMP1335, with subunits, protein:protein interactions and pigments not previously seen in other diatoms or red/green photosynthetic lineages. Combining structural, sequence, and phylogenetic analyses, the authors provide convincing evidence of conserved motifs crucial for the binding of FCPs, leading to interesting speculation about the mechanisms governing the assembly of PSI-FCP supercomplexes in diatoms and their implications for related PSI-LHC supercomplexes in plants. The findings set the basis for functional experiments that will further advance the fields of photosynthesis, bioenergy, ocean biogeochemistry, and understanding of evolutionary relationships between photosynthetic organisms.

eLife assessment

This valuable study by Wu et al presents data on bacterial cell organization, with the goal of demonstrating that the two structures that account for bacterial motility - the chemotaxis complex and the flagella - colocalize to the same pole in Pseudomonas aeruginosa cells and expose the regulation underlying their spatial organization and functioning. The subject is of importance and the manuscript is well written. However, the work is incomplete and the conclusions are too strong for the presented data. This manuscript will be of interest to cell biologists, mainly those studying bacteria, but not only, if the evidence is substantiated, the assumptions clarified, and the novelty is made clear during the revision process.

eLife assessment

This is a valuable study that utilizes proteomic and genetic approaches to identify the glycoprotein quality control factor malectin as a pro-viral host protein involved in the replication of coronavirus. The evidence supporting this conclusion is solid, although additional insight into the mechanistic basis of malectin-mediated viral replication would further strengthen this study. This work will be of interest to cell biologists studying the molecular mechanisms of glycoprotein quality control and virologists studying the host-pathogen interactions.

eLife assessment

This important study provides substantial technical development for neural circuit tracing in larval zebrafish, a widely used model for systems and developmental neurobiology, and the tool could greatly benefit neural circuit research by enabling a detailed investigation of circuit structure and function in a major model organism. The supporting evidence is solid, although a more detailed description of validation experiments would have increased confidence in the technique's utility. The work will interest zebrafish neurobiologists who are working on identifying novel neuronal connectivity patterns, provided that reagents generated in this study are made widely available; issues such as glial cell labeling, detailed toxicity analysis, and the impact of virus dose on tracing efficiency need further exploration to enhance the findings' applicability and robustness.

eLife assessment

The manuscript establishes a sophisticated mouse model for acute retinal artery occlusion (RAO) by combining unilateral pterygopalatine ophthalmic artery occlusion (UPOAO) with a silicone wire embolus and carotid artery ligation, generating ischemia-reperfusion injury upon removal of the embolus. This clinically relevant model is useful for studying the cellular and molecular mechanisms of RAO. The data overall are solid, presenting a novel tool for screening pathogenic genes and promoting further therapeutic research in RAO.

eLife assessment

The work investigates mechanisms necessary and sufficient for initiating tissue bending in the Cellular Potts Model. The authors emphasize how differences in implicit model assumptions, such as different constraints on cell shape change and cell rearrangement, may explain different outcomes in Cellular Potts Model and Vertex Model simulations. Despite incomplete evidence supporting the major claims due to a rather coarse-grained exploration of the model, the findings are valuable for the biophysics and computational biology communities, and cautions toward greater care in interpretation of model results.

eLife assessment

This important study presents the structure of human heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) in the acetyl-CoA bound state, providing the first description of the architecture of this family of integral membrane enzymes, and revealing the mode of acetyl-CoA binding. The structural work is convincing, with a high resolution and isotropic single-particle cryoEM map and an atomic model that is well-justified by the density map, with strong density for the acetyl-CoA ligand. However, experimental support for the molecular mechanism of the HS acetylation reaction and the impact of disease-causing mutations is incomplete. This work will be of interest to biochemists and structural biologists studying the structure and function of integral membrane enzymes, as well as those interested in genetic diseases resulting from mutations in this family of enzymes, such as mucopolysaccharidosis IIIC (MPS III-C).

eLife assessment

In this manuscript, Jain and colleagues explore whether increasing adult-born neurons is protective against status epilepticus and the development of spontaneous recurrent seizures (chronic epilepsy) in a mouse pilocarpine model of temporal lobe epilepsy. This is an important work that provides solid data, contradicting previous studies on suppressing chronic seizures by reduction in adult-born neurons.

eLife assessment

This important study examined the mechanisms underlying reduced excitability of ventral tegmental area dopamine neurons in mice that underwent a chronic mild unpredictable stress treatment. The authors identify NALCN and TRPC6 channels as key mechanisms that regulate spontaneous firing of ventral tegmental area dopamine neurons and examined their roles in reduced firing in mice that underwent a chronic mild unpredictable stress treatment. The authors' conclusions on neurophysiological data are supported by multiple approaches and are convincing, although the relevance of the behavioral results to human depression remains unclear.

eLife assessment

This study shows that retinal bipolar cell subtype-specific differences in the size of synaptic ribbon-associated vesicle pools contribute to the transient versus sustained kinetics of the responses of retinal ganglion cells. The findings are important and the data is extensive and solid, however, there is also the possibility that glutamate release could be modulated by the kinetics of presynaptic inhibition at bipolar cell terminals and this may contribute to mediating the transient and/or sustained kinetics of glutamate release. This work will be of broad interest to researchers working on synaptic transmission, retinal signal processing, and sensory neurobiology.

eLife assessment

This important study examined the dynamics of attentional reorientation in working memory by assessing alpha-band lateralization in EEG recordings and saccade bias and provides convincing evidence for a second stage of internal attentional deployment during WM. This work provides novel insights into the dynamic mechanism in WM and will be of broad interest and impact to cognitive neuroscience, including attention and working memory. Performing additional analysis to disentangle the roles of saccade and micro-saccade and to show behavioral relevance would further strengthen the conclusion.

eLife assessment

This valuable study investigates the contribution of far-red light photo-acclimated cyanobacteria to primary production in intertidal beachrock habitats. Though the study presents solid evidence, the text would benefit from an improved discussion section and some additional methodological details.

eLife assessment

This study presents important observations about how the human brain uses long-term priors (acquired during our lifetime of listening) to make predictions about expected sounds - an open question in the field of predictive processing. The evidence presented is solid and based on state-of-the-art statistical analysis, but limited by a relatively low N and low magnitude for the interaction effect.

eLife assessment

This work advances our understanding of transcriptional regulation of virulence and metabolic pathways in plant pathogenic bacteria. Solid evidence for the claims is provided by computational analysis of newly generated data on the genome-wide binding of 170 transcription factors to their target genes, together with experimental validation of the biological functions of some of these transcription factors. The findings and resources from this study will be valuable to researchers in the fields of systems biology, bacteriology, and plant-microbe interactions.

eLife assessment

This useful study reports that the Drosophila transcription factor sisterless A (sisA) regulates the expression of Sex-lethal (Sxl) in female germ cells. The data supporting claims regarding the genetic requirement of sisA are convincing, but the characterization of the cis-regulatory elements controlling Sxl expression in the female germline is viewed as incomplete. The work will be of significant interest to colleagues studying reproductive biology and sex determination.

eLife assessment

This important study uses single-cell RNA-seq to obtain a more granular understanding of cell subsets within allergic contact dermatitis in a model system with DNFB. The convincing data revela unique subpopulations of dermal fibroblasts as key responders to interferon gamma and likely as mediators of dermatitis. This study has many novel aspects and provides a unique resource as well.

eLife assessment

This paper presents valuable findings that gustation and nutrition might independently influence the preferred environmental temperature in flies. The evidence supporting the main claims is solid and well presented. The finding that flies might thus exhibit a cephalic phase response similar to mammals will be of value for future investigations.

eLife assessment

This valuable manuscript describes evidence of sex differences in specific corticostriatal projections during alcohol consumption, and this is noteworthy given the increasing rates/levels of drinking in females and their liability for Alcohol Use disorder. The authors provide solid evidence of the lateralisation of the activity of the circuit, but other evidence is incomplete, particularly with regard to how the drinking measure relates to intoxication. There are some inconsistencies that make it difficult to reconcile the photometry and behavioral data. The findings would benefit from causal assessment in the future. The findings will be of interest to researchers investigating functional circuitry underlying alcohol-driven behaviors.

eLife assessment

This paper introduces an efficient approach to identify subunits in the receptive fields of retinal ganglion cells. The general approach has been used in this application previously and this limits the conceptual advance of the paper. The improved speed is valuable, as it allows a more thorough exploration of the control parameters in this analysis and facilitates application to larger populations of cells. Validation of the approach is convincing. The paper would benefit from a more thorough exploration of the method and its limitations, or an extension of the new results about subunit populations.

eLife assessment

This valuable study examines the role of the interaction between cytoplasmic N- and C-terminal domains in voltage-dependent gating of Kv10.1 channels. The authors suggest that they have identified a hidden open state in Kv10.1 mutant channels, thus providing a window for observing early conformational transitions associated with channel gating. The evidence supporting the major conclusions is solid, but additional work is required to determine the molecular mechanism underlying the observations in this study. Learning the molecular mechanisms could be significant in understanding the gating mechanisms of the KCNH family and will appeal to biophysicists interested in ion channels and physiologists interested in cancer biology.

eLife assessment

This important study utilizes a comprehensive array of animal and cellular models, alongside various techniques, to elucidate the mechanism by which adipose tissue miR-802 contributes to inflammation and metabolic dysfunction in obesity. The data is solid, with clear, reproducible changes showing low variability among biological replicates and consistency across different models. However, some conclusions should be further substantiated with additional data to enhance the scope and strength of the manuscript.

eLife assessment

This important study investigates how memory representations are transformed over time (24h period). The work advances our understanding of the neural processes supporting the behavioral integration of memories for distinct events that are never experienced together in time but are linked by shared predictive cues. Evidence supporting the claims is solid, and reporting of additional comparisons would have strengthened the study.

eLife assessment

This important study uses convincing time-resolved proximity proteomics, validated with proximity ligation assays, to provide new insight into mechanical regulation of caveolin-1 complexes that form in migrating cells. Solid follow up experiments reveal a reciprocal relationship between mechanosensitive caveolae and RhoGTPase signalling in migrating cells, but evidence supporting a direct link between the newly identified factors with a specific caveolae subpopulation remains incomplete at this stage.

eLife assessment

The authors present a useful analysis of the phenotype of sheep in which the muscle developmental regulator myostatin has been mutated in a FGF5 knockout background. The goal was to produce sheep with a "double-muscled" phenotype, yet the genetically engineered sheep exhibited meat with a smaller cross-sectional area and higher number of muscle fibers. The work extends the extensive body of knowledge already published in this area. The authors provide evidence using in vitro experiments that Fosl1 regulates myogenesis, but the strength of evidence relating to the muscle phenotype and underlying cellular and molecular mechanism remains incomplete.

eLife assessment

This study presents solid results to demonstrate that arpin is expressed in the endothelium of blood vessels and that its deficiency leads to leaky blood vessels in in vivo and in vitro models. The work does not yet clarify the mechanistic connection between arpin and increased ROCK activity. The study adds some insights to our understanding of the complicated network of proteins that control this process, and it will be useful to individuals within this defined field of study.

eLife assessment

This study presents valuable findings that will allow for a better understanding of the targets of SMAD and Schnurri, transcription factors that act downstream in the BMP signalling pathway. The evidence presented in this manuscript is solid, but because the claims of a SMA-3/SMA-9 complex are not experimentally supported, they should be toned down. Revising the discussion to give a broader context of BMP-driven body size control would help the readers put this work in a larger context. This work will be of broad interest to colleagues studying BMP signalling across phyla.

eLife assessment

This study describes useful mouse models of knock-ins of human STING1 variants and an assessment of these variants' action in mouse immune cells. While the implications of the variants in the inflammatory response are of significant interest, limitations are still found in the authors' interpretation and conclusions made, and the evidence for the conclusion remains incomplete.

eLife assessment

This valuable study asks how Promyelocytic leukemia protein (PML) becomes associated with the nucleoli of cells (PML Nucleolar Associations, PNAs) upon various genotoxic stimuli. Using immunostaining analysis with induced DNA double-strand breaks (DSBs) in rDNA repeats, the authors provide solid evidence that PNAs are triggered mostly by the inhibition of topoisomerase and RNA polymerase I, which is augmented by homologous recombination but not by the non-homologous end joining double-strand break repair pathway. The findings have potential implications for a better understanding of how DNA damage in ribosomal DNA is repaired for genome stability. This paper is of interest to researchers in the fields of nuclear structure and DNA repair.

eLife assessment

This valuable study examines the activity and function of dorsomedial striatal neurons in estimating time. The authors used various causal and correlational techniques to investigate how these pathways collectively contribute to interval timing in mice and found that the direct and indirect striatal pathways perform opposing roles in processing elapsed time. The evidence is solid. The manuscript would interest neuroscientists examining how striatum contributes to behavior.

eLife assessment

This valuable study introduces SCellBOW, a novel tool leveraging natural language processing techniques to enhance cell clustering and infer survival risks from single-cell RNA sequencing data. The methodology and results are convincing, demonstrating superior clustering performance and the ability to assign risk scores to cancer cell clusters across multiple datasets. SCellBOW's unique approach promises significant advancements in understanding cancer cell heterogeneity and identifying aggressive cancer cell subgroups.

eLife assessment

This valuable study, which seeks to identify factors from the glial niche that support and maintain neural stem cells, reports a novel role for ferritin in this process. The authors provide solid evidence that defects in larval brain development in Drosophila, resulting from ferritin knockdown, can be attributed to impaired Fe-S cluster activity and ATP production. The findings of this well-conducted study will be of interest to oncologists and neurobiologists.

eLife assessment:

This useful study shows that the essential Acinetobacter baumannii gene Aeg1 likely plays an key role in cell division. The strength of the work is the discovery that the depletion of Aeg1 leads to cell filamentation and that gain-of-function mutations in cell division genes FtsB and FtsL rescue the lethality of Aeg1 depletion. However, Aeg1's localization pattern and its requirement for other division proteins' localizations require further characterization of the functionality of fluorescent fusion proteins, fluorescence images of higher quality, and improvements in statistic qualifications, leaving the study' evidence for Aeg1's exact role in cell division incomplete at this time. In conclusion, the critical role of Aeg1 in the assembly of the A. baumannii divisome has yet to be established unambiguously.

eLife assessment

Working with a diverse panel of field-grown rice accessions, this valuable study measures changes in transcript abundance, tests for patterns of selection on gene expression, and maps the genetic basis of variation in gene expression in normal and high salinity conditions. The authors provide solid evidence that salinity treatment increases the number of genes with mean expression levels away from the optimum, and that a relatively small number of genes are hotspots for genetic variants that affect genome-wide patterns of variation in gene expression under high salinity. The design, clarity, and interpretation of several statistical analyses can be improved, additional opportunities for integration among datasets and analyses could be realized, and genetic manipulation would be required to confirm the functional involvement of any specific genes in regulatory networks or organismal traits that confer adaptation to higher salinity conditions. The manuscript will not only be of interest to evolutionary biologists studying the genetics of complex traits, but it will also be a resource for plant biologists studying mechanisms of abiotic stress tolerance.

eLife assessment

This study provides new insights into the expression profile of ILCs that demonstrate a history of RAG expression. It examines in part the potential intrinsic regulation of RAG expression and seeks to understand how the epigenetic state of ILCs is established, although a full understanding of intrinsic factors is incomplete. The work provides an important molecular dataset, and with further strengthening of the understanding of intrinsic regulation, this paper would be of interest more broadly to cell biologists seeking to understand immune cell development.

eLife assessment

This study provides a valuable characterization of individual sarcomere's contractility and synchrony in spontaneously beating cardiomyocytes as a function of substrate stiffness. The authors, however, provide an incomplete explanation for the observed heterogeneous and stochastic dynamics, so that the work remains mainly descriptive. The work will be of interest to scientists working on muscle biophysics, nonlinear dynamics, and synchronization phenomena in biological systems.

eLife assessment

This study demonstrates a novel role for SIRT4; a mitochondrial deacetylase, shown to translocate into nuclei where it regulates RNA alternative splicing by modulating U2AF2 and the gene expression of CCN2 in tubular cells in response to TGF-β. This fundamental work substantially advances our understanding of kidney fibrosis development and offers a potential therapeutic approach. The evidence supporting the conclusions of a SIRT4-U2AF2-CCN2 axis activated by TGF-β is compelling and adds a new layer of complexity to the pathogenesis of chronic kidney disease.

eLife assessment

Zhao et al. report valuable adverse effects on cell proliferation, differentiation and gene expression, possibly linked to reduced binding activity of the transcription factor GTF2IRD1 to the transthyretin (TTR) promoter, in a human forebrain organoid model of Williams Syndrome (WS). The authors provide incomplete evidence of the effects of GTF2IRD1, a mutated gene in WS, on altering MAPK/ERK pathway activity, a well-recognized target in cell proliferation.

eLife assessment

The authors present a potentially useful approach of broad interest arguing that anterior cingulate cortex (ACC) tracks option values in decisions involving delayed rewards. The authors introduce the idea of a resource-based cognitive effort signal in ACC ensembles and link ACC theta oscillations to a resistance-based strategy. The evidence supporting these new ideas is incomplete and would benefit from additional detail and more rigorous analyses and computational methods.

eLife assessment

This important study builds on a previous publication, demonstrating that T. brucei has a continuous endomembrane system, which probably facilitates high rates of endocytosis. Using a range of cutting-edge approaches, the authors present compelling evidence that an actomyosin system, with the myosin TbMyo1 as an active molecular motor, is localized close to and can associate with the endosomal system in the bloodstream form of Trypanosoma brucei. It shows convincingly that both actin and Myo I play a role in the organization and integrity of the endosomal system: both RNAi-mediated depletion of Myo1, and treatment of the cells with latrunculin A resulted in endomembrane disruption. This work should be of interest to cell biologists and microbiologists working on the cytoskeleton, and unicellular eukaryotes.

eLife assessment

This is a useful study on sex differences in gene expression across organs of four mice taxa, although there are some shortcomings in the data analyses and interpretations that should to be better placed in the broader context of the current literature. Hence, the evidence in the current form is incomplete, with several overstated key conclusions.

eLife assessment

This paper provides valuable findings related to the impact and timing of exogenous interleukin 2 on the balance of exhausted (Tex) versus effector (Teff) that differentiate from precursors T cells (Tpex) during chronic viral infection. While the data appear solid, the overall claims that IL-2 suppresses Tpex are only partially supported, with the rationale for the timing of IL-2 treatment and its underlying mechanisms remaining unclear.

eLife assessment

This is a mechanistic study showing the effect of combining inhibition of autophagy (through ULK1/2) and KRAS (using sotorasib) on KRAS mutant NSCLC making the study valuable to cancer biologists and more broadly in a clinical setting. The evidence generated by GEM mouse models and cell lines is solid but could be further strengthened by increasing the mouse cohort size. This study holds translational relevance beyond NSCLC to other indications that carry KRAS mutations.

eLife assessment

This is a useful manuscript describing the competitive binding between Parkin domains to define the importance of dimerization in the mechanism of Parkin regulation and catalytic activity. The evidence supporting the importance of Parkin dimerization for an 'in trans' model of Parkin activity described in this manuscript is solid, but lacks more stringent and biochemical characterization of competitive binding that could provide more direct evidence to support the author's conclusions. This work will be of interest to those focused on defining the molecular mechanisms involved in ubiquitin ligase interactions, PINK-Parkin-mediated mitophagy, and mitochondrial organellar quality control.

eLife assessment

This study presents important findings on the different polymorphs of alpha-synuclein filaments that form at various pH's during in vitro assembly reactions with purified recombinant protein. Of particular note is the discovery of two new polymorphs (1M and 5A) that form in PBS buffer at pH 7. The strength of the evidence presented is convincing. The work will be of interest to biochemists and biophysicists working on protein aggregation and amyloids.

eLife assessment

Using multiple public datasets, this study investigates associations between retrotransposon element expression and methylation with age and inflammation. The study is valuable because a systematic analysis of retrotransposon element expression during human aging has been lacking, but the provided data must be considered incomplete due to the sole reliance on microarray expression data for the core analyses.

eLife assessment

This is a solid study that follows a well-established canvas for variant-to-gene prioritisation using 3D genomics, applying it to activated T cells. The authors go some way in validating the lists of candidate genes, as well as exploring the regulatory architecture of a candidate GWAS locus. Jointly with data from previous studies performing variant-to-gene assignment in activated CD4 T cells (and other immune cells), this work provides a useful additional resource for interpreting autoimmune disease-associated genetic variation.

eLife assessment

This valuable study demonstrates that AARS2 is crucial for protecting cardiomyocytes from ischemic stress by shifting energy metabolism towards glycolysis through PKM2, presenting a novel therapeutic target for myocardial infarction. The findings are supported by solid evidence, including cardiomyocyte-specific genetic modifications, functional assays, and ribosome profiling, which together robustly validate the AARS2-PKM2 signaling pathway's role in cardiac protection.

eLife assessment

This study provides compelling data that defines the structure of the S. cerevisiae APC/C. The structure reveals overall conservation of its mechanism of action compared to the human APC/C but some important differences that indicate that activation by co-activator binding and phosphorylation are not identical to the human APC/C. Thus this study will be of considerable value to the field, although the conclusions regarding the effect of phosphorylation would be strengthened by quantification of the phosphopeptides. Recent work on the role of APC7 in APC/C activity in neurones should also be discussed with respect to the mode of action of the APC/C in human versus budding yeast cells.

eLife assessment

This study assessed the virulence and immune responses of different M. tuberculosis lineages using a 3D in vitro granuloma model. The useful findings support the functional impact of M. tuberculosis natural diversity on host-pathogen interactions but are incomplete and only partially support the claims. The study will interest researchers working on mycobacteria and understanding how genetic diversity influences virulence and immunity outcomes.

eLife assessment

This valuable paper presents convincing evidence that changing the constraint of how long to stop at an intermediate target significantly influences the degree of coarticulation of two sequential reaching movements, as well as their response to mechanical perturbations. Using an optimal-control framework, the authors offer a normative explanation of how both co-articulated and separated sequential movement can be understood as an optimal solution to the task requirements.

eLife assessment

This is an important study that describes an elegant modelling driven approach to design of allosteric antagonists for CXCR4 that have a selective effect on receptor nanocluster formation, cell polarisation and chemotaxis, but spare binding of CXCL12 to the receptor and inhibition of adenylate cyclase. This enables selective targeting of processes dependent upon cell polarisation and chemotaxis without impacting signalling effects and may avoid some of the toxicity associated with antagonists that target CXCL12 binding and thus block all CXCR4 signalling. The revised manuscript offers convincing evidence to support the claims. The modelling work is better described and additional data has been presented that better illustrates the unique features of the new antagonist. The in vivo studies in the zebrafish model open a path to studies in mammalian models.

eLife assessment

This paper presents important computational modeling work that provides a mechanistic account for how memory representations become integrated or differentiated (i.e., having distinct neural representations despite being similar in content). The authors provide convincing evidence that simple unsupervised learning in a neural network model, which critically weakens connections of units that are moderately activated by multiple memories, can account for three empirical findings of differentiation in the literature. The paper also provides insightful discussion on the factors contributing to differentiation as opposed to integration, and makes new predictions for future empirical work.

eLife assessment

ImmCellTyper presents a useful toolkit for CyTOF data analysis, integrating BinaryClust for semi-supervised clustering and cell type annotation. The evidence supporting the findings is convincing, with appropriate and validated methodology. This tool will be helpful to researchers in immunology and cytometry, offering a robust solution for cell type identification and differential analysis.

eLife assessment

This valuable study investigates how the human brain flexibly adjusts its representations of the world as the environment continually changes. It utilizes a unique dataset in which participants view thousands of natural scenes across many fMRI sessions over multiple months. The evidence supporting the claims of the authors is incomplete, with statistical inference not always warranted. The study would interest a broad readership in cognitive neuroscience.

eLife assessment

This joint computational/experimental study demonstrates the ability of synthetic peptides derived from the stalk-tethered agonist in Polycystin-1 (PC1) to re-activate signaling by a stalkless C-terminal fragment of PC1. The study is valuable as it discovered peptide agonists for PC1 and the integrated in vitro and in silico approach is potentially applicable to the analysis of related systems. Following the revision, the line of evidence presented in the current manuscript is considered convincing.

eLife assessment

This valuable study analyzes the role of rpgrip1l encoding a ciliary transition zone component in the development of neuroinflammation and scoliotic phenotypes in zebrafish. Through proteomic and experimental validation in vivo, the authors demonstrated increased Annexin A2 expression and astrogliosis in the brains of scoliosis fish. Anti-inflammatory drug treatment restored normal spine development in these mutant fish, thus providing additional convincing evidence for the role of neuroinflammation in the development of scoliosis in zebrafish.

eLife assessment

This important work describes a compelling analysis of DNA damage-induced changes in nascent RNA transcripts, and a genome-wide screening effort to identify the responsible proteins. A significant discovery is the inability of arrested cells to undergo DNA damage-induced gene silencing, which, is attributed to an inability to mediate ATM-induced transcriptional repression. This work will be of general interest to the DNA damage, repair, and transcription fields, with a potential impact on the cancer field.

eLife assessment

This fundamental work substantially advances our understanding of the role of calcium-binding proteins 1 and 2 (CaBP1 and CaBP2) for generating sustained calcium currents in mouse inner hair cells and their capacity for indefatigable exocytosis. The evidence supporting the conclusions is compelling, with rigorous in vitro and in vivo physiological experiments and state-of-the-art microscopy. The work will be of broad interest to synaptic physiologists, cellular biochemists, and hearing researchers.

eLife assessment

The fundamental findings of this work substantially advance our understanding of the impact of the host on its gut microbes. The authors provided compelling evidence at single-cell resolution that the host can drive heterogeneity in the populations of gut microbes with significant consequences for the host physiology.

eLife assessment

In this valuable study, the authors sought to investigate the associations of age at breast cancer onset with the incidence of myocardial infarction and heart failure. Based on results from a series of compelling statistical analyses, the authors conclude that a younger onset age of breast cancer is associated with myocardial infarction and heart failure, highlighting the need to carefully monitor the cardiovascular status of women who have been diagnosed with breast cancer.

eLife assessment

Cav2 voltage-gated calcium channels play key roles in regulating synaptic strength and plasticity. In contrast to mammals, invertebrates like Drosophila encode a single Cav2 channel, raising questions on how diversity in Cav2 is achieved from a single gene. Here, the authors present convincing evidence that two alternatively spliced isoforms of the Cac gene (cacophony, also known as Dmca1A and nightblindA) enable diverse changes in Cav2 expression, localization, and function in synaptic transmission and plasticity. These valuable findings will be of interest to a variety of researchers.

eLife assessment

Guan and colleagues present solid arguments to address the question of how a single neural stem cell produces a defined number of progeny, and what influences its decommissioning. The focus of the experiments are two well-studied RNA-binding proteins: Imp and Syp. This is valuable work that will be of interest to the scientific community.

eLife assessment

This study by Nandy and colleagues examined relationships between behavioral state, neural activity, and trial-by-trial variability in the ability to detect weak visual stimuli. They present useful findings indicating that certain changes in arousal and eye-position stability, along with patterns of synchrony in the activity of neurons in different layers of cortical area V4, can show modest correspondences to changes in the ability to correctly detect a stimulus. At present, however, the findings are based on data and analyses that are somewhat incomplete but could be improved with further revisions.

eLife assessment

This paper proposes a valuable new method for the assessment of the mean kurtosis for diffusional kurtosis imaging by utilizing a recently introduced sub-diffusion model. The evidence supporting the claims that this technique is robust and accurate in brain imaging is solid; however, there is a need to include a summary of the clear limitations.

eLife assessment

In this useful study, the authors report the efficacy, hematological effects, and inflammatory response of the BPaL regimen (containing bedaquiline, pretomanid, and linezolid) compared to a variation in which Linezolid is replaced with the preclinical development candidate spectinamide 1599, administered by inhalation in tuberculosis-infected mice. The authors provide convincing evidence that supports the replacement of Linezolid in the current standard of care for drug-resistant tuberculosis. The work will be of interest to those studying tuberculosis treatment regimens.

eLife assessment

This study addresses a 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 argue that the main function is to enhance conspecific localization rather than communication as previously believed. The study provides a lot of valuable data, but the methods section is incomplete making it difficult to evaluate the claims.

eLife assessment

This important study correlates the size of various prefrontal brain regions in primate species with socioecological variables like foraging distance and population density. The evidence presented is solid but the approach and conclusions are limited to primates with well-defined gyri.

eLife assessment

This manuscript describes a creative approach using dual-component gRNAs to create a new class of molecular proximity sensors for genome editing. The authors demonstrate that this tool can be coupled with several different gene editing effectors, and the authors convincingly show that this functions as designed. This important study represents this first-of-its kind technology with key baseline activity metrics ready for future developmental approaches.

eLife assessment

The study is a valuable contribution to the question of evolutionary shifts in neuronal proliferation patterns and the timing of developmental progressions. The authors present solid support for the presence of type-II NB lineages in the beetle Tribolium with the same molecular characteristics as the counterparts in the fly Drosophila, but differences in lineage size and number. While presenting a number of interesting observations, further evidence will be required to show that the observed differences are indeed responsible for the differences in developmental timing of the central complex in the two insect species.

eLife assessment

This is a valuable study that provides CCR7-APEX2 proximity labelling mass spectrometry data that is expected to provide new insights into CCR7 signalling partners and pathways. The study is technically solid and easy to follow, however, there are some concerns that many of the highlighted findings are repetitive of prior work and that this is not clearly acknowledged. It would increase the impact of the study if the confirmatory nature of some findings were acknowledged. This is of value to the community, and there are likely multiple opportunities to use the APEX2 data set to extend these findings, strengthen some claims, and even explore a new pathway identified in the APEX2 data set.

eLife assessment

This is a valuable study providing solid evidence that the Mediator kinase module mediates an elevated inflammatory response, manifested by heightened cytokine levels, associated with Downs syndrome (DS) via transcriptional changes impacting cell signaling and metabolism, which has significance for the treatment of DS and other chronic inflammatory conditions. Particular strengths of the study include the combined experimental approaches of transcriptomics, untargeted metabolomics, cytokine screens, and the use of sibling-matched cell lines (trisomy 21 vs disomy 21) from various donors. Less certain is that the Mediator kinase plays a meaningful role in regulating mRNA splicing. Further evidence that nuclear receptors are activated by changes in lipid levels and that mitochondrial function is substantially reduced on Mediator kinase inhibition would strengthen the work.

eLife assessment

This manuscript presents valuable findings on two isolates of deep sea Lentisphaerae strains, which further our understanding of deep sea microbial life. The manuscript's primary claim is that phage isolates augment polysaccharide use in Pseudomonas bacteria, with preliminary evidence for the potential auxiliary metabolic genes in chronic phage infection and/or host proliferation. The strength of the evidence is overall solid and there are only minor weaknesses regarding the mechanism of polysaccharide use by the phages and the evidence for chronic infection. Overall, the data on Lentisphaerae strains will deepen our understanding of microbial life in the deep sea.

eLife assessment

This important study provides a new perspective on why preparatory activity occurs before the onset of movement. The authors report that when there is a cost on the inputs, the optimal inputs should start before the desired network output for a wide variety of recurrent networks. The authors present compelling evidence by combining mathematically tractable analyses in linear networks and numerical simulation in nonlinear networks.

eLife assessment

This is a potentially useful study that shows changes in the chromatin landscape of GABAergic neurons in induced pluripotent stem cells (iPSCs) derived from both Dravet Syndrome (DS) patients and healthy donors. The strength of the evidence is currently incomplete because the authors compared iPSCs from different individuals, rather than isogenic controls. A strategy for minimizing variability across cell lines is used, but the explanation is not complete. The revised manuscript adds RNAseq and qPCR measurements of the expression of the gene SCN1A, however these do not appear to agree, perhaps because of the way the qPCR measurements are normalized, and there is no measurement of Nav1.1, the gene product thought to be responsible for the majority of DS cases. Hence the evidence that there is reduced expression of SCN1A or its gene product is not complete and therefore it is difficult to evaluate whether or not the observed epigenetic changes are causal. The work would potentially be of interest to scientists who study development, developmental disorders, and epigenetic contributions to disease.

eLife assessment

This important study identifies the anti-inflammatory function of PEGylated PDZ peptides that are derived from the ZO-1 protein. Results from cellular and in vivo experiments tracking key inflammatory markers are compelling. Although the present study would benefit from investigating chronic inflammation conditions using microbe and protein data, the work provides a proof of concept for developing novel strategies against acute inflammatory conditions such as sepsis.

eLife assessment

This important study presents a novel pipeline for the large-scale genomic prediction of members of the non-ribosomal peptide group of pyoverdines based on a dataset from nearly 2000 Pseudomonas genomes. The advance presented in this study is based on convincing evidence. This study of bacterial siderophores has broad theoretical and practical implications beyond a singular subfield.

eLife assessment

This valuable study uses neuroanatomical techniques to investigate somatosensory projections from the elephant trunk to the brainstem. Given its unique specializations, understanding how the elephant trunk is represented within the brain is of general interest to evolutionary and comparative neuroscientists. The authors present solid evidence for the existence of a novel isomorphism in which the folds of the trunk are mapped onto the trigeminal nucleus; however, due to their unusual structure, some uncertainty remains about the identification and anatomical organization of nuclei within the elephant brainstem.

eLife assessment

This fundamental study provides insights into how pathogens respond, on a systemic level including several gene targets and clusters, to selected antimicrobial molecules. Compelling evidence is provided, through multi-omics and functional approaches, that very similar molecules originally designed to target the same bacterial protein act differently within the context of the whole set of cellular transcripts, expressed proteins, and pre-lethal metabolic changes. Given the rapid accumulation of omics data and the much slower capacity of extracting biologically relevant insights from big data, this work exemplifies how the development of sensitive data analysis is still a major necessity in modern research.

eLife assessment

This important paper addresses the process by which cryptic splice sites that occur randomly in exons are ignored by the splicing machinery. Integrating state-of- the-art genome-wide approaches such as CLIP-seq with the study of individual examples, this study convincingly implicates members of RBMX family of RNA binding proteins in such cryptic splice site suppression and showcases its importance for the fidelity of expression of genes with very large exons.

eLife assessment

This study presents a valuable finding that the blood-brain barrier functionality changes with age and differs between males and females. The analysis is solid, comprising a large and racially diverse dataset, and utilizes a contrast-agent-free MRI method. Since limited work has been done in the MRI field on the blood-brain barrier using this method, this study is of great interest to neuroimaging researchers and clinicians.

eLife assessment

Peng et al. reported important findings that 36THz high-frequency terahertz stimulation (HFTS) could suppress the activity of pyramidal neurons by enhancing the conductance of voltage-gated potassium channels. The significance of the findings in this paper is that chronic pain remains a significant medical problem, and there is a need to find non-pharmacological interventions for treatment. The authors present convincing evidence that high-frequency stimulation of the anterior cingulate cortex can alter neuronal activity and improve sensory pain behaviors in mice.

eLife assessment

This important research describes the sensory innervation of oral tumors, with potential implications for understanding cancer-induced alterations in motivation and anhedonia in a mouse model. These findings are solid and are supported by anatomical and transcriptional changes in the tumor that suggest sensory innervation, neural tracing, and neural activity measurements. While nerve innervation of the tumor and associated increase in brain activity is well-supported, future studies could enhance specificity by employing more targeted genetic and pharmacological tools to manipulate these circuits selectively.

eLife assessment

This important study reports findings on the GnRH pulse generator's role in androgen-exposed mouse models, providing further insights into PCOS pathophysiology and advancing the field of reproductive endocrinology. The experimental data were collected using cutting-edge methodologies and were solid. However, it is noteworthy that the findings, while interesting, are primarily applicable to mouse models, and their translation to human physiology requires cautious interpretation and further validation. This work will be of interest to endocrinologists and reproductive biologists.

eLife assessment

This study provides a potentially valuable understanding of the contribution of different striatal subregions, the anterior Dorsal Lateral Striatum (aDLS) and the posterior Ventrolateral Striatum (pVLS), to auditory discrimination learning. The combined methods used to probe this are compelling, yet the data presented are incomplete to support the conclusions. There is insufficient data visualization of learning vs. performance, and missing details about timing of manipulations and microPET imaging.

eLife assessment

This important study compared the brain development trajectories of humans and macaque monkeys to quantify different evolutionary effects of convergent and divergent neural pathways between the two species. The cross-species evidence is solid, based on brain age prediction models that were carefully developed by using public MRI datasets of both humans and macaque monkeys. The findings will be of interest to neuroscientists, developmental biologists, and evolutionary biologists.

eLife assessment

This important work offers an experimental structural characterization of the Tramtrack-like BTB/POZ domains in insects, revealing that these domains form stable hexameric assemblies. The structural evidence is convincing, and validated by fold prediction and evolutionary pathway analyses. This paper would be of interest to structural and evolutionary biologists.

eLife assessment

This important study explores and delineates multivariate mappings between brain structure and functional measures with latent dimensions of psychopathology. This work provides solid evidence for the existence of such mappings and charts the relationship between different neurobiological measures and distinct dimensions of psychopathology. This work will be of broad interest within the neuroscience field.

eLife assessment

This potentially important work presents a tool for performing phylogenetic taxonomic classification of DNA sequences. In terms of methodology, the work is compelling. The authors perform a benchmark experiment against current state-of-the-art tools using real and simulated datasets to demonstrate where the novel tool stands in the context of existing methods. However, the experimentation is still incomplete. It would benefit from a more thorough exploration of existing methods as well as data sets that better represent real-world use cases.

eLife assessment

In this study, Perez-Lopez and colleagues examine an important function of the chemokine CCL28 in mucosal host defenses against the gut bacterial pathogen Salmonella Typhimurium and lung pathogen Acinetobacter baumanii. They find that CCL28-CCR3 axis regulates neutrophil recruitment and function, and promotes bacterial clearance in one infectious context but exacerbates disease against the other pathogen. Therefore, CCL28 plays a critical role in mucosal immunity and neutrophil biology that differentially affects host defenses against pathogens.

Editors Assessment:

RAD-Seq (Restriction-site-associated DNA sequencing) is a cost-effective method for single nucleotide polymorphism (SNP) discovery and genotyping. In this study the authors performed a kinship analysis and pedigree reconstruction for two different cattle breeds (Angus and Xiangxi yellow cattle). A total of 975 cattle, including 923 offspring with 24 known sires and 28 known dams, were sampled and subjected to SNP discovery and genotyping using RAD-Seq. Producing a SNP panel with 7305 SNPs capturing the maximum difference between paternal and maternal genome information, and being able to distinguish between the F1 and F2 generation with 90% accuracy. Peer review helped highlight better the practical applications of this work. The combination of the efficiency of RNA-seq and advances in kinship analysis here can helpfully help improve breed management, local resource utilization, and conservation of livestock.

This evaluation refers to version 1 of the preprint

Editors Assessment: This work is part of a series of papers from the Hong Kong Biodiversity Genomics Consortium sequencing the rich biodiversity of species in Hong Kong (see https://doi.org/10.46471/GIGABYTE_SERIES_0006). This example assembles the genome of the black-faced spoonbill (Platalea minor), an emblematic wading bird from East Asia that is classified as globally endangered by the IUCN. This Data Release reporting a 1.24Gb chromosomal-level genome assembly produced using a combination of PacBio SMRT and Omni-C scaffolding technologies. BUSCO and Merqury validation were carried out, gene models created, and peer reviewers also requested MCscan synteny analysis. This showed the genome assembly had high sequence continuity with scaffold length N50=53 Mb. Presenting data from 14 individuals this will hopefully be a useful and valuable resources for future population genomic studies aimed at better understanding spoonbill species numbers and conservation.

*This evaluation refers to version 1 of the preprint *

eLife assessment

This study provides useful in vitro evidence to support a mechanism whereby dyslipidemia could accelerate renal functional decline through the activation of the AT1R/LOX1 complex by oxLDL and AngII. As such, it improves the knowledge regarding the complex interplay between dyslipidemia and renal disease and provides a solid basis for the discovery of novel therapeutic strategies for patients with lipid disorders. The methods, data, and analyses support the presented findings, although the observed variability and need for further in vivo validation require additional research in this key area.

eLife assessment

The study explored the influence of magnesium on phenotypic antibiotic resistance in two Vibrio model bacteria. This research is fundamental for revealing the phenotypic antibiotic resistance mechanism utilized by the specified model bacteria in elevated levels of magnesium. The study produced solid evidence indicating that in high concentrations of magnesium, the efficacy of selected antibiotics was diminished due to decreased biosynthesis of unsaturated fatty acids and PE, along with an increase in the biosynthesis of PG.

eLife assessment

This valuable study demonstrates how proximity labeling with streptavidin can be used to boost fluorescence signals in otherwise hard-to-label regions of cells. The experimental verification of amplification of fluorescence near epitope tags in phase-separated compartments is solid, demonstrating enhanced signal-to-noise compared to immunofluorescence. This study will be of particular interest to those using correlative light and electron microscopy or expansion microscopy when the signal is limiting or inaccessible.

eLife assessment

The authors made an important finding that CD29+/CD56+ progenitor cells isolated from human muscles have the potential to differentiate to tendons in vitro and in vivo. The author's approach to testing the tenogenesis of the CD29+/CD56+ progenitors is solid, and the conclusion is supported by enough evidence with minor flaws. This work will be of interest to the population who need tendon regeneration from their injury.

eLife assessment

In this potentially important study, the authors conducted atomistic simulations to probe the salt-dependent phase separation of the low-complexity domain of hnRN-PA1 (A1-LCD). The authors have identified both direct and indirect mechanisms of salt modulation, provided explanations for four distinct classes of salt dependence, and proposed a model for predicting protein properties from amino acid composition. There is a range of opinions regarding the strength of evidence, with some considering the evidence as incomplete due to the limitations in the length and complexity of the atomistic MD simulations. The work should be put into a better context in relation to previous studies of salt effects on protein phase separation.

eLife assessment

This manuscript reports important findings on the impact of maternal obesity on oocyte methylation and its transgenerational effects. The evidence presented to substantiate the major claims appears incomplete. This study would be of interest to biologists in the fields of epigenetics and metabolism.

eLife assessment

This study reports the adhesion G-protein-coupled receptor A3 (ADGRA3) as a possible target for activating adaptive thermogenesis in white and brown adipose tissue. The study provides valuable insights for scientists who study metabolism, obesity, and adipose tissue biology. Meanwhile, the experimental evidence supporting the claim is incomplete, and more rigorous approaches are needed to demonstrate the relevance of this receptor in adipose tissue biology.

eLife assessment

In an important fMRI study with an elegant experimental design and rigorous cross-decoding analyses, this work shows a solid dissociation between two parietal regions in visually processing actions. Specifically, aIPL is found to be sensitive to the causal effects of observed actions, while SPL is sensitive to the patterns of body motion involved in those actions. Additional analysis and explanation would help to determine the strength of evidence and the mechanistic underpinnings would benefit from closer consideration. Nevertheless, the work will be of broad interest to cognitive neuroscientists, particularly vision and action researchers.

eLife assessment

The authors have reported an important study in which they use a double-blind design to explore pharmacological manipulations in the context of a behavioral task. Despite a relatively small sample size, the findings are solid and motivate future explanations of the mechanism underlying their observations. The findings could be further strengthened by addressing some remaining concerns that relate to preprocessing, statistical details, and possible ocular artifacts.

eLife assessment

This study identified an innovative molecular mechanism linking diabetes to Alzheimer's disease (AD) risk, with important significance. The finding presents novel insights into AD pathogenesis and provides strong evidence about the mechanistic roles of Kallistatin, and the therapeutic potential of fenofibrate in AD. The experiments are well conducted, and the evidence is convincing.