eLife assessment

This important work describes the activation of astrocytes via the nuclear translocation of PKM2 in an animal model of multiple sclerosis. This study provides convincing evidence of the interaction between TRIM21 and PKM2 as the crucial molecular event leading to the translocation of PKM2 and a metabolic shift towards glycolysis dominance, fostering proliferation in stimulated astrocytes. This finding is significant as it underscores the potential of targeting glycolytic metabolism to mitigate neurological diseases mediated by astrocytes, offering a strong rationale for potential therapeutic interventions.

eLife assessment

Unlocking the potential of molecular genetic tools (optogenetics, chemogenetics, sensors, etc.) for the study of systems neuroscience in nonhuman primates requires the development of effective regulatory elements for cell-type specific expression to facilitate circuit dissection. This study provides a valuable building block, by carefully characterizing the laminar expression profile of two optogenetic enhancers, one designed for general GABA+ergic neurons (h56D) and the second (S5E2) for parvalbumin+ cell-type selective expression in the marmoset primary visual cortex. This study contributes solid evidence to our understanding of these tools but is limited by the understandably small number of animals used.

eLife assessment

This important study describes the discovery and further engineering of a red light-activated, chloride-conducting Channelrhodopsin (ACR) that could be used to inhibit neuronal activity. The evidence for the spectral confirmation and biophysical characterization of MsACR and raACR, and ion selectivity are solid; however, the evidence supporting the use of the tools in vivo is incomplete and missing proper controls. In addition, benchmarking against other inhibitory tools is somewhat missing. With the in vivo part strengthened, this paper would interest neuroscientists seeking more efficient ways to inhibit neuronal activity.

eLife assessment

This important study offers convincing evidence that fmo-4 plays essential roles in established lifespan interventions and downstream of its paralog fmo-2, a beneficial advancement in our understanding of this enzyme family that underscores their importance in longevity and stress resistance. The study also suggests a connection between fmo-4 and dysregulation of calcium signalling. The authors' conclusions and interpretations were generally based on solid genetic methodology and evidence.

eLife assessment

The study by Kleinman and Foster identifies a role for VTA dopamine signaling in modulating hippocampal replay and sharp-wave ripples, specifically highlighting how VTA inactivation leads to aberrant replay activities in scenarios without reward changes and during exposure to novel environments. This valuable work contributes to our understanding of the neurobiological mechanisms underlying spatial memory and learning, suggesting that dopamine plays a pivotal role in linking reward context and novelty to memory consolidation processes. However, the evidence as currently presented is incomplete. More rigorous statistical reporting and histological verification of the experimental approach, and a more consistent approach to experimental dosing and timing, which are crucial for confirming the reproducibility and reliability of the observed effects, are needed.

eLife assessment

This useful study reports a reanalysis of one experiment of a previously published report to characterize the dynamics of neural population codes during visual working memory in the presence of distracting information. The evidence supporting the claims of dynamic codes is incomplete, as only a subset of the original data is analyzed, there is only modest evidence for dynamic coding in the results, and the result might be affected by the signal-to-noise ratio. This research will be of interest to cognitive neuroscientists working on the neural bases of visual perception and memory.

eLife assessment

This study provides an in-depth exploration of the impact of X-linked ZDHHC9 gene mutations on cognitive deficits and epilepsy, with a particular focus on the expression and function of ZDHHC9 in myelin-forming oligodendrocytes (OLs). These valuable findings offer insights into ZDHHC9-related X-linked intellectual disability (XLID) and shed light on the regulatory mechanisms of palmitoylation in myelination. The experimental design and analysis of results are solid, providing a reference for further research in this field.

eLife assessment

This valuable study investigates the development of high-level visual responses in infants, finding that neural responses specific to faces are present by 4-6 months, and those to other object categories later. The study is methodologically solid, using state-of-the-art experimental design and analysis approaches. The findings should be of interest to researchers in the fields of cognitive psychology and neuroscience.

eLife assessment

This study presents important findings indicating that tinnitus patients have abnormal auditory prediction signals. The results are based on well-controlled experiments for a large cohort of patients. The reported observations constitute a new set of convincing evidence for the strong link between tinnitus and central auditory processing disorders and will be of interest to clinicians, auditory scientists, and neuroscientists studying prediction mechanisms.

eLife assessment

This study presents fundamental new findings introducing a new approach for the reprogramming of brain glial cells to corticospinal neurons. The data is highly compelling, with multiple lines of evidence demonstrating the success of this new assay. These exciting findings set the stage for future studies of the potential of these reprogrammed cells to form functional connections in vivo and their utility in clinical conditions where corticospinal neurons are compromised.

eLife assessment

This important study using engineered mouse models provides a first and compelling demonstration of a pathogenic phenotype associated with lack of expression of p53AS, an isoform of the p53 protein with a different C-terminus than canonical p53. The role of this isoform has been elusive so far and this first demonstration represents a substantial advance in our understanding of the complex role(s) of p53 isoforms. The revised manuscript adequately addresses previous concerns.

eLife assessment

This study presents a dataset obtained through a single cell RNA-Sequencing of sea cucumber regenerating intestine 9 days post evisceration. The data were collected and analyzed using standard single cells analysis from n=2 adult sea cucumbers captured from the wild, which represents a useful resource for future studies. Although cell type validation is attempted, it is performed on samples from the same 2 animals (and not independent samples), rendering the validation incomplete. Further, the RNA localization images provided in the paper could benefit from improved spatial context, and many strong statements in the discussion should be better justified and supported by the presented data. With the validation part strengthened, this paper would be of interest to development and regeneration fields.

eLife assessment

Transient receptor potential mucolipin 1 (TRPML1) functions as a lysosomal ion channel whose variants are associated with lysosomal storage disorder mucolipidosis type IV. This important report describes local and global structural changes driven by the binding of regulatory phospholipids and by mutations allosteric that allosterically cause gain or loss of channel function. Most of the claims related to the allosteric regulation of TRPML1 have solid support by two new cryo-EM structures, that of the gain of function Y404W mutant and that of the wild-type channel bound to the inhibitor PI(4,5)P2. The new cryo-EM findings are evaluated within the context of previously reported TRPML1 structures, and a proposed allosteric gating mechanism is partially supported by functional electrophysiology results.

eLife assessment

The study addresses a central question in systems neuroscience (validation of active inference models of exploration) using a combination of behavior, neuroimaging, and modelling. The data provided are useful but incomplete due to issues with multiple comparisons and lack of model validation.

eLife assessment

The study presents a valuable finding that the Endothelin B receptor (ETBR) expressed by the satellite glial cells (SGCs) in the dorsal root ganglions (DRG) inhibited sensory axon regeneration in both adult and aged mice. The evidence supporting most of the conclusions was solid, and the work will be of interest to neuroscientists working on axon regeneration and the involvement of non-neuronal cell types in regulating axon regeneration. Although the proposed mechanism is intriguing and the methodology is robust, the molecular mechanisms by which ETBR regulates axon regeneration are not fully elucidated.

eLife assessment

This is a very interesting study that links inflammatory reactivity and T-cell immunity in pathologies associated with pneumonia in the context of the aging process (telomerase functionality). The authors have relied on results from experiments using a mouse model (Terc-deletion), that is used in studies on aging. The questions are relevant, the methodology is appropriate, and the results represent a set of useful findings. However, on the whole, the evidence is not very strong owing to the low power of the study, some flaws in experimental design, lack of rigorous controls, and inadequate approaches to analyzing immune function, thus making the study incomplete in support of its claims.

eLife assessment

This valuable report describes the control of the activity of the RNA-activated protein kinase, PKR, by the Vaccinia virus K3 protein. A strength of the manuscript is the powerful combination of a yeast-based assay with high-throughput sequencing and its convincing experimental use to characterize large numbers of PKR variants. A minor weakness is that the scope of the screen conducted could still be extended, for example in terms of the segments of PKR included.

eLife Assessment:

This fundamental study substantially advances our understanding of the role of different-sized soil invertebrates in shaping the rates of leaf litter decomposition, using an experiment across seasons along an aridity gradient. The authors provide compelling evidence that the summed effects of all invertebrates (with large-sized invertebrates being more active in summer and small-sized invertebrates in winter) on decomposition rates result in similar levels of leaf litter decomposition across seasons. The work will be of broad relevance to ecosystem ecologists interested in soil food webs, and researchers interested in modeling carbon cycles to understand global warming.

eLife assessment

This valuable study identifies biallelic variants of DNAH3 in unrelated infertile men and reports infertility in DNAH3 knockout mice. The authors demonstrate that compromised DNAH3 activity decreases the expression of IDA-associated proteins in the spermatozoa of human patients and knockout mice, providing convincing evidence that DNAH3 is a novel pathogenic gene for asthenoteratozoospermia and male infertility. The study will be of substantial interest to clinicians, reproductive counselors, embryologists, and basic researchers working on infertility and assisted reproductive technology.

eLife assessment

This important study provides convincing evidence that both psychiatric dimensions (e.g. anhedonia, apathy, or depression) and chronotype (i.e., being a morning or evening person) influence effort-based decision-making. This is of importance to researchers and clinicians alike, who may make inferences about behaviour and cognition without taking into account whether the individual may be tested or observed out-of-sync with their phenotype. The current study can serve as a starting point for more targeted investigation of the relationship between chronotype, altered decision making and psychiatric illness.

eLife assessment

This study describes fundamental findings related to early disruptions in disinhibitory modulation exerted by VIP+ interneurons, in CA1 in a transgenic model of Alzheimer's disease pathology. The authors provide a compelling analysis at the cellular, synaptic, network, and behavioral levels on how these changes correlate and might be related to behavioral impairments during these early stages of AD pathology.

eLife assessment

This study presents valuable findings on an unresolved question of cerebellar physiology: Do synapses between Purkinje cells and granule cells, made by the ascending part of the granule cells' axon, have different properties than those made by parallel fibers? The authors conducted patch-clamp recordings on rat cerebellar slices and found a new type of plasticity in the synapses of the ascending part of granule cell axons. The experiments are well-designed with appropriate controls, and the study provides solid evidence for the new form of cerebellar synaptic plasticity.

eLife assessment

This study presents important findings on the differential activity of noradrenergic and dopaminergic input to dorsal hippocampus CA1 in head-fixed mice traversing a runway in a virtual environment that is familiar or novel. The data are rigorously analysed, and the observed divergence in the dynamics of activity in the dopaminergic and noradrenergic axons is solid. Future studies, using specific manipulations of the two distinct midbrain inputs combined with behavioral testing, are required to strengthen the claim that distinct signals to the hippocampus cause distinct behavioral effects.

eLife assessment

The authors present 16 new well-preserved specimens from the early Cambrian Chengjiang biota. These specimens potentially represent a new taxon which could be useful in sorting out the problematic topology of artiopodan arthropods - a topic of interest to specialists in Cambrian arthropods. The authors provide solid anatomical and phylogenetic evidence in support of a new interpretation of the homology of dorsal sutures in trilobites and their relatives.

eLife assessment

This study provides valuable new insights into how multisensory information is processed in the lateral cortex of the inferior colliculus, a poorly understood part of the auditory midbrain. By developing new imaging techniques that provide the first optical access to the lateral cortex in a living animal, the authors provide convincing in vivo evidence that this region contains separate subregions that can be distinguished by their sensory inputs and neurochemical profiles, as suggested by previous anatomical and in vitro studies. This work provides a foundation for future research exploring how this part of the auditory midbrain contributes to multisensory-based behavior.

eLife assessment

The work by Han and collaborators describes valuable findings on the role of Akkermansia muciniphila during ETEC infection. If confirmed, these findings will add to a growing list of beneficial properties of this organism. Although the strength of the evidence used to justify the conclusions in the manuscript is solid, the issues raised about the sequencing method used should be addressed.

eLife assessment

The aim of this valuable study is to uncover developmental roles of the neuropeptide prothoracicotropic hormone (PTTH) and ecdysone, which later regulate female receptivity of Drosophila melanogaster. The work combines spatially and temporally restricted genetic manipulation with behavior quantification to explore these molecular pathways and the neuronal substrates participating in the control of female sexual receptivity. At present, the implication of both signaling pathways in this process is convincing but the strength of the evidence is incomplete to support the main claim that PTTH pathway controls female sexual receptivity through the function of ecdysone in pC1 neurons.

eLife assessment

This study presents valuable findings on the relationship between prediction errors and brain activation in response to unexpected omissions of painful electric shocks. The strengths are the research question posed, as it has remained unresolved if prediction errors in the context of biologically aversive outcomes resemble reward-based prediction errors. The evidence is solid but there are weaknesses in the experimental design, where verbal instructions do not align with experienced outcome probabilities. It is further unclear how to interpret neural prediction error signaling in the assumed absence of learning. The work will be of interest to cognitive neuroscientists and psychologists studying appetitive and aversive learning.

eLife assessment

This useful study describes the second earliest known winged ovule without a capule in the Famennian of Late Devonian. Using solid mathematical analysis, the authors demonstrate that three-winged seeds are more adapted to wind dispersal than one-, two- and four-winged seeds. The manuscript will help the scientific community to understand the origin and early evolutionary history of wind dispersal strategy of early land plants.

eLife assessment

This valuable study provides in vivo evidence for the synchronization of projection neurons in the olfactory bulb at gamma frequency in an activity-dependent manner. This study uses optogenetics in combination with single-cell recordings to selectively activate sensory input channels within the olfactory bulb. The data are thoughtfully analyzed and presented; the evidence is solid, although some of the conclusions are only partially supported.

eLife assessment

To test if somatic mutations in cancer genomes are enriched with mutations in polyadenylation signal regions, the authors observed an increased enrichment of somatic mutations that may affect the function of polyA signals and confirmed that these mutations may influence gene expression through a minigene expression experiment. This important study advances our understanding of noncoding somatic mutations by identifying a novel class of mutations that affect 3'UTR polyadenylation signals enriched in tumor suppressor genes in cancer. The evidence supporting the conclusions is convincing, with rigorous statistical analyses and experimental validation.

eLife assessment

The manuscript reports fundamental findings that extra-embryonic visceral yolk sac endoderm is critical for NAD de novo synthesis during early organogenesis, and perturbations of this pathway may cause Congenital NAD Deficiency Disorder. The supporting evidence is solid. This work will be of interest to developmental biologists.

eLife assessment

The authors have developed a biosensor for programmed cell-death. They use this biosensor to provide valuable measurements of cell death in a specific early time window of development. However, the title and the discussion suggest a broader window of applicability of the results. The evidence supporting the claims is therefore incomplete. The authors should modify the introduction and discussion to examine their work in the context of extant literature and modify their title to reflect the conclusion that "Zebrafish live imaging reveals around 2%of motor neurons die through apoptosis during a 24-120 hour window in early development".

eLife assessment

This study evaluated the role of transcutaneous auricular vagal nerve stimulation (taVNS) in patients with subarachnoid hemorrhage (SAH) randomized to taVNS vs sham, finding that those with active taVNS exhibited increased parasympathetic activity. The findings are important and cross-disciplinary, while the level of evidence is solid.

eLife assessment

This valuable study investigates the role of Drp1 in early embryo development, providing solid evidence on how this protein influences mitochondrial localization and partitioning during the first embryonic divisions. The research employs the Trim-Away technique to eliminate Drp1 in zygotes, revealing critical insights into mitochondrial clustering, spindle formation, and embryonic development.

eLife assessment

This important paper implicates S-acylation of Cys-130 in recruitment of the inflammasome receptor NLRP3 to the Golgi, and it provides convincing evidence that S-acylation plays a key role in response to the stress induced by nigericin treatment. While Cys-130 does seem to play a previously unappreciated role in membrane association of NLRP3, further work will be needed to clarify the details of the mechanism.

eLife assessment

This manuscript presents important observations on the early changes that occur in calcium signaling, TMEM16a channel activation, and mitochondrial dysfunction in salivary gland cells in a murine model of autoimmune Sjögren's disease. The study reports that in response to DMXAA treatment which induces a murine model of Sjögren's disease, salivary gland cells show significant changes in saliva release, calcium signaling, TMEM16a activation, mitochondrial function, and sub-cellular morphology of the endoplasmic reticulum. The work is compelling and will be of strong interest to physiologists working on secretion, calcium signaling, and mitochondria.

eLife assessment

This manuscript provides an important advance in our understanding of the molecular events that promote osteoclast fusion. Compelling data support the conclusion that an oxidized form of the ubiquitous protein La promotes osteoclast fusion following enrichment at the cell surface of osteoclast progenitors. These data improve our understanding of the processes that regulate bone resorption and will be of broad interest to researchers in the fields of cell biology and musculoskeletal physiology.

eLife assessment

This study presents important findings linking circHMGCS1 and miR-4521 in diabetes-induced vascular endothelial dysfunction. Overall, the evidence supporting the claims of the authors is convincing. The work will be of interest to biomedical scientists working with cardiovascular and/or RNA biology, particularly those studying diabetes.

eLife assessment

This study investigates the mechanistic connection between glycosylation at the N162 site of the Fc gamma receptor FcγRIIIa and the regulation of NK cell-mediated antibody-dependent cytotoxicity. The compelling findings, derived from novel isotope labeling approaches and state-of-the-art NMR spectroscopy techniques, underscore the impact of glycan composition on receptor stability and immune function. This research offers fundamental insights that could aid in the development of more effective therapeutic antibodies. The manuscript will be of interest to researchers in the fields of immunology and therapeutic antibody development.

eLife assessment

This study provides useful evidence substantiating a role for long noncoding RNAs in liver metabolism and organismal physiology. Using murine knockout and knock-in models, the authors invoke a previously unidentified role for the lncRNA Snhg3 in fatty liver. The revised manuscript has improved and most studies are backed by solid evidence and will be of interest to the field of metabolism.

eLife assessment

This paper provides an important assessment of competition dynamics allowing coexistence of the carnivore guild within a large national park in China. Multiple surveying techniques (camera traps and DNA metabarcoding) provide convincing evidence that spatial segregation represents the main strategy of coexistence, while species have a certain degree of temporal and dietary overlap. Altogether, the manuscript provides information critical to the conservation and management agenda of the park.

eLife assessment

This paper makes fundamental contributions to understanding the mechanisms by which the conserved guidance cue UNC-6/Netrin controls the long-range growth and targeting of axons. Using state-of-the-art genetics and in vivo imaging, the authors provide solid support for the finding that UNC-6/Netrin can act via both chemotaxis and haptotaxis, though additional studies would be necessary to make these findings stronger. The paper's insights will be of interest to a variety of cell and developmental biologists and neuroscientists.

eLife assessment

This is a valuable study in the Jurkat T cell line that calls attention to phosphorylation of formin-like 1 β role and its role in polarization of CD63 positive extracellular vesicles (referred to as exosomes). The evidence presented in the Jurkat model is solid, but concerns have been raised about the statistical analysis and more details would be required to fully assess the significance of the results. For example, ANOVA is the method described, but it requires large amounts of normally distributed data in multiple groups and cannot be used to make pairwise comparisons within groups, which would require a post-hoc method (which is not discussed). In addition, the data showing forming-like 1 β in primary human T cells without and with a CAR are provided without quantification and don't investigate any of the novel claims, so doesn't address the relevance of Formin-like 1 β beyond the Jurkat model. Nonetheless, the consistent trends in the body of the study do provide reliable support for the claims.

eLife assessment

The intrinsic chirality of actin filaments (F-actin) is implicated in the chiral arrangement and movement of cellular structures, but it was unknown how opposite chiralities can arise when the chirality of F-actin is invariant. Kwong et al. present evidence that two actin filament-based cytoskeletal structures, transverse actin arcs and radial stress fibers, drive clockwise and anti-clockwise rotation, respectively. This fundamental work, which has broad implications for cell biology, is supported by compelling data.

eLife assessment

This important study presents work on the molecular mechanism driving asymmetric cell division and fate decisions during embryonic development of echinoids. The evidence supporting the claims of the authors is solid overall but with some concerns about quantification and a lack of explanation for some of the findings. The work will be of interest to developmental biologists and cell biologists working in the field of self-renewal.

eLife assessment

This manuscript describes the characterization of the conformational dynamics of two chemokine receptors at the single-molecule level using FRET. The authors make a convincing case for attributing the distinct interaction and pharmacology of the two receptors to differences in their conformational energy landscape. These important findings will be of interest to scientists working on activation mechanisms of GPCRs and signal transduction.

eLife assessment

This valuable contribution studies factors that impact molecular exchange between dense and dilute phases of biomolecular condensates through continuum models and coarse-grained simulations. The authors provide convincing evidence that interfacial resistance can cause molecules to bounce off the interface and limit mixing. Results like these can inform how experimental results in the field of biological condensates are interpreted.

eLife assessment

This manuscript reports a detailed model of juvenile rat somatosensory cortex, consisting of 4.2 million morphologically and biophysically detailed neuron models, arranged in space and connected according to diverse experimental data - a valuable tool for the field. The construction of the model is based on a solid methodology, but the supporting evidence is incomplete, as it is currently not emulating known local connection probabilities and variations in cortical thickness. It should be noted that, by necessity, such a large-scale model development involves many assumptions, interpolations, and decisions that could have compounding downstream effects on further analyses that may be difficult to disambiguate.

eLife assessment

This important study substantially advances our understanding of energy landscapes and their link to animal ontogeny. The evidence supporting the conclusions is compelling, with high-throughput telemetry data and advanced track segmentation methods used to develop and map energy landscapes. The work will be of broad interest to animal ecologists.

eLife assessment

This manuscript describes a novel computational method to investigate cell evolutionary trajectory for scRNA-seq samples. This is an important tool for estimating pseudotime in the evolutionary path through modelling the bifurcations in a Gaussian process. While the evaluation of the method is extensive and compelling, the reviewers suggested further analyses to ensure that the method is indeed robust. When these issues are addressed, this will be of substantive value to biologists interested in scRNA-seq bioinformatic methods.

eLife assessment

This important study reports numerous attempts to replicate reports on transgenerational inheritance of a learned behavior, pathogen avoidance, in C. elegans. While the authors observe parental effects that are limited to a single generation (also called intergenerational inheritance), the authors failed to find any evidence for transmission over multiple generations, or transgenerational inheritance. The experiments presented are meticulously described, making for compelling evidence that in the authors' hands transgenerational inheritance cannot be observed, although there remains the possibility that subtle differences in culture conditions or lab environment explain the failure to reproduce previous observations. Given the prominence of the original reports of transgenerational inheritance, the present study is of broad interest to anyone studying genetics, epigenetics, or learned behavior.

eLife assessment

The authors proposed a novel deep learning framework to estimate posterior distributions of tissue microstructure parameters. This provides a valuable methodology with practical implications for automatically estimating parameter distributions from different biophysical models. The experiments show solid evidence for generalizing the method to use data from different protocol acquisitions and work with models of varying complexity.

eLife assessment

This study shows that Znhit1, a regulator of chromatin and of the histone variant H2A.Z, is required for progression through meiotic prophase. It is an important observation that describes the role of epigenetics and gene expression during meiosis. The analysis is based on complementary approaches at the cytological, single-cell, and genomic levels that provide solid evidence for the role of Znhit1 in the control of gene expression and in the loading of H2A.Z in mouse spermatocytes.

eLife assessment

This work describes a convincingly validated non-invasive tool for in vivo metabolic phenotyping of aggressive brain tumors in mice brains. The analysis provides a valuable technique that tackles the unmet need for patient stratification and hence for early assessment of therapeutic efficacy. However, wider clinical applicability of the findings can be attained by expanding the work to include more diverse tumor models.

eLife assessment

This work presents valuable data demonstrating that a camelid single-domain antibody can selectively inhibit a key glycolytic enzyme in trypanosomes via an allosteric mechanism. The claim that this information can be exploited for the design of novel chemotherapeutics is incomplete and limited by the modest effects on parasite growth, as well as the lack of evidence for cellular target engagement in vivo.

eLife assessment

This important study reports the molecular function of the SARS-CoV-2 helicase NSP13, which inhibits the transcriptional activity of the YAP/TEAD complex in vitro and in vivo. The evidence supporting the authors' claims is solid, with rigorous cell biological assays and multi-omic studies. This work will be of interest to scientists studying COVID-19 infection and the Hippo-YAP signaling pathway.

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.