Evaluation Summary:

This paper addresses a very notable gap that exists between evolutionary computing and experimental evolution. While artificial and computational approaches have long been used as an analogy for biological systems (with studies that have produced findings relevant for evolutionary theory), few studies have directly used methods and results from evolutionary computing to directly inform the shape and structure of experimental evolution studies. This study's approach is creative, and its approaches and results may be of use to both computational and experimental audiences. Lastly, this study can spawn future ones that draw even more connections between evolutionary computation/artificial life and evolutionary theory.

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Evaluation Summary: 

This manuscript probes the mechanism of postsynaptic retinoic acid (RA) signaling on presynaptic function. BDNF has important roles in synaptic plasticity, but how retrograde BDNF signaling is controlled following synaptic inactivity is unclear. The authors use genetic tools to localize the action of different components of the pathway to pre- or post-synaptic compartments and use biochemical approaches to define a molecular link between retinoic acid and local translation of distinct BDNF transcripts. The findings presented here fill a gap in our knowledge regarding how presynaptic function is adaptively modulated by BDNF by highlighting the role of RA in this process. The experiments have been well-executed and the data provide compelling support for the model proposed by the authors.

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Evaluation Summary:

The authors report on the coordination mechanisms between oscillations recorded in the CA1 subfield of the hippocampus, prefrontal cortex, and olfactory bulb and cell ensemble activity in CA1 and prefrontal cortex that are associated with odor-cued decision making. The findings support the hypothesis that the beta rhythm plays a role in coordinating CA1-prefrontal cortex ensembles associated with an animal's accurate decisions. Sensory-guided decision-making is of broad significance to many readers who are studying executive functions and cognitive behaviors, and the observations reported in this manuscript provide insights into mechanisms that may support these functions and behaviors.

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Evaluation Summary:

Houy and co-workers investigated the function of Munc13-1 and ubMunc13-2 in chromaffin cells and the interaction with phorbol esters (PMA). They combined calcium uncaging, capacitance measurements, amperometry, and activity-dependent movements of the EGFP-labeled Munc13 proteins. This study reveals that phorbolesters have a stimulatory effect via ubMunc13-2 but an inhibitory effect via Munc13-1. These opposing effects of the two Munc13 paralogs are surprising considering the closely related domain architectures.

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Evaluation Summary:

In this manuscript, the authors specifically look at the interaction between epidural stimulation of the spinal cord and the descending input evoked voluntarily in 2 intact monkeys. The results show that spinal stimulation could facilitate or suppress voluntarily evoked EMG and wrist torque, depending on voluntarily evoked activity as well as the stimulation parameters. This shows that spinal stimulation could enhance the descending inputs in cases of partial lesions. The conclusions of this paper are well supported by data, although they could be made stronger with additional analysis and clarification.

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Evaluation Summary:

This manuscript will be of general interest to Drosophila researchers, whose work has long relied on the tools generated by the Gene Disruption Project (GDP). This manuscript provides a notable update on the work of the GDP. In it, the authors demonstrate the efficacy of new, streamlined transformation vectors, which they use to generate several hundred novel gene-specific Gal4 driver lines using CRISPR technology. The new vectors promise to allow the GDP to complete its goal of creating null mutations for every gene in the fly genome. The elegant functionality of the new vectors will also likely be of interest to workers outside of Drosophila.

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Evaluation Summary: 

This paper, which is of interest to membrane biologists and colleagues in signal transduction, examines the interesting question of whether LRRK2 recruitment to membranes may regulate its activity. Membrane association involves binding to membrane-tethered Rab GTPases via LRRK2's armadillo domain, and the authors propose an elegant feedforward mechanism to describe how recruitment could lead to Rab phosphorylation, but not all features of the feed-forward model are directly supported by data. 

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Evaluation Summary: 

This manuscript by Fox, Birman, and Gardner combines human behavioral experiments with spatial attention manipulation and computational modeling (image-computable convolutional neural network models) to investigate the computational mechanisms that may underlie improvements in behavioral performance when deploying spatial attention. Through carefully controlled manipulations of computational architecture and parameters, the authors dissociate the effects of different tuning properties (e.g. tuning gain vs. tuning shifts) and conclude that increases in gain are the primary means by which attention improves behavioral performance. The analyses and results are technically sound and clearly presented, but the generality of the conclusions is limited by certain modeling/task choices made in the work. 

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Evaluation Summary: 

This paper will be of interest to microbiologists, clinicians, and public health workers with an interest in the possible impact of antibiotic use and regulations. The scope of the study is unusually high, integrating economic and geographical factors as well as genomic data among others. However, reasonable alternative explanations can be identified such that the data do not strongly favor the preferred hypothesis put forward by the authors. 

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Evaluation Summary: 

This study finds that the levels of many immune markers are higher in vaginal samples in women taken after initiation of vaginal sex than before initiation of vaginal sex. This result may indicate that initiation of vaginal sex potentially influences vaginal immune responses, but it is possible that unmeasured confounding and selection bias might contribute to some of the difference across samples. This study will be of highest interest to those interested in how immune markers can change within individuals over time. 

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Evaluation Summary: 

The manuscript presents a high-quality quantitative analysis of plant embryo cell division in 3D. Authors combine computer modeling with detailed microscopy imaging to reveal underlying patterns and biases in cell divisions. The manuscript will likely be of interest to cell and developmental biologists. The conclusion can be straightened following additional analysis and data interpretation. 

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Evaluation Summary:

This manuscript explores the establishment and spread of antimalarial drug-resistant P. falciparum parasites using a combination of transmission modeling and model emulation. The authors add an important component to the broader understanding by jointly considering multiple factors driving drug resistance.

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Evaluation Summary:

This paper analyses the synaptic connections of two subsets of clock neurons in the Drosophila brain, the small ventral lateral neurons and the dorsal lateral neurons that control the sleep-wake behavior. The study reveals interesting features of the clock network, including the high heterogeneity of the LNd subset and the existence of non-clock cells that are predicted to act as "inter-clock neurons". The manuscript will be of interest to chronobiologists and neuroscientists working on neuronal networks, and it provides new insights into circadian clock network organization that may be of general value. The data analysis is rigorous, and the conclusions are justified by the data.

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Evaluation Summary:

This study provides a comprehensive analysis of the effects of polymorphism in an immune gene (the immunoglobulin E receptor Fcer1a) on immune responses, resistance to infection, and reproductive fitness in a wild rodent population. The authors claim to have found evidence for sex-specific effects of Fcer1a polymorphism, a result that would have broad implications for our understanding of the maintenance of genetic variation. The support for this claim is currently rather weak.

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Evaluation Summary:

This manuscript is of interest to several fields, in particular to microbiologists and structural biologists interested in pore-forming proteins and peptides. The data presented reveal insights into the mode of action of a newly identified peptide toxin secreted by Candida albicans (candidalysin). Using different techniques the authors propose and test a model for membrane perforation by candidalysin and identify an intriguing inactive mutant. While the presented data supports the main conclusions of the paper some of the initial assumptions need further assessment while the described mutants could benefit from more extensive characterization.

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Evaluation Summary:

The authors collected human samples from a rare cancer type in which evolutionary features have not been well-defined. They describe the clonal evolution through sampling at precancerous, primary tumour, and metastatic stages. Whole exome sequencing was performed and one of the mutation types was confirmed with other techniques.

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Evaluation Summary:

This work will be of interest for researchers studying the functions of microbial communities, microbial ecology and interactions. Using the Kombucha tea (KT) microbiome as a case study, Huang et al. provide a framework for simplifying complex communities into core communities that capture aspects of complex communities. Authors demonstrated that core communities can facilitate a mechanistic understanding of how microbes interact, especially when member species are individually culturable. The work presents a fresh, novel approach for the coarse-grained analysis of complex microbiomes.

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Evaluation Summary:

This manuscript analyses the inhibitory role of IL-10 producing regulatory T-cells in a mouse cytomegalovirus infection model. The authors report that IL-10 producing CD4+T-cells express genes of chronically activated Th1-cells, are clonally expanded and inhibit anti-viral T-cell responses via arginase, an enzyme that breaks down an essential amino acid for T-cell activation. The manuscript presents some novel and potentially important data; however, it requires the provision of additional experimental data and clarifications.

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Evaluation Summary:

This manuscript will be of interest to a broad audience of cancer biologists, especially those interested in esophageal cancer or treatment strategies involving ATR inhibition. It provides novel information about how FDA-approved antiretroviral compound Arbidol is a potential ATR inhibitor, which is of interest in the treatment of multiple tumor types. The key claims of the manuscript are supported by in silico, in vitro, and in vivo data.

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Evaluation Summary:

This manuscript will be of interest to stem cell and developmental biologists who aim to use newly emerging brain organoid models to understand the structure and function of the developing human brain. It presents a technological advance in imaging and describes an innovative method for labeling and tracking of cells within organoids to enable the assessment of dynamic processes within the intact organoid. The method is validated in a disease model and addresses a challenge in the field of human stem cell modeling of assessing cells within the 3D structure.

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Evaluation Summary:

This study provides computational predictions on optimal combinations of broadly neutralizing antibodies for treating HIV-1, based on the finding that population diversity alone permits the prediction of the timing of viral escape from broadly neutralizing antibodies. The idea behind the approach used is good, although the analyses and computational data/results highlight important limitations of the modeling approach. Nonetheless, the study should be of broad interest to those studying viral responses to therapeutic interventions as well as to both evolutionary and computational biologists.

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Evaluation Summary:

This paper is of potential interest to a broad audience in the fields of germ cell biology and cytoskeleton, as it implies a microtubule-based motor function in intra-manchette cargo transport in developing sperm tail. However, some conclusions of this paper require stronger experimental support.

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Evaluation Summary:

This study combines behavioral data from guinea pigs and data from a classifier model to ask what auditory features are important for classifying vocalisations. This study is likely to be of interest to both computational and experimental neuroscientists, in particular auditory neurophysiologists and cognitive and comparative neuroscientists. A strength of this work is that a model trained on natural calls was able to predict some aspects of responses to temporally and spectrally altered cues. However, additional data, analysis, or modelling would be required to support some of the stronger claims.

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Evaluation Summary:

In this manuscript, effective force-distance curves between cells are inferred for various tissues. This study is potentially interesting for researchers interested in tissue dynamics, because computer models of growing cellular tissues are becoming an increasingly important tool to understand experimental data and eventually predict medical interventions.

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Evaluation Summary:

This manuscript described a role of Vitamin C in promoting plasma cell differentiation by remodeling the epigenome via TET (Ten Eleven Translation) family proteins. Overall, most of experiments are properly executed, controlled and presented. This paper will be of interest to scientists in molecular immunologists, particularly those involved in of epigenetic mechanisms of B cell differentiation to plasma cells.

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Evaluation Summary:

The manuscript shows that OTOP proton channels are proton-gated with distinct pH sensitivities, and identifies regions on the proteins that alter pH-dependent gating. The main claims are well supported by the data. These findings are likely to be of interest to researchers studying acid/base physiology, sensory physiology, or ion channel biophysics.

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Evaluation Summary:

This manuscript puts forward a new toolkit of viruses for manipulation and visualization of zebrafish neural circuits. The authors overcome several challenges in the field and present a set of resources likely to be of high value to the zebrafish community.

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Evaluation Summary:

Hososhima et al. characterize a marine virus Heliorhodopsin as the first of its class to show ion transport activity. These bacteriorhodopsin homologs have been recently described and the present careful characterization of V2HeR3 represents an important step in the understanding of these interesting membrane proteins. Though the experiments are carried out carefully and the results, in general, support the conclusions, some experiments are needed and the interpretation of results needs to be clarified.

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Evaluation Summary:

This paper is of interest to neuroscientists studying the interaction between working memory, decision making, cell types, and neural oscillations. It introduces a detailed model of different brain areas which interact giving rise to the complex pattern of oscillations that are observed during a visual attention task. Additionally, the model reproduces the phase-dependent behavioral performance observed experimentally during such a task. This provides a new level of precision in our understanding of how rhythmic attention works in the brain.

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Evaluation Summary: 

This manuscript presents a creative, unique, and well-explained theoretical analysis of the shapes adopted by chromosome-attached microtubule bundles during manipulation with glass microneedles inside dividing cells. The overall conclusion is that the bundles are laterally anchored to other structures in the mitotic apparatus within several micrometers of their chromosome-attached ends, but relatively freer at their pole-proximal ends. This interesting work should appeal broadly to cell biologists and biophysicists. 

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Evaluation Summary:

This paper is mainly for an audience of genetic epidemiologists interested in the evaluation and portability of polygenic scores. The authors show that a polygenic risk score to predict prostate cancer risk is very informative for individuals that are classified on three different ancestry categories. The authors show that the polygenic risk score can be used to predict the risk to develop prostate cancer as a function of age. This paper provides evidence that genetic information could be used to provide guidance to clinicians on when to perform screenings to detect prostate cancer in patients.

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Evaluation Summary:

This manuscript contributes to a circuit-based understanding of how sweet and bitter tastes are integrated with hunger state to drive feeding initiation in Drosophila. Anatomical, behavioral, and neuronal activity data support a multi-step pathway from sensory input to motor output. This manuscript, thus, contributes to our understanding of how multiple sensory cues are integrated with an internal state to reach a behavioral decision.

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Evaluation Summary:

Through the use of multiplexed in situ hybridization with careful embryo staging, this manuscript represents exemplary documentation of dynamic gene expression patterns in early fly development. By comparison of these patterns in various mutant combinations, a simple logical model for specification of expression is proposed. This manuscript will be of broad significance to developmental biologists interested in embryo segmentation and gene regulatory networks underpinning patterning.

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Evaluation Summary:

This paper is of interest to scientists interested in the functions of the hippocampus, as well as those in the field of sensorimotor timing. The reported data and findings point towards the possibility that the hippocampus supports specific and generalized learning of short time intervals relevant to behavior. While the conclusions are mostly supported by the evidence, further clarification of methodology as well as additional analyses and discussion would strengthen the authors' conclusions.

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Evaluation Summary:

The authors use a combination of proteome-specific protein complex structures and publicly available ribosome profiling data to show that cotranslational assembly is favored by large N-terminal intermolecular interfaces. The manuscript represents an important contribution to the field of protein biosynthesis pathways by suggesting an intuitive evolutionary mechanism that can promote co-translational assembly pathways in mammalians, yeast, and bacteria.

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Evaluation Summary:

Second order conditioning is a higher form of learning where a previously conditioned stimulus (e.g. odor A by food) is used to condition the perception of another stimulus (e.g. odor B by odor A). Yamada et al. have used the fly to identify a neural circuit in the insect mushroom body underpinning second order conditioning. This work elegantly combines neural circuit mapping, electrophysiology and modeling to put forward a mechanistic model for this highly conserved form of learning.

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Evaluation Summary:

The authors measured the heartbeat and touch perception while people touched a variety of surfaces. The results indicate that people's heart rates and heartbeats vary systematically according to the type of touch performed and how difficult it was to perceive the grooved surfaces. The paradigm and the results appear very interesting though the specific analyses of choice and their presentation require some improvement to make a more convincing case.

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Evaluation Summary:

This paper is an impressive and deep look at a very important problem: understanding the genetic underpinnings of evolution acting on a quantitative trait. The authors analytically study the response to an abrupt shift in phenotypic optimum, in terms of both phenotype and genetic basis (how various alleles/loci contribute to this response). The basic assumptions are classic, but the methods and findings are new (especially finite population effects) and well supported by clear analytical approximations and extensive simulation checks. The main finding is that the relative contribution of large vs moderate effect alleles changes substantially and predictably over a long-term period after the shift, even though the phenotypic changes are already undetectable over this period.

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Evaluation Summary:

This study investigates on how weight loss by bariatric surgery or weight-matched dietary intervention impairs breast cancer growth as well as immunotherapy. This study can potentially provide some therapeutic intervention strategies on combining vertical sleeve gastrectomy and immunotherapy in treating breast cancer.

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Evaluation Summary:

This is an exemplary manuscript describing the creation of a novel mouse model to study bone marrow adipocytes. The authors demonstrate that these cells play a critical role in the pathophysiology of myeloid cell lineage regeneration as well as the maintenance of bone mass and hematopoietic progenitors during times of limited energy (e.g. caloric restriction).

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Evaluation Summary:

In this paper, Ekman and colleagues present novel evidence, using a visual sequence task in fMRI, that the early visual cortex (V1) and the hippocampus both represent perceptual sequences in the form of a predictive "successor" representation, where the current state is represented in terms of its future (successor) states in a temporally discounted fashion. In both brain structures, there was evidence for upcoming, but not preceding steps in the sequence, and these results were found only in the temporal but not spatial domain. This study suggests that the hippocampus and V1 represent temporally structured information in a predictive, future-oriented manner.

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Evaluation Summary:

This study provides evidence that murine acid ceramidase (Ac) is required for normal erythropoiesis and development of rodent malaria. The findings are of interest in understanding molecular processes involved in regulating erythropoiesis, as well as the potential to develop host-directed therapies for malarial parasites that target human reticulocytes.

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Evaluation Summary:

Haggerty et al. reported findings examining how changes in brain function are involved in alcohol binge drinking, with a selective focus on the synaptic and circuit alterations that occur in the anterior insular cortex inputs within the dorsolateral striatum. They show that chronic alcohol drinking produces glutamatergic synaptic adaptations and by stimulating this circuit, binge drinking could be reduced without altering either water consumption or general performance for select reinforcing, anxiogenic or locomotor behaviors. The results of this study may specifically improve our understanding of the neurocircuitry mediating a common alcohol use disorder associated behavior referred to as "front-loading" or excessive drinking during the very beginning of the session.

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Evaluation Summary:

This manuscript reports the complex interactions that take place in the uterus between the endometrium and the blastocyst during and after embryonic diapause, a period of suspended animation that occurs in some mammals including the mouse, the model used here. The authors showed that one gene, Foxa2, interacts with two other genes, Msx1 and LIF, to control the success and duration of diapause. This will be of broad interest to researchers in the field of developmental biology and reproduction. It is a carefully done study, providing new information on the complex process that is diapause in which an embryo goes into suspended animation until it receives appropriate signaling from the uterine endometrial secretions to reactivate.

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Evaluation Summary:

The authors study intergenerational adaptation patterns in four relatively closely related nematode species, using previously established experimental procedures. Phenotypic and transcriptomic data are used to compare responses to stress triggers in the offspring generation between the species. The authors conclude that at least some of the responses are evolutionary conserved.

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Evaluation Summary:

This paper is of interest for scientists studying human genetic adaptation and disease. The work improves on previous studies addressing the question of recent positive selection on genes underlying Mendelian diseases, by examining larger datasets of disease genes as well as carefully controlling for confounding factors that could result in disease genes and non-disease genes showing different patterns of genetic variation. The authors suggest that interference between strongly deleterious recessive mutations can reduce adaptation at disease genes, although this conclusion is weakened by the fact that the signal is only observed in Africa.

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Evaluation Summary:

This paper is of interest to a broad range of neuroscientists, particularly those interested in ApoE biology and Alzheimer's disease (AD), as it reveals a novel mechanism that counteracts AD-linked amyloid plaque burden and synapse dysfunction in mice. Overall, the methodology is sound, sophisticated, and employs animal models that more closely mimic human diseases, and the results are interesting and compelling. Whilst the mechanistic hypothesis proposed by the authors is consistent with the data, plausible alternative explanations remain.

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Evaluation Summary:

This manuscript presents a method to characterize diverse neural activity patterns arising from a small invertebrate circuit. This is of practical interest to invertebrate neuroscientists. The application of unsupervised methods to characterize qualitatively distinct regimes of spiking neural circuits is very interesting. The challenges and lessons learned in this study are therefore of broader interest to those seeking to quantitatively characterize large sets of neural data across many subjects. The survey could be improved by further validation of the derived clusters.

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Evaluation Summary:

There has been a great deal of recent interest in the neural basis for offset responses given their hypothesised importance to perception. This tests the relevance of offset responses to duration perception in a mouse model in addition to examining the brain basis. The work is thorough and well executed. The work demonstrates offset responses that occurs for the first time in auditory cortex distinct from A1 where prevention of offsets by activating cells causes worsening of behavioural performance.

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Evaluation Summary:

The manuscript addresses an important question with broad relevance to the fields of virology, reproductive biology and immunology, and cell death. The primary conclusion of viral-induced cell death is well supported. Some mechanistic details of the pathway remain unclear.

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Evaluation Summary:

This paper documents in wild bonobos significant physiological changes in response to becoming a sibling for the first time. The authors find that new siblings' cortisol increases dramatically, while their neopterin (a marker of immune function) decreases. This paper will be of interest to those who study development, life history transitions, and colleagues at the intersection of physiology and behavior, in particular in primates and other mammals with slow life histories.

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Evaluation Summary: 

This is an interesting study, conducted in mice, that demonstrates for the first time the presence of a large population of cytotoxic CD4+ T lymphocytes in infection with Trypanosoma cruzi, a relevant human pathogen. At present, the relevance of these cells in protective immunity engendered by the host remains unclear. Additional experiments are needed to characterize the functionality of these cytotoxic CD4 T cells vis-a-vis the canonical Th1 T cells. This paper can be of interest to scientists interested in immune responses to parasitic infections. 

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Evaluation Summary:

The manuscript will be of interest to a broad audience in structural biology, biochemistry, and enzymology. The work demonstrates the use of a cutting-edge approach in protein crystallography to investigate and visualize the complex mechanism of an enzyme, the paradigm being Mn-dependent ribonucleotide reductase R2b in complex with flavin-bound NrdI at different redox states. The work is timely and has implications for future investigation of complex biochemical processes.

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Evaluation Summary:

Using an impressive experimental design, Tang et al. analyzed the effects of intraspecific (genetic) and interspecific (species) diversity in ecosystem processes carried out by forest communities. The results show that both species and genotype diversity influence productivity via changes in overall functional diversity, herbivory, and soil fungal diversity. This study will be important to ecologists and environmentalists interested in ecosystem processes and restoration efforts.

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Evaluation Summary:

The manuscript shows an important role for Cav2.3 channels in SNI-mediated allodynia and firing properties of PV-expressing APT neurons. Mechanisms that underlie adaptations in chronic pain models are extremely important for the development of novel therapeutics for chronic pain and this could be a significant contribution in that regard. However, the discussion asserts that these studies are the "first direct evidence that supra-spinal Cav3.2 channels play a fundamental role in pain pathophysiology." This is an overstatement as Chen and colleagues examined the role of these channels in the anterior cingulate cortex in CCI-mediated neuropathic pain (Shen, et al., 2015, Molecular Pain).

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Evaluation Summary:

Ribeiro M et al investigate the ability of a novel bispecific CD19-CD47 antibody to enhance the cell mediated killing mediated by existing drug combinations - anti-CD20 plus PIK3d/CK1E inhibitor. The novelty of this study is the restriction to CD19 positive lymphoma cells, thus potentially avoiding toxicity to non-lymphoma lineages, and the gene expression profiling to identify up regulation of GPR183 after combined treatment of CD19/47 plus CD20/PI3K/CK1E vs CD19/47 alone. Genetic and drug studies suggest that GPR183 is essential for the full activity of the triplet drug combination.

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Evaluation summary:

This study investigates the neural basis of the hidden causal structure between visual and proprioceptive signals in the primate premotor and parietal circuit during reaching tasks executed in a virtual reality environment, where information between the two modalities can be dissociated. Modelling is used to characterize the proprioceptive drift of the monkeys when integrating bimodal information. The key novel result is that premotor neurons represent the integration of bimodal information for small disparities and the segregation for large disparities between the proprioceptive and visual information, while parietal cells show reaching tuning changes that support the updating sensory uncertainty between tasks. Overall, the experiments are technically sound, and the conclusions are mostly well supported. However, a simpler framing of the paper could make the main message easier to grasp, the analysis of Bayesian models seems to lack major details, the statistical reporting is below standard, and a large part of the extensive literature on the role of premotor and parietal cortex in visuomotor behavior is lacking.

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Evaluation Summary:

This paper suggests that assembly of CaV2.3 with b2a/b2e splice variants confers biophysical properties that enable these channels to contribute to calcium-dependent pacemaking in dopaminergic neurons. The findings could have implications for why these neurons are vulnerable to degeneration in Parkinson's disease. The work will be of interest to ion channel biophysicists and neuroscientists.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

The authors use a comparative genomics approach to predict gene function, in particular genes that have a role in eye development. After identifying the convergent loss of SERPINE3 with vision loss across mammals, the authors confirmed its involvement in eye development by characterizing zebrafish knockouts. This work highlights the power of comparative genomics to generate hypotheses that can be experimentally validated. This work is relevant to a broad audience interested in evolution and adaptation as well as for those studying eye development and eye pathologies.

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Evaluation Summary:

The authors provide evidence suggesting the gene expression profile of a specific subset of dendritic cells define features of specific forms of non-infectious uveitis. This work suggests specific pathways in these cells that may have mechanistic import in inflammatory eye disease. This manuscript is of interested to immunologists studying autoimmunity and ocular immunity. While the paper is largely descriptive, the data it presents should serve as a valuable resource for generating hypotheses about the pathogenesis of ocular autoimmune disease.

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Evaluation Summary:

This article proposes methodology and accompanying software for robustly fitting dose-response curves where response is a number between 0 and 1. When response is transformed using the common logistic transformation, values close to 0 or 1 become large in magnitude, unduly influencing the fitted curve after back-transformation and introducing bias in the estimate of certain parameters. The proposed approach, called Robust and Efficient Assessment of Potency, is less perturbed by these extreme measurements.

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Evaluation Summary:

This paper combines new and previously generated data on hand preference to show that hand preference strength, but not direction, is predicted by ecology and phylogeny across primates. By drawing on the most expansive data set to date on experimentally determined hand preference, it calls existing hypotheses on the evolution of hand preference into question and shows that the strength of lateralization in humans is uniquely extreme. Its results are of interest to evolutionary anthropologists, primatologists, and evolutionary morphologists. However, concerns about intraspecific variation and the accuracy of handedness estimates for poorly sampled species are incompletely addressed by the manuscript in its current form.

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Evaluation Summary:

The authors of this manuscript, which is of interest to the cancer community, identify the chromatin regulator WDR5 as a possible new drug target in triple negative breast cancer. Targeted therapeutics for this patient population are of high scientific and clinical interest, and the authors provide a compelling case that co-targeting WDR5 along with mTOR provides a promising new therapeutic strategy.

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Evaluation Summary:

This manuscript provides a detailed structural and biophysical characterization of several complexes of the p52 homodimer of NF kB and different DNA binding sites. The main topic is the investigation of why the central base pair(s) have a strong influence on the transcriptional activity of the homodimer. The authors correlate structural changes with measurements of kinetic on and off rates to develop a model that explains the differences in activity. The paper is of interest to all working on understanding how transcriptional activity is regulated.

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Evaluation Summary:

The long non-coding RNA HOTAIR has been widely reported to be overexpressed in many cancers, including breast cancer, and is strongly associated with disease progression and poor patient outcomes. A valuable new mouse model was developed for studying the functional effects of overexpressing HOTAIR and the mechanism of action of HOTAIR and used to demonstrate overexpression of HOTAIR promoted breast cancer metastasis to the lung. The mouse model and the conclusions will be of interest to researchers interested in improving treatment for breast cancer.

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Evaluation Summary:

This paper proposes that specializations in the outer hair cells' biophysical properties along the cochlea may allow them to amplify the reduced receptor potentials in a manner sufficient to explain all present experimental results. Moreover, the filtering provided by the hair cells may be beneficial for hearing soft high-frequency sounds because it decreases noise and harmonic distortions. Importantly, the amplitude of the relevant motions, even with the low-pass-filtered attenuation, are as large as those measured in the high frequency regions of the cochlea. The authors provide insights and suggestions but the paper lacks strong supportive experimental data to definitively resolve the claimed "apparent" membrane time constant conundrum.

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Evaluation Summary:

The manuscript describes several optimizations of classic DNA reporter constructs to monitor closely the dynamics of Wnt/β-catenin signalling during development using transgenic avian lines. As Wnt signalling pathway is essential in the homeostasis of vertebrate and invertebrate organisms, a robust tool to analyse finely the dynamics of Wnt/β-catenin pathway is of broad interest for the biology/biomedicine scientific communities.

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Evaluation Summary:

The authors describe the reconstitution of axonemal bending using polymerized microtubules, purified outer-arm dyneins, and synthesized DNA origami to cross-link two microtubules. The work is of interest for the field as it shows that bidirectional sliding and bending of microtubules can be generated by a minimal set of elements.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript describes a fluorospot-based assay as a model for a methodical, step-wise and rigorous approach - that combines multiple reagents in a complex system - to study the cross-reactivity of antibody to polymorphic antigens using the malaria vaccine candidate, VAR2CSA, as a model. The authors apply monoclonal antibodies and the corresponding B cells to validate their multiplexed assay before testing small number of samples from malaria exposed donors in a pilot application of the assay. The data support the conclusions. This information will attract the attention of immunologists and vaccinologists, who are primarily but not exclusively, involved in research on malaria.

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Evaluation Summary:

The authors have engineered an anti-CD73 chimeric antigen receptor (CAR) that they express in NK cells to counteract tumors bearing CD73, which contributes to the generation of immunosuppressive adenosine in the tumor microenvironment. This is a promising approach for a new anti-cancer immunotherapy and will be of interest to oncologists and cancer immunologists. The CAR-bearing NK cells show slightly enhanced tumor killing in vitro, but preliminary data show more promising results in mice. This could be due to the CD73 CAR blocking catalytic activity in the tumor microenvironment more effectively than directly promoting cytotoxicity responses.

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Evaluation Summary:

The authors report that neurons in V1 and V4 provide multiplex information of simultaneously presented objects. A combination of multi-single unit recordings, statistical modelling of neuronal responses and neuronal correlations analyses argues in favor of their claims. Pairs of neurons having similar object preferences tended to be positively correlated when both objects were presented, while pairs of neurons having different objects preferences tended to be negatively correlated. These patterns and others suggest that information about the two objects is multiplexed in time. There are, however, some unclear points that deserve discussion and further analysis that could more strongly support the claims.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This paper will be of interest to readers interested ligand-gated ion channels and their evolution. The authors show that ancestral AChR beta subunits reconstructed phylogenetically can form homomeric channels that open spontaneously. The work expands our understanding of agonist-independent AChR gating and highlights intriguing aspects of AChR evolution.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

Replication Factor C (RFC) is known to play a role in both DNA replication and DNA repair by loading a protein clamp called PCNA onto DNA junctions with a 3'-recessed end. The current paper elegantly demonstrates that RFC has a second DNA binding site that recognizes a single strand-double strand DNA with a 5'-recessed junction. The paper reports a series of interesting structures and confirms binding to both short gapped DNA and nicked DNA by RFC, causing local unwinding DNA at the ssDNA/dsDNA junctions. The paper, which is of interest to colleagues studying DNA replication and repair, should be improved through a few clarifications.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

Hart et al show that loss of mitochondrial complex I rescues succinate dehydrogenase deficient (SDH) cells. The experiments are well performed and the phenotype is potentially very interesting to researchers of cancer metabolism. The authors propose that rescue of SDH deficiency by complex I inhibition is caused by an increase in mitochondrial NADH which leads to a restoration of aspartate levels, which in turn rescues proliferation. To support the model, the authors do demonstrate that there are possible correlations of this phenotype to restored aspartate biosynthesis. However, they do not unambiguously establish a mechanism that fully defines how complex I inhibition rescues the proliferation of SDH deficient cells.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

The authors provide novel evidence that semaphorin signaling (SEMA3F) is engaged in the vascular endothelium and smooth muscle to confer atheroprotection. They show that SEMA3F reduces the activity of key enzyme Phosphoinositide 3-kinase to decrease smooth muscle cell proliferation, migration, and phenotype switching, which contributes to atheroprotection. The study has significant translational potential and yields a new therapeutic target.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

Mahalingam et al. report on a new software suite, ASAP, the assembly stitching and alignment pipeline, capable of montaging and aligning serial sections at a speed leading to total time shorter than image acquisition time. The software applies to both electron microscopy and array tomography, and more generally to any data set consisting of collections of 2D images in need of in-section montaging and cross-section registration. The result is a coarsely registered volume, ready for refining with existing software suits such as SEAMLESS by Macrina et al. (2021) towards subsequent processing, such as image segmentation and neuronal arbor reconstruction for cellular connectomics. This paper will be of special interest to researchers within the field of connectomics, but also to the broad class of scientists who perform large-scale microscopy. The establishment of fast, reliable and scalable image alignment software to process the millions of images produced by modern microscopes at the same speed as they are acquired is key to accelerate research in neuroscience and other fields. The key claims of the manuscript are well supported by the data, and the approaches used are thoughtful and rigorous.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

Using mass spectrometry, Crawford et al. identify aspartate aminotransferase 2 (Aat2) as a protein whose polysome-association is increased under oxidative stress in yeast. Aat2 deletion sensitizes yeast to oxidative stress, which is paralleled by an aberrantly elevated integrated stress response, although polysome-association of Aat2 and its effect on oxidative stress response are independent of its aminotransferase activity. This provides evidence that metabolic enzymes may "moonlight" as post-transcriptional regulators. The study will appeal to experts in the fields of biochemistry, genetics, cellular and molecular biology. The presented data mostly support the authors' conclusions, but there are a few technical issues that should be addressed. These include corroborating Aat2:ribosome association and characterizing the effects of non-catalytic Aat2 mutants on the integrated stress response.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer 3 agreed to share their name with the authors.)

Evaluation Summary:

Ivica et al. provide both functional and structural characterization of a relatively unstudied glycine receptor agonist that is structurally in between a full and partial agonist. The combination of cryogenic electron microscopy and electrophysiological approaches allows for complementary structural and functional investigations into the criteria that determine ligand efficacy at the glycine receptor. This manuscript will be of interest to both biophysical and pharmacological investigations of ligand-gated ion channels.

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Evaluation Summary:

This paper is of broad interest to investigators studying the function and regulation of protein scaffolds, dynamic protein structure, and the regulation of the postsynaptic density at excitatory synapses. The authors develop an integrated approach using fluorescence-based biochemical methods, disulfide mapping, and discrete molecular dynamic simulations to study the dynamic supertertiary conformation of the synaptic scaffold protein PSD95.

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Evaluation Summary:

This paper introduces Neuroscout, a new web-based platform for the analysis of fMRI data with a particular focus on naturalistic stimuli. It describes a new tool that will potentially be of great use to the neuroimaging community, and whose development is already quite mature and has a number of datasets ready to use online. Neuroscout as a tool will be of particular interest to neuroimagers and cognitive neuroscientists, but the conclusions drawn using the tool should be of interest to neuroscientists more broadly.

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Evaluation Summary:

A pathogen's generation interval directly affects estimates of its transmissibility (R), and the period of self-isolation or quarantine needed to prevent transmission. This study shows that the unmitigated generation interval of the original variant of SARS-CoV-2 is several days longer than previously estimated and that interventions have substantially decreased the effective generation interval. These findings improve our ability to model counterfactual intervention-free scenarios. Overall technically sound analyses support the conclusions, and extensive sensitivity analyses show that the findings are robust. However, sampling or ascertainment bias in this relatively small pre-intervention dataset or biased inputs could affect the accuracy of the reported estimates.

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Evaluation Summary:

This manuscript describes randomly generated small proteins of <50 amino acids that can rescue the growth of an auxotrophic mutant of Escherichia coli. The authors suggest that these proteins function by binding specifically to a regulatory element in the 5' UTR of the his operon RNA, altering RNA structure to increase expression. The study suggests that functional small proteins can evolve de novo and that newly evolved small proteins can function as regulators by binding RNA. This is an exciting idea, but the suggested mechanism involving the binding of the small proteins to RNA requires additional experimental support.

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Evaluation Summary:

This manuscript could be of interest to physicians and researchers in the field of vascular anomalies. The cohort of patients with lymphatic malformations is reasonably sized (n=30) and the claims made by the authors are supported by the data as well as by current knowledge in the field.

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Evaluation Summary:

This manuscript analyzes human blastocysts from in vitro fertilization for three subjects (a total of 55 blastocysts), demonstrating transmission of mosaic mutations at close to expected frequencies. These studies are the first of their kind and of translational relevance for the field of clinical genetics and prenatal genetic testing, with the potential to contribute to strategies to reduce genetic disease risk in future offspring.

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Evaluation Summary:

This interesting study identifies why or how the integrated stress response pathway regulates cell recovery upon proteotoxic stress, which is especially interesting in cancer cells resistant to proteasome inhibitors. The authors conclude that translation initiation of mRNAs encoding microtubule cytoskeleton, centrosome and ATF5 proteins is necessary to recover from proteotoxic stress. This paper will make a strong contribution to the literature.

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Evaluation Summary:

Wang et al., present a thorough analysis of specific neuronal lineages in the early larval ventral nervous system with the objective to relate the birth order to circuit connectivity and function. The stated key findings of the work are (1) the identification of sharp temporal cohort divisions for the lineages under investigation, (2) synapse formation between neurons of different lineages and temporal cohorts, and (3) the observation that output neurons in this instance are born prior to input neurons. The study raises the question of to what extent these findings can be generalized.

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Evaluation Summary:

This manuscript is one of the first broad epigenetic analyses in lung development and will be of interest to not only lung biologists but also to the field of epithelial developmental biology. Using paired transcriptomic and epigenetic data, they have uncovered a vast repertoire of signaling mechanisms underlying lung development. These findings have opened up the field's opportunities to understand and study novel pathways and have further defined a role for PI3 kinase signaling in lung development.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

Clement and colleagues describe and illustrate the endocasts of six Palaeozoic lungfish genera from superb 3D fossil material, which are very informative for the understanding of brain evolution of lungfishes, the extant sister group to land vertebrates. Rendering important anatomical details regarding brain evolution in lungfishes, and sarcopterygians in general, this work will be of broad interest to zoologists, including vertebrate paleontologists and neuroanatomists.

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Evaluation Summary:

Giant dsDNA viruses, with genomes in excess of 1Mb that encode more than a thousand genes, were only recently discovered and their study offers new opportunities to understand life's evolved mechanisms. In this manuscript, Villalta and colleagues report results on one of the most complex known viruses, the Mimivirus. Its genome is compacted into magnificent fibers comprising apparently repurposed GMC-type oxidoreductase paralogs assembled as a helical coat around genomic dsDNA. Cryo-EM and cryo-ET image analysis yielded a structural model of the fiber in multiple states. The authors also provide some evidence that additional viral enzymes, including RNA polymerases, exist within the fiber assemblies. Pending the resolution of certain issues that emerged in peer review, the study will be of broad interest to biologists.

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Evaluation Summary:

The paper would be of interest to neuroscientists and clinician scientists interested in better understanding the mechanism of deep brain stimulation (DBS) in the treatment of Parkinson's disease. Using a combination of electrical artifact-free calcium imaging and electrical stimulation, it probes the effects of stimulation on the neural dynamics of basal ganglia structures that correlate with motor improvement. The key claims are well supported with a convincing discussion of the caveats of the methods used.

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Evaluation Summary:

McGregor et al. establish a new reinforcement learning paradigm for songbirds, where instead of auditory feedback (white noise) they use mild cutaneous electrical stimulation as a reinforcer. Their data shows that this somatosensory stimulus can aversively drive pitch changes of a targeted syllable in similar manners as an auditory stimulus does. They further show that the anterior forebrain pathway (AFP) and dopaminergic projections to the AFP are necessary for this non-auditory vocal learning by electrolytically lesioning the output nucleus of the AFP and by depleting dopaminergic input to Area X. Their analysis is rigorous and their data convincingly show shared mechanisms for vocal reinforcement learning using white noise (auditory) or cutaneous electrical stimulation (non-auditory).

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Evaluation Summary:

Aida et al use a combination of novel experimental measurements and data processing to wrangle the complexity of bacterial growth for different media conditions. This study represents a clear example tackling the complexity of biological systems from the condition sides (~13,000 growth curves were measured) influencing the growth of a well-defined single specie of bacterium and with a reasonable first pass at data processing. The findings are ultimately simple (with essentially 3 conditions accounting all variability in the system) and easily interpretable.

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Evaluation Summary:

This study provides novel evidence that a dopamine D2 receptor antagonist enhances model-based control of behavior, whereas blocking opioid receptors has no effect on the trade-off between habitual responding and goal-directed planning. These conclusions are based on compelling behavioral and computational modeling data and will be of interest to cognitive neuroscientists and computational psychiatrists.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

In this paper, the authors find a link between the emergence of functional connectivity (FC) and changes in regional Cerebral Blood Flow (rCBF) in human infancy from birth to 24 months of age, which will be of interest to the increasing field investigating how the establishment of the brain's functional organization is linked to neurodevelopmental and psychiatric conditions. The data quality and complementarity are impressive for infants over this developmental period (0-2 years). Most of the key claims of the manuscript are well supported by the data. However, the relatively sparse sample and cross-sectional nature does limit interpretation.

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Evaluation Summary:

This manuscript will be of interest to developmental biologists and pediatric cardiologists. Addressing the role of NR2F transcription factors in the fish heart, it provides novel insight into atrial chamber patterning and the formation of pacemaker cells. High-quality data are presented supporting the novel finding of a requirement of nr2f1a for restricting the production of pacemaker cells. Yet, data are currently not conclusive in claiming transdifferentiation of atrial cells in the mutants.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This is an interesting report using computational tools and large amounts of prospective samples from clinical trials to identify different signatures. Using data collected early in the infection in outpatients, the authors aim to identify a set of plasma proteins that can predict a number of outcomes, including disease progression, control of viral shedding, and the onset of antibodies during COVID-19. This study adds to the understanding of the host immune response against COVID-19, as well as the potential of computational tools for the molecular taxonomy of immune responses.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This study applies super-resolution imaging to the distribution of Ca2+ release channels before and after adrenergic stimulation. They make comparisons between healthy and failing cardiomyocytes. The results are specifically applicable to the understanding of contractile function in cardiac failure.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

Bistable visual perception offers a unique window to study how perception arises and changes via an interaction between bottom-up and top-down processes. In three Magnetoencephalography (MEG) experiments with advanced neural state space analysis, this study demonstrates that two key aspects of bistable visual perception - perceptual content and perceptual stability - are mediated by slow cortical potential (SCP) and alpha-beta-band neural oscillations, respectively. The findings would be interesting for many fields, such as perception, consciousness, and attention.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This is a well-designed study that will be of interest to cognitive neuroscientists studying event perception and memory, particularly those interested in naturalistic paradigms. The main contribution is in growing our understanding of how interpretational differences of events are reflected in differences in neural representations of those events. While the presented results are convincing, it remains somewhat unclear what processes drive the observed effects, and thus what the role of the implicated brain regions is in memory updating.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript presents a combination of in vivo recording and optogenetic experiments that together with modeling brings a significant message: inhibition is functionally present in the newborn frontal cortex having major effects in EEG dynamics. The work challenges the view on the switch in GABAergic excitation to inhibition and extends phenomenological observations to human infant EEG data.

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Evaluation Summary:

This paper combines evolution experiments with genomic analysis of environmental samples to study the evolution of colistin resistance in E. coli. It highlights the importance of pre-existing genomic variations in clinical strains in driving the evolution of antibiotic resistance. The results presented here are relevant for clinical and non-clinical microbiologists studying antibiotic resistance to last-resort drugs like colistin. The design of the research is simple and elegant, and the genomic data analysis connects the in vitro findings to the real world. However, the authors could better align the experimental and clinical data, and better clarify their experimental design choices.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

Vaccines are a major influenza control strategy in swine, but perform sub-optimally and are under-utilized. The manuscript describes a detailed genetic characterization of influenza virus variants in vaccinated versus unvaccinated pigs. The results indicate that viral reassortment, which is an important process yielding new strange of importance to man and animals, may be less common in pigs that have been vaccinated against influenza.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This is a systematic review by meta-analysis about the effect of calcium supplementation on bone health in people under 35 years old. The authors found that calcium supplementation can significantly improve BMD and BMC in young people. Moreover, a better effect of calcium supplementation was shown in people who are at the plateau of their PBM. A unique feature of this study is that it focused on people at the age before achieving PBM or age at the plateau of PBM, which is different from previous studies that mainly focused on the elderly or children.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This paper describes a new dotplot-based approach for analyzing Low Complexity Regions (LCRs) in proteins. The work is validated against a single protein, compared to existing methods, and applied to the proteomes of several model systems. The work aims to show links between specific LCRs and biological function and subcellular location, and study conservation in LCRs amongst higher species.

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Evaluation Summary:

Jia et al. present an exciting machine learning framework named "Selfee" for unsupervised and objective analysis of animal behavior that should draw broad interest from researchers studying quantitative animal behavior. However, there are some unresolved issues for establishing credibility of the method that needs to be addressed.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

The manuscript reports results of a combined experimental and numerical investigation of magnetotactic bacteria in strong spatial confinement and under the influence of an external magnetic field. Single cells are trapped in micrometer-sized microfluidic chambers. A variety of trajectories are found, which depend on the chamber size and the strength of the magnetic field. A detailed understanding of swimming in simple controlled confinement is essential to predict the behavior of motile microorganisms in the complex environments of their natural habitat.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This work offers a simple explanation to a fundamental question in cell biology: what dictates the volume of a cell and of its nucleus, focusing on yeast cells. The central message is that all this can be explained by an osmotic equilibrium, using the classical Van't Hoff's Law. The novelty resides in an effort to provide actual numbers experimentally.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript by Kosillo and colleagues presents a series of carefully carried out experiments evaluating the impact of perturbing the mTORC1 and mTORC2 protein complexes selectively in mouse dopamine neurons. By utilizing dopamine neuron-specific Raptor and Rictor cKO mice, this paper elucidated which of these mTOR complexes are responsible for the regulation of dopamine neuronal functions, revealing the importance of mTORC1/2 signaling for the structure and function of dopamine neurons. This paper provided comprehensive data including structural, physiological, and biochemical alterations by genetic deletion of Raptor/Rictor in dopamine neurons.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This paper is of broad interest to researchers studying chromosome structure. Using a powerful reconstitution system, the authors dissect the function of the chromosome organising complex, condensin II. Several findings, if supported by some additional analyses, are surprising and thus have the potential to fuel further mechanistic studies of condensin function.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

This study describes the correlations between different membrane properties and the size of the soma of spinal alpha-motoneurons (MNs) using data from 40 experimental in vivo studies. The authors have distilled decades of research on motoneuron properties into a set of mathematical relationships that can guide both experimentalists and modelers interested in developing realistic models of populations of motoneurons. The key result is a complete table of the empirical relationships between the anatomical and physiological properties of MNs. Overall, the dataset approach is interesting, although a detailed analysis of the variability within and between datasets is urgently needed. In addition, a simpler framing of the paper could make the main message easier to grasp.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

Kang et al. studied the role of cystathionine beta-synthase , an enzyme involved in homocysteine catabolism, in the senescent state imposed by oncogenic Akt. They find that this enzyme facilitates the acquisition of features of senescence, and is frequently silenced in tumors, whereas re-expressing it reduces cell proliferation. This manuscript is potentially of interest to cancer biologists, particularly those studying oncogene-induced senescence and mechanisms of senescence escape in cancers.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This work seeks to resolve questions surrounding "unexplained variability in functional recovery" after experimental spinal cord injury in mice using virus-based retrograde tracing from cervical, thoracic and lumbar spinal cord injection sites, tissue clearing and cutting-edge imaging, to develop a supraspinal connectome or map of neurons in the brain that project to the spinal cord. They apply their methods to understand the differences in the connections between the brain and the cervical or lumbar spinal cord and to compare the connectome from intact mice to those of mice with mild, moderate and severe spinal cord injuries. This work will be of interest to neuroscientists interested in tissue clearing, viral labelling, and its applications to spinal cord injury.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This paper very nicely tackles a methodological problem in aligning different types of datasets (EM and light microscopy) to image embryonic nervous system development in the nematode C.elegans. The paper is important not just from a methodological standpoint, but also provides novel insights into nervous system development that will be of general interest to the reader. The latter deserves more attention in the manuscript.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This paper will be of great interest to the field of developmental neuroscience and social communication. The authors identified prenatal sensorimotor vocal precursors by detecting rhythmic orofacial movements related to vocalizations. These findings will provide new insights into the development of vocal behavior in primates. The data acquired by a highly quantitative approach support the major claims of the paper.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)