Evaluated articles

eLife assessment

The bacterial neurotransmitter:sodium symporter homoglogue LeuT is an well-established model system for understanding the fundamental basis for how human monoamine transporters, such as the dopamine and serotonin, couple ions with neurotransmitter uptake. Here the authors provide convincing data to show that K+ binding on the intraceullular side catalyses the return step of the transport cycle in LeuT by binding to one of the two sodium sites. The mechansitic consequences of K+ binding could either facilitate LeuT re-setting and/or prevent the rebinding and possible efflux of Na+ and substrate.

eLife Assessment

This fundamental study examines whether synaptic cell adhesion molecules neuroligin 1-3 resident on astrocytes, rather than neurons, exert effects on synaptic structure and function. With compelling evidence, including rigorous validation of neuroligin deletion efficiency in astrocytes and independent confirmation using human neuron-mouse glia co-cultures, the authors report that deletion of neuroligins 1-3 specifically in astrocytes does not alter synapse formation or astrocyte morphology in the hippocampus or visual cortex. This study provides definitive evidence highlighting the specific role of neuronal neuroligins rather than their astrocytic counterparts in synaptogenesis.

eLife assessment

This valuable study investigates how hierarchies are processed in the brain, using a paradigm that intends to bridge disparate domains (e.g., language/music and memory). The main findings are that hippocampus and medial prefrontal cortex are sensitive to hierarchy position, while the response in inferior frontal gyrus seems to vary with amount of experience with the hierarchy. Evidence supporting these claims is solid, and would be strengthened by additional methodological clarifications (e.g., as to why the particular analyses are most appropriate for the research question) and further discussion of limitations related to the study design (e.g., the possibility that the task does not require hierarchical representations).

eLife assessment

The manuscript describes the synergy among PI3Kbeta activators, providing compelling results concerning the mechanism of their activation. The particular strengths of the work arise to a great extend from the reconstitution system better mimicking the natural environment of the plasma membrane than previous setups have. The study will be a landmark contribution to the signaling field.

eLife assessment

This manuscript describes a fundamental strategy for developing isozyme-selective inhibitors of inositol hexakisphosphate kinases. The compelling evidence that subtle changes to the gatekeeper position can sensitize the inositol hexakisphosphate kinase mutant to allosteric inhibitors will undoubtedly inspire other analog-sensitive inhibitor studies. This manuscript will be of interest to researchers focusing on kinase regulation and inhibitor design.

eLife assessment

This is an important study highlighting a distinct role of WASP dependent actin foci in B cell antigen receptor signalling. The evidence supporting the conclusions is compelling. The proposal of higher molecular density in B cell receptor clustering leading to kinase exclusion and attenuated signalling is provocative as it contrasts with models for other antigen receptors.

eLife assessment

This study presents fundamental findings on the role of transcription readout and intron retention in transposon expression during aging in mammals. The evidence supporting the claims of the authors is compelling, strongly supporting the authors' claims. The work will be of interest to scientists studying aging, transcription regulation, and epigenetics.

eLife assessment

There was a range of opinion among three highly expert reviewers from different perspectives in the field. This is a significant topic and it was felt that the contribution at present is valuable to those in the field. However, it was agreed after consultation that the description of the simulation methodology was inadequate.

eLife assessment

This important study advances our understanding of the potential mechanisms of deep-sea adaptation and sheds light on the evolutionary history of hadal snailfish. Through comparative genomic analysis, the authors provide convincing evidence and propose hypotheses on the timing of trench colonization, population structure, and adaptations to the hadal snailfish genome in response to their environment.

eLife assessment

The authors pair single-cell sequencing technology with the LoopSeq synthetic long-read method to examine samples of hepatocellular carcinoma and benign liver, with the goal of identifying mutations and fusion transcripts specific to cancer cells. The authors present a valuable resource and the overall support for the major claims is solid.

eLife assessment

The authors present a solid statistical framework for using sibling phenotype data to assess whether there is evidence for de-novo or rare variants causing extreme trait values. Their valuable method is promising and will be of interest to researchers studying complex trait genetics.

eLife Assessment

This useful study examines relationships between tumor mutational burden and the response to immunotherapy, using new data sets along with publicly available data sets. The authors conclude that tumor mutational burden cut-offs are unreliable proxies for predicting the response to therapy, underpinned by solid evidence, but with several caveats and assumptions that leave the central question subject to further inquiry. In summary, this is an interesting study that adds to a growing body of work investigating the particular conditions governing the effectiveness of immunotherapy.

eLife assessment

This work presents important findings on the cellular and ultrastructural organization of the nervous system in the freshwater polyp Hydra. The authors present outstanding imaging data with convincing evidence to support their claims. The manuscript provides a starting point for further functional in vivo studies. The work will be of interest to developmental biologists and neurobiologists.

eLife assessment

This important study reports on a new method for the fabrication and the analysis of the transport through nuclear pore complexes mimic. Methods, data and analyses are convincing and show a clear correlation between the size of the nuclear pore complex mimic and its transport selectivity. This work will be of high interest to biologists and biophysicists working on the mechanosensitivity of nucleocytoplasmic transport.

eLife assessment

This valuable study examines the effects of different co-stimulatory pathways on gene expression and chromatin accessibility in T cells, in order to link the role of co-stimulatory proteins to genetic variants associated with inflammatory bowl disease (IBD). The work provides valuable insight into the role of alternative co-stimulatory proteins in controlling T cell responses. However, the data presented and the analyses performed are still incomplete and inconclusive with regards to IBD risk factors.

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

The authors generate a new formulation built upon a previous nanoparticle platform to generate a new system termed bicontinuous nanospheres (BCN), allowing for the dual incorporation of lipid and protein antigens. The authors generate mycolic acid (MA)-loaded BCN and perform a series of characterization studies to demonstrate the superior performance of this new formulation relative to the original one in terms of antigen persistence, a quality needed to sustain responses after vaccination. This work provides important new insights relevant to the TB vaccine field and it suggests that alternative antigens to proteins could be used in TB vaccine formulations. The data are convincing and will be of interest to individuals working on tuberculosis, vaccines and basic immunology.

eLife assessment

This is important work that examines hepatic acetate production via ACOT12/18 in starvation and diabetes. The investigators use solid loss of function strategies in cells, including mouse primary hepatocytes, and in vivo mouse experiments to show that ACOTs are necessary for normal acetate production in the context of fasting and type 1 diabetes. Given that acetate is commonly thought to primarily represent a fermentation product, this study is of interest as it describes hepatic pathways converting fatty acids to acetate.

eLife assessment

This paper will be of interest to scientists in the fields of virology, entomology, ecology and epidemiology as the paper explores the drivers of viral and host composition in natural and disturbed ecosystems. The data are of high quality and have been rigorously assessed.However, important additional information on the transmission ecology of these viruses and their relationship with the environment is lacking, making it difficult to interpret the results from a disease ecology perspective.

eLife assessment

The authors compellingly demonstrate that k-fiber length and dynamics are regulated at the level of individual fibers, even in the absence of focused poles, but that unfocused spindles fail to accurately segregate chromosomes, suggesting that coordination of k-fiber length by pole focusing is important for spindle function. This study provides important new information on spindle scaling, extending in an original manner previous work on this topic.