Evaluated articles

eLife assessment

This impressive study presents the most comprehensive analysis of the Argonautes, their small RNA partners, their targets, and their biological functions in any species to date. The work provides new insights into Argonaute-based pathways, it includes extensive validation of existing models, and describes overall a treasure-trove of reagents and datasets for future exploration of the vast Argonaute world in C. elegans.

eLife assessment

This study presents important findings on the hunting strategies and energy intake of a bat in the wild. It combines several methods (biologging, captive experiment, and DNA metabarcoding) to provide convincing evidence for the claims. While relevant for researchers in the broad field of animal ecology, in its the current form, the significance of the results may be hard to appreciate for a general audience.

eLife assessment

In this study, the authors presented the novel findings that PTH signaling plays a significant role in bone formation in hypertrophic chondrocyte (HC)-derived osteoblasts and MMP14 cleaves PTH1R and inhibits PTH signaling. These studies significantly contribute to our understanding of molecular mechanisms of postnatal bone formation and adult bone remodeling, especially the HC cells in this process. The study was well-designed and well-conducted. The data in this study are convincing and support the conclusion made by the authors.

eLife assessment

This paper should be a high priority for neuroscientists interested in the role of connectivity in generating cognitive functions, especially with respect to the cerebellum (which has more neurons than any other part of the human brain). This study makes a compelling case for convergent connectivity from cortex to cerebellum supporting a variety of cognitive functions in the cerebellum. However, insufficient details were provided for proper evaluation of claims, and some of the claims (such as directionality of cortico-cerebellar inferences) may not be supported by the analyses.

eLife assessment

This very well-written paper advances our understanding of the mechanism of activation of the thrombopoietin receptor (TpoR), a very important cytokine receptor that regulates megakaryocyte differentiation and platelet production. The authors supply an elegant combination of NMR and cell biology experiments to support their conclusions and the data are of high quality.

eLife assessment

This important study reports the physiological role of Ssh2 in spermatogenesis as a critical factor for acrosome biogenesis. Loss of SSh2 in round spermatids prevents the fusion of proacrosomal vesicles leading to fragmented acrosomes due to impaired actin bundling and dephosphorylation of COFILIN. This work would be more convincing if mutations in this gene could be identified in human infertile men. Moreover, the proposed mechanism needs cross-validation in future work.

eLife assessment

This paper is of potential interest for scientists who study bone marrow stem/progenitor cells, bone remodeling, and metabolism. Using Adipoq-Cre-based conditional deletion of Csf1 and scRNA-seq approaches, the authors provide compelling evidence that a subset of cells in murine bone marrow, characterized by AdipoQ expression, are a major source of M-CSF to regulate osteoclast formation and bone remodeling. This is a well-written, well-executed set of studies, the data from which largely support the above key claim.

eLife assessment

This study presents an important reanalysis of a prior dataset testing effects of D2 antagonism on choices in a delay discounting task. While the prior report using standard analyses showed no effects, the current study used a DDM to examine more carefully possible effects on different subcomponents of the decision process. This approach revealed compelling evidence of contrasting effects of D2 blockade on the effect of reward size differences and bias on choice behavior, findings which should be of broad interest to neuroscientists trying to understand dopamine function or the factors influencing choice behavior.

eLife assessment

Humanized transgenic mice represent an important tool for antibody discovery and vaccine profiling but their similarity to human immune responses has not been established so far. In this manuscript, Richardson et al. comprehensively characterize IgH repertoires of Ky mice that carry human immunoglobulin heavy (IgH) and light chain (Igk and l) genes. The data presented here will be useful for setting a foundation for the use of this model, as well as other similar transgenic models, in future studies.

eLife assessment

This is a valuable contribution to the SARS-CoV-2 modelling literature that will be of interest to infectious disease modellers studying the impact of spatially heterogeneous interventions for transmission control. The calibration and analysis of the proposed model is sound and and the results provide convincing evidence that supports the claim that localised interventions could potentially reduce societal impact while maintaining outbreak control. However, the paper provides little insight into what drives the regional diffusion in the Netherlands and how that diffusion could be affected by local lockdowns and a more thorough exploration of the model is warranted. There is also an opportunity to consider behavioural consequences, feasibility, and potential ethical implications of the proposed approach in greater depth.

eLife assessment

The effect of helminth infection on vaccination against tuberculosis infection and disease is an important area of study. In this manuscript, the authors build off of a large body of prior data showing that mycobacterial antigens upregulate MINCLE whilst the cytokine IL-4 downregulates MINCLE. As IL-4 is upregulated during Helminth infections, this can antagonize Th1/Th17 responses. By using two different models of helminth infection, the authors demonstrate an organ-specific impairment of Th17 responses in a vaccination setting with a MINCLE-dependent adjuvant. The work is topical and may have important translational implications for patients with tuberculosis and helminth co-infections and/or vaccination regimens for patients with helminth infections. The study will be of interest to individuals studying the convergence of different infectious diseases.

eLife assessment

Scientists had previously discovered that humans and neanderthals mated leading to parts of neanderthal DNA becoming part of the human genome today. More recently, it was found that a genetic region, carrying which has been associated with manifestation of severe COVID-19 symptoms, is one that was "introgressed" into humans from neanderthals. This region contains many genetic variants, and this study set out to identify which of these genetic variants may be causally involved in creating severe symptoms in response to COVID-19 infection. The main critiques of the study stem from details of the functional assays to establish the regulatory role of the 4 variants in creating severe COVID-19 symptoms. In particular, the two genes (critical chemokine receptor genes: CCR1 and CCR5) that the authors identify as down-regulated by these variants are actually up-regulated in severe COVID-19 patients, leading to doubt about the role of these variants in changing response to COVID-19 through the regulation of these genes. In that regard, it seems necessary to conduct follow-up experimental and computational analyses to establish the role of these variants in altering CCR1 and CCR5 gene expression.

eLife assessment

Host directed therapies (HDTs) have the potential to improve management of tuberculosis (TB) through shortening of the duration of standard 6-month chemotherapy and promoting recovery of respiratory sufficiency. Several such agents have come to the fore recently and in this study, the authors investigate the use of sertraline (SRT) and demonstrate that it potentiates the activity of anti-tubercular drugs in macrophages as well as in the murine model of TB infection. The authors propose a model whereby SRT acts through modulation of the inflammasome.

eLife assessment

The purpose of this study was to determine whether heme oxygenase -2 deficiency translates to deficiencies in motor neuron function. This paper plays a plausible mechanism by which heme oxygenase-2 deficiency can lead to obstructive apneas. Indeed, this is among the first papers to comprehensively describe a signaling pathway in motor neurons and the consequences of its deficiency. Furthermore, the work completed here may be relevant to other diseases in which motor neuron signal transmission is a key contributor.

eLife assessment

This study presents a valuable finding that the combined use of pyrotinib with dalpiciclib exhibits better therapeutic efficacy against HER2+/HR+ breast cancer cells. The evidence supporting the claims of the authors is rather solid. The work will be of interest to medical biologists and clinical doctors working on breast cancer.

eLife assessment

Upregulation of PCA3 and downregulation of PRUNE2 in prostate cancer were first discovered in this work, which innovatively demonstrated that PCA3 and PRUNE3 function as an oncogene and a tumor suppressor gene respectively. The conclusion is further enhanced by the use of two distinct patient cohorts, which highlights the clinical significance. Functional experiments will be needed to more comprehensively validate the findings.

eLife assessment

This valuable study by Sonobe et al uses transfected cells and patient iPSC-derived neurons to define mechanisms underlying translation of the antisense C4G2 RNA strand expressed in C9orf72-associated ALS and FTD. The authors design a series of constructs to explore the start codon required to produce toxic PR and prominent PG dipeptides in disease. Using these constructs they provide solid data that translation in the PR and PG reading frames occur due to the presence of AUG codons within the 5'UTR of the RNA strand. However, in its current form the paper is incomplete and the conclusions require additional experimental support.

eLife assessment:

This important study describes converging cellular phenotypes in human neural progenitor cells derived from individuals with differing genetic forms of autism spectrum disorders. These convincing data demonstrate that altered mTOR signaling occurs in all cases of autism examined in the study, providing a common starting point for understanding the etiology of neuronal deficits in autism. The work will be of broad interest to neurobiologists especially those studying molecular mechanisms of brain development and disease.

eLife assessment

This important study presents an interesting example of how complexities of communities may be reduced by showing that the joint effects of two or more species on a focal species are generally not additive, but rather dominated by the strongest single effect. The evidence, enabled by over 14,000 measurements using nanodroplet-based microfluidics, is compelling, although the generality of the conclusion awaits further studies. This paper is of interest to microbial ecologists.

eLife assessment

The work of Caspy and coworkers resolves the cryo-EM structures of stacked and unstacked PSII supercomplexes of Dunaliella, revealing unexpected connectivity and conformational flexibility, with intriguing implications for the function and regulation of photosynthesis.