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EXO1 has a structural role to promote the MLH1-MLH3 nuclease complex to process meiotic recombination intermediates into crossovers. Here, the authors demonstrate that EXO1 function depends on conserved interactions with the MSH4 subunit of MSH4-MSH5, the MLH1 subunit of MLH1-MLH3, and DNA.

Analyses of single-cell transcriptomic data from patients with VEXAS syndrome combined with xenotransplantation experiments in a mouse model of the disease provide insights on the mechanisms of clonal dominance of mutated cells leading to bone marrow failure

As is the case with humans, Helicobacter pylori shows genetic evidence of an origin in Africa and subsequent migrations to the rest of the world.

Robbiani and colleagues show that antibodies against specific chemokines are detected in COVID-19 convalescents and may modulate the inflammatory response and disease outcome.

Botanical extracts offer a valuable resource for identifying therapies. Zumerle, Sarill et al. show that a standardized extract of Salvia haenkei extends lifespan and healthspan in naturally aged mice by modulating inflammation and cellular senescence, and identify the constituent component luteolin as a senomorphic that disrupts the p16–CDK6 interaction.

Inactivation of pyruvate dehydrogenase A1 (PDHA1), a subunit of the pyruvate dehydrogenase complex (PDC) regulating mitochondrial metabolism, inhibits lipid biosynthesis and prostate cancer development in mouse and human xenograft tumor models.

Image background features can undesirably affect deep networks’ decisions. Here, the authors show that the optimization of Layer-wise Relevance Propagation explanation heatmaps can hinder such influence, improving out-of-distribution generalization.

Systemic light chain amyloidosis (AL) is caused by the production of toxic light chains and can be fatal, yet effective treatments are often not possible due to delayed diagnosis. Here the authors show that a machine learning platform analyzing light chain somatic mutations allows the prediction of light chain toxicity to serve as a possible tool for early diagnosis of AL.

The SAVE-MORE phase 3 study demonstrates the efficacy of anakinra, an IL-1α/β inhibitor, in patients with COVID-19 and high serum levels of soluble plasminogen activator receptor.

Understanding the dynamics of enzyme-substrate complexation provides an insight into potential drugs, but intermediate states are difficult to observe experimentally. Here, the authors use simulations and machine learning to analyse the binding of transition state inhibitors to purine nucleoside phosphorylase.

Stravalaci et al. examined recognition of SARS-CoV-2 by human soluble innate pattern recognition receptor. They report that pentraxin 3 and mannose-binding protein recognize viral nucleoprotein and spike, respectively. Mannose-binding lectin has antiviral activity, and human genetic polymorphisms of MBL2 are associated with more severe COVID-19.

Gene fusions involving the ERG transcription factor and point mutations in the ubiquitin ligase adaptor SPOP are two truncal mutations that are mutually exclusively present in prostate cancer. Here, the authors show that mutations in SPOP render prostate tumor cells sensitive to antiandrogen therapy and that the presence of ERG promotes sensitivity to high dose of androgen and SPOP inhibition.

Although the TMPRSS2-ERG gene fusion is the most common alteration in human prostate cancer, its involvement in disease progression remains unclear. Here, the authors demonstrate that ERG is methylated by Enhancer of zest homolog 2 leading to enhanced transcriptional and oncogenic activity.

In the Big Data era, a change of paradigm in the use of molecular dynamics is required. Trajectories should be stored under FAIR (findable, accessible, interoperable and reusable) requirements to favor its reuse by the community under an open science paradigm.

After its release, the endocannabinoid anandamide is taken up from the synaptic cleft by internalization by neurons and astrocytes. Although several lines of evidence suggest that the anandamide uptake itself is a carrier-mediated diffusion process, the molecular identity of the transporter was unknown until now. Here Fu et al. show that anandamide uptake is mediated by a novel protein named FAAH-like anandamide transporter (FLAT) that is generated as an alternative splicing product of the fatty acid amide hydrolase-1 (Faah) mRNA.

Photopharmacology manipulates the biological activity of small molecules by light. Using an X-ray laser, the authors follow the release of the drug azo-combretastatin A4 from tubulin and the concomitant structural changes over nine orders of magnitude in time.

A single-cell transcriptomic atlas from embryonal pons and forebrain provides insights into the developmental origins of pediatric brain tumors. The study identifies impaired differentiation of specific neural progenitors as a common mechanism underlying these cancers.

Transcriptional changes during prostate cancer progression are not yet fully understood. Here, the authors integrate a transcriptomics atlas of prostate cancer and validate it with preclinical models and single-cell RNA-seq, revealing the role of EZH2 and macrophage polarisation in tumour progression.

This study describes a class of small molecule compounds that promote ABCA1-dependent cholesterol efflux via a non-transcriptional mechanism, the identification of the molecular target by a chemical biology approach, and the potential of these agents for the treatment of chronic kidney diseases and potentially other diseases where lipid accumulation drives disease progression.

Focusing on two ill-characterized subtypes of medulloblastoma (group 3 and group 4), this study identifies prevalent genomic structural variants that are restricted to these two subtypes and independently bring together coding regions of GFI1 family proto-oncogenes with active enhancer elements, leading to their mutually exclusive oncogenic activation.

UNC5B is a Netrin-1 receptor expressed in endothelial cells that in the absence of ligand induces apoptosis. Here the authors identify an UNC5B splicing isoform that is insensitive to the pro-survival ligand Netrin-1 and is required for apoptosis-dependent blood vessel development.

Trypsin is a serine protease. Here the authors present the high resolution X-ray and neutron diffraction structures of uncomplexed and inhibitor bound trypsin that provide insights into the geometry of H-bonds in the active site of the enzyme and molecular dynamics simulations reveal the kinetics of ligand binding induced desolvation.

The NMR-derived structural model of the dynamic interaction between synaptotagmin-1 and the SNARE complex contributes to addressing the longstanding problem of how synaptotagmin-1 triggers neurotransmitter release.

A cryo-EM reconstruction with 2.2 Å resolution of the full-length RAD52 protein highlights the hydration shell of the DNA-binding region and the highly flexible C-terminal portion, obtained by combining SEC-SAXS and computational methods.

Intradialytic hypertension is not an uncommon complication in hemodialysis patients, and seems to be associated with adverse outcomes. This complex phenomenon is not well understood, and many uncertainties exist regarding its pathophysiologic mechanisms and appropriate treatment strategies. Many of the therapeutic approaches currently used come from expert recommendations rather than from the results of randomized clinical trials. In this Review, Locatelli et al. describe the possible pathophysiologic mechanisms of intradialytic hypertension, and consider potential treatment and management strategies.

The LifeTime initiative is an ambitious, multidisciplinary programme that aims to improve healthcare by tracking individual human cells during disease processes and responses to treatment in order to develop and implement cell-based interceptive medicine in Europe.