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Shukla and colleagues study the genomic and transcriptomic data of exceptional responders to immunotherapy in renal cell carcinoma and find that such responses could be related to tertiary lymphoid structures, clonal neoantigen load and altered metabolism.

The Legionella effector DrrA AMPylates the host protein Rab1 during infection, but the mechanism is still under debate. Here, the authors provide structural insights into the low-affinity DrrA:Rab1 interaction, showing that Rab1 allosterically activates DrrA through a non-conventional binding mechanism.

In this work, the authors report that heparin oligosaccharides have a significant impact on the highly dynamic behaviour of netrin-1 by inducing hierarchical and distinct super assemblies leading to unique, yet unknown netrin-1 filament formation.

Morphological changes in kidney glomerular ultrastructure and altered compression of the glomerular basement membrane are shown to correlate with albuminuria.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases such as chronic kidney disease (CKD). Here, the authors perform a sex-stratified, cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits, with results including identification of four novel loci associated with the CKD-defining trait eGFR.

Loading of antigenic peptides onto MHC-I is essential for adaptive immunity and requires the protein Tapasin. Here, the authors demonstrate that Tapasin levels are controlled by the RNF185/MBRL ERAD complex and that this process regulates MHC-I surface expression.

The environmental drivers of species diversity at the global level are difficult to define. This paper, using standardised methodologies, shows that the seasonality of primary production explains marine pioneer metazoan richness comparatively or better than other measures like sea surface temperature.

The Lon protease is an important protein degradation machine and is conserved across the three domains of life. Here, the authors describe a small proteotoxic stress-induced protein that functions as an allosteric activator of Lon.

The authors present the nearly-complete structure of the DT57C bacteriophage of the Siphovirus family, revealing the molecular architecture of its capsid, neck, tail and tail tip, and providing insights into the process of DNA ejection.

Prior studies have pointed to the role of spin-polarized hot electrons in ultrafast demagnetization. Here, by combining time and element resolved X-ray magnetic circular dichroism with theoretical calculations, Gupta et al quantitatively resolve both the effect of spin polarization and the current densities in ultrashort hot electron pulses.

T cell exhaustion was thought to be strictly associated only with chronic infections and tumours, but it turns out that acute infections also generate a subset of precursor T cells with exhaustion-like phenotypes.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

A trans-ancestry genome-wide association study of serum urate levels identifies 183 loci influencing this trait. Enrichment analyses, fine-mapping and colocalization with gene expression in 47 tissues implicate the kidney and liver as key target organs and prioritize potential causal genes.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Formation of urate and calcium pyrophosphate micro-crystals is responsible for painful inflammatory flares in gout and chondrocalcinosis. Here the authors show that the osmo-sensitive LRRC8 anion channel is involved with macrophage inflammasome activation by crystals involving cell volume regulation and ATP release leading to P2Y receptor activation.

Ultrafast quantum control of helium atoms is obtained by shaping the extreme ultraviolet pulses generated by a seeded free-electron laser.

Multi-omic analysis of a hiPSC-based CBFA2T3::GLIS2 leukemia model revealed the molecular characteristics of two alternative developmental trajectories: proliferative leukemogenic transformation or delayed, incomplete megakaryocyte differentiation.

The mechanism underlying packaging of the 8 segments of the influenza virus genome into virions is not well understood. Here, the authors use a multiplexed FISH assay to monitor the 8 segments in parallel in infected cells suggesting bundling routes during the packaging process.

DisCo is a deterministic droplet microfluidics tool for single-cell analysis on low cell input samples, which is demonstrated to profile individual intestinal organoids and in vivo-derived small tissues.

This paper develops two approaches for multiplexing cortical organoids and SCanSNP, a method for deconvolving cell identities, to trace neurodevelopmental trajectories at scale.

Defects in silicon carbide can act as single photon sources that also have the benefit of a host material that is already used in electronic devices. Here the authors demonstrate that they can control the distinguishability of the emitted photons by changing the defect spin state.

Inflammasome assembly promotes the cleavage and oligomerisation of gasdermin D (GSDMD) and subsequent pore formation. Here the authors raise nanobodies to human gasdermin and characterize the pore formation process mediated by GSDMD and how antagonistic nanobodies prevent pyroptosis.

Proteomic, transcriptomic, and genomic analysis has shown osteosarcoma (OS) to be a complex and heterogenous disease but revealed little about its carcinogenesis or potential therapeutic targets. Here, the authors profile the RNA interactome, transcriptome and proteome of cells derived from OS patients, identifying a targetable vulnerability to translation inhibition.

Here the authors report structures of pendrin, an anion exchanger, in complex with its substrate Cl⁻, I⁻, or HCO₃⁻, which reveal two anion binding sites in each protomer. The authors also identify binding sites of a pendrin inhibitor, niflumic acid.

The molecular joint of a nanorobotic arm can be wound up to store mechanical energy and then relaxed to drive the rotation of a DNA nanodevice.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

FLVCR2 is expressed in the blood–brain barrier of mouse and human, and is the major mediator of choline uptake into the brain.

HIV-1 hijacks a host ubiquitin ligase complex using viral infectivity factor Vif to degrade antiviral factor A3G. Here, Kouno et al. report the cryoEM structure of the A3G-Vif complex and A3G ubiquitination in vitro using solubility-enhanced variants.

A fundamental step in membrane protein biogenesis is their integration into the lipid bilayer with a defined orientation of each transmembrane segment. Here, the authors show that mutations in connexin 32 can cause failures in membrane integration which is detected by the ER chaperone machinery.

Miniature gut tubes grown in vitro from mouse intestinal stem cells are perfusable, can be colonized with microorganisms and exhibit a similar arrangement and diversity of specialized cell types to intestines in vivo.

Childhood acute lymphoblastic leukemia is characterised by a range of genetic aberrations. Here, the authors use multi-omics profiling of ALL cell lines to connect molecular phenotypes and drug responses to provide an interactive resource of drug sensitivity.

One third of all epilepsies are treatment-resistant. Here, the authors show in a genetic model of epilepsy that a repurposed drug can correct cell defects, brain circuits and seizure-like events by accelerating endocytosis.

Serine 118 phosphorylation drives conformational changes through the disruption of hydrophobic interactions between aromatic-rich clusters, showing how hydrophobic mutations can restore oestrogen receptor-mediated transcription.

The mechanisms directing chromatin remodeling complexes to genomic regions have remained elusive. Here, the authors show that lncRNAs direct SWI/SNF to cell type-specific enhancers, investigating an RNA-mediated layer of targeting specificity.

X-ray crystallographic analysis reveals features of the tandem catalytic domains of histone deacetylase 6 (HDAC6), their inhibition by small molecules and functional insights into the enzyme's role in tubulin deacetylation.

Antibiotic persisters are phenotypic variants within an isogenic bacterial population that are transiently tolerant to antibiotic treatment. Here, the authors provide evidence that cytoplasmic acidification, amplified by a compromised respiratory complex I, can act as a signaling hub for perturbed metabolic homeostasis in antibiotic persisters.

Serology is an important way to monitor SARS-CoV-2 infection in the population and support vaccine development. Here the authors develop a multiplex immunoassay including spike and nucleocapsid proteins of SARS-CoV-2 and the endemic human coronaviruses with high specificity and sensitivity.

Characterizing proteases in their native environment is still challenging. Here, the authors develop a proteomics workflow for analyzing protease-specific peptides from cell lysates in 96-well format, providing mechanistic insights into blood proteases and enabling the prediction of protease substrates.

Excitation using rotating polarized light and detection of periodic signals from rectangular nanoareas allows widef-ield super-resolution imaging of biological structures in cells and in tissue with reduced background.

An approach based on the average trajectory of moving particles allows for the quantification of the mechanics of living systems, namely, the non-equilibrium energy and viscoelastic properties of cells, in a non-invasive manner.

Clones expressing variants of the X-chromosome-linked STAG2 gene only form lymphocytes in the absence of Stag2^WT clones. Interactions between epigenetic clones can thus modulate the impact of X-chromosome-linked genetic diversity in a cell-type-specific manner.

Buparlisib/BKM120 is in phase 3 clinical trials as a phosphoinositide 3-kinase (PI3K) inhibitor. Here, Bohnackeret al. combine chemical biology and structural biology approaches to segregate BKM120’s biological actions, and suggest that it causes mitotic arrest predominantly by binding microtubules and disrupting their dynamics.

Here, the authors probe the mechanism of secondary nucleation inhibition of the BRICHOS domain of the lung surfactant protein (proSP-C) against α-Syn aggregation and amyloid formation using NMR and super-resolution fluorescence microscopy.

In real-world spatial navigation and observation tasks, oscillatory activity in the human brain encodes representations of self and others, with oscillatory power increasing at locations near the boundaries of the room.

Christenson et al. describe hue-selective neurons in the fruit fly optic lobe. Using a connectomics-constrained model combined with genetic manipulations of the circuit, they show that recurrent connections are critical for hue selectivity.