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Truncated version of adenylyl cyclase 3 acts as a cold-induced rheostat during long-term brown adipose tissue activation.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Thiophene S,S-dioxides are excellent substrates for cycloaddition reactions, but underused in target-oriented synthesis. Here the authors show how these heterocycles enable the asymmetric synthesis of tricyclic indolines, as well as the collective synthesis of the iconic Strychnos alkaloids. Computational studies rationalize the source of asymmetry and reveal a spontaneous SO₂ extrusion pathway.

Brown adipose tissue (BAT) thermogenesis counteracts obesity and promotes metabolic health. The role of long non-coding RNAs (lncRNAs) in the regulation of this process is not well understood. Here the authors identify a maternally expressed lncRNA, H19, that increases BAT oxidative metabolism and energy expenditure.

Giles et al. developed a method for noninvasive absorbance measurement of mitochondrial hemes to monitor the mitochondrial membrane potential in the perfused heart. They then applied this approach to show how the mitochondrial membrane potential changed during cardiac ischemia.

Pathogenic variants in UNC13A underlie a novel neurodevelopmental syndrome, with three subtypes defined by distinct genotypes with varying clinical and functional impacts characterized in cellular and animal models.

Synthetic cells have huge potential in model systems. Here, the authors engineer synthetic–living hybrid tumoroids that replicate tumour-immune interactions in 3D, study synthetic cells integration, and demonstrate systematic studies of immune evasion and T cell engager therapies.

Birds have evolved a unique sex chromosome dosage compensation mechanism involving the male-biased microRNA (miR-2954), which is essential for male survival by regulating the expression of dosage-sensitive Z-linked genes.

Hydrogen sulfide (H₂S) reversibly modifies low molecular weight and protein thiols to form persulfides (RSS⁻) and polysulfides (RS(S)nS⁻) for antioxidant defence and regulation of activity. Here, the authors report a sensitive LC-MS/MS procedure that separately traps and quantifies the sulfur atom of H₂S, the terminal sulfur atom of RSS and RS(S)nS-, and the internal sulfur atoms of RS(S)nS ⁻ as diagnostic products in biological samples.

A mass spectrometry-based approach globally identifies protein regulators of metabolism and reveals the role of LRRC58 in controlling cysteine catabolism.

Grasses have diverse inflorescence morphologies, but the underlying genetic mechanisms are unclear. Here, the authors report a TCP transcription factor COM1 affects cell growth through regulation of cell wall properties and promotes branch formation in non-Triticeae grasses but branch inhibition in barley (Triticeae).

Familial adenomatous polyposis (FAP) is an inherited gastrointestinal syndrome associated with duodenal adenoma formation. Here the authors show that IL17A-producing NKp44- group 3 innate lymphoid cells accumulate in FAP duodenal tissue and are associated with duodenal adenoma formation in patients with FAP.

Kornfeld and colleagues identify miRNAs that are dysregulated in brown adipose tissue in mouse models of obesity and ageing, and show that miR-328 targets Bace1 to promote brown adipogenesis.

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.

An integrated high-resolution genetic, physical and shotgun sequence assembly of the barley genome, one of the earliest domesticated and most important crops, is described; it will provide a platform for genome-assisted research and future crop improvement.

Stress on land is dynamic, entailing swift and drastic changes. Integrated time-course stress and co-expression analysis predict a gene regulatory network that retraces a web of ancient signal convergences shared by land plants and their algal sisters.

Single crystal diffraction is one of the most common and powerful tools for structural elucidation, but obtaining single crystals of adequate size and quality is not always trivial. Here, the authors report a method to crystallize inherently non-crystalline adamantane-like organic-inorganic clusters using π-π interactions between C₆₀ and nano-sized molecules.

Atomically thin transition metal dichalcogenides constitute an ideal platform to investigate solid state excitonic effects. Here, the authors provide experimental evidence of a localized biexciton in a monolayer of WSe₂, which induces an emission cascade of single photons.

Hegazy and colleagues demonstrate that epithelial oncostatin M receptor expression drives gut inflammation and tumor formation.

Heavier analogues of unsaturated organic molecules are of interest because of their bonding situation and their potential use in synthesis. Now, a Bi(I)-based allyl cation, which can be seen as a heavy congener of all-carbon π-allyl cations, has been reported. This complex serves as a synthon for Bi(I) transfer, enabling access to low-valent organobismuth compounds.

A 43-year dataset of rodents in the Hu region of China reveals how urbanization-induced changes to land-use configuration affect rodent community composition, including benefitting striped field mice, the primary local hosts of the zoonotic pathogen Hantaan virus.

Robbie Waugh, Nils Stein, Gary Muehlbauer and colleagues report the exome sequencing of 267 landraces and wild accessions of barley from diverse regions to study adaptations to different agricultural environments. They observe correlations of days to heading and height with environment and find that variation in flowering-associated genes has strong geographical structuring.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

The actin-spectrin meshwork constitutes a ubiquitous element of the cell cytoskeleton that may be organized in different architectures. Here, the authors observe in fibroblasts periodic arrays of spectrin only previously seen in neurons, and highlight their role in mechanically protecting the cell cortex.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

Inborn errors of the alternative NF-κB pathway in humans impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases

Roles of specific synaptic proteins in postsynaptic organization revealed by acute, Auxin-Inducible Degron 2 Technology-mediated degradation of synaptic fusion proteins, combined with real time measurements of consequences at individual synapses.

Lupu, Grainger, Kirschnick et al. show that, contrary to prevailing belief, the initial specification of mammalian lymphatic endothelial cells primarily occurs from previously unidentified mesenchymal angioblasts rather than from venous endothelium.

An activator of DNA polymerase γ restores function to disease-causing mutant variants and demonstrates a potential route to treatments for inherited mitochondrial disorders involving POLG mutations.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

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.

The sorting and assembly machinery (SAM) mediates mitochondrial β-barrel protein folding and membrane insertion. A cryo-EM structure of the yeast SAM complex bound to an early eukaryotic β-barrel intermediate reveals a multipoint guidance mechanism.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

A genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

A single exometabolite produced by an opportunistic bacterial pathogen of the root microbiome enhances host susceptibility to salt stress and promotes plant disease in complex soil systems.

The SRP-type GTPase FlhF modulates the localization and quantity of flagella in bacteria through unclear mechanisms. Here, the authors show that FlhF interacts with the polar landmark protein HubP and the flagellar C-ring protein FliG, thus restricting the formation of developing flagellar structures to the cell pole.

Stress is recognized as risk factor for the development of type 2 diabetes. Here Balsevich et al. show that the stress responsive co-chaperone FKBP5 regulates glucose metabolism in mice by modulating AS160 phosphorylation, glucose transporter expression and muscle glucose uptake.

A climatic record from desert speleothems shows that the central Arabian interior experienced recurrent humid intervals over the past 8 million years, which likely facilitated mammalian dispersals between Africa and Eurasia.

The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies.

Multiview light-sheet microscopy is a powerful tool for imaging relatively large biological samples over long periods of time, but scattering can limit image quality. Here, the authors combine multiview light-sheet imaging with electronic confocal slit detection to improve image quality, double acquisition speed and streamline data fusion.

This Review highlights recent advances in polyploid genome analysis and breeding, emphasizing methodological innovations and the importance of deciphering genome complexity to accelerate genetic improvement in polyploid crops.

Using a high-quality chromosome-scale assembly of the faba bean genome, the genetic basis of seed size and hilum colour is explored.