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A20, encoded by TNFAIP3, is a negative-feedback inhibitor of NF-κB. Grey and colleagues identify natural human variants of TNFAIP3, which lower A20 activity and increase autoinflammatory responses. These alleles were inherited by descendants of Denisovans who crossed the Wallace Line to inhabit Oceania.

Vespignani and Smyth present an economic theory of risk in critical minerals they term the “back-ended risk premium.” They apply AI approaches to reduce this risk premium and lower costs in energy transition.

Cryo-electron microscopy structures of NMDA receptors in open and apo states reveal the molecular mechanism underlying the dual ligand requirement for its channel gating and opening.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

Familial myeloid malignancies have recently been classified as separate disease entities. Here, using whole-exome sequencing of affected pedigrees - the authors highlight genetic variants associated with these conditions.

Edge conductance plays a central role in the electronic transport properties of graphitic interfaces. Here, the authors present a method to distinguish edge from bulk transport in twisted graphitic junctions and show that their relative contribution depends on the stacking configuration and the potential drop across the interface.

PAPP-A substrate selectivity underlies the tight regulation of IGF signaling. Here, the authors report cryo-EM structures of dimeric PAPP-A in its substrate-free form and in complex with a peptide substrate, which combined with biochemical assays provide a mechanism for PAPP-A substrate binding and selectivity.

Here, Simwela et al. perform a whole genome CRISPR/Cas9 screen on Mycobacterium tuberculosis infected primary macrophages and identify the GID/CTLH complex as a modulator of host cell physiology capable of promoting bacterial survival and growth.

The tau protein is theorized to spread transneuronally in Alzheimers disease, though this theory remains unproven in humans. Our simulations of epidemic-like protein spreading across human brain networks support this theory, and suggest the spreading dynamics are modified by β-amyloid

Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.

Antigen-activated B cells are short lived in the absence of a second signal provided by CD4⁺ T cells or cytokines. Zikherman and colleagues report that the NR4A family of nuclear receptors (NUR77 and NOR-1) are responsible for enforcing this ‘tolerance’ to self-antigen (signal 1 only) and explain, in part, why B cells are dependent upon a second signal.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

Cells sense mechanical force through PIEZO1 channels. Here, authors show that both microgeometry and aspiration force mediate the PIEZO1 activity, and also alter F-actin organization, further amplifying PIEZO1 activity along membrane.

HMG-CoA reductase (HMGCR) is regulated by UBIAD1 and Insigs and initializes cholesterol synthesis. Here authors show that the sterol sensing domain of HMGCR undergoes conformational changes to regulate its degradation via binding its protein modulators.

Although Huntington’s disease (HD) is a well-studied genetic disorder, less is known about the epigenetic changes underlying it. Here, the authors characterize DNA methylation levels in tissues from patients, a mouse huntingtin (Htt) gene knock-in model, and a transgenic HTT sheep model, and provide evidence that HD is accompanied by DNA methylation changes in these three species.

Temporal multi-omic analysis of tissues from rats undergoing up to eight weeks of endurance exercise training reveals widespread shared, tissue-specific and sex-specific changes, including immune, metabolic, stress response and mitochondrial pathways.

The Sequencing Quality Control (SEQC) consortium shows that junction discovery and differential gene expression profiling with RNA-seq can be robust but transcript-level and absolute measurements remain challenging.

Biological sex affects all aspects of animal physiology. Using the model C. elegans, the authors show that metabolomes are highly sex-specific and include a vast space of yet unidentified metabolites that may control development and lifespan.

Earlier methods for droplet network stabilization require extremely precise control and manipulation with considerable energy consumption, making them difficult to implement. Here, the authors present 2D interfacial networks, formed by irreversible interfacial interactions between polymer chains dissolved in one liquid and ligands dissolved in a second immiscible liquid at random points along the chains.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Results of the TRACERx study shed new light into the association between body composition and body weight with survival in individuals with non-small cell lung cancer, and delineate potential biological processes and mediators contributing to the development of cancer-associated cachexia.

Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.

Cell fate commitment involves transcription factor activity and changes in chromatin architecture. Here the authors show that CAF-1 maintains lineage fidelity by controlling chromatin accessibility at specific sites; suppressing CAF-1 triggers differentiation of myeloid stem and progenitor cells into a mixed lineage state.

John Chute and his colleagues show that the cytokine EGF protects mouse bone marrow hematopoietic stem cells from radiation injury. EGF signaling in these cells inhibited cell death through repression of the proapoptotic protein PUMA. EGF administration rescued mice from death after total-body irradiation, suggesting a new therapeutic strategy for radioprotection.

In the TRACERx cohort of 171 patients with lung cancer, the ultrasensitive detection of ctDNA improves preoperative patient stratification, also in early-stage disease.

Magnetotail reconnection plays an important role in explosive energy conversion. Here, the authors show direct evidence of super-thermal electrons up to 300 keV within X-line region in Earth’s magnetotail, indicating effective electron acceleration due to turbulence.

Multiomics analysis of right colon tissues identifies a distinct immune gene signature associated with greater risk of and shorter time to dysplasia in patients with primary sclerosing cholangitis, but not in patients with inflammatory bowel disease.

Zikherman and colleagues uncover a new mechanism by which B cells recognize virus-like antigen display as a stand-alone danger signal (independent of nucleic acid cargo) that does not rely exclusively on avidity and BCR cross-linking.

Sta Maria et al. use 2D MRI to study brains from mice deficient in Mbnl1 and/or Mbnl2 as these Muscleblind-like proteins are thought to play a role in Myotonic Dystrophy Type I (DM1). They show brain region-specific reductions in white and gray matter that could help to explain the variability in the brain structural alterations reported in DM1.

Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.

Systematic characterization of longitudinal tau variability in human Alzheimer’s disease using an unbiased subtyping algorithm reveals four trajectories of tau deposition with distinct clinical features.

Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

Individuals with Chuvash polycythemia have an increased red blood cell count and are prone to developing blood clots. Although mutations affecting the VHL protein are known to be causative, the underlying molecular mechanisms have been unclear. Ryan C Russell et al. now show that VHL targets the key signaling molecule JAK2 for degradation by forming a complex with the SOCS1 protein. The authors also show that JAK2 inhibition has beneficial effects in a mouse model of this disease, pointing to a new therapeutic strategy.

The interplay between amyloid and tau pathology in Alzheimer’s disease is still not well understood. Here, the authors show that amyloid-related increased in soluble p-tau is related to subsequent accumulation of tau aggregates and cognitive decline in early stage of the disease.

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.

Although head direction cells are known to encode information related to an organism's heading, it is unclear how the brain integrates this with information provided by fixed environmental features. In this study, the authors show that the retrosplenial complex is important for encoding heading and facing direction based on local landmarks and that this process generalizes across different environments that have similar geometry.

Monica Justice and colleagues performed a genetic suppressor screen in Mecp2-null mice, which recapitulate symptoms of Rett syndrome, a neurological disease with autistic features. They identify a nonsense suppressor mutation in Sqle, which encodes a rate-limiting enzyme in cholesterol synthesis, and show that treatment of Mecp2 mutant mice with statins improves symptoms and increases longevity.

Gilean McVean and colleagues report the results of a large-scale clinical genome sequencing project spanning a broad spectrum of disorders. They identify factors influencing successful genetic diagnosis and highlight the challenges of interpreting findings for genetically heterogeneous disorders.

Tumour heterogeneity in clear cell renal cell carcinoma (ccRCC) remains to be investigated. Here, the integration of spatial omics, transcriptional and chromatin accessibility profiling at the single-nucleus level and bulk proteogenomics data reveal markers and pathways important for ccRCC.

Genetic fine-mapping and CRISPRi screens identify functional variants and their target genes associated with Alzheimer’s disease in microglia. The variant rs7922621 modulates AD risk through control of TSPAN14 expression in this cell type.

Implementing point spread function (PSF) engineering in high-throughput microscopy has proved challenging. Here, the authors propose a compact PSF engineering approach, which allows for enhanced depth of field and for the recovery of 3D information using single snapshots.