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The ZFTA–RELA fusion, an oncogene for ependymomas, promotes the production of itaconate, and its dependence on this metabolite represents a new therapeutic target for this cancer.

Using activity-based chemical probes, oncogenic IDH1-R132H but not the wild type was found to acquire a unique autopalmitoylation at C269. This mutant-specific modification is critical for the enzyme’s abnormal activity in cancer.

In this study, authors employ fragment-based lead discovery to identify WRN inhibitors. The fragment hits reveal an additional allosteric pocket and uncover a previously uncharacterized structural conformation of the WRN helicase domain with unique orientations of the ATPase domains

HIV-1 integrase is critical for viral DNA integration and RNA packaging at distinct stages of the replication cycle. Here, authors report structures of integrase assemblies, revealing how structural plasticity imparts the protein with dual functionality.

Snakebite envenoming is a significant public health problem in India, particularly in rural tropical and subtropical regions. Here, the authors report findings from a community-based cross-sectional study in India on the incidence, clinical outcomes, and costs associated with snake bites.

The cortex fuels essential physiological processes with glucose-derived carbon, while gliomas fuel their aggressiveness by rerouting glucose carbon pathways and scavenging alternative carbon sources such as environmental amino acids, providing a potential therapeutic target.

Analyses of the nationally representative Indian Council of Medical Research–India Diabetes survey reported that Indian diets are characterized by high intakes of low-quality carbohydrates associated with 14–30% higher cardiometabolic risk, which can be reduced by substituting carbohydrates with protein.

Phylogenetic analysis shows that site-exclusion methods produce erratic phylogenetic estimates of mitochondrial origin and support an origin of mitochondria within Alphaproteobacteria.

Here the authors investigate the underlying genetic mechanisms for pathogenic variant carrier phenotype heterogeneity using exomes and clinical phenotypes from the UK and Mt. Sinai BioMe Biobanks and observed translational potential for all three mechanisms.

Context-dependent, responsive synthetic promoters are crucial for a wide range of applications, yet currently available options are limited. Here, authors develop a library of thousands of candidate promoters based on binding motifs of hundreds transcription factors for use in mammalian cells.

This analysis of individuals of admixed genetic ancestries suggests that complex trait causal variant effect sizes are, by and large, similar across ancestries, and discusses the implications for the study of these and other diverse populations.

In cells with microsatellite instability, expanded TA-dinucleotide repeats form cruciform structures that stall replication forks and cause chromosome shattering in the absence of the WRN helicase.

Phenotype imputation increases the effective sample size of major depressive disorder cases in UK Biobank, enhancing study power and polygenic risk score (PRS) accuracy. A new pleiotropy metric enables assessment of PRS specificity and comparison among different PRS models.

SARS-CoV-2 variants have accumulated multiple defining mutations within their spike glycoproteins. Here, the authors report a structural basis for broad neutralization of several variants by a heavy chain antibody fragment and provide a mutational analysis focusing on antibody evasion, receptor engagement, and spike protein structure.

Precisely tuning the genetic response to environmental stimuli is a key step in engineering synthetic biology systems. Here, the authors profile 8269 IPTG-induced promoters to deconstruct the relationship between sequence architecture and gene expression.

Variance components analysis may be used for a variety of applications including heritability estimation and association mapping. Here, the authors present a computationally efficient method, scalable to extremely large GWAS datasets, and use it for heritabilty analysis of 22 traits from UK Biobank

Next-generation sequencing of pooled samples tagged with sample-specific molecular barcodes enables the testing, for SARS-CoV-2 RNA, of thousands of nasal or saliva samples in a single run without the need for RNA extraction.

Chemically driven blockade of PU.1 binding sites leads to its genome-wide redistribution. PU.1 network rewiring causes human acute myeloid leukemia cells to differentiate.

Analysis of real traits in the UK Biobank demonstrates that large uncertainty in polygenic risk score (PRS) estimates at the individual level impacts the interpretation of subsequent analyses such as PRS-based stratification.

Pediatric brain cancers are lethal malignancies driven by less-differentiated stem-like cells. Here the authors show that these cells exhibit distinct mitochondrial metabolism programs with targetable vulnerabilities.

Notch1 is frequently activated promoting T-cell acute lymphoblastic leukaemia (T-ALL). Here, the authors show that Notch1 induces oxidative phosphorylation dependency in T-ALL and synergism when inhibiting both mitochondrial complex I and glutaminolysis in preclinical murine and human xenograft models.

Inspired by the biologics of hematophagous organisms such as leeches, the authors in this work design and create inhibtors of thrombin and factor Xa by linking exosite-binding aptamers with small molecule active site inhibtors. They coin these inhibitors EXACT inhibitors.

Gaggioli, Lo et al. show that the histone methyltransferase EHMT2/G9a catalyses heterochromatin assembly at stressed replication forks. Untimely heterochromatin disassembly by demethylase KDM3A exposes forks to PRIMPOL-mediated genome instability.

Multiple types of DNA damage can lead to mutations in normal cells, ultimately contributing to the development of cancer. Here, the authors redefine the spectrum of mutational signatures linked to a particular type of DNA damage to uncover the protective role of specialized DNA repair mechanisms.

An analysis of AlphaFold protein structure predictions shows that while in many cases the predictions are highly accurate, there are also many instances where the predicted structures or parts of predicted structures do not agree with experimentally resolved data. Therefore, care must be taken when using these predictions for informing structural hypotheses.

A small molecule enhances targeted gene integration at therapeutically relevant loci in human primary cells.

Combined omics techniques lead to the functional assignment of four enzymes involved in a new methionine salvage pathway linking polyamine metabolism with isoprenoid biosynthesis. This reaction sequence involves a homolog of nature's most abundant protein, the CO₂-fixing enzyme RubisCO.

Thyroidectomy is frequently the treatment offered to patients with low-risk papillary thyroid microcarcinoma (PTMC). Here, the authors perform a multicentre online survey to a cohort of patients with PTMC showing that heightened regret may not be an experience of a minority of clinically low-risk PTMC patients and is primarily due to lower postoperative quality of life.

Non-small cell lung cancers with inactivating SMARCA4 mutations are currently undruggable. Here, the authors show that the absence of SMARCA4/2 reduces chromatin accessibility at the CCND1 locus, leading to a subsequent reduction in cyclin D1 expression, which promotes vulnerability of these cancers to CDK4/6 inhibition.

Blood clotting is a complex process involving platelet adhesion and clot stiffening. Here the authors present a microfluidic system to recapitulate the dynamic changes in clot mechanics under physiological shear.

Deep whole-genome sequencing of 300 individuals from 142 diverse populations provides insights into key population genetic parameters, shows that all modern human ancestry outside of Africa including in Australasians is consistent with descending from a single founding population, and suggests a higher rate of accumulation of mutations in non-Africans compared to Africans since divergence.

By taking advantage of stimulated Raman spectroscopy and fibre-laser technology, virtual histology images can be obtained in real time in the operating room, with diagnostic quality comparable with that achieved via conventional histopathology.

Targeting genotype-independent abnormalities may overcome therapy resistance in glioblastoma despite intratumoral genomic heterogeneity. Here, the authors show that glioblastoma radiation resistance is promoted by purine metabolism and can be overcome by inhibitors of purine synthesis.

Relatively little is known about the first hematopoietic stem and progenitor cells to arrive in the fetal bone marrow. Here they characterize the frequency, function, and molecular identity of fetal BM HSPCs and their bone marrow niche, and show that most BM HSPCs have little hematopoietic function until birth.

Single-particle cryo-EM is a powerful method for macromolecular structure determination. Here the authors demonstrate that Ewald sphere curvature correction, sub-Angstrom pixilation and per-particle CTF refinement can improve map quality and resolution and present the 1.86 Å cryo-EM structure of an adeno-associated virus serotype 2 variant.