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Androgen activity in the male embryonic hindbrain prolongs hindbrain differentiation in male individuals and drives sex differences in the incidence and prognosis of posterior fossa type A (PFA) ependymoma, an aggressive childhood brain tumour.

MCL1 is an anti-apoptotic protein associated with cancer and therapy resistance. Here, the authors show that MCL1 regulates mTORC1 signalling and metabolism, explaining MCL1-inhibition reported cardiotoxicity, which can be mitigated by dietary leucine supplementation.

CRISPR/Cas9 screens have identified genetic contributions to many phenotypes. However, studying combinations of genes or regulatory elements remains challenging. Here, the authors use CRISPR/Cas12a to overcome those challenges and enable new approaches to study combinatorial genetic mechanisms.

FUT10 and FUT11, originally annotated as α1,3-fucosyltransferases, are actually protein O-fucosyltransferases participating in a non-canonical ER quality control pathway for EMI domain-containing protein secretion.

Tendons exhibit limited healing capacity and the role of lymphatic vessels in tendon regeneration is largely overlooked. Here they compare control and injured tendon cells from both neonatal and adult mice and identify lymphatic vessels as key regenerative niche elements.

Gonzalez et al. use a viral evolutionary approach to generate cross-species compatible AAV (ccAAVs) vectors. They describe a highly potent new variant, AAV.cc47, with enhanced transduction efficiency over AAV serotype 9 and show its efficacy in different mouse models, pigs and non-human primates.

Cryo-electron microscopy structures of the human lysosomal transmembrane protein LYCHOS show that it comprises a transporter-like domain fused to a G-protein-coupled receptor, and that the transporter domain is similar to the plant PIN family.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

Antibodies against SARS-CoV-2 continue to evolve 6 to 12 months after infection in patients who have recovered from COVID-19, increasing in potency and breadth with time.

Mitochondria that are transported from satellite glial cells in dorsal root ganglia to peripheral sensory neurons through tunneling nanotube-like structures provide protection against peripheral neuropathy.

OSCA/TMEM63 proteins act as both ion channels and mechanically activated lipid scramblases. They translocate lipids through open pores, with cholesterol inhibiting scrambling, aiding membrane remodeling and cell resilience under mechanical stress.

Structurally resolving glycans remains a challenge. Here, the authors analyse influenza H3 hemagglutinin glycan evolution to show that over five decades of glycan incorporation highly impact structural stability and epitope accessibility, particularly in the head domain, providing key insights for vaccine design.

’Layer-by-layer (LbL) assembly is currently one of the most widely used techniques for the fabrication of multicomponent architectures with nanometer scale control but achieving control over the 3D structure, and thus the ability to predict and understand the device performance, is challenging. Here, the authors use neutron scattering to determine the average conformation of individual deuterated polyelectrolyte chains inside LbL assembled films.

Therapeutics delivery by using non-viral vectors presents several challenges in the design of an appropriate polymeric structure. Here, the authors report a series of highly branched, biodegradable polymers which show high transfection efficiency in human multipotent adipose derived stem cells and primary astrocytes.

Dysregulation of the TNF receptor signaling complex (TNF-RSC) promotes the onset of autoinflammatory conditions. Here the authors show that two adapter proteins, TANK and AZI2, mediate the recruitment of the kinase TBK1 to TNF-RSC to protect the mice from TNF-induced cell death and autoinflammation.

CAR and PXR receptors are known to regulate metabolism, however, there is no dual human ligand suitable for therapy. Here, the authors show a CAR agonist/PXR antagonist, MI-883, which regulates cholesterol/bile acid homeostasis by leveraging CAR and PXR activations in plasma cholesterol regulation.

Cagrilintide is a long-acting agonist of amylin and calcitonin receptors in late phase trials for obesity. Here, authors present structures of cagilintide with each target receptor, revealing the molecular basis for its non-selective action.

An adipocyte-targeting gene-carrier complex is shown to selectively transfect mature adipocytes by binding to the protein prohibitin and to lead to the metabolic recovery and to more than 20% body-weight reduction in obese mice.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Intradermal microneedles for the co-delivery of mRNA and near-infrared fluorescent microparticles are used in combination with deep learning-based image analysis for the simultaneous administration of therapeutics and registry of patient information records into the skin.

Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most common genetic cause of hypertrophic cardiomyopathy. Here, the authors present an AAV9-based gene therapy system with an optimized expression cassette with minimal promoter and cis-regulatory elements that can ameliorate cardiac functions and prolong survival in a murine MYBPC3-deficient model.

The B-cell receptor of primary mouse B cells can be engineered to affinity mature an HIV-1-entry inhibitor in vivo.

Protein synthesis suppression protects breast cancer cells from clinically relevant stresses like hypoxia. Here, the authors show that unique mRNA isoforms that govern stem cell-like phenotypes escape translational repression to drive tumor progression and chemoresistance.

Pappalardi and colleagues identify a potent noncovalent DNMT1-selective inhibitor with improved tolerability and efficacy in preclinical AML models compared with clinically validated covalent pan-DNMT inhibitors.

This protocol sets up a bioluminescent repair reporter system using engineered Gaussia and Vargula luciferases for noninvasive tracking of homology-directed repair and nonhomologous end joining, respectively, induced by SceI meganuclease, SpCas9 or SpCas9 D10A nickase-mediated editing.

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.

Experiments in mouse and hamster models show that monoclonal antibody combinations, using antibodies that correspond to products in clinical development, largely retain their efficacy in protecting against currently prevailing variant strains of SARS-CoV-2.

The double-strand break sensor MRE11 is identified as a pivotal mediator of cGAS activation in response to multiple types of DNA damage.

Systematic assessment of cofactor dependencies of nine transcription factors (TFs) and promoters finds that TFs use unique cofactor combinations to modulate distinct steps in transcription, whereas promoter elements fit into discrete groups where their rate-limiting step for activation influences cofactor compatibility.

Treatments to prevent thrombosis are suboptimal. Here, the authors identify a lead an antithrombotic drug targeting polyphosphate based on switchable protonation states for the anion-binding groups, demonstrating antithrombotic activity in multiple mouse models, not causing bleeding, and well tolerated.

Here, the authors generated and analyzed run-on sequencing data to observe transcription in species across the tree of life to uncover the origins of the promoter-proximal pause.

The development of native-like envelope trimers has been a major focus in the efforts to produce HIV vaccines. Here the authors demonstrate the production and characterization of virus-like nanoparticles displaying trimeric HIV-1 antigens with the potential to elicit broadly neutralizing antibodies.

A major goal of HIV-1 vaccine development is to produce antigens that can induce broadly neutralizing antibodies. Here the authors examine the underlying causes of HIV-1 envelope metastability and design uncleaved, prefusion-optimized gp140 trimers with potential for use as HIV-1 vaccine antigens.

Following their synthesis, eukaryotic messenger RNAs have a 7-methylguanosine cap added to their 5′ ends to protect the mRNAs from degradation. Here it is shown that, in vitro and in yeast, caps lacking a methyl group are recognized by the Rai1 protein, which clips off the incomplete cap. The data provide evidence that Rai1 is part of a quality-control mechanism that monitors, and promotes the digestion of, aberrant mRNAs that might arise during stress conditions.

There is increasing evidence that epigenetic mechanisms contribute to therapeutic resistance in cancer. Here the authors study AML patient samples and a mouse model of non-genetic resistance and find that transcriptional plasticity drives stable epigenetic resistance, and identify regulators of enhancer function as important modulators of resistance.

The light-sensitive LOV domain was engineered into the TurboID enzyme, creating ‘LOV-Turbo’. LOV-Turbo enables optogenetic control over proximity labeling, increasing the spatiotemporal precision of this technique.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

Addition of a specific set of transcription factors reprograms somatic cell nuclei to a pluripotent state. Sequential addition of these factors, rather than the simultaneous exposure used in standard protocols, improves reprogramming efficiency. This sequential method favours a transition through a state with enhanced mesenchymal characteristics before driving an epithelial transformation on the way to the pluripotent state.

Charles Mullighan, Jinghui Zhang and colleagues characterize a subtype of B-progenitor acute lymphoblastic leukemia with deregulated DUX4 and ERG. They find that aberrant DUX4 activation results in loss of ERG function, either through deletion or by the induction a novel transforming ERG isoform, ERGalt, that inhibits wild-type ERG activity.

Das et al. show that the correct editing activity of the methionyl tRNA synthetase, regulated by AIMP3, is required to prevent the accumulation of homocysteine and the resulting cardiomyocyte cell death and cardiac dysfunction.

A rapid labelling and immunopurification-based method is used to isolate melanosomes and profile their labile metabolites, revealing that MFSD12 has a key role in cysteine import into melanosomes and lysosomes.