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Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

The authors report that, in mice without hepatic insulin signaling, diets high in fructose cause acute hepatic steatosis without increasing hepatic de novo lipogenesis, dependent upon hepatic follistatin secretion and associated adipose insulin resistance.

Snakes are capable of non-planar gaits, such as sidewinding. Now observations of juvenile anacondas reveal another non-planar gait resembling an S shape. Calculations show how topological dynamics of active filaments enable such movements.

Perineural invasion and cancer-induced nerve injury of tumour-associated nerves are associated with poor response to anti-PD-1 therapy, which can be reversed by combining anti-PD-1 therapy with anti-inflammatory interventions.

Here the authors generate a live-attenuated Zika vaccine based on a clinically proven dengue virus serotype-2 vaccine backbone and show that one dose protects mice and non-human primates from Zika virus infection.

It is unclear whether providing the results of abdominal aortic calcification imaging to patients improves diet parameters. This randomized trial shows that this intervention does not lead to improvements in fruit and vegetable intake, while showing an effect on some cardiovascular disease risk factors used as secondary outcomes.

CRISPR-based transcriptional activation (CRISPRa) is a powerful tool for controlling gene expression. Here, Liang et al. show that commonly used CRISPRa systems are surprisingly toxic to cells due to their potent activation domains, informing the application and development of this technology.

Study shows PTSD predisposition shares distinct genes and genomic regions with several cardiovascular conditions. Here the findings reveal neuronal, immune, and metabolic pathways, and repurposed drug targets that further the understanding of the comorbidity.

Mosquitoes are major vectors for the transmission of many serious pathogens. This study uses genome-wide CRISPR screens in the mosquito, Anopheles gambiae, to reveal new insights into mosquito fitness and the function of clodronate-liposome mediated immune cell ablation.

Living materials align with sustainability goals, but usually face challenges such as limited environmental adaptability and restricted cellular functionality. Here, the authors report a sustainable plasticizer-assisted thermoplastic molding process to develop silk protein-based living plastics with dense structures, functioning as protective matrices for encapsulated microorganisms.

The International Brain Laboratory presents a brain-wide electrophysiological map obtained from pooling data from 12 laboratories that performed the same standardized perceptual decision-making task in mice.

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.

Soft electronic probes for measuring neural activity can be made scalably in an initially planar form and turned into various three-dimensional geometries through a controlled rolling method.

Wang et al. show that pregnane X receptor (PXR), a well-known DNA-binding nuclear receptor, has mRNA stabilization functions when in the cytoplasm, thus unveiling a noncanonical perspective to understand and target PXR as an RNA-binding protein.

An analysis of data from the Sherlock-Lung study provides insight into the mutational processes that contribute to lung cancer in never smokers, and looks at the possible role of factors such as air pollution and passive smoking.

A wireless, minimally invasive emergency rescue device is developed for the active burst-release of stable particulate forms of peptide and hormone drugs into subcutaneous sites in mice.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Antimicrobial resistance genes that have been mobilized between bacterial species represent a subset of the naturally occurring resistome. Here, the authors compare the abundance, diversity and geographical patterns of acquired resistance genes with latent resistance genes in global sewage metagenomes.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

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.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

Analyses of layer 5 cortical pyramidal neurons in 10 mammalian species show that human neurons are distinct in that they do not follow the expected allometric relationship between neuron size and membrane conductance.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

A soft mesh microelectrode array can seamlessly integrate in developing brains, enabling long-term, stable mapping of how single-neuron activity and population dynamics emerge and evolve during brain development.

An analysis identifies human monoclonal antibodies that potently neutralize wild-type SARS-CoV-2 and protect animals from disease, including two that synergize in a cocktail, suggesting that these could be candidates for use as therapeutic agents for the treatment of COVID-19 in humans.

Patient-derived xenografts (PDX) could contribute to understanding how colorectal cancer (CRC) responds to targeted therapies like cetuximab. Here, the authors characterise the response to cetuximab in 231 CRC PDXs using multiomics and develop an integrative ensemble classifier - CeSta - to predict sensitivity to cetuximab.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

The Zika viral protease NS2B-NS3 is a crucial target for antiviral drug development due to its role in processing viral polyproteins. Here, the authors utilize crystallographic fragment screening and deep mutational scanning to identify binding sites for resistance-resilient inhibitors.

Fc–Fc gamma receptor interactions and alveolar macrophages contribute to ancestral vaccine-induced control of infection with SARS-CoV-2 variants in mice.

Tubulin mutations cause a group of disorders named tubulinopathies. Here, the authors show that specific variants in the tubulin TUBB impair primary cilia formation, putting forward primary cilia defects as a pathogenic factor in some tubulinopathy cases.

Quantifying lipid and water content in tissues non-invasively is difficult, and no method exists to quantify lipids in blood non-invasively. Here the authors develop an imaging approach called shortwave infrared meso-patterned imaging (SWIR-MPI) to detect and spatially map tissue water and lipids in preclinical models.

Mutual paracrine regulation of the cytokines GREM1 and SPP1 mediate mesenchymal and epithelial cell fate in pancreatic cancer.

TDP-43 dysfunction in ALS/FTD causes faulty splicing of the KCNQ2 ion channel, leading to toxic protein buildup, neuron hyperactivity and a potential new biomarker and treatment target using RNA-based therapies.

Limited tumor cell delivery is a major challenge for the efficacious delivery of siRNAs to silence traditionally undruggable oncogenes. Here the authors optimize siRNAs for in situ binding to albumin through C18 lipid modifications and show the application of the lead conjugate structure for targeting MCL1 in orthotopic breast tumors in mice.

The C-X-C chemokine receptor type 4 (CXCR4) pathway is a key regulator of cancer metastasis. Here, the authors present a method to block CXCR4 and thereby inhibit breast cancer metastasis by developing a liposome that presents CXCR4-binding peptides in a multivalent fashion.

In vivo experiments and clinical cohort analyses show that hypoxia-inducible factor 2 (HIF2)-induced parathyroid hormone-related protein (PTHrP) expression contributes to cachexia in the context of renal cell carcinoma (RCC). The pathway can be targeted by HIF2 inhibitors, including belzutifan, which may reduce cachexia in patients with RCC.

The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

Here, the authors leverage whole-genome sequencing from >88,000 diverse individuals to uncover 18 BMI-related genetic signals, including novel variants in participants of African genetic ancestry, highlighting the value of diversity in genetic discovery.

A new specific, small-molecule activator of the PI3Kα isoform (UCL-TRO-1938) identified through high-throughput screening can transiently activate PI3K signalling and biological responses in cells and tissues, with potential therapeutic applications in tissue protection and regeneration.

The authors present a deep learning approach to uncover complex genetic effects on circulating protein levels. They reveal new interactions and dominance patterns using UK Biobank proteomics data.

T-cell engager (TCE)-based immunotherapy requires further development in solid tumors due to limited T cell penetration, immunosuppressive tumor microenvironment and toxicity. The authors here develop a glypican-3 targeting mRNA TCE (MTS105) which manifests superior T cell activation and tumor regression hepatocellular carcinoma mice model comparing to conventional TCE, and safety with cynomolgus monkey studies.

Dual cyclin A/B RxL inhibitors selectively kill small cell lung cancer cells and other cancer cells with high E2F activity.

The choroid plexus (ChP) provides molecular cues for brain development. However, the underlying mechanisms are unclear. This study identifies an apocrine secretion mechanism in the ChP that modulates the CSF protein composition and instructs cortical development.

Enterololin is a narrow-spectrum antibiotic that selectively kills Enterobacteriaceae in vitro and in a mouse model of adherent-invasive Escherichia coli gut infection. AI-guided mechanism-of-action studies identified LolCDE as its molecular target.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

The development of liposome-based drug delivery systems has been hindered by the systemic toxicity and limited duration of effect due to insufficient drug loading and leakage of payload. Here the authors address these issues by designing aromatized liposomes that feature increased drug loading and slowed release compared to conventional liposomes.

Nanoparticle elasticity is thought to play an important role in drug delivery, but is little studied. Here, the authors use nanolipogels with tunable moduli to study the effect of particle elasticity on in vitro cellular uptake and in vivo tumor uptake, finding that stiffer particles are not as easily internalized.