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Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Large-scale plasma proteomics of 10,527 samples from the Global Neurodegeneration Proteomics Consortium identified shared and disease-specific pathways in Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia.

Huang et al. show that ADAM9 loss upregulates PAI-1, promoting its interaction with KRAS and resulting in selective lysosomal degradation of KRAS. They also identify a small-molecule inhibitor of ADAM9 with therapeutic benefits in the context of PDAC.

In a prespecified interim analysis of the randomized, double-blind phase 3 COMPASSION-15 trial, patients with advanced HER2-negative gastric/GEJ cancer treated with the anti-PD-L1/CTLA-4 bispecific Ab cadonilimab plus chemotherapy showed significantly improved overall survival compared with patients treated with placebo plus chemotherapy as first-line treatment.

Candida tropicalis is a cause of invasive candidiasis infection in humans that has been increasingly associated with azole drug resistance. In this study, the authors investigate the genetic basis for azole resistance through analysis of whole-genome sequencing and multilocus sequence typing data.

Fan, Shang, Song, Chen et al. identify the Integrator–PP2A complex (INTAC) as a key regulator of cancer cell sensitivity to BET inhibitors through directly interacting with the RACK7–KDM5 complex to orchestrate epigenetic silencing in a catalytic-independent manner.

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer with poor prognosis. Here the authors performed multi-omics analysis of human samples to investigate the mutational landscape of PSC and show three subgroups of PSC with distinct biology, prognosis and potential therapeutic strategies.

Frequencies for motor kinematics are encoded by the cerebellum through population tuning of firing probabilities, which leads to cerebellar oscillations and corresponding motions.

In patients with locally advanced resectable oral squamous cell carcinoma (OSCC), the risk of recurrence and metastasis following treatment is high. Here, a phase I clinical trial reports safety and pathological response of neoadjuvant camrelizumab and apatinib in patients with locally advanced resectable OSCC.

Inactivating PPP2R1A mutations correlate with better survival after immune checkpoint blockade in patients with ovarian clear cell carcinoma, suggesting that targeting the phosphatase 2A (PP2A) pathway may represent an effective startegy for improving responses to immunotherapy.

The authors present a reference genome for Hordeum I-genome species. This work unravels genomic features that drive adaptation to salt and alkali environments and could aid in improving crop resilience.

Xu, Meng, St-Germain et al. report that S1P in HDL induces a calcium signalling cascade involving E-Syt1 that ultimately promotes the formation of contact sites between the endoplasmic reticulum and the plasma membrane, as well as HDL-derived cholesterol transport.

Necroptosis in cancer cells remains incompletely understood. Here, the authors show that inhibition of FGFR2 could induce necroptosis via crosstalk between the NF2-Hippo-YAP and RIP1-MST1-MLKL pathways and shapes an immunosuppressive tumor microenvironment.

Here, the authors show that mechanical loading promotes subchondral bone osteocytes to secrete extracellular vesicles containing miR-23b-3p, which accelerates osteoarthritis progression by inhibiting mitophagy and disrupting cartilage metabolism.

In this multicenter phase 1 trial, treatment with IBI343, a CLDN18.2-targeting antibody–drug conjugate, was safe and showed encouraging clinical responses in patients with advanced gastric or gastroesophageal junction adenocarcinoma.

The role of KLF10 in exercise-mediated anti-obesity effects is not clear. Here, the authors show that exercise-induced adipose KLF10 interacts with FOXO1 and recruits KDM4A to transactivate lipolytic genes, which defends against obesity in male mice.

In the OptiTROP-Breast01 phase 3 trial, patients with metastatic triple-negative breast cancer who received the TROP2-targeted antibody–drug conjugate sacituzumab tirumotecan experienced longer progression-free survival than patients treated with chemotherapy.

The hair follicle bulge contains epithelial stem cells that contribute to follicle formation during each hair cycle. Here the authors differentiate human induced pluripotent stem cells into folliculogenic epithelial stem cells, which can produce all hair follicle lineages including a stem cell population.

Precise and reliable gene delivery remains technically challenging. Here, the authors show that rationally designed frameshifting splicing can be used to express genes only in targeted cell types, with the potential to enhance the specificity AAV gene delivery.

Under low-protein conditions, decrease of protein NUFIP1 is found to impair DNA damage response and induce necroptosis in the intestine, thereby contributing to intestinal inflammation in male mice with inflammatory bowel disease.

Circulating tumour cells can be useful for monitoring disease progression but how they survive in the circulatory system is unclear. Here, the authors use single-cell sequencing of circulating tumour cells from multiple vascular sites in liver cancer patients and identify genes that may help the cells survive.

Rice stripe virus deploys its SP protein to dismantle SERRATE condensates in rice cells, blocking microRNA production and enhancing viral spread. This discovery reveals how viruses can hijack host phase separation to modulate gene regulation.

Mechanistic understanding of cancer drug resistance is often fragmented. Here, the authors use the proteome-wide Cellular Thermal Shift Assay, revealing drug-induced resistance responses encompassing activation of translation synthesis and a protein ensemble labelled the Auxiliary DNA Damage Repair.

The origin and progression of lung adenocarcinoma (LUAD) are still poorly understood. Here, the authors analyse LUAD composition and progression in patient samples using single-cell RNA-seq and multiplex imaging, revealing a potential transcriptional divergence from alveolar type 2 cells.

Isoprene emissions are commonly estimated using satellite measurements and model simulations. Here, using eddy covariance, the authors report higher emission rates over the Amazon forest than those estimated with these techniques and a relationship between terrain elevation and isoprene emissions.

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

Nanotwinning strategies are widely recognized for their ability to substantially enhance the mechanical properties of materials. Here diamond with both penetrating and interlocked twins was synthesized, yielding a hardness of 276 GPa, which can be explained by diamond models that feature diverse twin configurations and dimensions.

An analysis of the effect of mesophyll diffusion on the dynamics of the uptake of carbonyl sulfide by plants estimates global contemporary gross primary productivity to be 157 (±8.5) petagrams of carbon per year.

RNA binding protein Quaking (QKI) is known for its broad function in pre-mRNA splicing and modification and its association with several neurodevelopmental disorders. Here the authors reveal that QKI-mediated regulation of RNA splicing is indispensable to cardiac development and contractile physiology.

Resistance to tyrosine kinase inhibitors (TKI) is a limitation to their use in treating chronic myelogenous leukemia (CML). Here, the authors show that targeting the ubiquitin peptidase USP47 overcomes TKI resistance and eliminates leukaemia stem/progenitor cells in primary and xenograft CML murine models.

In this study, the authors perform an interactome study of Zika virus (ZIKV) 5’UTR stem-loop B region and identify two host factors, interleukin enhancer binding factor 3 (ILF3) and DEAH-box helicase 9 (DHX9), that positively regulate antiviral RNAi to inhibit virus replication and ZIKV-induced microcephaly in vivo.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

The aetiology of primary biliary cholangitis (PBC) remains unclear. Here, the authors find that the numbers of DUOX2⁺ ACE2 ⁺ small cholangiocytes in human and mouse livers are inversely associated with disease severity, and present data indicating that they may be the target of polymeric immunoglobulin receptor (pIgR) -mediated humoral responses, suggesting that preservation of these cells and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.

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.

Accumulation of visceral fat, linked to adipocyte expansion and overgrowth, is the most detrimental aspect of obesity, and a major cause of obesity comorbidities. We develop a cationic nanomedicine based on polyamidoamine dendrimers that specifically targets visceral fat and shrinks adipocytes, inhibiting diet-induced obesity and improving metabolic health in murine models.

A quantum microsatellite, with a payload weighing only 23 kilograms, in combination with portable ground stations that weigh merely 100 kilograms, is capable of performing space-to-ground real-time quantum key distribution.

Immunotherapy, the reactivation of the immune system to recognize cancer cells, can be accompanied by severe adverse effects. Here, the authors use pharmacovigilance and genomic data to be able to predict which patients might be susceptible to such severe events.

Populations speaking Austronesian languages are numerous and widespread, but their history remains controversial. Here, the authors analyse genetic data from Southeast Asia and show that all populations harbour ancestry most closely related to aboriginal Taiwanese, while some also contain a component closest to Austro-Asiatic speakers.

Lan et al. demonstrate the high performance of plasma p-tau217 in detecting and tracking multiple aspects of Alzheimer’s disease pathology, outperforming other plasma tau biomarkers across two Chinese cohorts (GHABS and Huashan) and the North American ADNI cohort.