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Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

In the kidney, maintaining permeability of the filtration barrier is critical. Here, Sachs W. et al show that homeostasis of podocytes and glomerular endothelial cells relies on differing proteasome constitutions which orchestrate endocytic activity in addition to protein degradation.

Flavivirus infection or vaccination can induce cross-reactive immune responses. Here, the authors show how previous immunization with the tick-borne encephalitis virus vaccine affects the immune response to the yellow fever vaccine, suggesting that the yellow fever vaccine virus conceals epitopes shared with other flaviviruses in flavivirus-naive but not flavivirus-pre-exposed individuals.

This study shows that the mobile genetic elements of Listeria monocytogenes exhibit a structured but interconnected network of genetic exchanges. The authors found dense interconnections of similar sequences among phages, plasmids and transposons.

nELISA miniaturizes the sandwich immunoassay and transforms it into a massively scalable platform for quantitative proteomics.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Zebrafish show robust heart regeneration after injury. Here they show that zebrafish cardiomyocytes experience replication stress, which BMP signaling alleviates via a conserved mechanism of replication fork restart, suggesting a potential for anti-aging and regenerative therapies.

A giant planet candidate roughly the size of Jupiter but more than 14 times as massive is observed by TESS and other instruments to be transiting the white dwarf star WD 1856+534.

A set of three papers in Nature reports a new proteomics resource from the UK Biobank and initial analysis of common and rare genetic variant associations with plasma protein levels.

A preclinical covalent compound, CMX410, contains a aryl fluorosulfate warhead that targets the acyltransferase domain of Mtb Pks13, an essential enzyme in cell-wall biosynthesis, making it a promising candidate for tuberculosis treatment regimens.

Few studies have suggested that enteric glial cells (EGCs) promote colorectal cancer growth. Here the authors show that EGC-derived IL-6 promotes the expansion of tumorigenic SPP1⁺ tumor-associated macrophages, associated with worse disease outcome.

External cycling regenerates nitrogen oxides from the NO_x oxidative reservoir, NO_z. Aircraft observations reveal NO_x external cycling compensates for NO_x aging, sustaining NO_x distribution and production of OH radicals far from NO_x emission sources

Some brain lesions recover in multiple sclerosis, while others do not; however, the underlying mechanisms are unclear. Here, the authors show that microglia-derived TGFα orchestrates immune control and tissue repair, and that intranasal delivery of TGFα in the autoimmune encephalomyelitis model promotes lesion resolution.

Interleukin (IL)-1β has been shown to promote tumour growth in non-small cell lung cancer (NSCLC). Here the authors show using chemo-immunotherapy resistant mouse tumour models that IL-1β improves CD8 T cell recruitment in a CXCL10-dependent manner and IL-1β therapy could be a useful adjunct to chemotherapy and anti-PD-1.

Childhood mortality is a global health problem. Plasma lipopolysaccharide levels, inflammatory stool biomarkers and proteomics were used in a nested case-cohort in sub-Saharan Africa and South Asia to predict mortality and decode immune mechanisms.

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

Copy number alterations in stem cells impair neural crest differentiation and set the stage for neuroblastoma-like traits and tumours. This study hints at early tumourigenesis mechanisms and finds developmental gene signatures linked to prognosis.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

An extensive RNA binding protein atlas (RBPome) for primary T cells would be a useful resource. Here the authors use two different methods to characterise the mouse and human T cell RBPome and show regulation of Roquin-1/2 dependent and independent pathways.

Few mouse models recapitulate the complexity of triple negative breast cancer (TNBC). Here, the authors develop and characterise a TNBC mouse model harbouring two common TNBC mutations: amplification of the oncogene MYC and deletion of the tumour suppressor PTEN.

Tumour-reactive CD8⁺ T cells are enriched in functional clusters with tumour cells and/or antigen-presenting cells and can be isolated and expanded from clinical samples.

A survey of potency and efficacy of 2,025 clinically relevant two-drug combinations against 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines identifies rare synergistic effects of anticancer drugs, informing rational combination treatments for specific cancer subtypes.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Studying specific cellular responses elicited by compartmented cAMP signals in real time has been difficult. A new method called SMICUS overcomes this challenge and reveals a resident pool of nuclear PKA that can convert cAMP signals to rapid responses.

A neural network trained on diverse datasets improves prediction of HLA class II epitope presentation.

The study provides a comprehensive transcriptomic atlas of the human gastrointestinal tract across the lifespan, highlighting inflammation-induced changes in epithelial stem cells that alter mucosal architecture and promote further inflammation.

A tri-omic atlas of the mouse brain from postnatal day 0 to P21 reveals that layer-specific projection neurons have a role in coordinating axonogenesis and myelination.

The bone marrow is a common site of metastasis for neuroblastoma patients. Here, the authors perform single cell RNA-seq and ATAC-seq of bone marrow aspirates from 16 subjects and show conservation of tumor cell plasticity in metastases and identify tumor-to-bone marrow cell signals that trigger tumor promoting monocytes.

The lysosomal enzyme beta-glucocerebrosidase is a key player and promising therapeutic target in Parkinson’s disease. Here, Dobert et al. leveraged cryo-EM to solve the protein structure of the enzyme in complex with its lysosomal transporter LIMP-2.

The clinical detection of fluorescent protoporphyrin IX during glioma-resection surgery can be improved via a microscope that pairs stimulated Raman histology and two-photon excitation fluorescence microscopy.

Pampols-Perez et al. identify the mechanosensitive ion channel PIEZO2 as a novel marker for embryonic coronary artery endothelial cells and as a critical regulator of coronary vascular remodeling. They show that in a distinct subset of coronary endothelial cells, PIEZO2 translates mechanically activated ionic currents into biological signals guiding coronary artery morphogenesis.

The human host factors LSD1, CoREST and ZNF217 are important in maintaining Epstein–Barr virus latency, and the depletion of these factors or inhibition of LSD1 can trigger Epstein–Barr virus reactivation and sensitize infected cells to ganciclovir treatment.

Highly pathogenic avian influenza H5N1 viruses cause mass mortality in birds and have infected over 50 mammalian species, including humans. Here, the authors report the use of a propagation-defective vesicular stomatitis virus replicon vaccine in captive birds, which provides protection against lethal H5N1 challenge.

An integrated genomic analysis of 456 human pancreatic ductal adenocarcinomas identifies four subtypes defined by transcriptional expression profiles and show that these are associated with distinct histopathological characteristics and differential prognosis.

Shlien and colleagues report on 300 patients from the SickKids Cancer Sequencing program and identify clinically actionable variants in 56% of the patients by profiling somatic and germline data at multiple clinical time points.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Sosa et al. find that hippocampal neural activity in mice encodes both environmental location and experience relative to rewards, spanning distances far from reward, through parallel and flexible population-level codes.

Somatic small variants in cancer genomes are identified in both short-read and long-read data.

PCSK9 regulates low density lipoprotein-cholesterol import and determines organ preference of metastatic pancreatic ductal adenocarcinoma, with PCSK9-low cells metastasizing to the liver and PCSK9-high cells preferring the lung.

To mark the 20th anniversary of Nature Reviews Neurology, we have asked leaders of neurological societies across the world to reflect on progress over the past two decades and consider what the future holds for neurology in their region. Here, we speak to Fernando Cendes, Vice President of the Pan American Federation of Neurology.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

The subset of chronic lymphocytic leukemia (CLL) expressing the IGLV3- 21R110 BCR light chain often shows an aggressive clinical course. Here the authors report the development and characterization of IGLV3-21R110- targeted CAR T cells, showing selective targeting and eradication of IGLV3- 21R110 expressing CLL cells.

A quantitative fluorescence-activated cell sorting method for generating fully human conformational antibodies against amyloid aggregates associated with neurodegenerative disorders—without the need for immunization—has now been developed. Engineered antibodies obtained using this approach show properties rivaling those of clinical-stage antibodies specific for tau and α-synuclein amyloid aggregates.

Using a multi-omics approach to analyse meconium and stool samples from babies during the first few days of life, the authors show that the gut is detectably colonized within 16 h of birth, with Escherichia coli dominating, and that this correlates with proteome and metabolome changes including the fermentation of amino acids.