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TREM2 is an important AD risk factor playing essential roles in the microglial response to amyloid pathology. Here, authors show using a TREM2 reporter mouse that TREM2 levels are critical for efficacy of TREM2 agonism informing current clinical efforts.

Wide-bandgap perovskite solar cells suffer from instability under rapid thermal cycling. Here, Sun et al. investigate the degradation mechanism, showing that temperature-induced structural strain, phase transition, and increased non-radiative defects drive the degradation processes.

H3K4 methylation is required for defining active chromatin states in Xenopus embryos, ensuring faithful zygotic genome activation and successful embryonic development.

u-Segment3D is a universal framework that translates and enhances 2D instance segmentations to a 3D consensus instance segmentation without training data. It performs well across diverse datasets, including cells with complex morphologies.

We show that FOXF2 maintains cerebrovascular function through Tie2 signaling, and that pharmacological activation of Tie2 with AKB-9778 rescues deficits in cerebral small vessel disease and stroke.

Cancer patients are at increased risk for severe bacterial infections due to immune dysfunction. Here, the authors show that chronic tumor-derived G-CSF drives NAMPT/NAD-dependent neutrophil dysfunction from the progenitor stage, and that targeting this pathway restores infection control.

Dynamic control of components is required for large-scale quantum photonic networks. Here, Kapfingeret al. show dynamic control of the interaction between two coupled photonic crystal nanocavities forming a photonic molecule. Tuning is achieved by using an electrically generated radio frequency surface acoustic wave.

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.

The microbiota influences the cytotoxicity of chemotherapy in patients with colorectal cancer but the impact on metastatic relapse is less clear. Here, the authors report that chemotherapy-induced intestinal mucositis induces systemic immune changes via production the microbial metabolite, indole-3-propionic acid (IPA), preventing metastases.

Antibodies targeting the spike protein of coronaviruses are potential candidates for therapeutic development. Here, Bertoglio et al. use phage display to select anti-SARS-CoV-2 spike antibodies from the human naïve universal antibody gene libraries HAL9/10 that block interaction with ACE2 receptor to inhibit infection.

The study reports the application of data-driven techniques to structural neuroimaging data of people with recent-onset psychosis or recent-onset depression and matched controls for the prediction of transdiagnostic clinical symptom severity and clinical outcomes.

Olfactory deficits occur early in Alzheimer’s disease (AD). Here, the authors identify that loss of locus coeruleus axons in the olfactory bulb underlies impaired olfaction in an AD mouse model and provide translational evidence for similar deficits in humans.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

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.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Extracellular matrix (ECM) remodeling is a hallmark of fibrosis thought to be driven by mesenchymal cells. Here, the authors discover that YAP-TEAD/LOX axis is activated in distal lung epithelial cells, which contributes to ECM remodeling in pre-clinical models of pulmonary fibrosis.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

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.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

Natural products have historically made a major contribution to pharmacotherapy, but also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization. This Review discusses recent technological developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — that are enabling a revitalization of natural product-based drug discovery.

Gonzalez-Gallego et al. developed a fully iPS-cell-based human three-dimensional blood–brain barrier (BBB) model and used it to study roles of the stroke risk gene FOXF2 in BBB dysregulation, demonstrating its applicability for mechanistic research and drug development.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

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.

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.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

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.

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.

Endothelial cells can support leukocyte extravasation without causing vascular leakage, but the exact mechanism underlying this process has not been fully elucidated. Here the authors show that it is regulated through actomyosin-based endothelial pore confinement, which requires local endothelial RhoA activation.

SNURPORTIN-1, encoded by the SNUPN gene, plays a key role in the nuclear import of spliceosomal small nuclear ribonucleoproteins, however its physiological function remains unclear. Here the authors report that recessive SNUPN mutations cause a distinct subtype of childhood muscular dystrophy and reveal SNURPORTIN-1’s role in muscle homeostasis, offering insights for new therapeutic strategies.

A genome-wide association study and Metabochip meta-analysis of body mass index (BMI) detects 97 BMI-associated loci, of which 56 were novel, and many loci have effects on other metabolic phenotypes; pathway analyses implicate the central nervous system in obesity susceptibility and new pathways such as those related to synaptic function, energy metabolism, lipid biology and adipogenesis.

A DNA-binding protein, DnaA, regulates the initiation of chromosomal replication in bacteria. Here, Olivi et al. show that the bacterial chromosome sequesters DnaA in a growth rate-dependent manner, suggesting a role for titration in the coordination of DNA replication.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Timothy Frayling, Joel Hirschhorn, Peter Visscher and colleagues report a meta-analysis of genome-wide association studies for adult height in 253,288 individuals. They identify 697 variants in 423 loci significantly associated with adult height and find that these variants cluster in pathways involved in growth and together explain one-fifth of the heritability for this trait.

Artificial intelligence (AI) system is known to improve dermatologists’ diagnostic accuracy for melanoma. This group applies the eye-tracking technology on dermatologists when diagnosing dermoscopic images of melanomas and reports improved balanced diagnostic accuracy when using an X(explainable) AI system comparing to the standard one.

Periventricular heterotopia (PH) is associated with neurodevelopmental delay. Here authors report patient-derived organoids with FAT4 and DCHS1 mutations mimic PH features, showing hyperactivity, synaptic changes and cell morphological alterations.

Forced expression of C-X-C chemokine receptor type 6 in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer.

Progressive respiratory failure is the primary cause of death in patients with COVID-19, but pathologies in other tissues may also occur. Here the authors report that adrenal tropism of SARS-CoV-2 is associated with adrenalitis, reduced adrenal cortisol levels and severe adrenal damage in a post-mortem case series of patients with severe fatal COVID-19.

The authors defined a roadmap for investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders. Their proof-of-concept study using the largest available common variant data sets for schizophrenia and volumes of several (mainly subcortical) brain structures did not find evidence of genetic overlap.