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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.

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.

Single-nucleus and spatial, whole-transcriptome profiling of 43 pancreatic adenocarcinomas provides a refined molecular and cellular classification, highlighting a new neoadjuvant treatment-associated neural-like progenitor tumor cell state.

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.

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.

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.

Radiotherapy induces expression of the EGFR ligand amphiregulin, which promotes metastasis growth at remote sites in mouse models and human patients by shifting myeloid cells towards an immunosuppressive state.

Targeted protein degradation of cell-surface glycoproteins suppresses cancer in mice.

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.

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.

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.

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.

Neuropil regions across the fly brain are activated by locomotion. Here, authors show that this movement-related activity involves most neurons in the dorsal fly brain, including genetically defined neurons with known, seemingly unrelated functions.

Woermann and colleagues describe a deaminase-independent function for APOBEC3A in initiating chromosomal instability and STING-dependent metastasis in human and mouse pancreatic cancer.

Human immunodeficiency virus type 1 (HIV-1)-neutralizing responses can persist for several years, even at low antigen levels, suggesting that an HIV-1 vaccine may be able to elicit a durable antibody response.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Controversy exists over the function of plasma membrane versus intracellular vesicular LAT in T-cell receptor signaling. Here the authors use high resolution imaging of the temporal dynamics of LAT involvement to show that both sources of LAT are required, but at distinct stages.

By exploiting the relationship between the transcription factor MYC and the transferrin receptor, where the level of transferrin receptor 1 expression may indicate activation of the MYC oncogenic pathway, Jason Holland and his colleagues have developed a novel PET radiotracer to quantitatively and noninvasively measure MYC activity. The ⁸⁹Zr-desferrioxamine transferrin PET radiotracer was tested in several murine models of inflammation and MYC-driven prostate cancer.

COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.

Howard Chang, Ravindra Majeti and colleagues define the chromatin accessibility and transcriptional landscapes in 13 human primary blood cell types and in acute myeloid leukemia cells. They identify potential regulators governing hematopoietic differentiation and genetic elements linked to regulatory evolution in cancer cells.

Mitochondria are asymmetrically inherited during cell division, a process that can affect cell fate and lifespan. Here the authors describe a mechanism for mitochondrial quality control in yeast that maintains a reservoir of high-functioning mitochondria in mother cells and preserves maternal reproductive capacity.

Craft and colleagues show that follicular helper T cells progress through transcriptionally and functionally distinct stages that provide specific signals for germinal center regulation.

The intratumoural injection of recombinantly expressed cytokines bound tightly to the common vaccine adjuvant aluminium hydroxide leads to weeks-long retention of the cytokines in the tumours with minimal side effects, as shown in multiple syngeneic mouse models.

Koh et al. show that loci active in differentiated effector T cells are poised in early T precursors before the expression of T cell antigen receptors in a manner dependent on the chromatin remodeling complex mammalian SWItch/Sucrose Non-Fermentable and the PU.1–RUNX1 and BCL11B–RUNX1 complexes.

Ancestral sequence inference, directed evolution, structural analysis, NMR, and molecular dynamics simulations illuminate how enantioselective activity arises during the evolutionary trajectory of chalcone isomerase from a noncatalytic ancestor.

Duplications of gene segments can allow novel physiological adaptations to evolve. A detailed analysis of the TCAF gene family in primates and archaic humans suggest rapid duplication and diversification in this gene family is associated with cold or dietary adaptations.

Alum coupled to protein immunogens via site-specific phosphoserine-containing linkers enhances long-lived B cell responses and can selectively direct antibodies toward protective neutralizing epitopes.

Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.

An example of hybrid incompatibility between maize and teosinte reveals a selfish toxin–antidote system mediated by small RNAs that may have contributed to the origin of maize.

The Human Microbiome Project Consortium has established a population-scale framework to study a variety of microbial communities that exist throughout the human body, enabling the generation of a range of quality-controlled data as well as community resources.

The immediate early gene Arc has been implicated in many forms of synaptic plasticity. This report finds that in mice lacking Arc, the visual cortex remains unmodified by deprivation or experience, suggesting that Arc expression is among the mechanisms that are critical for experience-dependent plasticity.

Molecular alterations in ctDNA of patients with mantle cell lymphoma uncovers mutations in SWI–SNF associated with resistance to ibrutinib and venetoclax combination and provide a rationale for restoring sensitivity through Bcl-xL inhibition.

Electron cryo-microscopy density maps of mouse TMEM16A reconstituted in nanodiscs or solubilized in detergent reveal two functional states of calcium-activated chloride channels.

Computational methods for the de novo design of conformationally restricted peptides produce exceptionally stable short peptides stabilized by backbone cyclization and/or internal disulfide bonds that are promising starting points for a new generation of peptide-based drugs.

A deep-learning-based strategy is used to design artificial luciferases that catalyse the oxidative chemiluminescence of diphenylterazine with high substrate specificity and catalytic efficiency.

Med-PaLM, a state-of-the-art large language model for medicine, is introduced and evaluated across several medical question answering tasks, demonstrating the promise of these models in this domain.

Masopust and colleagues show that mucosal tissue-resident memory T cells proliferate in situ in response to local antigen and dominate the local recall response.

Congenital heart disease (CHD) is a disorder that occurs in ∼1% of live births. Here the authors describe a genome-wide allele-specific expression analyses in CHD patients, identifying five new genes involved in CHD and showing that paternally-expressed imprinted genes are monoallelic, while maternally-expressed imprinted genes are biallelic.

The proteasome complexes, composed of 20S core particles and one or two regulatory particles (proteasome activators), degrade most eukaryotic proteins. Here, the authors identify a sequence motif and resolve its interactions mediating the activation of the human 20S proteasome.

GWAS have identified risk loci for osteoarthritis (OA), but the causal variants still have to be determined. Here, the authors apply a massively-parallel reporter assay to screen 1,605 candidate SNPs in 35 OA loci, which prioritizes six SNPs in four loci, one of which, rs4730222, is characterized in more detail.

Protein antigens, such as HIV envelope protein, require adjuvants for high immunogenicity. Here the authors show that a combined adjuvant approach with slow antigen delivery and potent ISCOMs adjuvant primes robust germinal center activity and humoral immunity in non-human primates. pSer-modified antigen shifts immunodominance to allow subdominant epitope-targeting of rare B cells.

We quantify mitochondrial DNA copy number and heteroplasmy levels and study their association with nuclear genetic loci in population-scale biobanks.

Fluorescent protein reporters based on GFP exist, but have intrinsic disadvantages. Here the authors incorporate pH, Ca²⁺ and protein–protein interaction sensing modalities into de novo designed mini-fluorescence-activating proteins (mFAPs), with increased photostability and smaller size, which bind a range of DFHBI chromophore variants.

Papsdorf et al. show that mono-unsaturated fatty acids extend lifespan of C. elegans through induction of peroxisomes and lipid droplets in fat tissues and of a lipid signature predictive of decreased lipid oxidation.