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Progressive diseases tend to be heterogeneous in their underlying aetiology mechanism, disease manifestation, and disease time course. Here, Young and colleagues devise a computational method to account for both phenotypic heterogeneity and temporal heterogeneity, and demonstrate it using two neurodegenerative disease cohorts.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

Jacks and colleagues demonstrate the effects of neoantigen expression level on T-cell priming and immune surveillance during tumor development and progression and explore implications for immunotherapies, using in vivo models of colorectal cancer.

Structural comparison of predicted viral protein structures with known protein structures suggests taxonomic relationships and functions for up to 25% of unannotated viral proteins, including many with putative functions in host immune evasion.

MaizeCODE maps active regulatory regions tied to maize domestication traits in a diverse panel of tissues and inbreds. It reveals bi-directional enhancer RNAs and the molecular conflicts between activity and silencing of non-coding regions.

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.

Fine-tuning the RoseTTAFold structure prediction network on protein structure denoising tasks yields a generative model for protein design that achieves outstanding performance on a wide range of protein structure and function design challenges.

Targeted protein degradation (TPD) can be employed to eliminate disease-causing proteins. Here, the authors present CYpHER, a TPD tool that uses molecules engineered for intracellular target release with drug recycling via transferrin receptor. CYpHER induces depletion of extracellular targets in vitro and in xenograft tumours.

Cristinziano et al. report the use of bacteriophages and dual beta lactam antibiotics to treat a patient with a Mycobacterium abscessus sternal wound infection. One of the phages was epigenetically modified for specificity to the M. abscessus strain.

A rare case of asymptomatic dominantly inherited Alzheimer’s reveals confined tau pathology and unique proteomic features, highlighting potential resilience mechanisms decades beyond expected onset.

Computationally designed sensors map the activity and signaling environment of Ras.

This study finds that sST2 is a disease-causing factor for Alzheimer’s disease. Higher sST2 levels impair microglial Aβ clearance in APOE4⁺ female individuals. A genetic variant, rs1921622, is associated with a reduction in sST2 level and protects against AD in APOE4⁺ female individuals.

Generation of memory B cells is crucial for protective immunity to infectious agents. Cyster and colleagues show that the transcription factor Hhex interacting with Tle3 promotes memory B cell generation.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Analysis of behaviour, physiology, anatomy and connectomics in Drosophila shows how direction-specific visual information is transformed onto downstream premotor networks and converted into appropriate motor responses.

The Somatic Mosaicism across Human Tissues Network aims to create a reference catalogue of somatic mosaicism across different tissues and cells within individuals.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Engagement of T cell receptors (TCRs) induces the formation of microclusters that mediate the downstream signalling events. Here the authors show, using high resolution TIRF-SIM and live cell imaging, that ZAP70 and LAT are recruited to TCR with distinct kinetics, with the delayed ZAP70-TCR association modulated by TCR-induced calcium flux.

PIEZO2 is expressed in the bladder urothelium and sensory neurons innervating the lower urinary tract and is a key mechanosensor for the control of urination.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

The kākāpō is an intensively managed parrot endemic to New Zealand. Using genome sequencing data for all living kākāpō together with long-term phenotypic data, the authors devise an approach to identify genetic associations with fitness traits, which is informing species recovery plans.

Cyster and colleagues show that CD97–CD55 interactions, which trigger Gα₁₃–ARHGEF–Rho cytoskeletal signaling, are needed for proper MZ B cell positioning/retention in the spleen and for optimal antibody responses to T cell-independent antigens.

The RNA endonuclease CPSF3 was identified as the cellular efficacy target of the small molecule JTE-607, revealing pre-mRNA processing as a vulnerability in cancers such as Ewing’s sarcoma that are characterized by aberrant transcription.

Even if it doesn't trigger action potential, a slight somatic depolarization can still spread and modulate the neurotransmitter release at distant sites along axons. Here, the authors find that depolarization in the cerebellar molecular layer interneurons can affect presynaptic neurotransmitter release in a calcium-dependent and voltage-sensitive Ca²⁺ channel–dependent manner.

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.

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

Designed novel protein nanoparticle technology integrates antibody targeting and responds to changes in environmental conditions to release protected molecular cargoes, opening new applications for precision medicine.

The use of PET for detection of Aβ in the brain in AD has limitations; studies also indicate that retinal changes, including Aβ deposition, occur in AD. Here the authors demonstrate the potential to use in vivo retinal hyperspectral imaging as a surrogate for brain accumulation of Aβ.

The sustained release of both hydrophilic and hydrophobic immunomodulators for metastatic melanoma by nanoscale liposomal polymeric gels administered intratumorally or systemically is demonstrated. It is also shown that such a co-delivery approach delays tumour growth and increases the survival of tumour-bearing mice, and that its efficacy results from the activation of both innate and adaptative immune responses.

Deep X-ray limits are placed on the source of the closest fast radio burst, FRB 20200120E, ruling out an ultraluminous X-ray source or a young extragalactic pulsar embedded in a Crab-like nebula as its origin.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

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.

Most genomics research cohorts are made up of participants of European ancestry, which limits the reach of precision medicine. Here, the authors describe the genetic diversity in the All of Us research program, which is enriched in underrepresented ancestries.

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.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

Nsp15 is an endoribonuclease that helps coronaviruses evade detection of host immune sensors. Here, the authors combine biochemistry, NMR, and cryo-EM to show that spontaneous base flipping drives specificity in double stranded RNA substrates.

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.

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.

The BIN1 SNP rs744373 is associated with higher CSF tau and phosphorylated tau levels. Here the authors show, using PET imaging, that this SNP is associated with tau accumulation in the brain as well as impaired memory in older individuals without dementia.

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.

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.

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.

Whether Alzheimer’s disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

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.