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In this work, authors utilise a pan-resistant Pseudomonas aeruginosa in vivo infection model to demonstrate antibiotic re-sensitisation with bacteriophage therapy.

In a recent clinical trial for oral administration of cipargamin in individuals with malaria, there was an emergence of recrudescent parasites with a G358S mutation in PfATP4. In this work, the authors investigate the effect of this mutation on the function of the ATPase, on parasite growth and susceptibility to antimalarial drugs.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

In the TRACERx cohort of 171 patients with lung cancer, the ultrasensitive detection of ctDNA improves preoperative patient stratification, also in early-stage disease.

Genetic heterogeneity and clonal evolution contribute to cancer progression. Here Ma et al.use deep whole-exome sequencing to identify recurrently mutated pathways and clonal architecture in pediatric acute lymphoblastic leukaemia, shedding light on the evolutionary trajectory from diagnosis to relapse

In areas such as animal research and agriculture a single sex is often required in abundance, leading to wasted resources and ethical considerations. Here the authors develop a CRISPR/Cas9 mediated synthetic lethal system that enables the production of single sex offspring that can be repurposed for use in multiple organisms.

The impact of intratumour heterogeneity on immune surveillance and clinical outcomes has not been adequately explored in malignant pleural mesothelioma (MPM). Here the authors analyse the influence of evolution on the survival and immune landscape of MPM patients using multi-region sequencing data.

The study of the brain’s low-dimensional topology enables the dynamic tracking of changes in neural activity. Here authors show how the reshaping of low-dimensional trajectories of brain activity sustain cognition following focal neural perturbations.

Analyses of phenotypic variety in Fungi show that fungal body plans diversified episodically over time and appear distinct because of the extinction of intermediate forms, similar to what has been described in animals.

Lung adenocarcinoma is often curable when diagnosed at an early stage, but a subsection of patients will progress. Here, the authors use multi-omics profiling to show that gene expression data can predict clinical outcome.

The neocortex is a mammalian-specific structure that is responsible for higher functions but details of how it evolved are lacking. Here the authors show that the transposable element family MER130 is highly enriched among the enhancers in the developing mouse neocortex, suggesting a role in the evolution of this structure.

Mutations in components of the MAP kinase pathway are associated with a group of syndromes known as RASopathies. Here, the authors identify gain-of-function mutations in BRAF in patients with RASopathies and congenital hypopituitarisms.  This article demonstrates a central role for BRAF in the development of the hypothalamo-pituitary axis leading to endocrine deficiencies in patients with RASopathies.

Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

This algorithm uses the soft-clipped, unaligned parts of a sequence read to map structural variation in cancer genomes with high predictive accuracy.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

An estimated area of 215 million hectares has the potential for natural forest regeneration across tropical forested countries and biomes, representing an above-ground carbon sequestration potential of 23.4 Gt C.

A multiomic approach profiles the three-dimensional, epigenetic and mutational landscapes of 80 metastatic prostate cancer biopsies. Hi-C experiments identify an extrachromosomal circular DNA at the AR locus associated with therapy resistance.

Microbial communities drive all biogeochemical processes on Earth through spatiotemporal resource partitioning. This study shows how a few mutations in an evolved community can result in niche-differentiated ecotypes, whose interplay synergistically improves productivity of the interacting community across sediment and groundwater subpopulations.

Although immune checkpoint blockade is a standard treatment for patients with malignant mesothelioma, only a minority of patients exhibit radiological response. In a phase II clinical trial (MIST4) investigating the efficacy, safety and molecular correlates of response following treatment with atezolizumab and bevacizumab, the authors demonstrate that the gut microbiota may modulate responsiveness to treatment.

Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.

Yao et al. observe and characterize genomic redistribution of the PBAF complexes upon PBRM1 loss, leading to sustained RELA occupancy by SMARCA4, activation of the NF-kB pathway and enhanced kidney tumourigenesis.

A sequencing chemistry that separates nucleotide identification from nucleotide incorporation achieves high accuracy.

Citizen science taps the efforts of non-experts. Here, authors describe Drugit, an extension of the crowdsourcing game Foldit, and its use in designing a non-peptide binder of Von Hippel Lindau E3 ligase for use with proteolysis targeting chimeras.

BET-bromodomain inhibitors could be used to treat medulloblastoma tumors with Myc amplifications. Here, the authors show that both the response and resistance to BET inhibitors in mice is mediated by bHLH/homeobox transcription factors.

Multi-ancestry genome-wide analyses identify new risk loci for age-related macular degeneration. Ancestry-specific analyses identify distinct effects at major risk loci, including smaller effect sizes for CFH risk alleles in haplotypes of African ancestry.

Ruth Loos and colleagues report results of a large genome-wide association study for body mass index. They identify 18 new loci associated with this trait, some of which map near key hypothalamic regulators of energy balance.

Kyle Gaulton, Mark McCarthy, Andrew Morris and colleagues report fine mapping and genomic annotation of 39 established type 2 diabetes susceptibility loci. They find that the set of potential causal variants is enriched for overlap with FOXA2 binding sites in human islet and liver cells, and they show that a likely causal variant near MTNR1B increases FOXA2-bound enhancer activity, providing a molecular mechanism to explain the effect of this locus on disease risk.

Gene expression is regulated by enhancers and super-enhancers, which can be identified by chromatin profiling. Here, the authors surveyed gastric cancer samples and cell lines to identify enhancer elements exhibiting somatic alterations.

Analysis of autosomal recessive coding variants in 29,745 trios from the DDD study and GeneDx provides insights into the genetic architecture of developmental disorders across ancestrally diverse populations.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

Somasekar Seshagiri, James Brugarolas and colleagues report the mutational landscape of 167 non–clear cell renal cell carcinomas (nccRCCs) from multiple subtypes. They identify subtype-specific driver mutations and gene fusions, including ones involving MITF, which result in expression of the anti-apoptotic protein BIRC7 and might thus indicate candidates for treatment with BIRC7 inhibitors.

Rebecca Fitzgerald and colleagues used genome sequence analyses to study the progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) and found that the majority of recurrently mutated genes in EAC were also mutated in precursor lesions and that only mutations in TP53 and SMAD4 were stage specific.

Somatic mutations obtained from laser microdissected biopsies of human tissues are used to reconstruct the developmental phylogenies of these tissues back to the zygote.

Chronic myelomonocytic leukaemia is classified as proliferative (pCMML) or dysplastic based on the white blood cell counts but biological differences are unclear. Here, the authors show genetic, transcriptomic and epigenomic differences between these two subtypes establishing that pCMML is RAS-pathway driven and that inhibiting RAS-driven PLK1 expression is a viable therapeutic target.

The incidence of esophageal squamous cell carcinoma varies significantly across different geographical regions. Mutational signature analysis of tumors sampled from high- and low-incidence areas suggests that these variations may not be explained by mutagenic exposures.

Risk variants for ALS and FTD in the synaptic gene UNC13A increase the expression of an UNC13A cryptic exon in neurons with TDP-43 depletion.

The earliest known human burial in Africa, that of a young child, is dated to around 78,000 years ago.

Malignant rhabdoid tumours (MRT) have been suggested to originate in the ectoderm-derived neural crest. Here, the authors analyse MRTs using phylogenetics, scRNA-seq, and patient-derived organoids; they find evidence for an MRT origin in the neural crest lineage and suggest differentiation treatment with HDAC/mTOR inhibitors.

Neuroendocrine carcinomas (NECs) arise from different anatomic sites, but have similar histological and clinical features. Here, the authors show that the epigenetic landscape of a range of NECs converges towards a common epigenetic state, while distinct subtypes occur within neuroendocrine prostate cancer contributing to intratumor heterogeneity in clinical samples.

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

Here the authors describe a simple reverse genetics method that relies on overlapping cDNA fragments for generation of positive-strand viruses including SARS-CoV-2 and characterize them in vitro and in vivo.

Using a multi-OMICS approach, Haas et al identify 54 human genes and 16 host-targeting chemical compounds that regulate influenza A virus infection in lung epithelial cells, including AHNAK and COBP1 which are also essential for SARS-CoV-2 infection.

The molecular mechanisms that maintain thymic epithelial cell (TEC) identity throughout life are incompletely understood. Here, the authors demonstrate that the transcription factor, Ovol2, maintains post-natal TECs by preventing their epithelial-to-mesenchymal transition.

MLKL is regarded as an executor of the necroptotic inflammatory cell death pathway. Here authors show, by introducing a mutation into mouse MLKL representing a frequently occurring human single nucleotide polymorphism, that MLKL mutations could critically alter the inflammatory response and the clearance of Salmonella from organs upon infection.

Using whole-genome and single-cell RNA sequencing data of patients with multiple myeloma treated with carfilzomib, lenalidomide, dexamethasone and daratumumab, Maura et al. identify distinct genomic drivers and microenvironment changes affecting outcome.