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Using degron approaches, the authors show that cancer cells experiencing prolonged DNA methylation loss—without substantial DNA damage—undergo non-canonical senescence. This has important potential implications for cancer treatment.

The validation of inhibitors targeting PurF, a novel drug target for tuberculosis drug discovery, is described.

Sadhu et al. identify and functionally validate ferredoxin-1 (FDX1) as a determinant of cholesterol metabolism and cardiovascular risk in Asian populations.

Manchado and colleagues combine CRISPR screening and transcriptomics to identify INPP5A as a dependency and therapeutic target in uveal melanoma driven by mutations in GNAQ/GNA11 and show that IP4 levels correlate with sensitivity to INPP5A loss.

Chondrosarcomas are heterogenous tumours of the bone cartilage and have highly variable prognoses. Here, the authors perform a multi-omics analysis, revealing molecular features that can stratify clinical outcomes.

Prostaglandin E2 from the tumour microenvironment impairs interleukin-2 sensing by tumour-infiltrating lymphocytes, restricting proliferative response and promoting T cell death via metabolic impairment and ferroptosis. 

Structural variations (SV) contribute to inter-individual variability. Here, the authors describe a first-generation multi-ancestry Asian SV catalogue containing 73,035 SVs from 8392 Singaporeans to provide insights into Asian SV diversity.

Ryanodine receptor type 1 (RyR1) are involved in skeletal muscle contraction. Here, the authors show that a transient calcium leak in response to exercise-induced post translational modifications of RyR1 causes mitochondrial remodeling to improve respiration.

Analysis of 20 chemical and morphological plant traits at diverse sites across 6 continents shows that the transition from semi-arid to arid zones is associated with an unexpected 88% increase in trait diversity.

The authors show that sphingolipids, a class of fat molecules, accumulate in skeletal muscle during aging. They demonstrate that reducing sphingolipids improves age-related fitness in mice by enhancing the myogenic response of muscle and present genetic evidence that these findings may also translate to humans.

Sepsis induces a period of immunosuppression which can be problematic in the face of subsequent infectious challenge. Here the authors show the presence of PD-L1 expressing regulatory plasma cells that can inhibit T cells in a murine model and in patients with sepsis.

Anoxia─lack of oxygen─commonly occurs during ischaemic heart disease. Using yeast, worms and mice, Hannich et al. show that anoxia-associated tissue injury and cell death are due to accumulation of a non-canonical sphingolipid, 1-deoxydihydroceramide, that damages the cytoskeleton.

Lazarevic and colleagues show that the transcription factor EGR2 controls a transcriptional program specific to pathogenic T_H17 cells in the CNS.

Fetal brain development is dependent on the maternal supply of long chain polyunsaturated fatty acids (LC-PUFAs). Here, the authors show that pregnancy-induced liver-X-receptor (LXR) signaling in the maternal liver promotes the synthesis of LC-PUFA-containing phospholipids for export to the fetus.

In patient with glioblastoma, a major cause of resistance to chemotherapy and radiotherapy is the high degree to intratumoral heterogeneity and cell plasticity. Here, the authors demonstrate that chemoradiation induces the reprograming of glioblastoma cells into an invasive and vessel co-opting state, termed VC-Resist, capable of promoting resistance to therapy.

Here, using murine models of prostate cancer, the authors show that reduced fecal microbiota alpha-diversity correlates with increased prostate tumor burden, and that Omega-3 prebiotic supplementation reduces prostate cancer up-grading associated with a reduction of gut Ruminococcaceae and fecal butyrate levels.

Histone post-translational modifications control several fundamental processes on DNA. Here, the authors describe a conserved phosphorylation of histone H3 on the globular core and show that it loosens the nucleosome and regulates DNA repair.

The study shows, by using hematopoietic chimeric mice, that mucosal immune cell-derived enkephalins play a pivotal role in maintaining gut homeostasis including visceral sensitivity and normal behavior in mice.

Most melanoma patients do not respond to anti-PD1 therapy. Here, the authors show that TNFα blockade synergizes with anti-PD-1 by preventing anti-PD-1-induced CD8+ T cell death and TIM-3 expression on such cells.

IgA-secreting plasma cells that originate in the intestine are found in the meninges, where they protect the brain against pathogens.

Clinically significant genetic variation in Asian populations is under-characterized. Here, the authors show the diversity in prevalence and spectrum of human disease and pharmacogenetic variants in a multi-ethnic Asian population.

The transcriptional regulation of mitochondrial oxidative phosphorylation gene expression is poorly understood. Using the developing Drosophila flight muscle, the authors identify the transcription factor M1BP as a new major regulator of this process.

There are many patients who do not respond to immune checkpoint inhibitor (ICI) immunotherapy. Here, the authors show a significant negative correlation between sphingosine kinase-1 (SK1) expression and survival for ICI-treated melanoma patients, and further show that targeting SK1 improves response to ICI in mouse cancer models.

Chikungunya virus is a mosquito transmitted untreatable emergent pathogen that causes joint pain and fever. Here the authors perform a host genome-wide loss-of-function screen to identify targets for chikungunya antiviral drugs and validate hits using a mouse model of chikungunya infection.

Termination of RNA polymerase II (RNAPII) transcription is an essential step of gene expression. Here the authors provide evidence that in fission yeast termination of ncRNA genes occurs by a cleavage-dependent mechanism involving recruitment of mRNA 3′ end processing factors and requires the conserved Ysh1/CPSF-73 and Dhp1/XRN2 nucleases.

Using the FANTOM5 CAGE expression atlas, the authors show that bidirectional capped RNAs are a signature feature of active enhancers and identify over 40,000 enhancer candidates from over 800 human cell and tissue samples across the whole human body.

Capturing the 5′ end of transcripts from an input of only 1,000 cells and linking the transcription start sites to downstream sequences allows the analysis of complex transcriptome architecture.

In contrast with conventional views, ultra-large-scale atomistic simulations show that the staged character of strain hardening of metals originates from crystal rotation, whereas the dislocation behaviours remain the same across all the stages.

In a mouse model of breast cancer, asparagine bioavailability strongly influences metastasis and this is correlated with the production of proteins that regulate the epithelial-to-mesenchymal transition, which provides at least one potential mechanism for how a single amino acid could regulate metastatic progression.

High-throughput yeast two-hybrid screening is used to generate the largest C. elegans interactome resource available thus far. Using an empirical quality control framework presented in Venkatesan et al., also online, the data set is evaluated for quality and is used to estimate the total size of the worm interactome.

A catalogue of human long non-coding RNA genes and their expression profiles across samples from major human primary cell types, tissues and cell lines.