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High IL1RL1 correlates with poor survival in acute myeloid leukemia. A stress-driven IL-33/IL1RL1 loop induces leukemogenesis and a tolerogenic immune environment. Targeting this axis with bispecific antibodies offers a promising treatment.

How neural crest development is specifically regulated by splicing factors and its vulnerability to splicing dysregulation remains unclear. Here, the authors identify neural crest-specific and somite-specific splicing complexes that confer distinct susceptibility to splicing perturbation.

Therapeutic checkpoint for acute myeloid leukemia requires further investigations. The authors here identify ST2⁺ Treg cells facilitate AML growth by inducing CD8⁺ T cell depletion and exhaustion, while targeting ST2 by antibodies depletes ST2⁺ Treg cells and improves AML prognosis.

Trained and validated on multimodal data from 14.5 million images from multicountry datasets, a foundation model is shown to increase diagnostic and referral accuracy of clinicians when used as an assistant in a trial involving 16 ophthalmologists and 668 patients.

Here the authors provide exploratory analyses of a clinical trial evaluating immunogenicity of inactivated and mRNA SARS-CoV-2 vaccines, and show that CoronaVac primed groups have disparate T cell responses and nucleocapsid specific antibodies compared to BNT162b2 that may protect in the absence of robust neutralizing antibody responses.

The lack of appropriate models restricts pre-clinical research for nasopharyngeal carcinoma (NPC). Here the authors report the development and characterization of NPC patient-derived xenografts (PDXs), and EBV positive NPC cell line from patient tumor, and suggest their potential use in future NPC research.

Using a globally coordinated strategic conservation framework to plan an increase in ocean protection through marine protected areas can yield benefits for biodiversity, food provisioning and carbon storage.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

Convergent strains, those containing characteristics of both multidrug-resistant & hypervirulent Klebsiella pneumoniae, are a global threat to public health. In this work, authors analyse convergent isolates from the United States and reveal unexpectantly low virulence.

Cdk5-mediated phosphorylation of endophilin B1 is shown to be required for autophagy induction in starved neurons, by promoting endophilin B1 dimerization and recruitment of the autophagy regulator UVRAG. This effect leads to neuronal loss in models of Parkinson’s disease.

Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.

Using a knock-in strategy to ablate a Cdk5-targeted serine phosphorylation site on residue 478 of the TrkB receptor, the authors demonstrate the role of this phosphorylation in activity-dependent functional and structural plasticity, as well as in learning and memory. They further show that TIAM1 and Rac1 act downstream of TrkB S478 phosphorylation during spine remodeling.

Using a high-quality chromosome-scale assembly of the faba bean genome, the genetic basis of seed size and hilum colour is explored.

How cells coordinate chromatin dynamics with the cell cycle machinery to promote genome duplication during S phase is still a matter of study. Here the authors reveal by in vitro reconstitution assays that the AAA + -ATPase containing Yta7 protein in S. cerevisiae promotes chromatin.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

Understanding the structural basis for the inhibition of archaeal eukaryotic-like RNA polymerases (RNAPs) during virus infection is of interest for drug design. Here, the authors present the cryo-EM structures of apo Sulfolobus acidocaldarius RNAP and the RNAP complex structures with two regulatory factors, RIP and TFS4 that inhibit transcription and discuss their inhibitory mechanisms.

Genome-wide association meta-analyses identify 26 risk loci for epilepsy, including 19 loci specific to genetic generalized epilepsy. Prioritized candidate genes implicate synaptic processes and overlap with targets of antiseizure medications.

Structural studies on the yeast transcription coactivator complex SAGA (Spt–Ada–Gcn5–acetyltransferase) provide insights into the mechanism of initiation of regulated transcription by this multiprotein complex, which is conserved among eukaryotes.

The crystal structure of the complete 14-subunit RNA polymerase (Pol) I from yeast is determined, providing insights into its unique architecture and the possible functional roles of its components.

Multimodal AI combines different types of data to improve decision-making in fields such as healthcare and engineering, but work so far has focused on vision and language models. To make these systems more usable in the real world, Liu et al. discuss the need to develop approaches with deployment in mind from the start, working closely with experts across relevant disciplines.

Cytosolic coat proteins capture secretory cargo and sculpt membrane carriers for intracellular transport, such as COPII which mediates Endoplasmic Reticulum to Golgi trafficking of thousands of cargoes. Here authors visualise the complete, membrane-assembled COPII coat by cryo-electron tomography and subtomogram averaging, revealing the full network of interactions within and between coat layers.

Increased risk of premature cardiovascular disease in systemic lupus erythematosus (SLE) is not well understood, but in animal models, the Janus kinase inhibitor tofacitinib improves related phenotypes. Here the authors report a Phase 1 double-blind randomized trial that shows tofacitinib is safe and well tolerated in in patients with SLE.

A meta-analysis of exome-wide association studies for blood lipid levels in East Asian populations identifies a novel coding variant. Exome array data from the Global Lipids Genetics Consortium were integrated and led to the discovery of novel and population-specific variants associated with cholesterol and triglycerides.

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

High-throughput methods based on droplet microfluidics and size-exclusion selection allow for the identification of genetic and cellular drivers of syncytium formation induced by the spike protein of SARS-CoV-2 and of inhibitors of such cell–cell fusion.

Sexual dimorphism in genetic vulnerability to schizophrenia, systemic lupus erythematosus and Sjögren’s syndrome is linked to differential protein abundance from alleles of complement component 4.

During gene transcription, RNA polymerase (Pol) II moves forward along DNA and synthesizes mRNA. However, Pol II can also move backwards and stall, which is important for regulatory purposes or when the polymerase hits an obstacle such as a nucleosome. This arrested state is reactivated by the transcription factor TFIIS. Here, a crystal structure is presented of a backtracked yeast Pol II complex in which the backtracked RNA can be observed, plus a structure of a backtracked complex that contains TFIIS. A model is presented for Pol II backtracking, arrest and reactivation during transcription elongation.

Imidazolopiperazines (IZPs) are a class of compounds under clinical development for malaria, but their mechanism of action is unclear. Here, the authors show that IZPs inhibit the parasite’s secretory pathway, affecting protein trafficking and export.

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.

The archaeal RNA transcription machinery does not have a dedicated helicase factor. Here, the authors report the three-dimensional architecture of the open complex of DNA, RNA polymerase and its associated factors from M. jannaschii, providing a possible mechanism for promoter DNA melting.

Eukaryotic origin firing depends on assembly of the Cdc45-MCM-GINS (CMG) helicase, which requires the leading-strand polymerase Pol ɛ. Here the authors present a structural analysis of a CMG Pol ɛ on a DNA fork, providing insight on the steps leading productive helicase engagement to the DNA junction.

Pseudomonas aeruginosa bacteremia is presumed to be a ‘dead-end’ for the pathogen and to have no impact on transmission. Here the authors show, in mice, that the bacteria can spread from the bloodstream via the gallbladder to the intestines and feces, leading to transmission to uninfected animals.

Mitochondrial DNA is transcribed by a single-subunit RNA polymerase (mtRNAP) that is distantly related to the RNAP of bacteriophage T7. Together with biochemical data, the crystal structure of the mtRNAP elongation complex with DNA template and RNA transcript elucidates the elongation mechanism of mtRNAP and reveals striking differences as compared with the T7 transcription system.

This study uses gene expression predictors for the dorsolateral prefrontal cortex and other brain regions to perform a transcriptomic imputation analysis of schizophrenia, identifying 413 genic associations across 13 brain regions and 36 significantly enriched pathways.

Routine eye clinic imaging could help screen patients with cardiovascular risk as studies indicate strong associations between biomarkers in the retina and the heart. This potential is supported by a multimodal study, employing a deep learning model, that can infer cardiac functional indices based on retinal images and demographic data.

A randomized trial in patients hospitalized with COVID-19 showed no benefit and potentially increased harm associated with the use of convalescent plasma, with subgroup analyses suggesting that the antibody profile in donor plasma is critical in determining clinical outcomes.

Transcript cleavage factors such as eukaryotic TFIIS assist the resumption of transcription following RNA pol II backtracking. Here the authors find that one of the Sulfolobus solfataricus TFIIS homolog—TFS4—has evolved into a potent RNA polymerase inhibitor potentially involved in antiviral defense.

Identification of response biomarkers is a key step towards the development of personalised care. Here, Jayson et al. identify plasma Tie2 as a biomarker for the response of the tumor vasculature to anti-angiogenics in patients with metastatic colorectal cancer, suggesting that monitoring Tie2 levels may help guide therapy in the clinics.

Analysis of the FGF14-SCA27B repeat locus identifies a common 5′-flanking insertion that represents the major allele, is present exclusively on nonpathogenic alleles, enhances repeat stability and increases chromatin accessibility.

Multi-ancestry genome-wide association analyses identify new risk loci for Parkinson’s disease, and fine-mapping and co-localization analyses implicate candidate genes whose expression is associated with disease susceptibility.

Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.

NuA4 is a highly conserved histone acetyltransferase complex that functions in transcription and DNA repair. Four groups have recently determined the structure of NuA4 from two different yeasts using cryo-EM, revealing important mechanistic details of its function and allowing a detailed comparison to the related SAGA complex.