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Previous studies of Teneurins identified an uncharacterized family of Teneurin-like proteins in bacteria. Here, the authors show these proteins are widespread across both Gram groups but limited to certain species, where they form barrel-like structures that encapsulate a toxin and are co-expressed with potent immunity genes.

Thrombin is a key proinflammatory protease regulating leukocyte trafficking at sites of vascular injury. Here the authors show that balanced thrombin interactions with platelet proteins PAR4, GPIbα and fibrin plays a major role in regulating this process.

A red blood cell haemostatic mechanism induced by dying ECs functions independently of platelets and fibrin.

Early drivers of T2D include ectopic fat accumulation that impairs insulin sensitivity. Here, the authors show that GLP1/GCGR dual agonism provides multimodal benefits in obese male mice by reducing liver fat and improving insulin sensitivity resulting in endogenous β-cell recovery.

The anti-tumour effect of immune checkpoint inhibitors is potentiated by CD137 agonists in preclinical models, but translation of these results to the clinical practice is hampered by toxicity. Authors describe here a human CD137xPD-L1 bispecific antibody with improved anti-cancer activity whilst maintaining low toxicity in non-human primates.

Clear cell renal cell carcinoma (ccRCC) bears the hallmark loss of VHL but remains incurable. Here, the authors identify the SLC1A1 dicarboxylic amino acid transporter as an actionable, oncogenic, HIF-independent, metabolic dependency in VHL-deficient ccRCCs.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Robbins and colleagues show that cigarette smoke-induced endothelial dysfunction enables atherosclerotic plaque macrophages to drive abdominal aortic aneurysm formation in a mouse model of atherosclerosis.

Bovine fibroblast cell line generation without genetic modification is characterized. A technoeconomic analysis demonstrates the potential for price-competitive, scaled-up cultivated beef production.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

DART (drug acutely restricted by tethering) enables the manipulation of native receptors on genetically defined neurons. This work describes second-generation DART reagents for manipulating GABA_A and AMPA receptors with higher cellular specificity than previously achieved.

Diabetes is associated with an increased thrombotic response, but the mechanism is unknown. Here the authors demonstrate that compressive force activates integrin α_IIbβ₃ on discoid diabetic platelets and that platelet aggregates can be eliminated by PI 3-kinase inhibition, but not by anti-thrombotics aspirin or clopidogrel.

Isolation and optimization of antibodies targeting the malaria parasite may offer the potential for immediate protection as a prophylactic intervention to prevent severe disease.

The lipid kinase PI3KC2α is essential for embryogenesis, yet its role in adult homeostasis is unknown. Here, the authors show that PI3KC2α regulates the structure of the internal membrane reserves of murine megakaryocytes and platelets, affecting the platelets’ adhesiveness and prothrombotic function.

Upconversion nanoparticles offer the potential for deep tissue biological imaging. Here, Chen et al. develop super resolution optical imaging in the near-infrared for imaging with sub-50 nm resolution through almost 100 microns of tissue.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

In male mouse germline development, the precise DNA methylation of young, active transposons requires a two-step process in which SPIN1 and SPOCD1 mark young LINE1 elements before the piRNA pathway triggers DNA methylation.

The TRAIP E3 ubiquitin ligase is essential for genome integrity, mutations lead to primordial dwarfism in patients. Here, the authors show that TRAIP degradation in S-phase, results in cell arrest due to DNA damage caused by replication-transcription conflicts.

Discovering molecular pathways that sensitize cells to poly(ADP-ribose) polymerase (PARP)- trapping inhibitors is important for anti-cancer therapy. Here, the authors report that inactivation of the CHD6 chromatin remodelling enzyme sensitizes cells to PARP inhibitors via reduced abasic site repair, PARP-1 accumulation on chromatin, and replication stress.

Irradiation treatment for cancer therapy often causes irreparable damage to adult organs. Knox and colleagues study irradiated mouse submandibular salivary glands and find that restoring parasympathetic nerve function with the neurotrophic factor neurturin improves regeneration.

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.

The thalamic nucleus reuniens coordinates oscillations between the hippocampus and medial prefrontal cortex during emotional memory retrieval. Here the authors show that theta-paced optogenetic stimulation of this network can suppress the retrieval of aversive memories and prevent fear relapse after extinction.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

Iron overload can be either hereditary or acquired via transfusions, and current treatments include the use of iron chelators that have adverse effects in some patients. Here the authors modify siderocalin to enhance iron excretion in urine, and demonstrate therapeutic efficacy in iron overload mouse models.

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.

Antibody production is the main effector function of B cells. Rawlings and colleagues show that Trypanosome cruzi induces rapid IL-17 production by B cells that is required for parasite control.

A transmembrane O-glycoprotein podoplanin (PDPN) expressed on fibroblastic reticular cells is the activating ligand for platelet receptor CLEC-2; this interaction leads to perivenular release of sphingosine-1-phosphate and expression of VE-cadherin on high endothelial venules, a key process for the maintenance of vascular integrity in lymph nodes.

How the neural crest gains its pluripotency-like stem cell potential is unclear. Here, the authors show that the entire post-gastrula ectoderm maintains expression of pluripotency genes, leading to the high stem cell capacity in the neural crest.

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.

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.

The T cell receptor β-chain is expressed in two isoforms, TRBC1 and TRBC2, with clonally expanded mature T cell lymphomas expressing one of them exclusively, while healthy T cells randomly express either TRBC1 or TRBC2. Here authors show structure-based design of a TRBC2-specific antibody, and depletion of malignant T cells carrying TRBC1 or TRBC2 with CAR-T cells against the cognate receptor chain in murine models.

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.

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.

Platelets express negatively charged phosphatidylserine (PS) on their plasma membrane when propagating coagulation within a developing thrombus. Here the authors show that an adaptor protein 14-3-3 regulates mitochondrial function and PS exposure and thus platelet procoagulant activity, promising a new therapy to reduce thrombosis.

New tuberculosis therapies, targeting respiratory chain components of Mycobacterium tuberculosis, are under development. Here the authors show that, contrary to common belief, some of these components are not essential for pathogen viability and/or virulence in animal models of infection.

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.

Arginine methylation has been reported to regulate AKT-associated signalling. Here, the authors show that PRMT5-mediated arginine methylation promotes AKT activity and induces tumourigenesis.

Here, the authors characterize two distinct T_reg cell populations in the visceral adipose tissue of lean and high-fat diet-fed mice. ST2⁺ T_reg cells are dominant in male mice and are transcriptionally driven by GATA3 and PPARγ, regulators that limit the differentiation of the more female-dominant population of CXCR3⁺ T_reg cells that are T-bet dependent. Functional distinctions are also evident in glucose tolerance and adipose inflammation.

Oxidized products of low-density lipoproteins (LDLs) activate platelets through CD36, demonstrating a link between deregulated lipoprotein levels, oxidative stress and thrombosis (pages 1086–1095).

Presented is a study of gene regulation during development using a combination of chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) and directed differentiation of mouse embryonic stem cells inducibly expressing epitope-tagged transcription factors.

Using an in silico network-based discovery approach, the authors identified sildenafil as a repurposable drug for Alzheimer’s disease. Analyzing insurance claims data from over 7 million individuals, they found that sildenafil usage was associated with a reduced risk of Alzheimer’s disease diagnosis.

Alcoholism and post-traumatic stress disorder are frequently co-morbid. The authors show that chronic intermittent exposure to ethanol impairs extinction of fear conditioning in mice. In vivo recordings showed that extinction encoding was impaired in infralimbic medial prefrontal cortical (mPFC) neurons, which are associated with downregulation of the NMDA receptor subunit GluN1 in mPFC.

Dorsal membrane ruffles in macrophages accompany pathogen contact and appear before macropinocytosis and phagocytosis. Here, the authors show that these structures are the sites of the accumulation of Toll-like receptor 4 complexes involved in the signalling cascade activated by bacterial lipopolysaccharide.

In this study, Mazzoni et al. describe the mechanism behind the combinatorial action of transcription factors in cell type specification. Specifically, the authors reveal that Isl1 cooperates with Phox2a or Lhx3 in programming modules that regulate differential specification of spinal motor neurons vs. cranial motor neurons.

Activation of integrin αIIbβ3 at the surface of platelets is required for their aggregation and for thrombus formation. Here Xu et al. identify apolipoprotein A-IV as a novel ligand for platelet αIIbβ3 integrin, and find it inhibits platelet aggregation and thrombosis.

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.