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It remains unknown why only some sickle cell disease (SCD) patients develop lung thrombosis. Here, the authors show that an extracellular vesicle-dependent mechanism prevents lung thrombosis in SCD and how a CD39 polymorphism impairs this protection to promote lung thrombosis in subset of patients.

Here the authors show that PARP inhibition activates SIRT-1–FOXO1 signaling to drive transcriptional and metabolic reprogramming of CD8⁺ T cells into central memory T cells with superior recall capacity and efficacy in adoptive therapy.

Cancer immunotherapy benefits from antibody-lectin chimeras that block glyco-immune checkpoints.

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.

The authors present Gemini, their bifunctional replicon platform capable of functioning as either self-amplifying RNA (saRNA) or self-amplifying DNA (saDNA).

The emergence of SARS-CoV-2 variants resistant to neutralizing antibodies poses a constant threat. Here, the authors identify a camelid antibody targeting ACE2 which broadly inhibits infection and provides antiviral protective effects in vivo after nasal inoculation.

Plasma cells (PC) contribute to the pathogenesis of autoimmune diseases by secreting autoantibodies. Strategies to target pathogenic PCs are thus required. Here, the authors profile different PC subsets in naïve and lupus-prone mice and report the emergence and expansion of a CD19^– PC subset in diseased mice that could compromise the effectiveness of CD19-targeting therapies.

The enteric nervous system integrates microbial cues to regulate gut function. Using an optogenetic gut culture model, authors show lineage- and frequency-specific neuronal control of immune responses and barrier integrity, shaped by gut microbes.

The authors found that the Alzheimer’s disease-associated protein tau, widely considered pathogenic when hyperphosphorylated, has a natural function as part of the innate immune system in the brain and can protect against herpes simplex virus 1.

Scourzic et al. show that germinal centre B cells display an enhanced ability to reprogram to induced pluripotent stem cells compared to mature B cells. This ability indicates their higher plasticity level and is T follicular helper cell-dependent.

Identifying jets originating from heavy quarks plays a fundamental role in hadronic collider experiments. In this work, the ATLAS Collaboration describes and tests a transformer-based neural network architecture for jet flavour tagging based on low-level input and physics-inspired constraints.

After spinal cord injury, lesion-remote astrocytes acquire heterogeneous, spatially restricted reactivity states that shape neuroinflammation, neural repair and neurological recovery.

The enzyme ABHD18 is shown to have a key role in cardiolipin metabolism in mitochondria, offering a potential route for a small-molecule treatment of the rare genetic disease Barth syndrome.

Clear cell renal cell carcinoma (ccRCC) usually metastasizes to the lungs. Here, the authors discover that SWI/SNF ATPase subunit SMARCA4 silencing of HLF regulates ccRCC lung metastasis by modulating the integration of collagen's mechanical cues with the actin cytoskeleton through leupaxin.

Adjuvants are an important component of modern vaccines. Here, the authors employ a phenotypic screen of ~200k compounds and identify PVP-057, a TLR3 agonist with a simple scalable 3-step synthesis, as an adjuvant that induces durable humoral and cellular immunity to varicella-zoster virus (VZV) gE in mice.

Whether and how hypothalamic neurons can lose or change their identity in adulthood has remained elusive. Here, the authors show that mature pro-opiomelanocortin (Pomc) neurons contain invisible ‘Ghost’ subsets with atypical identities that are recruited in response to obesogenic stimuli.

The major site of action for obesity treatments based on GLP1R agonists is at the level of the brainstem where neurons share receptors for GLP-1 and GFRAL. Here, authors show two pathways downstream of GFRAL neurons, which are required for the weight-reducing actions of GDF15 and GLP1RA.

Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.

The replicative helicase CMG is targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP. This study describes how the de-ubiquitylating enzyme USP37 protects genome stability by preventing premature TRAIP-dependent CMG unloading when replication stress impedes timely termination.

The balance between radial progenitors and intermediate precursors to generate upper-layer neurons during the development and evolution of the cerebral cortex is mediated by members of the tuberous sclerosis complex.

Here authors identify GluN2D-containing NMDA receptors on interneurons as a specific target for rapid antidepressant action. Blocking GluN2D restores stress-impaired plasticity and mimics the effects of ketamine with fewer side effects.

Transferrin receptor (TfR) and CD98hc are increasingly used to enable more effective drug delivery to the central nervous system. Here, the authors reveal comprehensive and distinct brain cellular and whole body biodistribution patterns of TfR- and CD98hc-binding molecules.

A set of neurons in the peri-locus coeruleus region controls arousal and avoidance states, providing an understanding of the neurobiological basis of arousal and exploratory behaviours.

Aging impairs the regenerative capacity of skeletal muscle stem cells. Here, the authors identify a stem cell-specific fibronectin splice variant and show that its cell-autonomous secretion through the TGFβ1-Smad3-Srsf1 pathway can be targeted to restore tissue repair in aged mice

The role of vascular plasticity in brain function remains poorly understood. Here, the authors demonstrate that a significant portion of blood vessels in the adult brain periodically occlude and regress, a process that is associated with a reduction in neuronal activity.

White matter (WM) astrocytes differ significantly from gray matter astrocytes, with WM astrocytes in the forebrain exhibiting unique proliferation capacity, which is absent in cerebellar WM, suggesting region-specific astrocyte generation.

The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.

Mutations in glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher’s disease and are the most common risk factor for Parkinson’s disease. Using a fusion protein comprising GCase and a transferrin receptor antibody fragment, the authors show that the transferrin receptor pathway can be therapeutically exploited to both pass the blood-brain barrier and efficiently target lysosomal GCase deficiency.

Chromosomal instability leads to aneuploidy, a state of karyotype imbalance. By inducing controlled chromosome mis-segregation, Santaguida and colleagues show that aneuploidy can also instigate chromosomal instability.

In the eye, intraocular pressure (IOP) regulation is critical for proper vision. High IOP can result in glaucoma a blinding disease. Here the authors show that tyrosine kinase FYN controls IOP by phosphorylating VE-cadherin, a key component in cell junctions.

α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase, and its expression in CD4 + T-cells has been linked to remission status in rheumatoid arthritis. Here the authors report that pharmacological inhibition of ABHD11 modulates T-cell effector function via increased 24,25-epoxycholesterol biosynthesis and subsequent liver X receptor activation.

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).

EXO1 performs multiple roles in DNA replication and DNA damage repair (DDR), but its role in DDR-deficient cancers remains unclear. Here, the authors find EXO1 loss as synthetic lethal with many DDR genes involved in various cancers, including genes from Fanconi Anaemia pathway, BRCA1-A complex, and spliceosome factor ZRSR2; such interactions represent potential clinical targets.

An NNMT inhibitor reduces tumour burden and metastasis in multiple mouse cancer models and restores immune checkpoint blockade efficacy by decreasing cancer-associated-fibroblast-mediated recruitment of myeloid-derived suppressor cells and reinvigorating CD8⁺ T cell activation.

Microglia, the brain’s immune cells, suppress neuronal activity in response to synaptic ATP release and alter behavioural responses in mice.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

Targeted protein degradation of cell-surface glycoproteins suppresses cancer in mice.

Walking requires continual integrated information about the dynamic internal and external environment. This study reveals a pathway whereby the somatosensory cortex directly influences motor behavior based on integrated spatiotemporal information.

Hachem et al. show that AMPAR signaling drives the acute activation of ependymal-derived neural stem/progenitor cells after spinal cord injury and that this mechanism can be targeted therapeutically to harness the endogenous regenerative potential of the spinal cord.

Inhibitors of the protein kinase Wee1 are promising drugs for cancer therapy. Here, the authors show that these drugs activate the integrated stress response via GCN2, synergising with mRNA translation defects. They suggest strategies such as PROTACs or ISR inhibitors to improve WEE1 mediated toxicity.

Orofacial movements for feeding can be triggered, coordinated and rhythmically organised at the level of the brainstem. Here, the authors show two nuclei can organise the stereotyped movements for ingesting fluids in mammals, these neuronal groups are marked by expression of Phox2b and are located in the intermediate reticular formation of the medulla and around the motor nucleus of the trigeminal nerve.

Yin et al. show that motor learning is delayed in mice with 16p11.2 deletion, associated with abnormal ensemble activity and delayed spine remodeling in motor cortex and reduced activity of of locus coeruleus noradrenergic neurons. The motor-related abnormalities were rescued by activation of ocus coeruleus noradrenergic neurons.

This study provides a single-cell and spatial atlas of the prometastatic tumor microenvironment in esophageal squamous cell carcinoma and characterizes the immunosuppressive function of GPR116⁺ pericytes in cancer metastasis and immune evasion.

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.

Loss of PP2A activity is often associated with cancer but the underlying mechanism remains unclear. Here, the authors show that decreased methylation of PP2A catalytic C subunit caused by loss of LCMT-1 in prostate cancer abrogates the tumor suppressor activity of PP2A on AR/MED1-dependent gene expression, proposing decreased methyl-PP2A-C as a prognostic marker for prostate cancer progression.

Fresh basaltic glass preserved in a sample of volcanic breccia record a single eruptive event at the Alpha Ridge around 90 Ma, suggesting that parts of the ridge were emergent during the final stages of magmatism in the High Arctic Large Igneous Province, according to geochemical and geochronological analysis of the sample.