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Engineered mucus-tethering bispecific nanobodies neutralize and entrap viruses to enhance mucosal immunity, preventing influenza infection and limiting SARS-CoV-2 transmission.

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.

Hexokinase detachment from the outer mitochondrial membrane is shown to support aerobic glycolysis in cancer cells. Differential localization of the HK1 isoform to the outer mitochondrial membrane, compared to the HK2 isoform, explains the conditional essentiality of HK2 in cancer cells cultured in physiologic media.

Tubulin mutations cause a group of disorders named tubulinopathies. Here, the authors show that specific variants in the tubulin TUBB impair primary cilia formation, putting forward primary cilia defects as a pathogenic factor in some tubulinopathy cases.

Here they identify a short-lived vascular endothelial progenitor pool that predominantly vascularizes the mouse liver during postnatal growth and contributes to liver size control.

The authors report that, in mice without hepatic insulin signaling, diets high in fructose cause acute hepatic steatosis without increasing hepatic de novo lipogenesis, dependent upon hepatic follistatin secretion and associated adipose insulin resistance.

Virus-like particles are engineered to edit human hematopoietic cells in vivo.

Formation of the energy-producing machinery in the proximal tubule of the nephron is an essential step in differentiation. The authors show that mitochondrial localization depends on LRRK2, the activity of which is modulated by fluid flow.

Gene therapies often fail to reach tissues beyond the liver after intravenous delivery. Here, authors present MARVEL, a strategy that combines red blood cell hitchhiking with VEGF-induced vascular permeabilization to enhance lung targeting and deep tissue gene expression.

Arp2/3 complex forms branched actin networks that drive cell and organelle motility. Here, authors show that Coro7 targets branch junctions by binding Arp2/3 complex and actin filaments, promoting debranching, and supporting ER–Golgi transport.

Yamazoe et al. show that B cell-derived autoantibodies contribute to the development of atrial fibrillation, suggesting that targeting the humoral immune response may represent a viable therapeutic approach.

A combination of gnotobiotic mouse models, transcriptomics, circuit tracing and chemogenetic manipulations identifies neuronal circuits that integrate microbial signals in the gut with regulation of the sympathetic nervous system.

The cell populations that contribute to healing and scar tissue formation following tendon injury are poorly defined. Here the authors show that cells originating from the tendon epitenon give rise to both tenogenic and fibrotic populations and that ablation of pro-fibrotic epitenon-derived cells improves recovery.

The role of non-cancer cells infected by oncolytic viruses (OV) in cancer regression remains elusive. Here the authors engineer OV-sensitive and OV-resistant cancer cell lines and show that OV infection of non-cancer cells can elicit effective antitumour immunity via enhancing DC function and CD8⁺ T cell activation.

A subcortical circuit that regulates food consumption in mice is described, involving neurons in the ventromedial hypothalamus that are directly linked to motor centres that regulate feeding and jaw movements.

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

Processes to destroy per- and polyfluoroalkyl substances (PFASs) can produce gas-phase and aerosol-phase products of incomplete destruction (PIDs), which are often overlooked. This Review outlines PFAS destruction technologies and explores approaches to detect associated PID emissions, providing frameworks to evaluate and mitigate potential risks to human and environmental health.

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 role of autoantibodies in bullous pemphigoid (BP) and their impact on keratinocytes and the response to BP pathology remains underexplored. By leveraging transcriptomics analysis and large-scale protein assays, here the authors identify keratinocyte MyD88 as a regulator of the pro-inflammatory response in BP, uncovering the role of keratinocytes in this disease pathology.

Lundgren et al. show that in response to transient cold exposure, a distinct subpopulation of brown adipocytes carries out a lipogenic response involving production of acylcarnitines, which enables an improved thermogenic response to secondary cold exposure.

Proteinuric kidney diseases are on the rise and have limited treatment options. Here, the authors show soluble urokinase receptor (suPAR) orchestrates viral response proteinuria (VRP) which occurs in response to certain viral infections and podocyte integrin engagement.

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.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Intranasal inoculation of BALB/c and C57BL/6J mice with the bovine H5N1 clade 2.3.4.4b virus  results in rapid fatal disease characterized with high viral titers in lung and brain. Interestingly, only the C57BL/6J mice develop neurologic disease.

Schneeberger et al. show that glutamatergic neurons within the dorsal raphe nucleus of the brainstem are enriched with the orexin 1 receptor Hcrtr1, which can be pharmacologically targeted to treat obesity in mice.

Ubiquitination may control protein stability or function. Here the authors show that an ubiquitination enzyme, Hectd3, ubiquitinates Stat3 and Malt1 to modulate their function but not degradation in T cells, and thereby promoting the differentiation of pathogenic Th17 cells and susceptibility to a mouse model of multiple sclerosis.

Human collaboration with a team of artificial intelligence (AI) agents powered by large language models was used to efficiently design a complex interdisciplinary research project leading to the design of novel nanobodies against SARS-CoV-2 spike protein.

Given its immunosuppressive effect in glioblastoma (GBM), targeting the TIGIT-CD155 axis presents an attractive therapeutic strategy. Here, the authors develop an adoptive natural killer (iNK) cells therapy with anti-CD155 synNotch-inducible CD73 antibody production to reverse the effect of TIGIT-CD155 signaling for the treatment of GBM.

Osteoclasts are derived from circulating myeloid cells to mediate bone repair, maintenance and remodeling. Here, the authors show that the lung also recruits and reprograms monocytes and alveolar macrophages into osteoclast-like cells to clear pathogenic particles from the airspace.

Impaired myocardial metabolic flexibility is associated with cardiac dysfunction in diabetes and heart failure. McCommis et al. reveal a critical role for mitochondrial pyruvate use in cardiac function, and use dietary interventions to enhance cardiac fat metabolism in dilated cardiomyopathy.

Unimolecular integration of NMDA receptor antagonism with GLP-1 receptor agonism effectively reverses obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease.

Verginadis et al. show that ATF4 regulates Col1a1 expression and collagen biosynthesis in perivascular cancer-associated fibroblasts, thereby supporting angiogenesis and progression in melanoma and pancreatic cancer.

Macrophages perform diverse functions during immune responses, but the molecular mechanisms by which physical properties of the tissue regulate macrophage behavior remain unknown. Here the authors find that Piezo1 is a mechanosensor of stiffness, and that its activity modulates macrophage polarization responses.

An orally bioavailable small-molecule active-site inhibitor of the phosphatases PTPN2 and PTPN1, ABBV-CLS-484, demonstrates immunotherapeutic efficacy in mouse models of cancer resistant to PD-1 blockade.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

Although the hedgehog (HH) pathway is known to be deregulated in medulloblastoma, inhibitors of the pathway have shown disappointing clinical benefit. Using single-cell sequencing in a mouse model of the disease, the authors show that the response to the HH pathway inhibitor vismodegib is cell-type specific.

Studying RNA dynamics in vivo often relies on fluorogenic approaches, but these can be hampered by factors such as limited sensitivity and sample autofluorescence. Here, the authors describe an ultrasensitive platform for RNA imaging, which features RNA tags that recruit light-emitting luciferase fragments.

Here, Reedy et al. use a human airway culture model to show that fungal melanin blocks the secretion of pro-inflammatory chemokines resulting in diminished immune responses to Aspergillus fumigatus and Pseudomonas aeruginosa.

KDM4C regulates cathepsin L-mediated histone H3 N-terminal tail clipping through grainyhead-like 2 (GRHL2) methylation in breast cancer. This link between the cellular redox state and chromatin remodeling might represent a therapeutic target in KDM4C-amplified tumors.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Immunogenicity concerns preclude the use of bacterial kynureninases for cancer immunotherapy, while the human variant lacks the desired therapeutic effect. A human kynureninase enzyme has now been evolved to reach the activity and substrate specificity of its bacterial counterpart.

S.Typhimurium can grow selectively on tumours and decreases the cellular levels of the multidrug resistance transporter Pgp. Here, the authors reveal the SipA-dependent mechanism of Pgp down-regulation and produce a SipA-based gold nanoparticle that increases sensitivity to the anticancer drug doxorubicin.

The molecular mechanisms underlying tumour initiation remain elusive. Here, the authors use spatiotemporally controlled oncogene activation and tumour suppressor inhibition with multi-omics to unveil the role of YAP-mediated oral epithelial progenitor cell reprogramming into tumour-initiating cells.

A non-invasive in vivo positron emission tomography imaging approach detects inflammatory disease using various preclinical models.

Sudan virus (SUDV) outbreaks in Uganda created public health concerns due to a lack of approved vaccines. In this study, the authors develop a repRNA SUDV vaccine and demonstrate full protection of a single dose of this vaccine in a lethal SUDV guinea pig model.

Grimes and colleagues integrate multiomic features to create a framework that allows the isolation of discrete cell states across hematopoiesis and exploit the underlying gene regulatory networks to identify lineage restriction within multilineage progenitors.

Transcription termination or pausing during DNA replication in bacteria and humans results in DNA damage with exposed 3′ single-stranded DNA ends and mutations.

Histone H2AX is a central regulator in DNA repair. Here, the authors show that the H2AX C-terminal linker mediates recruitment of 53BP1, a mechanism which evolved to function independently of the canonical phospho-ubiquitin axis important for DNA repair regulation.