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A clinical cohort-based biomarker study in patients with metastatic renal cell carcinoma demonstrates that blood levels of soluble mucosal addressin cell adhesion molecule-1 are prognostic for survival in patients treated with tyrosine kinase inhibitors and immune checkpoint inhibitors and may serve as a surrogate marker for gut dysbiosis based on integrated data from three clinical trials.

Across 13 longitudinal studies (3,737 adults), the authors show that brain atrophy parallels memory loss, with a stronger coupling in later life. APOE ε4 increases decline, yet genetic risk does not modify the brain–memory relationship.

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.

The authors develop and characterise a selective Greatwall inhibitor, C-604, and show that its cytotoxicity stems from PP2A-B55α hyperactivation. They identify B55α and Greatwall levels as biomarkers of responses to Greatwall-targeted therapy.

CD3 bispecific antibodies (bsAbs) have demonstrated promising clinical responses in hematological malignancies but clinical benefit in solid tumors has been limited. Here the authors report that pre-treatment vaccination promotes the infiltration of tumor-(un)related effector CD8 T cells, improving the efficacy of CD3 bsAbs in solid tumors.

There is still a need to improve understanding of dengue-specific immunity. Here, by analyzing the antibody response in a pediatric cohort the authors show that the protective capacity of neutralizing antibodies depends on infection history and serotype, but its estimation varies by assay condition and virion maturation.

Multiple types of DNA damage can lead to mutations in normal cells, ultimately contributing to the development of cancer. Here, the authors redefine the spectrum of mutational signatures linked to a particular type of DNA damage to uncover the protective role of specialized DNA repair mechanisms.

The components of the tumour microenvironment contribute to prostate cancer initiation and progression. Here the authors perform single-cell RNA sequencing and spatial transcriptomics analysis of prostate cancer stroma from mouse models at different stages of the disease and develop a gene signature to predict distant metastasis in patients.

Pathogenic variants in UNC13A underlie a novel neurodevelopmental syndrome, with three subtypes defined by distinct genotypes with varying clinical and functional impacts characterized in cellular and animal models.

European forest tree species experienced strong climatic fluctuations over Quaternary. In spite of these pronounced environmental changes, population genomic analyses reveal that major forest tree species managed to retain their evolutionary potential over the period.

Epithelial cells express two isoforms of cytoplasmic actin, γ- and β-actin, and whether isoform-specific functions exist is debated. Here, the authors report a feedback circuitry whereby γ-actin regulates the expression of β-actin and nonmuscle myosin-2A, and modulate apical membrane cortex mechanics and cytoplasmic tight junction protein dynamics.

Primary cilia are cell organelles disrupted in developmental diseases and cancer. Here, the authors identify cilia regulators that generate a specific cilia membrane lipid, which may help to better understand diseases caused by mutations in PI3-kinase subunits.

KRAS G12C mutant selective inhibitors targeting inactive state have been approved for use in non-small cell lung cancer (NSCLC). Here, using models derived from a patient with NSCLC who progressed on sotorasib (KRAS G12C inhibitor), the authors identify increased KRAS GTP loading as an adaptive resistance mechanism which could be targeted with KRAS G12C inhibitors selective to the GTP active state.

The authors identified a cell population in Drosophila follicles that elaborate filopodia penetrating the oocyte they are contacting. These somatic cells are essential during oogenesis to regulate polarity and germline development of the future embryo.

By deciphering the molecular fingerprint of cells treated with host-directed therapies targeting protein translation, the authors identified a rational approach to select for broad-spectrum antivirals with potential to counteract future pandemic viruses.

IL-36 receptor is crucial for host defense and tissue repair. Here, the authors describe identification and characterization of low molecular weight inhibitors of the IL-36 receptor using encoded library technologies. This represents a rare example of small molecules inhibiting a member of IL-1 receptor family.

Host versus graft reaction is a major impediment to CAR-T cell immune therapy in allogeneic settings. Authors show here that CAR-T cells, engineered to be deficient in MHC I expression but to express the NK inhibitor HLA-E, are resistant to destruction by both T and NK cells of the host.

Enzymes of central metabolism tend to assemble into transient supramolecular complexes. Here, the authors stoichiometrically perturbed the supramolecular complex of TCA cycle enzymes in B. subtilis and propose that MDH-ICD clustering causes 2-oxoglutartae sequestration by reducing its diffusion rate, a mechanism that has evolved to regulate flux through the carbon-nitrogen metabolic branch-point.

Neugebauer et al. show activation of the usually silenced embryonic factor DUX4 by herpesviruses in vitro and in patients, and demonstrate that depletion of DUX4 by nanobody degraders abrogates viral replication.

G protein-coupled receptors (GPCRs) are expressed in different cell types of the brain. Their joint network function remains unclear due to lack of molecular tools allowing functional dissection targeting a single type of GPCR. Here the authors use optogenetics and show how serotonergic 5-HT2A receptors act across excitatory and inhibitory neurons in mouse visual cortex.

Authors present both preclinical data in mice and clinical data from humans in support of the hypothesis that stress negatively affects bone growth and repair. These effects are mediated by neutrophil-derived catecholamines inhibiting cartilage-to-bone transition via β2-adrenoceptor signaling in chondrocytes.

The DREPAGLOBE lentiviral-based gene therapy for sickle cell disease is safe. However, its efficacy depends on the number of infused hematopoietic stem cells (HSCs) and intrinsic, engraftment impairing inflammatory alterations in HSCs.

The transition of androgen receptor-dependent prostate cancer to a therapy resistant cancer with neuroendocrine phenotype is an important process that remains poorly understood. Here, the authors show that PKCλ/ι-loss promotes epigenetic reprogramming resulting in a TGFβ resistance programme via transcriptional upregulation of translational machinery.

Alzheimer’s disease (AD) is characterized by lipid abnormalities which are not well understood. Here, the authors investigate the role of Stearoyl-CoA desaturase (SCD) in a mouse model of AD. They show that inhibiting SCD activity induces major brain and immune cell transcriptional changes and restores dendritic structure and learning and memory.

The spatial architecture of multiple myeloma remains to be explored. Here, the authors perform bulk and single cell sequencing for samples from newly diagnosed patients and reveal gene signatures associated with focal lesions and spatial heterogeneity in the tumour microenvironment.

Distributed multi-omic digitization of clinical specimen across multiple sites is a prerequisite for turning molecular precision medicine into reality. Here, the authors show that coordinated proteotype data acquisition is feasible using standardized MS data acquisition and analysis strategies.

Tracheal tuft cells have been shown to facilitate the recruitment of immune cells during infection of the airways. Here the authors show that P. aeruginosa lung infection in mice activates tuft cells to release ATP which subsequently activates DC and promotes IL-17A secreting T cells.

Myeloid cell populations play a critical role in lung cancer progression. Here, the authors use scRNA-seq and spatial transcriptomics to identify changes in the phenotype of macrophages within the tumour microenvironment.

Here the authors report asperigimycins, fungal ribosomally synthesized and post-translationally modified peptides with a heptacyclic scaffold. After chemically modifying them for nanomolar anticancer activity, CRISPR screening identifies SLC46A3 as a key transporter for their uptake in cells.

Antimicrobial resistance genes that have been mobilized between bacterial species represent a subset of the naturally occurring resistome. Here, the authors compare the abundance, diversity and geographical patterns of acquired resistance genes with latent resistance genes in global sewage metagenomes.

Accurate repair of DNA damage is crucial for genome stability and preventing disease. Here, the authors adapt single-cell omics technologies to map the location of repair proteins across the human genome, showing formation of multi-way chromatin hubs in response to damage.

Radiation therapy (RT) has been shown to improve responses to immunotherapy in preclinical cancer models, but deep responses in patients are still rare. Here the authors provide immunological insights into the response to RT and CTLA4 inhibition in tumor bearing mice and show that agonistic CD40 therapy improves response to the combination of RT and immune checkpoint inhibition.

It is commonly assumed that bacterial cells within biofilms are glued together by matrix components, but the details are poorly understood. Here, Moreau et al. show how dynamic changes in attractive and repulsive interactions between cells and various matrix components drive biofilm growth and disassembly in Vibrio cholerae.

Wall teichoic acids glycosylation is critical for bacterial virulence and antimicrobial resistance. Here, the authors characterized RmlT, a critical rhamnosyltransferase in Listeria monocytogenes, revealing its structure, catalytic mechanism, and potential as a target for anti-virulence therapies.

In this work, authors combine high resolution imaging and machine learning to infer drug susceptibility in the absence of antimicrobial exposure, with the goal of their method to be transposed to diagnostics and study of the impact of any perturbation on bacterial cells.

Surface acoustic waves have previously been used, in conjunction with electric currents and assisting magnetic fields, to manipulate magnetization. Here, Rivelles, Yanes, and coauthors succeed in driving magnetic domain walls solely with surface acoustic waves, an important milestone in acoustically controlled spintronic devices.’

Mendelian randomization (MR) identifies causal relationships from observational data but has increased error rates when the genetic variants used as instruments come from a single region, a typical scenario when assessing molecular traits like protein or metabolite levels as risk factors. Here the authors introduce a single-region pleiotropy-robust MR method, validating the method on three ground truth sources, showing its capability to identify disease-causing molecular traits.

Whether multimorbidity accelerates brain Aβ deposition in humans remains largely unknown. Here, the authors demonstrate that higher self-reported multimorbidity burden predicts increased brain Aβ accumulation rates in the ADNI cohort.

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.

Intermediate-length repeat expansions in ATXN-2 are the strongest genetic risk factor for ALS. Here, the authors combine patient-derived motor neurons and organoids with mouse models to dissect the pathogenic effects of ATXN2 intermediate expansions.

Food allergy is triggered by IgE, but some individuals are not allergic to peanuts despite making peanut-specific IgE, and are considered peanut-tolerant. Here, the authors identify differences in blood immune cell composition of peanut-allergic and tolerant infants using mass cytometry, which may help uncover the mechanism of allergic tolerance.

Norovirus genotype GII.17 has been linked with a recent increase in cases in Europe and the Americas. Here, the authors investigate the genetic diversity and mutational patterns, and phenotypic differences associated with the recent circulating strain.

Parabens are preservatives widely used in consumer products including cosmetics and food. Here the authors demonstrate that maternal paraben exposure may contribute to childhood overweight development by an altered neuronal appetite regulation.

Periaqueductal gray (PAG) inputs control hunting, but foraging-inducing PAG cells were unidentified. Here, authors show that in mice activity in the projection of vgat PAG cells to the zona incerta is sufficient and necessary for food-seeking.

Immune surveillance is critical to prevent the development and progression of cutaneous squamous cell carcinoma (cSCC). Here, the authors show that epithelial-mesenchymal plasticity in cancer cells is associated with changes in their immune checkpoint ligand profile during mouse cSCC progression, which dictates differential responses to immune checkpoint blockade.

Prime editing is a next-generation approach for precision genome engineering. Here the authors design a nuclease-based prime editor that leverages DNA repair pathways for targeted genomic insertions.

Myotonic dystrophy type 1 (DM1) is characterized by debilitating neurological symptoms. Dinca et al. demonstrate the pronounced impact of DM1 on the morphology and RNA metabolism of astrocytes. Their findings suggest astroglial pathology in DM1 brain dysfunction.

An adjuvanted SARS-CoV-2 spike-ferritin nanoparticle vaccine can elicit antibodies with relatively broad sarbecovirus activity in non-human primates. Here, the authors isolate and structurally characterize several monoclonal antibodies providing insights into the targeted epitopes and broad reactivity.

Low efficiency of target DNA integration remains a challenge in genome engineering. Here the authors perform large-scale compound library and genetic screens to identify targets that enhance gene editing: they see that combined DNA-PK and Polϴ inhibition with potent compounds increases editing efficiency and precision.

RB1 mutations are seen in 40-60% of sporadic osteosarcoma. Here, the authors demonstrate a selective sensitivity to PARP inhibitors in RB1-mutated osteosarcoma-derived cell lines that is not associated with canonical signatures indicative of a homologous recombination defect.