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N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients.

Single-cell transcriptome profiling of mouse embryos and newborn pups is combined with previously published data to construct a tree of cell-type relationships tracing development from zygote to birth.

In this first-in-human phase 1 dose-escalation trial of OMO-103, a MYC inhibitor, in patients with solid tumors, treatment was safe and showed preliminary clinical activity along with demonstrated target engagement and identification of potential pharmacodynamic markers.

Hsp chaperones stabilize the inactive conformation of androgen receptor (AR) and are released upon hormone-induced AR activation. Here, the authors locate the Hsp binding region on AR, and show that Hsp70 reduces AR aggregation and promotes AR degradation in cellular and mouse models of a neuromuscular disorder.

Lauria et al. show that SMN, the loss of which causes spinal muscular atrophy (SMA), preferentially positions ribosomes within the first five codons of SMA-related mRNAs and enhances their translation.

The peripheral nervous system uses neuroimmune cardiovascular interfaces to assemble a structural artery–brain circuit, and therapeutic intervention in the artery–brain circuit attenuates atherosclerosis.

Single-molecule analyses using a DNA substrate with a bridge linker reveals a role of PAXX in molecular bridging of double-strand breaks to facilitate NHEJ-mediated repair.

In this phase 1 trial of a personalized, neoantigen-specific autologous T cell therapy, BNT221, when given as monotherapy in patients with metastatic melanoma refractory to PD-1 and CTLA-4 inhibitor regimens, the therapy was safe and showed preliminary clinical activity and neoantigen-specific T cell responses.

MicroRNA targets predicted by a variety of computational tools can be validated using a quantitative targeted proteomics approach, using stable isotope labeling and selected reaction monitoring mass spectrometry. The authors used this method to confirm predicted let-7 and miR-58 targets in Caenorhabditis elegans.

Multi-omic analysis of a hiPSC-based CBFA2T3::GLIS2 leukemia model revealed the molecular characteristics of two alternative developmental trajectories: proliferative leukemogenic transformation or delayed, incomplete megakaryocyte differentiation.

The c-Jun transcription factor can mediate a cell's response to TNFa. Here, Riesenberg et al. show in melanoma cells that c-Jun has an inverse relationship with the key melanocyte transcription factor MITF and that high c-Jun levels contribute to melanoma heterogeneity and an inflammatory microenvironment.

An efficient HIV-1 vaccine will likely depend on eliciting broadly neutralizing antibodies (bnAb). Here the authors analyze the B cell repertoire in macaques and knock-in mice in response to sequential immunization with Env variants that induce a bnAb targeting the CD4-binding site of Env in a HIV-1 infected individual.

Fungal pathogens are recognised and phagocytosed by macrophages in the early stages of infection. Here, Onyishi et al. identify a crosstalk between Toll Like Receptor 4 and Macrophage Scavenger Receptor 1 in the regulation of Cryptococcus neoformans uptake.

Stress granules, cellular structures essential for stress response, require poly(ADP-ribose) as a multivalent scaffold. Here, the authors show that disrupting poly(ADP-ribose) binding to PARP13 alters granule size, dynamics, and maturation, despite PARP13 lacking ADPribosyltransferase activity.

Interferon-α (IFN-α) is linked to type 1 diabetes (T1D), but how IFN-α impacts auto-antigen presentation is still unclear. Here the authors compare resting and IFN-α-treated islet β cells in vitro to find IFN-α inducing increased HLA-B expression, presentation of alternative epitopes, and activation of HLA-B-restricted T cells, thereby serving clues for T1D onset.

The authors find that the insulin receptor forms dynamic clusters during insulin signaling and that these clusters become dysfunctional in insulin resistance. This dysfunction is partially rescued by metformin, a drug used to treat type 2 diabetes.

Wiskott-Aldrich syndrome is caused by mutations in WASP, but the underlying mechanisms remain to be explored. Here the authors reveal that WASP deficiency results in aberrant RNA splicing, and that WASP regulates the transcription of splicing factor genes and co-transcriptional RNA splicing via a phase-separation process that involves splicing factors and nascent RNA.

HIV-1 TAR RNA plays key roles in viral replication, transcription, and translation. Here, Bou-Nader et al., portray the structure, dynamics, and interactions of a complete TAR RNA, and uncovers a convergent viral strategy to evade innate immunity.

Acute stress can help individuals to respond to challenging events, although chronic stress leads to maladaptive changes. Here, the authors present a multi omic analysis profiling acute stress-induced changes in the mouse hippocampus, providing a resource for the scientific community.

The spatial organization of cell surface receptors is critical for cell signaling and drug action. Here, the authors develop an optoproteomic method for mapping surface protein interactions, revealing cellular responses to antibodies, drugs and viral particles as well as immunosynapse signaling events.

Local delivery of mRNA-based immunotherapy represents an option for cancer therapy. Here the authors report that intratumoral delivery of lipid nanoparticle-formulated mRNA encoding IL-21, IL-7, and 4-1BBL induces systemic anti-tumor immunity in preclinical cancer models.

Coxiella burnetti primarily infects alveolar macrophages and causes an acute form of pneumonia called Q fever. Cunha et al. describe a type IV secretion effector, termed IcaA, expressed by Coxiella burnetiithat inhibits inflammasome activation and therefore may contribute to innate immune evasion by bacteria.

A metallo-organic hybrid material prepared by reduction of a palladium salt in the presence of cinchona alkaloids shows moderate enantioselectivity in organic transformations. The metal retains some chiral character after extraction of the dopant, selectively readsorbing the original alkaloid and showing different responses to clockwise and anticlockwise circularly polarized light.

The adrenal medulla secretes hormones required for the fight-or-flight response, and its specialized cells need to be maintained throughout life. This study uses mouse models to pinpoint the stem cells of this organ and demonstrates how these ensure the turnover of specialized cells.

The mesothelium supports homeostasis and regeneration, yet its development origins remain unclear. Here, the authors uncovered the earliest mesothelium progenitor cells in zebrafish, linking Hand2 gene function to mesothelium formation and its re-activation to mesothelioma tumors.

Biotin is an essential enzyme cofactor and two pathways for the generation of the biotin precursor pimeloyl-ACP are known. Here, the authors identify and characterize a third pathway for biotin precursor synthesis involving BioZ and they also present the Agrobacterium tumefaciens BioZ crystal structure.

Inhibition of intestinal MYC is shown to have beneficial metabolic effects by promoting GLP-1 secretion and reducing ceramide production.

Gounari and colleagues examine how the Wnt–β-catenin signaling axis in regulatory T cells promotes inflammatory bowel disease and colonic dysplasia. Activated β-catenin induces epigenetic changes that alter expression of genes co-regulated by Foxp3 and TCF-1.

Somatic mutations are identified from circulating cell-free DNA using a single-molecule-based lowpass whole-genome sequencing method. The regional distribution of mutations can identify a tumor-specific mutational profile in patients with cancer and can be used to monitor patients through treatment.

Autophagy mediated by the conjugation pathway for ubiquitin-like proteins plays a key role in controlling homeostasis in eukaryotic cells. Here the authors provide a molecular basis for allosteric activation of the E2 ligase Atg3, uncovering the mechanism underlying Atg8 lipidation and a novel mechanism regulating E1-E2-E3-mediated ubiquitin-like protein conjugation.

Interleukin-7 receptor alpha (IL7Ra) is important for lymphoid cell development but its role in leukaemogenesis is not clear. Here, the authors generate a knock-in murine model to show that activating mutations in IL7Ra can initiate precursor B-cell acute lymphoblastic leukaemia.

Synthetic hydrogels and immune organs-on-chip mimicking human immune tissue developed from blood samples allow effective modelling of immune responses and B cell disorders, with implications for the development of improved immunotherapies and vaccines.

Dotti and colleagues performed an unbiased, high-throughput screen of kinase inhibitors to identify a three-kinase inhibitor cocktail capable of preserving a stem-cell-like subset in chimeric antigen receptor T cells.

Using the ORI of plasmids used in enhancer assays as the sole core promoter and inhibiting the interferon I response triggered by plasmid transfection greatly reduces false positive and negative results in single-candidate and massively parallel enhancer assays and enables genome-wide enhancer screens.

Microstructures from the 3.5-billion-year-old Apex Chert have been interpreted as the remains of ancient cyanobacteria. Geochemical analyses suggest similar structures at the same location are instead haematite-filled fractures, although carbonaceous material in the surrounding matrix is consistent with the presence of microbes at this time.

A probe reports absolute sodium levels in acidic organelles with single-organelle resolution.

Celiac disease is characterized by intolerance to gluten, a cereal protein. Here, the authors show that neprosin, a glutamate peptidase from the pitcher plant, efficiently cleaves gluten components under physiological conditions in vitro and in the gut of mice.

Methylmalonic acidemia is an inherited metabolic disease caused by loss or mutation of the enzyme MMUT. Here the authors use cell and animal models to show that MMUT mutations lead to defective mitophagy and stress in kidney cells, contributing to the pathogenesis in methylmalonic acidemia patients.

Coherent radio emission with a long (nearly 6.5 h) period has been detected from both magnetic poles of a rotating compact object, offering insights into the evolution and emission mechanism of compact radio transients.

Mucida and colleagues examine how the gut epithelial microenvironment alters CD4⁺ T cells during their conversion into intraepithelial lymphocytes. They reveal a stepwise process involving chromatin accessibility and transcription changes triggered by ThPOK downregulation.

A 50 microRNA-based dynamic risk score for stratifying individuals with and without type 1 diabetes was developed using samples obtained from multicenter and multiethnic cohorts.

Inhibition of YBX1, a downstream target of the Janus kinase JAK2, sensitizes myeloproliferative neoplasm cells to JAK and could provide a means to eradicate such cells in human haematopoietic cancers.

Liang et al. study the impact of ERα antagonist/degraders against different Esr1 mutations in murine models and find that inhibition of mutant ERα induces lineage plasticity, which is also observed in Esr1-wild-type mice with long-term estrogen deprivation.

Limited experimental platforms exist for assessing quantitative sequence-function relationships for multiple antibodies. Here, authors develop a deep-sequencing based technology called MAGMA-seq, that determines the quantitative properties of antibody libraries.

Paris et al. show that after injury or influenza infection alveolar type II cells signal via a STAT3–BDNF axis that activates the TrkB receptor on mesenchymal niche cells and enhances alveolar repair.

HIV infection results in T cell dysfunction. Kaufmann and colleagues demonstrate that HIV infection results in an alterated differentation of HIV-specific CD4⁺ T cells that is only partially reversed by antiretroviral therapy and generation of dysfunctional T cells with a follicular helper-like phenotype.

Somatically determined preferential allelic expression of select genes that when mutated cause inborn errors of immunity corresponds with disease phenotypes, suggesting that the penetrance and expressivity of monogenic disorders is also dependent on the ‘transcriptotype’.

The authors show that dynamics of protein phosphorylation in the vertebrate cell cycle is largely attributable to CDK-mediated regulation of intrinsically disordered proteins that are involved in biomolecular condensate formation.