Search

Rauh et al. developed a selective MCL1 inhibitor that is efficacious in hematological and solid tumors and has the advantage of limited cardiotoxicity because of more rapid clearance of the drug in vivo.

The geographic spread of mosquito insecticide resistance has unclear evolutionary origins. Here, the authors identify partial sweeps at resistance genes on two chromosomes from two species of mosquitoes, characterizing their global distribution.

Endogenous retroviruses, or genomic relics of ancient viral infection, have been associated with certain neurodegenerative diseases. Here, Liu et al. report a pathway by which reactivated viral gene products contribute to intercellular protein aggregate spreading.

Integrative genomic and transcriptomic analyses reveal molecular events defining Richter transformation from CLL, and highlight the potential of cell-free DNA for early detection.

Despite their clinical potential, cytokines can often be highly toxic in patients, due to their systemic activity. Here, the authors present a strategy to engineer immunocytokines with very high targeting efficacies using mutant cytokines linked to nanobodies that only become active when bound to a specific cell marker.

Hepatitis B and D viruses require docking to the NTCP receptor protein for cell entry, an interaction that can be blocked by the drug bulevirtide. Here the authors use cryo-EM to reveal the structural basis of bulevirtide activity.

Plant hormones, such as auxin, coordinate plant development. In this study, an auxin transporter—PIN8—that is expressed in the male gametophyte ofArabidopsis thaliana, is found to regulate cellular homoeostasis and maintain optimal levels of auxin for pollen development.

For sexually reproducing organisms, experimental models to study the evolution of primary sex-determining loci are scarce. This study shows male-determining loci on  proto-Y chromosomes of the housefly, containing the same gene, can genomically diverge into regions of various complexity.

In an analysis of long-term safety events in 783 patients treated with T cell therapy in 38 trials, 2.3% of patients developed second primary malignancies, and vector integration analyses revealed no pathological insertions.

Resistance to BRAFV600E inhibitors often occurs in melanoma patients. Here, the authors describe a potential mechanism of acquired drug resistance mediated by tumor-associated B cells-derived IGF-1.

Myasthenia gravis (MG) is a rare autoantibody-mediated disease affecting the neuromuscular junction. Here, the authors discover common genetic variation associated with the disease, increasing understanding of the genetic basis.

Oakhurst rockshelter in South Africa documents marked cultural change during the Holocene, but genome-wide data from ancient human individuals at the site now demonstrate a remarkable degree of genetic continuity over the last 9,000 years: the contemporary ‡Khomani San and Karretjiemense from South Africa still show direct signs of relatedness to the Oakhurst hunter-gatherers.

Sestan et al. find a conserved mechanism during systemic viral infection in which γδ T cells produce IFNγ to increase pancreatic insulin secretion, lowering blood glucose and then enhancing type I interferon-mediated protection against viral infection.

The authors defined a roadmap for investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders. Their proof-of-concept study using the largest available common variant data sets for schizophrenia and volumes of several (mainly subcortical) brain structures did not find evidence of genetic overlap.

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

Rhythmic trafficking of dendritic cells to the tumour draining lymph node governs a circadian response of tumour-antigen-specific CD8⁺ T cells that is dependent on the circadian expression of the co-stimulatory molecule CD80.

This study describes a class of small molecule compounds that promote ABCA1-dependent cholesterol efflux via a non-transcriptional mechanism, the identification of the molecular target by a chemical biology approach, and the potential of these agents for the treatment of chronic kidney diseases and potentially other diseases where lipid accumulation drives disease progression.

Adipose tissue (AT) inflammation is strongly associated with obesity and constitutes an obesogenic memory upon weight loss. Here, the authors show that intermittent fasting leads to an adipocyte p53-signaling dependent emergence of lipid-associated macrophages in visceral AT of obese mice which limits the systemic fasting response.

Electronic highways were realized by means of epitaxially grown graphene nanoribbons on SiC substrates. Here, the authors use spatially-resolved two-point probe and conductive AFM measurements, supplemented by tight-binding calculations, to image the one-dimensional ballistic transport channels.

The nuclear pore complex (NPC) is known to regulate p53 signaling and this has mainly been linked to peripheral NPC subunits. Here the authors show that Nup155 from the NPC inner ring regulates the p53 pathway by controlling p21 translation while also being a target of p53-mediated repression.

Type 2 conventional dendritic cells (cDC2) are important immune activators in adults, but their development and functions at the neonatal stage remain unclear. Here the authors show, using fate-mapping and single-cell RNA sequencing, that neonatal cDC2 come from multiple origins, but converge functionally as potent immune activators upon proper stimuli.

In a mouse model, maternal obesity during pregnancy can lead to fatty liver disease in the offspring, driven by aberrant developmental programming of Kuppfer cells.

Iron metabolism is linked to type 2 diabetes. Here the authors describe a mechanism through which cellular iron deficiency caused by loss of Irp2 impairs Cdkal1 function, resulting in inaccurate proinsulin translation, impaired proinsulin processing and reduced insulin secretion.

Primary lymphomas of the central nervous system (PCNSL) are defined as diffuse large B-cell lymphomas (DLBCL) confined to the CNS. Here, the authors complete whole genome sequencing and RNA-seq to characterize 51 PCNSLs, and find common mutations in immune pathways and upregulated TERT expression and find distinct pathway differences between DLBCL and other primary CNS lymphomas.

Artificial intelligence has become popular as a cancer classification tool, but there is distrust of such systems due to their lack of transparency. Here, the authors develop an explainable AI system which produces text- and region-based explanations alongside its classifications which was assessed using clinicians’ diagnostic accuracy, diagnostic confidence, and their trust in the system.

Xavier Argout and colleagues report the draft genome of Theobroma cacao, the tropical crop that is the source of chocolate. The sequence assembly covers approximately 80% of the genome.

An adeno-associated virus (AAV) vector encoding a variant of human lipoprotein lipase was recently approved in Europe as the first gene therapy for the treatment of LPL deficiency. Here Manfred Schmidt and his colleagues report their analysis of AAV integration sites after injection of the gene therapy construct in LPL-deficient patients and in mice.

The regulation of tumor inflammation is incompletely understood and the role of B cells is unclear. Here, the authors show that a specific subtype of B cells is induced in melanoma and required to recruit T lymphocytes and elicit inflammation.

Repeat expansions in the FGF14 gene can cause late-onset cerebellar ataxia (SCA27B), however the defining features of pathogenic expansions remain uncertain. Here, the authors compare the sequence and structure of FGF14 repeat expansions in patients and controls, leading them to suggest a lower pathogenic threshold and emphasizing the importance of sequencing the full expansion for accurate interpretation.

Multiomic phenotyping provides molecular insights into complex physiological processes and pathologies. The study uses 18 omics platforms to analyze biofluids from 391 participants. It constructs a comprehensive molecular network based on omics integration, revealing insights into diabetes and other traits.

Chromatin is organized in higher order A and B compartments, reflecting active and inactive chromatin. Here, the authors provide evidence that in cardiac myocytes DNA methylation is established in preformed chromatin compartments and may be dispensable for higher order chromatin organization.

Karin Tuschl, Philippa Mills and colleagues report mutations in the manganese (Mn) transporter gene SLC39A14in childhood-onset parkinsonism-dystonia. Using functional recapitulation, the authors also show that slc39A14 loss-of-function in zebrafish can lead to Mn dysregulation and locomotor impairment.

In the TRACERx cohort of 171 patients with lung cancer, the ultrasensitive detection of ctDNA improves preoperative patient stratification, also in early-stage disease.

Genome-wide association analyses identify new risk loci for heart failure and its subtypes, extending understanding of the underlying biological pathways and disease mechanisms.

The accuracy of melanoma diagnosis can vary considerably among clinicians, impacting both patient outcomes and the performance of related AI tools. Here, the authors systematically assess interrater variability among expert pathologists reviewing histopathological images and clinical metadata of melanoma-suspicious lesions collected at eight German hospitals.

The translation initiation complex mediates tumor immune escape in melanoma by controlling STAT1 mRNA levels and T lymphocyte–induced PD-L1 expression.

Intestinal dysbiosis is associated with an ever-growing list of autoimmune diseases. Here the authors show that both mice and humans with autoimmune arthritis can have dysbiosis and barrier leakiness prior to major signs of inflammatory arthritis, and treatment of mice with a zonulin antagonist can limit collagen-induced arthritis.

Until now, fully sequenced human genomes of the indigenous hunter-gatherer peoples of southern Africa have been limited to recently diverged populations. The complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and of a Bantu from southern Africa are now presented. The extent of whole-genome and exome diversity is characterized; the observed genomic differences may help to pinpoint genetic adaptations to an agricultural lifestyle.

Neumüller and colleagues identify and characterize potent HER2 exon 20 insertion-selective inhibitors with efficacy, which preserve wild-type epidermal growth factor receptor signaling in preclinical models of non-small cell lung cancer in vivo.

Haematopoietic stem cells (HSC) are responsible for blood cell generation and reside in the bone marrow. Here, the authors show that macrophages in the bone marrow originate from embryonic or adult haematopoietic lineages and that embryo-derived macrophages are important for the establishment of the HSC pool.

A longitudinal evolutionary analysis of 126 lung cancer patients with metastatic disease reveals the timing of metastatic divergence, modes of dissemination and the genomic events subject to selection during the metastatic transition.

Analyses of multiregional tumour samples from 421 patients with non-small cell lung cancer prospectively enrolled to the TRACERx study reveal determinants of tumour evolution and relationships between intratumour heterogeneity and clinical outcome.

In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy.

Keyl et al. present an explainable artificial intelligence model-based real-world data analysis from over 15,000 patients across 38 cancer types, identified key prognostic marker interactions, and confirmed these in an external lung cancer cohort.

Na_X is an atypical member of the voltage-gated sodium channel family that may contribute to Na⁺ homeostasis. Here, the authors describe the structural and functional attributes of the human Na_X channel to reveal new insights into its physiology.