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Drug resistance remains a major challenge in cancer treatment. Here, the authors identify Connexin43 as target that enhances BRAF/MEKi efficacy by interfering with DNA repair pathways, overcoming drug resistance. They develop an mRNA therapy that improves efficacy and sensitizes resistant cells.

Hu et al. discovered that the truncated form of human epidermal growth factor receptor 2 (HER2), called p95HER2, drives tumor progression and resistance to the antibody–drug conjugate trastuzumab deruxtecan in HER2⁺ breast cancer. Blocking p95HER2 restores antitumor immunity.

ICeChIP (internally calibrated ChIP) uses spiked-in, defined nucleosomal standards to overcome the pitfalls of traditional ChIP experiments, enabling the measurement of antibody specificity and the absolute measurement of histone modification density at genomic loci.

Gamboa et al. develop a chimeric antigen receptor (CAR) T cell therapeutic strategy based on synthetic antigens that are delivered to the tumor by lipid nanoparticles and demonstrate the therapeutic efficacy of their approach using CAR T cells directed against the synthetic antigen.

This study showed that vagal sensory neurons in the nodose ganglia selectively encode specific cytokines, enabling real-time body-brain communication of immune signals. This neural encoding of cytokines is disrupted during inflammation associated with a colitis model.

Allelic losses occurring in cancer cells have been suggested as potential targets for therapy. Here, the authors show how recurring loss of heterozygosity of a drug metabolic gene in colorectal cancers can be exploited using a low molecular weight compound.

In this study, the authors describe SANA, a nitroalkene derivative of salicylate, as a potential activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue. Preclinical and clinical data from this paper also suggest that SANA improves glucose homeostasis and promotes weight loss in mice and humans.

The human ADAR enzyme can deaminate additional transcripts for therapeutic A-to-G RNA base editing using an antisense guide RNA. Here, authors engineer a universal guide RNA scaffold from the U7 snRNA, boosting editing efficiency from minimal doses, especially in organs with limited AAV delivery.

Fluorogenic RNA aptamers such as Mango are powerful tools for RNA imaging. An ultrabright RNA-activated fluorophore with improved photophysical performance has now been developed using a structure-informed, fragment-based screening approach. This system was studied using high-resolution crystallography and applied to image RNA in cells.

Belz and colleagues show that GFI1, a transcriptional repressor that recruits histone-modifying enzymes, is necessary for the generation and maintenance of stem cell memory CD8⁺ T cells.

Fatty liver disease exacerbates atherosclerosis, but the underlying mechanisms remain unclear. Here, the authors show that D-dopachrome tautomerase (D-DT/MIF-2) acts as an atypical chemokine, promoting both atherosclerosis and hepatic lipid accumulation.

Advances in beta cell differentiation have propelled cell therapies for diabetes into the clinic; this Review outlines the lessons learned from early-phase trials and discusses the clinical, manufacturing and regulatory challenges that must now be overcome.

Bennett et al. conducted a population-based study in adolescents and young adults with gliomas, revealing the specific molecular alterations and identifying potential subclassifications and targets.

CDK12 is a therapeutic target and cancer gene required for genome integrity. Here, the Authors show that loss or inhibition of CDK12 leads to persistent transcription of damaged genes, and triggers transcription replication conflicts leading to selective cell death in Myc- driven tumors.

Irradiation treatment for cancer therapy often causes irreparable damage to adult organs. Knox and colleagues study irradiated mouse submandibular salivary glands and find that restoring parasympathetic nerve function with the neurotrophic factor neurturin improves regeneration.

High-dose oral vitamin D₃ supplements have previously been shown to be beneficial in children receiving standard therapy for uncomplicated severe acute malnutrition. This randomised controlled trial shows that the same intervention, given in addition to standard therapy, did not improve anthropometric or neurodevelopmental outcomes in children with complicated severe acute malnutrition in Pakistan.

The RNA for ALS- and frontotemporal dementia-associated C9ORF72 gene is exported from nucleus via an unknown mechanism. This study shows that reduction of nuclear export adaptor SRSF1 can alleviate neuronal cell death and nuclear export of C9ORF72 inDrosophilaand patient-derived induced motor neurons.

Inborn errors of the alternative NF-κB pathway in humans impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases

Lung fibrosis development involves alveolar macrophages, with mechanisms that are incompletely understood. Here, the authors show that alveolar macrophages mediate the disassembly of pleuro-alveolar junctions, driving fibrosis via connective tissue transfer, and demonstrate that targeting this process can reverse chronic fibrosis in mice.

Antibody immunoprophylaxis for HIV-1 will require effective concentration of biologics at mucosal sites of exposure for effectivity. Here the authors show that infused Fc-modified VRC01LS antibody has increased levels in blood, in the female genital tract and male rectal tissue, compared to native antibody VRC01. VRC01LS is detectable for more than year at the sites of sexual HIV transmission.

CRISPR-CasRx effectively reduces ALS- and FTD-causing C9orf72 sense and antisense repeat derived RNAs and proteins in cell lines, patient iPSC-neurons and two independent mouse models of C9orf72 repeat expansion.

Illness signals from the gut reactivate and strengthen flavour representations in the amygdala to support learning from delayed postingestive feedback.

Marketplace is an occasional product review section that highlights a selection of new products that are directly applicable to the genetics community. We welcome suggestions for future features.

Model systems to study SARS-CoV-2 infection are required to better understand the immune response. Here the authors use a lung and macrophage co-culture system by differentiation of human pluripotent stem cells to better understand the phenotype and gene expression changes in host lung cells and macrophages after SARS-CoV-2 infection in vitro.

Here, the authors generated a genome-wide map of the global targets bound by HNF4A and HNF1A in beta cells and hepatic cells, and highlighted notable downstream pathways and target genes that may influence beta cell function. This approach also shed light on a potentially activating effect of a HNF4A type 2 diabetes risk variant.

Vitamin D is precursor of the steroid hormone calcitriol and has important functions throughout the body, including increasing intestinal absorption of calcium, magnesium and phosphate. Vitamin D deficiency has been linked with a range of disorders, including several bone diseases. However, large trials of vitamin D supplementation have produced mixed results. Here, experts from around the world discuss several key questions in the vitamin D research and clinical fields.

Davies et al. show that skin PD-1⁺Vδ1⁺ cells show a transcriptional program of tissue residence and self-renewal, are functionally distinct from colocalized PD-1⁺CD8⁺ T cells and retain effector function that is derepressed by checkpoint blockade.

A coding variant of the PAX4 transcription factor (p.Arg192His) is uniquely associated with Type 2 Diabetes in East Asian populations. Here, the authors show that two different coding gene variants of PAX4, p.Arg192His and the newly identified p.Tyr186X, can influence pancreatic beta cell development, identity, and function.

Ferriero et al. show that liver fibrosis reduces the efficiency of AAV-based gene therapy by limiting liver uptake and altering vector distribution to other organs. The impact of fibrosis varies depending on the AAV variant, highlighting the need for tailored approaches in fibrotic diseases.

The reasons for epistasis, wherein mutations interact non-additively, are often not fully understood. Now it is found that shifting the rate-limiting step from substrate binding to the chemical reaction step during the directed evolution of β-lactamase correlates with epistasis.

Here the authors connect inherited Apolipoprotein E genotype with the risk of developing Alzheimer’s disease by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Amyloid-beta.

Recombinant proteins in complex solutions are typically detected with tag-specific antibodies in Western blots. Here, the author describes an antibody-free alternative in which tagged proteins are detected directly in polyacrylamide gels via fluorophore-labelling of the tagged protein using a ligase.

Adrian Hill and colleagues report a genome-wide association study for tuberculosis in cohorts from Ghana and The Gambia. They identify a host susceptibility loci for pulmonary tuberculosis disease at 18q11.2.

Liver resident CD8 T cells have an essential role in immunopathology in a mouse model of nonalcoholic steatohepatitis, by becoming auto-aggressive following sequential transcriptional and metabolic activation steps .

Basophils constitute <1% of peripheral blood leukocytes. Piliponsky and colleagues show that basophils serve as a critical component of antibacterial responses by secreting tumor necrosis factor at early time points after systemic infection.

Lipidomics revealed that neurons of patients with ALS/FTD have reduced levels of polyunsaturated fatty acid (PUFA)-containing phospholipids. Increasing neuronal PUFA levels increased survival of Drosophila models of ALS/FTD and patient neurons, suggesting that interventions that increase neuronal PUFA levels in patients with ALS/FTD may also be beneficial.

T cell hyporesponsiveness is generally framed in terms of tolerance induction. Hayday and colleagues show that attenuating TCR responsiveness is also critical for the development of innate-like T cells that mediate the surveillance of dysregulated tissues.

The thymus is essential for T cell maturation and selection, and thymic defects result in severe immune problems. Here the authors identify a thymus cell population that is expandable in vitro, and can repopulate natural thymic matrix to generate tissue that supports mature T cell development in vitro and in vivo.

Cross-linking mass spectrometry is widely used to elucidate protein structures and interactions. Here, the authors generate an extensive peptide library to benchmark the most common cross-link search engines with frequently used cross-linking reagents in low and high complex sample systems.

The role of microglia in amyotrophic lateral sclerosis (ALS) is unclear. Here, the authors show that iPSC microglia from C9orf72-ALS patients are toxic to motor neurons and identify microglial MMP9 as a potential therapeutic target.

Agroforestry is a natural climate solution providing ecological and socio-economic benefits at local scales, however whether it reduces deforestation at landscape scale is still unclear. Authors use causal inference to examine the effects of agroforestry on deforestation across Southeast Asia.