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Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P value

Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells. Pancreatic β-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential (1-5); understanding the [...]

The inclusion of microexons by alternative splicing occurs frequently in neuronal proteins. The roles of these sequences are largely unknown, and changes in their degree of inclusion are associated with neurodevelopmental disorders 1 . We have previously shown that decreased inclusion of a 24-nucleotide neuron-specific microexon in CPEB4, a RNA-binding protein that regulates translation through cytoplasmic changes in poly(A) tail length, is linked to idiopathic autism spectrum disorder (ASD) 2 . Why this microexon is required and how small changes in its degree of inclusion have a dominant-negative effect on the expression of ASD-linked genes is unclear. Here we show that neuronal CPEB4 forms condensates that dissolve after depolarization, a transition associated with a switch from translational repression to activation. Heterotypic interactions between the microexon and a cluster of histidine residues prevent the irreversible aggregation of CPEB4 by competing with homotypic interactions between histidine clusters. We conclude that the microexon is required in neuronal CPEB4 to preserve the reversible regulation of CPEB4-mediated gene expression in response to neuronal stimulation., Competing Interests: Competing interests: K.L.-L. holds stock options in and is a consultant for Peptone. X.S. is a scientific founder and advisor of Nuage Therapeutics. All other authors declare no competing interests., (© 2024. The Author(s).)

Astronomers have found more than a dozen planets transiting stars that are 10-40 million years old 1 , but younger transiting planets have remained elusive. The lack of such discoveries may be because planets have not fully formed at this age or because our view is blocked by the protoplanetary disk. However, we now know that many outer disks are warped or broken 2 ; provided the inner disk is depleted, transiting planets may thus be visible. Here we report observations of the transiting planet IRAS 04125+2902 b orbiting a 3-million-year-old, 0.7-solar-mass, pre-main-sequence star in the Taurus Molecular Cloud. The host star harbours a nearly face-on (30 degrees inclination) transitional disk 3 and a wide binary companion. The planet has a period of 8.83 days, a radius of 10.7 Earth radii (0.96 Jupiter radii) and a 95%-confidence upper limit on its mass of 90 Earth masses (0.3 Jupiter masses) from radial-velocity measurements, making it a possible precursor of the super-Earths and sub-Neptunes frequently found around main-sequence stars. The rotational broadening of the star and the orbit of the wide (4 arcseconds, 635 astronomical units) companion are both consistent with edge-on orientations. Thus, all components of the system are consistent with alignment except the outer disk; the origin of this misalignment is unclear., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Various bacteria are suggested to contribute to colorectal cancer (CRC) development 1-5 , including pks + Escherichia coli, which produces the genotoxin colibactin that induces characteristic mutational signatures in host epithelial cells 6 . However, it remains unclear how the highly unstable colibactin molecule is able to access host epithelial cells to cause harm. Here, using the microbiota-dependent ZEB2-transgenic mouse model of invasive CRC 7 , we demonstrate that the oncogenic potential of pks + E. coli critically depends on bacterial adhesion to host epithelial cells, mediated by the type 1 pilus adhesin FimH and the F9 pilus adhesin FmlH. Blocking bacterial adhesion using a pharmacological FimH inhibitor attenuates colibactin-mediated genotoxicity and CRC exacerbation. We also show that allelic switching of FimH strongly influences the genotoxic potential of pks + E. coli and can induce a genotoxic gain-of-function in the probiotic strain Nissle 1917. Adhesin-mediated epithelial binding subsequently allows the production of the genotoxin colibactin in close proximity to host epithelial cells, which promotes DNA damage and drives CRC development. These findings present promising therapeutic routes for the development of anti-adhesive therapies aimed at mitigating colibactin-induced DNA damage and inhibiting the initiation and progression of CRC, particularly in individuals at risk for developing CRC., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Multidrug-resistant bacterial pathogens like vancomycin-resistant Enterococcus faecium (VREfm) are a critical threat to human health 1 . Daptomycin is a last-resort antibiotic for VREfm infections with a novel mode of action 2 , but for which resistance has been widely reported but is unexplained. Here we show that rifaximin, an unrelated antibiotic used prophylactically to prevent hepatic encephalopathy in patients with liver disease 3 , causes cross-resistance to daptomycin in VREfm. Amino acid changes arising within the bacterial RNA polymerase in response to rifaximin exposure cause upregulation of a previously uncharacterized operon (prdRAB) that leads to cell membrane remodelling and cross-resistance to daptomycin through reduced binding of the antibiotic. VREfm with these mutations are spread globally, making this a major mechanism of resistance. Rifaximin has been considered 'low risk' for the development of antibiotic resistance. Our study shows that this assumption is flawed and that widespread rifaximin use, particularly in patients with liver cirrhosis, may be compromising the clinical use of daptomycin, a major last-resort intervention for multidrug-resistant pathogens. These findings demonstrate how unanticipated antibiotic cross-resistance can undermine global strategies designed to preserve the clinical use of critical antibiotics., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Systemic immune responses caused by chronic hypercholesterolaemia contribute to atherosclerosis initiation, progression and complications 1 . However, individuals often change their dietary habits over time 2 , and the effects of an alternating high-fat diet (HFD) on atherosclerosis remain unclear. Here, to address this relevant issue, we developed a protocol using atherosclerosis-prone mice to compare an alternating versus continuous HFD while maintaining similar overall exposure periods. We found that an alternating HFD accelerated atherosclerosis in Ldlr -/- and Apoe -/- mice compared with a continuous HFD. This pro-atherogenic effect of the alternating HFD was also observed in Apoe -/- Rag2 -/- mice lacking T, B and natural killer T cells, ruling out the role of the adaptive immune system in the observed phenotype. Discontinuing the HFD in the alternating HFD group downregulated RUNX1 3 , promoting inflammatory signalling in bone marrow myeloid progenitors. After re-exposure to an HFD, these cells produced IL-1β, leading to emergency myelopoiesis and increased neutrophil levels in blood. Neutrophils infiltrated plaques and released neutrophil extracellular traps, exacerbating atherosclerosis. Specific depletion of neutrophils or inhibition of IL-1β pathways abolished emergency myelopoiesis and reversed the pro-atherogenic effects of the alternating HFD. This study highlights the role of IL-1β-dependent neutrophil progenitor reprogramming in accelerated atherosclerosis induced by alternating HFD., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Most kidney cancers are metabolically dysfunctional 1-4 , but how this dysfunction affects cancer progression in humans is unknown. We infused 13 C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U- 13 C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2- 13 C]acetate and [U- 13 C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site., (© 2024. The Author(s).)

The upper airway is an important site of infection, but immune memory in the human upper airway is poorly understood, with implications for COVID-19 and many other human diseases 1-4 . Here we demonstrate that nasal and nasopharyngeal swabs can be used to obtain insights into these challenging problems, and define distinct immune cell populations, including antigen-specific memory B cells and T cells, in two adjacent anatomical sites in the upper airway. Upper airway immune cell populations seemed stable over time in healthy adults undergoing monthly swabs for more than 1 year, and prominent tissue resident memory T (T RM ) cell and B (B RM ) cell populations were defined. Unexpectedly, germinal centre cells were identified consistently in many nasopharyngeal swabs. In subjects with SARS-CoV-2 breakthrough infections, local virus-specific B RM  cells, plasma cells and germinal centre B cells were identified, with evidence of local priming and an enrichment of IgA + memory B cells in upper airway compartments compared with blood. Local plasma cell populations were identified with transcriptional profiles of longevity. Local virus-specific memory CD4 + T RM cells and CD8 + T RM cells were identified, with diverse additional virus-specific T cells. Age-dependent upper airway immunological shifts were observed. These findings provide new understanding of immune memory at a principal mucosal barrier tissue in humans., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Expansion of antigen-experienced CD8 + T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer 1 . Interleukin-2 (IL-2) acts as a key regulator of CD8 + cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability 2,3 . Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE 2 ), a known negative regulator of immune response in the tumour microenvironment 4,5 , is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8 + TILs via the PGE 2 receptors EP2 and EP4. Mechanistically, PGE 2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ c chain, resulting in defective assembly of IL-2Rβ-IL2Rγ c membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE 2  signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE 2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential., (© 2024. The Author(s).)

AIRE is an unconventional transcription factor that enhances the expression of thousands of genes in medullary thymic epithelial cells and promotes clonal deletion or phenotypic diversion of self-reactive T cells 1-4 . The biological logic of AIRE's target specificity remains largely unclear as, in contrast to many transcription factors, it does not bind to a particular DNA sequence motif. Here we implemented two orthogonal approaches to investigate AIRE's cis-regulatory mechanisms: construction of a convolutional neural network and leveraging natural genetic variation through analysis of F1 hybrid mice 5 . Both approaches nominated Z-DNA and NFE2-MAF as putative positive influences on AIRE's target choices. Genome-wide mapping studies revealed that Z-DNA-forming and NFE2L2-binding motifs were positively associated with the inherent ability of a gene's promoter to generate DNA double-stranded breaks, and promoters showing strong double-stranded break generation were more likely to enter a poised state with accessible chromatin and already-assembled transcriptional machinery. Consequently, AIRE preferentially targets genes with poised promoters. We propose a model in which Z-DNA anchors the AIRE-mediated transcriptional program by enhancing double-stranded break generation and promoter poising. Beyond resolving a long-standing mechanistic conundrum, these findings suggest routes for manipulating T cell tolerance., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)