Explore the vast range of titles available.

Background Genetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation. However, the link between these processes remains unclear and hampers our understanding of tissue homeostasis and cancer development. Results Here, we collect a literature-based repertoire of 3355 well-known or predicted drivers of cancer and non-cancer somatic evolution in 122 cancer types and 12 non-cancer tissues. Mapping the alterations of these genes in 7953 pan-cancer samples reveals that, despite the large size, the known compendium of drivers is still incomplete and biased towards frequently occurring coding mutations. High overlap exists between drivers of cancer and non-cancer somatic evolution, although significant differences emerge in their recurrence. We confirm and expand the unique properties of drivers and identify a core of evolutionarily conserved and essential genes whose germline variation is strongly counter-selected. Somatic alteration in even one of these genes is sufficient to drive clonal expansion but not malignant transformation. Conclusions Our study offers a comprehensive overview of our current understanding of the genetic events initiating clone expansion and cancer revealing significant gaps and biases that still need to be addressed. The compendium of cancer and non-cancer somatic drivers, their literature support, and properties are accessible in the Network of Cancer Genes and Healthy Drivers resource at http://www.network-cancer-genes.org/ .

Arabidopsis thaliana accessions have adapted to growth in a wide range of climates. Variation in flowering and alignment of vernalization response with winter length are central to this adaptation. Vernalization involves the epigenetic silencing of the floral repressor FLC via a conserved Polycomb (PRC2) mechanism involving trimethylation of Lys 27 on histone H3 (H3K27me3). We found that variation for response to winter length maps to cis polymorphism within FLC. A rare combination of four polymorphisms localized around the nucleation region of a PHD-Polycomb complex determines a need for longer cold. Chromatin immunoprecipitation experiments indicate that these polymorphisms influence the accumulation of H3K27me3 in Arabidopsis accession Lov-1, both at the nucleation site and over the gene body. Quantitative modulation of chromatin silencing through cis variation may be a general mechanism contributing to evolutionary change.

We have explored the genetic basis of variation in vernalization requirement and response in Arabidopsis accessions, selected on the basis of their phenotypic distinctiveness. Phenotyping of F2 populations in different environments, plus fine mapping, indicated possible causative genes. Our data support the identification of FRI and FLC as candidates for the major-effect QTL underlying variation in vernalization response, and identify a weak FLC allele, caused by a Mutator-like transposon, contributing to flowering time variation in two N. American accessions. They also reveal a number of additional QTL that contribute to flowering time variation after saturating vernalization. One of these was the result of expression variation at the FT locus. Overall, our data suggest that distinct phenotypic variation in the vernalization and flowering response of Arabidopsis accessions is accounted for by variation that has arisen independently at relatively few major-effect loci.

Ewan Pearson and colleagues report a genome-wide association study for glycemic response to metformin in individuals with type 2 diabetes. They identify variants near ATM associated with treatment success. Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success ( n = 3,920, P = 2.9 × 10 −9 , odds ratio = 1.35, 95% CI 1.22–1.49) at a locus containing ATM , the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM , a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

In response, we describe an adapted version of our high-throughput live virus microneutralisation assay for mucosal samples to establish the effect of fourth dose intramuscular mRNA vaccination on neutralising antibodies against six SARS-CoV-2 variants (Omicron BA.1, BA.2, BA.5, BQ.1.1, XBB.1.5, and XBB.1.16) in paired serum and mucosal samples from 149 participants (appendix p 4)2 enrolled in the University College London Hospital and Francis Crick Institute Legacy study (NCT04750356).2–6 Mucosal samples were self-collected via nasopharyngeal swabs into viral transport media. Importantly, parenteral vaccination boosts total mucosal neutralising capacity. Since this boost occurs in individuals both with and without previous mucosal challenge from infection, our data argue against a closed system of mucosal immunity only triggered by a mucosal challenge, such as infection.7 Similarly, we identified a positive correlation between serum and mucosal neutralisation that was most apparent in individuals with previous infections, thus showing that infection propagates antibodies in both serum and mucosal compartments, and arguing against large mucosal-only locally produced antibody after infection.8 Furthermore, similar quantities of mucosal neutralisation after equivalent numbers of exposures to SARS-CoV-2 spike proteins—via infection or vaccination—suggest that further boosts with intramuscular vaccines can enhance and potentially broaden mucosal neutralising capacity, as we have seen in the serum compartment. The viral transport medium sampling approach described here enables large-scale sample collection and testing for mucosal neutralisation required for vaccine evaluation,9 and will allow further exploration of cross-compartment neutralisation—for both present and future generation vaccines—including those directly generating a mucosal response.

The emergence of SARS-CoV-2 variants and COVID-19 vaccination have resulted in complex exposure histories. Rapid assessment of the effects of these exposures on neutralising antibodies against SARS-CoV-2 infection is crucial for informing vaccine strategy and epidemic management. We aimed to investigate heterogeneity in individual-level and population-level antibody kinetics to emerging variants by previous SARS-CoV-2 exposure history, to examine implications for real-time estimation, and to examine the effects of vaccine-campaign timing. Our Bayesian hierarchical model of antibody kinetics estimated neutralising-antibody trajectories against a panel of SARS-CoV-2 variants quantified with a live virus microneutralisation assay and informed by individual-level COVID-19 vaccination and SARS-CoV-2 infection histories. Antibody titre trajectories were modelled with a piecewise linear function that depended on the key biological quantities of an initial titre value, time the peak titre is reached, set-point time, and corresponding rates of increase and decrease for gradients between two timing parameters. All process parameters were estimated at both the individual level and the population level. We analysed data from participants in the University College London Hospitals–Francis Crick Institute Legacy study cohort (NCT04750356) who underwent surveillance for SARS-CoV-2 either through asymptomatic mandatory occupational health screening once per week between April 1, 2020, and May 31, 2022, or symptom-based testing between April 1, 2020, and Feb 1, 2023. People included in the Legacy study were either Crick employees or health-care workers at three London hospitals, older than 18 years, and gave written informed consent. Legacy excluded people who were unable or unwilling to give informed consent and those not employed by a qualifying institution. We segmented data to include vaccination events occurring up to 150 days before the emergence of three variants of concern: delta, BA.2, and XBB 1.5. We split the data for each wave into two categories: real-time and retrospective. The real-time dataset contained neutralising-antibody titres collected up to the date of emergence in each wave; the retrospective dataset contained all samples until the next SARS-CoV-2 exposure of each individual, whether vaccination or infection. We included data from 335 participants in the delta wave analysis, 223 (67%) of whom were female and 112 (33%) of whom were male (median age 40 years, IQR 22–58); data from 385 participants in the BA.2 wave analysis, 271 (70%) of whom were female and 114 (30%) of whom were male (41 years, 22–60); and data from 248 participants in the XBB 1.5 wave analysis, 191 (77%) of whom were female, 56 (23%) of whom were male, and one (<1%) of whom preferred not to say (40 years, 21–59). Overall, we included 968 exposures (vaccinations) across 1895 serum samples in the model. For the delta wave, we estimated peak titre values as 490·0 IC50 (95% credible interval 224·3–1515·9) for people with no previous infection and as 702·4 IC50 (300·8–2322·7) for people with a previous infection before omicron; the delta wave did not include people with a previous omicron infection. For the BA.2 wave, we estimated peak titre values as 858·1 IC50 (689·8–1363·2) for people with no previous infection, 1020·7 IC50 (725·9–1722·6) for people with a previous infection before omicron, and 1422·0 IC50 (679·2–3027·3) for people with a previous omicron infection. For the XBB 1.5 wave, we estimated peak titre values as 703·2 IC50 (415·0–3197·8) for people with no previous infection, 1215·9 IC50 (511·6–7338·7) for people with a previous infection before omicron, and 1556·3 IC50 (757·2–7907·9) for people with a previous omicron infection. Our study shows the feasibility of real-time estimation of antibody kinetics before SARS-CoV-2 variant emergence. This estimation is valuable for understanding how specific combinations of SARS-CoV-2 exposures influence antibody kinetics and for examining how COVID-19 vaccination-campaign timing could affect population-level immunity to emerging variants. Wellcome Trust, National Institute for Health Research University College London Hospitals Biomedical Research Centre, UK Research and Innovation, UK Medical Research Council, Francis Crick Institute, and Genotype-to-Phenotype National Virology Consortium.

Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children’s ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child’s cognitive abilities at age twelve. Understanding the genetic basis of cognitive traits could aid the development of numeracy and literacy skills in children. Here the authors show that reading and mathematics have a large overlapping genetic component and suggest that a child's learning environment has a key role in creating differences between them.

Jenefer Blackwell, Peter Donnelly and colleagues report a genome-wide association study for visceral leishmaniasis using studies from India and Brazil, with replication in an additional Indian study. They identify common variants at the HLA-DRB1 – HLA-DQA1 HLA class II region associated with susceptibility to visceral leishmaniasis. To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1 – HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P combined = 2.76 × 10 −17 and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30–1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1 – HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1 – HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.

Nationwide, over half of higher education faculty are mid-career. While they play vital roles sustaining their institutions, relatively little systematic attention has been paid to meeting their particular needs. This paper describes a professional renewal retreat program tailored to this \"keystone\" group of faculty (Chang, 2006). It is grounded in the theoretical constructs of \"generativity\" (vs. \"stagnation\") (Erikson, 1964/1993), of \"agentic\" and \"communion-oriented\" senses of self (Bakan, 1964, Grossbaum & Bates, 2002), and of \"growth\" or \"mastery\" (vs. \"fixed\") mindsets (Dweck, 2006). Detailed analyses of reflections of 47 retreat participants before, during and after the program are presented and discussed.