Covalent inhibitors of the RAS binding domain of PI3Kα impair tumor growth driven by RAS and HER2.

Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3K's role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block the ability of RAS to activate PI3K activity.

Stress reactivity moderates the association between stressful life events and depressive symptoms in adolescents: Results from a population-based study.

Background: A large body of evidence links stressful life events with depression. However, little is understood about the role of perceived impact in this association.

Methods: We performed regression analysis to investigate whether self-reported stress reactivity (derived by regressing the impact-weighted life event score on the unweighted score) moderated the association between stressful life events and depressive symptoms in adolescents from the Avon Longitudinal Study of Parents and Children cohort (n = 4791), controlling for age at outcome, sex, ethnicity, and maternal education.

Maximizing insights from longitudinal epigenetic age data: simulations, applications, and practical guidance.

Background: Epigenetic age (EA) is an age estimate, developed using DNA methylation (DNAm) states of selected CpG sites across the genome. Although EA and chronological age are highly correlated, EA may not increase uniformly with time. Departures, known as epigenetic age acceleration (EAA), are common and have been linked to various traits and future disease risk.

Transient patterns of advanced brain ageing in female adolescents with anorexia nervosa.

Background: Anorexia nervosa is a psychiatric disorder characterised by undernutrition, significantly low body weight and large, although possibly transient, reductions in brain structure. Advanced brain ageing tracks accelerated age-related changes in brain morphology that have been linked to psychopathology and adverse clinical outcomes.

Aim: The aim of the current case-control study was to characterise cross-sectional and longitudinal patterns of advanced brain age in acute anorexia nervosa and during the recovery process.

Exploring associations between psychotic experiences and structural brain age: a population-based study in late adolescence.

Neuroimaging studies show advanced structural "brain age" in schizophrenia and related psychotic disorders, potentially reflecting aberrant brain ageing or maturation. The extent to which altered brain age is associated with subthreshold psychotic experiences (PE) in youth remains unclear. We investigated the association between PE and brain-predicted age difference (brain-PAD) in late adolescence using a population-based sample of 117 participants with PE and 115 without PE (aged 19-21 years) from the Avon Longitudinal Study of Parents and Children.

Search for Time-Dependent CP Violation in D^{0}→π^{+}π^{-}π^{0} Decays.

A measurement of time-dependent CP violation in D^{0}→π^{+}π^{-}π^{0} decays using a pp collision data sample collected by the LHCb experiment in 2012 and from 2015 to 2018, corresponding to an integrated luminosity of 7.7  fb^{-1}, is presented. The initial flavor of each D^{0} candidate is determined from the charge of the pion produced in the D^{*}(2010)^{+}→D^{0}π^{+} decay.

Mapping prenatal predictors and neurobehavioral outcomes of an epigenetic marker of neonatal inflammation - A longitudinal population-based study.

Background: DNA methylation levels at specific sites can be used to proxy C-reactive protein (CRP) levels, providing a potentially more stable and accurate indicator of sustained inflammation and associated health risk. However, its use has been primarily limited to adults or preterm infants, and little is known about determinants for - or offspring outcomes of - elevated levels of this epigenetic proxy in cord blood. The aim of this study was to comprehensively map prenatal predictors and long-term neurobehavioral outcomes of neonatal inflammation, as assessed with an epigenetic proxy of inflammation in cord blood, in the general pediatric population.

The source craters of the martian meteorites: Implications for the igneous evolution of Mars.

Approximately 200 meteorites come from ~10 impact events on the surface of Mars, yet their pre-ejection locations are largely unknown. Here, we combine the results of diverse sets of observations and modeling to constrain the source craters for several groups of martian meteorites. We compute that ejection-paired groups of meteorites are derived from lava flows within the top 26 m of the surface.

Prenatal stress and gestational epigenetic age: No evidence of associations based on a large prospective multi-cohort study.

Psychological stress during pregnancy is known to have a range of long-lasting negative consequences on the development and health of offspring. Here, we tested whether a measure of prenatal early-life stress was associated with a biomarker of physiological development at birth, namely epigenetic gestational age, using foetal cord-blood DNA-methylation data. Longitudinal cohorts from the Netherlands (Generation R Study [Generation R], n = 1,396), the UK (British Avon Longitudinal Study of Parents and Children [ALSPAC], n = 642), and Norway (Mother, Father and Child Cohort Study [MoBa], n1 = 1,212 and n2 = 678) provided data on prenatal maternal stress and genome-wide DNA methylation from cord blood and were meta-analysed (pooled n = 3,928).

Consortium Profile: The Methylation, Imaging and NeuroDevelopment (MIND) Consortium.

Epigenetic processes, such as DNA methylation, show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of mental health and other brain-based phenotypes. However, little is known about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research in this area is almost entirely comprised of cross-sectional studies in adults.

Modification of χ_{c1}(3872) and ψ(2S) Production in pPb Collisions at sqrt[s_{NN}]=8.16 TeV.

The LHCb Collaboration measures production of the exotic hadron χ_{c1}(3872) in proton-nucleus collisions for the first time. Comparison with the charmonium state ψ(2S) suggests that the exotic χ_{c1}(3872) experiences different dynamics in the nuclear medium than conventional hadrons, and comparison with data from proton-proton collisions indicates that the presence of the nucleus may modify χ_{c1}(3872) production rates. This is the first measurement of the nuclear modification factor of an exotic hadron.

Maximizing Insights from Longitudinal Epigenetic Age Data: Simulations, Applications, and Practical Guidance.

Background: Epigenetic Age (EA) is an age estimate, developed using DNA methylation (DNAm) states of selected CpG sites across the genome. Although EA and chronological age are highly correlated, EA may not increase uniformly with time. Departures, known as epigenetic age acceleration (EAA), are common and have been linked to various traits and future disease risk.

Impact of Anti-Discrimination Legislation on Access to Gender-affirming Care: A Commercial Claims Analysis.

Objective: To examine the temporal relationship between the anti-discrimination rules of the Affordable Care Act, which took full effect in 2017, and the incidence of commercial claims for gender-affirming care, as well as cost sharing for these services.

Methods: We used a previously described algorithm to define a cohort of gender-diverse adults in the MarketScan Commercial Claims and Encounters Database. Claims for gender-affirming medical and surgical care were identified using International Classification of Diseases and Current Procedural Terminology codes plus pharmacy data; the annual incidence of surgical claims was calculated.

Seizure control via pH manipulation: a phase II double-blind randomised controlled trial of inhaled carbogen as adjunctive treatment of paediatric convulsive status epilepticus (Carbogen for Status Epilepticus in Children Trial (CRESCENT)).

Background: Paediatric convulsive status epilepticus is the most common neurological emergency presenting to emergency departments. Risks of resultant neurological morbidity and mortality increase with seizure duration. If the seizure fails to stop within defined time-windows, standard care follows an algorithm of stepwise escalation to more intensive treatments, ultimately resorting to induction of general anaesthesia and ventilation.

The role of loneliness and social isolation in mediating the relationship between childhood maltreatment and schizophrenia: A genetically informed approach.

Observational studies have found loneliness and social isolation to mediate the relationship between childhood maltreatment and schizophrenia. Limitations with observational studies (e.g.

Genetics impact risk of Alzheimer's disease through mechanisms modulating structural brain morphology in late life.

Background: Alzheimer's disease (AD)-related neuropathological changes can occur decades before clinical symptoms. We aimed to investigate whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or increasing brain atrophy, respectively.

Methods: We used bidirectional two-sample Mendelian randomisation to estimate the effects between genetic liability to AD and global and regional cortical thickness, estimated total intracranial volume, volume of subcortical structures and total white matter in 37 680 participants aged 8-81 years across 5 independent cohorts (Adolescent Brain Cognitive Development, Generation R, IMAGEN, Avon Longitudinal Study of Parents and Children and UK Biobank).

Pandemic effects on social capital in residents and non-residents of Chinese immigrant enclaves in Philadelphia.

The COVID-19 pandemic's effect on established Chinese ethnic enclaves, which faced socio-economic disruptions as well as anti-Asian sentiment, is unknown. We compared the pandemic's effect on social capital among residents and non-residents of Chinese ethnic enclaves in Philadelphia. Despite declines in group participation and citizenship activity (joining with others or speaking with local officials to address a neighborhood problem), the pandemic increased support received from other individuals and cognitive social capital (e.

Emergency department discharge practices for children with acute wheeze and asthma: a survey of discharge practice and review of safety netting instructions in the UK and Ireland.

Objective: Recovery from acute wheeze and asthma attacks should be supported with safety netting, including treatment advice. We evaluated emergency department (ED) discharge practices for acute childhood wheeze/asthma attacks to describe variation in safety netting and recovery bronchodilator dosing.

Design: Two-phase study between June 2020 and September 2021, comprising (1) Departmental discharge practice survey, and (2) Analysis of written discharge instructions for caregivers.

MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment.

Amplitude Analysis of the B^{0}→K^{*0}μ^{+}μ^{-} Decay.

An amplitude analysis of the B^{0}→K^{*0}μ^{+}μ^{-} decay is presented using a dataset corresponding to an integrated luminosity of 4.7  fb^{-1} of pp collision data collected with the LHCb experiment. For the first time, the coefficients associated to short-distance physics effects, sensitive to processes beyond the standard model, are extracted directly from the data through a q^{2}-unbinned amplitude analysis, where q^{2} is the μ^{+}μ^{-} invariant mass squared.

Gestational epigenetic age and ADHD symptoms in childhood: a prospective, multi-cohort study.

Epigenetic age acceleration (EAA), defined as the difference between chronological age and epigenetically predicted age, was calculated from multiple gestational epigenetic clocks (Bohlin, EPIC overlap, and Knight) using DNA methylation levels from cord blood in three large population-based birth cohorts: the Generation R Study (The Netherlands), the Avon Longitudinal Study of Parents and Children (United Kingdom), and the Norwegian Mother, Father and Child Cohort Study (Norway). We hypothesized that a lower EAA associates prospectively with increased ADHD symptoms. We tested our hypotheses in these three cohorts and meta-analyzed the results (n = 3383).