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Abstract The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8+ T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8+ T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity.

Abstract Background Digital tools have the capacity to complement and enhance clinical care for young people at risk of suicide. Despite the rapid rise of digital tools, their rate of integration into clinical practice remains low. The poor uptake of digital tools may be in part due to the lack of best-practice guidelines for clinicians and services to safely apply them with this population. Methods A Delphi study was conducted to produce a set of best-practice guidelines for clinicians and services on integrating digital tools into clinical care for young people at risk of suicide. First, a questionnaire was developed incorporating action items derived from peer-reviewed and grey literature, and stakeholder interviews with 17 participants. Next, two independent expert panels comprising professionals (academics and clinical staff; n = 20) and young people with lived experience of using digital technology for support with suicidal thoughts and behaviours (n = 29) rated items across two consensus rounds. Items reaching consensus (rated as “essential” or “important” by at least 80% of panel members) at the end of round two were collated into a set of guidelines. Results Out of 326 individual items rated by the panels, 188 (57.7%) reached consensus for inclusion in the guidelines. The endorsed items provide guidance on important topics when working with young people, including when and for whom digital tools should be used, how to select a digital tool and identify potentially harmful content, and identifying and managing suicide risk conveyed via digital tools. Several items directed at services (rather than individual clinicians) were also endorsed. Conclusions This study offers world-first evidence-informed guidelines for clinicians and services to integrate digital tools into clinical care for young people at risk of suicide. Implementation of the guidelines is an important next step and will hopefully lead to improved uptake of potentially helpful digital tools in clinical practice.

Abstract Efficient generation of cardiomyocytes from human-induced pluripotent stem cells (hiPSCs) is important for their application in basic and translational studies. Space microgravity can significantly change cell activities and function. Previously, we reported upregulation of genes associated with cardiac proliferation in cardiac progenitors derived from hiPSCs that were exposed to space microgravity for 3 days. Here we investigated the effect of long-term exposure of hiPSC-cardiac progenitors to space microgravity on global gene expression. Cryopreserved 3D hiPSC-cardiac progenitors were sent to the International Space Station (ISS) and cultured for 3 weeks under ISS microgravity and ISS 1 G conditions. RNA-sequencing analyses revealed upregulation of genes associated with cardiac differentiation, proliferation, and cardiac structure/function and downregulation of genes associated with extracellular matrix regulation in the ISS microgravity cultures compared with the ISS 1 G cultures. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes mapping identified the upregulation of biological processes, molecular function, cellular components, and pathways associated with cell cycle, cardiac differentiation, and cardiac function. Taking together, these results suggest that space microgravity has a beneficial effect on the differentiation and growth of cardiac progenitors.

The deployment of photovoltaic (PV) systems has increased globally to meet renewable energy targets. Intermittent PV power generated due to cloud-induced variability introduces reliability and grid stability issues at higher penetration levels. Variability in power generation can induce voltage fluctuations within the distribution system and cause adverse effects on power quality. Therefore, it is essential to quantify resource variability to mitigate an intermittent power supply. In this study, we propose a new scheme to classify the sky conditions that are based on two common variability metrices: daily clear-sky index and normalized aggregate ramp rates. The daily clear-sky index estimates the cloudiness in the sky, and ramp rates account for the variability introduced in the system generation due to sudden cloud movements. This classification scheme can identify clear-sky, highly variable, low intermittent, high intermittent and overcast days. By performing a Chi-square test on the training and test sets, we obtain Chi-square statistic values greater than 3 with p-value > 0.05. This indicates that the distribution of the training and test clusters are similar, indicating the robustness of the proposed sky classification scheme. We have demonstrated the applicability of the scheme with diverse datasets to show that the proposed classification scheme can be homogenously applied to any dataset globally despite their temporal resolution. Using various case studies, we demonstrate the potential applications of the scheme for understanding resource allocation, site selection, estimating future intermittency due to climate change, and cloud enhancement effects. The proposed sky classification scheme enhances the precision and reliability of solar energy forecasts, optimizing system performance and maximizing energy production efficiency. This improved accuracy is crucial for variability control and planning, ensuring optimal output from PV plants.

BACKGROUND: Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking behaviors and DNA repair genes, but further work is required to identify susceptibility variants. METHODS: To identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous LC GWAS (29 266 patients, 56 450 controls) by meta-analysis. Colocalization was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic risk scores (PRS) were tested within an independent validation cohort (1 666 LC patients vs 6 664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumor resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided. RESULTS: The GWAx-GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as subgenome-wide significant variants related to expression quantitative trait loci and/or smoking propensity, assisted in LC genetic risk prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45; P

Fragile X Syndrome (FXS), the leading monogenic cause of intellectual disability and autism spectrum disorder, is caused by expansion of a CGG trinucleotide repeat in the 5'-UTR of the Fragile X Mental Retardation-1 (FMR1) gene. Epigenetic silencing of FMR1 results in loss of the Fragile X Mental Retardation Protein (FMRP). Although most studies to date have focused on excitatory neurons, recent evidence suggests that GABAergic inhibitory networks are also affected. To investigate human GABAergic neurogenesis, we established a method to reproducibly derive inhibitory neurons from multiple FXS and control human pluripotent stem cell (hPSC) lines. Electrophysiological analyses suggested that the developing FXS neurons had a delay in the GABA functional switch, a transition in fetal development that converts the GABAA channel's function from depolarization to hyperpolarization, with profound effects on the developing brain. To investigate the cause of this delay, we analyzed 14 400 single-cell transcriptomes from FXS and control cells at 2 stages of GABAergic neurogenesis. While control and FXS cells were similar at the earlier time point, the later-stage FXS cells retained expression of neuroblast proliferation-associated genes and had lower levels of genes associated with action potential regulation, synapses, and mitochondria compared with controls. Our analysis suggests that loss of FMRP prolongs the proliferative stage of progenitors, which may result in more neurons remaining immature during the later stages of neurogenesis. This could have profound implications for homeostatic excitatory-inhibitory circuit development in FXS, and suggests a novel direction for understanding disease mechanisms that may help to guide therapeutic interventions.

Developmental disability rates may vary by the season or month in which children are born. However, the seasonal mechanisms, such as climate, underlying these variations are unclear. Previous studies focused on high-latitude regions, leaving this climate hypothesis only partially tested. We analyzed rates of developmental disabilities in 3- to 5-year-old children from a tropical climate--South Florida--from 2004 to 2015 (N = 79,047) using a time-series analysis to identify peaks in diagnoses based on birth months. Children with speech impairments were more likely to be born in March, April, and September, a novel finding. Children with developmental delays were more likely to be born in September and October, consistent with studies in colder regions. In contrast to prior studies, there were no effects of birth month for language impairment or autism spectrum disorder. We highlight potential prenatal mechanisms that may contribute to the seasonal variations in some developmental disabilities.