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Cryptococcus neoformans is an environmental pathogen that remodels its cellular physiology to survive within mammals and, in susceptible hosts, cause life-threatening meningoencephalitis. Of the many distinctions between the external environment and mammalian tissues, CO 2 concentration in the host is two orders of magnitude higher than in the environment and represents a critical stress for C. neoformans . C. neoformans strains that do not replicate at host CO 2 concentrations are less virulent in mouse models of infection, further supporting CO 2 tolerance as a virulence trait. To further understand the genetic determinants of C. neoformans CO 2 tolerance, we performed a near genome-wide screen for deletion mutants with altered CO 2 fitness using a competitive growth assay. A total of 301 of 4,692 deletion mutants showed altered CO 2 tolerance (245 reduced fitness; 56 increased fitness) demonstrating the global effect of host CO 2 on C. neoformans physiology. Based on this data set as well as a metabolomic analysis of C. neoformans adaptation to host CO 2 , we show that remodeling of central carbon metabolism, oxidative stress buffering, and membrane homeostasis represent an integrated response to CO 2 stress that is mediated in part by the TOR-Ypk1 signaling axis. We propose that CO 2 -induced capsule formation leads to reduced cellular glucose which, in turn, triggers remodeling of central carbon metabolism toward utilization of alternative carbon sources and increased mitochondrial respiration/reactive oxygen generation. Thus, these data provide a near genome-wide profile of the genetic determinants of C. neoformans CO 2 tolerance as well as a model for how this important environmental human fungal pathogen alters its physiology to proliferate in the host.

Cryptococcus neoformans is an environmental pathogen that remodels its cellular physiology to survive within mammals and, in susceptible hosts, cause life-threatening meningoencephalitis. Of the many distinctions between the external environment and mammalian tissues, CO.sub.2 concentration in the host is two orders of magnitude higher than in the environment and represents a critical stress for C. neoformans. C. neoformans strains that do not replicate at host CO.sub.2 concentrations are less virulent in mouse models of infection, further supporting CO.sub.2 tolerance as a virulence trait. To further understand the genetic determinants of C. neoformans CO.sub.2 tolerance, we performed a near genome-wide screen for deletion mutants with altered CO.sub.2 fitness using a competitive growth assay. A total of 301 of 4,692 deletion mutants showed altered CO.sub.2 tolerance (245 reduced fitness; 56 increased fitness) demonstrating the global effect of host CO.sub.2 on C. neoformans physiology. Based on this data set as well as a metabolomic analysis of C. neoformans adaptation to host CO.sub.2, we show that remodeling of central carbon metabolism, oxidative stress buffering, and membrane homeostasis represent an integrated response to CO.sub.2 stress that is mediated in part by the TOR-Ypk1 signaling axis. We propose that CO.sub.2 -induced capsule formation leads to reduced cellular glucose which, in turn, triggers remodeling of central carbon metabolism toward utilization of alternative carbon sources and increased mitochondrial respiration/reactive oxygen generation. Thus, these data provide a near genome-wide profile of the genetic determinants of C. neoformans CO.sub.2 tolerance as well as a model for how this important environmental human fungal pathogen alters its physiology to proliferate in the host.

is an environmental pathogen that remodels its cellular physiology to survive within mammals and, in susceptible hosts, cause life-threatening meningoencephalitis. Of the many distinctions between the external environment and mammalian tissues, CO concentration in the host is 2 orders of magnitude higher than in the environment and represent a critical stress for . strains that do not replicate at host CO concentrations are less virulent in mouse models of infection, further supporting CO tolerance as a virulence trait. To further understand the genetic determinants of CO tolerance, we performed a near genome-wide screen for deletion mutants with altered CO fitness using a competitive growth assay. A total of 301 of 4698 deletion mutants showed altered CO tolerance (245 reduced fitness; 51 increased fitness) demonstrating the global effect of host CO on physiology. Based on this data set as well as a metabolomic analysis of adaptation to host CO , we show that remodeling of central carbon metabolism, oxidative stress buffering and membrane homeostasis represent an integrated response to CO stress that is mediated in part by the TOR-Ypk1 signaling axis. We propose that CO -induced capsule formation leads to reduced cellular glucose which, in turn, triggers remodeling of central carbon metabolism toward utilization of alternative carbon sources and increased mitochondrial respiration/reactive oxygen generation. Thus, these data provide a near genome-wide profile of the genetic determinants CO tolerance as well as a model for how this important environmental human fungal pathogen alters its physiology to proliferate in the host.

Cryptococcus neoformans is an environmental pathogen that remodels its cellular physiology to survive within mammals and, in susceptible hosts, cause life-threatening meningoencephalitis. Of the many distinctions between the external environment and mammalian tissues, CO2 concentration in the host is 2 orders of magnitude higher than in the environment and represent a critical stress for C. neoformans. C. neoformans strains that do not replicate at host CO2 concentrations are less virulent in mouse models of infection, further supporting CO2 tolerance as a virulence trait. To further understand the genetic determinants of C. neoformans CO2 tolerance, we performed a near genome-wide screen for deletion mutants with altered CO2 fitness using a competitive growth assay. A total of 301 of 4698 deletion mutants showed altered CO2 tolerance (245 reduced fitness; 51 increased fitness) demonstrating the global effect of host CO2 on C. neoformans physiology. Based on this data set as well as a metabolomic analysis of C. neoformans adaptation to host CO2, we show that remodeling of central carbon metabolism, oxidative stress buffering and membrane homeostasis represent an integrated response to CO2 stress that is mediated in part by the TOR-Ypk1 signaling axis. We propose that CO2-induced capsule formation leads to reduced cellular glucose which, in turn, triggers remodeling of central carbon metabolism toward utilization of alternative carbon sources and increased mitochondrial respiration/reactive oxygen generation. Thus, these data provide a near genome-wide profile of the genetic determinants of C. neoformans CO2 tolerance as well as a model for how this important environmental human fungal pathogen alters its physiology to proliferate in the host.

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the “Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders” consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.

IntroductionDevelopments in blood biomarkers (BBMs) in dementia call for studies that evaluate their diagnostic, prognostic and societal implications in real-world populations. Such evidence is essential to support the safe and effective integration of BBMs into clinical practice.Methods and analysisThe REAl world Dementia OUTcomes study (READ-OUT) is a UK-based, multi-site study that assesses the prognostic and diagnostic utility of BBMs in people attending memory assessment services (‘secondary care’). READ-OUT phase 1 is a 3-year observational study of 3165 people representative of the UK population, with up-sampling of under-represented groups and proactive recruitment to include individuals missing from secondary care memory services. Participants are over the age of 45, able to provide a blood sample and willing to consent to linkage with electronic health records. The baseline study visit includes venepuncture and questionnaire assessment of quality of life and health resource usage. A subsample of the full cohort will have further venepuncture and questionnaires at a 52-week follow-up. READ-OUT substudies will evaluate BBMs’ test–retest reliability, the impact of processing delays and the feasibility of self-collected blood-spot samples. The clinical utility of BBMs will be assessed against diagnosis, outcomes from electronic health records, corollary data and health economic data. Results of the observational study discussed in this protocol will inform the design of a randomised controlled trial to test the cost-effectiveness, acceptability and clinical utility of disclosed BBM results.Ethics and disseminationThe study has received Research Ethics Committee approval (REC reference 24/WA/0330) and approval through the Health Research Authority/Health and Care Research Wales (IRAS project 342412). Anonymised study data will be stored on the Dementia Platform UK (DPUK) Data Portal (https://portal.dementiasplatform.uk) and made available through a managed access process, subject to the DPUK Data Access Agreement.

Background: The SITLESS programme comprises exercise referral schemes and self-management strategies and has been evaluated in a trial in Denmark, Spain, Germany and Northern Ireland. The aim of this qualitative study was to understand the implementation and contextual aspects of the intervention in relation to the mechanisms of impact and to explore the perceived effects. Methods: Qualitative methodologies were nested in the SITLESS trial including 71 individual interviews and 12 focus groups targeting intervention and control group participants from postintervention to 18-month follow-up in all intervention sites based on a semi-structured topic guide. Results: Overarching themes were identified under the framework categories of context, implementation, mechanisms of impact and perceived effects. The findings highlight the perceived barriers and facilitators to older adults’ engagement in exercise referral schemes. Social interaction and enjoyment through the group-based programmes are key components to promote adherence and encourage the maintenance of targeted behaviours through peer support and connectedness. Exit strategies and signposting to relevant classes and facilities enabled the maintenance of positive lifestyle behaviours. Conclusions: When designing and implementing interventions, key components enhancing social interaction, enjoyment and continuity should be in place in order to successfully promote sustained behaviour change.

Manual scoring of polysomnography data is labor-intensive and time-consuming, and most existing software does not account for subjective differences and user variability. Therefore, we evaluated a supervised machine learning algorithm, Somnivore , for automated wake-sleep stage classification. We designed an algorithm that extracts features from various input channels, following a brief session of manual scoring, and provides automated wake-sleep stage classification for each recording. For algorithm validation, polysomnography data was obtained from independent laboratories, and include normal, cognitively-impaired, and alcohol-treated human subjects (total = 52), narcoleptic mice and drug-treated rats (total = 56), and pigeons ( = 5). Training and testing sets for validation were previously scored manually by 1-2 trained sleep technologists from each laboratory. -measure was used to assess precision and sensitivity for statistical analysis of classifier output and human scorer agreement. The algorithm gave high concordance with manual visual scoring across all human data (wake 0.91 ± 0.01; N1 0.57 ± 0.01; N2 0.81 ± 0.01; N3 0.86 ± 0.01; REM 0.87 ± 0.01), which was comparable to manual inter-scorer agreement on all stages. Similarly, high concordance was observed across all rodent (wake 0.95 ± 0.01; NREM 0.94 ± 0.01; REM 0.91 ± 0.01) and pigeon (wake 0.96 ± 0.006; NREM 0.97 ± 0.01; REM 0.86 ± 0.02) data. Effects of classifier learning from single signal inputs, simple stage reclassification, automated removal of transition epochs, and training set size were also examined. In summary, we have developed a polysomnography analysis program for automated sleep-stage classification of data from diverse species. Somnivore enables flexible, accurate, and high-throughput analysis of experimental and clinical sleep studies.

Background This study details the within-trial economic evaluation and long-term economic model of SITLESS, a multi-country, three-armed randomized controlled trial comparing a combined intervention of exercise referral schemes (ERS) enhanced by self-management strategies (SMS) against ERS alone and usual care (UC). Methods A cost-utility analysis, conducted from the base-case perspective of the National Health Service and personal and social services, estimated the incremental cost per incremental quality-adjusted life year (QALY) and years in full capability (YFC). A secondary analysis combined the costs with a broad set of outcomes within a cost-consequence framework, from a societal perspective. A Markov-type decision-analytic model was developed to project short-term changes in physical activity to long-term outcomes and costs, over a 5- and 15-year time horizon. Results The results of the within-trial analysis show that SMS+ERS is highly likely to be cost-effective compared to ERS alone (ICER €4270/QALY), but not compared to UC. Participants allocated to the SMS+ERS group also showed an improvement in YFC compared to ERS alone and UC. The long-term analysis revealed that SMS+ERS is likely to be a cost-effective option compared to ERS and UC over a 5-year, but not with a 15-year horizon, being then dominated by ERS alone. Conclusion This research provides new evidence that SMS is a cost-effective add-on to ERS strategies. This economic evaluation informs the case for further, cost-effective, refinement of lifestyle change programmes targeted to older adults, with the aim of ultimately reducing the impact of non-communicable diseases in this population.