Cell to cell signaling via AKT causes T cell differentiation and collapse of tumour stroma

Adoptive Cell Therapy of cancer using T cells is entering mainstream practice after years as a research method. Central to the efficacy of this “living therapy” is the function of the T cells transferred. T-cells, like other primary tissue cells, undergo differentiation and death. Clinical and preclinical data shows that lesser differentiated, less glycolytic, and more proliferative-capable cells used for the adoptive transfer yield superior tumor responses. This introductory section will describe discoveries which elucidate and control T-cell differentiation and function for the improvement of adoptive cell therapy. Namely by use of inhibition of the PI3k/AKT pathways, and through the discovery of a dual function of death and differentiation by the canonical death receptor Fas, which can be parsed apart with a mutation from valine to cysteine at the 194 position (C194V), differentiation can be withheld while leaving cell proliferation unhindered during T-cell stimulation and expansion. The data also reveals that the differentiation signal caused by extracellular Fas ligation passes through AKT, revealing both Fas and AKT as points of intervention for targeting differentiation along the same pathway. From further investigation, this introduction will describe the effect of AKT inhibition on T-cell differentiation on a transciptional and metabolic level. The data reveals AKT inhibition promoted FOXO1 intranuclear organization, which creates a more naive-like phenotype to the cells, and lower glycolytic status, another phenotype associated with persistent and long-lived cells. Furthermore, this control of AKT and Fas in T-cells yields benefits in several modalities of pre-clinical models of adoptive T-cell immunotherapy of cancer, in both use of a chimeric antigen receptor (CAR) and with use of Tumor Infiltrating Lymphocytes (TIL). Finally, the real-world applicability of the finding including the use of AKT inhibition in current approved Adoptive T-cell immunotherapies will be discussed

Model Predictive Control and Fault Detection and Diagnostics of a Building Heating, Ventilation, and Air Conditioning System

The paper presents Model Predictive Control (MPC) and Fault Detection and Diagnostics (FDD) technologies, their on-line implementation, and results from several demonstrations conducted for a large-size HVAC system. The two technologies are executed at the supervisory level in a hierarchical control architecture as extensions of a baseline Building Management System (BMS). The MPC algorithm generates optimal set points for the HVAC actuator loops which minimize energy consumption while meeting equipment operational constraints and occupant comfort constraints. The MPC algorithm is implemented using a new tool, the Berkeley Library for Optimization Modeling (BLOM), which generates automatically an efficient optimization formulation directly from a simulation model. The FDD algorithm detects and classifies in real-time potential faults of the HVAC actuators based on data from multiple sensors. The performance and limitations of FDD and MPC algorithms are illustrated and discussed based on measurement data recorded from multiple tests

Impacts of Climate Change on indirect human exposure to pathogens and chemicals from agriculture

Objective: Climate change is likely to affect the nature of pathogens and chemicals in the environment and their fate and transport. Future risks of pathogens and chemicals could therefore be very different from those of today. In this review, we assess the implications of climate change for changes in human exposures to pathogens and chemicals in agricultural systems in the United Kingdom and discuss the subsequent effects on health impacts. Data sources: In this review, we used expert input and considered literature on climate change ; health effects resulting from exposure to pathogens and chemicals arising from agriculture ; inputs of chemicals and pathogens to agricultural systems ; and human exposure pathways for pathogens and chemicals in agricultural systems. Data synthesis: We established the current evidence base for health effects of chemicals and pathogens in the agricultural environment ; determined the potential implications of climate change on chemical and pathogen inputs in agricultural systems ; and explored the effects of climate change on environmental transport and fate of different contaminant types. We combined these data to assess the implications of climate change in terms of indirect human exposure to pathogens and chemicals in agricultural systems. We then developed recommendations on future research and policy changes to manage any adverse increases in risks. Conclusions: Overall, climate change is likely to increase human exposures to agricultural contaminants. The magnitude of the increases will be highly dependent on the contaminant type. Risks from many pathogens and particulate and particle-associated contaminants could increase significantly. These increases in exposure can, however, be managed for the most part through targeted research and policy changes

Predicting major adverse cardiovascular events for secondary prevention: protocol for a systematic review and meta-analysis of risk prediction models

Introduction: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. With advances in early diagnosis and treatment of CVD and increasing life expectancy, more people are surviving initial CVD events. However, models to stratifying disease severity risk in patients with established CVD for effective secondary prevention strategies are inadequate. Multivariable prognostic models to stratify CVD risk may allow personalised treatment interventions. This review aims to systematically review the existing multivariable prognostic models for the recurrence of CVD or major adverse cardiovascular events in adults with established CVD diagnosis.Methods and analysis: Bibliographic databases (Ovid MEDLINE, EMBASE, PsycINFO and Web of Science) will be searched, from database inception to April 2020, using terms relating to the clinical area and prognosis. Hand search of the reference lists of included studies will also be done to identify additional published studies. No restrictions on language of publications will be applied. Eligible studies present multivariable models (derived or validated) of adults (aged 16 years and over) with an established diagnosis of CVD, reporting at least one of the components of the primary outcome of major adverse cardiovascular events (defined as either coronary heart disease, stroke, peripheral artery disease, heart failure or CVD-related mortality). Reviewing will be done by two reviewers independently using the pre-defined criteria. Data will be extracted for included full-text articles. Risk of bias will be assessed using the Prediction model study Risk Of Bias Assessment Tool (PROBAST). Prognostic models will be summarised narratively. If a model is tested in multiple validation studies, the predictive performance will be summarised using a random-effects meta-analysis model to account for any between-study heterogeneity

Research inventory of child health: A report on roadmaps for the future of child health research in Europe

RICHE was the response to a call under HEALTH-2009-3.3-5, with the title of 'European child health research platform'. The call text asked us to “address the diversity and fragmentation in child health research in Europe in an inclusive multidisciplinary way, identifying existing research programmes in Member States, recent advances and identification of gaps to explore road maps for the future of child health research in Europe”. Project structure A consortium, with a final total of 23 partners, and two associate (i.e. unfunded) partners, responded to this call. We designed a project with a linear structure, where the main focus of activity moved from work on the Inventory, and Indicators and Measurement, in Year 1, to work on Gaps in Year 2, finishing with the preparation of the Roadmap in year 3. The final 6 months (Year 4) were largely dissemination. The Platform, which is instantiated in our website, supported all of the other parts,, and was a focus for communication and dissemination throughout the project. Each workpackage focused on a specific area of work, but each fed into its successors, and all leaders and partners worked closely together. Each group produced a number of technical reports and other outputs. The final output was a Roadmap for future investment in European child health research. This has been widely disseminated, and has fed at Commission level and National level into the Horizon 2020 call preparation process. RICHE Roadmap The RICHE Roadmap is based upon a sound, scientific evidence base, which we had gathered as part of our earlier work. The project prepared an inventory of child health research and of measurements and indicators of child health in Europe (WP1 and WP2) . This was collated using a web platform – which can be found at www.childhealthresearch.eu. In addition to this exercise, a formal study of the gaps in child health research was undertaken by carrying out surveys and interviews of researchers and research users across Europe (WP3). This allowed our initial views on the research gaps to be refined and corrected by an iterative process, involving, both project partners, and the wider scientific community, so seeking grounding and validation for this key phase. These results formed the basis for the RICHE Roadmap. The Roadmap is based on a life-course perspective. It covers the important phases of a child’s development, including maternal health, and pregnancy, through to adolescence and the protective and risk factors, and health services encountered throughout childhood and adolescence as he or she moves towards adulthood. RICHE looked upstream to identify where more work needed to be done to prevent avoidable physical and mental ill-health, disability and death in the population of European children aged 0-18 years. This shows how the many influences and outcomes of children’s health are interrelated; a pattern reflected in the Roadmap. The work necessarily involved a series of value judgements, especially on setting priorities, because there are no objective and unconditionally valid answers to the question “Is there enough research on this topic?”, nor to the question “Is this a topic of significance?”. Nevertheless, the RICHE Roadmap uses an inclusive and transparent process to explain the recommendations it made, and the subjects it chose, making our values, and the reasons for judgements as explicit as possible. The report is organised into broad subject areas, that reflect the key ‘gaps’ in knowledge about children and young people, or about particular aspects of their lifestyle and health. These key areas, and selected findings within each area, are briefly summarised here. Life Course and Lifestyle This section focuses on children as they age, and recognises the importance of continuing to research how factors before conception, during gestation and in the very early years of life can affect present and future health. The challenges that children face as they grow up are also highlighted – these can be created because of policy decisions that fail to take account of children and young people’s lives or because of the pervasive influences of individual circumstances that act ask protective or risk factors for children’s actions. The concept of resilience in childhood is also highlighted, and how research needs to focus on this important and powerful means of improving children’s lives. A key issue, throughout the life course, is mental health and well-being. Fostering well-being in children from birth, and throughout childhood will provide numerous individual and societal benefits. It deserves a greater research focus. Socio-economic and Cultural Factors The socio-economic and cultural environment in which a child is born and grows up has a potent effect on a child’s health and well-being. Inequity and inequalities in health, between and within nations depending on socio-economic circumstances, are known to affect health outcomes. Those in the poorest areas have worse health, and shorter lives than those in the wealthiest areas. Other groups are at risk of marginalisation from health services and from opportunities that can maximise their health. These include migrant children where the question is how best to support their integration into their new societies and communities, while retaining their individual identity; children in the state care system have poor health and social outcomes, so improving these, by focused research is important for the future health of these children; children from minority population groups, in particular those who travel across nations, such as the Roma, need to have focused attention, to ensure that their health outcomes begin to match those of the general European child population. Social and Community Networks The main influences on children and young people are their immediate family and community networks. This extends from the influence of the family as a warm and nurturing environment in which to grow up – and conversely a place of the most profound danger and threat if such a family environment is toxic; to the wider influence of school, and finally the broader community. Becoming engaged and involved in community life is beneficial for the entire population, not just for the children and young people directly involved. It is an aspect of children and young people’s experience that is important for well-being and social inclusion. Environment The term 'environment' covers several different concepts, and the RICHE Roadmap describes the physical, virtual and also the perceived environment – all of which interlink in children’s lives, and have a profound effect on their health and development. These include the physical environment, the virtual (digital) environment, physical safety, including injury prevention, and protection form crime, anti-social behaviour and violence (both as perpetrators and victims). Complex Health Issues The majority of children in Europe are healthy, and ill-health is not a characteristic of this population as it is in, for example, an ageing population. However, there are certain health issues that affect children, and as such can blight an entire lifetime. Our Roadmap does not cover clinical issues, but takes a population perspective. There are certain disorders that have a population-wide effect and are prevalent enough in the child population to warrant particular attention from a public health viewpoint. Four specific areas of concern were identified – overweight and obesity, mental health, sexual and reproductive health, and neuro-developmental disorders. Health Services The main research needs of the health services focuses on the prevention of poor health. Comparing health services across Europe and evaluating the means of conveying health promotion messages are important directions for health research to investigate. Indicators need developing which reflect the effect of preventive actions, particularly among younger children. Vulnerable populations, such as those in deprived communities, need to have health prevention services particularly targeted. There is little systematic evaluation of such interventions, which compromises the development of new interventions and their implementation. Those who do not access services and those who need particular attention can be identified. Public Health Infrastructure Health surveillance is essential so that health needs can be identified and addressed effectively for the benefit of the child population. Yet, many existing sources of data are neither analysed, nor made available in a child-centric way. Children need to be made more visible in the data so that they can have more effective health promotion and health care on a population level. Specific examples include work on autism and morbidity due to injury. Europe also needs to establish proper measures and indicators of children’s health and children’s lives. We cannot act properly without first identifying and measuring the problem. Electronic health records are an emerging technology that has great potential, both for research, and for improved access to care. They need to be developed and investigated further to encourage their use across the European Union. Improving Research Capacity It is necessary to ensure that there are enough resources, both to do research, and to make use of the research findings. To sustain research activity, specialist training for junior child health researchers is needed, as are sufficient resources to maintain a critical mass of researchers and provide attractive career paths for them. Children and young people as subjects of research need to continue to be safeguarded by a consistently ethical framework, and information collected about children needs to be accurate, comprehensive and used intelligently so that interventions and services can be correctly directed. Using the roadmap The roadmap is a complex document, addressed to a number of different stakeholders. One key group are those who make decision bout research finding priorities. We have disseminated the roadmap widely at EU level, to reach into the process of priority setting for Horizon 2020. This has been done thought National Contact Points in each partner country, through relevant NGO's, and by sending copes to and meeting with relevant parts of the European Commission. Readers using the roadmap will most likely use it in two ways, first to make a general case for investment in Child Health Research, and secondly to target that investment, by considering the questions we have identified, and reviewing our justifications for these choices. We do not expect our work to determine future investments in child health, but we are confident that using our work would lead to better decisions overall. Conclusions Our core value is to put children first in our work. We take the rights of the child seriously, and we are conscious that many children do not have the opportunity to exercise the right to health and healthcare that European children they ought to have. The topics in this Roadmap are pragmatic in that they are researchable (within the grasp of presently available research methods and resources) and that are likely to have a significant effect on the lives of European children. This will go a considerable distance in improving the health and well-being of European children who may not have benefited from Europe’s good fortune up until this point. At the very least, the RICHE Roadmap aims to begin a serious conversation across Europe about the need for research to focus on children and how this will ultimately benefit all members of the European population. There is a need for children to become substantially more visible in European society. At present many children’s lives are invisible to health surveillance and to research. Sometimes they are submerged with their families, as in the case of Roma or for children of illegal and undocumented immigrant families. Even in well-documented societies, children’s circumstances are invisible as data are collected from the perspective of economically active adults, or households. Therefore, an overarching recommendation in this road map is the establishment of a European Child Health Observatory with a simple remit to make European Children, and their lives, health and attainment of rights more visible. We also recommend continuing and extending the discussion to the edge of existing child health boundaries, to address topics such as the effects on children’s health of urban design and architecture, fiscal policy (which can affect many health issues), welfare, or health effects of immigration policy. The RICHE Roadmap hopes to point the way in which children can be fully recognised and respected as forming a valuable population and whose health and well-being contributes to the health of our present and future European society

Measurement of the B0-anti-B0-Oscillation Frequency with Inclusive Dilepton Events

The $B^0$-$\bar B^0$ oscillation frequency has been measured with a sample of 23 million \B\bar B pairs collected with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we select events in which both B mesons decay semileptonically and use the charge of the leptons to identify the flavor of each B meson. A simultaneous fit to the decay time difference distributions for opposite- and same-sign dilepton events gives $\Delta m_d = 0.493 \pm 0.012{(stat)}\pm 0.009{(syst)}$ ps$^{-1}$.Comment: 7 pages, 1 figure, submitted to Physical Review Letter

Measurement of D-s(+) and D-s(*+) production in B meson decays and from continuum e(+)e(-) annihilation at √s=10.6 GeV

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APSNew measurements of Ds+ and Ds*+ meson production rates from B decays and from qq̅ continuum events near the Υ(4S) resonance are presented. Using 20.8 fb-1 of data on the Υ(4S) resonance and 2.6 fb-1 off-resonance, we find the inclusive branching fractions B(B⃗Ds+X)=(10.93±0.19±0.58±2.73)% and B(B⃗Ds*+X)=(7.9±0.8±0.7±2.0)%, where the first error is statistical, the second is systematic, and the third is due to the Ds+→φπ+ branching fraction uncertainty. The production cross sections σ(e+e-→Ds+X)×B(Ds+→φπ+)=7.55±0.20±0.34pb and σ(e+e-→Ds*±X)×B(Ds+→φπ+)=5.8±0.7±0.5pb are measured at center-of-mass energies about 40 MeV below the Υ(4S) mass. The branching fractions ΣB(B⃗Ds(*)+D(*))=(5.07±0.14±0.30±1.27)% and ΣB(B⃗Ds*+D(*))=(4.1±0.2±0.4±1.0)% are determined from the Ds(*)+ momentum spectra. The mass difference m(Ds+)-m(D+)=98.4±0.1±0.3MeV/c2 is also measured.This work was supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the Swiss NSF, A. P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R01NS109858, to VAG); the Paul A. Marks Scholar Program at the Columbia University Vagelos College of Physicians and Surgeons (to VAG); a TIGER grant from the TAUB Institute at the Columbia Vagelos College of Physicians and Scientists (to VAG); the Swiss National Science Foundation (SNF 31003A-179371, to TH); the European Joint Program on Rare Diseases (EJP RD+SNF 32ER30-187505, to TH); the Swiss Cancer League (KFS-4999-02-2020, to GD); the EPFL institutional fund (to GD); the Kristian Gerhard Jebsen Foundation (to GD); the Swiss National Science Foundation (SNSF) (310030_184926, to GD); the Swiss Foundation for Research on Muscle Disease (FSRMM, to MAL); the Natural Science and Engineering Research Council of Canada (Discovery Grant 2020-04241, to JEB); the Italian Ministry of Health Young Investigator Grant (GR-2011-02347754, to EL); the Fondazione Istituto di Ricerca Pediatrica – Città della Speranza (18-04, to EL); the Wroclaw Medical University (SUB.E160.21.004, to RS); the National Science Centre, Poland (2017/27/B/NZ5/0222, to RS); Telethon Undiagnosed Diseases Program (TUDP) (GSP15001); the Temple Street Foundation/Children’s Health Foundation Ireland (RPAC 19-02, to IK); the Deutsche Forschungsgemeinschaft (DFG) (PO2366/2–1, to BP); the Instituto de Salud Carlos III, Spain (to ELM, EBS, and BMD); the National Natural Science Foundation of China (81871079 and 81730036, to HG and KX); and the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH (R01 DK115574, to SSC).The DEFIDIAG study is funded by grants from the French Ministry of Health in the framewok of the national French initiative for genomic medicine. The funders were not involved in the study design, data acquisition, analysis, or writing of the manuscript. Funding for the DECIPHER project was provided by Wellcome. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.S