\u3cem\u3eDENND5B\u3c/em\u3e Regulates Intestinal Triglyceride Absorption and Body Mass

Regulation of lipid absorption by enterocytes can influence metabolic status in humans and contribute to obesity and related complications. The intracellular steps of chylomicron biogenesis and transport from the Endoplasmic Reticulum (ER) to the Golgi complex have been described, but the mechanisms for post-Golgi transport and secretion of chylomicrons have not been identified. Using a newly generated Dennd5b−/− mouse, we demonstrate an essential role for this gene in Golgi to plasma membrane transport of chylomicron secretory vesicles. In mice, loss of Dennd5b results in resistance to western diet induced obesity, changes in plasma lipids, and reduced aortic atherosclerosis. In humans, two independent exome sequencing studies reveal that a common DENND5B variant, p.(R52K), is correlated with body mass index. These studies establish an important role for DENND5B in post-Golgi chylomicron secretion and a subsequent influence on body composition and peripheral lipoprotein metabolism

How do the prevalence and relative risk of non-suicidal self-injury and suicidal thoughts vary across the population distribution of common mental distress (the p factor)? Observational analyses replicated in two independent UK cohorts of young people

Funder: National Institute for Health Research; FundRef: http://dx.doi.org/10.13039/501100000272Objectives: To inform suicide prevention policies and responses to youths at risk by investigating whether suicide risk is predicted by a summary measure of common mental distress (CMD (the p factor)) as well as by conventional psychopathological domains; to define the distribution of suicide risks over the population range of CMD; to test whether such distress mediates the medium-term persistence of suicide risks. Design: Two independent population-based cohorts. Setting: Population based in two UK centres. Participants: Volunteers aged 14–24 years recruited from primary healthcare registers, schools and colleges, with advertisements to complete quotas in age-sex-strata. Cohort 1 is the Neuroscience in Psychiatry Network (n=2403); cohort 2 is the ROOTS sample (n=1074). Primary outcome measures: Suicidal thoughts (ST) and non-suicidal self-injury (NSSI). Results: We calculated a CMD score using confirmatory bifactor analysis and then used logistic regressions to determine adjusted associations between risks and CMD; curve fitting was used to examine the relative prevalence of STs and NSSI over the population distribution of CMD. We found a dose–response relationship between levels of CMD and risk of suicide. The majority of all subjects experiencing ST and NSSI (78% and 76% in cohort 1, and 66% and 71% in cohort 2) had CMD scores no more than 2 SDs above the population mean; higher scores indicated the highest risk but were, by definition, infrequent. Pathway mediation models showed that CMD mediated the longitudinal course of both ST and NSSI. Conclusions: NSSI and ST in youths reflect CMD that also mediates their persistence. Universal prevention strategies reducing levels of CMD in the whole population without recourse to screening or measurement may prevent more suicides than approaches targeting youths with the most severe distress or with psychiatric disorders

Training of Instrumentalists and Development of New Technologies on SOFIA

This white paper is submitted to the Astronomy and Astrophysics 2010 Decadal Survey (Astro2010)1 Committee on the State of the Profession to emphasize the potential of the Stratospheric Observatory for Infrared Astronomy (SOFIA) to contribute to the training of instrumentalists and observers, and to related technology developments. This potential goes beyond the primary mission of SOFIA, which is to carry out unique, high priority astronomical research. SOFIA is a Boeing 747SP aircraft with a 2.5 meter telescope. It will enable astronomical observations anywhere, any time, and at most wavelengths between 0.3 microns and 1.6 mm not accessible from ground-based observatories. These attributes, accruing from the mobility and flight altitude of SOFIA, guarantee a wealth of scientific return. Its instrument teams (nine in the first generation) and guest investigators will do suborbital astronomy in a shirt-sleeve environment. The project will invest $10M per year in science instrument development over a lifetime of 20 years. This, frequent flight opportunities, and operation that enables rapid changes of science instruments and hands-on in-flight access to the instruments, assure a unique and extensive potential - both for training young instrumentalists and for encouraging and deploying nascent technologies. Novel instruments covering optical, infrared, and submillimeter bands can be developed for and tested on SOFIA by their developers (including apprentices) for their own observations and for those of guest observers, to validate technologies and maximize observational effectiveness.Comment: 10 pages, no figures, White Paper for Astro 2010 Survey Committee on State of the Professio

Cell-free, high-density lipoprotein-specific phospholipid efflux assay predicts incident cardiovascular disease

BACKGROUND. Cellular cholesterol efflux capacity (CEC) is a better predictor of cardiovascular disease (CVD) events than HDLcholesterol (HDL-C) but is not suitable as a routine clinical assay.METHODS. We developed an HDL-specific phospholipid efflux (HDL-SPE) assay to assess HDL functionality based on whole plasma HDL apolipoprotein-mediated solubilization of fluorescent phosphatidylethanolamine from artificial lipid donor particles. We first assessed the association of HDL-SPE with prevalent coronary artery disease (CAD): study I included NIH severe-CAD (n = 50) and non-CAD (n = 50) participants, who were frequency matched for sex, BMI, type 2 diabetes mellitus, and smoking; study II included Japanese CAD (n = 70) and non-CAD (n = 154) participants. We also examined the association of HDL-SPE with incident CVD events in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study comparing 340 patients with 340 controls individually matched for age, sex, smoking, and HDL-C levels.RESULTS. Receiver operating characteristic curves revealed stronger associations of HDL-SPE with prevalent CAD. The AUCs in study I were as follows: HDL-SPE, 0.68; apolipoprotein A-I (apoA-I), 0.62; HDL-C, 0.63; and CEC, 0.52. The AUCs in study II were as follows: HDL-SPE, 0.83; apoA-I, 0.64; and HDL-C, 0.53. Also longitudinally, HDL-SPE was significantly associated with incident CVD events independent of traditional risk factors with ORs below 0.2 per SD increment in the PREVEND study (P &lt; 0.001).CONCLUSION. HDL-SPE could serve as a routine clinical assay for improving CVD risk assessment and drug discovery.</p

Cell-free, high-density lipoprotein-specific phospholipid efflux assay predicts incident cardiovascular disease

BACKGROUND. Cellular cholesterol efflux capacity (CEC) is a better predictor of cardiovascular disease (CVD) events than HDLcholesterol (HDL-C) but is not suitable as a routine clinical assay.METHODS. We developed an HDL-specific phospholipid efflux (HDL-SPE) assay to assess HDL functionality based on whole plasma HDL apolipoprotein-mediated solubilization of fluorescent phosphatidylethanolamine from artificial lipid donor particles. We first assessed the association of HDL-SPE with prevalent coronary artery disease (CAD): study I included NIH severe-CAD (n = 50) and non-CAD (n = 50) participants, who were frequency matched for sex, BMI, type 2 diabetes mellitus, and smoking; study II included Japanese CAD (n = 70) and non-CAD (n = 154) participants. We also examined the association of HDL-SPE with incident CVD events in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study comparing 340 patients with 340 controls individually matched for age, sex, smoking, and HDL-C levels.RESULTS. Receiver operating characteristic curves revealed stronger associations of HDL-SPE with prevalent CAD. The AUCs in study I were as follows: HDL-SPE, 0.68; apolipoprotein A-I (apoA-I), 0.62; HDL-C, 0.63; and CEC, 0.52. The AUCs in study II were as follows: HDL-SPE, 0.83; apoA-I, 0.64; and HDL-C, 0.53. Also longitudinally, HDL-SPE was significantly associated with incident CVD events independent of traditional risk factors with ORs below 0.2 per SD increment in the PREVEND study (P &lt; 0.001).CONCLUSION. HDL-SPE could serve as a routine clinical assay for improving CVD risk assessment and drug discovery.</p

Cell-free, high-density lipoprotein-specific phospholipid efflux assay predicts incident cardiovascular disease

BACKGROUND. Cellular cholesterol efflux capacity (CEC) is a better predictor of cardiovascular disease (CVD) events than HDLcholesterol (HDL-C) but is not suitable as a routine clinical assay.METHODS. We developed an HDL-specific phospholipid efflux (HDL-SPE) assay to assess HDL functionality based on whole plasma HDL apolipoprotein-mediated solubilization of fluorescent phosphatidylethanolamine from artificial lipid donor particles. We first assessed the association of HDL-SPE with prevalent coronary artery disease (CAD): study I included NIH severe-CAD (n = 50) and non-CAD (n = 50) participants, who were frequency matched for sex, BMI, type 2 diabetes mellitus, and smoking; study II included Japanese CAD (n = 70) and non-CAD (n = 154) participants. We also examined the association of HDL-SPE with incident CVD events in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study comparing 340 patients with 340 controls individually matched for age, sex, smoking, and HDL-C levels.RESULTS. Receiver operating characteristic curves revealed stronger associations of HDL-SPE with prevalent CAD. The AUCs in study I were as follows: HDL-SPE, 0.68; apolipoprotein A-I (apoA-I), 0.62; HDL-C, 0.63; and CEC, 0.52. The AUCs in study II were as follows: HDL-SPE, 0.83; apoA-I, 0.64; and HDL-C, 0.53. Also longitudinally, HDL-SPE was significantly associated with incident CVD events independent of traditional risk factors with ORs below 0.2 per SD increment in the PREVEND study (P &lt; 0.001).CONCLUSION. HDL-SPE could serve as a routine clinical assay for improving CVD risk assessment and drug discovery.</p

Diet and Energy-Sensing Inputs Affect TorC1-Mediated Axon Misrouting but Not TorC2-Directed Synapse Growth in a Drosophila Model of Tuberous Sclerosis

The Target of Rapamycin (TOR) growth regulatory system is influenced by a number of different inputs, including growth factor signaling, nutrient availability, and cellular energy levels. While the effects of TOR on cell and organismal growth have been well characterized, this pathway also has profound effects on neural development and behavior. Hyperactivation of the TOR pathway by mutations in the upstream TOR inhibitors TSC1 (tuberous sclerosis complex 1) or TSC2 promotes benign tumors and neurological and behavioral deficits, a syndrome known as tuberous sclerosis (TS). In Drosophila, neuron-specific overexpression of Rheb, the direct downstream target inhibited by Tsc1/Tsc2, produced significant synapse overgrowth, axon misrouting, and phototaxis deficits. To understand how misregulation of Tor signaling affects neural and behavioral development, we examined the influence of growth factor, nutrient, and energy sensing inputs on these neurodevelopmental phenotypes. Neural expression of Pi3K, a principal mediator of growth factor inputs to Tor, caused synapse overgrowth similar to Rheb, but did not disrupt axon guidance or phototaxis. Dietary restriction rescued Rheb-mediated behavioral and axon guidance deficits, as did overexpression of AMPK, a component of the cellular energy sensing pathway, but neither was able to rescue synapse overgrowth. While axon guidance and behavioral phenotypes were affected by altering the function of a Tor complex 1 (TorC1) component, Raptor, or a TORC1 downstream element (S6k), synapse overgrowth was only suppressed by reducing the function of Tor complex 2 (TorC2) components (Rictor, Sin1). These findings demonstrate that different inputs to Tor signaling have distinct activities in nervous system development, and that Tor provides an important connection between nutrient-energy sensing systems and patterning of the nervous system

The impact of the initial COVID-19 outbreak on young adults’ mental health: a longitudinal study of risk and resilience factors

Few studies assessing the effects of COVID-19 on mental health include prospective markers of risk and resilience necessary to understand and mitigate the combined impacts of the pandemic, lockdowns, and other societal responses. This population-based study of young adults includes individuals from the Neuroscience in Psychiatry Network (n = 2403) recruited from English primary care services and schools in 2012–2013 when aged 14–24. Participants were followed up three times thereafter, most recently during the initial outbreak of the COVID-19 outbreak when they were aged between 19 and 34. Repeated measures of psychological distress (K6) and mental wellbeing (SWEMWBS) were supplemented at the latest assessment by clinical measures of depression (PHQ-9) and anxiety (GAD-7). A total of 1000 participants, 42% of the original cohort, returned to take part in the COVID-19 follow-up; 737 completed all four assessments [mean age (SD), 25.6 (3.2) years; 65.4% female; 79.1% White]. Our findings show that the pandemic led to pronounced deviations from existing mental health-related trajectories compared to expected levels over approximately seven years. About three-in-ten young adults reported clinically significant depression (28.8%) or anxiety (27.6%) under current NHS guidelines; two-in-ten met clinical cut-offs for both. About 9% reported levels of psychological distress likely to be associated with serious functional impairments that substantially interfere with major life activities; an increase by 3% compared to pre-pandemic levels. Deviations from personal trajectories were not necessarily restricted to conventional risk factors; however, individuals with pre-existing health conditions suffered disproportionately during the initial outbreak of the COVID-19 pandemic. Resilience factors known to support mental health, particularly in response to adverse events, were at best mildly protective of individual psychological responses to the pandemic. Our findings underline the importance of monitoring the long-term effects of the ongoing pandemic on young adults’ mental health, an age group at particular risk for the emergence of psychopathologies. Our findings further suggest that maintaining access to mental health care services during future waves, or potential new pandemics, is particularly crucial for those with pre-existing health conditions. Even though resilience factors known to support mental health were only mildly protective during the initial outbreak of the COVID-19 pandemic, it remains to be seen whether these factors facilitate mental health in the long term