Log Fano varieties over function fields of curves

Consider a smooth log Fano variety over the function field of a curve. Suppose that the boundary has positive normal bundle. Choose an integral model over the curve. Then integral points are Zariski dense, after removing an explicit finite set of points on the base curve.Comment: 18 page

The Danish High Risk and Resilience Study-VIA 11: Study Protocol for the First Follow-Up of the VIA 7 Cohort -522 Children Born to Parents With Schizophrenia Spectrum Disorders or Bipolar Disorder and Controls Being Re-examined for the First Time at Age 11.

Introduction: Offspring of parents with severe mental illness have an increased risk of developing mental illnesses themselves. Familial high risk cohorts give a unique opportunity for studying the development over time, both the illness that the individual is predisposed for and any other diagnoses. These studies can also increase our knowledge of etiology of severe mental illness and provide knowledge about the underlying mechanisms before illness develops. Interventions targeting this group are often proposed due to the potential possibility of prevention, but evidence about timing and content is lacking. Method: A large, representative cohort of 522 7-year old children born to parents with schizophrenia, bipolar disorder or controls was established based on Danish registers. A comprehensive baseline assessment including neurocognition, motor functioning, psychopathology, home environment, sociodemographic data, and genetic information was conducted from January 1, 2013 to January 31, 2016. This study is the first follow-up of the cohort, carried out when the children turn 11 years of age. By assessing the cohort at this age, we will evaluate the children twice before puberty. All instruments have been selected with a longitudinal perspective and most of them are identical to those used at inclusion into the study at age 7. A diagnostic interview, motor tests, and a large cognitive battery are conducted along with home visits and information from teachers. This time we examine the children's brains by magnetic resonance scans and electroencephalograms. Measures of physical activity and sleep are captured by a chip placed on the body, while we obtain biological assays by collecting blood samples from the children. Discussion: Findings from the VIA 7 study revealed large variations across domains between children born to parents with schizophrenia, bipolar and controls, respectively. This study will further determine whether the children at familial risk reveal delayed developmental courses, but catch up at age 11, or whether the discrepancies between the groups have grown even larger. We will compare subgroups within each of the familial high risk groups in order to investigate aspects of resilience. Data on brain structure and physical parameters will add a neurobiological dimension to the study

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding: Bill & Melinda Gates Foundation

Modulating mitophagy in mitochondrial disease

Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue. The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signaling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. Type 1 mitophagy due to nutrient starvation is dependent on PI3K (phosphoinositide 3-kinase) for autophagosome formation but independent of mitophagy proteins, PINK1 (PTEN-induced putative kinase 1) and Parkin. Whereas type 2 mitophagy that occurs due to damage is dependent on PINK1 and Parkin but does not require PI3K. Autophagy and mitophagy play an important role in human disease and hence could serve as therapeutic targets for the treatment of mitochondrial as well as neurodegenerative disorders. Therefore, we reviewed drugs that are known modulators of autophagy (AICAR and metformin) and may effect this by activating the AMP-activated protein kinase signaling pathways. Furthermore, we reviewed data available on supplements, such as Coenzyme Q and the quinone idebenone, that we assert rescue increased mitophagy in mitochondrial disease by benefiting mitochondrial function

Assessing the differences between the IntCal and Greenland ice-core time scales for the last 14,000 years via the common cosmogenic radionuclide variations

Variations in galactic cosmic rays reaching the Earth's atmosphere produce globally synchronous variations in the production rates of cosmogenic radionuclides. In consequence, they leave their imprint in tree-ring 14C and ice-core 10Be records. By identifying this signal and correcting for the known geochemical influences on the radionuclides, it is possible to compare and synchronize the tree-ring chronology and the Greenland ice-core time scale. Here, we compare the IntCal13 and the GICC05 time scales for the last 14,000 years via identification and synchronization of the common short-term variations in the ice-core 10Be and tree-ring 14C records most likely induced by variations in the solar modulation of galactic cosmic rays. We conclude that systematic time-scale differences have to be accounted for if ice-core and 14C-dated records are compared on decadal time scales. These are mostly within the uncertainties of the time scales and the method proposed here. However, for large parts of the mid to late Holocene (i.e. after 7000 yrs BP) the best agreement between ice-core 10Be and tree-ring 14C records is obtained for time shifts outside the stated errors of the respective time scales. A transfer function is proposed that can be applied to synchronize the GICC05 ice-core time scale to the radiocarbon time scale