Cosmological simulations of black hole growth: AGN luminosities and downsizing

In this study, we present a detailed, statistical analysis of black hole growth and the evolution of active galactic nuclei (AGN) using cosmological hydrodynamic simulations run down to $z=0$. The simulations self-consistently follow radiative cooling, star formation, metal enrichment, black hole growth and associated feedback processes from both supernovae typeII/Ia and AGN. We consider two simulation runs, one with a large co-moving volume of $(500\ \mathrm{Mpc})^3$and one with a smaller volume of$(68\ \mathrm{Mpc})^3$but with a by a factor of almost 20 higher mass resolution. Consistently with previous results, our simulations can widely match observed black hole properties of the local Universe. Furthermore, our simulations can successfully reproduce the evolution of the bolometric AGN luminosity function for both the low-luminosity and the high-luminosity end up to$z=3.0$. In addition, the smaller but higher resolution run is able to match the observational data of the low bolometric luminosity end at higher redshifts$z=3-4$. We also perform a direct comparison with the observed soft and hard X-ray luminosity functions of AGN, including an empirical correction for a torus-level obscuration, and find a similarly good agreement. These results nicely demonstrate that the observed "anti-hierarchical" trend in the AGN number density evolution (i.e. the number densities of luminous AGN peak at higher redshifts than those of faint AGN) is self-consistently predicted by our simulations. Implications of this downsizing behaviour on active black holes, their masses and Eddington-ratios are discussed. Overall, the downsizing behaviour in the AGN number density as a function of redshift can be mainly attributed to the evolution of the gas density in the resolved vicinity of a (massive) black hole. (shortened)Comment: 24 pages, 15 figures, 1 table, accepted for publication in MNRAS, the analysis is updated using a simulation run with a cosmological volume of (500Mpc)^3 containing 2*1,564^3 particle

Interleukin-22 predicts severity and death in advanced liver cirrhosis: a prospective cohort study

Background: Interleukin-22 (IL-22), recently identified as a crucial parameter of pathology in experimental liver damage, may determine survival in clinical end-stage liver disease. Systematic analysis of serum IL-22 in relation to morbidity and mortality of patients with advanced liver cirrhosis has not been performed so far. Methods: This is a prospective cohort study including 120 liver cirrhosis patients and 40 healthy donors to analyze systemic levels of IL-22 in relation to survival and hepatic complications. Results: A total of 71% of patients displayed liver cirrhosis-related complications at study inclusion. A total of 23% of the patients died during a mean follow-up of 196 +/- 165 days. Systemic IL-22 was detectable in 74% of patients but only in 10% of healthy donors (P 18 pg/ml, n = 57) showed significantly reduced survival compared to patients with regular ([less than or equal to]18 pg/ml) levels of IL-22 (321 days versus 526 days, P = 0.003). Other factors associated with overall survival were high CRP ([greater than or equal to]2.9 mg/dl, P = 0.005, hazard ratio (HR) 0.314, confidence interval (CI) (0.141 to 0.702)), elevated serum creatinine (P = 0.05, HR 0.453, CI (0.203 to 1.012)), presence of liver-related complications (P = 0.028, HR 0.258 CI (0.077 to 0.862)), model of end stage liver disease (MELD) score [greater than or equal to]20 (P = 0.017, HR 0.364, CI (0.159 to 0.835)) and age (P = 0.011, HR 1.047, CI (1.011 to 1.085)). Adjusted multivariate Cox proportional-hazards analysis identified elevated systemic IL-22 levels as independent predictors of reduced survival (P = 0.007, HR 0.218, CI (0.072 to 0.662)). Conclusions: In patients with liver cirrhosis, elevated systemic IL-22 levels are predictive for reduced survival independently from age, liver-related complications, CRP, creatinine and the MELD score. Thus, processes that lead to a rise in systemic interleukin-22 may be relevant for prognosis of advanced liver cirrhosis

Cryptosporidium parvum infection alters the intestinal mucosa transcriptome in neonatal calves: implications for immune function

One of the leading causes of infectious diarrhea in newborn calves is the apicomplexan protozoan Cryptosporidium parvum (C. parvum). However, little is known about its immunopathogenesis. Using next generation sequencing, this study investigated the immune transcriptional response to C. parvum infection in neonatal calves. Neonatal male Holstein-Friesian calves were either orally infected (N = 5) or not (CTRL group, N = 5) with C. parvum oocysts (gp60 subtype IIaA15G2R1) at day 1 of life and slaughtered on day 7 after infection. Total RNA was extracted from the jejunal mucosa for short read. Differentially expressed genes (DEGs) between infected and CTRL groups were assessed using DESeq2 at a false discovery rate < 0.05. Infection did not affect plasma immunohematological parameters, including neutrophil, lymphocyte, monocyte, leucocyte, thrombocyte, and erythrocyte counts as well as hematocrit and hemoglobin concentration on day 7 post infection. The immune-related DEGs were selected according to the UniProt immune system process database and were used for gene ontology (GO) and pathway enrichment analysis using Cytoscape (v3.9.1). Based on GO analysis, DEGs annotated to mucosal immunity, recognizing and presenting antigens, chemotaxis of neutrophils, eosinophils, natural killer cells, B and T cells mediated by signaling pathways including toll like receptors, interleukins, tumor necrosis factor, T cell receptor, and NF-KB were upregulated, while markers of macrophages chemotaxis and cytosolic pattern recognition were downregulated. This study provides a holistic snapshot of immune-related pathways induced by C. parvum in calves, including novel and detailed feedback and feedforward regulatory mechanisms establishing the crosstalk between innate and adaptive immune response in neonate calves, which could be utilized further to develop new therapeutic strategies

Investigation of Body Development in Growing Holstein Heifers With Special Emphasis on Body Fat Development Using Bioelectrical Impedance Analysis

This study analyzed skeletal development, body condition, and total body fat development of growing heifers. A total of 144 female primiparous Holstein cattle from four commercial dairy farms with different degrees of stillbirth rates were examined during the rearing period. This included measurements in body condition, fat tissue, metabolic, and endocrine factors. Pelvic measurements and the sacrum height were analyzed to assess skeletal development. The body condition was classified via body condition scoring, bioelectrical impedance analysis (BIA), back fat thickness measurements, and the body mass. For the first time, BIA was used as an appropriate method to evaluate the fat tissue content of cattle throughout the rearing period. This analysis technique can be performed on heifers aged 8–15 months. Throughout that period, the fat content decreased while the skeletal development increased. In addition, high free fatty acid concentrations in serum of the animals with high frame development were found, supporting our hypothesis that stored energy of body fat deposits is used for skeletal growth. Furthermore, we were able to demonstrate complex endocrine relationships between fat metabolism and skeletal growth by using specific markers, such as leptin, insulin growth factor-1 (IGF-1), and estradiol (E2). Food analysis showed high crude protein (CP) levels in the total mixed ration above recommendation for daily protein intake of all farms. However, there was a positive correlation between CP and the body frame measurements in our study. In summary, we established a novel regression formula for BIA analysis (“BIA-Heine”) in heifers to evaluate the body composition throughout different ages and physiological stages in the development of heifers. This special formula allows the evaluation of fat tissue without a whole-body analysis and therefore provides an innovative technique for animal welfare support

Lifestyle Intervention with or without Lay Volunteers to Prevent Type 2 Diabetes in People with Impaired Fasting Glucose and/or Nondiabetic Hyperglycemia:A Randomized Clinical Trial

Importance:  Nearly half of the older adult population has diabetes or a high-risk intermediate glycemic category, but we still lack trial evidence for effective type 2 diabetes prevention interventions in most of the current high-risk glycemic categories. Objective:  To determine whether a group-based lifestyle intervention (with or without trained volunteers with type 2 diabetes) reduced the risk of progression to type 2 diabetes in populations with a high-risk glycemic category. Design, Setting, and Participants: The Norfolk Diabetes Prevention Study was a parallel, 3-arm, group-based, randomized clinical trial conducted with up to 46 months of follow-up from August 2011 to January 2019 at 135 primary care practices and 8 intervention sites in the East of England. We identified 141 973 people at increased risk of type 2 diabetes, screened 12 778 (9.0%), and randomized those with a high-risk glycemic category, which was either an elevated fasting plasma glucose level alone (≥110 and <126 mg/dL [to convert to millimoles per liter, multiply by 0.0555]) or an elevated glycated hemoglobin level (≥6.0% to <6.5%; nondiabetic hyperglycemia) with an elevated fasting plasma glucose level (≥100 to <110 mg/dL).Interventions A control arm receiving usual care (CON), a theory-based lifestyle intervention arm of 6 core and up to 15 maintenance sessions (INT), or the same intervention with support from diabetes prevention mentors, trained volunteers with type 2 diabetes (INT-DPM). Main Outcomes and Measures:  Type 2 diabetes incidence between arms.Results:  In this study, 1028 participants were randomized (INT, 424 [41.2%] [166 women (39.2%)]; INT-DPM, 426 [41.4%] [147 women (34.5%)]; CON, 178 [17.3%] [70 women (%39.3)]) between January 1, 2011, and February 24, 2017. The mean (SD) age was 65.3 (10.0) years, mean (SD) body mass index 31.2 (5) (calculated as weight in kilograms divided by height in meters squared), and mean (SD) follow-up 24.7 (13.4) months. A total of 156 participants progressed to type 2 diabetes, which comprised 39 of 171 receiving CON (22.8%), 55 of 403 receiving INT (13.7%), and 62 of 414 receiving INT-DPM (15.0%). There was no significant difference between the intervention arms in the primary outcome (odds ratio [OR], 1.14; 95% CI, 0.77-1.7; P = .51), but each intervention arm had significantly lower odds of type 2 diabetes (INT: OR, 0.54; 95% CI, 0.34-0.85; P = .01; INT-DPM: OR, 0.61; 95% CI, 0.39-0.96; P = .033; combined: OR, 0.57; 95% CI, 0.38-0.87; P = .01). The effect size was similar in all glycemic, age, and social deprivation groups, and intervention costs per participant were low at $153 (£122). Conclusions and Relevance:  The Norfolk Diabetes Prevention lifestyle intervention reduced the risk of type 2 diabetes in current high-risk glycemic categories. Enhancing the intervention with DPM did not further reduce diabetes risk. These translatable results are relevant for current diabetes prevention efforts

Remote Sensing of Antarctic Sea Ice with Coordinated Aircraft and Satellite Data Acquisitions

Remote sensing of Antarctic sea ice is required to characterize properties of the vast sea ice cover to understand its long-term increase in contrast to the decrease of Arctic sea ice. For this objective, the OIB/TanDEM-X Coordinated Science Campaign (OTASC) was successfully conducted in 2017 to obtain contemporaneous and collocated remote sensing data from NASA's Operation IceBridge (OIB) and the German Aerospace Center (DLR) TanDEM-X Synthetic Aperture Radar (SAR) system at X-band together with Sentinel-1 and RADARSAT-2 SARs at C-band in conjunction with WorldView satellite spectral sensors, surface measurements, and field observations. The Weddell Sea and the Ross Sea were two primary regions while SAR data were also collected over six other regions in the Southern Ocean. Satellite SAR data included both polarimetric and interferometric capabilities to infer snow and sea ice information in three dimensions (3D), while OIB/P-3 aircraft data include snow radar together with altimeter data for snow and sea ice observations in 3D over the Weddell Sea. Across the Ross Sea, IcePOD and AntNZ/York-University flights were carried out together with satellite SAR data acquisitions

Increased Memory Conversion of Naïve CD8 T Cells Activated during Late Phases of Acute Virus Infection Due to Decreased Cumulative Antigen Exposure

Background: Memory CD8 T cells form an essential part of protective immunity against viral infections. Antigenic load, costimulation, CD4-help, cytokines and chemokines fluctuate during the course of an antiviral immune response thus affecting CD8 T cell activation and memory conversion. Methodology/Principal Findings: In the present study, naïve TCR transgenic LCMV-specific P14 CD8 T cells engaged at a late stage during the acute antiviral LCMV response showed reduced expansion kinetics but greater memory conversion in the spleen. Such late activated cells displayed a memory precursor effector phenotype already at the peak of the systemic antiviral response, suggesting that the environment determined their fate during antigen encounter. In the spleen, the majority of late transferred cells exhibited a central memory phenotype compared to the effector memory displayed by the early transferred cells. Increasing the inflammatory response by exogenous administration of IFNc, PolyI:C or CpG did not affect memory conversion in the late transferred group, suggesting that the diverging antigen load early versus later during acute infection had determined their fate. In agreement, reduction in the LCMV antigenic load after ribavirin treatment enhanced the contribution of early transferred cells to the long lasting memory pool. Conclusions/Significance: Our results show that naïve CD8 cells, exposed to reduced duration or concentration of antigen during viral infection convert into memory more efficiently, an observation that could have significant implications fo

Effects of the Norfolk diabetes prevention lifestyle intervention (NDPS) on glycaemic control in screen-detected type 2 diabetes: a randomised controlled trial

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials: The dataset used in this publication is available from the corresponding author on reasonable request.Background The purpose of this trial was to test if the Norfolk Diabetes Prevention Study (NDPS) lifestyle intervention, recently shown to reduce the incidence of type 2 diabetes in high-risk groups, also improved glycaemic control in people with newly diagnosed screen-detected type 2 diabetes. Methods We screened 12,778 participants at high risk of type 2 diabetes using a fasting plasma glucose and glycosylated haemoglobin (HbA1c). People with screen-detected type 2 diabetes were randomised in a parallel, three-arm, controlled trial with up to 46 months of follow-up, with a control arm (CON), a group-based lifestyle intervention of 6 core and up to 15 maintenance sessions (INT), or the same intervention with additional support from volunteers with type 2 diabetes trained to co-deliver the lifestyle intervention (INT-DPM). The pre-specified primary end point was mean HbA1c compared between groups at 12 months. Results We randomised 432 participants (CON 149; INT 142; INT-DPM 141) with a mean (SD) age of 63.5 (10.0) years, body mass index (BMI) of 32.4 (6.4) kg/m2, and HbA1c of 52.5 (10.2) mmol/mol. The primary outcome of mean HbA1c at 12 months (CON 48.5 (9.1) mmol/mol, INT 46.5 (8.1) mmol/mol, and INT-DPM 45.6 (6.0) mmol/mol) was significantly lower in the INT-DPM arm compared to CON (adjusted difference −2.57 mmol/mol; 95% CI −4.5, −0.6; p = 0.007) but not significantly different between the INT-DPM and INT arms (−0.55 mmol/mol; 95% CI −2.46, 1.35; p = 0.57), or INT vs CON arms (−2.14 mmol/mol; 95% CI −4.33, 0.05; p = 0.07). Subgroup analyses showed the intervention had greater effect in participants  65 years old; p = 0.007). The use of oral hypoglycaemic medication was associated with a significantly lower mean HbA1c but only within the INT-DPM arm compared to CON (−7.0 mmol/mol; 95% CI −11.5, −2.5; p = 0.003). Conclusion The NDPS lifestyle intervention significantly improved glycaemic control after 12 months in people with screen-detected type 2 diabetes when supported by trained peer mentors with type 2 diabetes, particularly those receiving oral hypoglycaemics and those under 65 years old. The effect size was modest, however, and not sustained at 24 months. Trial registration ISRCTN34805606. Retrospectively registered 14.4.16National Institute for Health Research (NIHR