Recently, a standard test case suite for 2-D linear transport on the sphere was proposed to assess important aspects of accuracy in geophysical fluid dynamics with a "minimal" set of idealized model ...configurations/runs/diagnostics. Here we present results from 19 state-of-the-art transport scheme formulations based on finite-difference/finite-volume methods as well as emerging (in the context of atmospheric/oceanographic sciences) Galerkin methods. Discretization grids range from traditional regular latitude-longitude grids to more isotropic domain discretizations such as icosahedral and cubed-sphere tessellations of the sphere. The schemes are evaluated using a wide range of diagnostics in idealized flow environments. Accuracy is assessed in single- and two-tracer configurations using conventional error norms as well as novel diagnostics designed for climate and climate-chemistry applications. In addition, algorithmic considerations that may be important for computational efficiency are reported on. The latter is inevitably computing platform dependent. The ensemble of results from a wide variety of schemes presented here helps shed light on the ability of the test case suite diagnostics and flow settings to discriminate between algorithms and provide insights into accuracy in the context of global atmospheric/ocean modeling. A library of benchmark results is provided to facilitate scheme intercomparison and model development. Simple software and data sets are made available to facilitate the process of model evaluation and scheme intercomparison.
The aim of this investigation was to identify pathogenic variants of the ryanodine receptor 2 (
RYR2
) gene in a cohort of persons aged 0–40 years who died of sudden unexpected death syndrome (SUD), ...including a cohort of infants who died of sudden infant death syndrome (SIDS). We genetically screened 29 of the 105 exons of the
RYR2
gene associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 74 cases of SUD without reported structural abnormalities of the heart. Cases were selected from the case database at the Institute of Forensic Medicine, and subsequent mutational screening by DNA sequencing was performed to detect variants in DNA samples extracted from blood samples of deceased persons. A total of 7 of the examined 74 cases were heterozygous for a rare sequence variant in the
RYR2
gene. We identified five novel missense variants (p.Q486H, p.D1872N, p.G2367R, p.E4213D, and p.H4579Y), one synonymous variant (p.L4767L), and one previously reported missense variant (p.G4315E). Follow-up studies were possible in family members of three probands (p.Q486H, p.D1872N, and p.H4579Y), and clinical examinations were conducted in family members of two of these probands (p.Q486H and p.H4579Y). In conclusion, we identified a higher prevalence of variants in the CPVT-associated gene
RYR2
than in a previously reported cohort of SIDS (9.4% vs. 1–2%). Segregation studies show that one variant (p.H4579Y) co-segregates with CPVT and is presumed to be pathogenic.
Diabetic nephropathy is associated with insulin resistance, and low-grade inflammation and activation of the complement system may contribute to this cascade. Mannan-binding lectin (MBL) activates ...the complement system, and elevated MBL concentrations have been observed in normoalbuminuric type 1 diabetic patients. The aim of this study was to assess whether MBL is associated with diabetic nephropathy in type 1 diabetes, and whether there is an association between MBL and low-grade inflammatory markers or insulin resistance.
A total of 191 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based upon their AER. Patients with normal AER (n=67) did not take antihypertensive medication, while patients with microalbuminuria (n=62) or macroalbuminuria (n=62) were all treated with an ACE inhibitor. As a measure of insulin sensitivity we used estimated glucose disposal rate. MBL was measured by an immunofluorometric assay, C-reactive protein by a radioimmunoassay and IL-6 by high-sensitivity enzyme immunoassay.
Patients with normal AER (median interquartile range: 1,154 microg/l 180-2,202 microg/l) had lower levels of MBL than patients with microalbuminuria (1,713 microg/l 724-2,760 microg/l; p=0.029) or macroalbuminuria (1,648 microg/l 568-3,394 microg/l; p=0.019). There was a significant correlation between MBL and estimated glucose disposal rate, but not between MBL and C-reactive protein or IL-6 levels in univariate analysis. However, in a multiple regression analysis, HbA1c was the single variable independently associated with MBL (beta+/-SEM: 0.26+/-0.08; p=0.003).
MBL concentrations are increased in type 1 diabetic patients with diabetic nephropathy. MBL was not associated with low-grade inflammatory markers.
Tumor surveillance of natural killer (NK) cells is mediated by the cytotoxicity receptor natural-killer group 2 member D (NKG2D). Ligands for NKG2D are generally not expressed on healthy cells, but ...induced on the surface of malignant cells. To date, NKG2D ligand (NKG2D-L) induction was mainly described to depend on the activation of the DNA damage response, although the molecular mechanisms that regulate NKG2D-L expression remain largely unknown. Here, we show that the acetyltransferases CBP (CREB-binding protein) and p300 play a crucial role in the regulation of NKG2D-L on tumor cells. Loss of CBP/p300 decreased the basal cell surface expression of human ligands and reduced the upregulation of MICA/B and ULBP2 in response to histone deacetylase inhibitors or DNA damage. Furthermore, CBP/P300 deficiency abrogated the sensitivity of stressed cells to NK cell-mediated killing. CBP/p300 were also identified as major regulators of mouse NKG2D ligand RAE-1 in vitro and in vivo using the Eμ-Myc lymphoma model. Mechanistically, we observed an enhanced activation of the CBP/p300 binding transcription factor CREB (cAMP response element-binding protein) correlating to the NKG2D-L upregulation. Moreover, increased binding of CREB and CBP/p300 to NKG2D-L promoters and elevated histone acetylation were detectable. This study provides strong evidence for a major role of CBP and p300 in orchestrating NKG2D-L induction and consequently immunosurveillance of tumors in mice and humans. These findings might help to develop novel immunotherapeutic approaches against cancer.
This essay offers a critical overview of how neoliberal colonialism has nurtured wildlife crime in many contexts, and discusses future research avenues opened by incorporating a critique of ...neoliberalism into wildlife criminology studies. Specifically we suggest neoliberalism’s tendency to convert nature into alienable property and exclude people who do not accept subjugation as eco-rational subjects has created its own brand of wildlife crime by construing those participating in previously acceptable subsistence and recreational activities as criminal deviants. We suggest this phenomenon is widespread, occurring in North America, Europe, and the global south, and promotes ever more draconian deterrence models for addressing wildlife crime. We conclude by suggesting that future research should include analyses of (1) how people violating harvest regulations frame the political context and its impact on their livelihoods, (2) how the subjectification process linked to neoliberal colonialism influences wildlife crime, (3) how alienation of labor contributes to illegal wildlife harvest, and (4) the spatial geography of how neoliberal colonialism influences illegal wildlife harvest.
BACKGROUNDThe reported incidence of hepatocellular carcinoma (HCC) among patients with primary biliary cirrhosis (PBC) varies from 0.7–3.8%, whereas in cirrhotic patients the risk is considerably ...higher. Age, male sex, cirrhosis, and portal hypertension are reported risk factors. It has been suggested that ursodeoxycholic acid (UDCA) may protect against HCC. We aimed to define risk factors for the development of HCC at the time of PBC diagnosis and to identify, among patients treated with UDCA for a long term, a subgroup that could benefit from screening.
METHODSProspective multicenter cohort study of patients with established PBC treated with 13–15 mg/kg/day UDCA. Age, sex, antimitochondrial antibodies, bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, aspartate amino transferase, cirrhosis, portal hypertension, Mayo Risk Score, prognostic class (based on bilirubin and albumin levels), and response to UDCA (normalization of bilirubin and/or albumin levels) were analyzed as potential risk factors in Cox regression analysis.
RESULTSThree hundred and seventy-five patients were included, median follow-up was 9.7 years. HCC occurred in nine patients, corresponding with an annual incidence of 0.2%. The factor significantly associated with the development of HCC was the response to UDCA (P<0.001). The risk for HCC was highest in the group of nonresponders to UDCAthe 10 years incidence of HCC was 9% and the 15 years incidence was 20%. The number needed to screen in this subgroup was 11.
CONCLUSIONIn UDCA treated PBC patients the risk of HCC is relatively low. The main risk factor for HCC in this study was the absence of biochemical response to UDCA after 1-year treatment.
The melting dynamics of laser excited InSb have been studied with femtosecond x-ray diffraction. These measurements observe the delayed onset of diffusive atomic motion, signaling the appearance of ...liquidlike dynamics. They also demonstrate that the root-mean-squared displacement in the 111 direction increases faster than in the 110 direction after the first 500 fs. This structural anisotropy indicates that the initially generated fluid differs significantly from the equilibrium liquid.
Aims
Hydrogen sulphide levels are reduced in many disease states, including diabetes and end‐stage renal disease. We aimed to determine whether urinary sulphate excretion, as a proxy for hydrogen ...sulphide, was associated with progression of diabetic nephropathy.
Methods
We conducted a post‐hoc study of a prospective, randomized, controlled trial on the effect of a low vs. normal protein diet for 4 years, on decline of renal function in patients with Type 1 diabetes and diabetic nephropathy. We excluded patients with less than three measurements of glomerular filtration rate assessed by 51Cr‐EDTA plasma clearance (GFR) and less than 1 year of follow‐up (n = 10), leaving 72 patients eligible for analyses. We studied both association of rate of decline in GFR and association of the combined endpoint of end‐stage renal disease and death with baseline 24‐h urinary sulphate excretion.
Results
Sulphate excretion was significantly associated with the slope of GFR (rs = –0.28, P = 0.02). In a multivariate regression model, sulphate excretion was a significant determinant of decline in GFR, independent of age, gender, blood pressure, HbA1c, smoking, albuminuria, baseline GFR and diet group (P < 0.01). In addition, adjusted r2 increased from 5% in a model with the aforementioned risk factors to 22% when sulphate excretion was included in the model. Cox regression revealed a hazard ratio of 0.34 (95% CI 0.13–0.88, P = 0.026) for each natural log unit increase in urinary sulphate excretion.
Conclusion
High urinary sulphate excretion was significantly associated with slower decline in 51Cr‐EDTA‐assessed GFR in diabetic nephropathy, independent of known progression promoters.
Ovarian cancer has a high case-fatality ratio, largely due to late diagnosis. Epidemiologic risk prediction models could help identify women at increased risk who may benefit from targeted prevention ...measures, such as screening or chemopreventive agents.
We built an ovarian cancer risk prediction model with epidemiologic risk factors from 202,206 women in the European Prospective Investigation into Cancer and Nutrition study.
Older age at menopause, longer duration of hormone replacement therapy, and higher body mass index were included as increasing ovarian cancer risk, whereas unilateral ovariectomy, longer duration of oral contraceptive use, and higher number of full-term pregnancies were decreasing risk. The discriminatory power (overall concordance index) of this model, as examined with five-fold cross-validation, was 0.64 (95% confidence interval (CI): 0.57, 0.70). The ratio of the expected to observed number of ovarian cancer cases occurring in the first 5 years of follow-up was 0.90 (293 out of 324, 95% CI: 0.81-1.01), in general there was no evidence for miscalibration.
Our ovarian cancer risk model containing only epidemiological data showed modest discriminatory power for a Western European population. Future studies should consider adding informative biomarkers to possibly improve the predictive ability of the model.
Objective
The objective of this study was to pool, harmonise and re-analyse national accelerometer data from adults in four European countries in order to describe population levels of sedentary time ...and physical inactivity.
Methods
Five cross-sectional studies were included from England, Portugal, Norway and Sweden. ActiGraph accelerometer count data were centrally processed using the same algorithms. Multivariable logistic regression analyses were conducted to study the associations of sedentary time and physical inactivity with sex, age, weight status and educational level, in both the pooled sample and the separate study samples.
Results
Data from 9509 participants were used. On average, participants were sedentary for 530 min/day, and accumulated 36 min/day of moderate to vigorous intensity physical activity. Twenty-three percent accumulated more than 10 h of sedentary time/day, and 72% did not meet the physical activity recommendations. Nine percent of all participants were classified as high sedentary and low active. Participants from Norway showed the highest levels of sedentary time, while participants from England were the least physically active. Age and weight status were positively associated with sedentary time and not meeting the physical activity recommendations. Men and higher-educated people were more likely to be highly sedentary, while women and lower-educated people were more likely to be inactive.
Conclusions
We found high levels of sedentary time and physical inactivity in four European countries. Older people and obese people were most likely to display these behaviours and thus deserve special attention in interventions and policy planning. In order to monitor these behaviours, accelerometer-based cross-European surveillance is recommended.
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