Why Formal Objections to the Error Theory are Sound

Recent debate about the error theory has taken a ‘formal turn’. On the one hand, there are those who argue that the error theory should be rejected because of its difficulties in providing a convincing formal account of the logic and semantics of moral claims. On the other hand, there are those who claim that such formal objections fail, maintaining that arguments against the error theory must be of a substantive rather than a formal kind. In this paper, we argue that formal objections to the error theory cannot be eschewed but must be met head-on

Effects of Various Commercially Available Enrichment Options on Handling and Chronic Stress Markers in Female ICR Mice

Although social housing of mice generally is preferred, mice must be individually housed in some situations. In these cases, enhanced attention to environmental enrichment is encouraged, but few studies assess the wellbeing of mice provided various enrichments. In this study, we used female ICR mice to evaluate enrichment strategies that encouraged natural behaviors including foraging, exercise, sheltering, and socialization. After 3 mo of exposure to the assigned enrichment strategy, wellbeing was assessed by evaluating behavioral and physiologic differences between groups. The results suggested that the use of red-tinted igloos may decrease markers of mouse wellbeing. However, none of the selected strategies yielded measures of wellbeing indicating improvement as compared to individually housed mice with no enrichment (negative control). Furthermore, measures were not significantly different between paired mice and individually housed mice with no enrichment

Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure

Human papillomavirus seroprevalence and seroconversion following baseline detection of nine human papillomavirus types in young women

Background: Estimates of the humoral immune response to incident human papillomavirus (HPV) infections are limited. Methods: In this post hoc analysis of 3875 women aged 16-23 years from a 4-valent HPV vaccine trial (NCT00092482), HPV seroprevalence on day 1 was measured with a 9-valent HPV (HPV 6/11/16/18/31/33/45/ 52/58) competitive Luminex immunoassay and compared with cervical/external genital HPV detection by po-lymerase chain reaction. In the control group, among women who were HPV DNA-negative on day 1, sero-conversion following initial HPV detection was estimated using Kaplan-Meier methods. Results: Type-specific HPV seropositivity among women with no day 1 cervical/external genital HPV detection was 0.6%-3.6%. Women with any 9-valent HPV (9vHPV) cervical/external genital detection (796/3875; 20.5%) had concordant seropositivity ranging from 13.4% (HPV 45) to 38.5% (HPV 6). Among women in the control group who were negative for all HPV types on day 1, seroconversion by month 30 after initial detection ranged from 29% (HPV 45) to 75% (HPV 16). Conclusions: Humoral immune response to HPV is variable and dynamic, depending on type-specific exposure. This longitudinal analysis provides insight into the relationship between incident infection and seropositivity

Investigation of E. coli and Virus Reductions Using Replicate, Bench-Scale Biosand Filter Columns and Two Filter Media

The biosand filter (BSF) is an intermittently operated, household-scale slow sand filter for which little data are available on the effect of sand composition on treatment performance. Therefore, bench-scale columns were prepared according to the then-current (2006–2007) guidance on BSF design and run in parallel to conduct two microbial challenge experiments of eight-week duration. Triplicate columns were loaded with Accusand silica or crushed granite to compare virus and E. coli reduction performance. Bench-scale experiments provided confirmation that increased schmutzdecke growth, as indicated by decline in filtration rate, is the primary factor causing increased E. coli reductions of up to 5-log10. However, reductions of challenge viruses improved only modestly with increased schmutzdecke growth. Filter media type (Accusand silica vs. crushed granite) did not influence reduction of E. coli bacteria. The granite media without backwashing yielded superior virus reductions when compared to Accusand. However, for columns in which the granite media was first backwashed (to yield a more consistent distribution of grains and remove the finest size fraction), virus reductions were not significantly greater than in columns with Accusand media. It was postulated that a decline in surface area with backwashing decreased the sites and surface area available for virus sorption and/or biofilm growth and thus decreased the extent of virus reduction. Additionally, backwashing caused preferential flow paths and deviation from plug flow; backwashing is not part of standard BSF field preparation and is not recommended for BSF column studies. Overall, virus reductions were modest and did not meet the 5- or 3-log10 World Health Organization performance targets

UCP2 Regulates the Glucagon Response to Fasting and Starvation

Glucagon is important for maintaining euglycemia during fasting/starvation, and abnormal glucagon secretion is associated with type 1 and type 2 diabetes; however, the mechanisms of hypoglycemia-induced glucagon secretion are poorly understood. We previously demonstrated that global deletion of mitochondrial uncoupling protein 2 (UCP2−/−) in mice impaired glucagon secretion from isolated islets. Therefore, UCP2 may contribute to the regulation of hypoglycemia-induced glucagon secretion, which is supported by our current finding that UCP2 expression is increased in nutrient-deprived murine and human islets. Further to this, we created α-cell–specific UCP2 knockout (UCP2AKO) mice, which we used to demonstrate that blood glucose recovery in response to hypoglycemia is impaired owing to attenuated glucagon secretion. UCP2-deleted α-cells have higher levels of intracellular reactive oxygen species (ROS) due to enhanced mitochondrial coupling, which translated into defective stimulus/secretion coupling. The effects of UCP2 deletion were mimicked by the UCP2 inhibitor genipin on both murine and human islets and also by application of exogenous ROS, confirming that changes in oxidative status and electrical activity directly reduce glucagon secretion. Therefore, α-cell UCP2 deletion perturbs the fasting/hypoglycemic glucagon response and shows that UCP2 is necessary for normal α-cell glucose sensing and the maintenance of euglycemia