The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKCζ.

Chronic glucocorticoid exposure is associated with the development of insulin resistance. We showed that glucocorticoid-induced insulin resistance was attenuated upon ablation of Angptl4, a glucocorticoid target gene encoding the secreted protein angiopoietin-like 4, which mediates glucocorticoid-induced lipolysis in white adipose tissue. Through metabolomic profiling, we revealed that glucocorticoid treatment increased hepatic ceramide concentrations by inducing enzymes in the ceramide synthetic pathway in an Angptl4-dependent manner. Angptl4 was also required for glucocorticoids to stimulate the activities of the downstream effectors of ceramide, protein phosphatase 2A (PP2A) and protein kinase Cζ (PKCζ). We further showed that knockdown of PP2A or inhibition of PKCζ or ceramide synthesis prevented glucocorticoid-induced glucose intolerance in wild-type mice. Moreover, the inhibition of PKCζ or ceramide synthesis did not further improve glucose tolerance in Angptl4-/- mice, suggesting that these molecules were major downstream effectors of Angptl4. Overall, our study demonstrates the key role of Angptl4 in glucocorticoid-augmented hepatic ceramide production that induces whole-body insulin resistance

Candida albicans colonization and dissemination from the murine gastrointestinal tract : the influence of morphology and Th17 immunity

This article is protected by copyright. All rights reserved. This work was supported by the Wellcome Trust (086558, 080088, 102705), a Wellcome Trust Strategic Award (097377) and a studentship from the University of Aberdeen. D.K. was supported by grant 5R01AI083344 from the National Institute of Allergy and Infectious Diseases and by a Voelcker Young Investigator Award from the Max and Minnie Tomerlin Voelcker Fund.Peer reviewedPublisher PD

An ANGPTL4-ceramide-protein kinase Cζ axis mediates chronic glucocorticoid exposure-induced hepatic steatosis and hypertriglyceridemia in mice.

Chronic or excess glucocorticoid exposure causes lipid disorders such as hypertriglyceridemia and hepatic steatosis. Angptl4 (angiopoietin-like 4), a primary target gene of the glucocorticoid receptor in hepatocytes and adipocytes, is required for hypertriglyceridemia and hepatic steatosis induced by the synthetic glucocorticoid dexamethasone. Angptl4 has also been shown to be required for dexamethasone-induced hepatic ceramide production. Here, we further examined the role of ceramide-mediated signaling in hepatic dyslipidemia caused by chronic glucocorticoid exposure. Using a stable isotope-labeling technique, we found that dexamethasone treatment induced the rate of hepatic de novo lipogenesis and triglyceride synthesis. These dexamethasone responses were compromised in Angptl4-null mice (Angptl4-/-). Treating mice with myriocin, an inhibitor of the rate-controlling enzyme of de novo ceramide synthesis, serine palmitoyltransferase long-chain base subunit 1 (SPTLC1)/SPTLC2, decreased dexamethasone-induced plasma and liver triglyceride levels in WT but not Angptl4-/- mice. We noted similar results in mice infected with adeno-associated virus-expressing small hairpin RNAs targeting Sptlc2. Protein phosphatase 2 phosphatase activator (PP2A) and protein kinase Cζ (PKCζ) are two known downstream effectors of ceramides. We found here that mice treated with an inhibitor of PKCζ, 2-acetyl-1,3-cyclopentanedione (ACPD), had lower levels of dexamethasone-induced triglyceride accumulation in plasma and liver. However, small hairpin RNA-mediated targeting of the catalytic PP2A subunit (Ppp2ca) had no effect on dexamethasone responses on plasma and liver triglyceride levels. Overall, our results indicate that chronic dexamethasone treatment induces an ANGPTL4-ceramide-PKCζ axis that activates hepatic de novo lipogenesis and triglyceride synthesis, resulting in lipid disorders

Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart

The muscular ventricular septum separates the flow of oxygenated and de-oxygenated blood in air-breathing vertebrates. Defects within it, termed muscular ventricular septal defects (VSDs), are common, yet less is known about how they arise than rarer heart defects. Mutations of the cardiac transcription factor NKX2-5 cause cardiac malformations, including muscular VSDs. We describe here a genetic interaction between Nkx2-5 and Sarcospan (Sspn) that affects the risk of muscular VSD in mice. Sspn encodes a protein in the dystrophin-glycoprotein complex. Sspn knockout (Sspn(KO)) mice do not have heart defects, but Nkx2-5(+/−)/Sspn(KO) mutants have a higher incidence of muscular VSD than Nkx2-5(+/−) mice. Myofibers in the ventricular septum follow a stereotypical pattern that is disrupted around a muscular VSD. Subendocardial myofibers normally run in parallel along the left ventricular outflow tract, but in the Nkx2-5(+/−)/Sspn(KO) mutant they commonly deviate into the septum even in the absence of a muscular VSD. Thus, Nkx2-5 and Sspn act in a pathway that affects the alignment of myofibers during the development of the ventricular septum. The malalignment may be a consequence of a defect in the coalescence of trabeculae into the developing ventricular septum, which has been hypothesized to be the mechanistic basis of muscular VSDs

Climate change could increase the geographic extent of Hendra virus spillover risk

Disease risk mapping is important for predicting and mitigating impacts of bat-borne viruses, including Hendra virus (Paramyxoviridae:Henipavirus), that can spillover to domestic animals and thence to humans. We produced two models to estimate areas at potential risk of HeV spillover explained by the climatic suitability for its flying fox reservoir hosts, Pteropus alecto and P. conspicillatus. We included additional climatic variables that might affect spillover risk through other biological processes (such as bat or horse behaviour, plant phenology and bat foraging habitat). Models were fit with a Poisson point process model and a log-Gaussian Cox process. In response to climate change, risk expanded southwards due to an expansion of P. alecto suitable habitat, which increased the number of horses at risk by 175–260% (110,000–165,000). In the northern limits of the current distribution, spillover risk was highly uncertain because of model extrapolation to novel climatic conditions. The extent of areas at risk of spillover from P. conspicillatus was predicted shrink. Due to a likely expansion of P. alecto into these areas, it could replace P. conspicillatus as the main HeV reservoir. We recommend: (1) HeV monitoring in bats, (2) enhancing HeV prevention in horses in areas predicted to be at risk, (3) investigate and develop mitigation strategies for areas that could experience reservoir host replacements

Warped Kaluza-Klein Dark Matter

Warped compactifications of type IIB string theory contain natural dark matter candidates: Kaluza-Klein modes along approximate isometry directions of long warped throats. These isometries are broken by the full compactification, including moduli stabilization; we present a thorough survey of Kaluza-Klein mode decay rates into light supergravity modes and Standard Model particles. We find that these dark matter candidates typically have lifetimes longer than the age of the universe. Interestingly, some choices for embedding the Standard Model in the compactification lead to decay rates large enough to be observed, so this dark matter sector may provide constraints on the parameter space of the compactification.Comment: 37pp; v2. references, minor clarificatio

Tumor site immune markers associated with risk for subsequent basal cell carcinomas.

BackgroundBasal cell carcinoma (BCC) tumors are the most common skin cancer and are highly immunogenic.ObjectiveThe goal of this study was to assess how immune-cell related gene expression in an initial BCC tumor biopsy was related to the appearance of subsequent BCC tumors.Materials and methodsLevels of mRNA for CD3ε (a T-cell receptor marker), CD25 (the alpha chain of the interleukin (IL)-2 receptor expressed on activated T-cells and B-cells), CD68 (a marker for monocytes/macrophages), the cell surface glycoprotein intercellular adhesion molecule-1 (ICAM-1), the cytokine interferon-γ (IFN-γ) and the anti-inflammatory cytokine IL-10 were measured in BCC tumor biopsies from 138 patients using real-time PCR.ResultsThe median follow-up was 26.6 months, and 61% of subjects were free of new BCCs two years post-initial biopsy. Patients with low CD3ε CD25, CD68, and ICAM-1 mRNA levels had significantly shorter times before new tumors were detected (p = 0.03, p = 0.02, p = 0.003, and p = 0.08, respectively). Furthermore, older age diminished the association of mRNA levels with the appearance of subsequent tumors.ConclusionsOur results show that levels of CD3ε, CD25, CD68, and ICAM-1 mRNA in BCC biopsies may predict risk for new BCC tumors

Climatic suitability influences species specific abundance patterns of Australian flying foxes and risk of Hendra virus spillover

Hendra virus is a paramyxovirus of Australian flying fox bats. It was first detected in August 1994, after the death of 20 horses and one human. Since then it has occurred regularly within a portion of the geographical distribution of all Australian flying fox (fruit bat) species. There is, however, little understanding about which species are most likely responsible for spillover, or why spillover does not occur in other areas occupied by reservoir and spillover hosts. Using ecological niche models of the four flying fox species we were able to identify which species are most likely linked to spillover events using the concept of distance to the niche centroid of each species. With this novel approach we found that 20 out of 27 events occur disproportionately closer to the niche centroid of two species (P. alecto and P. conspicillatus). With linear regressions we found a negative relationship between distance to the niche centroid and abundance of these two species. Thus, we suggest that the bioclimatic niche of these two species is likely driving the spatial pattern of spillover of Hendra virus into horses and ultimately humans

Fishbowl Discussions: Promoting Collaboration between Mathematics and Partner Disciplines

A National Consortium for Synergistic Undergraduate Mathematics via Multi-institutional Interdisciplinary Teaching Partnerships project (SUMMIT-P) is a collaboration of institutions focused on revising first- and second-year mathematics courses with the help of partner disciplines with prerequisite mathematics courses. This paper describes the fishbowl discussion technique used by the consortium members to encourage interdisciplinary conversation. Vignettes describing the results of conversations that occurred at several consortium member institutions are provided by the co-authors