FTY720/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in diet-induced nonalcoholic fatty liver disease in mice

Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver dysfunction, is a metabolic disease that begins with steatosis. Sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate (S1P), have recently received attention for their potential roles in insulin resistance and hepatic steatosis. FTY720/fingolimod, a prodrug for the treatment of multiple sclerosis, is phosphorylated in vivo to its active phosphorylated form by sphingosine kinase 2 and has been shown to interfere with the actions of S1P and to inhibit ceramide biosynthesis. Therefore, in this study we investigated the effects of FTY720 in a diet-induced animal model of NAFLD (DIAMOND) that recapitulates the hallmarks of the human disease. The oral administration of FTY720 to these mice fed a high-fat diet and sugar water improved glucose tolerance and reduced steatosis. In addition to decreasing liver triglycerides, FTY720 also reduced hepatic sphingolipid levels, including ceramides, monohexosylceramides, and sphingomyelins, particularly the C16:0 and C24:1 species, as well as S1P and dihydro-S1P. FTY720 administration decreased diet-induced fatty acid synthase (FASN) expression in DIAMOND mice without affecting other key enzymes in lipogenesis. FTY720 had no effect on the expression of SREBP-1c, which transcriptionally activates FASN. However, in agreement with the notion that the active phosphorylated form of FTY720 is an inhibitor of histone deacetylases, FTY720-P accumulated in the liver, and histone H3K9 acetylation was markedly increased in these mice. Hence, FTY720 might be useful for attenuating FASN expression and triglyceride accumulation associated with steatosis. Keywords: lipogenesis; sphingolipids; sphingosine-1-phosphate

Wrist actimetry circadian rhythm as a robust predictor of colorectal cancer patients survival

The disruption of the circadian timing system (CTS), which rhythmically controls cellular metabolism and proliferation, accelerated experimental cancer progression. A measure of CTS function in cancer patients could thus provide novel prediction information for outcomes, and help to identify novel specific therapies. The rest-activity circadian rhythm is a reliable and non-invasive CTS biomarker, which was monitored using a wrist watch accelerometer for 2 days in 436 patients with metastatic colorectal cancer. The relative percentage of activity in-bed versus out-of-bed (I < O) constituted the tested CTS measure, whose prognostic value for overall survival (OS) and progression-free survival (PFS) was determined in a pooled analysis of three patient cohorts with different treatment exposures. Median OS was 21.6 months [17.8–25.5] for patients with I < O above the median value of 97.5% as compared to 11.9 months [10.4–13.3] for those with a lower I < O (Log-rank p < 0.001). Multivariate analyses retained continuous I < O as a joint predictor of both OS and PFS, with respective hazard ratios (HR) of 0.954 (p < 0.001) and 0.970 (p < 0.001) for each 1% increase in I < O. HRs had similar values in all the patient subgroups tested. The circadian physiology biomarker I < O constitutes a robust and independent quantitative predictor of cancer patient outcomes, that can be easily and cost-effectively measured during daily living. Interventional studies involving 24-h schedules of clock-targeted drugs, light intensity, exercise and/or meals are needed for testing the relevance of circadian synchronization for the survival of patients with disrupted rhythms

Assessment of the relative success of sporozoite inoculations in individuals exposed to moderate seasonal transmission

Background: The time necessary for malaria parasite to re-appear in the blood following treatment (re-infection time) is an indirect method for evaluating the immune defences operating against pre-erythrocytic and early erythrocytic malaria stages. Few longitudinal data are available in populations in whom malaria transmission level had also been measured. Methods: One hundred and ten individuals from the village of Ndiop (Senegal), aged between one and 72 years, were cured of malaria by quinine (25 mg/day oral Quinimax T in three equal daily doses, for seven days). Thereafter, thick blood films were examined to detect the reappearance of Plasmodium falciparum every week, for 11 weeks after treatment. Malaria transmission was simultaneously measured weekly by night collection of biting mosquitoes. Results: Malaria transmission was on average 15.3 infective bites per person during the 77 days follow up. The median reappearance time for the whole study population was 46.8 days, whereas individuals would have received an average one infective bite every 5 days. At the end of the follow-up, after 77 days, 103 of the 110 individuals (93.6%; CI 95% [89.0-98.2]) had been re-infected with P. falciparum. The median reappearance time ('re-positivation') was longer in subjects with patent parasitaemia at enrolment than in parasitologically-negative individuals (58 days vs. 45.9; p = 0.03) and in adults > 30 years than in younger subjects (58.6 days vs. 42.7; p = 0.0002). In a multivariate Cox PH model controlling for the sickle cell trait, G6PD deficiency and the type of habitat, the presence of parasitaemia at enrolment and age >= 30 years were independently predictive of a reduced risk of re-infection (PH = 0.5 [95% CI: 0.3-0.9] and 0.4; [95% CI: 0.2-0.6] respectively). Conclusion: Results indicate the existence of a substantial resistance to sporozoites inoculations, but which was ultimately overcome in almost every individual after 2 1/2 months of natural challenges. Such a study design and the results obtained suggest that, despite a small sample size, this approach can contribute to assess the impact of intervention methods, such as the efficacy vector-control measures or of malaria pre-erythrocytic stages vaccines

Thermal Emission of WASP-14b Revealed with Three Spitzer Eclipses

Exoplanet WASP-14b is a highly irradiated, transiting hot Jupiter. Joshi et al. calculate an equilibrium temperature Teq of 1866 K for zero albedo and reemission from the entire planet, a mass of 7.3 +/- 0.5 Jupiter masses and a radius of 1.28 +/- 0.08 Jupiter radii. Its mean density of 4.6 g/cm3 is one of the highest known for planets with periods less than 3 days. We obtained three secondary eclipse light curves with the Spitzer Space Telescope. The eclipse depths from the best jointly fit model are $0.224\%$ +/- $0.018\%$ at 4.5 {\mu}m and $0.181\%$ +/- $0.022\%$ at 8.0 {\mu}m. The corresponding brightness temperatures are 2212 +/- 94 K and 1590 +/- 116 K. A slight ambiguity between systematic models suggests a conservative 3.6 {\mu}m eclipse depth of $0.19\%$ +/- $0.01\%$ and brightness temperature of 2242 +/- 55 K. Although extremely irradiated, WASP-14b does not show any distinct evidence of a thermal inversion. In addition, the present data nominally favor models with day night energy redistribution less than $~30\%$. The current data are generally consistent with oxygen-rich as well as carbon-rich compositions, although an oxygen-rich composition provides a marginally better fit. We confirm a significant eccentricity of e = 0.087 +/- 0.002 and refine other orbital parameters.Comment: 16 pages, 16 figure

Learning lessons from field surveys in humanitarian contexts: a case study of field surveys conducted in North Kivu, DRC 2006-2008

Survey estimates of mortality and malnutrition are commonly used to guide humanitarian decision-making. Currently, different methods of conducting field surveys are the subject of debate among epidemiologists. Beyond the technical arguments, decision makers may find it difficult to conceptualize what the estimates actually mean. For instance, what makes this particular situation an emergency? And how should the operational response be adapted accordingly. This brings into question not only the quality of the survey methodology, but also the difficulties epidemiologists face in interpreting results and selecting the most important information to guide operations. As a case study, we reviewed mortality and nutritional surveys conducted in North Kivu, Democratic Republic of Congo (DRC) published from January 2006 to January 2009. We performed a PubMed/Medline search for published articles and scanned publicly available humanitarian databases and clearinghouses for grey literature. To evaluate the surveys, we developed minimum reporting criteria based on available guidelines and selected peer-review articles. We identified 38 reports through our search strategy; three surveys met our inclusion criteria. The surveys varied in methodological quality. Reporting against minimum criteria was generally good, but presentation of ethical procedures, raw data and survey limitations were missed in all surveys. All surveys also failed to consider contextual factors important for data interpretation. From this review, we conclude that mechanisms to ensure sound survey design and conduct must be implemented by operational organisations to improve data quality and reporting. Training in data interpretation would also be useful. Novel survey methods should be trialled and prospective data gathering (surveillance) employed wherever feasible

Implanted Satellite Transmitters Affect Sea Duck Movement Patterns at Short and Long Timescales

Studies of the effects of transmitters on wildlife often focus on survival. However, sublethal behavioral changes resulting from radio-marking have the potential to affect inferences from telemetry data and may vary based on individual and environmental characteristics. We used a long-term, multi-species tracking study of sea ducks to assess behavioral patterns at multiple temporal scales following implantation of intracoelomic satellite transmitters. We applied state-space models to assess short-term behavioral patterns in 476 individuals with implanted satellite transmitters, as well as comparing breeding site attendance and migratory phenology across multiple years after capture. In the short term, our results suggest an increase in dispersive behavior immediately following capture and transmitter implantation; however, behavior returned to seasonally average patterns within ~5 days after release. Over multiple years, we found that breeding site attendance by both males and females was depressed during the first breeding season after radio-marking relative to subsequent years, with larger relative decreases in breeding site attendance among males than females. We also found that spring and breeding migrations occurred later in the first year after radio-marking than in subsequent years. Across all behavioral effects, the severity of behavioral change often varied by species, sex, age, and capture season. We conclude that, although individuals appear to adjust relatively quickly (i.e. within 1 week) to implanted satellite transmitters, changes in breeding phenology may occur over the longer term and should be considered when analyzing and reporting telemetry data

Spatially Explicit Network Analysis Reveals Multi‐Species Annual Cycle Movement Patterns of Sea Ducks

Conservation of long‐distance migratory species poses unique challenges. Migratory connectivity, that is, the extent to which groupings of individuals at breeding sites are maintained in wintering areas, is frequently used to evaluate population structure and assess use of key habitat areas. However, for species with complex or variable annual cycle movements, this traditional bimodal framework of migratory connectivity may be overly simplistic. Like many other waterfowl, sea ducks often travel to specific pre‐ and post‐breeding sites outside their nesting and wintering areas to prepare for migration by feeding extensively and, in some cases, molting their flight feathers. These additional migrations may play a key role in population structure, but are not included in traditional models of migratory connectivity. Network analysis, which applies graph theory to assess linkages between discrete locations or entities, offers a powerful tool for quantitatively assessing the contributions of different sites used throughout the annual cycle to complex spatial networks. We collected satellite telemetry data on annual cycle movements of 672 individual sea ducks of five species from throughout eastern North America and the Great Lakes. From these data, we constructed a multi‐species network model of migratory patterns and site use over the course of breeding, molting, wintering, and migratory staging. Our results highlight inter‐ and intra‐specific differences in the patterns and complexity of annual cycle movement patterns, including the central importance of staging and molting sites in James Bay, the St. Lawrence River, and southern New England to multi‐species annual cycle habitat linkages, and highlight the value of Long‐tailed Ducks (Calengula haemalis) as an umbrella species to represent the movement patterns of multiple sea duck species. We also discuss potential applications of network migration models to conservation prioritization, identification of population units, and integrating different data streams