Analysis of the El Niño/La Niña-Southern Oscillation variability and malaria in the Estado Sucre, Venezuela

The last decade has seen an unprecedented, worldwide acceleration of environmental and climate changes. These processes impact the dynamics of natural systems, which include components associated with human communities such as vector-borne diseases. The dynamics of environmental and climate variables, altered by global change as reported by the Intergovernmental Panel on Climate Change, affect the distribution of many tropical diseases. Complex systems, e.g. the El Niño/La Niña-Southern Oscillation (ENSO), in which environmental variables operate synergistically, can provoke the reemergence and emergence of vector-borne diseases at new sites. This research investigated the influence of ENSO events on malaria incidence by determining the relationship between climate variations, expressed as warm, cold and neutral phases, and their relation to the number of malaria cases in some north-eastern municipalities of Venezuela (Estado Sucre) during the period 1990-2000. Significant differences in malaria incidence were found, particularly in the La Niña ENSO phases (cold) of moderate intensity. These findings should be taken into account for surveillance and control in the future as they shed light on important indicators that can lead to reduced vulnerability to malaria

Nonlocal Transport Processes and the Fractional Cattaneo-Vernotte Equation

The Cattaneo-Vernotte equation is a generalization of the heat and particle diffusion equations; this mathematical model combines waves and diffusion with a finite velocity of propagation. In disordered systems the diffusion can be anomalous. In these kinds of systems, the mean-square displacement is proportional to a fractional power of time not equal to one. The anomalous diffusion concept is naturally obtained from diffusion equations using the fractional calculus approach. In this paper we present an alternative representation of the Cattaneo-Vernotte equation using the fractional calculus approach; the spatial-time derivatives of fractional order are approximated using the Caputo-type derivative in the range (0,2]. In this alternative representation we introduce the appropriate fractional dimensional parameters which characterize consistently the existence of the fractional space-time derivatives into the fractional Cattaneo-Vernotte equation. Finally, consider the Dirichlet conditions, the Fourier method was used to find the full solution of the fractional Cattaneo-Vernotte equation in analytic way, and Caputo and Riesz fractional derivatives are considered. The advantage of our representation appears according to the comparison between our model and models presented in the literature, which are not acceptable physically due to the dimensional incompatibility of the solutions. The classical cases are recovered when the fractional derivative exponents are equal to 1

Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons

The efficiency of first-generation adenoviral vectors as gene delivery tools is often limited by the short duration of transgene expression, which can be related to immune responses and to toxic effects of viral proteins. In addition, readministration is usually ineffective unless the animals are immunocompromised or a different adenovirus serotype is used. Recently, adenoviral vectors devoid of all viral coding sequences (helper-dependent or gutless vectors) have been developed to avoid expression of viral proteins. In mice, liver-directed gene transfer with AdSTK109, a helper-dependent adenoviral (Ad) vector containing the human α1-antitrypsin (hAAT) gene, resulted in sustained expression for longer than 10 months with negligible toxicity to the liver. In the present report, we have examined the duration of expression of AdSTK109 in the liver of baboons and compared it to first- generation vectors expressing hAAT. Transgene expression was limited to approximately 3-5 months with the first-generation vectors. In contrast, administration of AdSTK109 resulted in transgene expression for longer than a year in two of three baboons. We have also investigated the feasibility of circumventing the humoral response to the virus by sequential administration of vectors of different serotypes. We found that the ineffectiveness of readministration due to the humoral response to an Ad5 first-generation vector was overcome by use of an Ad2-based vector expressing hAAT. These data suggest that long-term expression of transgenes should be possible by combining the reduced immunogenicity and toxicity of helper-dependent vectors with sequential delivery of vectors of different serotypes

Exercise Increases Serum Fibroblast Growth Factor 21 (FGF21) Levels

Fibroblast growth factor 21 (FGF21) increases glucose uptake. It is unknown if FGF21 serum levels are affected by exercise.This was a comparative longitudinal study. Anthropometric and biochemical evaluation were carried out before and after a bout of exercise and repeated after two weeks of daily supervised exercise. The study sample was composed of 60 sedentary young healthy women. The mean age was 24±3.7 years old, and the mean BMI was 21.4±7.0 kg/m². The anthropometric characteristics did not change after two weeks of exercise. FGF21 levels significantly increased after two weeks of exercise (276.8 ng/l (142.8-568.6) vs. (460.8 (298.2-742.1), p<0.0001)). The delta (final-basal) log of serum FGF21, adjusted for BMI, showed a significant positive correlation with basal glucose (r = 0.23, p = 0.04), mean maximal heart rate (MHR) (r = 0.54, p<0.0001), mean METs (r = 0.40, p = 0.002), delta plasma epinephrine (r = 0.53, p<0.0001) and delta plasma FFAs (r = 0.35, p = 0.006). A stepwise linear regression model showed that glucose, MHR, METs, FFAs, and epinephrine, were factors independently associated with the increment in FGF21 after the exercise program (F = 4.32; r² = 0.64, p<0.0001).Serum FGF21 levels significantly increased after two weeks of physical activity. This increment correlated positively with clinical parameters related to the adrenergic and lipolytic response to exercise.ClinicalTrials.gov NCT01512368

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of truncating variants with 72% having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes

Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. Video Abstract [Figure presented] Keywords: type 2 diabetes (T2D); genetics; disease mechanism; SLC16A11; MCT11; solute carrier (SLC); monocarboxylates; fatty acid metabolism; lipid metabolism; precision medicin

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants