Infection rate of Aedes aegypti mosquitoes with dengue virus depends on the interaction between temperature and mosquito genotype.

Dengue fever is the most prevalent arthropod-transmitted viral disease worldwide, with endemic transmission restricted to tropical and subtropical regions of different temperature profiles. Temperature is epidemiologically relevant because it affects dengue infection rates in Aedes aegypti mosquitoes, the major vector of the dengue virus (DENV). Aedes aegypti populations are also known to vary in competence for different DENV genotypes. We assessed the effects of mosquito and virus genotype on DENV infection in the context of temperature by challenging Ae. aegypti from two locations in Vietnam, which differ in temperature regimes, with two isolates of DENV-2 collected from the same two localities, followed by incubation at 25, 27 or 32°C for 10 days. Genotyping of the mosquito populations and virus isolates confirmed that each group was genetically distinct. Extrinsic incubation temperature (EIT) and DENV-2 genotype had a direct effect on the infection rate, consistent with previous studies. However, our results show that the EIT impacts the infection rate differently in each mosquito population, indicating a genotype by environment interaction. These results suggest that the magnitude of DENV epidemics may not only depend on the virus and mosquito genotypes present, but also on how they interact with local temperature. This information should be considered when estimating vector competence of local and introduced mosquito populations during disease risk evaluation.

Temporal genetic stability of Stegomyia aegypti (= Aedes aegypti) populations.

The mosquito Stegomyia aegypti (= Aedes aegypti) (Diptera: Culicidae) is the primary vector of viruses that cause yellow fever, dengue and Chikungunya fever. In the absence of effective vaccines, the reduction of these diseases relies on vector control strategies. The success of these strategies is tightly linked to the population dynamics of target populations. In the present study, 14 collections from St. aegypti populations separated by periods of 1-13 years were analysed to determine their temporal genetic stability. Although temporal structure is discernible in most populations, the degree of temporal differentiation is dependent on the population and does not obscure the geographic structure of the various populations. The results suggest that performing detailed studies in the years prior to and after population reduction- or modification-based control interventions at each target field site may be useful in assessing the probability of success.

Seasonal Genetic Changes of Aedes aegypti (Diptera: Culicidae) Populations in Selected Sites of Cebu City, Philippines.

Aedes aegypti (L.) is the primary vector of dengue virus in the Philippines, where dengue is endemic. We examined the genetic changes of Ae. aegypti collected from three selected sites in Cebu city, Philippines, during the relatively wet (2011-2012) and dry seasons (2012 and 2013). A total of 493 Ae. aegypti adults, reared in the laboratory from field-collected larvae, were analyzed using 11 microsatellite loci. Seasonal variation was observed in allele frequencies and allelic richness. Average genetic differentiation (DEST=0.018; FST=0.029) in both dry seasons was higher, due to reduced Ne, than in the wet season (DEST=0.006; FST=0.009). Thus, average gene flow was higher in the wet season than in the dry seasons. However, the overall FST estimate (0.02) inclusive of the two seasons showed little genetic differentiation as supported by Bayesian clustering analysis. Results suggest that during the dry season the intense selection that causes a dramatic reduction of population size favors heterozygotes, leading to small pockets of mosquitoes (refuges) that exhibit random genetic differentiation. During the wet season, the genetic composition of the population is reconstituted by the expansion of the refuges that survived the preceding dry season. Source reduction of mosquitoes during the nonepidemic dry season is thus recommended to prevent dengue re-emergence in the subsequent wet season.

Compositional divergence and convergence in arbuscular mycorrhizal fungal communities.

In spite of the controversy that they have generated, neutral models provide ecologists with powerful tools for creating dynamic predictions about beta-diversity in ecological communities. Ecologists can achieve an understanding of the assembly rules operating in nature by noting when and how these predictions are met or not met. This is particularly valuable for those groups of organisms that are challenging to study under natural conditions (e.g., bacteria and fungi). Here, we focused on arbuscular mycorrhizal fungal (AMF) communities and performed an extensive literature search that allowed us to synthesize the information in 19 data sets with the minimal requisites for creating a null hypothesis in terms of community dissimilarity expected under neutral dynamics. In order to achieve this task, we calculated the first estimates of neutral parameters for several AMF communities from different ecosystems. Communities were shown either to be consistent with neutrality or to diverge or converge with respect to the levels of compositional dissimilarity expected under neutrality. These data support the hypothesis that divergence occurs in systems where the effect of limited dispersal is overwhelmed by anthropogenic disturbance or extreme biological and environmental heterogeneity, whereas communities converge when systems have the potential for niche divergence within a relatively homogeneous set of environmental conditions. Regarding the study cases that were consistent with neutrality, the sampling designs employed may have covered relatively homogeneous environments in which the effects of dispersal limitation overwhelmed minor differences among AMF taxa that would lead to environmental filtering. Using neutral models we showed for the first time for a soil microbial group the conditions under which different assembly processes may determine different patterns of beta-diversity. Our synthesis is an important step showing how the application of general ecological theories to a model microbial taxon has the potential to shed light on the assembly and ecological dynamics of communities.

Do GLP-1RAs and SGLT-2is reduce cardiovascular events in women with type 2 diabetes? A systematic review and meta-analysis.

AIMS: The risk of cardiovascular disease is often underestimated in women. This leads to a delay in controlling the risk factors for cardiovascular disease and even delays in prescribing medications with cardiovascular benefit. Our aim was to explore if glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter-2 inhibitor (SGLT-2i) medications would reduce cardiovascular events in women with type 2 diabetes when atherosclerotic cardiovascular disease (ASCVD) predominates. MATERIALS AND METHODS: We searched for randomized trials comparing GLP-1RA or SGLT-2i to placebo in people with type 2 diabetes and had a primary outcome exploring major adverse cardiovascular events (MACE). Data concerning women were then extracted. A sensitivity and subgroup analyses were performed according to the class of diabetes medication. RESULTS: A total of 9 trials (GLP-1RA in 6 trials and SGLT-2i in 3) were included. Of the 84,258 participants enrolled, 30,784 (37%) participants were women. Pooled results showed a statistically significant lower incidence of MACE favouring diabetes medications (GLP-1RA or SGLT-2i) compared to placebo (RR [95%CI]=0.87 [0.80, 0.94]). On restricting the analysis to GLP-1RA then to SGLT-2i, results remained significant with GLP-1RA but not SGLT-2i. CONCLUSIONS: In women with type 2 diabetes who either have increased cardiovascular risk or established cardiovascular disease and ASCVD predominates, GLP-1RA significantly reduce the incidence of MACE while SGLT-2i result in a non-significant reduction. SGLT-2i may have comparable effect when examined in more studies. GLP-1RA and SGLT-2i should be considered without delay in women with type 2 diabetes and increased risk for cardiovascular disease.

Genetic polymorphisms in varied environments.

Thirteen experimenital populationis of Drosophila willistoni were maintained in cages, in some of which the environments were relatively constant and in others varied. After 45 weeks, the populations were assayed by gel electrophoresis for polymorphisms at 22 protein loci. The average heterozygosity per individual and the average unmber of alleles per locus were higher in populations maintained in heterogeneous environments than in populations in more constant enviroments.

Genetics and the origin of a vector population: Aedes aegypti, a case study.

Thirty-four population samples representing the worldwide distribution of the mosquito Aedes aegypti were analyzed for variation at 19 to 22 enzyme-coding genes. A multivariate discriminant analysis revealed that the genetic differences among populations in six geographic regions and between two subspecies enable one to determine the regional origin of a population. Such studies of population genetics may have quite general applicability in studying vector-borne diseases.

A high-efficiency power cycle in which hydrogen is compressed by absorption in metal hydrides.

A high-efficiency power cycle is proposed in which molecular hydrogen gas is used as a working fluid in a regenerative closed Brayton cycle. The hydrogen gas is compressed by an absorption-desorption cycle on metal hydride (FeTiH(x)) beds. Low-temperature solar or geothermal heat (temperature about 100 degrees C) is used for the compression process, and high-temperature fossil fuel or nuclear heat (temperature about 700 degrees C) supplies the expansion work in the turbine. Typically, about 90 percent of the high-temperature heat input is converted to electricity, while about 3 kilowatts of low-temperature heat is required per kilowatt of electrical output.

Comparing once-weekly semaglutide to incretin-based therapies in patients with type 2 diabetes: a systematic review and meta-analysis.

AIMS: Our aim was to compare once-weekly semaglutide to incretin-based therapies - defined as either dipeptidyl peptidase-4 inhibitors (DPP-4i) or other glucagon-like peptide-1 receptor agonist (GLP-1RA) - in patients with type 2 diabetes. METHODS: We searched for randomized trials comparing once-weekly semaglutide to other incretin-based therapies in patients with type 2 diabetes. We pooled trials that compared semaglutide to other GLP-1RA together, and those comparing semaglutide to DPP-4i together. The primary outcome was the change in haemoglobin A1c over time. RESULTS: Five trials met our inclusion criteria. There was a significantly greater reduction in haemoglobin A1c favouring semaglutide when compared to other GLP-1RA or DPP-4i [MD (95% CI) = -0.38% (-0.62, -0.15) and -1.14% (-1.53, -0.75) respectively]. There was a significantly greater weight loss favouring semaglutide when compared to other GLP-1RA or DPP-4i [MD (95% CI) = -2.50 kg (-3.91, -1.09) and -3.19 kg (-3.66, -2.72) respectively]. The proportion of patients achieving glycaemic goals and goal weight loss was greater in semaglutide-treated patients when compared to either other GLP-1RA or DPP-4i. However, semaglutide-treated patients had a significantly higher incidence of gastrointestinal side effects. CONCLUSIONS: While both once-weekly semaglutide and other incretin-based therapies can reduce haemoglobin A1c, semaglutide causes a more potent haemoglobin A1c reduction and greater weight loss when compared to other incretin-based therapies. However, this potent effect of semaglutide was associated with a higher incidence of gastrointestinal side effects. Additional studies are needed to determine whether this marked reduction in both haemoglobin A1c and body weight may translate into improved cardiovascular outcomes.

Effects of interleukin-6 -174C/G and metallothionein 1A +647A/C single-nucleotide polymorphisms on zinc-regulated gene expression in ageing.

Decreased zinc ion availability in ageing is associated with altered immune response. One of the main regulators of zinc availability is metallothionein. Metallothionein induction is under the control of interleukin-6, a pro-inflammatory cytokine whose production is associated with poor ageing. The production of interleukin-6 is controlled, in part, by variability in the -174 nucleotide position. Under conditions of chronic inflammation, such as in ageing, zinc release by metallothionein is limited and may reduce zinc availability. Understanding the precise nature of the interactions between interleukin-6 and metallothioneins will aid in identifying individuals who are at risk of zinc deficiency. In the current study, we used gene arrays to investigate the effects of in vitro zinc supplementation on gene expression in elderly donors with described interleukin-6 and metallothionein 1a polymorphisms. Ingenuity Pathway Analysis identified several zinc-responsive genetic networks uniquely regulated only in elderly individuals with the pro-inflammatory interleukin-6 polymorphism. These include zinc-dependent decreased transcription of pro-inflammatory cytokines and alterations in metabolic regulatory pathways. The genomic effects of zinc increased in significance in the presence of the metallothionein 1a +647 C/A transition, suggesting that the interleukin-6 and metallothionein 1a genes act in a concerted manner to control zinc-regulated gene expression.

Pharmacometrics at FDA: evolution and impact on decisions.

Drug development and regulatory decisions are driven by information that is compiled primarily from clinical trials and other supportive experiments, but also through clinical experience in the post-market period. The wisdom of these decisions determines the efficiency of drug development, the decision to approve the drug, and the resultant drug product quality including guidance on how to use the product known as the label. Although the decisions are usually simple in nature (e.g., trial design and project progression at the company, product and labeling approval at the Food and Drug Administration (FDA)), the information informing the decision is complex and diverse.

Impact of pharmacometric reviews on new drug approval and labeling decisions--a survey of 31 new drug applications submitted between 2005 and 2006.

Exploratory analyses of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression are often referred to as the pharmacometrics (PM) analyses. The objective of the current report is to assess the role of PM, at the Food and Drug Administration (FDA), in drug approval and labeling decisions. We surveyed the impact of PM analyses on New Drug Applications (NDAs) reviewed over 15 months in 2005-2006. The survey focused on both the approval and labeling decisions through four perspectives: clinical pharmacology primary reviewer, their team leader, the clinical team member, and the PM reviewer. A total of 31 NDAs included a PM review component. Review of NDAs involved independent quantitative evaluation by FDA pharmacometricians. PM analyses were ranked as important in regulatory decision making in over 85% of the 31 NDAs. Case studies are presented to demonstrate the applications of PM analysis.

Differential effects of in vitro zinc treatment on gene expression in peripheral blood mononuclear cells derived from young and elderly individuals.

Mild zinc deficiency, which is prevalent in vegetarians, diseased individuals, and the general aging population, depresses immunity and increases risk of disease in later life. However, human zinc intervention trials have produced conflicting results, perhaps because many of these trials included young or zinc-sufficient subjects. Since heterogeneity of the adult population may impact on response to dietary zinc, nutrigenomic approaches aimed at understanding the impact of zinc on modulation of gene and protein activities may aid in identifying subsets of the population-in particular the aging population-with increased risk of zinc deficiency who might receive benefit from a dietary zinc intervention and in this way may influence the success of the intervention. In the current study we used nutrigenomic approaches to investigate the impact of age on zinc-regulated gene expression in peripheral blood mononuclear cells. Ingenuity Pathway Analysis (Ingenuity Systems, Redwood City, CA) identified several genetic networks and functional canonical pathways which appeared responsive to zinc that were differentially regulated in young and elderly individuals. These include tryptophan metabolism, eicosanoid signaling, p38 mitogen-activated protein kinase (MAPK) signaling, integrin signaling, purine metabolism, G-protein-coupled receptor signaling, and most significantly, peroxisome proliferator-activated receptor (PPAR) signaling. These data suggest that age impacts strongly on the transcriptional effects of zinc and provides evidence to support the hypothesis that young and elderly individuals may respond differentially to zinc intervention.

Why has model-informed precision dosing not yet become common clinical reality? lessons from the past and a roadmap for the future.

Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become "widespread clinical practice," among those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap.

Intraspecific competition between ectomycorrhizal Pisolithus microcarpus isolates impacts plant and fungal performance under elevated CO2 and temperature.

Root systems are simultaneously colonized by multiple individuals of mycorrhizal fungi. Intraspecific competitive interactions between fungal isolates are likely to affect both fungal and plant performance and be influenced by abiotic factors. Here, we assessed the impact of intraspecific competition between three Pisolithus microcarpus isolates on the establishment of, and benefit derived from, symbioses with Eucalyptus grandis seedlings. We investigated the outcomes of competition under ambient and elevated temperature and CO2 concentration ([CO2]) in a factorial design. We observed a reduction in mycelium growth, mycorrhiza formation and seedling mass when two P. microcarpus isolates were co-inoculated on a single E. grandis seedling. Isolates invested more in mycelium than in mycorrhizas in the presence of a competitor. All isolates responded negatively to elevated [CO2] and positively to elevated temperature, which led to no changes on the outcomes of the interactions with changing conditions. However, the presence of a competitor hindered the positive response of P. microcarpus isolates to warming, which resulted in larger negative effects of competition under elevated temperature than under ambient conditions. Our study highlights the need to consider how competition affects individual fungal responses as well as plant performance when trying to predict the impacts of climate change.

Simulations to Predict Clinical Trial Outcome of Bevacizumab Plus Chemotherapy vs. Chemotherapy Alone in Patients With First-Line Gastric Cancer and Elevated Plasma VEGF-A.

To simulate clinical trials to assess overall survival (OS) benefit of bevacizumab in combination with chemotherapy in selected patients with gastric cancer (GC), a modeling framework linking OS with tumor growth inhibition (TGI) metrics and baseline patient characteristics was developed. Various TGI metrics were estimated using TGI models and data from two phase III studies comparing bevacizumab plus chemotherapy vs. chemotherapy as first-line therapy in 976 GC patients. Time-to-tumor-growth (TTG) was the best TGI metric to predict OS. TTG, Eastern Cooperative Oncology Group (ECOG) score, albumin level, and Asian ethnicity were significant covariates in the final OS model. The model correctly predicted a decreased hazard ratio favorable to bevacizumab in patients with high baseline plasma VEGF-A above the median of 113.4 ng/L. Based on trial simulations, in trials enrolling patients with elevated baseline plasma VEGF-A (500 patients per arm), the expected hazard ratio was 0.82 (95% prediction interval: 0.70-0.95), independent of ethnicity.

Computer simulation of lipid diffusion in a two-component bilayer. The effect of adsorbing macromolecules.

We have modelled the effects of macromolecular adsorption upon lipid lateral diffusion in a two-component lipid bilayer or monolayer, which is at a temperature above both of the main transition temperatures. One set of lipids (binders, b) can bind to the macromolecules with a free energy of binding, FB, while the other set does not bind (non-binders, nb). We assumed that no phase separation of the lipids occurs in the absence of adsorbed macromolecules. We represented the lipid bilayer/monolayer by a triangular lattice, each site of which is occupied by a lipid molecule. Adsorbed macromolecules were represented by hexagons covering nH sites, and we defined a probability per unit of time, p, that a hexagon attempts to adsorb onto the lattice. We considered two sizes of hexagons, nH = 7 (Size-1) and nH = 19 (Size-2) and disallowed or permitted adsorbed hexagons to move laterally on the lattice. We calculate the lipid relative diffusion coefficients, Dnb, and Db, for three characteristic time-regimes, (i) tau c << tau a, (ii) tau c approximately tau a and (iii) tau c >> tau a, where tau c and tau a are the times for proteins to adsorb/desorb or for lipids to move from site to site, respectively. We obtain analytical expressions for Dnb and Db in the first case and calculate them using computer simulation in the other two cases. We found that (i) D alpha (iii) < or = D alpha (ii) < or = D alpha (i) (alpha = nb, b); (ii) D alpha could display a shoulder as a function of FB for low values of p; (iii) compared to cases in which lateral diffusion was disallowed, the lateral diffusion of absorbed hexagons appeared to have little effect on Dnb, but could cause Db to increase by 50%. (iv) Scatter in the calculated values of D via simulation appeared to be largest for Size-1 hexagons, and could be understood as a consequence of the large interfacial region between areas free of hexagons and areas 'covered' by hexagons. Our results suggest that it is advisable to measure Db, since Dnb might show little change from 1.0 for the values of F and p appropriate to the system being studied.

The effects of endothelin-A receptor blockade during the progression of pacing-induced congestive heart failure.

OBJECTIVES: We sought to identify the effects of endothelin (ET) subtype-A (ET(A))) receptor blockade during the development of congestive heart failure (CHF) on left ventricle (LV) function and contractility. BACKGROUND: Congested heart failure causes increased plasma levels of ET and ET(A) receptor activation. METHODS: Yorkshire pigs were assigned to four groups: 1) CHF: 240 beats/min for 3 weeks; n=7; 2) CHF/ET(A)-High Dose: paced for 2 weeks then ET(A) receptor blockade (BMS 193884, 50 mg/kg, b.i.d.) for the last week of pacing; n=6; 3) CHF/ET(A)-Low Dose: pacing for 2 weeks then ET(A) receptor blockade (BMS 193884, 12.5 mg/kg, b.i.d.) for the last week, n=6; and 4) CONTROL: n=8. RESULTS: Left ventricle fractional shortening decreased with CHF compared with control (12+/-1 vs. 39+/-1%, p < 0.05) and increased in the CHF/ET(A) High and Low Dose groups (23+/-3 and 25+/-1%, p < 0.05). The LV peak wall stress and wall force increased approximately twofold with CHF and remained increased with ET(A) receptor blockade. With CHF, systemic vascular resistance increased by 120%, was normalized in the CHF/ET(A) High Dose group, and fell by 43% from CHF values in the Low Dose group (p < 0.05). Plasma catecholamines increased fourfold in the CHF group and were reduced by 48% in both CHF/ET(A) blockade groups. The LV myocyte velocity of shortening was reduced with CHF (32+/-3 vs. 54+/-3 microm/s, p < 0.05), was higher in the CHF/ET(A) High Dose group (39+/-1 microm/s, p < 0.05), and was similar to CHF values in the Low Dose group. CONCLUSIONS: ET(A) receptor activation may contribute to the progression of LV dysfunction with CHF.

Apparent selection of enzyme alleles in laboratory populations of Drosophila.

Twelve laboratory populations of recently collected Drosophila willistoni were begun with different frequencies of alleles at three enzyme loci, six populations at 25 degrees and six at 19 degrees . Periodic sampling of the populations allowed monitoring of the frequency changes in allozymes over time.-At Lap-5 (a locus coding for leucine amino peptidase), three alleles converged to the same frequencies in all populations at both temperatures. The apparent equilibrium frequency of the major allele was about.75; this is different from the frequency (.57) found in the natural population from which the experimental populations were begun. Allele frequency changes at the esterase-5 locus (Est-5) were slower but consistent in all cages. It is difficult to determine if an equilibrium has been reached. However, the frequency of the rare allele in all cages is about the same as in wild populations, 5%. Alleles at both Lap-5 and Est-5 are non-randomly associated with inversions in the chromosomes onto which they map. Because of these associations, it is impossible to unambiguously attribute the change in allele frequencies to selection at the loci being observed.-After one year, no significant gene frequency changes were detected at Est-7, the third locus studied.

Population genetics of Drosophila amylase. II. Geographic patterns in D. pseudoobscura.

Morph frequencies of three related polymorphisms were determined in ten natural populations of Drosophila pseudoobscura. They are the well-known inversion polymorphism of the third chromosome and the polymorphism for alpha-amylase produced by the structural gene Amy (which resides on the third chromosome). The third polymorphism was for tissue-specific expression of Amy in adult midguts; a total of 13 different patterns of activity have been observed. The preceding paper (Powell and Lichtenfels 1979) reports evidence that the variation in Amy expression is under polygenic control. Here we show that the polymorphism for midgut patterns occurs in natural populations and is not an artifact of laboratory rearing.--From population to population, Amy allele frequencies and frequencies of inversions belonging to different phylads vary coordinately. The geographic variation in alpha-amylase midgut activity patterns is uncorrelated with that for the other two types of polymorphisms. Furthermore, no correlation was detected between activity pattern(s) and Amy genotype(s) when both were assayed in the same individual.--These results imply that whatever the evolutionary-ecological forces are that control frequencies of the structural gene variants, they are not the same factors that control the frequencies of polymorphic genetic factors responsible for the tissue-specific expression of the enzyme.