Fitness consequences of altered feeding behavior in immune-challenged mosquitoes

Background: Malaria-infected mosquitoes have been reported to be more likely to take a blood meal when parasites are infectious than when non-infectious. This change in feeding behavior increases the likelihood of malaria transmission, and has been considered an example of parasite manipulation of host behavior. However, immune challenge with heat-killed Escherichia coli induces the same behavior, suggesting that altered feeding behavior may be driven by adaptive responses of hosts to cope with an immune response, rather than by parasite-specific factors. Here we tested the alternative hypothesis that down-regulated feeding behavior prior to infectiousness is a mosquito adaptation that increases fitness during infection. Methods: We measured the impact of immune challenge and blood feeding on the fitness of individual mosquitoes. After an initial blood meal, Anopheles stephensi Liston mosquitoes were experimentally challenged with heat-killed E. coli at a dose known to mimic the same temporal changes in mosquito feeding behavior as active malaria infection. We then tracked daily egg production and survivorship of females maintained on blood-feeding regimes that either mimicked down-regulated feeding behaviors observed during early malaria infection, or were fed on a four-day feeding cycle typically associated with uninfected mosquitoes. Results: Restricting access to blood meals enhanced mosquito survival but lowered lifetime reproduction. Immune-challenge did not impact either fitness component. Combining fecundity and survival to estimate the population-scale intrinsic rate of increase (r), we found that, contrary to the mosquito adaptation hypothesis, mosquito fitness decreased if blood feeding was delayed following an immune challenge. Conclusions: Our data provide no support for the idea that malaria-induced suppression of blood feeding is an adaptation by mosquitoes to reduce the impact of immune challenge. Alternatively, the behavioral alterations may be neither host nor parasite adaptations, but rather a consequence of constraints imposed on feeding by activation of the mosquito immune response, i.e. non-adaptive illness-induced anorexia. Future work incorporating field conditions and different immune challenges could further clarify the effect of altered feeding on mosquito and parasite fitness

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Rethinking the extrinsic incubation period of malaria parasites

The time it takes for malaria parasites to develop within a mosquito, and become transmissible, is known as the extrinsic incubation period, or EIP. EIP is a key parameter influencing transmission intensity as it combines with mosquito mortality rate and competence to determine the number of mosquitoes that ultimately become infectious. In spite of its epidemiological significance, data on EIP are scant. Current approaches to estimate EIP are largely based on temperature-dependent models developed from data collected on parasite development within a single mosquito species in the 1930s. These models assume that the only factor affecting EIP is mean environmental temperature. Here, we review evidence to suggest that in addition to mean temperature, EIP is likely influenced by genetic diversity of the vector, diversity of the parasite, and variation in a range of biotic and abiotic factors that affect mosquito condition. We further demonstrate that the classic approach of measuring EIP as the time at which mosquitoes first become infectious likely misrepresents EIP for a mosquito population. We argue for a better understanding of EIP to improve models of transmission, refine predictions of the possible impacts of climate change, and determine the potential evolutionary responses of malaria parasites to current and future mosquito control tools

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations