The insulin signaling pathway in \u3cem\u3eDrosophila melanogaster\u3c/em\u3e: A nexus revealing an Achilles\u27 heel in DDT resistance

Insecticide resistance is an ongoing challenge in agriculture and disease vector control. Here, we demonstrate a novel strategy to attenuate resistance. We used genomics tools to target fundamental energy-associated pathways and identified a potential “Achilles\u27 heel” for resistance, a resistance-associated protein that, upon inhibition, results in a substantial loss in the resistance phenotype. Specifically, we compared the gene expression profiles and structural variations of the insulin/insulin-like growth factor signaling (IIS) pathway genes in DDT-susceptible (91-C) and -resistant (91-R) Drosophila melanogaster (Drosophila) strains. A total of eight and seven IIS transcripts were up- and down-regulated, respectively, in 91-R compared to 91-C. A total of 114 nonsynonymous mutations were observed between 91-C and 91-R, of which 51.8% were fixed. Among the differentially expressed transcripts, phosphoenolpyruvate carboxykinase (PEPCK), down-regulated in 91-R, encoded the greatest number of amino acid changes, prompting us to perform PEPCK inhibitor–pesticide exposure bioassays. The inhibitor of PEPCK, hydrazine sulfate, resulted in a 161- to 218-fold decrease in the DDT resistance phenotype (91-R) and more than a 4- to 5-fold increase in susceptibility in 91-C. A second target protein, Glycogen synthase kinase 3β (GSK3β-PO), had one amino acid difference between 91-C and 91-R, and the corresponding transcript was also down-regulated in 91-R. A GSK3β-PO inhibitor, lithium chloride, likewise reduced the resistance but to a lesser extent than did hydrazine sulfate for PEPCK. We demonstrate the potential role of IIS genes in DDT resistance and the potential discovery of an “Achilles\u27 heel” against pesticide resistance in this pathway

Genomic Legacy of the African Cheetah, Acinonyx jubatus

Background Patterns of genetic and genomic variance are informative in inferring population history for human, model species and endangered populations. Results Here the genome sequence of wild-born African cheetahs reveals extreme genomic depletion in SNV incidence, SNV density, SNVs of coding genes, MHC class I and II genes, and mitochondrial DNA SNVs. Cheetah genomes are on average 95 % homozygous compared to the genomes of the outbred domestic cat (24.08 % homozygous), Virunga Mountain Gorilla (78.12 %), inbred Abyssinian cat (62.63 %), Tasmanian devil, domestic dog and other mammalian species. Demographic estimators impute two ancestral population bottlenecks: one \u3e100,000 years ago coincident with cheetah migrations out of the Americas and into Eurasia and Africa, and a second 11,084–12,589 years ago in Africa coincident with late Pleistocene large mammal extinctions. MHC class I gene loss and dramatic reduction in functional diversity of MHC genes would explain why cheetahs ablate skin graft rejection among unrelated individuals. Significant excess of non-synonymous mutations in AKAP4 (p\u3c0.02), a gene mediating spermatozoon development, indicates cheetah fixation of five function-damaging amino acid variants distinct from AKAP4 homologues of other Felidae or mammals; AKAP4 dysfunction may cause the cheetah’s extremely high (\u3e80 %) pleiomorphic sperm. Conclusions The study provides an unprecedented genomic perspective for the rare cheetah, with potential relevance to the species’ natural history, physiological adaptations and unique reproductive disposition

Tirofiban for Stroke without Large or Medium-Sized Vessel Occlusion

The effects of the glycoprotein IIb/IIIa receptor inhibitor tirofiban in patients with acute ischemic stroke but who have no evidence of complete occlusion of large or medium-sized vessels have not been extensively studied. In a multicenter trial in China, we enrolled patients with ischemic stroke without occlusion of large or medium-sized vessels and with a National Institutes of Health Stroke Scale score of 5 or more and at least one moderately to severely weak limb. Eligible patients had any of four clinical presentations: ineligible for thrombolysis or thrombectomy and within 24 hours after the patient was last known to be well; progression of stroke symptoms 24 to 96 hours after onset; early neurologic deterioration after thrombolysis; or thrombolysis with no improvement at 4 to 24 hours. Patients were assigned to receive intravenous tirofiban (plus oral placebo) or oral aspirin (100 mg per day, plus intravenous placebo) for 2 days; all patients then received oral aspirin until day 90. The primary efficacy end point was an excellent outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. Secondary end points included functional independence at 90 days and a quality-of-life score. The primary safety end points were death and symptomatic intracranial hemorrhage. A total of 606 patients were assigned to the tirofiban group and 571 to the aspirin group. Most patients had small infarctions that were presumed to be atherosclerotic. The percentage of patients with a score of 0 or 1 on the modified Rankin scale at 90 days was 29.1% with tirofiban and 22.2% with aspirin (adjusted risk ratio, 1.26; 95% confidence interval, 1.04 to 1.53, P = 0.02). Results for secondary end points were generally not consistent with the results of the primary analysis. Mortality was similar in the two groups. The incidence of symptomatic intracranial hemorrhage was 1.0% in the tirofiban group and 0% in the aspirin group. In this trial involving heterogeneous groups of patients with stroke of recent onset or progression of stroke symptoms and nonoccluded large and medium-sized cerebral vessels, intravenous tirofiban was associated with a greater likelihood of an excellent outcome than low-dose aspirin. Incidences of intracranial hemorrhages were low but slightly higher with tirofiban

Opacity of Parametric Discrete Event Systems: Models, Decidability, and Algorithms

Finite automata (FAs) model is a popular tool to characterize discrete event systems (DESs) due to its succinctness. However, for some complex systems, it is difficult to describe the necessary details by means of FAs model. In this paper, we consider a kind of extended finite automata (EFAs) in which each transition carries a predicate over state and event parameters. We also consider a type of simplified EFAs, called Event-Parameters EFAs (EP-EFAs), where the state parameters are removed. Based upon these two parametric models, we investigate the problem of opacity analysis for parametric DESs. First of all, it is shown that EFAs model is more expressive than EP-EFAs model. Secondly, it is proved that the opacity properties for EFAs are undecidable in general. Moreover, the decidable opacity properties for EP-EFAs are investigated. We present the verification algorithms for current-state opacity, initial-state opacity and infinite-step opacity, and then discuss the complexity. This paper establishes a preliminary theory for the opacity of parametric DESs, which lays a foundation for the opacity analysis of complex systems.Comment: 13 pages, 9 figure

Clay Minerals and Sr-Nd Isotope Compositions of Core CG 1601 in the Northwest Pacific: Implications for Material Source and Rare Earth Elements Enrichments

Deep-sea sediments generally refer to the sediments distributed on the seafloor with a depth of more than 2000 m. Many rare earth elements and yttrium (REY)-rich sediments were recently discovered in the sea area of Minamitorishima Island, Northwest Pacific. To understand the material source and REY enrichments of sediments in this area, here, we performed clay minerals and Sr-Nd isotopes analyses on gravity core GC1601 gained in the Southeast Sea area of Minamitorishima Island. The clay mineral composition of the core is very similar to that of terrigenous materials, and its montmorillonite/illite (M/I) ratio ranges from 0.09 to 0.20 with an average of 0.15, indicating that the sediments in the study area should be mainly dominated by terrestrial sources, consistent with the results of Sr-Nd isotope study. Considering that the study area is far away from the mainland and in the downwind direction of the East Asian monsoon, we propose that the terrigenous material of the sediments in the study area is likely East Asian dust. The εNd values of GC1601 show a positive correlation with P2O5, Co, Ni, and Cu, and have an increasing trend with increasing depth, approaching that of the seawater, indicating that the sedimentary environment in the area is relatively stable. Although the total REY content (ΣREY) of the core increases with depth, due to the large supply of terrigenous materials for the sediments, it is difficult for the study area to form high-grade REY-rich muds