Sandfly-Borne Phlebovirus Isolations from Turkey: New Insight into the Sandfly fever Sicilian and Sandfly fever Naples Species

BackgroundMany studies have presented virus sequences which suggest the existence of a variety of putative new phleboviruses transmitted by sandflies in the Old World. However, in most of these studies, only partial sequences in the polymerase or the nucleoprotein genes were characterised. Therefore to further our understand of the presence and potential medical importance of sandfly-borne phleboviruses that circulate in southern Anatolia, we initiated field campaigns in 2012 and 2013 designed to identify, isolate and characterise phleboviruses in sandflies in this regionConclusions/SignificanceThe results indicate that a variety of phleboviruses are co-circulating in this region of southern Anatolia. Based on our studies, these new viruses clearly belong to genetic groups that include several human pathogens. However, whether or not Toros and Zerdali viruses can infect humans and cause diseases such as sandfly fever remains to be investigated.     

Wing morphology variations in a natural population of Phlebotomus tobbi Adler and Theodor 1930

Cutaneous leishmaniasis (CL) is highly endemic in the Cukurova region, located on the crossroads of main refugee routes from the Middle East to Europe on the eastern Mediterranean part of Turkey. Our purpose was to investigate the phenotypic variation of Phlebotomus tobbi, the known vector of CL in the region, during one active season. Sand flies and microclimatic data were collected monthly from May to October, 2011, from five locations in six villages in the study area. A geometric morphometric approach was used to investigate wing morphology. Shape analyses revealed that males collected in May and June comprised one group, while specimens collected in August, September, and October formed a second group. Specimens from July were found to be distributed within these two groups. A similar distribution pattern was observed for females, but specimens from October were represented as the third district group. Significant size variation was detected for both sexes between months. Wing size and temperature were negatively correlated for females, but there was no temperature effect for males. Wing size of both sexes was increased in correlation to increasing relative humidity. Males were found to have smaller wings with increasing population density.     

Dilated cardiomyopathy in a spider monkey (Ateles paniscus)

Background A spider monkey with severe dyspnea was referred to our clinic. Methods and Results Radiographs revealed an enlarged cardiac silhouette. Ventricular tachycardia and ST segment depression were also diagnosed after an ECG. These findings coupled with the postmortem examination confirmed dilatative cardiomyopathy. Conclusions This case is worthy of presentation since dilatative cardiomyopathy has been rarely encountered in spider monkeys.     

Palbociclib,a selective CDK4/6 inhibitor,restricts cell survival and epithelial-mesenchymal transition in Panc-1 and MiaPaCa-2 pancreatic cancer cells

The mortality rate of pancreatic cancer has close parallels to its incidence rate because of limited therapeutics and lack of effective prognosis. Despite various novel chemotherapeutics combinations, the 5-year survival rate is still under 5%. In the current study, we aimed to modulate the aberrantly activated PI3K/AKT pathway and epithelial-mesenchymal transition (EMT) signaling with the treatment of CDK4/6 inhibitor PD-0332991 (palbociclib) in Panc-1 and MiaPaCa-2 pancreatic cancer cells. It was found that PD-0332991 effectively reduced cell viability and proliferation dose-dependently within 24 hours. In addition, PD-0332991 induced cell cycle arrest at the G1 phase by downregulation of aberrant expression of CDK4/6 through the dephosphorylation of Rb in each cell lines. Although PD-0332991 treatment increased epithelial markers and decreased mesenchymal markers, the nuclear translocation of β-catenin was not prevented by PD-0332991 treatment, especially in MiaPaCa-2 cells. Effects of PD-0332991 on the regulation of PI3K/AKT signaling and its downstream targets such as GSK-3 were cell type-dependent. Although the activity of AKT was inhibited in both cell lines, the phosphorylation of GSK-3β at Ser9 increased only in Panc-1. In conclusion, PD-0332991 induced cell cycle arrest and reduced the cell viability of Panc-1 and MiaPaCa-2 cells. However, PD-0332991 differentially affects the regulation of the PI3K/AKT pathway and EMT process in cells due to its distinct influence on Rb and GSK-3/β-catenin signaling. Understanding the effect of PD-0332991 on the aberrantly activated signaling axis may put forward a new therapeutic strategy to reduce the cell viability and metastatic process of pancreatic cancer.     

APT102, a novel adpase, cooperates with aspirin to disrupt bone metastasis in mice

Platelets contribute to the development of metastasis, the most common cause of mortality in cancer patients, but the precise role that anti-platelet drugs play in cancer treatment is not defined. Metastatic tumor cells can produce platelet alphaIIb beta3 activators, such as ADP and thromboxane A(2) (TXA(2)). Inhibitors of platelet beta3 integrins decrease bone metastases in mice but are associated with significant bleeding. We examined the role of a novel soluble apyrase/ADPase, APT102, and an inhibitor of TXA(2) synthesis, acetylsalicylic acid (aspirin or ASA), in mouse models of experimental bone metastases. We found that treatment with ASA and APT102 in combination (ASA + APT102), but not either drug alone, significantly decreased breast cancer and melanoma bone metastases in mice with fewer bleeding complications than observed with alphaIIb beta3 inhibition. ASA + APT102 diminished tumor cell induced platelet aggregation but did not directly alter tumor cell viability. Notably, APT102 + ASA treatment did not affect initial tumor cell distribution and similar results were observed in beta3-/- mice. These results show that treatment with ASA + APT102 decreases bone metastases without significant bleeding complications. Anti-platelet drugs such as ASA + APT102 could be valuable experimental tools for studying the role of platelet activation in metastasis as well as a therapeutic option for the prevention of bone metastases.     

CDP-choline-induced contractions in the mouse gastric fundus through purinoceptors and Rho/Rho-kinase signalling

AimsThis study aimed to investigate the effects of cytidine-5′-diphosphocholine (CDP-choline), an endogenous lipid precursor, on the reactivity of the mouse gastric fundus and to determine the mechanism(s) mediating its effects.Main methodsPossible contractile effect of CDP-choline (10^? 5–10^? 2 M) was investigated in the absence and presence of a muscarinic receptor antagonist, atropine (3 × 10^? 6 M), an acetylcholine esterase inhibitor, physostigmine (10^? 6 M), a Na⁺ channel blocker, tetrodotoxin (TTX, 3 × 10^? 6 M), a Rho-kinase inhibitor, Y-27632 (10^? 5 M), a purinoceptor antagonist, suramin (2 × 10^? 4 M), a nitric oxide synthase inhibitor, N^G-nitro-L-arginine (L-NA, 3 × 10^? 4 M), a Ca²⁺ channel blocker, nifedipine (10^? 6 M), an α₇ nicotinic receptor antagonist, methyllycaconitine citrate (MLA, 10^? 6 M) and a G protein (G_i/o) inhibitor, pertussis toxin (PTX, 2 μg/ml). The metabolites of CDP-choline, namely choline (10^? 4–10^? 2 M), cytidine 5′-triphosphate (CTP, 10^? 5–10^? 2 M), cytidine (10^? 5–10^? 2 M) and cytidine monophosphate (CMP, 10^? 3–10^? 2 M) were also tested. Besides, phosphorylation of MYPT1, which indicates Rho-kinase activity, was also detected.Key findingsCDP-choline produced contractions in a concentration-dependent manner. The contractions were not affected by atropine, physostigmine, TTX, PTX, MLA or L-NA. However, Y-27632, suramin or nifedipine partly reduced these contractions. CDP-choline increased phosphorylation of MYPT1. Among CDP-choline metabolites, cytidine had no contractile effects. However, choline induced considerable contractions, which were sensitive to atropine. CMP and CTP had also contractile activity, comparable to that of CDP-choline.SignificanceThese results suggest that CDP-choline produced contraction through, at least in part, purinoceptors and Rho/Rho-kinase signalling in the mouse gastric fundus.     

Altitudinal variation in the morphometric characteristics of Aedes vexans Meigen from northeastern Turkey

Body size is one of the most significant features of organisms and is correlated with a large number of ecological and physiological variables. Similar to size, biological shape is one of the most conspicuous aspects of an organism's phenotype and provides a link between the genotype and the environment. Body size may change with altitude and also habitat differences associated with altitude may affect the biological shape and some morphological characteristics. Four populations of Aedes vexans Meigen occurring in different ecological subregions at altitudes between 808–1,620 m in the Aras Valley from northeastern Turkey were compared using traditional and geometric morphometrics. When the wing shape differences of populations were analyzed by UPGM, the cluster analyses recognized two main groups of populations. Gödekli (808 m) comprised the first group while Zülfikar (848 m), Sürmeli (944 m), and Cilehane (1,620 m) populations comprised the second group. In the second group, Zülfikar and Cilehane populations showed a similar grouping pattern while Sürmeli appeared as a different group. Centroid sizes were used as measures of overall wing size differences among different regions. Aedes vexans from the Sürmeli region had relatively larger wings.     

A GIPC1-Palmitate Switch Modulates Dopamine Drd3 Receptor Trafficking and Signaling

Palmitoylation is involved in several neuropsychiatric and movement disorders for which a dysfunctional signaling of the dopamine D3 receptor (Drd3) is hypothesized. Computational modeling of Drd3''s homologue, Drd2, has shed some light on the putative role of palmitoylation as a reversible switch for dopaminergic receptor signaling. Drd3 is presumed to be palmitoylated, based on sequence homology with Drd2, but the functional attributes afforded by Drd3 palmitoylation have not been studied. Since these receptors are major targets of antipsychotic and anti-Parkinsonian drugs, a better characterization of Drd3 signaling and posttranslational modifications, like palmitoylation, may improve the prospects for drug development. Using molecular dynamics simulations, we evaluated in silico how Drd3 palmitoylation could elicit significant remodeling of the C-terminal cytoplasmic domain to expose docking sites for signaling proteins. We tested this model in cellulo by using the interaction of Drd3 with the G-alpha interacting protein (GAIP) C terminus 1 (GIPC1) as a template. From a series of biochemical studies, live imaging, and analyses of mutant proteins, we propose that Drd3 palmitoylation acts as a molecular switch for Drd3-biased signaling via a GIPC1-dependent route, which is likely to affect the mode of action of antipsychotic drugs.