Dual role of the p38 MAPK/cPLA2MAPK/cPLA_2 pathway in the regulation of platelet apoptosis induced by ABT-737 and strong platelet agonists

p38 Mitogen-activated protein (MAP) kinase is involved in the apoptosis of nucleated cells. Although platelets are anucleated cells, apoptotic proteins have been shown to regulate platelet lifespan. However, the involvement of p38 MAP kinase in platelet apoptosis is not yet clearly defined. Therefore, we investigated the role of p38 MAP kinase in apoptosis induced by a mimetic of BH3-only proteins, ABT-737, and in apoptosis-like events induced by such strong platelet agonists as thrombin in combination with convulxin (Thr/Cvx), both of which result in p38 MAP kinase phosphorylation and activation. A p38 inhibitor (SB202190) inhibited the apoptotic events induced by ABT-737 but did not influence those induced by Thr/Cvx. The inhibitor also reduced the phosphorylation of cytosolic phospholipase $A_2$ (cPLA2), an established p38 substrate, induced by ABT-737 or Thr/Cvx. ABT-737, but not Thr/Cvx, induced the caspase 3-dependent cleavage and inactivation of cPLA2. Thus, p38 MAPK promotes ABT-737-induced apoptosis by inhibiting the cPLA2/arachidonate pathway. We also show that arachidonic acid (AA) itself and in combination with Thr/Cvx or ABT-737 at low concentrations prevented apoptotic events, whereas at high concentrations it enhanced such events. Our data support the hypothesis that the p38 MAPK-triggered arachidonate pathway serves as a defense mechanism against apoptosis under physiological conditions

Bromodomain and extra-terminal protein mimic JQ1 decreases inflammation in human vascular endothelial cells: Implications for pulmonary arterial hypertension

Background and objective Nuclear factor kappa B (NF-kB)-mediated inflammatory gene expression and vascular endothelial cell proliferation/remodelling are implicated in the pathophysiology of the fatal disease, pulmonary arterial hypertension (PAH). Bromodomain and extra-terminal (BET) proteins are essential for the expression of a subset of NF-kB-induced inflammatory genes. BET mimics including JQ1+ prevent binding of BETs to acetylated histones and down-regulate the expression of selected genes. Methods The effects of JQ1+ on the proliferation of primary human pulmonary microvascular endothelial cells (HPMECs) from healthy subjects were measured by bromodeoxyuridine (BrdU) incorporation. Cell cycle progression was assessed by flow cytometry; mRNA and protein levels of cyclin-dependent kinases (CDKs), inhibitors and cytokines were determined by reverse transcription-quantitative PCR (RT-qPCR), Western blotting or ELISA. Histone acetyltransferase (HAT) and deacetylase (HDAC) activities were determined in nuclear extracts from whole lung of PAH and control patients. Results JQ1+ significantly inhibited IL6 and IL8 (IL6 and CXCL8) mRNA and protein in HPMECs compared with its inactive enantiomer JQ1−. JQ1+ decreased NF-kB p65 recruitment to native IL6 and IL8 promoters. JQ1+ showed a concentration-dependent decrease in HPMEC proliferation compared with JQ1−-treated cells. JQ1+ induced G1 cell cycle arrest by increasing the expression of the CDK inhibitors (CDKN) 1A (p21cip) and CDKN2D (p19INK4D ) and decreasing that of CDK2, CDK4 and CDK6. JQ1+ also inhibited serum-stimulated migration of HPMECs. Finally, HAT activity was significantly increased in the lung of PAH patients. Conclusion Inhibition of BETs in primary HPMECs decreases inflammation and remodelling. BET proteins could be a target for future therapies for PAH

The use of microarrays for the identification of the origin of genes of avian influenza viruses in wild birds

Forty-two strains of avian influenza viruses were isolated from the wild waterfowls’ feces in the city of Moscow. These viruses, as well as reference strains and some experimental reassortants, were analyzed by microarrays. The microarrays contained 176 probes to the different segments of influenza virus genome. The microarray helps to determine 1) the hemagglutinin and neuraminidase proteins subtype; 2) the primary structure of the C-terminal sequence of the viral NS1 protein, which serves as a ligand for the PDZ domain; 3) the presence of stop codons in the reading frame of PB1-F2 as well as the N66S substitution in the PB1-F2 viral protein; 4) the presence of the polybasic site for hemagglutinin cleavage. The viruses of the H3N1, H3N6, H3N8, H4N6, H1N1, H5N3, and H11N9 subtypes were identified from the group of wild birds’ isolates. All isolates contained the ESEV sequence at the C-terminus of the NS1 protein and the full-length reading frame for the PB1-F2 protein. The replacement of N66S in PB1-F2 was found in six strains. However, the presence of the ESEV sequence (ligand of PDZ domain) in the NS1 virus protein and the N66S substitution in PB1-F2 did not lead to the pathogenicity of these viruses for mice. All isolates demonstrated high yield growth in chicken embryos and were infectious and immunogenic for mice, but did not induce any clinical symptoms.Forty-two strains of avian influenza viruses were isolated from the wild waterfowls’ feces in the city of Moscow. These viruses, as well as reference strains and some experimental reassortants, were analyzed by microarrays. The microarrays contained 176 probes to the different segments of influenza virus genome. The microarray helps to determine 1) the hemagglutinin and neuraminidase proteins subtype; 2) the primary structure of the C-terminal sequence of the viral NS1 protein, which serves as a ligand for the PDZ domain; 3) the presence of stop codons in the reading frame of PB1-F2 as well as the N66S substitution in the PB1-F2 viral protein; 4) the presence of the polybasic site for hemagglutinin cleavage. The viruses of the H3N1, H3N6, H3N8, H4N6, H1N1, H5N3, and H11N9 subtypes were identified from the group of wild birds’ isolates. All isolates contained the ESEV sequence at the C-terminus of the NS1 protein and the full-length reading frame for the PB1-F2 protein. The replacement of N66S in PB1-F2 was found in six strains. However, the presence of the ESEV sequence (ligand of PDZ domain) in the NS1 virus protein and the N66S substitution in PB1-F2 did not lead to the pathogenicity of these viruses for mice. All isolates demonstrated high yield growth in chicken embryos and were infectious and immunogenic for mice, but did not induce any clinical symptoms

Adiabatic description of nonspherical quantum dot models

Within the effective mass approximation an adiabatic description of spheroidal and dumbbell quantum dot models in the regime of strong dimensional quantization is presented using the expansion of the wave function in appropriate sets of single-parameter basis functions. The comparison is given and the peculiarities are considered for spectral and optical characteristics of the models with axially symmetric confining potentials depending on their geometric size making use of the total sets of exact and adiabatic quantum numbers in appropriate analytic approximations

Elevated plasma CXCL12 alpha is associated with a poorer prognosis in pulmonary arterial hypertension.

Recent work in preclinical models suggests that signalling via the pro-angiogenic and proinflammatory cytokine, CXCL12 (SDF-1), plays an important pathogenic role in pulmonary hypertension (PH). The objective of this study was to establish whether circulating concentrations of CXCL12α were elevated in patients with PAH and related to mortalit

The Role of Sialyl Glycan Recognition in Host Tissue Tropism of the Avian Parasite Eimeria tenella

Eimeria spp. are a highly successful group of intracellular protozoan parasites that develop within intestinal epithelial cells of poultry, causing coccidiosis. As a result of resistance against anticoccidial drugs and the expense of manufacturing live vaccines, it is necessary to understand the relationship between Eimeria and its host more deeply, with a view to developing recombinant vaccines. Eimeria possesses a family of microneme lectins (MICs) that contain microneme adhesive repeat regions (MARR). We show that the major MARR protein from Eimeria tenella, EtMIC3, is deployed at the parasite-host interface during the early stages of invasion. EtMIC3 consists of seven tandem MAR1-type domains, which possess a high specificity for sialylated glycans as shown by cell-based assays and carbohydrate microarray analyses. The restricted tissue staining pattern observed for EtMIC3 in the chicken caecal epithelium indicates that EtMIC3 contributes to guiding the parasite to the site of invasion in the chicken gut. The microarray analyses also reveal a lack of recognition of glycan sequences terminating in the N-glycolyl form of sialic acid by EtMIC3. Thus the parasite is well adapted to the avian host which lacks N-glycolyl neuraminic acid. We provide new structural insight into the MAR1 family of domains and reveal the atomic resolution basis for the sialic acid-based carbohydrate recognition. Finally, a preliminary chicken immunization trial provides evidence that recombinant EtMIC3 protein and EtMIC3 DNA are effective vaccine candidates

Analysis of Lyme-borreliosis disease for 2020-2021 in Yekaterinburg

The aim of the study - to identify clinical and laboratory features in children with Lyme borreliosis in the Sverdlovsk region for 2020-2021Цель исследования - выявить клинические и лабораторные особенности у детей с Лайм-боррелиозом в Свердловской области за 2020-2021 г