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71.
72.
Primrose Raphael Yuichi Takakuwa Sumie Manno Shih-Chun Liu Athar H. Chishti Manjit Hanspal 《Molecular and biochemical parasitology》2000,110(2)
The malaria parasite Plasmodium falciparum undergoes distinct morphologic changes during its 48-h life cycle inside human red blood cells. Parasite proteinases appear to play important roles at all stages of the erythrocytic cycle of human malaria. Proteases involved in erythrocyte rupture and invasion are possibly required to breakdown erythrocyte membrane skeleton. To identify such proteases, soluble cytosolic extract of isolated trophozoites/schizonts was incubated with erythrocyte membrane ghosts or spectrin-actin depleted inside-out vesicles, which were then analyzed by SDS-PAGE. In both cases, a new protein band of 155 kDa was detected. The N-terminal peptide sequencing established that the 155 kDa band represents truncated ankyrin. Immunoblot analysis using defined monoclonal antibodies confirmed that ankyrin was cleaved at the C-terminus. While the enzyme preferentially cleaved ankyrin, degradation of protein 4.1 was also observed at high concentrations of the enzyme. The optimal activity of the purified enzyme, using ankyrin as substrate, was observed at pH 7.0–7.5, and the activity was strongly inhibited by standard inhibitors of cysteine proteinases (cystatin, NEM, leupeptin, E-64 and MDL 28 170), but not by inhibitors of aspartic (pepstatin) or serine (PMSF, DFP) proteinases. Furthermore, we demonstrate that protease digestion of ankyrin substantially reduces its interaction with ankyrin-depleted membrane vesicles. Ektacytometric measurements showed a dramatic increase in the rate of fragmentation of ghosts after treatment with the protease. Although the role of ankyrin cleavage in vivo remains to be determined, based on our findings we postulate that the parasite-derived cysteine protease activity cleaves host ankyrin thus weakening the ankyrin-band 3 binding interactions and destabilizing the erythrocyte membrane skeleton, which, in turn, facilitates parasite release. Further characterization of the enzyme may lead to the development of novel antimalarial drugs. 相似文献
73.
A tripartite cytolytic toxin formed by Vibrio cholerae proteins with flagellum-facilitated secretion
Aftab Nadeem Raghavendra Nagampalli Eric Toh Athar Alam Si Lhyam Myint Thomas V. Heidler Mitesh Dongre Nikola Zlatkov Hudson Pace Fouzia Bano Anders Sjstedt Marta Bally Bernt Eric Uhlin Sun Nyunt Wai Karina Persson 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(47)
The protein MakA was discovered as a motility-associated secreted toxin from Vibrio cholerae. Here, we show that MakA is part of a gene cluster encoding four additional proteins: MakB, MakC, MakD, and MakE. MakA, MakB, and MakE were readily detected in culture supernatants of wild-type V. cholerae, whereas secretion was very much reduced from a flagellum-deficient mutant. Crystal structures of MakA, MakB, and MakE revealed a structural relationship to a superfamily of bacterial pore-forming toxins. Expression of MakA/B/E in Escherichia coli resulted in toxicity toward Caenorhabditis elegans used as a predatory model organism. None of these Mak proteins alone or in pairwise combinations were cytolytic, but an equimolar mixture of MakA, MakB, and MakE acted as a tripartite cytolytic toxin in vitro, causing lysis of erythrocytes and cytotoxicity on cultured human colon carcinoma cells. Formation of oligomeric complexes on liposomes was observed by electron microscopy. Oligomer interaction with membranes was initiated by MakA membrane binding followed by MakB and MakE joining the assembly of a pore structure. A predicted membrane insertion domain of MakA was shown by site-directed mutagenesis to be essential for toxicity toward C. elegans. Bioinformatic analyses revealed that the makCDBAE gene cluster is present as a genomic island in the vast majority of sequenced genomes of V. cholerae and the fish pathogen Vibrio anguillarum. We suggest that the hitherto-unrecognized cytolytic MakA/B/E toxin can contribute to Vibrionaceae fitness and virulence potential in different host environments and organisms.Vibrio cholerae is known as the cause of cholera, a disease that can lead to fatal dehydration (1). The disease is caused by a few serogroups, and the main factor behind the symptoms is the cholera toxin (CT) encoded by genes located on a prophage mobile genetic element (CTX-φ) that induce severe disruption of intestinal cell function, leading to watery, secretory diarrhea (2). Most serogroups do not cause cholera, as they do not possess the genes for CT, but they cause other diseases [e.g., skin, wound, and gastrointestinal infections as well as bacteremia (3)]. The natural reservoirs of V. cholerae are aquatic sources such as rivers, brackish waters, and estuaries and are often associated with copepods, aquatic plants, and shellfish (4). The factors and mechanisms allowing V. cholerae and other Vibrionaceae to survive and thrive in harsh natural environments are of major interest to researchers (5).V. cholerae is motile by virtue of a single polar flagellum. The flagellum export machinery and the virulence-associated type-III secretion system (fT3SS and vT3SS, respectively) are suggested to share a common ancestor (6), explaining their similar structure and molecular organization. The vT3SS allows the delivery of effector proteins through a hollow channel directly to the eukaryotic host cell (7), and flagellar proteins are delivered via the fT3SS channel during flagellum assembly. In the bacterial cytoplasm, effectors secreted by the vT3SS are stabilized by chaperones to prevent aggregation. These chaperones are often encoded by genes adjacent to those encoding the effectors (8). Flagellar proteins are similarly protected by chaperones before they are transported to the growing distal end of the flagellum (9).We use Caenorhabditis elegans as a predatory organism model for identifying and assessing V. cholerae factors, other than CT, that may contribute to bacterial survival and persistence (10). With this model, we discovered a cytotoxin, MakA (motility-associated killing factor A), which we demonstrated to be an essential factor for the cytotoxic activity of V. cholerae in both C. elegans and Danio rerio (zebrafish) (11). We also demonstrated that secretion of MakA occurs via the flagellum in a manner that is undocumented in V. cholerae. Our crystal structure of MakA revealed similarities to ClyA (11), the pore-forming toxin first identified in nonpathogenic Escherichia coli (12, 13) and, subsequently, also in Salmonella enterica (14). ClyA from E. coli is expressed from a monocistronic operon and oligomerizes into a dodecameric pore upon release via membrane vesicles (13, 15, 16). MakA is also structurally related to two proteins from Bacillus cereus, the hemolysin BL binding component B (HBL-B) and the NheA component of the Nhe nonhemolytic enterotoxin. Both of these are considered components of tripartite toxins (17). Recently, a tripartite toxin, AhlABC, was identified and structurally characterized as a pore-forming toxin in Aeromonas hydrophila, and the structure of soluble AhlB shares the general structure described for MakA (18). A similar toxin complex of three proteins, SmhABC from Serratia marcescens, was also reported (19). However, if and how the Ahl and Smh proteins are released during normal growth, or if there is a dedicated secretion system, remain unclear.Here, we identify the proteins from the five V. cholerae genes, vca0880 through vca0884, that are coexpressed from the operon makDCBAE and analyze the crystal structures of MakA, MakB, and MakE. Our in vitro studies revealed that an equimolar combination of the MakA/B/E proteins acted as a tripartite cytotoxin causing lysis of red blood cells and cytotoxicity to epithelial cells. Examination of a large number of bacterial genomes revealed that the mak operon is present in many V. cholerae and other Vibrionaceae strains. These include Vibrio (Listonella) anguillarum, an inhabitant of estuarine and marine coastal ecosystems worldwide and the etiological agent of vibriosis in warm- and cold-water fish (20). The identification and structural characterization of the Mak proteins in V. cholerae presented here reveals a hitherto-unrecognized potential of many pathogenic Vibrionaceae strains to produce the tripartite Mak cytolytic toxin. 相似文献
74.
75.
Long‐term neuromuscular outcomes of west nile virus infection: A clinical and electromyographic evaluation of patients with a history of infection
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Parveen Athar MD Rodrigo Hasbun MD Melissa S. Nolan PhD Lucrecia Salazar MD Steven P. Woods PsyD Kazim Sheikh MD Kristy O. Murray DVM PhD 《Muscle & nerve》2018,57(1):77-82
Introduction: Neuromuscular clinical manifestations during acute West Nile virus (WNV) infection are well documented; however, long‐term neurologic outcomes still require investigation. Methods: We conducted a long‐term follow‐up study in patients with history of WNV infection. Of the 117 patients who participated in neurologic and neurocognitive evaluations, 30 were referred for neuromuscular and electrodiagnostic evaluation based on abnormal findings. Results: We found that 33% of these patients (10 of 30) showed abnormalities on nerve conduction and/or needle electromyography due to primary or secondary outcomes of WNV infection. Most common electrodiagnostic findings and causes of long‐term disability were related to anterior horn cell poliomyelitis (WNV poliomyelitis). Electrical data on these patient populations were similar to those observed in chronic poliomyelitis. Discussion: With more than 16,000 cases of WNV neuroinvasive disease reported across the USA since 1999, understanding clinical outcomes from infection will provide a resource for physicians managing long‐term care of these patients. Muscle Nerve 57 : 77–82, 2018 相似文献
76.
77.
78.
Neda Sepahi Athar Rasekh Jahromi Yahya Daneshbod Elahe Nimi Hoveidi 《Gynecological endocrinology》2017,33(6):429-432
microRNAs (miRNAs) are negative regulators in a variety of cellular processes that occur in endometriosis. Therefore, functional polymorphisms in miRNA and miRNA binding sites may affect gene expression and contribute to susceptibility of endometriosis. In this study, we evaluated the association of two miRNA related polymorphisms, mir-126 rs4636297 and TGFβRI rs334348, with endometriosis risk and its severity. This case-control study was done on 157 endometriosis patients and 252 healthy women as a control group. Tetra amplification refractory mutation system-polymerase chain reaction (tetra-ARMS PCR) was designed to determine the polymorphisms. Our finding showed significant differences in genotype frequency of mir-126 rs4636297 between the groups (χ2?=?6.26, p?=?0.044). A significant protection against endometriosis was found for mir-126 rs4636297 in allele (G versus A allele: OR?=?0.695, 95% CI?=?0.519–0.931, p?=?0.015) and genotype (GG versus AA genotype: OR?=?0.451, 95%CI?=?0.233–0.873, p?=?0.018). Significant association was also observed between the A allele and severity of endometriosis (OR?=?0.478, 95%CI?=?0.297–0.768, p?=?0.002). Moreover, we found a significant association between AA genotype with the risk of endometriosis (OR?=?0.493, 95%CI?=?0.250–0.970, p?=?0.041) and its severity (OR?=?0.240, 95%CI?=?0.065–0.883, p?=?0.032) regarding TGFβRI rs334348 polymorphism. These finding suggest that, for the first time, mir-126 rs4636297 and TGFβRI rs334348 polymorphisms may influence individual’s susceptibility to endometriosis and its severity. 相似文献
79.
M. Kamran Athar MD Sidharth Bagga MD Nanda Nair DO Vivek Punjabi MD Karen Vito RN Christa Schorr RN MSN David R. Gerber DO FCCP 《Journal of critical care》2011,26(4):335-341
Purpose
Although transfusion has been linked to the development of atrial fibrillation (AF) in cardiac surgical patients, this association has not been investigated in patients with acute myocardial infarction (AMI). Evidence supports an inflammatory mechanism in the development of AF, and red cell transfusions also elicit an inflammatory response. We therefore sought to evaluate whether packed red blood cell transfusion increases the risk of AF, ventricular tachycardia (VT), and other arrhythmias and conduction abnormalities in patients with AMI.Materials and Methods
This is a retrospective study on patients with AMI and no prior history of AF, admitted to a critical care area and entered in Project Impact database from 08/2003-12/2007. Primary outcome measures were new-onset cardiac arrhythmias or conduction disturbances.Results
Transfused patients had significantly higher incidences of AF (4.7% vs 1.3%, P = .008), cardiac arrest (9.5% vs 1.7%, P < .001) and heart block (3.4% vs 0.1%, P < .001), and a trend toward a higher incidence of VT (3.4% vs 1.3%, P = .058). Multivariate regression analysis confirmed transfusion as an independent risk factor for “non-lethal” cardiac events (AF/heart block; odds ratio [OR], 4.7 [1.9-11.9]; P = .001), “lethal” events (VT/cardiac arrest; OR, 2.4 [1.1-5]; P = .016), and all cardiac events (OR, 2.8 [1.5-65.1]; P = .001). Transfused patients had significantly longer length of stay (P < .0001) and significantly higher mortality rates than nontransfused patients (OR, 3 [1.7-5.5]; P < .001).Conclusions
Packed red blood cell transfusion is independently associated with an increased risk of new-onset cardiac arrhythmias and conduction abnormalities in the setting of AMI, even after controlling for traditional risk factors. 相似文献80.