The Epstein-Barr Virus G-Protein-Coupled Receptor Contributes to Immune Evasion by Targeting MHC Class I Molecules for Degradation

Epstein-Barr virus (EBV) is a human herpesvirus that persists as a largely subclinical infection in the vast majority of adults worldwide. Recent evidence indicates that an important component of the persistence strategy involves active interference with the MHC class I antigen processing pathway during the lytic replication cycle. We have now identified a novel role for the lytic cycle gene, BILF1, which encodes a glycoprotein with the properties of a constitutive signaling G-protein-coupled receptor (GPCR). BILF1 reduced the levels of MHC class I at the cell surface and inhibited CD8+ T cell recognition of endogenous target antigens. The underlying mechanism involves physical association of BILF1 with MHC class I molecules, an increased turnover from the cell surface, and enhanced degradation via lysosomal proteases. The BILF1 protein of the closely related CeHV15 c1-herpesvirus of the Rhesus Old World primate (80% amino acid sequence identity) downregulated surface MHC class I similarly to EBV BILF1. Amongst the human herpesviruses, the GPCR encoded by the ORF74 of the KSHV c2-herpesvirus is most closely related to EBV BILF1 (15% amino acid sequence identity) but did not affect levels of surface MHC class I. An engineered mutant of BILF1 that was unable to activate G protein signaling pathways retained the ability to downregulate MHC class I, indicating that the immune-modulating and GPCR-signaling properties are two distinct functions of BILF1. These findings extend our understanding of the normal biology of an important human pathogen. The discovery of a third EBV lytic cycle gene that cooperates to interfere with MHC class I antigen processing underscores the importance of the need for EBV to be able to evade CD8+ T cell responses during the lytic replication cycle, at a time when such a large number of potential viral targets are expressed

Field trial of three different Plasmodium vivax-detecting rapid diagnostic tests with and without evaporative cool box storage in Afghanistan

<p>Abstract</p> <p>Background</p> <p>Accurate parasitological diagnosis of malaria is essential for targeting treatment where more than one species coexist. In this study, three rapid diagnostic tests (RDTs) (AccessBio CareStart (CSPfPan), CareStart PfPv (CSPfPv) and Standard Diagnostics Bioline (SDBPfPv)) were evaluated for their ability to detect natural <it>Plasmodium vivax </it>infections in a basic clinic setting. The potential for locally made evaporative cooling boxes (ECB) to protect the tests from heat damage in high summer temperatures was also investigated.</p> <p>Methods</p> <p>Venous blood was drawn from <it>P. vivax </it>positive patients in Jalalabad, Afghanistan and tested against a panel of six RDTs. The panel comprised two of each test type; one group was stored at room temperature and the other in an ECB. RDT results were evaluated against a consensus gold standard based on two double-read reference slides and PCR. The sensitivity, specificity and a measure of global performance for each test were determined and stratified by parasitaemia level and storage condition.</p> <p>Results</p> <p>In total, 306 patients were recruited, of which 284 were positive for <it>P. vivax</it>, one for <it>Plasmodium malariae </it>and none for <it>Plasmodium falciparum</it>; 21 were negative. All three RDTs were specific for malaria. The sensitivity and global performance index for each test were as follows: CSPfPan [98.6%, 95.1%], CSPfPv [91.9%, 90.5%] and SDBPfPv [96.5%, 82.9%], respectively. CSPfPv was 16% less sensitive to a parasitaemia below 5,000/μL. Room temperature storage of SDBPfPv led to a high proportion of invalid results (17%), which reduced to 10% in the ECB. Throughout the testing period, the ECB maintained ~8°C reduction over ambient temperatures and never exceeded 30°C.</p> <p>Conclusions</p> <p>Of the three RDTs, the CSPfPan test was the most consistent and reliable, rendering it appropriate for this <it>P. vivax </it>predominant region. The CSPfPv test proved unsuitable owing to its reduced sensitivity at a parasitaemia below 5,000/μL (affecting 43% of study samples). Although the SDBPfPv device was more sensitive than the CSPfPv test, its invalid rate was unacceptably high. ECB storage reduced the proportion of invalid results for the SDBPfPv test, but surprisingly had no impact on RDT sensitivity at low parasitaemia.</p

A Critical Role of a Cellular Membrane Traffic Protein in Poliovirus RNA Replication

Replication of many RNA viruses is accompanied by extensive remodeling of intracellular membranes. In poliovirus-infected cells, ER and Golgi stacks disappear, while new clusters of vesicle-like structures form sites for viral RNA synthesis. Virus replication is inhibited by brefeldin A (BFA), implicating some components(s) of the cellular secretory pathway in virus growth. Formation of characteristic vesicles induced by expression of viral proteins was not inhibited by BFA, but they were functionally deficient. GBF1, a guanine nucleotide exchange factor for the small cellular GTPases, Arf, is responsible for the sensitivity of virus infection to BFA, and is required for virus replication. Knockdown of GBF1 expression inhibited virus replication, which was rescued by catalytically active protein with an intact N-terminal sequence. We identified a mutation in GBF1 that allows growth of poliovirus in the presence of BFA. Interaction between GBF1 and viral protein 3A determined the outcome of infection in the presence of BFA

Computer work and musculoskeletal disorders of the neck and upper extremity: A systematic review

<p>Abstract</p> <p>Background</p> <p>This review examines the evidence for an association between computer work and neck and upper extremity disorders (except carpal tunnel syndrome).</p> <p>Methods</p> <p>A systematic critical review of studies of computer work and musculoskeletal disorders verified by a physical examination was performed.</p> <p>Results</p> <p>A total of 22 studies (26 articles) fulfilled the inclusion criteria. Results show limited evidence for a causal relationship between computer work per se, computer mouse and keyboard time related to a diagnosis of wrist tendonitis, and for an association between computer mouse time and forearm disorders. Limited evidence was also found for a causal relationship between computer work per se and computer mouse time related to tension neck syndrome, but the evidence for keyboard time was insufficient. Insufficient evidence was found for an association between other musculoskeletal diagnoses of the neck and upper extremities, including shoulder tendonitis and epicondylitis, and any aspect of computer work.</p> <p>Conclusions</p> <p>There is limited epidemiological evidence for an association between aspects of computer work and some of the clinical diagnoses studied. None of the evidence was considered as moderate or strong and there is a need for more and better documentation.</p

From a water resource to a point pollution source: the daily journey of a coastal urban stream

The aim of this study was to understand how a stream ecosystem that flows from its fountainhead to its mouth inside a city, changes from a water resource to a point pollution source. A multidisciplinary descriptive approach was adopted, including the short-term temporal and spatial determination of physical, chemical, biological and ecotoxicological variables. Results showed that water quality rapidly decreases with increasing urbanization, leading the system to acquire raw sewage attributes even in the first hundred meters after the fountainheads. Despite the tidal circulation near the stream mouth being restricted by shallowness, some improvement of the water quality was detected in this area. The multidisciplinary evaluation showed to be useful for obtaining a more realistic understanding of the stream degradation process, and to forecast restoration and mitigation measures