Microstructural white matter alterations associated with migraine headaches: a systematic review of diffusion tensor imaging studies

Brain Imaging and Behavior - The pathophysiology of migraine as a headache disorder is still undetermined. Diffusion tensor imaging (DTI) has significantly improved our knowledge about brain...     

Role of capsid sequence and immature nucleocapsid proteins p9 and p15 in Human Immunodeficiency Virus type 1 genomic RNA dimerization

HIV-1 genomic RNA (gRNA) dimerization is important for viral infectivity and is regulated by proteolytic processing of the Gag precursor protein (Pr55gag) under the direction of the viral protease. The processing occurs in successive steps and, to date, the step associated with formation of a wild-type (WT) level of gRNA dimers has not been identified. The primary cleavage divides Pr55gag into two proteins. The C-terminal polypeptide is termed NCp15 (NCp7-p1-p6) because it contains the nucleocapsid protein (NC), a key determinant of gRNA dimerization and packaging. To examine the importance of precursor polypeptides NCp15 and NCp9 (NCp7-p1), we introduced mutations that prevented the proteolytic cleavages responsible for the appearance of NCp9 or NCp7. Using native Northern blot analysis, we show that gRNA dimerization was impaired when both the secondary (p1-p6) and tertiary (p7-p1) cleavage sites of NCp15 were abolished, but unaffected when only one or the other site was abolished. Though processing to NCp9 therefore suffices for a WT level of gRNA dimerization, we also show that preventing cleavage at the p7-p1 site abolished HIV-1 replication. To identify the minimum level of protease activity compatible with a WT level of gRNA dimers, we introduced mutations Thr26Ser and Ala28Ser in the viral protease to partially inactivate it, and we prepared composite HIV-1 resulting from the cotransfection of various ratios of WT and protease-inactive proviral DNAs. The results reveal that a 30% processing of Pr55gag into mature capsid proteins (CA/CA-p2) yielded a WT level of gRNA dimers, while a 10% Pr55gag processing hardly increased gRNA dimerization above the level seen in protease-inactive virions. We found that full gRNA dimerization required less than 50% WT NC in complementation asssays. Finally, we show that if we destroy alpha helix 1 of the capsid protein (CA), gRNA dimerization is impaired to the same extent as when the viral protease is inactivated. Cotransfection studies show that this CA mutation, in contrast to the NC-disabling mutations, has a dominant negative effect on HIV-1 RNA dimerization, viral core formation, and viral replication. This represents the first evidence that a capsid mutation can affect HIV-1 RNA dimerization.     

Low Helicobacter pylori eradication rates with 4- and 7-day regimens in an Iranian population

BACKGROUND: In Iran, there is insufficient information on the efficacy of Helicobacter pylori eradication regimens shorter than 10 days. This study aims at assessing the efficacy of 4- and 7-day H. pylori eradication regimens in a high-incidence area of gastric cancer in Iran. METHODS: Subjects with an endoscopic diagnosis of gastritis, positive urease test, and a histological diagnosis of chronic gastritis were enrolled. Patients were randomly assigned to one of three groups: AOC7 (1000 mg amoxicillin, 20 mg omeprazole, and 500 mg clarithromycin twice daily for 7 days), FOT4 (200 mg furazolidone, 20 mg omeprazole, and 500 mg tetracycline twice daily for 4 days) and FOT7 (the same treatment as the FOT4 group but for 7 days). Sensitivity to these antibiotics was determined in all isolates recovered from culture. The efficacy of eradication was assessed 8 weeks after the end-of-treatment by the 14C-urea breath test. RESULTS: One hundred and twenty-eight patients were enrolled in the study. Culture was positive for 84 patients and none of these were resistant to amoxicillin, tetracycline or furazolidone, 1.2% were resistant to clarithromycin and 32.1% to metronidazole. Forty-five, 41 and 42 patients were randomly allocated to the AOC7, FOT4, and FOT7 groups, respectively. The intention-to-treat eradication rates were 35.5, 17.1, and 23.8% for the AOC7, FOT4, and FOT7 groups, respectively. CONCLUSION: Treatment regimens of 4 or 7 days are unacceptable for H. pylori infection in Iran, even in the presence of a favorable sensitivity profile.     

Stable copper complexes derived from nitrogen sugars]

This paper describes the synthesis of six new well-defined, stable cupric complexes of the general formula Cu(Ligand)2 in which the organic ligand is a nitrogen-bearing sugar derivative. Some of these compounds showed a border-line cytotoxic activity.     

Protective effects of gallic acid against methotrexate-induced toxicity in rats

Background: Methotrexate, as a chemotherapy drug, can cause chronic liver damage and oxidative stress. Aim of this study was to evaluate the preventive effect of gallic acid (GA) on methotrexate (MTX)-induced oxidative stress in rat liver.

Methods: Twenty-eight male rats were randomly divided into four groups as control, MTX (20?mg/kg, i.p.), MTX?+?GA (30?mg/kg/day, orally) and GA treated. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were used as biochemical markers of MTX-induced hepatic injury. Malondialdehyde (MDA) and glutathione (GSH) levels and hepatic antioxidant enzymes activities including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) were assayed in liver tissue. The expression of SOD2 and GPx1 genes were evaluated by real-time RT-PCR and liver histopathology was evaluated by light microscopy.

Results: The result obtained from current study showed that GA remarkably reduced MTX-induced elevation of AST, ALT and ALP and increased MTX-induced reduction in GSH content, GPx, CAT and SOD activity as well as GPx1 and SOD2 gene expressions. Histological results showed that MTX led to liver damage and GA could improve histological changes.

Conclusions: Our results indicate that GA ameliorates biochemical and oxidative stress parameters in the liver of rats exposed to MTX.     

Brain pathway differences between Parkinson’s disease patients with and without REM sleep behavior disorder

Sleep and Breathing - REM (rapid eye movement) sleep behavior disorder (RBD) is characterized by increased muscle tone and violent limb movements and is a usual symptom of the early stages of...     

The expression of GAS5, THRIL,and RMRP lncRNAs is increased in T cells of patients with rheumatoid arthritis

Clinical Rheumatology - Long non-coding RNAs (lncRNAs) comprise a large and diverse group of non-coding RNAs (ncRNAs) with important regulatory roles in various biological processes, including the...     

UVRAG is required for virus entry through combinatorial interaction with the class C-Vps complex and SNAREs

Enveloped viruses exploit the endomembrane system to enter host cells. Through a cascade of membrane-trafficking events, virus-bearing vesicles fuse with acidic endosomes and/or lysosomes mediated by SNAREs triggering viral fusion. However, the molecular mechanisms underlying this process remain elusive. Here, we found that UV-radiation resistance-associated gene (UVRAG), an autophagic tumor suppressor, is required for the entry of the prototypic negative-strand RNA virus, including influenza A virus and vesicular stomatitis virus, by a mechanism independent of IFN and autophagy. UVRAG mediates viral endocytic transport and membrane penetration through interactions with the class C vacuolar protein sorting (C-Vps) tethering complex and endosomal glutamine-containing SNAREs [syntaxin 7 (STX7), STX8, and vesicle transport through t-SNARE homolog 1B (Vti1b)], leading to the assembly of a fusogenic trans-SNARE complex involving vesicle-associated membrane protein (VAMP8), but not VAMP7. Indeed, UVRAG stimulates VAMP8 translocation to virus-bearing endosomes. Inhibition of VAMP8, but not VAMP7, significantly reduces viral entry. Our data indicate that UVRAG, in concert with C-Vps, regulates viral entry by assembling a specific fusogenic SNARE complex. Thus, UVRAG governs downstream viral entry, highlighting an important pathway capable of potential antiviral therapeutics.Viruses are obligate intracellular parasites that must enter host cells for replication. Although some viruses penetrate cells directly through the plasma membrane, most take advantage of existing portals of entry evolved for nutrient uptake and receptor signaling while moving within the endosomal apparatus of the cell to reach the site for replication (1). Among the best-studied examples is vesicular stomatitis virus (VSV), a prototype of the Rhabdoviridae, which has long been used as a model to understand viral entry mechanisms and host endosome biology (1). Although it is established that transport to the acidic endosome is required for release of VSV and other negative-strand RNA viruses, such as influenza A virus (IAV) (1, 2), the molecular machinery that ferries these viruses through the endomembrane remains poorly understood. Moreover, the ride is not free for the virus because the lysosome station on the endocytic pathway is a potentially hazardous environment that degrades viral components and reports infection. How the virus traffics within, and eventually escapes from, specific endosomal organelles before lysosome degradation is another important question in virus entry.Evidence shows that endocytic transport is not a random priming event hitchhiked by the virus, but an important strategy the virus exploits to route itself to a specific compartment for fusion and genome release (1). This process is achieved by SNARE-regulated sequential fusion between virion-containing vesicles and intracellular organelles, including early endosomes, late endosomes (LEs), and lysosomes (3). Fusogenic trans-SNARE complexes are assembled to form a four-helix bundle consisting of glutamine (Q) a-, Qb-, and Qc-SNAREs embedded in one membrane and arginine (R)-SNAREs embedded in the other (3). Specifically, syntaxin 7 (STX7; Qa), Vti1b (Qb), and STX8 (Qc) on the LE, when paired with VAMP7 (R), mediate the LE fusion with the lysosome, but when paired with VAMP8 (R), regulate homotypic fusion of the LEs (4). The upstream process regulating LE-associated SNARE pairing relies on the class C vacuolar protein sorting (Vps) complex (hereafter referred to as C-Vps), composed of Vps11, Vps16, Vps18, and Vps33 as core subunits (5, 6). A recent study indicated that C-Vps interaction with endosomal Q-SNAREs allows the assembly of fusogenic trans-SNAREs leading to vesicle fusion (5). The C-Vps complex was also found to mediate the entry of Ebola virus (7), but the mechanism of action remains unknown.Our previous studies identified UV-radiation resistance-associated gene (UVRAG) as a positive regulator of the C-Vps complex, which interacts with C-Vps through its C2 domain (8). Deletion of UVRAG causes a C-Vps phenotype, and it blocks endosomal maturation and down-regulation of cell surface receptors targeted for lysosomal degradation (8). Furthermore, UVRAG has a unique activity in autophagy, where it forms a complex with Beclin1 and activates Beclin1-associated class III PI3K activity (9, 10). Our recent work further established that UVRAG patrols chromosomal stability and endoplasmic reticulum-Golgi homeostasis independent of autophagy (11, 12). Despite these findings, the functionality of UVRAG in a cell’s response to virus infection has not yet been examined. In this study, we demonstrate that UVRAG has a distinct role in mediating virus entry, working in concert with C-Vps and the endosomal SNAREs during late endocytic membrane fusion. We have also identified specific SNAREs and their interactions that are reprogrammed by the virus to assist in their entry and infection.