Specific inhibition of hepatitis C virus replication by cyclosporin A

The difficulty in eradicating hepatitis C virus (HCV) infection is attributable to the limited treatment options against the virus. Recently, cyclosporin A (CsA), a widely used immunosuppressive drug, has been reported to be effective against HCV infection [J. Gastroenterol. 38 (2003) 567], although little is understood about the mechanism of its action against HCV. In this study, we investigated the anti-viral effects of CsA using an HCV replicon system. Human hepatoma Huh7 cells were transfected with an HCV replicon expressing a chimeric gene encoding a luciferase reporter and neomycin phosphotransferase (Huh7/Rep-Feo). Treatment of the Huh7/Rep-Feo cells with CsA resulted in suppression of the replication of the HCV replicon in a dose-dependent manner, with an IC50 of approximately 0.5 microg/ml. There were no changes in the rate of cell growth or viability, suggesting that the effect of CsA against HCV is specific and not due to cytotoxicity. In contrast, FK506, another immunosuppressive drug, did not suppress HCV replication. CsA did not activate interferon-stimulated gene responses, suggesting that its action is independent of that of interferon. In conclusion, CsA inhibits HCV replication in vitro specifically at clinical concentrations. Further defining its mode of action against HCV replication potentially may be important for identifying novel molecular targets to treat HCV infection.     

Discovery of potential diagnostic and vaccine antigens in herpes simplex virus 1 and 2 by proteome-wide antibody profiling

Routine serodiagnosis of herpes simplex virus (HSV) infections is currently performed using recombinant glycoprotein G (gG) antigens from herpes simplex virus 1 (HSV-1) and HSV-2. This is a single-antigen test and has only one diagnostic application. Relatively little is known about HSV antigenicity at the proteome-wide level, and the full potential of mining the antibody repertoire to identify antigens with other useful diagnostic properties and candidate vaccine antigens is yet to be realized. To this end we produced HSV-1 and -2 proteome microarrays in Escherichia coli and probed them against a panel of sera from patients serotyped using commercial gG-1 and gG-2 (gGs for HSV-1 and -2, respectively) enzyme-linked immunosorbent assays. We identified many reactive antigens in both HSV-1 and -2, some of which were type specific (i.e., recognized by HSV-1- or HSV-2-positive donors only) and others of which were nonspecific or cross-reactive (i.e., recognized by both HSV-1- and HSV-2-positive donors). Both membrane and nonmembrane virion proteins were antigenic, although type-specific antigens were enriched for membrane proteins, despite being expressed in E. coli.     

Predetermined Flake Production at the Lower/Middle Paleolithic Boundary: Yabrudian Scraper-Blank Technology

While predetermined débitage technologies are recognized beginning with the middle Acheulian, the Middle Paleolithic is usually associated with a sharp increase in their use. A study of scraper-blank technology from three Yabrudian assemblages retrieved from the early part of the Acheulo-Yabrudian complex of Tabun Cave (ca. 415–320 kyr) demonstrates a calculated and preplanned production, even if it does not show the same complexity and elaboration as in the Levallois technology. These scraper dominated assemblages show an organization of production based on an intensive use of predetermination blank technology already in place at the end of the Lower Paleolithic of the Levant. These results provide a novel perspective on the differences and similarities between the Lower and Middle Paleolithic industries. We suggest that there was a change in the paradigm in the way hominins exploited stone tools: in many Middle Paleolithic assemblages the potential of the stone tools for hafting was a central feature, in the Lower Paleolithic ergonometric considerations of manual prehension were central to the design of blanks and tools.     

On estimation of phenetic relationships of Altai Osmans (<Emphasis Type="Italic">Oreoleuciscus</Emphasis>, Cyprinidae) from three lakes in Mongolia by skull characters

By four meristic and 14 morphometric characters of the skull the phenetic relationships of Altai Osmans of the genus Oreoleuciscus from lakes Ust-Nur (the Selenga Basin), Sangiyn-Dalai-Nur (the Khangai Highland), and Orog-Nur (Lake Valley) are estimated. Principal components analysis is performed. No interpopulational differences by the set of meristic characters are found. By the set of morphometric characters the specimens from Lake Ust-Nur in the space of principal components are separated from specimens from two other lakes while the distributions of specimens from Lake Sangiyn-Dalai-Nur and Orog-Nur overlap. With consideration of estimates of similarity in the structure of interpopulational differences it is assumed that separation of the phyletic line common for populations of lakes Ust-Nur and Orog-Nur from the phyletic line of population of Lake Sangiyn-Dalai-Nur preceded separation of phyletic lines of populations from lakes Ust-Nur and Orog-Nur.     

Macro- and microscopic morphology of the flank scales of families Lutjanidae and Serranidae from the Persian Gulf Coral Reefs (Teleosts: Perciformes)

Macro- and microscopic characteristics of flank scales for 12 species were investigated from the Persian Gulf Coral Reefs. In Lutjanus argentimaculatus and L. russellii (family Lutjanidae), the scales of different flank regions were not different, while four characters showed variation in the scale of L. lutjanus i.e., scale shape (pentagonal, hexagonal and square), anterior margin (waved, scalloped and smooth), focus shape (circular and oblong) and focus position (postero-central and central), displayed variation. Scale type (ctenoid) and posterior margin (transforming ctenii) did not show variation and could be considered to be specific in this family. In Epinephelus chlorostigma (family Serranidae), the scales of flank regions did not display variation, while in E. areolatus, E. diacanthus and E. radiates, the scales showed considerable variation. The most variable characters were scale shape, posterior margin and focus shape. Therefore, in fish systematics studies on the base of scale, it is particularly important to compare scales from the same flank regions. Also, some criteria such as size-dependent alternation, ontogenetic changes and variation between flank regions, should be considered. This study supports the potential of scale morphology to help for the understanding of fish diversity in the coral reef ecosystem.     

The Therapeutic Potential of PI3K/Akt/mTOR Inhibitors in Breast Cancer: Rational and Progress

Breast cancer (BC) is the most commonly diagnosed cancer in women. The PI3K/AKT/mTOR pathway is among the most frequently dysregulated pathways in patients with BC. The activation of this pathway is associated with increased cell growth and clinical outcome, and its overexpression is associated with a poor prognosis. It has been proposed that it may be of importance as a potential therapeutic target in the treatment of BC. The aim of current review is to provide an overview of the potential utility of PI3K/Akt/mTOR inhibitors in patients with BC, with particular emphasis on recent preclinical and clinical studies. J. Cell. Biochem. 119: 213–222, 2018. © 2017 Wiley Periodicals, Inc.     

Reducing GBA2 Activity Ameliorates Neuropathology in Niemann-Pick Type C Mice

The enzyme glucocerebrosidase (GBA) hydrolyses glucosylceramide (GlcCer) in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk factor for Parkinsonism. Disturbed metabolism of GlcCer may therefore play a role in neuropathology. Besides lysosomal GBA, cells also contain a non-lysosomal glucosylceramidase (GBA2). Given that the two β-glucosidases share substrates, we speculated that over-activity of GBA2 during severe GBA impairment might influence neuropathology. This hypothesis was studied in Niemann-Pick type C (Npc1 ^-/-) mice showing secondary deficiency in GBA in various tissues. Here we report that GBA2 activity is indeed increased in the brain of Npc1 ^-/- mice. We found that GBA2 is particularly abundant in Purkinje cells (PCs), one of the most affected neuronal populations in NPC disease. Inhibiting GBA2 in Npc1 ^-/- mice with a brain-permeable low nanomolar inhibitor significantly improved motor coordination and extended lifespan in the absence of correction in cholesterol and ganglioside abnormalities. This trend was recapitulated, although not to full extent, by introducing a genetic loss of GBA2 in Npc1 ^-/- mice. Our findings point to GBA2 activity as therapeutic target in NPC.