bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of Hepatitis C Virus Core Protein Multimerization and Membrane Envelopment: Revelation of a Cascade of Core-Membrane Interactions
Authors: Ai Li-Shuang , Lee Yu-Wen , Chen Steve S.-L. 
Published: July 2009

ABSTRACT

The molecular basis underlying hepatitis C virus (HCV) core protein maturation and morphogenesis remains elusive. We characterized the concerted events associated with core protein multimerization and interaction with membranes. Analyses of core proteins expressed from a subgenomic system showed that the signal sequence located between the core and envelope glycoprotein E1 is critical for core association with endoplasmic reticula (ER)/late endosomes and the core's envelopment by membranes, which was judged by the core's acquisition of resistance to proteinase K digestion. Despite exerting an inhibitory effect on the core's association with membranes, (Z-LL)
2
-ketone, a specific inhibitor of signal peptide peptidase (SPP), did not affect core multimeric complex formation, suggesting that oligomeric core complex formation proceeds prior to or upon core attachment to membranes. Protease-resistant core complexes that contained both innate and processed proteins were detected in the presence of (Z-LL)
2
-ketone, implying that core envelopment occurs after intramembrane cleavage. Mutations of the core that prevent signal peptide cleavage or coexpression with an SPP loss-of-function D219A mutant decreased the core's envelopment, demonstrating that SPP-mediated cleavage is required for core envelopment. Analyses of core mutants with a deletion in domain I revealed that this domain contains sequences crucial for core envelopment. The core proteins expressed by infectious JFH1 and Jc1 RNAs in Huh7 cells also assembled into a multimeric complex, associated with ER/late-endosomal membranes, and were enveloped by membranes. Treatment with (Z-LL)
2
-ketone or coexpression with D219A mutant SPP interfered with both core envelopment and infectious HCV production, indicating a critical role of core envelopment in HCV morphogenesis. The results provide mechanistic insights into the sequential and coordinated processes during the association of the HCV core protein with membranes in the early phase of virus maturation and morphogenesis.
The Carboxy-Terminal Tail of Human Cytomegalovirus (HCMV) US28 Regulates both Chemokine-Independent and Chemokine-Dependent Signaling in HCMV-Infected Cells
Authors: Stropes Melissa P. , Schneider Olivia D. , Zagorski William A. , Miller Jeanette L. C. , Miller William E. 
Published: July 2009

ABSTRACT
The human cytomegalovirus (HCMV)-encoded G-protein-coupled receptor (GPCR) US28 is a potent activator of a number of signaling pathways in HCMV-infected cells. The intracellular carboxy-terminal domain of US28 contains residues critical for the regulation of US28 signaling in heterologous expression systems; however, the role that this domain plays during HCMV infection remains unknown. For this study, we constructed an HCMV recombinant virus encoding a carboxy-terminal domain truncation mutant of US28, FLAG-US28/1-314, to investigate the role that this domain plays in US28 signaling. We demonstrate that US28/1-314 exhibits a more potent phospholipase C-β (PLC-β) signal than does wild-type US28, indicating that the carboxy-terminal domain plays an important role in regulating agonist-independent signaling in infected cells. Moreover, HMCV-infected cells expressing the US28/1-314 mutant exhibit a prolonged calcium signal in response to CCL5, indicating that the US28 carboxy-terminal domain also regulates agonist-dependent signaling. Finally, while the chemokine CX3CL1 behaves as an inverse agonist or inhibitor of constitutive US28 signaling to PLC-β, we demonstrate that CX3CL1 functions as an agonist with regard to US28-stimulated calcium release. This study is the first to demonstrate that the carboxy terminus of US28 controls US28 signaling in the context of HCMV infection and indicates that chemokines such as CX3CL1 can decrease constitutive US28 signals and yet simultaneously promote nonconstitutive US28 signals.
The Hepatitis C Virus Core Protein Contains a BH3 Domain That Regulates Apoptosis through Specific Interaction with Human Mcl-1
Authors: Mohd-Ismail Nur Khairiah , Deng Lin , Sukumaran Sunil Kumar , Yu Victor C. , Hotta Hak , Tan Yee-Joo 
Published: July 2009

ABSTRACT

The hepatitis C virus (HCV) core protein is known to modulate apoptosis and contribute to viral replication and pathogenesis. In this study, we have identified a Bcl-2 homology 3 (BH3) domain in the core protein that is essential for its proapoptotic property. Coimmunoprecipitation experiments showed that the core protein interacts specifically with the human myeloid cell factor 1 (Mcl-1), a prosurvival member of the Bcl-2 family, but not with other prosurvival members (Bcl-X
L
and Bcl-w). Moreover, the overexpression of Mcl-1 protects against core-induced apoptosis. By using peptide mimetics, core was found to release cytochrome
c
from isolated mitochondria when complemented with Bad. Thus, core is a bona fide BH3-only protein having properties similar to those of Noxa, a BH3-only member of the Bcl-2 family that binds preferentially to Mcl-1. There are three critical hydrophobic residues in the BH3 domain of the core protein, and they are essential for the proapoptotic property of the core protein. Furthermore, the genotype 1b core protein is more effective than the genotype 2a core protein in inducing apoptosis due to a single-amino-acid difference at one of these hydrophobic residues (residue 119). Replacing this residue in the J6/JFH-1 infectious clone (genotype 2a) with the corresponding amino acid in the genotype 1b core protein produced a mutant virus, J6/JFH-1(V119L), which induced significantly higher levels of apoptosis in the infected cells than the parental J6/JFH-1 virus. Furthermore, the core protein of J6/JFH-1(V119L), but not that of J6/JFH-1, interacted with Mcl-1 in virus-infected cells. Taken together, the core protein is a novel BH3-only viral homologue that contributes to the induction of apoptosis during HCV infection.
Molecular Mechanism of BST2/Tetherin Downregulation by K5/MIR2 of Kaposi's Sarcoma-Associated Herpesvirus
Authors: Mansouri Mandana , Viswanathan Kasinath , Douglas Janet L. , Hines Jennie , Gustin Jean , Moses Ashlee V. , Früh Klaus 
Published: July 2009

ABSTRACT
K3/MIR1 and K5/MIR2 of Kaposi's sarcoma-associated herpesvirus (KSHV) are viral members of the membrane-associated RING-CH (MARCH) ubiquitin ligase family and contribute to viral immune evasion by directing the conjugation of ubiquitin to immunostimulatory transmembrane proteins. In a quantitative proteomic screen for novel host cell proteins downregulated by viral immunomodulators, we previously observed that K5, as well as the human immunodeficiency virus type 1 (HIV-1) immunomodulator VPU, reduced steady-state levels of bone marrow stromal cell antigen 2 (BST2; also called CD317 or tetherin), suggesting that BST2 might be a novel substrate of K5 and VPU. Recent work revealed that in the absence of VPU, HIV-1 virions are tethered to the plasma membrane in BST2-expressing HeLa cells. By targeting BST2, K5 might thus similarly overcome an innate antiviral host defense mechanism. Here we establish that despite its type II transmembrane topology and carboxy-terminal glycosylphosphatidylinositol (GPI) anchor, BST2 represents a bona fide target of K5 that is downregulated during primary infection by and reactivation of KSHV. Upon exit of the protein from the endoplasmic reticulum, lysines in the short amino-terminal domain of BST2 are ubiquitinated by K5, resulting in rapid degradation of BST2. Ubiquitination of BST2 is required for degradation, since BST2 lacking cytosolic lysines was K5 resistant and ubiquitin depletion by proteasome inhibitors restored BST2 surface expression. Thus, BST2 represents the first type II transmembrane protein targeted by K5 and the first example of a protein that is both ubiquitinated and GPI linked. We further demonstrate that KSHV release is decreased in the absence of K5 in a BST2-dependent manner, suggesting that K5 contributes to the evasion of intracellular antiviral defense programs.
Selective-Advantage Profile of Human Immunodeficiency Virus Type 1 Integrase Mutants Explains In Vivo Evolution of Raltegravir Resistance Genotypes
Authors: Quercia Romina , Dam Elisabeth , Perez-Bercoff Danielle , Clavel François 
Published: July 2009

ABSTRACTThe emergence of human immunodeficiency virus type 1 resistance to raltegravir, an integrase strand transfer inhibitor, follows distinct and independent genetic pathways, among which the N155H and Q148HKR pathways are the most frequently encountered in treated patients. After prolonged viral escape, mutants of the N155H pathway are replaced by mutants of the Q148HKR pathway. We have examined the mechanisms driving this evolutionary pattern using an approach that assesses the selective advantage of site-directed mutant viruses as a function of drug concentration. These selective-advantage curves revealed that among single mutants, N155H had the highest and the widest (1 to 500 nM) selective-advantage profile. Despite the higher 50% inhibitory concentration, Q148H displayed a lower and narrower (10 to 100 nM) selective-advantage profile. Among double mutants, the highest and widest selective-advantage profile was seen with G140S+Q148H. This finding likely explains why N155H can be selected early in the course of RAL resistance evolution in vivo but is later replaced by genotypes that include Q148HKR.
Interactions between Viral and Prokaryotic Pathogens in a Mixed Infection with Cardiovirus and Mycoplasma
Authors: Lidsky Peter V. , Romanova Lyudmila I. , Kolesnikova Marina S. , Bardina Maryana V. , Khitrina Elena V. , Hato Stanleyson V. , van Kuppeveld Frank J. M. , Agol Vadim I. 
Published: July 2009

ABSTRACT

In the natural environment, animal and plant viruses often share ecological niches with microorganisms, but the interactions between these pathogens, although potentially having important implications, are poorly investigated. The present report demonstrates, in a model system, profound mutual effects of mycoplasma and cardioviruses in animal cell cultures. In contrast to mycoplasma-free cells, cultures contaminated with
Mycoplasma hyorhinis
responded to infection with encephalomyocarditis virus (EMCV), a picornavirus, but not with poliovirus (also a picornavirus), with a strong activation of a DNase(s), as evidenced by the TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) immunofluorescence assay and electrophoretic analysis of host DNA. This degradation was reminiscent of that observed upon apoptosis but was caspase independent, judging by the failure of the specific pan-caspase inhibitor Q-VD-OPh to prevent it. The electrophoretic mobility of the enzyme responsible for DNA degradation and dependence of its activity on ionic conditions strongly suggested that it was represented by a DNase(s) of mycoplasma origin. In cells not infected with EMCV, the relevant DNase was dormant. The possibility is discussed that activation of the mycoplasma DNase might be linked to a relatively early increase in permeability of plasma membrane of the infected cells caused by EMCV. This type of unanticipated virus-mycoplasma “cooperation” may exemplify the complexity of pathogen-host interactions under conditions when viruses and microorganisms are infecting the same host. In the course of the present study, it was also demonstrated that pan-caspase inhibitor zVAD(OMe).fmk strongly suppressed cardiovirus polyprotein processing, illustrating an additional pitfall in investigations of viral effects on the apoptotic system of host cells.
The critical elements of the patch management process
Authors: Gerace Thomas , Cavusoglu Huseyin 
Published: July 2009

Introduction

"After the flames from the slammer's attack were doused and the technology industry caught up on its lost sleep, we started asking questions. Why did this happen? Could we have prevented it? What can we do to keep such a thing from happening again?"
These are some of the questions that the security industry asks after every major security incident. Today most security incidents are caused by flaws in software, called vulnerabilities. It is estimated that there are as many as 20 flaws per thousand lines of software code. Computer Emergency Response Team/Coordination Center (CERT/CC) statistics reveal that the number of vulnerabilities reported has increased dramatically over the years, from only 171 in 1995 to 8064 in 2006. Along with vulnerabilities, the sophistication of attack tools has also advanced over time. Using the interconnected nature of the Internet and automated attack tools, attackers exploit software vulnerabilities at an alarming rate to cause serious damage to organizations.
Although the ultimate solution to fix software vulnerabilities is application of patches, until a few years ago the term "patch management" was not in the general vocabulary of even the most advanced information technology staff. Today, "patch management" is not only in the common vernacular of most IT staff, but it is also one of the most essential responsibilities of IT departments. Security threats stemming from the exploitation of vulnerabilities pose serious risks to corporations, including unauthorized access to systems, corruption or modification of data, and unavailability of system resources to authorized users. Systematically applying patches to vulnerable systems through effective patch management can effectively reduce the number of security lapses. It is estimated that 95% of security breaches could be prevented by keeping systems up-to-date with necessary patches. Though recognized as important for security, many organizations do not have a clear understanding of the elements of patch management and how these elements impact the success of the patch management process.
High dynamic range—a gateway for predictive ancient lighting
Authors: Gonçalves Alexandrino , Magalhães Luís , Moura João , Chalmers Alan 
Published: July 2009

In the last few years, the number of projects involving historical reconstruction has increased significantly. Recent technologies have proven a powerful tool for a better understanding of our cultural heritage through which to attain a glimpse of the environments in which our ancestors lived. However, to accomplish such a purpose, these reconstructions should be presented to us as they may really have been perceived by a local inhabitant, according to the illumination and materials used back then and, equally important, the characteristics of the human visual system.
The human visual system has a remarkable ability to adjust itself to almost all everyday scenarios. This is particularly evident in extreme lighting conditions, such as bright light or dark environments. However, a major portion of the visible spectra captured by our visual system cannot be represented in most display devices. High dynamic range imagery is a field of research which is developing techniques to correct such inaccuracies. This new viewing paradigm is perfectly suited for archaeological interpretation, since its high contrast and chromaticity can present us with an enhanced viewing experience, closer to what an inhabitant of that era may have seen.
In this article we present a case study of the reconstruction of a Roman site. We generate high dynamic range images of mosaics and frescoes from one of the most impressive monuments in the ruins of Conimbriga, Portugal, an ancient city of the Roman Empire. To achieve the requisite level of precision, in addition to having a precise geometric 3D model, it is crucial to integrate in the virtual simulation authentic physical data of the light used in the period under consideration. Therefore, in order to create a realistic physical-based environment, we use in our lighting simulations real data obtained from simulated Roman luminaries of that time.
Follicle ablation increases offspring size in a lizard with a low clutch frequency
Authors: Ji Xiang , Xia Yuan , Wang Zheng 
Published: July 2009

AbstractStudies of lizards and snakes have shown that an experimental reduction of offspring number sometimes, but not always, results in an increase in offspring size. We applied the “follicle ablation” technique to an oviparous lacertid lizard (Eremias argus) to test the hypothesis that offspring size can be easily altered by manipulating clutch size in species with a low clutch frequency. Our manipulation of clutch size had the effect of inducing variation in egg size in the first post-surgical clutch, with follicle-ablated females producing fewer larger eggs than did controls. Follicle-ablated females produced a second post-surgical clutch as normally as did controls. The proportional amount of resources allocated to reproduction did not shift seasonally in E. argus, but females normally switched from producing a larger number of smaller eggs early in the breeding season to a smaller number of larger eggs later in the season. Females used in this study never produce more than two clutches per breeding season. Therefore, our data validate the hypothesis tested. Our data also provide an inference that maximization of reproductive success could be achieved in females of E. argus by diverting a larger enough, rather than an extraordinarily high, fraction of the available energy to individual offspring in single reproductive episodes.
Modelling the range of Syrian spadefoot toad (Pelobates syriacus) with combination of GIS-based approaches
Authors: Serbinova Irina , Gavashelishvili Alexander , Tarkhnishvili David 
Published: July 2009

AbstractSyrian spadefoot toads (Pelobates syriacus) are found from Balkan Peninsula throughout the Caucasus, Middle East, and Northern Iran. However, the range of this species is sufficiently mapped only in Balkans. Based on the detailed mapping of the species in Georgia, we analysed the environmental factors influencing species occurrence and produced spatial models for the entire range. Nine models based on the logistic regression, discriminant function analysis, and classification tree analysis, all showed significant influence of the vegetation index and maximum summer temperature on the species distribution. The habitat suitability models based on the presence-only data (Mahalanobis distance estimation and Maximum Entropy approach) had a better performance than the models based on the presence-absence data. The habitat suitability models included two variables only, identified as significant in all preliminary analyses. The area identified as suitable by presence-only models strongly increases when a few environmental variables are included in the analysis. When only two variables are considered, the model predicted large areas north of the actual range. Competition with the related common spadefoot toad (P. fuscus) might have a role on the position of the northern limit of the range of P. syriacus. Within the predicted range, use of breeding sites is negatively associated with presence of fish. Breeding pond preferences of P. syriacus were particularly similar to those of the lake frog (Rana ridibunda), although the latter species uses appropriate habitats more extensively.
Habitat selection and range size of grass snakes Natrix natrix in an agricultural landscape in southern England
Authors: Reading Christopher , Jofré Gabriela 
Published: July 2009

AbstractThe range sizes and habitat preferences of nine adult European grass snakes (Natrix natrix) were determined from radio-tracking data obtained within a landscape of mixed deciduous woodland and pastoral fields in southern England. These data were analysed using RANGES7v0.81 software. Concave polygons resulted in overall individual range size estimates that varied between 0.18-9.41 ha. However, for individuals that were radio-tracked for more than one season, annual range size estimates ranged between 1.29 ha and 3.56 ha and some snakes shifted their range between seasons. Grass snakes showed a strong preference for habitat boundaries and interfaces and an avoidance of woodland, and fields that were used for grazing. The attributes common to habitats that snakes preferred were a combination of basking site availability and a close proximity to relatively dense vegetation that offered potential protection from predators. The attributes common to habitats that snakes avoided were a lack of basking sites in woodland, and cover, in fields. Grass snakes selected banks as hibernation sites, the majority of which were within woodland.
Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor–related protein
Authors: Suzuki Yasuhiro , Nagai Nobuo , Yamakawa Kasumi , Kawakami Junichi , Lijnen H. Roger , Umemura Kazuo 
Published: July 2009

Abstract
Tissue-type plasminogen activator (t-PA) is approved for treatment of ischemic stroke patients, but it increases the risk of intracranial bleeding (ICB). Previously, we have shown in a mouse stroke model that stromelysin-1 (matrix metalloproteinase-3 [MMP-3]) induced in endothelial cells was critical for ICB induced by t-PA. In the present study, using bEnd.3 cells, a mouse brain–derived endothelial cell line, we showed that MMP-3 was induced by both ischemic stress and t-PA treatment. This induction by t-PA was prevented by inhibition either of low-density lipoprotein receptor–related protein (LRP) or of nuclear factor-κB activation. LRP was up-regulated by ischemic stress, both in bEnd.3 cells in vitro and in endothelial cells at the ischemic damage area in the mouse stroke model. Furthermore, inhibition of LRP suppressed both MMP-3 induction in endothelial cells and the increase in ICB by t-PA treatment after stroke. These findings indicate that t-PA deteriorates ICB via MMP-3 induction in endothelial cells, which is regulated through the LRP/nuclear factor-κB pathway.
Defining prior therapy in myelodysplastic syndromes and criteria for relapsed and refractory disease: implications for clinical trial design and enrollment
Authors: Sekeres Mikkael A. , Steensma David P. 
Published: July 2009

Abstract
The recent approval of 3 drugs for the treatment of myelodysplastic syndromes (MDSs) has resulted in a revolution in therapeutic options that was absent a decade ago. At the same time, the changing MDS environment is raising new challenges in clinical trial design and defining new indications for MDS drugs. Many current trials still rely on IPSS-based enrollment criteria, despite the well-recognized limitations of the IPSS. Clinical trialists designing studies struggle with several important trial design challenges, including which patients constitute the “previously treated” and “relapsed/refractory” MDS populations, and how specifically to define disease “progression.” This article considers some of these issues as they relate to study design, including how to identify certain MDS populations and define disease progression.