bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determinants of the Hepatitis C Virus Nonstructural Protein 2 Protease Domain Required for Production of Infectious Virus
Authors: Dentzer Thomas G. , Lorenz Ivo C. , Evans Matthew J. , Rice Charles M. 
Published: October 2009

ABSTRACT
The hepatitis C virus (HCV) nonstructural protein 2 (NS2) is a dimeric multifunctional hydrophobic protein with an essential but poorly understood role in infectious virus production. We investigated the determinants of NS2 function in the HCV life cycle. On the basis of the crystal structure of the postcleavage form of the NS2 protease domain, we mutated conserved features and analyzed the effects of these changes on polyprotein processing, replication, and infectious virus production. We found that mutations around the protease active site inhibit viral RNA replication, likely by preventing NS2-3 cleavage. In contrast, alterations at the dimer interface or in the C-terminal region did not affect replication, NS2 stability, or NS2 protease activity but decreased infectious virus production. A comprehensive deletion and mutagenesis analysis of the C-terminal end of NS2 revealed the importance of its C-terminal leucine residue in infectious particle production. The crystal structure of the NS2 protease domain shows that this C-terminal leucine is locked in the active site, and mutation or deletion of this residue could therefore alter the conformation of NS2 and disrupt potential protein-protein interactions important for infectious particle production. These studies begin to dissect the residues of NS2 involved in its multiple essential roles in the HCV life cycle and suggest NS2 as a viable target for HCV-specific inhibitors.
Downregulation of the T-Cell Receptor by Human Immunodeficiency Virus Type 2 Nef Does Not Protect against Disease Progression
Authors: Feldmann Jérôme , Leligdowicz Aleksandra , Jaye Assan , Dong Tao , Whittle Hilton , Rowland-Jones Sarah L. 
Published: October 2009

ABSTRACTChronic immune activation is thought to play a major role in human immunodeficiency virus (HIV) pathogenesis, but the relative contributions of multiple factors to immune activation are not known. One proposed mechanism to protect against immune activation is the ability of Nef proteins from some HIV and simian immunodeficiency virus strains to downregulate the T-cell receptor (TCR)-CD3 complex of the infected cell, thereby reducing the potential for deleterious activation. HIV type 1 (HIV-1) Nef has lost this property. In contrast to HIV-1, HIV-2 infection is characterized by a marked disparity in the disease course, with most individuals maintaining a normal life span. In this study, we examined the relationship between the ability of HIV-2 Nef proteins to downregulate the TCR and immune activation, comparing progressors and nonprogressors. Representative Nef variants were isolated from 28 HIV-2-infected individuals. We assessed their abilities to downregulate the TCR from the surfaces of CD4 T cells. In the same individuals, the activation of peripheral lymphocytes was evaluated by measurement of the expression levels of HLA-DR and CD38. We observed a striking correlation of the TCR downregulation efficiency of HIV-2 Nef variants with immune activation in individuals with a low viral load. This strongly suggests that Nef expression can influence the activation state of the immune systems of infected individuals. However, the efficiency of TCR downregulation by Nef was not reduced in progressing individuals, showing that TCR downregulation does not protect against progression in HIV-2 infection.
Molecular Characterization of a Novel Gammaretrovirus in Killer Whales (
Orcinus orca
)
Authors: LaMere Sarah A. , St. Leger Judy A. , Schrenzel Mark D. , Anthony Simon J. , Rideout Bruce A. , Salomon Daniel R. 
Published: October 2009

ABSTRACT

There are currently no published data documenting the presence of retroviruses in cetaceans, though the occurrences of cancers and immunodeficiency states suggest the potential. We examined tissues from adult killer whales and detected a novel gammaretrovirus by degenerate PCR. Reverse transcription-PCR also demonstrated tissue and serum expression of retroviral mRNA. The full-length sequence of the provirus was obtained by PCR, and a TaqMan-based copy number assay did not demonstrate evidence of productive infection. PCR on blood samples from 11 healthy captive killer whales and tissues from 3 free-ranging animals detected the proviral DNA in all tissues examined from all animals. A survey of multiple cetacean species by PCR for
gag
,
pol
, and
env
sequences showed homologs of this virus in the DNA of eight species of delphinids, pygmy and dwarf sperm whales, and harbor porpoises, but not in beluga or fin whales. Analysis of the bottlenose dolphin genome revealed two full-length proviral sequences with 97.4% and 96.9% nucleotide identity to the killer whale gammaretrovirus. The results of single-cell PCR on killer whale sperm and Southern blotting are also consistent with the conclusion that the provirus is endogenous. We suggest that this gammaretrovirus entered the delphinoid ancestor's genome before the divergence of modern dolphins or that an exogenous variant existed following divergence that was ultimately endogenized. However, the transcriptional activity demonstrated in tissues and the nearly intact viral genome suggest a more recent integration into the killer whale genome, favoring the latter hypothesis. The proposed name for this retrovirus is killer whale endogenous retrovirus.
Reconstitution of the Ancestral Glycoprotein of Human Endogenous Retrovirus K and Modulation of Its Functional Activity by Truncation of the Cytoplasmic Domain
Authors: Hanke Kirsten , Kramer Philipp , Seeher Sandra , Beimforde Nadine , Kurth Reinhard , Bannert Norbert 
Published: October 2009

ABSTRACT
Endogenous retroviruses present in the human genome provide a rich record of ancient infections. All presently recognized elements, including the youngest and most intact proviruses of the human endogenous retrovirus K(HML-2) [HERV-K(HML-2)] family, have suffered postinsertional mutations during their time of chromosomal residence, and genes encoding the envelope glycoprotein (Env) have not been spared these mutations. In this study, we have, for the first time, reconstituted an authentic Env of a HERV-K(HML-2) provirus by back mutation of putative postinsertional amino acid changes of the protein encoded by HERV-K113. Aided by codon-optimized expression, we demonstrate that the reconstituted Env regained its ability to be incorporated into retroviral particles and to mediate entry. The original ancient HERV-K113 Env was synthesized as a moderately glycosylated gp95 precursor protein cleaved into surface and transmembrane (TM) subunits. Of the nine N-linked oligosaccharides, four are part of the TM subunit, contributing 15 kDa to its apparent molecular mass of 41 kDa. The carbohydrates, as well as the cytoplasmic tail, are critical for efficient intracellular trafficking, processing, stability, and particle incorporation. Whereas deletions of the carboxy-terminal 6 residues completely abrogated cleavage and virion association, more extensive truncations slightly enhanced incorporation but dramatically increased the ability to mediate entry of pseudotyped lentiviruses. Although the first HERV-K(HML-2) elements infected human ancestors about 30 million years ago, our findings indicate that their glycoproteins are in most respects remarkably similar to those of classical contemporary retroviruses and can still mediate efficient entry into mammalian cells.
Effects of Acute and Chronic Murine Norovirus Infections on Immune Responses and Recovery from Friend Retrovirus Infection
Authors: Ammann Christoph G. , Messer Ronald J. , Varvel Kimberly , DeBuysscher Blair L. , LaCasse Rachel A. , Pinto Amelia K. , Hasenkrug Kim J. 
Published: October 2009

ABSTRACT
Murine norovirus (MNV) is a highly infectious but generally nonpathogenic agent that is commonly found in research mouse colonies in both North America and Europe. In the present study, the effects of acute and chronic infections with MNV on immune responses and recovery from concurrent Friend virus (FV) infections were investigated. No significant differences in T-cell or NK-cell responses, FV-neutralizing antibody responses, or long-term recovery from FV infection were observed. We conclude that concurrent MNV infections had no major impacts on FV infections.
Importance of Covalent and Noncovalent SUMO Interactions with the Major Human Cytomegalovirus Transactivator IE2p86 for Viral Infection
Authors: Berndt Anja , Hofmann-Winkler Heike , Tavalai Nina , Hahn Gabriele , Stamminger Thomas 
Published: October 2009

ABSTRACT
The major transactivator protein IE2p86 of human cytomegalovirus (HCMV) has previously been shown to undergo posttranslational modification by the covalent attachment of SUMO proteins, termed SUMOylation, which occurs at two lysine residues located at amino acid positions 175 and 180. Mutation of the acceptor lysines resulted in the abrogation of IE2p86 SUMOylation in mammalian cells and a strong reduction of IE2p86-mediated transactivation. In this paper, we identify an additional SUMO interaction motif (SIM) within IE2p86, which mediates noncovalent binding to SUMO, as shown by yeast two-hybrid analyses. Transient-expression experiments revealed that an IE2p86 SIM mutant exhibited significantly reduced SUMOylation, strongly suggesting that noncovalent SUMO interactions affect the efficacy of covalent SUMO coupling. In order to define the relevance of IE2p86 SUMO interactions for viral replication, recombinant viruses originating from two different HCMV strains (AD169 and VR1814) were generated. Analysis of viruses expressing SUMOylation-negative IE2p86 revealed strongly impaired replication due to reduced viral DNA and protein accumulation, as well as diminished initiation of immediate-early gene expression. The additional introduction of the SIM mutation into the viral genome did not further compromise viral replication but resulted in altered expression of viral proteins at late times postinfection. In summary, this paper clearly shows that IE2p86 SUMOylation is necessary for efficient replication of the HCMV laboratory strain AD169 and the clinical isolate VR1814 and thus for the in vivo function of this viral transcription factor.
Insights into the Evolutionary History of an Emerging Livestock Pathogen: Porcine Circovirus 2
Authors: Firth Cadhla , Charleston Michael A. , Duffy Siobain , Shapiro Beth , Holmes Edward C. 
Published: October 2009

ABSTRACT

Porcine circovirus 2 (PCV2) is the primary etiological agent of postweaning multisystemic wasting syndrome (PMWS), one of the most economically important emerging swine diseases worldwide. Virulent PCV2 was first identified following nearly simultaneous outbreaks of PMWS in North America and Europe in the 1990s and has since achieved global distribution. However, the processes responsible for the emergence and spread of PCV2 remain poorly understood. Here, phylogenetic and cophylogenetic inferences were utilized to address key questions on the time scale, processes, and geographic diffusion of emerging PCV2. The results of these analyses suggest that the two genotypes of PCV2 (PCV2a and PCV2b) are likely to have emerged from a common ancestor approximately 100 years ago and have been on independent evolutionary trajectories since that time, despite cocirculating in the same host species and geographic regions. The patterns of geographic movement of PCV2 that we recovered appear to mimic those of the global pig trade and suggest that the movement of asymptomatic animals is likely to have facilitated the rapid spread of virulent PCV2 around the globe. We further estimated the rate of nucleotide substitution for PCV2 to be on the order of 1.2 × 10
−3
substitutions/site/year, the highest yet recorded for a single-stranded DNA virus. This high rate of evolution may allow PCV2 to maintain evolutionary dynamics closer to those of single-stranded RNA viruses than to those of double-stranded DNA viruses, further facilitating the rapid emergence of PCV2 worldwide.
Low-pain, high-gain multicore programming in Haskell
Authors: Al Zain Abdallah Deeb I. , Hammond Kevin , Berthold Jost , Trinder Phil , Michaelson Greg , Aswad Mustafa 
Published: October 2009

With the emergence of commodity multicore architectures, exploiting tightly-coupled parallelism has become increasingly important. Functional programming languages, such as Haskell, are, in principle, well placed to take advantage of this trend, offering the ability to easily identify large amounts of fine-grained parallelism. Unfortunately, obtaining real performance benefits has often proved hard to realise in practice.
This paper reports on a new approach using middleware that has been constructed using the Eden parallel dialect of Haskell. Our approach is "low pain" in the sense that the programmer constructs a parallel program by inserting a small number of higher-order algorithmic skeletons at key points in the program. It is "high gain" in the sense that we are able to get good parallel speedups. Our approach is unusual in that we do not attempt to use shared memory directly, but rather coordinate parallel computations using a message-passing implementation. This approach has a number of advantages. Firstly, coordination, i.e. locking and communication, is both confined to limited shared memory areas, essentially the communication buffers, and is also isolated within well-understood libraries. Secondly, the coarse thread granularity that we obtain reduces coordination overheads, so locks are normally needed only on (relatively large) messages, and not on individual data items, as is often the case for simple shared-memory implementations. Finally, cache coherency requirements are reduced since individual tasks do not share caches, and can garbage collect independently.
We report results for two representative computational algebra problems. Computational algebra is a challenging application area that has not been widely studied in the general parallelism community. Computational algebra applications have high computational demands, and are, in principle, often suitable for parallel execution, but usually display a high degree of irregularity in terms of both task and data structure. This makes it difficult to construct parallel applications that perform well in practice. Using our system, we are able to obtain both extremely good processor utilisation (97%) and very good absolute speedups (up to 7.7) on an eight-core machine.
Declarative aspects of memory management in the concurrent collections parallel programming model (abstract only)
Authors: Budimlic Zoran , Chandramowlishwaran Aparna M. , Knobe Kathleen , Lowney Geoff N. , Sarkar Vivek , Treggiari Leo 
Published: October 2009

Concurrent Collections (CnC) is a declarative parallel language that allows the application developer to express their parallel application as a collection of high-level computations called steps that communicate via single-assignment data structures called items.
A CnC program is specified in two levels. At the bottom level, an existing imperative language implements the computations within the individual computation steps. At the top level, CnC describes the relationships (ordering constraints) among the steps. The memory management mechanism of the existing imperative language manages data whose lifetime is within a computation step. A key limitation in the use of CnC for long-running programs is the lack of memory management and garbage collection for data items with lifetimes that are longer than a single computation step. Although the goal here is the same as that of classical garbage collection, the nature of problem and therefore nature of the solution is distinct. The focus of this paper is the memory management problem for these data items in CnC.
We introduce a new declarative slicing annotation for CnC that can be transformed into a reference counting procedure for memory management. Preliminary experimental results obtained from a Cholesky example show that our memory management approach can result in space reductions for CnC data items of up to 28x relative to the baseline case of standard CnC without memory management.
Determinants and Correlation of Systemic and Cervical Concentrations of Total IgA and IgG
Authors: Safaeian Mahboobeh , Kemp Troy , Falk Roni T. , Rodriguez Ana Cecilia , Hildesheim Allan , Williams Marcus , Porras Carolina , Herrero Rolando , Pinto Ligia A. 
Published: October 2009

Abstract
We compared systemic and cervical total IgA and IgG during the menstrual cycle among 154 women who attended clinic visits at follicular/early, periovulatory/mid, and luteal/late phases of menstrual cycle. Paired serum and cervical secretions were tested at each visit for total IgA and IgG using ELISA. Geometric mean titers for systemic IgA and IgG were 1.92 and 8.25 mg/mL, respectively. There were no differences in titers by menstrual cycle phase, neither were they correlated to cervical titers (ρ = 0.17 and 0.16, respectively). The lack of correlation between systemic and cervical total IgA and IgG suggests that systemic concentrations are not reflective of cervical levels. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2672–6)
Chromosome 3p12.3-p14.2 and 3q26.2-q26.32 Are Genomic Markers for Prognosis of Advanced Nasopharyngeal Carcinoma
Authors: Sheu Jim Jinn-Chyuan , Lee Chia-Huei , Ko Jenq-Yuh , Tsao George S.W. , Wu Chung-Chun , Fang Chih-Yeu , Tsai Fuu-Jen , Hua Chun-Hung , Chen Chi-Long , Chen Jen-Yang 
Published: October 2009

Abstract
Purpose: Nasopharyngeal carcinoma is an epithelial malignancy with a remarkable racial and geographic distribution. Previous cytogenetic studies have shown nasopharyngeal carcinoma to be characterized by gross genomic aberrations. However, identification of susceptible gene loci in advanced nasopharyngeal carcinoma has been poorly discussed.
Experimental Design: A genome-wide survey of gene copy number changes was initiated with two nasopharyngeal carcinoma cell lines by array-based comparative genomic hybridization analysis. These alterations were confirmed by a parallel analysis with the data from the gene expression microarray and were validated by quantitative PCR. Clinical association of the defined target genes was analyzed by fluorescence in situ hybridization on 48 metastatic tumors.
Results: A high percentage of genes were consistently altered in dosage and expression levels with gain on 3q26.2-q26.32 and losses on 3p12.3-p14.2 and 9p21.3-p23. Six candidate genes, GPR160 (3q26.2-q27), SKIL (3q26), ADAMTS9 (3p14.2-p14.3), LRIG1 (3p14), MPDZ (9p22-p24), and ADFP (9p22.1) were validated by quantitative PCR. Fluorescence in situ hybridization studies revealed amplification of GPR160 (in 25% of cases) and SKIL (33%); and deletion of ADAMTS9 (30%), LRIG1 (35%), MPDZ (15%), and ADFP (15%). Clinical association analyses indicated a poor survival rate with genetic alterations at the defined 3p deletion (P = 0.0012) and the 3q amplification regions (P = 0.0114).
Conclusion: The combined microarray technologies suggested novel candidate oncogenes, amplification of GPR160 and SKIL at 3q26.2-q26.32, and deletion of tumor suppressor genes ADAMTS9 and LRIG1 at 3p12.3-p14.2. Altered expression of these genes may be responsible for malignant progression and could be used as potential markers for nasopharyngeal carcinoma. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2709–16)
Obesity and Cancer: The Role of Dysfunctional Adipose Tissue
Authors: van Kruijsdijk Rob C.M. , van der Wall Elsken , Visseren Frank L.J. 
Published: October 2009

Abstract
Overweight and obesity are health problems of epidemic proportions, increasing the risk not only of cardiovascular disease and type 2 diabetes mellitus but also of various types of cancer. Obesity is strongly associated with changes in the physiological function of adipose tissue, leading to insulin resistance, chronic inflammation, and altered secretion of adipokines. Several of these factors, such as insulin resistance, increased levels of leptin, plasminogen activator inhibitor-1, and endogenous sex steroids, decreased levels of adiponectin, and chronic inflammation, are involved in carcinogenesis and cancer progression. This article reviews these mechanisms, focusing on adipose tissue dysfunction as a unifying causal factor. Although understanding of the link between obesity and cancer might provide therapeutic targets, preventing overweight and obesity still remains number one priority. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2569–78)
Soy Intake is Associated with Increased 2-Hydroxylation and Decreased 16α-Hydroxylation of Estrogens in Asian-American Women
Authors: Fuhrman Barbara J. , Pfeiffer Ruth , Xu Xia , Wu Anna H. , Korde Larissa , Gail Mitchell H. , Keefer Larry K. , Veenstra Timothy D. , Hoover Robert N. , Ziegler Regina G. 
Published: October 2009

AbstractIntroduction: In Asian and Asian-American women, soy consumption is associated with reduced breast cancer risk, perhaps due to its effects on estrogen production or metabolism. In a sample of Asian-American women, we investigated the associations of usual adult soy intake with the urinary concentrations of 15 estrogens and estrogen metabolites (EM) measured using liquid chromatography-tandem mass spectrometry.Methods: Participants included 430 Chinese-American, Japanese-American, and Filipino-American women, ages 20 to 55 years, and living in San Francisco-Oakland (California), Los Angeles (California), or Oahu (Hawaii). They were postmenopausal (n = 167) or premenopausal in luteal phase (n = 263) when 12-hour urine samples were collected. Robust linear regression was used to assess soy tertiles as predictors of log-transformed EM measures. Individual and grouped EM were considered as concentrations (pmol/mg creatinine) and as percentages of total EM (%EM).Results: Factor analysis confirmed that EM groups defined by metabolic pathways appropriately captured covariation in EM profiles. Total EM concentrations were not significantly associated with soy in premenopausal or postmenopausal women. Among all women, %2-hydroxylated EM and %4-hydroxylation pathway EM were 16% higher (Ptrend = 0.02) and 19% higher (Ptrend = 0.03) in the highest versus lowest soy tertiles, respectively. In contrast, 16% hydroxylated EM were 11% lower (Ptrend &lt; 0.01). Results were consistent across ethnic and menopausal groups and after adjustment for westernization measured by birthplace (Asia or United States).Discussion: Findings suggest that regular soy intake is associated with increased ratios of 2:16-pathway EM and with higher relative levels of 4-hydroxylated EM. The observed variations in estrogen metabolism might modify breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2751–60)