bluuebunny/crossref_metadata_2025_split huggingface dataset:
Current and Future Pharmacotherapies of Premature Ejaculation
Authors: Hellstrom Wayne J.G. 
Published: August 2006

ABSTRACT

Introduction
There are currently no oral or topical agents approved by government regulation agencies for the management of premature ejaculation (PE).

Aim
To review pharmacologic therapies for treatment of PE.

Methods
The Sexual Medicine Society of North America hosted a State of the Art Conference on Premature Ejaculation on June 24–26, 2005 in collaboration with the University of South Florida. The purpose was to have an open exchange of contemporary research and clinical information on PE.

Main Outcome Measure
Data were obtained by extensive examination of peer-reviewed published literature.

Results
Chronic administration of selective serotonin reuptake inhibitors (SSRIs) is associated with an increased adverse event profile encompassing dry mouth, nausea, drowsiness, and reduced libido. Their use may also facilitate the development of other sexual dysfunctions, such as anejaculation and erectile dysfunction (ED). Phosphodiesterase-5 (PDE-5) inhibitors have also been investigated for the management of PE, as an indirect consequence of their ability to prolong erections. Trials have found PDE-5 inhibitors to be appropriate for men with PE secondary to ED, or when they are used in conjunction with other agents such as SSRIs. Trials of topical formulations that contain either anesthetic agents or other ingredients report significant increases in ejaculatory latency times; however, long-term safety and efficacy studies are lacking. New agents are being developed specifically for the management of PE. Among these are a topical formulation and numerous oral agents. Only one agent—dapoxetine hydrochloride (DPX)—has undergone Phase III trials. DPX is a serotonin transport inhibitor (STI) with a pharmacokinetic profile conducive to on-demand dosing for the management of PE. Unlike the current oral agents, DPX has a rapid onset of action and is effective from the first dose.

Conclusions
Well-designed clinical trials utilizing appropriate outcome measurements are needed to provide safe and effective pharmacologic options for men with PE.
A descriptive analysis of producers’ attitudes toward biotechnology: a five‐state comparison
Authors: Lawson Michael E. , Stover Ronald , Hirai Satoko 
Published: August 2006

AbstractThis paper lists the results of a survey randomly administered to traditional and organic agricultural producers in five midwestern states. One of the purposes of the survey was to compare these producers in terms of their beliefs regarding the practical challenges in the use of genetically modified organisms (GMOs) and their attitudes and values about GMOs. Results indicated that while the traditional producers generally represented a homogenous group in terms of these criteria, there were some marked differences visa via the organic producers.
Transmission of Elk and Deer Prions to Transgenic Mice
Authors: Tamgüney Gültekin , Giles Kurt , Bouzamondo-Bernstein Essia , Bosque Patrick J. , Miller Michael W. , Safar Jiri , DeArmond Stephen J. , Prusiner Stanley B. 
Published: August 2006

ABSTRACT

Chronic wasting disease (CWD) is a fatal prion disease in deer and elk. Unique among the prion diseases, it is transmitted among captive and free-ranging animals. To facilitate studies of the biology of CWD prions, we generated five lines of transgenic (Tg) mice expressing prion protein (PrP) from Rocky Mountain elk (
Cervus elaphus nelsoni
), denoted Tg(ElkPrP), and two lines of Tg mice expressing PrP common to white-tailed deer (
Odocoileus virginianus
) and mule deer (
Odocoileus hemionus
), denoted Tg(DePrP). None of the Tg(ElkPrP) or Tg(DePrP) mice exhibited spontaneous neurologic dysfunction at more than 600 days of age. Brain samples from CWD-positive elk, white-tailed deer, and mule deer produced disease in Tg(ElkPrP) mice between 180 and 200 days after inoculation and in Tg(DePrP) mice between 300 and 400 days. One of eight cervid brain inocula transmitted disease to Tg(MoPrP)4053 mice overexpressing wild-type mouse PrP-A in ∼540 days. Neuropathologic analysis revealed abundant PrP amyloid plaques in the brains of ill mice. Brain homogenates from symptomatic Tg(ElkPrP) mice produced disease in 120 to 190 days in Tg(ElkPrP) mice. In contrast to the Tg(ElkPrP) and Tg(DePrP) mice, Tg mice overexpressing human, bovine, or ovine PrP did not develop prion disease after inoculation with CWD prions from among nine different isolates after >500 days. These findings suggest that CWD prions from elk, mule deer, and white-tailed deer can be readily transmitted among these three cervid species.
Gender Susceptibility to Chronic Hepatitis C Virus Infection Associated with Interleukin 10 Promoter Polymorphism
Authors: Paladino Natalia , Fainboim Hugo , Theiler Graciela , Schroder Teresa , Muñoz Alberto Eduardo , Flores Ana Claudia , Galdame Omar , Fainboim Leonardo 
Published: August 2006

ABSTRACTElevated levels of interleukin 10 (IL-10) were previously described for chronically hepatitis C virus (HCV)-infected patients. We determined by a sequence-specific oligonucleotide probing technique the IL-10 promoter genotypes in 286 Argentinean HCV patients grouped according to disease outcome. The GG genotype (position −1082) is known to be associated with high IL-10 production, GA is considered an intermediate producer, and AA is associated with low IL-10 production. We found an increase in frequency of the GG genotype in female patients who do not eliminate the virus (RNA+). In these patients, the GG frequency was 0.19, versus 0.10 in controls (P= 0.03). This association became more significant in those RNA+female patients with elevated hepatic transaminases (GG frequency of 0.25;P= 0.0013). Additionally, this genotype frequency was higher in noncirrhotic female patients than in controls (GG frequency for noncirrhotic female patients was 0.31;P= 0.009). In RNA−patients, the GA frequency was elevated compared with that in controls (GA frequency of 0.76 in RNA−patients versus 0.48 in controls;P= 0.01), that in all HCV patients (GA frequency of 0.43;P= 0.001), and that in RNA+patients (GA frequency of 0.40;P= 0.0005). We conclude that a gender effect is observed with women carrying the GG high IL-10 producer genotype. The higher levels of IL-10 present in those individuals are associated with a higher risk of an inefficient clearance of the HCV and the development of a chronic HCV infection together with a lower risk of progression to cirrhosis in female patients.
Oligomerization of Hantavirus Nucleocapsid Protein: Analysis of the N-Terminal Coiled-Coil Domain
Authors: Alminaite Agne , Halttunen Vera , Kumar Vibhor , Vaheri Antti , Holm Liisa , Plyusnin Alexander 
Published: August 2006

ABSTRACT

Hantaviruses constitute a genus in the family
Bunyaviridae
. They are enveloped negative-strand RNA viruses with a tripartite genome encoding the nucleocapsid (N) protein, the two surface glycoproteins Gn and Gc, and an RNA-dependent RNA polymerase. The N protein is the most abundant component of the virion; it encapsidates genomic RNA segments forming ribonucleoproteins and participates in genome transcription and replication as well as virus assembly. In the course of RNA encapsidation, N protein forms intermediate trimers via head-to-head and tail-to-tail interactions. We analyzed the amino-terminal trimerization domain (amino acid residues 1 to 77) of Tula hantavirus using computer modeling, mammalian two-hybrid assay, and immunofluorescence assay. The results obtained were consistent with the existence of an antiparallel coiled-coil stabilized by interactions between hydrophobic residues. Residues L44, V51, and L58 were important for the N-N interaction; other residues, e.g., L25 and V32, also made a contribution, albeit a modest one. Our alignments of the N-terminal domain of the hantaviral N proteins suggest the coiled-coil structure, and hence the mode of N-protein oligomerization, is conserved among hantaviruses.
Inhibition of the Type I Interferon Response by the Nucleoprotein of the Prototypic Arenavirus Lymphocytic Choriomeningitis Virus
Authors: Martínez-Sobrido Luis , Zúñiga Elina I. , Rosario Debralee , García-Sastre Adolfo , de la Torre Juan Carlos 
Published: August 2006

ABSTRACTThe prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a formidable battle horse for the study of viral immunology, as well as viral persistence and associated diseases. Investigations with LCMV have uncovered basic mechanisms by which viruses avoid elimination by the host adaptive immune response. In this study we show that LCMV also disables the host innate defense by interfering with beta interferon (IFN-β) production in response to different stimuli, including infection with Sendai virus and liposome-mediated DNA transfection. Inhibition of IFN production in LCMV-infected cells was caused by an early block in the IFN regulatory factor 3 (IRF-3) activation pathway. This defect was restored in cells cured of LCMV, indicating that one or more LCMV products are responsible for the inhibition of IRF-3 activation. Using expression plasmids encoding individual LCMV proteins, we found that expression of the LCMV nucleoprotein (NP) was sufficient to inhibit both IFN production and nuclear translocation of IRF-3. To our knowledge, this is the first evidence of an IFN-counteracting viral protein in theArenaviridaefamily. Inhibition of IFN production by the arenavirus NP is likely to be a determinant of virulence in vivo.
Extremely Low Exposure of a Community to Severe Acute Respiratory Syndrome Coronavirus: False Seropositivity due to Use of Bacterially Derived Antigens
Authors: Leung D. T. M. , van Maren W. W. C. , Chan F. K. L. , Chan W. S. , Lo A. W. I. , Ma C. H. , Tam F. C. H. , To K. F. , Chan P. K. S. , Sung J. J. Y. , Lim P. L. 
Published: August 2006

ABSTRACTEstimates of seropositivity to a new infectious agent in a community are useful to public health. For severe acute respiratory syndrome (SARS), the figures are conflicting. Herein, we screened 12,000 people in a community stricken by SARS 10 months previously and found 53 individuals (0.44%) who had immunoglobulin G antibodies to the SARS coronavirus (SARS-CoV) nucleocapsid (N) produced in bacteria. However, only seven of these (group 1) had sera which also reacted with the native N antigen expressed in SARS-CoV-infected Vero cells, N-transfected 293T cells, and tissues of infected SARS patients. Of these, six individuals had had SARS previously. The remaining person, as well as the 46 other individuals (group 2), were healthy and had no history of SARS. Group 1 antibodies recognized epitopes located slightly differently in N from those of group 2 antibodies, and a mouse hybridoma antibody resembling the former type was generated. Unusually, group 2 antibodies appeared to recognize cross-reactive bacterial epitopes that presumably were posttranslationally modified in eukaryotes and hence were probably not induced by SARS-CoV or related coronaviruses but rather by bacteria. The N antigen is thus highly unique. The extremely low rate (0.008%) of asymptomatic SARS infection found attests to the high virulence of the SARS-CoV virus.
Modulation of the Unfolded Protein Response by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein
Authors: Chan Ching-Ping , Siu Kam-Leung , Chin King-Tung , Yuen Kwok-Yung , Zheng Bojian , Jin Dong-Yan 
Published: August 2006

ABSTRACT
Perturbation of the function of endoplasmic reticulum (ER) causes stress leading to the activation of cell signaling pathways known as the unfolded protein response (UPR). Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) uses ER as a site for synthesis and processing of viral proteins. In this report, we demonstrate that infection with SARS-CoV induces the UPR in cultured cells. A comparison with M, E, and NSP6 proteins indicates that SARS-CoV spike (S) protein sufficiently induces transcriptional activation of several UPR effectors, including glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein. A substantial amount of S protein accumulates in the ER. The expression of S protein exerts different effects on the three major signaling pathways of the UPR. Particularly, it induces GRP78/94 through PKR-like ER kinase but has no influence on activating transcription factor 6 or X box-binding protein 1. Taken together, our findings suggest that SARS-CoV S protein specifically modulates the UPR to facilitate viral replication.
Amino Acids in the Basic Domain of Epstein-Barr Virus ZEBRA Protein Play Distinct Roles in DNA Binding, Activation of Early Lytic Gene Expression, and Promotion of Viral DNA Replication
Authors: Heston Lee , El-Guindy Ayman , Countryman Jill , Dela Cruz Charles , Delecluse Henri-Jacques , Miller George 
Published: August 2006

ABSTRACT
The ZEBRA protein of Epstein-Barr virus (EBV) drives the viral lytic cycle cascade. The capacity of ZEBRA to recognize specific DNA sequences resides in amino acids 178 to 194, a region in which 9 of 17 residues are either lysine or arginine. To define the basic domain residues essential for activity, a series of 46 single-amino-acid-substitution mutants were examined for their ability to bind ZIIIB DNA, a high-affinity ZEBRA binding site, and for their capacity to activate early and late EBV lytic cycle gene expression. DNA binding was obligatory for the protein to activate the lytic cascade. Nineteen mutants that failed to bind DNA were unable to disrupt latency. A single acidic replacement of a basic amino acid destroyed DNA binding and the biologic activity of the protein. Four mutants that bound weakly to DNA were defective at stimulating the expression of Rta, the essential first target of ZEBRA in lytic cycle activation. Four amino acids, R183, A185, C189, and R190, are likely to contact ZIIIB DNA specifically, since alanine or valine substitutions at these positions drastically weakened or eliminated DNA binding. Twenty-three mutants were proficient in binding to ZIIIB DNA. Some DNA binding-proficient mutants were refractory to supershift by BZ-1 monoclonal antibody (epitope amino acids 214 to 230), likely as the result of the increased solubility of the mutants. Mutants competent to bind DNA could be separated into four functional groups: the wild-type group (eight mutants), a group defective at activating Rta (five mutants, all with mutations at the S186 site), a group defective at activating EA-D (three mutants with the R179A, S186T, and K192A mutations), and a group specifically defective at activating late gene expression (seven mutants). Three late mutants, with a Y180A, Y180E, or K188A mutation, were defective at stimulating EBV DNA replication. This catalogue of point mutants reveals that basic domain amino acids play distinct functions in binding to DNA, in activating Rta, in stimulating early lytic gene expression, and in promoting viral DNA replication and viral late gene expression. These results are discussed in relationship to the recently solved crystal structure of ZEBRA bound to an AP-1 site.
Genome of Horsepox Virus
Authors: Tulman E. R. , Delhon G. , Afonso C. L. , Lu Z. , Zsak L. , Sandybaev N. T. , Kerembekova U. Z. , Zaitsev V. L. , Kutish G. F. , Rock D. L. 
Published: August 2006

ABSTRACTHere we present the genomic sequence of horsepox virus (HSPV) isolate MNR-76, an orthopoxvirus (OPV) isolated in 1976 from diseased Mongolian horses. The 212-kbp genome contained 7.5-kbp inverted terminal repeats and lacked extensive terminal tandem repetition. HSPV contained 236 open reading frames (ORFs) with similarity to those in other OPVs, with those in the central 100-kbp region most conserved relative to other OPVs. Phylogenetic analysis of the conserved region indicated that HSPV is closely related to sequenced isolates of vaccinia virus (VACV) and rabbitpox virus, clearly grouping together these VACV-like viruses. Fifty-four HSPV ORFs likely represented fragments of 25 orthologous OPV genes, including in the central region the only known fragmented form of an OPV ribonucleotide reductase large subunit gene. In terminal genomic regions, HSPV lacked full-length homologues of genes variably fragmented in other VACV-like viruses but was unique in fragmentation of the homologue of VACV strain Copenhagen B6R, a gene intact in other known VACV-like viruses. Notably, HSPV contained in terminal genomic regions 17 kbp of OPV-like sequence absent in known VACV-like viruses, including fragments of genes intact in other OPVs and approximately 1.4 kb of sequence present only in cowpox virus (CPXV). HSPV also contained seven full-length genes fragmented or missing in other VACV-like viruses, including intact homologues of the CPXV strain GRI-90 D2L/I4R CrmB and D13L CD30-like tumor necrosis factor receptors, D3L/I3R and C1L ankyrin repeat proteins, B19R kelch-like protein, D7L BTB/POZ domain protein, and B22R variola virus B22R-like protein. These results indicated that HSPV contains unique genomic features likely contributing to a unique virulence/host range phenotype. They also indicated that while closely related to known VACV-like viruses, HSPV contains additional, potentially ancestral sequences absent in other VACV-like viruses.
Translocation of
Tomato Bushy Stunt Virus
P19 Protein into the Nucleus by ALY Proteins Compromises Its Silencing Suppressor Activity
Authors: Canto Tomas , Uhrig Joachim F. , Swanson Maud , Wright Kathryn M. , MacFarlane Stuart A. 
Published: August 2006

ABSTRACT

The P19 protein of
Tomato bushy stunt virus
is a potent suppressor of RNA silencing and, depending on the host species, is required for short- and long-distance virus movement and symptom production. P19 interacts with plant ALY proteins and relocalizes a subset of these proteins from the nucleus to the cytoplasm. Here we showed that coexpression by agroinfiltration in
Nicotiana benthamiana
of P19 and the subset of ALY proteins that are not relocalized from the nucleus interfered with the ability of P19 to suppress RNA silencing. We demonstrated that this interference correlates with the relocation of P19 from the cytoplasm into the nucleus, and by constructing and analyzing chimeric ALY genes, we showed that the C-terminal part of the central, RNA recognition motif of ALY is responsible for interaction with P19, relocalization or nonrelocalization of ALY, and inhibition of silencing suppression by P19. We studied the interaction of ALY and P19 by using the technique of bimolecular fluorescence complementation to show that these proteins associate physically in the nucleus but not detectably in the cytoplasm, and we present a model to explain the dynamics of this interaction.
Complete Genome Sequence of the Broad Host Range Single-Stranded RNA Phage PRR1 Places It in the
Levivirus
Genus with Characteristics Shared with Alloleviviruses
Authors: Ruokoranta Tanja M. , Grahn A. Marika , Ravantti Janne J. , Poranen Minna M. , Bamford Dennis H. 
Published: August 2006

ABSTRACT

Single-stranded RNA (ssRNA) bacteriophages of the family
Leviviridae
infect gram-negative bacteria. They are restricted to a single host genus. Phage PRR1 is an exception, having a broad host range due to the promiscuity of the receptor encoded by the IncP plasmid. Here we report the complete genome sequence of PRR1. Three proteins homologous with those of other ssRNA phages, i.e., maturation, coat, and replicase proteins, were identified. A fourth protein has a lysis function. Comparison of PRR1 with other members of the
Leviviridae
family places PRR1 in the genus
Levivirus
with some characteristics more similar to those of members of the genus
Allolevivirus
.
The Virion Host Shutoff Protein (U
L
41) of Herpes Simplex Virus 1 Is an Endoribonuclease with a Substrate Specificity Similar to That of RNase A
Authors: Taddeo Brunella , Roizman Bernard 
Published: August 2006

ABSTRACT

Earlier, our laboratory reported that purified glutathione
S
-transferase-virion host shutoff (GST-
vhs
) protein exhibited endoribonucleolytic activity in in vitro assays using as substrates in vitro-transcribed regions of IEX-1 mRNA. Here, we report that studies of the cleavage patterns of synthetic RNA oligonucleotides defined the activity of GST-
vhs
as being similar to that of RNase A. Thus, GST-
vhs
cleaved the RNA at the 3′ end of single-stranded cytidine and uridine residues. Since the GST-m
vhs
nuclease-defective mutant protein failed to cleave the synthetic RNAs, the results unambiguously attribute the activity to
vhs
.
Vaccinia Virus Entry into Cells via a Low-pH-Dependent Endosomal Pathway
Authors: Townsley Alan C. , Weisberg Andrea S. , Wagenaar Timothy R. , Moss Bernard 
Published: August 2006

ABSTRACT
Previous studies established that vaccinia virus could enter cells by fusion with the plasma membrane at neutral pH. However, low pH triggers fusion of vaccinia virus-infected cells, a hallmark of viruses that enter by the endosomal route. Here, we demonstrate that entry of mature vaccinia virions is accelerated by brief low-pH treatment and severely reduced by inhibitors of endosomal acidification, providing evidence for a predominant low-pH-dependent endosomal pathway. Entry of vaccinia virus cores into the cytoplasm, measured by expression of firefly luciferase, was increased more than 10-fold by exposure to a pH of 4.0 to 5.5. Furthermore, the inhibitors of endosomal acidification bafilomycin A1, concanamycin A, and monensin each lowered virus entry by more than 70%. This reduction was largely overcome by low-pH-induced entry through the plasma membrane, confirming the specificities of the drugs. Entry of vaccinia virus cores with or without brief low-pH treatment was visualized by electron microscopy of thin sections of immunogold-stained cells. Although some virus particles fused with the plasma membrane at neutral pH, 30 times more fusions and a greater number of cytoplasmic cores were seen within minutes after low-pH treatment. Without low-pH exposure, the number of released cores lagged behind the number of virions in vesicles until 30 min posttreatment, when they became approximately equal, perhaps reflecting the time of endosome acidification and virus fusion. The choice of two distinct pathways may contribute to the ability of vaccinia virus to enter a wide range of cells.
Crystal Structure of the Receptor-Binding Protein Head Domain from
Lactococcus lactis
Phage bIL170
Authors: Ricagno Stefano , Campanacci Valérie , Blangy Stéphanie , Spinelli Silvia , Tremblay Denise , Moineau Sylvain , Tegoni Mariella , Cambillau Christian 
Published: August 2006

ABSTRACT

Lactococcus lactis
, a gram-positive bacterium widely used by the dairy industry, is subject to lytic phage infections. In the first step of infection, phages recognize the host saccharidic receptor using their receptor binding protein (RBP). Here, we report the 2.30-Å-resolution crystal structure of the RBP head domain from phage bIL170. The structure of the head monomer is remarkably close to those of other lactococcal phages, p2 and TP901-1, despite any sequence identity with them. The knowledge of the three-dimensional structures of three RBPs gives a better insight into the module exchanges which have occurred among phages.