bluuebunny/crossref_metadata_2025_split huggingface dataset:
Internal and External Integration for Product Development: The Contingency Effects of Uncertainty, Equivocality, and Platform Strategy
Authors: Koufteros Xenophon , Vonderembse Mark , Jayaram Jayanth 
Published: January 2005

ABSTRACTEffective product development requires firms to unify internal and external participants. As companies attempt to create this integrated environment, two important questions emerge. Does a high level of internal integration lead to a higher level of external integration? In the context of product development, this study considers whether internal integration in the form of concurrent engineering practices affects the level of external integration as manifested by customer integration, supplier product integration, and supplier process integration. External integration, in turn, may influence competitive capabilities, namely product innovation performance and quality performance. Second, using contingency theory, do certain contextual variables moderate the linkages between integration strategy (external and internal) and performance? Specifically, this study considers whether uncertainty, equivocality, and platform development strategy change the relationships among internal integration, external integration, and competitive capabilities. Data collected from 244 manufacturing firms across several industries were used to test these research questions. The results indicate that both internal and external integration positively influence product innovation and quality and ultimately, profitability. With respect to contingency effects, the results indicate that equivocality moderates the relationships between integration and performance.
Heart Rate Variability in Patients with Essential Hyperhidrosis: Dynamic Influence of Sympathetic and Parasympathetic Maneuvers
Authors: Kaya Dayimi , Karaca Semsettin , Barutcu Irfan , Esen Ali Metin , Kulac Mustafa , Esen Ozlem 
Published: January 2005

Background: Essential hyperhidrosis has been associated with an increased activity of the sympathetic system. In this study, we investigated cardiac autonomic function in patients with essential hyperhidrosis and healthy controls by time and frequency domain analysis of heart rate variability (HRV). Method: In this study, 12 subjects with essential hyperhidrosis and 20 healthy subjects were included. Time and frequency domain parameters of HRV were obtained from all of the participants after a 15‐minute resting period in supine position, during controlled respiration (CR) and handgrip exercise (HGE) in sitting position over 5‐minute periods in each stage. Results: Baseline values of HRV parameters including RR interval, SDNN and root mean square of successive R‐R interval differences, low frequency (LF), high frequency (HF), normalized unit of high frequency (HFnu), normalized unit of low frequency (LFnu), and LF/HF ratio were identical in two groups. During CR, no difference was detected between the two groups with respect to HRV parameters. However, the expected increase in mean heart rate (mean R‐R interval) did not occur in hyperhidrotic group, whereas it did occur in the control group (Friedman's P = 0.000). Handgrip exercise induced significant decrease in mean R‐R interval in both groups and no difference was detected between the two groups with respect to the other HRV parameters. When repeated measurements were compared with two‐way ANOVA, there was statistically significant difference only regarding mean heart rate in two groups (F = 6.5; P = 0.01). Conclusion: Our overall findings suggest that essential hyperhidrosis is a complex autonomic dysfunction rather than sympathetic overactivity, and parasympathetic system seems to be involved in pathogenesis of this disorder.
Effect of the September 11, 2001 Terrorist Attack on a State Highway Patrol Trooper's Heart Rate Variability
Authors: Riediker Michael , Herbst Margaret C. , Devlin Robert B. , Griggs Thomas R. , Bromberg Philip A. , Cascio Wayne E. 
Published: January 2005

Background: On September 11, 2001, terrorists attacked the United States. By coincidence, a North Carolina highway patrol trooper was wearing an ambulatory ECG Holter monitor at this time as part of an air pollution study. Methods: Heart rate variability parameters were analyzed: standard deviation of normal to normal beat intervals (SDNN) and percentage of interval differences >50 ms (PNN50). Results: The trooper's heart rate variability changed immediately after learning about the terrorist attacks. Heart rate increased and PNN50 decreased, while SDNN increased strongly. Conclusions: These changes suggest strong emotional sympathetic stress associated with parasympathetic withdrawal in response to the news about the terrorist attack.
Subtle Mutational Changes in the SU Protein of a Natural Feline Leukemia Virus Subgroup A Isolate Alter Disease Spectrum
Authors: Chandhasin Chandtip , Coan Patricia N. , Levy Laura S. 
Published: January 2005

ABSTRACTFeLV-945 is a representative isolate of the natural feline leukemia virus (FeLV) variant predominant in non-T-cell malignant, proliferative, and degenerative diseases in a geographic cohort. The FeLV-945 surface glycoprotein (SU) is closely related to natural horizontally transmissible FeLV subgroup A (FeLV-A) but was found to differ from a prototype to a larger extent than the members of FeLV-A differ among themselves. The sequence differences included point mutations restricted largely to the functional domains of SU, i.e., VRA, VRB, and PRR. Despite the sequence differences in these critical domains, measurements of receptor utilization, including host range and superinfection interference, confirmed the assignment of FeLV-945 to subgroup A. Other proviruses isolated from the cohort contained similar sequence hallmarks and were assigned to FeLV subgroup A. A provirus from cat 1046 contained a histidine-to-proline change at SU residue 6 within an SPHQ motif that was previously identified as a critical mediator of fusion events during virus entry. The 1046 pseudotype virus entered cells only in the presence of the soluble cofactor FeLIX provided intrans, but it retained an ecotropic host range even in the presence of FeLIX. The mutational changes in FeLV-945 were shown to confer significant functional differences compared to prototype FeLV-A viruses. The substitution of FeLV-945 envelope gene sequences for FeLV-A/61E sequences conferred a small but statistically significant replicative advantage in some feline cells. Moreover, substitution of the unique FeLV-945 long terminal repeat and envelope gene for those of FeLV-A/61E altered the disease spectrum entirely, from a thymic lymphoma of a T-cell origin to an as yet uncharacterized multicentric lymphoma that did not contain T cells.
Rearrangement of Simian Virus 40 Regulatory Region Is Not Required for Induction of Progressive Multifocal Leukoencephalopathy in Immunosuppressed Rhesus Monkeys
Authors: Dang Xin , Axthelm Michael K. , Letvin Norman L. , Koralnik Igor J. 
Published: January 2005

ABSTRACT
Rearrangements of the JC virus (JCV) regulatory region (RR) are consistently found in the brains of patients with progressive multifocal leukoencephalopathy (PML), whereas the archetype RR is present in their kidneys. In addition, the C terminus of the large T antigen (T-Ag) shows greater variability in PML than does the rest of the coding region. To determine whether similar changes in simian virus 40 (SV40) are necessary for disease induction in monkeys, we sequenced the SV40 RR and the C terminus of the T-Ag from the brain of simian/human immunodeficiency virus (SHIV)-infected monkey 18429, which presented spontaneously with an SV40-associated PML-like disease, as well as from the peripheral blood mononuclear cells (PBMC), kidneys, and brains of SV40-seronegative, SHIV-infected monkeys 21289 and 21306, which were inoculated with the 18429 brain SV40 isolate. These animals developed both SV40-associated PML and meningoencephalitis. Thirteen types of SV40 RR were characterized. Compared to the SV40 archetype, we identified RRs with variable deletions in either the origin of replication, the 21-bp repeat elements, or the late promoter, as well as deletions or duplications of the 72-bp enhancer. The archetype was the most prominent RR in the brain of monkey 18429. Shortly after inoculation, a wide range of RRs could be found in the PBMC of monkeys 21289 and 21306. However, the archetype RR became the predominant type in their blood, kidneys, and brains at the time of sacrifice. On the contrary, the T-Ag C termini remained identical in all compartments of the three animals. These results indicate that unlike JCV in humans, rearrangements of SV40 RR are not required for brain disease induction in immunosuppressed monkeys.
The Ataxia Telangiectasia-Mutated and Rad3-Related Protein Is Dispensable for Retroviral Integration
Authors: DeHart Jason L. , Andersen Joshua L. , Zimmerman Erik S. , Ardon Orly , An Dong Sung , Blackett Jana , Kim Baek , Planelles Vicente 
Published: January 2005

ABSTRACT

Integration into the host cell DNA is an essential part of the retroviral life cycle and is required for the productive replication of a retrovirus. Retroviral integration involves cleavage of the host DNA and insertion of the viral DNA, forming an integration intermediate that contains two gaps, each with a viral 5′ flap. The flaps are then removed, and the gap is filled by as yet unidentified nuclease and polymerase activities. It is thought that repair of these gaps flanking the site of retroviral integration is achieved by host DNA repair machinery. The ATM and Rad3-related protein (ATR) is a member of the phosphatidylinositol 3 kinase-related family of protein kinases that play a major role in sensing and triggering repair of DNA lesions in mammalian cells. In an effort to examine the role of ATR in retroviral integration, we used RNA interference to selectively downregulate ATR and measured integration efficiency. In addition, we examined the possible role that Vpr may play in enhancing integration and, in particular, whether activation of ATR by Vpr (Roshal et al., J. Biol. Chem.
278:
25879-25886, 2003) will favor human immunodeficiency virus type 1 integration. We conclude that cells in which ATR has been depleted are competent for retroviral integration. We also conclude that the presence of Vpr as a virion-bound protein does not enhance integration of a lentivirus vector in dividing cells.
Preferential Use of CXCR4 by R5X4 Human Immunodeficiency Virus Type 1 Isolates for Infection of Primary Lymphocytes
Authors: Yi Yanjie , Shaheen Farida , Collman Ronald G. 
Published: January 2005

ABSTRACTCoreceptor specificity of human immunodeficiency virus type 1 (HIV-1) strains is generally defined in vitro in cell lines expressing CCR5 or CXCR4, but lymphocytes and macrophages are the principal targets in vivo. CCR5-using (R5) variants dominate early in infection, but strains that use CXCR4 emerge later in a substantial minority of subjects. Many or most CXCR4-using variants can use both CXCR4 and CCR5 (R5X4), but the pathways that are actually used to cause infection in primary cells and in vivo are unknown. We examined several R5X4 prototype and primary isolates and found that they all were largely or completely restricted to CXCR4-mediated entry in primary lymphocytes, even though lymphocytes are permissive for CCR5-mediated entry by R5 strains. In contrast, in primary macrophages R5X4 isolates used both CCR5 and CXCR4. The R5X4 strains were also more sensitive than R5 strains to CCR5 blocking, suggesting that interactions between the R5X4 strains and CCR5 are less efficient. These results indicate that coreceptor phenotyping in transformed cells does not necessarily predict utilization in primary cells, that variability exists among HIV-1 isolates in the ability to use CCR5 expressed on lymphocytes, and that many or most strains characterized as R5X4 are functionally X4 in primary lymphocytes. Less efficient interactions between R5X4 strains and CCR5 may be responsible for the inability to use CCR5 on lymphocytes, which express relatively low CCR5 levels. Since isolates that acquire CXCR4 utilization retain the capacity to use CCR5 on macrophages despite their inability to use it on lymphocytes, these results also raise the possibility that a CCR5-mediated macrophage reservoir is required for sustained infection in vivo.
Capped RNA Transcripts of Full-Length cDNA Clones of Swine Hepatitis E Virus Are Replication Competent When Transfected into Huh7 Cells and Infectious When Intrahepatically Inoculated into Pigs
Authors: Huang Y. W. , Haqshenas G. , Kasorndorkbua C. , Halbur P. G. , Emerson S. U. , Meng X. J. 
Published: January 2005

ABSTRACT
Swine hepatitis E virus (swine HEV), the first animal strain of HEV to be isolated, is a zoonotic agent. We report here the construction and in vitro and in vivo characterizations of infectious cDNA clones of swine HEV. Eight overlapping fragments spanning the entire genome were amplified by reverse transcription-PCR and assembled into a full-length cDNA clone, clone C, which contained 14 mutations compared to the consensus sequence of swine HEV. RNA transcripts from clone C were not infectious, as determined by intrahepatic inoculation into pigs and by in vitro transfection of Huh7 cells. Multiple site-based site-directed mutagenesis was performed to generate three new cDNA clones (pSHEV-1, pSHEV-2, and pSHEV-3) which differed from each other. The transfection of capped RNA transcripts into human liver Huh7 cells resulted in the synthesis of both ORF2 capsid and ORF3 proteins, indicating that the cDNA clones were replication competent. Each of the three clones resulted in active swine HEV infections after the intrahepatic inoculation of pigs with capped RNA transcripts. The patterns of seroconversion, viremia, and fecal virus shedding for pigs inoculated with RNA transcripts from clones pSHEV-2 and pSHEV-3 were similar to each other and to those for pigs inoculated with wild-type swine HEV, suggesting that the nucleotide differences between these two cDNA clones were not critical for replication. Pigs inoculated with RNA transcripts from clone pSHEV-1, which contained three nonsilent mutations in the ORF2 capsid gene, had a delayed appearance of seroconversion and fecal virus shedding and had undetectable viremia. The availability of these infectious cDNA clones affords us an opportunity to understand the mechanisms of cross-species infection by constructing chimeric human and swine HEVs.
Complete Genomic Sequence of Human Coronavirus OC43: Molecular Clock Analysis Suggests a Relatively Recent Zoonotic Coronavirus Transmission Event
Authors: Vijgen Leen , Keyaerts Els , Moës Elien , Thoelen Inge , Wollants Elke , Lemey Philippe , Vandamme Anne-Mieke , Van Ranst Marc 
Published: January 2005

ABSTRACTCoronaviruses are enveloped, positive-stranded RNA viruses with a genome of approximately 30 kb. Based on genetic similarities, coronaviruses are classified into three groups. Two group 2 coronaviruses, human coronavirus OC43 (HCoV-OC43) and bovine coronavirus (BCoV), show remarkable antigenic and genetic similarities. In this study, we report the first complete genome sequence (30,738 nucleotides) of the prototype HCoV-OC43 strain (ATCC VR759). Complete genome and open reading frame (ORF) analyses were performed in comparison to the BCoV genome. In the region between the spike and membrane protein genes, a 290-nucleotide deletion is present, corresponding to the absence of BCoV ORFs ns4.9 and ns4.8. Nucleotide and amino acid similarity percentages were determined for the major HCoV-OC43 ORFs and for those of other group 2 coronaviruses. The highest degree of similarity is demonstrated between HCoV-OC43 and BCoV in all ORFs with the exception of the E gene. Molecular clock analysis of the spike gene sequences of BCoV and HCoV-OC43 suggests a relatively recent zoonotic transmission event and dates their most recent common ancestor to around 1890. An evolutionary rate in the order of 4 × 10−4nucleotide changes per site per year was estimated. This is the first animal-human zoonotic pair of coronaviruses that can be analyzed in order to gain insights into the processes of adaptation of a nonhuman coronavirus to a human host, which is important for understanding the interspecies transmission events that led to the origin of the severe acute respiratory syndrome outbreak.
Efficient Inhibition of Hepatitis B Virus Infection by Acylated Peptides Derived from the Large Viral Surface Protein
Authors: Gripon Philippe , Cannie Isabelle , Urban Stephan 
Published: January 2005

ABSTRACT

The lack of an appropriate in vitro infection system for the major human pathogen hepatitis B virus (HBV) has prevented a molecular understanding of the early infection events of HBV. We used the novel HBV-infectible cell line HepaRG and primary human hepatocytes to investigate the interference of infection by HBV envelope protein-derived peptides. We found that a peptide consisting of the authentically myristoylated N-terminal 47 amino acids of the pre-S1 domain of the large viral envelope protein (L protein) specifically prevented HBV infection, with a 50% inhibitory concentration (IC
50
) of 8 nM. The replacement of myristic acid with other hydrophobic moieties resulted in changes in the inhibitory activity, most notably by a decrease in the IC
50
to picomolar concentrations for longer unbranched fatty acids. The obstruction of HepaRG cell susceptibility to HBV infection after short preincubation times with the peptides suggested that the peptides efficiently target and inactivate a receptor at the hepatocyte surface. Our data both shed light on the molecular mechanism of HBV entry into hepatocytes and provide a basis for the development of potent hepadnaviral entry inhibitors as a novel therapeutic concept for the treatment of hepatitis Β.
Computational Design of Antiviral RNA Interference Strategies That Resist Human Immunodeficiency Virus Escape
Authors: Leonard Joshua N. , Schaffer David V. 
Published: January 2005

ABSTRACT
Recently developed antiviral strategies based upon RNA interference (RNAi), which harnesses an innate cellular system for the targeted down-regulation of gene expression, appear highly promising and offer alternative approaches to conventional highly active antiretroviral therapy or efforts to develop an AIDS vaccine. However, RNAi is faced with several challenges that must be overcome to fully realize its promise. Specifically, it degrades target RNA in a highly sequence-specific manner and is thus susceptible to viral mutational escape, and there are also challenges in delivery systems to induce RNAi. To aid in the development of anti-human immunodeficiency virus (anti-HIV) RNAi therapies, we have developed a novel stochastic computational model that simulates in molecular-level detail the propagation of an HIV infection in cells expressing RNAi. The model provides quantitative predictions on how targeting multiple locations in the HIV genome, while keeping the overall RNAi strength constant, significantly improves efficacy. Furthermore, it demonstrates that delivery systems must be highly efficient to preclude leaving reservoirs of unprotected cells where the virus can propagate, mutate, and eventually overwhelm the entire system. It also predicts how therapeutic success depends upon a relationship between RNAi strength and delivery efficiency and uniformity. Finally, targeting an essential viral element, in this case the HIV TAR region, can be highly successful if the RNAi target sequence is correctly selected. In addition to providing specific predictions for how to optimize a clinical therapy, this system may also serve as a future tool for investigating more fundamental questions of viral evolution.
Identification of the Membrane-Active Regions of the Severe Acute Respiratory Syndrome Coronavirus Spike Membrane Glycoprotein Using a 16/18-Mer Peptide Scan: Implications for the Viral Fusion Mechanism
Authors: Guillén Jaime , Pérez-Berná Ana J. , Moreno Miguel R. , Villalaín José 
Published: January 2005

ABSTRACT
We have identified the membrane-active regions of the severe acute respiratory syndrome coronavirus (SARS CoV) spike glycoprotein by determining the effect on model membrane integrity of a 16/18-mer SARS CoV spike glycoprotein peptide library. By monitoring the effect of this peptide library on membrane leakage in model membranes, we have identified three regions on the SARS CoV spike glycoprotein with membrane-interacting capabilities: region 1, located immediately upstream of heptad repeat 1 (HR1) and suggested to be the fusion peptide; region 2, located between HR1 and HR2, which would be analogous to the loop domain of human immunodeficiency virus type 1; and region 3, which would correspond to the pretransmembrane region. The identification of these membrane-active regions, which are capable of modifying the biophysical properties of phospholipid membranes, supports their direct role in SARS CoV-mediated membrane fusion, as well as facilitating the future development of SARS CoV entry inhibitors.
Human Immunodeficiency Virus Type 1 Vectors with Alphavirus Envelope Glycoproteins Produced from Stable Packaging Cells
Authors: Strang Blair L. , Takeuchi Yasuhiro , Relander Thomas , Richter Johan , Bailey Ranbir , Sanders David A. , Collins Mary K. L. , Ikeda Yasuhiro 
Published: January 2005

ABSTRACT

Alphavirus glycoproteins have broad host ranges. Human immunodeficiency virus type 1 (HIV-1) vectors pseudotyped with their glycoproteins could extend the range of tissues that can be transduced in both humans and animal models. Here, we established stable producer cell lines for HIV vectors pseudotyped with alphavirus Ross River virus (RRV) and Semliki Forest virus (SFV) glycoproteins E2E1. RRV E2E1-stable clones could routinely produce high-titer pseudotyped vectors for at least 5 months. SFV E2E1-stable clones, however, produced relatively low titers. We examined the properties of RRV E2E1-pseudotyped vectors [HIV-1(RRV)] and compared them with amphotropic murine leukemia virus Env- and vesicular stomatitis virus glycoprotein G-pseudotyped vectors. HIV-1(RRV) displayed a number of characteristics which would be advantageous in ex vivo and in vivo experiments, including resistance to inactivation by heat-labile components in fresh human sera and thermostability at 37°C. Upon single-step concentration by ultracentrifugation of HIV-1(RRV), we could achieve vector stocks with titers up to 6 × 10
7
IU/ml. HIV-1(RRV) efficiently transduced cells from several different species, including murine primary dendritic cells, but failed to transduce human and murine T cells as well as human hematopoietic stem cells (HSC). These results indicate that HIV-1(RRV) could be used in a number of applications including animal model experiments and suggest that expression of RRV cellular receptors is limited or absent in certain cell types such as T cells and human HSC.