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PubMed2005

Analysis and function of prototype foamy virus envelope N glycosylation.

The prototype foamy virus (PFV) glycoprotein, which is essential for PFV particle release, displays a highly unusual biosynthesis, resulting in posttranslational cleavage of the precursor protein into three particle-associated subunits, i.e., leader peptide (LP), surface (SU), and transmembrane (TM). Glycosidase digestion of metabolically labeled PFV particles revealed the presence of N-linked carbohydrates on all subunits. The differential sensitivity to specific glycosidases indicated that all oligosaccharides on LP and TM are of the high-mannose or hybrid type, whereas most of those attached to SU, which contribute to about 50% of its molecular weight, are of the complex type. Individual inactivation of all 15 potential N-glycosylation sites in PFV Env demonstrated that 14 are used, i.e., 1 out of 2 in LP, 10 in SU, and 3 in TM. Analysis of the individual altered glycoproteins revealed defects in intracellular processing, support of particle release, and infectivity for three mutants, having the evolutionarily conserved glycosylation sites N8 in SU or N13 and N15 in the cysteine-rich central "sheets-and-loops" region of TM inactivated. Examination of alternative mutants with mutations affecting glycosylation or surrounding sequences at these sites indicated that inhibition of glycosylation at N8 and N13 most likely is responsible for the observed replication defects, whereas for N15 surrounding sequences seem to contribute to a temperature-sensitive phenotype. Taken together these data demonstrate that PFV Env and in particular the SU subunit are heavily N glycosylated and suggest that although most carbohydrates are dispensable individually, some evolutionarily conserved sites are important for normal Env function of FV isolates from different species.

Amino Acid Sequence↗
PubMed2005

RNA interference-mediated virus clearance from cells both acutely and chronically infected with the prototypic arenavirus lymphocytic choriomeningitis virus.

Several arenaviruses, including Lassa fever virus, cause severe, often lethal hemorrhagic fever in humans. No licensed vaccines are available in the United States, and currently there is no efficacious therapy to treat this viral infection. Therefore the importance of developing effective antiviral approaches to combat pathogenic arenaviruses is clear. Moreover, the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is an important model for the study of viral persistence and associated diseases, as well as for exploring therapies to treat viral chronic infections. The use of small interfering RNAs (siRNAs) to downregulate gene expression via RNA interference (RNAi) has emerged as a powerful genetic tool for the study of gene function. In addition, the successful use of siRNAs to target a variety of animal viruses has led us to consider RNAi as a potential novel antiviral strategy. We have investigated the use of RNAi therapy against LCMV. Here, we show that siRNAs targeting sequences within the viral L polymerase and Z mRNAs inhibit LCMV multiplication in cultured cells. Unexpectedly, the antiviral efficacy of RNAi-based therapy against LCMV was highly dependent on the method used to deliver effector siRNA molecules. Thus, transfection of chemically synthesized siRNA pools to L and Z was ineffective in preventing virus multiplication. In contrast, targeting of the same viral L and Z gene products with siRNAs produced inside cells using a replication-deficient recombinant adenovirus expression system inhibited LCMV multiplication very efficiently. Notably, transduction with the replication-deficient recombinant adenovirus expression system to Z and L effectively cured persistently LCMV-infected cells, suggesting the feasibility of using RNAi therapy to combat viral chronic infections by riboviruses.

Adenoviridae↗
PubMed2005

Virulent variants emerging in mice infected with the apathogenic prototype strain of the parvovirus minute virus of mice exhibit a capsid with low avidity for a primary receptor.

The mechanisms involved in the emergence of virulent mammalian viruses were investigated in the adult immunodeficient SCID mouse infected by the attenuated prototype strain of the parvovirus Minute Virus of Mice (MVMp). Cloned MVMp intravenously inoculated in mice consistently evolved during weeks of subclinical infection to variants showing altered plaque phenotypes. All the isolated large-plaque variants spread systemically from the oronasal cavity and replicated in major organs (brain, kidney, liver), in sharp contrast to the absolute inability of the MVMp and small-plaque variants to productively invade SCID organs by this natural route of infection. The virulent variants retained the MVMp capacity to infect mouse fibroblasts, consistent with the lack of genetic changes across the 220-to-335 amino acid sequence of VP2, a capsid domain containing main determinants of MVM tropism. However, the capsid of the virulent variants shared a lower affinity than the wild type for a primary receptor used in the cytotoxic infection. The capsid gene of a virulent variant engineered in the MVMp background endowed the recombinant virus with a large-plaque phenotype, lower affinity for the receptor, and productive invasiveness by the oronasal route in SCID mice, eventually leading to 100% mortality. In the analysis of virulence in mice, both MVMp and the recombinant virus similarly gained the bloodstream 1 to 2 days postoronasal inoculation and remained infectious when adsorbed to blood cells in vitro. However, the wild-type MVMp was cleared from circulation a few days afterwards, in contrast to the viremia of the recombinant virus, which was sustained for life. Significantly, attachment to an abundant receptor of primary mouse kidney epithelial cells by both viruses could be quantitatively competed by wild-type MVMp capsids, indicating that virulence is not due to an extended receptor usage in target tissues. We conclude that the selection of capsid-receptor interactions of low affinity, which favors systemic infection, is a major evolutionary process in the adaptation of parvoviruses to new hosts and in the cause of disease.

Animals↗
PubMed2005

B1 lymphocytes and myeloid dendritic cells in lymphoid organs are preferential extratumoral sites of parvovirus minute virus of mice prototype strain expression.

Due to their oncolytic properties and apathogenicity, autonomous parvoviruses have attracted significant interest as possible anticancer agents. Recent preclinical studies provided evidence of the therapeutic potential of minute virus of mice prototype strain (MVMp) and its recombinant derivatives. In a murine model of hemangiosarcoma, positive therapeutic outcome correlated with high intratumoral expression of MVMp-encoded genes in tumors and lymphoid organs, especially in tumor-draining lymph nodes. The source and relevance of this extratumoral expression, which came as a surprise because of the known fibrotropism of MVMp, remained unclear. In the present study, we investigated (i) whether the observed expression pattern occurs in different tumor models, (ii) which cell population is targeted by the virus, and (iii) the immunological consequences of this infection. Significant MVMp gene expression was detected in lymphoid tissues from infected tumor-free as well as melanoma-, lymphoma-, and hemangiosarcoma-bearing mice. This expression was especially marked in lymph nodes draining virus-injected tumors. Fluorescent in situ hybridization analysis, multicolor fluorescence-activated cell sorting, and quantitative reverse transcription-PCR revealed that MVMp was expressed in rare subpopulations of CD11b (Mac1)-positive cells displaying CD11c+ (myeloid dendritic cells [MDC]) or CD45B (B220+ [B1 lymphocytes]) markers. Apart from the late deletion of cytotoxic memory cells (CD8+ CD44+ CD62L-), this infection did not lead to significant alteration of the immunological profile of cells populating lymphoid organs. However, subtle changes were detected in the production of specific proinflammatory cytokines in lymph nodes from virus-treated animals. Considering the role of B1 lymphocytes and MDC in cancer and immunological surveillance, the specific ability of these cell types to sustain parvovirus-driven gene expression may be exploited in gene therapy protocols.

Animals↗
PubMed2005

Characterization of prototype foamy virus gag late assembly domain motifs and their role in particle egress and infectivity.

Foamy viruses (FV) are unusual among retroviruses since they require both Gag and Env structural proteins for particle egress. Recently significant progress has been made towards the mechanistic understanding of the viral release process, in particular that of retroviruses, and the viral domains and cellular pathways involved. However little is currently known about domains of FV structural proteins and cellular proteins engaged in this process. By mutational analysis of sequence motifs in prototype FV (PFV) Gag, bearing homology to known late assembly (L) domains, a PSAP motif with L domain function that was functionally interchangeable by heterologous L domains was identified. In contrast the inactivation of a PPPI motif had no significant influence on PFV particle release, although mutant viral particles displayed reduced infectivity. Similarly mutation of an evolutionary conserved YXXL motif revealed no classical L-domain function but resulted in release of noninfectious viruslike particles. Biochemical and electron microscopy analysis demonstrated that these mutant particles incorporated all viral structural proteins but contained aberrantly capsid structures, suggesting a role in capsid assembly for this PFV Gag sequence motif. In line with the mutational analysis, overexpression of dominant negative (DN) mutants and wild-type TSG101 but not the DN mutant of AIP-1/ALIX reduced PFV particle release and infectivity. Furthermore, DN mutants of Vps4A, Vps4B, and CHMP3 inhibited PFV egress and infectivity. Taken together these results demonstrate that PFV, like other viruses, requires components of the vacuolar protein sorting (VPS) machinery for egress and enters the VPS pathway through interaction with TSG101.

Amino Acid Motifs↗
PubMed1996

Prospective study of the clinical value of determining circulating IgA-alpha 1-antitrypsin complex using a prototype ELISA kit in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the clinical value of determining circulating IgA-alpha 1-antitrypsin (IgA-AT) complex in rheumatoid arthritis. METHODS: The IgA-AT complex was assayed by a prototype ELISA kit using a specific monoclonal antibody against the complex. RESULTS: The median level of serum IgA-AT complex in rheumatoid patients (2.26 AU ml-1) was significantly higher than in osteoarthritis patients (1.37 AU ml-1, P < 0.05) and healthy volunteers (1.03 AU ml-1, P < 0.001). The concentration of IgA-AT complex in rheumatoid arthritis patients at baseline was correlated with the number of painful joints (P < 0.05), number of swollen joints (P < 0.01), erythrocyte sedimentation rate (P < 0.05), and modified Lansbury index (P < 0.01). The median serum level of IgA-AT complex in rheumatoid patients at baseline was higher than that at three months (P < 0.01), six months (P < 0.01), and 12 months (P < 0.01) after the start of treatment. The difference and ratio of IgA-AT complex levels before and after treatment were significantly associated with radiographic progression. CONCLUSIONS: The findings validate the usefulness of determining IgA-AT complex using ELISA in the management of rheumatoid arthritis.

Adult↗
PubMed1984

Assessment of a prototype implantable cardioverter for ventricular tachycardia. Relation between synchronisation of sensing and origin of the tachycardia.

The feasibility of internal cardioversion for ventricular tachycardia using a prototype of an implantable cardioverter which delivers a low energy discharge via an intracardiac lead and its acceptability to the patient were studied. The cardioverting discharge was synchronised to the apical right ventricular electrogram. In 29 episodes of ventricular tachycardia (RR interval 250-700 ms) the apical electrogram was reliably sensed. The interval from the onset of the QRS complex to the marker of sensing of the electrogram was significantly greater in the 15 episodes arising from the left ventricle than in the 14 episodes arising from the right ventricle; in three cases of ventricular tachycardia arising from the left ventricle the interval exceeded 100 ms. In all cases except one, however, sensing occurred within the first 80% of the QRS complex. In two episodes (RR interval 150 and 190 ms--that is, less than the refractory period of the unit) sensing of the electrogram was unreliable. The unit successfully terminated 10 of 15 episodes of ventricular tachycardia using energies ranging between 0.01 and 1.0 J, but 19 of the 23 discharges delivered to conscious patients caused varying degrees of discomfort. Sensing within 100 ms of the onset of the QRS complex (-20% to 83% of QRS) permitted effective and safe termination of ventricular tachycardia. Although there was neither acceleration of tachycardia nor ventricular fibrillation, subthreshold discharges advanced the next local ventricular electrogram in seven instances. An external low energy cardioverter connected to an intracardiac lead is a useful alternative to repeated external direct current shocks.

Adolescent↗
PubMed1990

Evaluation of a prototype for a reference platelet counter.

A semiautomated single channel aperture-impedance particle counter was developed as a prototype for a reference platelet count for assigning values to reference preparations used in automated blood cell counts. The instrument is equipped with sheath flow and an aperture orifice of 50 microns in diameter and 60 microns in length to eliminate non-axial flow and minimise coincidence errors. Use of fixed volume and red blood cell:platelet ratios obviate dilution errors. The counter was assessed in accordance with the International Committee for Standardization in Haematology protocol for evaluation of automated blood cell counters. The counter provided a high level of linearity and precision, accurate coincidence correction, controlled volume, stability and negligible carryover.

Erythrocyte Count↗
PubMed1978

A rapid fluorescent focus-inhibition test for determining dengue neutralizing antibody and for identifying prototype dengue viruses.

Neutralizing antibody to dengue virus in human and animal sera was assayed by the rapid fluorescent focus-inhibition test (RFFIT). Neutralizing-antibody titers could be detected after only 24 h compared to 5--6 days required by the plaque-reduction test. The RFFIT is more definitive than the conventional complement fixation (CF) or hemagglutination-inhibition (HI) test in identifying prototype dengue viruses, is reproducible, and is applicable to the routine detection of neutralizing antibodies to dengue viruses.

Antibodies, Viral↗
PubMed1996

Hardware prototypes of a Boolean neural network and the simulated annealing optimization method.

Boolean Neural Network is a neural network that operates with binary weight values of "1" and "0". Otherwise it is formally analogous to the Multilayer Perceptron (MLP). Simulated Annealing is a stochastic optimization methods that is suitable for performing nonlinear multivariable optimization tasks. Training a Boolean Neural Network is a well-suited problem to this algorithm. However, the Simulated Annealing method is computationally heavy, which makes the training procedure slow. The training speed can be improved by using custom designed hardware for the whole system including the optimization method and the neural network. Hardware prototypes of a Boolean Neural Network and the Simulated Annealing optimization method have been designed using discrete components. The Boolean Neural Network implementation is basically a dynamically configurable feedforward network of Boolean logic gates of two inputs. The Simulated Annealing implementation is a general purpose hardware tool for multivariable optimization tasks. Here it is applied to do supervised training of the Boolean Neural Network hardware.

Algorithms↗
PubMed2005

A novel artificial prosthetic replacement for the proximal interphalangeal joint of the hand--from concept to prototype.

This article describes the development of a proximal interphalangeal (PIP) joint prosthesis based on the principles of replicating anatomical surface components, the use of macrolocking intramedullary stem and the use of a cobalt-chrome alloy material. The design features are intended to obtain an optimal range of motion while retaining stability and longevity. The final prototype, for which a patent has been filed, is described.

Chromium Alloys↗
PubMed2005

Femtosecond laser photoelectron spectroscopy on atoms and small molecules: prototype studies in quantum control.

We review prototype studies in the area of quantum control with femtosecond lasers. We restrict this discussion to atoms and diatomics under gas-phase collision-free conditions to allow for a comparison between theory and experiment. Both the perturbative regime and the nonperturbative regime of the light-matter interaction are addressed. To that end, atomic/molecular beam techniques are combined together with femtosecond laser techniques and energy-resolved photoelectron spectroscopy and ion detection. Highly detailed information on the laser-induced quantum dynamics is extracted with the help of kinetic energy-resolved photoelectron spectroscopy.

Ions↗
PubMed2001

X-ray beam equalization: feasibility and performance of an automated prototype system in a phantom and swine.

PURPOSE: To investigate the feasibility of an automated implementation of a beam equalization technique and to evaluate the experimental performance of the prototype system. MATERIALS AND METHODS: X-ray beam equalization involved the process of low-dose image acquisition, attenuator thickness calculation, mask generation, mask positioning, equalized image acquisition, and mask reshaping. The entire equalization process was performed in approximately 7 seconds. The equalized images were assessed both qualitatively and quantitatively by using a humanoid phantom and a swine animal model. The general image quality was assessed for the ability to visualize arterial branches and other anatomic structures. The level of equalization was quantitatively assessed by segmenting the images into an 8 x 8 matrix of square regions. RESULTS: The ratio of the root-mean-squared variance for the equalized and unequalized images from humanoid phantom and swine animal studies was 0.49 and 0.59, respectively. Furthermore, qualitative assessment of the images showed substantial improvement in image quality and visualization of arterial branches after beam equalization in phantom and animal studies. CONCLUSION: Automated area beam equalization is feasible and improves image quality in previously underpenetrated regions of the image.

Animals↗
PubMed1983

Digital radiography of the chest: clinical experience with a prototype unit.

A prototype digital unit dedicated to chest radiography was used to examine 50 selected patients for a comparison study of the capability of digital images and conventional chest radiographs to reveal normal anatomic structures and a variety of pathologic states. The images in both modes were submitted for interpretation to seven experienced radiologists and a standardized questionnaire completed for each. Visibility of seven anatomic structures in the mediastinum was consistently better on the digital images than on the conventional radiographs. With minor exceptions, pathologic states were equally well seen in the two systems. Despite the less familiar viewing format of the digital images, the mean confidence levels achieved were higher than for those on the conventional radiographs; this difference was statistically significant both for normal anatomic structures (p = 0.001) and pathologic states (p = 0.01). The advantages and disadvantages of the digital technique are discussed.

Adult↗
PubMed1983

Digital radiography of the chest: design features and considerations for a prototype unit.

The general features of a prototype digital chest unit are described along with the rationale for the choice of design factors employed. It is shown that the scanning-slit, linear-detector-array approach employed can, with available x-ray tube technology, achieve a spatial resolution of 1 cy/mm and detector radiation levels comparable with those obtained with conventional screen-film systems. Also discussed are the unit's exposure latitude and its ability virtually to eliminate scatter.

Computers↗
PubMed1985

Prototype coil for magnetic resonance imaging of the female breast. Work in progress.

Magnetic resonance imaging (MRI) of the breast was performed in 35 women using a prototype breast coil at 0.15 T. The distribution of fibroglandular and fatty tissues was demonstrated sufficiently well to permit correlation with the mammographic patterns of Wolfe, and it was possible to identify 1-cm cysts. The signal intensity of the cysts varied from low to high as repetition time (TR) and echo time (TE) using the spin echo technique (TR/TE) were prolonged from 250/30 to 1,000/120. In two women, fibroadenomas were seen as low-intensity, smoothly marginated lesions surrounded by fat. A range of in vivo observed T1 values is summarized for normal and pathologic tissues. It is concluded that MRI of the female breast, currently in the developmental phase, is feasible and further evaluation is indicated.

Adipose Tissue↗
PubMed1985

Digital chest radiography: performance evaluation of a prototype unit.

Measurements of the physical performance of a prototype digital chest unit (DCU) are presented. The parameters evaluated were entrance skin exposure, system exposure response and dynamic range, system modulation transfer function (MTF), image noise levels, detective quantum efficiency (DQE) of the detector, and scatter suppression efficiency. Compared with conventional chest imaging systems, the unit has markedly greater exposure latitude, limited spatial resolution, a lower detector DQE, and virtually scatter-free images. Routine clinical exposure levels are comparable with the 1982 national average.

Equipment Design↗
PubMed1997

Gd-EOB-DTPA and Yb-EOB-DTPA: two prototypic contrast media for CT detection of liver lesions in dogs.

PURPOSE: To characterize computed tomographic (CT) attenuation of iodine, gadolinium, and ytterbium in vitro and to study CT liver enhancement after administration of two prototypic hepatocyte-directed contrast media in dogs. MATERIALS AND METHODS: Samples with increasing concentrations of iodine, gadolinium, and ytterbium were measured for CT attenuation in a water phantom at tube voltages of 80, 120, and 137 kV. Three groups of five adult beagle dogs each received a 0.5 mmol/kg dose of either gadoxetic acid disodium (gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid [EOB-DTPA]) or Yb-EOB-DTPA as intravenous infusions or Yb-EOB-DTPA as an intravenous bolus injection. RESULTS: At 120 kV, in vitro CT attenuation of gadolinium and ytterbium exceeded that of iodine by 41% and 45%, respectively, when measured at equal mass concentrations (in milligrams per milliliter of saline). In dogs, CT liver enhancement values above the precontrast liver attenuation were 32.6 HU +/- 2.3, 31.4 HU +/- 1.1, and 33.4 HU +/- 5.2 after 0.5 mmol/kg Gd-EOB-DTPA or Yb-EOB-DTPA infusion or Yb-EOB-DTPA bolus, respectively. The values were not significantly different (P > .05) CONCLUSION: Both Gd-EOB-DTPA and Yb-EOB-DTPA provide excellent CT liver enhancement in dogs. CT liver enhancement is not significantly altered by either the absorbing element (gadolinium vs ytterbium) or the mode of application (infusion vs bolus).

Animals↗