bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Distinction between Pathogenic and Infectious Properties of the Prion Protein
Authors: Chiesa Roberto , Piccardo Pedro , Quaglio Elena , Drisaldi Bettina , Si-Hoe San Ling , Takao Masaki , Ghetti Bernardino , Harris David A. 
Published: June 2003

ABSTRACT

Tg(PG14) mice express a prion protein (PrP) with a nine-octapeptide insertion associated with a human familial prion disease. These animals spontaneously develop a fatal neurodegenerative disorder characterized by ataxia, neuronal apoptosis, and accumulation in the brain of an aggregated and weakly protease-resistant form of mutant PrP (designated PG14
spon
). Brain homogenates from Tg(PG14) mice fail to transmit disease after intracerebral inoculation into recipient mice, indicating that PG14
spon
, although pathogenic, is distinct from PrP
Sc
, the infectious form of PrP. In contrast, inoculation of Tg(PG14) mice with exogenous prions of the RML strain induces accumulation of PG14
RML
, a PrP
Sc
form of the mutant protein that is infectious and highly protease resistant. Like PrP
Sc
, both PG14
spon
and PG14
RML
display conformationally masked epitopes in the central and octapeptide repeat regions. However, these two forms differ profoundly in their oligomeric states, with PG14
RML
aggregates being much larger and more resistant to dissociation. Our analysis provides new molecular insight into an emerging puzzle in prion biology, the discrepancy between the infectious and neurotoxic properties of PrP.
Human Immunodeficiency Virus Type 2 Reverse Transcriptase Activity in Model Systems That Mimic Steps in Reverse Transcription
Authors: Post Klara , Guo Jianhui , Howard Kathryn J. , Powell Michael D. , Miller Jennifer T. , Hizi Amnon , Le Grice Stuart F. J. , Levin Judith G. 
Published: June 2003

ABSTRACT
Human immunodeficiency virus type 2 (HIV-2) infection is a serious problem in West Africa and Asia. However, there have been relatively few studies of HIV-2 reverse transcriptase (RT), a potential target for antiviral therapy. Detailed knowledge of HIV-2 RT activities is critical for development of specific high-throughput screening assays of potential inhibitors. Here, we have conducted a systematic evaluation of HIV-2 RT function, using assays that model specific steps in reverse transcription. Parallel studies were performed with HIV-1 RT. In general, under standard assay conditions, the polymerase and RNase H activities of the two enzymes were comparable. However, when the RT concentration was significantly reduced, HIV-2 RT was less active than the HIV-1 enzyme. HIV-2 RT was also impaired in its ability to catalyze secondary RNase H cleavage in assays that mimic tRNA primer removal during plus-strand transfer and degradation of genomic RNA fragments during minus-strand DNA synthesis. In addition, initiation of plus-strand DNA synthesis was much less efficient with HIV-2 RT than with HIV-1 RT. This may reflect architectural differences in the primer grip regions in the p66 (HIV-1) and p68 (HIV-2) palm subdomains of the two enzymes. The implications of our findings for antiviral therapy are discussed.
STAT Protein Interference and Suppression of Cytokine Signal Transduction by Measles Virus V Protein
Authors: Palosaari Heidi , Parisien Jean-Patrick , Rodriguez Jason J. , Ulane Christina M. , Horvath Curt M. 
Published: June 2003

ABSTRACT

Measles virus, a paramyxovirus of the
Morbillivirus
genus, is responsible for an acute childhood illness that infects over 40 million people and leads to the deaths of more than 1 million people annually (C. J. Murray and A. D. Lopez, Lancet 349:1269-1276, 1997). Measles virus infection is characterized by virus-induced immune suppression that creates susceptibility to opportunistic infections. Here we demonstrate that measles virus can inhibit cytokine responses by direct interference with host STAT protein-dependent signaling systems. Expression of the measles V protein prevents alpha, beta, and gamma interferon-induced transcriptional responses. Furthermore, it can interfere with signaling by interleukin-6 and the non-receptor tyrosine kinase, v-Src. Affinity purification demonstrates that the measles V protein associates with cellular STAT1, STAT2, STAT3, and IRF9, as well as several unidentified partners. Mechanistic studies indicate that while the measles V protein does not interfere with STAT1 or STAT2 tyrosine phosphorylation, it causes a defect in IFN-induced STAT nuclear accumulation. The defective STAT nuclear redistribution is also observed in measles virus-infected cells, where some of the STAT protein is detected in cytoplasmic bodies that contain viral nucleocapsid protein and nucleic acids. Interference with STAT-inducible transcription may provide a novel intracellular mechanism for measles virus-induced cytokine inhibition that links innate immune evasion to adaptive immune suppression.
Classical Swine Fever Virus Interferes with Cellular Antiviral Defense: Evidence for a Novel Function of Npro
Authors: Ruggli Nicolas , Tratschin Jon-Duri , Schweizer Matthias , McCullough Kenneth C. , Hofmann Martin A. , Summerfield Artur 
Published: June 2003

ABSTRACTClassical swine fever virus (CSFV) replicates efficiently in cell lines and monocytic cells, including macrophages (MΦ), without causing a cytopathic effect or inducing interferon (IFN) secretion. In the present study, the capacity of CSFV to interfere with cellular antiviral activity was investigated. When the porcine kidney cell line SK-6 was infected with CSFV, there was a 100-fold increased capacity to resist to apoptosis induced by polyinosinic-polycytidylic acid [poly(IC)], a synthetic double-stranded RNA. In MΦ, the virus infection inhibited poly(IC)-induced alpha/beta IFN (type I IFN) synthesis. This interference with cellular antiviral defense correlated with the presence of the viral Nprogene. Mutants lacking the Nprogene (ΔNproCSFV) did not protect SK-6 cells from poly(IC)-induced apoptosis, despite growth properties and protein expression levels similar to those of the wild-type virus. Furthermore, ΔNproCSFV did not prevent poly(IC)-induced type I IFN production in MΦ but rather induced type I IFN in the absence of poly(IC) in both MΦ and the porcine kidney cell line PK-15, but not in SK-6 cells. With MΦ and PK-15, an impaired replication of the ΔNproCSFV compared with wild-type virus was noted. In addition, ΔNproCSFV, but not wild-type CSFV, could interfere with vesicular stomatitis virus replication in PK-15 cells. Taken together, these results provide evidence for a novel function associated with CSFV Nprowith respect to the inhibition of the cellular innate immune system.
Vaccine-Induced Immunity in Baboons by Using DNA and Replication-Incompetent Adenovirus Type 5 Vectors Expressing a Human Immunodeficiency Virus Type 1
gag
Gene
Authors: Casimiro Danilo R. , Tang Aimin , Chen Ling , Fu Tong-Ming , Evans Robert K. , Davies Mary-Ellen , Freed Daniel C. , Hurni William , Aste-Amezaga Jose M. , Guan Liming , Long Romnie , Huang Lingyi , Harris Virginia , Nawrocki Denise K. , Mach Henryk , Troutman Robert D. , Isopi Lynne A. , Murthy Krishna K. , Rice Karen , Wilson Keith A. , Volkin David B. , Emini Emilio A. , Shiver John W. 
Published: June 2003

ABSTRACT

The cellular immunogenicity of formulated plasmid DNA and replication-defective human adenovirus serotype 5 (Ad5) vaccine vectors expressing a codon-optimized human immunodeficiency virus type 1
gag
gene was examined in baboons. The Ad5 vaccine was capable of inducing consistently strong, long-lived CD8
+
-biased T-cell responses and in vitro cytotoxic activities. The DNA vaccine-elicited immune responses were weaker than those elicited by the Ad5 vaccine and highly variable; formulation with chemical adjuvants led to moderate increases in the levels of Gag-specific T cells. Increasing the DNA-primed responses with booster doses of either Ad5 or modified vaccinia virus Ankara vaccines suggests a difference in the relative levels of cytotoxic and helper responses. The implications of these results are discussed.
Direct Evidence that C-Peptide Inhibitors of Human Immunodeficiency Virus Type 1 Entry Bind to the gp41 N-Helical Domain in Receptor-Activated Viral Envelope
Authors: Kilgore Nicole R. , Salzwedel Karl , Reddick Mary , Allaway Graham P. , Wild Carl T. 
Published: June 2003

ABSTRACT
While it has been established that peptides modeling the C-helical region of human immunodeficiency virus type 1 gp41 are potent in vivo inhibitors of virus replication, their mechanism of action has yet to be determined. It has been proposed, but never directly demonstrated, that these peptides block virus entry by interacting with gp41 to disrupt the formation or function of a six-helix bundle structure. Using a six-helix bundle-specific monoclonal antibody with isolate-restricted Env reactivity, we provide the first direct evidence that, in receptor-activated viral Env, C-peptide entry inhibitors bind to the gp41 N-helical coiled-coil to form a peptide/protein hybrid structure and, in doing so, disrupt native six-helix bundle formation.
Episomal Persistence of Recombinant Adenoviral Vector Genomes during the Cell Cycle In Vivo
Authors: Ehrhardt Anja , Xu Hui , Kay Mark A. 
Published: June 2003

ABSTRACT
Previously we showed that recombinant adenoviral helper-dependent (HD) vectors result in long-term transgene expression levels in vivo which slowly declined by 95% over a period of 1 year. In this study, we further establish that this was not predominantly immune mediated. To determine if cell turnover was responsible for the loss of transgene expression, we induced rapid hepatocyte cell cycling in mouse liver, by performing a surgical two-thirds partial hepatectomy. We observed a 55 and 65% reduction in transgene expression levels and a 50 and 71% loss of vector genomes for the HD vector and the first-generation adenoviral vector. In sharp contrast, in nonviral, episomal plasmid DNA-injected mice, transgene expression levels and DNA copy numbers decreased by 95 and 99%, respectively. These findings suggest that cell division alone was not the primary reason for the slow decrease in transgene expression levels and that recombinant adenoviral vectors have a more robust mechanism for maintaining persistence during cell cycling. Several potential mechanisms are proposed.
Short-Term Effect of Zidovudine on Plasma and Genital Human Immunodeficiency Virus Type 1 and Viral Turnover in These Compartments
Authors: Mbori-Ngacha Dorothy , Richardson Barbra A. , Overbaugh Julie , Panteleeff Dana DeVange , Nduati Ruth , Steele Matt , John-Stewart Grace 
Published: June 2003

ABSTRACT

The effect of zidovudine on plasma and genital human immunodeficiency virus type 1 (HIV-1) was determined in 42 antiretroviral-naive HIV-1-seropositive women in Nairobi. After 7 days of zidovudine treatment, HIV-1 RNA levels decreased by 0.5 to 1.1 log
10
in plasma and genital secretions. HIV-1 RNA half-life following zidovudine treatment was 4.7, 1.3, and 0.9 days in plasma, cervix, and vagina, respectively, and significantly shorter in genital secretions than in plasma (
P
< 0.001). Defining the short-term effect of zidovudine on plasma and genital HIV-1 is important for improving perinatal HIV-1 interventions.
INCIDENCE DIVISOR
Authors: BARLET D. , KADDAR M. 
Published: June 2003

Let Z be a complex manifold of dimension n+1 and (Xs)s∈S be an analytic family of n-cycles (not necessarily compact) parametrized by a reduced analytic complex space S. Denote by X the graph of this family and p1 (resp. p2) the canonical projection of S × Z on S (resp. on Z). The construction of Barlet-Magnusson assigns to each n+1-codimensionnal subspace in Z which is assumed to be a local complete intersection and to satisfy: C1[Formula: see text] is proper and finite on its image which is nowhere dense in S, an effective Cartier divisor ΣY in S. Nice functorial properties of this correspondance are proven. The purpose of this article is to generalize this result in several directions: using the relative fundamental class of the family (Xs)s∈S in Deligne cohomology, we prove the following results: (1) ΣY depends only on the cycle underlying the locally complete intersection ideal defining Y in Z (2) we generalize the construction of the incidence divisor which is Cartier and effective for any cycle Y (no nilpotent structure on Y is needed) satifying the weaker condition C2[Formula: see text] is proper and generically finite on its image which is nowhere dense in S and we extend the nice functorial properties to this case.
Postprandial Systolic Blood Pressure Responses of Older People in Residential Care: Association with Risk of Falling
Authors: Le Couteur David G. , Fisher Alex A. , Davis Michael W. , McLean Allan J. 
Published: June 2003

<i>Background:</i> The association between postprandial blood pressure, falls and medications is controversial. <i>Objective:</i> To investigate cardiovascular responses to meals in elderly people together with clinical associations and therapeutic issues. <i>Methods:</i> A cross-sectional observational study of 179 semi-independent older people (age 83.2 ± 7.0 years) in residential care facilities was undertaken. Data on the frequency of falls, medical and medication history and measurement of blood pressure before and after a breakfast meal, and then after standing and walking after the meal were documented. <i>Results:</i> Postprandial hypotension (≧20 mm Hg fall in systolic blood pressure (SBP)) and low absolute SBP (≤115 mm Hg) were common after meals and exacerbated by standing. Risk factors for low postprandial SBP included use of selective serotonin reuptake inhibitors (OR = 4.3, CI 1.4–13.1, p = 0.006), antipsychotic medications (OR = 5.2, CI 1.4–19.2, p = 0.007) and a history of smoking (OR = 4.7, CI 1.5–14.9, p = 0.005). Antihypertensive therapy ameliorated the postprandial decline in blood pressure. The incidence of falls was increased only in the 10% of subjects with low postprandial SBP. <i>Conclusions:</i> Significant adverse cardiovascular change is common after meals in older people and a postprandial SBP of <115 mm Hg was associated with a history of falls. Selective serotonin reuptake inhibitors and antipsychotic medications were associated with low postprandial SBP, which may provide a mechanism for their association with falls. Hypertension was positively and antihypertensive therapy negatively associated with postprandial hypotension.
Sex Differences in Rabbit Masseter Muscle Function
Authors: English Arthur W. , Widmer Charles G. 
Published: June 2003

The proportions of fibers of different phenotypes in the rabbit masseter muscle differ strikingly in adult males and females. Muscles from females contain similar proportions of small fibers that express both the slow/β and cardiac α myosin heavy chain (MyHC) isoforms and larger fibers containing the IIa MyHC isoform. In muscles from males, nearly 80% of fibers are of the IIa phenotype. To evaluate the functional significance of these sex differences, we used finely graded intramuscular microstimulation to study the contractile properties of masseter motor units in >6-month-old male and female rabbits. Twitch forces and torques in males were significantly greater in magnitude than those of females. Greater proportions of units that produced larger forces/torques were encountered in the males. The same motor units produced force or torque more rapidly in males than in females, principally because units in which twitch rise times were >22 ms were found only in females. The forces applied to the mandible and the torques generated about the right mandibular condyle were studied during cortically evoked rhythmic activation of the masticatory muscles. The overall range of torque rise times and the magnitudes of the peak torques did not differ between sexes. The mean rise time was significantly shorter and the mean peak torque was significantly greater in males. We conclude that sex differences in fiber phenotype proportions are reflected in sex differences in motor unit properties and in the function of these motor units during rhythmic activation.
Determination of Regional Bone Blood Flow by Means of Fluorescent Microspheres Using an Automated Sample-Processing Procedure
Authors: Anetzberger H. , Thein E. , Walli A.K. , Messmer K. 
Published: June 2003

The determination of regional blood flow utilizing fluorescent microspheres (FMs) is an established method for numerous organs. Recent progress, in particular the automation of sample processing, has further improved this method. However, the FM method (reference sample technique), which allows repetitive measurement of regional organ blood flow, has so far not been used for the determination of blood flow in bone. The aim of the present study was to establish FM for the quantification of regional bone blood flow (RBBF). Female, anesthetized New Zealand rabbits (n = 6) received left ventricular injections of different amounts of FM at six subsequent time points. In order to examine the precision of RBBF determination, two different FM species were injected simultaneously at the sixth injection. At the end of the experiments the femoral and tibial condyles of each hind limb were removed and the fluorescence intensity in the tissue samples was measured by an automated procedure. In an in vitro study we have shown that acid digestion of the crystalline matrix has no effect on the fluorescence characteristics of FM. The determination of the number of spheres per tissue sample revealed that depending on the tissue sample size up to 3 × 10<sup>6</sup> spheres/injection were necessary to obtain about 400 microspheres in the individual bone samples. RBBF values of the tibial and femoral condyles did not differ at various injection intervals. The tibial blood flow values varied between 6.6 ± 1.1 and 8.5 ± 1.4 ml/min/100 g and were significantly higher than those of the femur (4.3 ± 1.1 to 6.0 ± 1.8 ml/min/100 g). The bone blood flow values obtained by simultaneous injection of two FM species correlated significantly (r = 0.96, slope = 1.06, intercept = 0.05), the mean difference was 0.39 ± 1.11 ml/min/100 g. Our data demonstrate that the measurement of RBBF by means of FM allows a valid determination of RBBF.
Role of Granulocyte-Macrophage Colony-Stimulating Factor on Apoptosis Induced by Ischemia-Reperfusion in the Intestinal Epithelium
Authors: Bedirli A. , Soyuer I. , Muhtaroglu S. , Guler I. 
Published: June 2003

<i>Background:</i> To evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on ischemia-reperfusion-induced apoptosis in the intestinal epithelium. <i>Methods:</i> In this study, 50 male Wistar albino rats were used. After midline laparotomy superior mesenteric artery (SMA) was identified only in the sham group, while 60 min of ischemia and 2 h of reperfusion were performed in the control group. In the treatment groups, after 15, 30 and 60 min of ischemia, respectively, 1 µg/kg GM-CSF was administered subcutaneously, followed by 2 h of reperfusion. Malondialdehyde (MDA), campothecin (CAM), an indicator of DNA fragmentation, and histopathology were evaluated in the intestinal mucosa. <i>Results:</i> Tissue MDA levels were found significantly high in all groups at various times of ischemia and 2 h of reperfusion compared with the sham group (p < 0.001). Administration of GM-CSF following 60 min of ischemia caused a significant increase in the MDA levels compared with the control group (6,430 ± 725 vs. 4,174 ± 565 nmol/g protein for jejunum. 7,576 ± 618 vs. 4,938 ± 809 nmol/g protein for ileum, p < 0.05). Intestinal ischemia and reperfusion resulted in a significant increase in tissue CAM levels (p < 0.05). The highest CAM value was found in the group in which 60 min of ischemia and 2 h of reperfusion were performed (50 ± 3.2 ng/ml for jejunum, 52.8 ± 2.7 ng/mg for ileum). Compared with the control group, GM-CSF administration following 1 h of ischemia aggravated the tissue injury. <i>Conclusions:</i> Apoptosis was induced in the small intestine by ischemia-reperfusion. GM-CSF increased the apoptosis of intestinal epithelial cells and exacerbated mucosal injury due to ischemia-reperfusion.
Androgen Therapy in Constitutional Delay of Growth
Authors: Lampit Meir , Hochberg Ze’ev 
Published: June 2003

<i>Background/Aims:</i> Two modalities of androgen therapy prevail in the treatment of constitutional delay of growth (CDG): monthly injections of testosterone or daily tablets of the non-aromatizable oxandrolone. The present study was undertaken to prospectively compare both compounds and dose. <i>Methods: </i>Thirty patients with CDG were the subjects of this study. The protocol required that they all be at age 12–14 years with a bone age delay of more than 2 ‘years’, height less than –2 SDS and growth velocity less than –0.5 SDS. The subjects were at a Tanner stage 1 or 2 and testicular volume were no larger than 4 ml. They were randomly assigned into 3 treatment groups: group 1 patients received monthly injections of 25 mg testosterone propionate-enanthate; group 2 patients received monthly injections of 50 mg testosterone propionate-enanthate; group 3 patients received oral oxandrolone at a weekly dose of 0.7 mg/kg. Treatment was given for a period of 6 months and follow-up commenced 6 months later and yearly thereafter for 2 years. <i>Results:</i> Height velocity and height increased significantly only in groups 2 and 3. Bone age advanced most in group 2. Puberty progressed faster in that group as compared with group 3. The predicted adult height before and 2 years after completion of treatment remained unchanged in the two testosterone groups. It increased significantly in the oxandrolone group from a mean 169.8 cm before therapy to a mean 177.5 cm 2 years after completion of therapy. Peak GH levels were significantly higher on both testosterone 50 mg and oxandrolone, as compared to pretreatment levels. The increment was significantly greater in group 2 as was the increment in serum IGF-1 and IGFBP3. <i>Conclusions:</i> These results imply that 6 months of testosterone injections at a dose of 50 mg, but not 25 mg, is an effective and safe treatment for patients with CDG, with no considerable impact on final height prediction. On the other hand, daily oxandrolone treatment, starting at age 12–14 years, may increase the predicted final adult height.
Effect of Hospitalization on Intraocular Pressure in Patients with Normal-Tension Glaucoma
Authors: Kashiwagi Kenji , Kohno Kyoko , Tsukahara Shigeo 
Published: June 2003

<i>Objective:</i> To investigate the effect of hospitalization on intraocular pressure (IOP) in patients with normal-tension glaucoma (NTG). <i>Methods:</i> The study was conducted in 52 patients with a definite diagnosis of NTG. The correlation between IOP measured from 9.00 a.m. to 12.00 p.m. on an outpatient basis within 3 months each prior to and after hospitalization (ambulatory IOP) and IOP measured during the same time period after admission (inpatient IOP) was investigated in NTG patients. <i>Results:</i> Inpatient IOP (13.9 ± 2.4 mm Hg) was significantly lower than ambulatory IOP (15.2 ± 2.1 mm Hg), with a difference of 1.3 ± 2.0 mm Hg (p < 0.01). The difference between inpatient IOP and ambulatory IOP was negatively correlated with inpatient IOP (r = 0.58, p < 0.01). <i>Conclusions:</i> These results revealed that hospitalization decreased IOP in NTG patients, with the decrease being particularly pronounced in cases of low ambulatory IOP. Interpretation of inpatient IOP should be carefully included in glaucoma treatment.