bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetics of fibrin clot structure: a twin study
Authors: Dunn Emma J. , Ariëns Robert A. , de Lange Marlies , Snieder Harold , Turney John H. , Spector Timothy D. , Grant Peter J. 
Published: November 2003

AbstractCoronary artery thrombosis following plaque rupture is an important feature of myocardial infarction, and studies have highlighted the role of coagulation in this condition. Although genetic and environmental influences on the variance in coagulation protein concentrations have been reported, there are no data on the heritability of structure/function of the final phenotype of the coagulation cascade, the fibrin clot. To assess genetic and environmental contributions to fibrin structure, permeation and turbidity studies were performed in 137 twin pairs (66 monozygotic, 71 dizygotic). The environmental influence (e2) on pore size (Ks) (e2 = 0.61 [95% confidence interval (CI), 0.45-0.80]) and fiber size (e2 = 0.54 [95% CI, 0.39-0.73]) was greater than the heritability (h2 = 0.39 [95% CI, 0.20-0.55] and 0.46 [95% CI, 0.27-0.62], respectively). After correction for fibrinogen levels, the environmental effect persisted for Ks (e2 = 0.61), but genetic influence assumed a greater importance in determining fiber size (h2 = 0.73). Multivariate analysis revealed an overlap in the influence of genetic and environmental factors on fibrinogen levels, Ks, and fiber size. Factor XIII B subunit showed environmental and genetic correlation with fibrinogen and fiber size and a genetic correlation with Ks. The results indicate that genetic and environmental influences are important in determining fibrin clot structure/function.
Negative regulation of FcϵRI-mediated mast cell activation by a ubiquitin-protein ligase Cbl-b
Authors: Qu Xiujuan , Sada Kiyonao , Kyo Shinkou , Maeno Koichiro , Miah S. M. Shahjahan , Yamamura Hirohei 
Published: November 2003

AbstractAggregation of the high-affinity immunoglobulin E (IgE) receptor (FcϵRI) on mast cells induces a number of biochemical events, including protein-tyrosine phosphorylation leading to degranulation and multiple cytokine gene transcription. Here, we have demonstrated that a second member of the Cbl family of ubiquitin-protein ligase Cbl-b translocates into the lipid raft after FcϵRI engagement. Overexpression of Cbl-b in the lipid raft inhibits FcϵRI-mediated degranulation and cytokine gene transcription through the distinct mechanism. A point mutation of Cys373 in the RING finger domain of Cbl-b abrogates the suppression of FcϵRI-mediated degranulation but not cytokine gene transcription. The antigen-induced tyrosine phosphorylation of FcϵRI, Syk, phospholipase C-γ (PLC-γ), activation of c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK), inhibitor of nuclear factor κB kinase (IKK), and Ca++ influx were all suppressed in the cells overexpressing Cbl-b in the lipid raft. In particular, the expression amount of Gab2 protein and thereby its FcϵRI-mediated tyrosine phosphorylation were dramatically down-regulated by ubiquitin-protein ligase activity of Cbl-b. These results suggest that Cbl-b is a negative regulator of both Lyn-Syk-LAT and Gab2mediated complementary signaling pathways in FcϵRI-mediated mast cell activation.
Von Willebrand factor C1C2 domain is involved in platelet adhesion to polymerized fibrin at high shear rate
Authors: Keuren Jeffrey F. W. , Baruch Dominique , Legendre Paulette , Denis Cécile V. , Lenting Peter J. , Girma Jean-Pierre , Lindhout Theo 
Published: November 2003

AbstractFibrin is actively involved in platelet reactions essential for thrombus growth, in which von Willebrand factor (VWF) might be an important mediator. The aim of this study was to localize VWF domains that bind to fibrin and to determine their relevance in platelet adhesion. VWF binds specifically to fibrin with an apparent Kd of 2.2 μg/mL. Competition in the presence of 2 complementary fragments, SpIII (residues 1-1365) and SpII (residues 1366-2050), indicated that the high affinity binding site for fibrin is located in the C-terminal part, thus distinct from the A domains. Comparison of 2 deleted rVWF (ΔD4B-rVWF, ΔC1C2-rVWF) suggested that the C1C2 domains contained a fibrin binding site. This site is distinct from RGD, as shown by binding of D1746G-rVWF to fibrin. Perfusion studies at high shear rate demonstrated that C1C2 domains were required for optimal platelet adhesion to fibrin. With the use of a VWF-deficient mouse model, it was found that plasma VWF is critical for platelet tethering and adhesion to fibrin. These results suggest a dual role of fibrin-bound VWF in thrombus formation: first, fibrin-bound VWF is critical in the recruitment of platelets by way of glycoprotein (GP) Ib, and, second, it contributes to stationary platelet adhesion by way of binding to activated αIIbβ3.
Functional differences between hepcidin 1 and 2 in transgenic mice
Authors: Lou Dan-Qing , Nicolas Gaël , Lesbordes Jeanne-Claire , Viatte Lydie , Grimber Gisèle , Szajnert Marie-France , Kahn Axel , Vaulont Sophie 
Published: November 2003

AbstractHepcidin is a 25-amino acid peptide involved in iron homeostasis in mice and humans. It is produced in the liver from a larger precursor, and it is detectable in blood and urine. In contrast to the human genome, which contains only one copy of the gene, the mouse genome contains 2 highly similar hepcidin genes, hepc1 and hepc2, which are, however, considerably divergent at the level of the corresponding mature 25-amino acid peptide. This striking observation led us to ask whether hepc1 and hepc2 performed the same biologic activity with regard to iron metabolism in the mouse. We recently described the severe iron-deficient anemia phenotype in transgenic mice overexpressing hepc1 in the liver. Here we report that, in contrast to the hepc1-transgenic mice, none of the 7 founder hepc2-transgenic animals suffered from anemia. They all developed normally with hematologic parameters similar to the nontransgenic littermates. Hepc2 transgenic mRNA level was found to be very high for all lines compared with the level of hepc1 transgene mRNA necessary to produce severe anemia. These data provide evidence that hepc2 does not act on iron metabolism like hepc1 and give clues for the identification of amino acids important for the iron-regulatory action of the mature 25-amino acid peptide. (Blood. 2004;103:2816-2821)
The worldwide distribution of the VHL 598C&gt;T mutation indicates a single founding event
Authors: Liu Enli , Percy Melanie J. , Amos Christopher I. , Guan Yongli , Shete Sanjay , Stockton David W. , McMullin Mary F. , Polyakova Lydia A. , Ang Sonny O. , Pastore Yves D. , Jedlickova Katerina , Lappin Terry R. J. , Gordeuk Victor , Prchal Josef T. 
Published: November 2003

Abstract
The first congenital defect of hypoxia-sensing homozygosity for VHL 598C&gt;T mutation was recently identified in Chuvash polycythemia. Subsequently, we found this mutation in 11 unrelated individuals of diverse ethnic backgrounds. To address the question of whether the VHL 598C&gt;T substitution occurred in a single founder or resulted from recurrent mutational events in human evolution, we performed haplotype analysis of 8 polymorphic markers covering 340 kb spanning the VHL gene on 101 subjects bearing the VHL 598C&gt;T mutation, including 72 homozygotes (61 Chuvash and 11 non-Chuvash) and 29 heterozygotes (11 Chuvash and 18 non-Chuvash), and 447 healthy unrelated individuals from Chuvash and other ethnic groups. The differences in allele frequencies for each of the 8 markers between 447 healthy controls (598C) and 101 subjects bearing the 598T allele (P &lt; 10–7) showed strong linkage disequilibrium. Haplotype analysis indicated a founder effect. We conclude that the VHL 598C&gt;T mutation, the most common defect of congenital polycythemia yet found, was spread from a single founder 14 000 to 62 000 years ago.
Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis
Authors: Wilson Nicholas S. , El-Sukkari Dima , Villadangos José A. 
Published: November 2003

AbstractDendritic cells (DCs) change their antigen-presenting properties during maturation. Immature DCs efficiently capture antigens, but are reported to be impaired in their processing and presenting capacity. Upon an encounter with an inflammatory stimulus, DCs undergo a maturation process that leads to efficient presentation of antigens captured at the time of activation, but precludes processing of antigens encountered at later time points. The mechanisms that underlie these developmental changes are controversial. Thus, it is unclear whether immature DCs can present self antigens, and which are the checkpoints that regulate antigen presentation in immature and mature DCs. We have characterized these mechanisms using DCs derived directly from lymphoid organs. Immature lymphoid organ DCs constitutively presented self peptides bound to major histocompatibility complex class II (MHCII) molecules, but these MHCII-peptide complexes were degraded quickly after their transient expression on the cell surface. During maturation, MHC II endocytosis was down-regulated, so that newly generated MHC II–peptide complexes accumulated on the plasma membrane. Simultaneously, MHC II synthesis was down-regulated, thus preventing the turnover of the MHC II–peptide complexes that accumulated early during maturation. Our results demonstrate that immature DCs constitutively present self antigens in the lymphoid organs and characterize the molecular basis of the capacity of DCs to provide “antigenic memory” in vivo.
In vivo exit of c-kit+/CD49dhi/β7+ mucosal mast cell precursors from the bone marrow following infection with the intestinal nematode Trichinella spiralis
Authors: Pennock Joanne L. , Grencis Richard K. 
Published: November 2003

AbstractWe have used the parasite helminth Trichinella spiralis to study the generation and differentiation of mast cell progenitors in the bone marrow of mice, as this infection triggers an intestinal mastocytosis which correlates with parasite expulsion. C-kit+ mast cell progenitors have previously been defined by methylcellulose colony-forming units and by limiting dilution assays in vitro. In vivo experiments have demonstrated the essential requirement by mast cells for specific integrin expression. We have defined 2 c-kit+ populations in the bone marrow, one of which coexpresses CD49d/β7 integrin, a marker essential for small intestine immigration. We have confirmed the phenotype of these cells by using antagonistic anti-c-kit antibody in vivo. Our data show that the loss of c-kit+/β7+ cells from the bone marrow correlates with their appearance in the blood and precedes detection of mature mast cells in the gut by 3 days. This exit correlates with an increase in soluble stem cell factor (SCF) in the serum, suggesting that the c-kit/SCF interaction may be chemotactic or haptotactic in nature. This study shows that during infection the bone marrow environment generates mast cells destined for the intestinal mucosa before their exit into the periphery, indicating a clear interplay between infection site and hematopoietic tissue. (Blood. 2004;103:2655-2660)
Regulation of Insulin-Like Growth Factor (IGF)-I Action by Matrix Metalloproteinase-3 Involves Selective Disruption of IGF-I/IGF-Binding Protein-3 Complexes
Authors: Fowlkes John L. , Serra Delila M. , Bunn R. Clay , Thrailkill Kathryn M. , Enghild Jan J. , Nagase Hideaki 
Published: November 2003

AbstractIGF-I and IGF-II play important roles in growth and development via interactions with cell-surface receptors; however, in nature, IGFs are sequestered by at least six soluble, high-affinity IGF-binding proteins (IGFBPs), namely IGFBPs 1–6. Herein, we demonstrate that the stromal cell-derived extracellular matrix-degrading metalloproteinase stromelysin 1 (matrix metalloproteinase 3) disrupts IGF/IGFBP-3 complexes and liberates free, intact IGFs, leading to phosphorylation of cell surface type 1 IGF receptors and cellular proliferation. Tissue inhibitor of metalloproteinases (TIMP-1) or an antibody to the type 1 IGF receptor mitigates IGF-mediated cellular proliferation. Thus, these studies suggest that matrix metalloproteinases, beyond their effects on extracellular matrix turnover, regulate cellular proliferation by modulating the bioavailability of IGFs, an event critical for such diverse phenomena as embryo development, morphogenesis, angiogenesis, and tumorigenesis.
Differential Expression of a Cutaneous Corticotropin-Releasing Hormone System
Authors: Slominski Andrzej , Pisarchik Alexander , Tobin Desmond J. , Mazurkiewicz Joseph E. , Wortsman Jacobo 
Published: November 2003

AbstractWe completed the mapping of a cutaneous CRH signaling system in two species with widely different determinants of skin functions, humans and mice. In human skin, the CRH receptor (CRH-R) 1 was expressed in all major cellular populations of epidermis, dermis, and subcutis with CRH-R1α being the most prevalent isoform. The CRH-R2 gene was expressed solely in hair follicle keratinocytes and papilla fibroblasts, whereas CRH-R2 antigen was localized predominantly in hair follicles, sebaceous and eccrine glands, muscle and blood vessels. In mouse skin, the CRH-R2 gene and protein were widely expressed in all cutaneous compartments and in cultured normal and malignant melanocytes. CRH-binding protein mRNA was present in dermal fibroblasts, melanoma cells, and sc fat of human skin and undetectable in mouse skin. The urocortin II gene was expressed equally in mouse and human skin. Taken together with our previous investigations, the present studies document the preferential expression of CRH-R1 in human skin, which mirrors CRH-R2 expression patterns in human and mouse skin. They are likely reflecting different functional activities of human and mouse skin. The adnexal location of CRH-R2 suggests a role for the receptor in hair growth. The differential interspecies CRH signaling expression pattern probably reflects adaptation to species-specific skin function determinants.
Activation of the Retinoid X Receptor Suppresses Appetite in the Rat
Authors: Ogilvie Kathleen M. , Saladin Régis , Nagy Tim R. , Urcan Mary S. , Heyman Richard A. , Leibowitz Mark D. 
Published: November 2003

AbstractThe retinoid X receptor (RXR), a ubiquitously expressed intracellular receptor, regulates pathways controlling glucose, triglycerides, cholesterol, and bile acid metabolism. In addition to its role in those metabolic pathways, we reported that RXR activation with a pan agonist [e.g. LG100268 (LG268)] decreases both body weight gain (BWG) and food consumption (FC) in obese, insulin-resistant rodents. In parallel with those changes in energy balance, we show here that activation of RXR pathways results in adipose tissue remodeling, particularly within sc fat where the rate of apoptosis is increased 5-fold. This change may underlie the selective decrease in fat mass observed in Zucker fatty rats treated with LG268 for 6 wk. Because FC is strongly correlated with BWG in treated animals, we hypothesized that regulation of FC might be the primary mechanism underlying reduced BWG during RXR agonist administration. Importantly, decreased FC is due to decreased meal size, suggestive of induced satiety rather than malaise and/or aversion to food. Furthermore, administration of LG268 directly into the brain via intracerebroventricular injection also reduces FC, BWG, and insulin, whereas the elevation in triglycerides observed after oral administration is absent. The latter observation suggests that RXR actions on energy balance and lipid homeostasis are separable. Therefore, ligand-mediated activation of either an RXR homodimer or an unidentified heterodimeric complex regulates pathways controlling energy balance at least in part via a central nervous system-mediated mechanism.
Photoperiod Influences the Effects of Exercise and Food Restriction on an Antigen-Specific Immune Response in Siberian Hamsters
Authors: Bilbo Staci D. , Nelson Randy J. 
Published: November 2003

AbstractEnvironmental conditions influence the onset and severity of illness and infection and may compromise survival. Energetically challenging conditions during winter may directly induce death through hypothermia, starvation, or shock. The ability to forecast and prepare for the arrival of challenging conditions associated with winter (e.g. low temperatures, decreased food) likely confers survival advantages. Siberian hamsters (Phodopus sungorus) stop reproduction and reduce body mass (∼25%) during short, winter-like day lengths, resulting in energetic savings. Hamsters also increase circulating glucocorticoids and lymphocytes (e.g. T cells, NK cells), and exhibit enhanced antigen-specific delayed-type-hypersensitivity (DTH) responses in the skin during short days (SDs). We tested the hypothesis that Siberian hamsters use SD lengths to signal the onset of winter to mediate the energetic trade-offs among body mass, reproductive function, and immune function. Long-day (LD; 16 h light, 8 h dark) and SD (8 h light, 16 h dark) hamsters were either food restricted (25%) or provided ad libitum (ad lib) food for 4 wk; half of all hamsters in each food condition had voluntary access to a running wheel, and half remained sedentary. SD hamsters enhanced DTH responses compared with LD hamsters under sedentary ad lib conditions. Exercise enhanced DTH in LD hamsters regardless of food intake. Furthermore, food-restriction did not significantly influence DTH in LD hamsters. In contrast, food-restriction suppressed DTH in SD hamsters regardless of activity condition, and exercise modestly enhanced DTH only in SD hamsters with ad lib access to food. In sum, moderate energetic deficiency suppressed DTH in SD (but not LD) hamsters, and this suggests that hamsters may have evolved to enhance immune responses during winter in preparation for increased metabolic stressors.
Inhibition of Testicular Steroidogenesis by the Xenoestrogen Bisphenol A Is Associated with Reduced Pituitary Luteinizing Hormone Secretion and Decreased Steroidogenic Enzyme Gene Expression in Rat Leydig Cells
Authors: Akingbemi Benson T. , Sottas Chantal M. , Koulova Anna I. , Klinefelter Gary R. , Hardy Matthew P. 
Published: November 2003

AbstractExposure of humans to bisphenol A (BPA), a monomer in polycarbonate plastics and a constituent of resins used in food packaging and dentistry, is significant. In this report exposure of rats to 2.4 μg/kg·d (a dose that approximates BPA levels in the environment) from postnatal d 21–35 suppressed serum LH (0.21 ± 0.05 ng/ml; vs. control, 0.52 ± 0.04; P &lt; 0.01) and testosterone (T) levels (1.62 ± 0.16 ng/ml; vs. control, 2.52 ± 0.21; P &lt; 0.05), in association with decreased LHβ and increased estrogen receptor β pituitary mRNA levels as measured by RT-PCR. Treatment of adult Leydig cells with 0.01 nm BPA decreased T biosynthesis by 25% as a result of decreased expression of the steroidogenic enzyme 17α-hydroxylase/17–20 lyase. BPA decreased serum 17β-estradiol levels from 0.31 ± 0.02 ng/ml (control) to 0.22 ± 0.02, 0.19 ± 0.02, and 0.23 ± 0.03 ng/ml in rats exposed to 2.4 μg, 10 μg, or 100 mg/kg·d BPA, respectively, from 21–35 d of age (P &lt; 0.05) due to its ability to inhibit Leydig cell aromatase activity. Exposures of pregnant and nursing dams, i.e. from gestation d 12 to postnatal d 21, decreased T levels in the testicular interstitial fluid from 420 ± 34 (control) to 261 ± 22 (P &lt; 0.05) ng/ml in adulthood, implying that the perinatal period is a sensitive window of exposure to BPA. As BPA has been measured in several human populations, further studies are warranted to assess the effects of BPA on male fertility.
A comparison of survival lifetime of the Provox® and the Provox®2 voice prosthesis
Authors: Lequeux T. , Badreldin A. , Saussez S. , Thill M. P. , Oujjan L. , Chantrain G. 
Published: November 2003

The Provox® (Atos Medical AB, Hörby, Sweden) voice prosthesis was developed between 1988 and 1990 and has been used at our centre with regular success since 1993. Since 1996, a second generation of Provox® (Provox®2) has been used, which can be inserted by an anterograde technique. The aim of this study is to compare the survival lifetime of both voice prostheses. The survival time of the two voice prostheses were compared retrospectively in 152 devices placed in 38 patients. A Kaplan-Meier analysis was performed to determine the survival lifetimes and a log rank test was performed to compare the two curves. Clinical factors affecting the lifetime were also analysed with a Kaplan-Meier plot.The median survival lifetime of the Provox® and Provox®2 were 303 and 144 days respectively. The Kaplan-Meier estimation shows that this difference is statistically significant (p=0.02). It is considered an early failure if it occurs within the first three months. There was a larger number of early failures with the Provox®2 than with the Provox® (p=0.04). Neither the gender nor the age affected the lifetime of the devices. Radiotherapy seemed to lengthen the lifetime of the first valve.The survival lifetime of the second generation Provox®2 valve is shorter than the lifetime of the first generation Provox®. This could be due to the difference in elasticity of these valves that could lead to a different level of colonization and invasion of the valves by micro-organisms.
The Legitimation of al-Hakam b. al-ᶜAs: Umayyad Government in Seventh-Century Kirman
Authors: Sears Stuart D. 
Published: November 2003

The umayyads faced many challenges in consolidating their authority in the years after the first fitna (35–41 H. /656–61 C.E.). Among these were frequent revolts by Kharijites. While the Umayyads suppressed most of the revolts with little trouble until the second fitna (60–72/680–92), the ideological foundations of Kharijite resistance and the wide sympathy it enjoyed had serious consequences. It undermined the informal traditions upon which the caliphate was based. This was not simply a problem for the caliph in Damascus but more critically for governors exercising authority in distant provinces where caliphal influence proved weak and opposition movements propagated with relative ease.While little is known of Kirman's history during this period, one of its governors, al-Hakam b. al-ᶜAs, addressed these challenges in the fifties/mid 670s by appealing to an inchoate absolutism. He promulgated legends on his coins linking himself and his government to God.
Iranian Perspectives on Security in the Persian Gulf
Authors: Taremi Kamran 
Published: November 2003

Iran is the most Important Regional Player in the Persian Gulf. It has the region's strongest military. No other navy in the region matches Iran’s. Its GNP is larger than that of most other littoral states and its industrial base more sophisticated. It is also by far the most populous state in the Gulf. Geographically, Iran borders the entire northern shores of the Persian Gulf. Iranian territory also forms the northern side of the Strait of Hormuz. This and multiple islands in the vicinity of the strait give Iran the ability to control this strategic choke point. Consequently, Iranian views on security in the Persian Gulf are worthy of special attention.This paper explores these views in an attempt to answer such questions as: What are Iranian perspectives on Gulf security? What are the factors that have shaped these perspectives? How have these perspectives influenced policy and how have they evolved over time?