bluuebunny/crossref_metadata_2025_split huggingface dataset:
IQGAP2 functions as a GTP-dependent effector protein in thrombin-induced platelet cytoskeletal reorganization
Authors: Schmidt Valentina A. , Scudder Lesley , Devoe Craig E. , Bernards André , Cupit Lisa D. , Bahou Wadie F. 
Published: April 2003

Abstract
Human blood platelets are anucleate cells whose response to extracellular stimuli results in actin cytoskeleton rearrangements, thereby providing the critical initial step in the regulation of hemostasis. The serine protease α-thrombin, known to activate platelets by cleavage of a family of protease-activated receptors (PARs), is the most potent physiologic activator of human platelets, though downstream effector proteins uniquely linked to platelet cytoskeletal actin polymerization remain largely uncharacterized. The gene encoding the putative rac1/cdc42 effector protein IQGAP2 was identified within the PAR gene cluster at 5q13, flanked telomeric byPAR1 and encompassing PAR3. Immunofluorescence microscopy demonstrated IQGAP2 expression in filopodial extensions of activated platelets and colocalized with F-actin in lamellipodia and filopodia of IQGAP2-transfected COS1 cells. Platelet activation by α-thrombin, but not saturating concentrations of fibrillar collagen or adenosine 5′-diphosphate, uniquely assemble an IQGAP2/arp2/3–actin cytoplasmic complex, an association regulated by guanosine triphosphate rac1 ([GTP]rac1) but not by [GTP]cdc42. Likewise, only thrombin-activated platelets resulted in rapid translocation of IQGAP2 to the platelet cytoskeleton. These observations identify a physiologic scaffolding function for IQGAP2 and establish the presence of a functional genomic unit in humans uniquely evolved to regulate thrombin-induced platelet cytoskeletal actin reorganization.
Stimulation of osteoprotegerin production is responsible for osteosclerosis in mice overexpressing TPO
Authors: Chagraoui Hédia , Tulliez Micheline , Smayra Tarek , Komura Emiko , Giraudier Stéphane , Yun Theodore , Lassau Nathalie , Vainchenker William , Wendling Françoise 
Published: April 2003

AbstractMyelofibrosis and osteosclerosis are prominent features arising in mice overexpressing thrombopoietin (TPO). The pivotal role of transforming growth factor β1 (TGF-β1) in the pathogenesis of myelofibrosis has been documented, but the mechanisms mediating osteosclerosis remain unclear. Here, we used mice deficient in osteoprotegerin (OPG), a secreted inhibitor of bone resorption, to determine whether osteosclerosis occurs through a deregulation of osteoclastogenesis. Marrow cells from opg-deficient mice (opg−/−) or wild-type (WT) littermates were infected with a retrovirus encoding TPO and engrafted into anopg−/− or WT background for long-term reconstitution. The 4 combinations of graft/host (WT/WT,opg−/−/opg−/−,opg−/−/WT, and WT/opg−/−) were studied. Elevation of TPO and TGF-β1 levels in plasma was similar in the 4 experimental groups and all the mice developed a similar myeloproliferative syndrome associated with severe myelofibrosis. Osteosclerosis developed in WT hosts engrafted with WT or opg−/− hematopoietic cells and was associated with increased OPG levels in plasma and decreased osteoclastogenesis. In contrast,opg−/− hosts exhibited an osteoporotic phenotype and a growth of bone trabeculae was rarely seen. These findings suggest that osteosclerosis in mice with TPO overexpression occurs predominantly via an up-regulation of OPG in host stromal cells leading to disruption of osteoclastogenesis.
Combined carrier status of prothrombin 20210A and factor XIII-A Leu34 alleles as a strong risk factor for myocardial infarction: evidence of a gene-gene interaction
Authors: Butt Christopher , Zheng Hong , Randell Edward , Robb Desmond , Parfrey Patrick , Xie Ya-Gang 
Published: April 2003

Abstract
Studies associating the prothrombin 20210G>A (FII 20210A), factor V Leiden (FVL), and factor XIII Leu34 (FXIII-A Leu34) alleles with myocardial infarction (MI) have yielded conflicting results. Complicated gene-gene interactions, small sample sizes, and heterogeneous genetic and environmental backgrounds may contribute to opposing findings. Simultaneous analysis of multiple gene variants in a large sample size from a genetically isolated population may overcome these weaknesses. Genotyping was performed in 500 MI patients and 500 control subjects from the genetically isolated Newfoundland population to determine the prevalence of the FII 20210A, FVL, and FXIII-A Leu34 variants and their association with MI. Gene-gene interactions were also analyzed. The prevalence of the FII 20210A allele was higher in MI patients (3.2%) than in control subjects (1.0%;P = .015). The FII 20210A allele was also 5.6-fold higher in MI patients younger than 51 years than in age-matched control subjects (P = .04). FVL showed 3.9-fold higher prevalence in young patients than in patients older than 50 years (P = .004) and 2.7-fold higher than in age-matched control subjects (P = .007). Furthermore, the prevalence of combined carriers of the FXIII-A L34 and FII 20210A alleles was 12-fold higher in MI patients than in control subjects (P = .002) and with 92% penetrance. There was disequilibrium of the FXIII-A Leu34 allele to MI patients carrying the FII 20210A allele as a genetic background. Based on our data, we determined that (1) the FII 20210A allele is a risk factor for MI, possibly important for early onset; (2) FVL may predispose for early-onset MI; (3) the FXIII-A Leu34 allele predisposes for MI in males only; however, (4) interaction between the FII 20210A and FXIII-A Leu34 alleles forms a synergistic coeffect that strongly predisposes for MI, placing combined carriers at high risk for MI.
Multiple myeloma tumor progression in the 5T2MM murine model is a multistage and dynamic process of differentiation, proliferation, invasion, and apoptosis
Authors: Asosingh Kewal , De Raeve Hendrik , Van Riet Ivan , Van Camp Benjamin , Vanderkerken Karin 
Published: April 2003

AbstractAt clinical presentation, multiple myeloma (MM) is already a well-established disease. The processes involved in earlier stages are, however, unknown. Here the 5T2MM murine model was used to analyze differentiation, proliferation, invasion, and apoptosis of MM cells during disease progression. Naive mice were injected with 5T2MM cells and from the onset of the experiment 3 mice were killed each week until the end stage. Myeloma cells were isolated from the bone marrow and selected by sequential gating of 5T2MM idiotype+ cells by flow cytometry. Microscopic analysis of these sorted 5T2MM idiotype+ cells confirmed their identity as true myeloma cells. Based on serum paraprotein concentration and bone marrow tumor load, 3 disease stages were distinguished: a quiescent stage, an intermediate stage, and an end stage, of slow, moderate, and accelerated tumor progression, respectively. In the quiescent stage, the majority of the myeloma cells were CD45+CD138−IL-6Rα+, corresponding to an immature, invasive, and apoptosis-resistant phenotype. In the end stage the majority of the myeloma cells had differentiated into CD45−CD138+IL-6Rα− cells, corresponding to a mature, less invasive, and apoptosis-sensitive phenotype. In the intermediate stage a gradual transition from the quiescent toward the end stage was observed. In line with these data, analysis of sorted 5T2MM cells demonstrated a significant decrease in invasive capacity and a significant increase in (dexamethasone-induced) apoptosis sensitivity and in proliferation during the disease progression. These data suggest that myeloma disease progression is a multistage and dynamic process of differentiation, proliferation, invasion, and apoptosis.
Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML)
Authors: Guan Yinghui , Gerhard Brigitte , Hogge Donna E. 
Published: April 2003

AbstractAlthough many acute myeloid leukemia (AML) colony-forming cells (CFCs) and long-term culture–initiating cells (LTC-ICs) directly isolated from patients are actively cycling, quiescent progenitors are present in most samples. In the current study,3H-thymidine (3H-Tdr) suicide assays demonstrated that most NOD/SCID mouse leukemia-initiating cells (NOD/SL-ICs) are quiescent in 6 of 7 AML samples. AML cells in G0, G1, and S/G2+M were isolated from 4 of these samples using Hoechst 33342/pyroninY staining and cell sorting. The progenitor content of each subpopulation was consistent with the 3H-Tdr suicide results, with NOD/SL-ICs found almost exclusively among G0 cells while the cycling status of AML CFCs and LTC-ICs was more heterogeneous. Interestingly, after 72 hours in serum-free culture with or without Steel factor (SF), Flt-3 ligand (FL), and interleukin-3 (IL-3), most G0 AML cells entered active cell cycle (percentage of AML cells remaining in G0 at 72 hours, 1.2% to 37%, and 0% to 7.6% in cultures without and with growth factors [GFs], respectively) while G0 cells from normal lineage-depleted bone marrow remained quiescent in the absence of GF. All 4 AML samples showed evidence of autocrine production of 2 or more of SF, FL, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, 3 of 4 samples contained an internal tandem duplication of theFLT3 gene. In summary, quiescent leukemic cells, including NOD/SL-ICs, are present in most AML patients. Their spontaneous entry into active cell cycle in short-term culture might be explained by the deregulated GF signaling present in many AMLs.
Aberrant development of Plasmodium falciparum in hemoglobin CC red cells: implications for the malaria protective effect of the homozygous state
Authors: Fairhurst Rick M. , Fujioka Hisashi , Hayton Karen , Collins Kathleen F. , Wellems Thomas E. 
Published: April 2003

Abstract
Although selection of hemoglobin C (HbC) by malaria has been speculated for decades, only recently have epidemiologic studies provided support for HbC protection against malaria in West Africa. A reduced risk of malaria associated with the homozygous CC state has been attributed to the inability of CC cells to support parasite multiplication in vitro. However, there have been conflicting data and conclusions regarding the ability of CC red cells to support parasite replication. Reports that parasites cannot multiply in CC cells in vitro contrast with detection of substantial parasite densities in CC patients with malaria. We have therefore investigated Plasmodium falciparum growth in CC cells in vitro. Our data show that the multiplication rate of several P falciparum lines is measurable in CC cells, but lower than that in AA (HbA-normal) cells. A high proportion of ring forms and trophozoites disintegrates within a subset of CC cells, an observation that accounts for the overall lower replication rate. In addition, knobs present on the surface of infected CC cells are fewer in number and morphologically aberrant when compared with those on AA cells. Events in malaria pathogenesis that involve remodeling of the erythrocyte surface and the display of parasite antigens may be affected by these knob abnormalities. Our data suggest that only a subset of CC cells supports normal parasite replication and that components of malaria protection associated with the CC state may affect the parasite's replication capacity and involve aberrant knob formation on CC cells.
Duodenal nonheme iron content correlates with iron stores in mice, but the relationship is altered by Hfe gene knock-out
Authors: Simpson Robert J. , Debnam Edward S. , Laftah Abas H. , Solanky Nita , Beaumont Nick , Bahram Seiamak , Schümann Klaus , Srai S. Kaila S. 
Published: April 2003

AbstractHereditary hemochromatosis is a common iron-loading disorder found in populations of European descent. It has been proposed that mutations causing loss of function of HFE gene result in reduced iron incorporation into immature duodenal crypt cells. These cells then overexpress genes for iron absorption, leading to inappropriate cellular iron balance, a persistent iron deficiency of the duodenal mucosa, and increased iron absorption. The objective was to measure duodenal iron content in Hfe knock-out mice to test whether the mutation causes a persistent decrease in enterocyte iron concentration. In both normal and Hfe knock-out mice, duodenal nonheme iron content was found to correlate with liver iron stores (P < .001, r = 0.643 and 0.551, respectively), and this effect did not depend on dietary iron levels. However, duodenal iron content was reduced in Hfe knock-out mice for any given content of liver iron stores (P < .001).
A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human β-globin gene transfer
Authors: Rivella Stefano , May Chad , Chadburn Amy , Rivière Isabelle , Sadelain Michel 
Published: April 2003

AbstractPatients affected by β-thalassemia major require lifelong transfusions because of insufficient or absent production of the β chain of hemoglobin (Hb). A minority of patients are cured by allogeneic bone marrow transplantation. In the most severe of the hitherto available mouse models of β-thalassemia, a model for human β-thalassemia intermedia, we previously demonstrated that globin gene transfer in bone marrow cells is curative, stably raising Hb levels from 8.0-8.5 to 11.0-12.0 g/dL in long-term chimeras. To fully assess the therapeutic potential of gene therapy in the context of a lethal anemia, we now have created an adult model of β0-thalassemia major. In this novel model, mice engrafted with β-globin–null (Hbbth3/th3) fetal liver cells succumb to ineffective erythropoiesis within 60 days. These mice rapidly develop severe anemia (2-4 g/dL), massive splenomegaly, extramedullary hematopoiesis (EMH), and hepatic iron overload. Remarkably, most mice (11 of 13) treated by lentivirus-mediated globin gene transfer were rescued. Long-term chimeras with an average 1.0-2.4 copies of the TNS9 vector in their hematopoietic and blood cells stably produced up to 12 g/dL chimeric Hb consisting of muα2:huβ2tetramers. Pathologic analyses indicated that erythroid maturation was restored, while EMH and iron overload dramatically decreased. Thus, we have established an adult animal model for the most severe of the hemoglobinopathies, Cooley anemia, which should prove useful to investigate both genetic and pharmacologic treatments. Our findings demonstrate the remarkable efficacy of lentivirus-mediated globin gene transfer in treating a fulminant blood disorder and strongly support the efficacy of gene therapy in the severe hemoglobinopathies.
Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma
Authors: Pasqualucci Laura , Migliazza Anna , Basso Katia , Houldsworth Jane , Chaganti R. S. K. , Dalla-Favera Riccardo 
Published: April 2003

Abstract
The BCL6 proto-oncogene encodes a transcriptional repressor whose expression is deregulated by chromosomal translocations in approximately 40% of diffuse large B-cell lymphomas (DLBCLs). The BCL6 regulatory sequences are also targeted by somatic hypermutation in germinal center (GC) B cells and in a fraction of all GC-derived lymphomas. However, the functional consequences of these mutations are unknown. Here we report that a subset of mutations specifically associated with DLBCL causes deregulated BCL6 transcription. These mutations affect 2 adjacent BCL6 binding sites located within the first noncoding exon of the gene, and they prevent BCL6 from binding its own promoter, thereby disrupting its negative autoregulatory circuit. These alterations were found in approximately 16% of DLBCLs devoid of chromosomal translocations involving the BCL6 locus, but they were not found in normal GC B cells. This study establishes a novel mechanism for BCL6 deregulation and reveals a broader involvement of this gene in DLBCL pathogenesis.
Impaired neutrophil maturation in truncated murine G-CSF receptor–transgenic mice
Authors: Mitsui Tetsuo , Watanabe Sumiko , Taniguchi Yoshihiro , Hanada Sachiyo , Ebihara Yasuhiro , Sato Takeshi , Heike Toshio , Mitsuyama Masao , Nakahata Tatsutoshi , Tsuji Kohichiro 
Published: April 2003

AbstractSevere congenital neutropenia (SCN) is a hematopoietic disorder characterized by neutropenia in peripheral blood and maturation arrest of neutrophil precursors in bone marrow. Patients with SCN may evolve to have myelodysplastic syndrome or acute myelocytic leukemia. In approximately 20% of SCN cases, a truncation mutation is found in the cytoplasmic region of the granulocyte colony-stimulating factor receptor (G-CSFR). We then generated mice carrying murine wild-type G-CSFR and its mutants equivalent to truncations at amino acids 718 and 731 in human G-CSFR, those were reported to be related to leukemic transformation of SCN. Although numbers of peripheral white blood cells, red blood cells, and platelets did not differ among mutant and wild-type G-CSFR transgenic (Tg) mice, both of the mutant receptor Tg mice had one third of peripheral neutrophil cell counts compared with wild-type receptor Tg mice. The mutant receptor Tg mice also showed impaired resistance to the infection with Staphylococcus aureus. Moreover, bone marrow of these Tg mice had an increased percentage of immature myeloid cells, a feature of SCN. This maturation arrest was also observed in in vitro cultures of bone marrow cells of truncated G-CSFR Tg mice under G-CSF stimulation. In addition, clonal culture of bone marrow cells of the truncated G-CSFR Tg mice showed the hypersensitivity to G-CSF in myeloid progenitors. Our Tg mice may be useful in the analysis of the role of truncated G-CSFR in SCN pathobiology.
The differential parameter method for multifrequency airborne resistivity mapping
Authors: Huang Haoping , Fraser Douglas C. 
Published: April 2003

Helicopter EM resistivity mapping began to be accepted as a means of geologic mapping in the late 1970s. The data were first displayed as plan maps and images. Some 10 years later, sectional resistivity displays became available using the same “pseudolayer” half‐space resistivity algorithm developed by Fraser and the new centroid depth algorithm developed by Sengpiel. Known as Sengpiel resistivity sections, these resistivity/depth images proved to be popular for the display of helicopter electromagnetic (EM) data in conductive environments. A limitation of the above resistivity and depth algorithms is that the resulting Sengpiel section may imply that the depth of exploration of the EM system is substantially less than is actually the case. For example, a target at depth may be expressed in the raw data, but its appearance on the Sengpiel section may be too shallow (which is a problem with the depth algorithm), or it may not even appear at all (which is a problem with the resistivity algorithm). An algorithm has been adapted from a ground EM analytic method that yields a parameter called the differential resistivity, which is plotted at the differential depth. The technique yields the true resistivity when the half‐space is homogeneous. It also tracks a dipping target with greater sensitivity and to greater depth than does the Sengpiel display method. The input parameters are the apparent resistivity and apparent depth from the pseudolayer half‐space algorithm and the skin depth for the various frequencies. The output parameters are differential resistivity and differential depth, which are computed from pairs of adjacent frequencies.
Controlled Markov set-chains with discounting
Authors: Kurano Masami , Song Jinjie , Hosaka Masanori , Huang Youqiang 
Published: April 2003

In the framework of discounted Markov decision processes, we consider the case that the transition probability varies in some given domain at each time and its variation is unknown or unobservable.To this end we introduce a new model, named controlled Markov set-chains, based on Markov set-chains, and discuss its optimization under some partial order.Also, a numerical example is given to explain the theoretical results and the computation.
Bounds for the total variation distance between the binomial and the Poisson distribution in case of medium-sized success probabilities
Authors: Weba Michael 
Published: April 2003

In applied probability, the distribution of a sum ofnindependent Bernoulli random variables with success probabilitiesp1,p2,…,pnis often approximated by a Poisson distribution with parameter λ =p1+p2+pn. Popular bounds for the approximation error are excellent for small values, but less efficient for moderate values ofp1,p2,…,pn.Upper bounds for the total variation distance are established, improving conventional estimates if the success probabilities are of medium size. The results may be applied directly, e.g. to approximation problems in risk theory.
On waiting times to populate an environment and a question of statistical inference
Authors: Bruss F. Thomas , Slavtchova-Bojkova M. 
Published: April 2003

The mathematical model we consider here is the classical Bienaymé–Galton–Watson branching process modified with immigration in the state zero.We study properties of the waiting time to explosion of the supercritical modified process, i.e. that time until all beginning cycles which die out have disappeared. We then derive the expected total progeny of a cycle and show how higher moments can be computed. With a view to applications the main goal is to show that any statistical inference from observed cycle lengths or estimates of total progeny on the fertility rate of the process must be treated with care. As an example we discuss population experiments with trout.
Base Generation by the Photolysis of an Amineimide with Triplet-sensitizers and Its Use for an Epoxide/Thiol Curing System
Authors: Katogi Shigeki , Yusa Masami , Shirai Masamitsu , Tsunooka Masahiro 
Published: April 2003

Abstract
Sensitized base generation from an amineimide is achieved by using triplet-sensitizers having a triplet energy of more than 289 kJ·mol−1, which enables the lower temperature curing of an epoxide/thiol system with a low UV dose.
Production of Hydrogen and Nanocarbon from Direct Decomposition of Undiluted Methane on High-nickeled Ni–Cu–Alumina Catalysts
Authors: Chen Jiuling , Li Xiumin , Li Yongdan , Qin Yongning 
Published: April 2003

Abstract
Very active and stable high-nickeled Ni–Cu–alumina catalysts were used to produce hydrogen and nanocarbon by direct decomposition of undiluted methane at 773–1013 K. The growth way of nanocarbon depends on reaction temperatures and may be related with the catalyst stability.
Genetic variants of serum butyrylcholinesterase in Chilean Mapuche Indians
Authors: Acuña M. , Eaton L. , Ramírez N.R. , Cifuentes L. , Llop E. 
Published: April 2003

AbstractWe estimated the frequencies of serum butyrylcholinesterase (BChE) alleles in three tribes of Mapuche Indians from southern Chile, using enzymatic methods, and we estimated the frequency of allele BCHE*K in one tribe using primer reduced restriction analysis (PCR‐PIRA). The three tribes have different degrees of European admixture, which is reflected in the observed frequencies of the atypical allele BCHE*A: 1.11% in Huilliches, 0.89% in Cuncos, and 0% in Pehuenches. This result is evidence in favor of the hypothesis that BCHE*A is absent in native Amerindians. The frequencies of BCHE*F were higher than in most reported studies (3.89%, 5.78%, and 4.41%, respectively). These results are probably due to an overestimation of the frequency of allele BCHE*F, since none of the 20 BCHE UF individuals (by the enzymatic test) individuals analyzed showed either of the two DNA base substitutions associated with this allele. Although enzymatic methods rarely detect the presence of allele BCHE*K, PCR‐PIRA found the allele in an appreciable frequency (5.76%), although lower than that found in other ethnic groups. Since observed frequencies of unusual alleles correspond to estimated percentages of European admixture, it is likely that none of these unusual alleles were present in Mapuche Indians before the arrival of Europeans. Am J Phys Anthropol 121:000–000, 2003. © 2003 Wiley‐Liss, Inc.