bluuebunny/crossref_metadata_2025_split huggingface dataset:
CONTINUOUS AND HYBRID PETRI NETS
Authors: ALLA HASSANE , DAVID RENÉ 
Published: May 2003

Petri nets are widely used to model discrete event dynamic systems (computer systems, manufacturing systems, communication systems…). When a PN contains a large number of tokens, the number of reachable states explodes. This is a practical limitation to the use of Petri nets. Continuous models may provide very good approximations for discrete event systems: this is the basic idea leading to the definition of continuous Petri nets. A continuous PN is a model in which the marking of each place is a real number. In a timed continuous PN, a firing speed is associated with each transition (this basic model is unique although the firing speed may be defined in several ways). Various timed continuous PN models have been defined and they correspond to a specific calculation of the firing speeds. They provide good approximations for performance evaluation when a PN contains a large number of tokens. Modeling a number of parts in a buffer by a real number may generally be an acceptable approximation. However, the state of a machine, up or down, cannot be modeled by a real number. This naturally leads to the idea of hybrid PNs, containing a discrete part and a continuous part. Autonomous and timed hybrid PNs are presented. A large of the presentation is informal and intuitive. Three examples illustrate the application of the different models.
Novel pathways of F-actin polymerization in the human neutrophil
Authors: Chodniewicz David , Zhelev Doncho V. 
Published: May 2003

AbstractRecently we demonstrated the existence of a phosphatidylinositol 3-kinase (PI3K)–independent F-actin polymerization during neutrophil pseudopod extension. Here we examine the use of the PI3K-dependent and PI3K-independent pathways of activation by the N-formyl peptide receptor and the chemokine receptors, and the priming of the 2 pathways by granulocyte-macrophage colony-stimulating factor (GM-CSF) and insulin. The inhibition of PI3K activity with wortmannin showed that rate of pseudopod extension stimulated with N-formyl-Met-Leu-Phe (fMLP was mostly dependent on PI3K, while the rate of interleukin-8 (IL-8)–stimulated pseudopod extension was less dependent on PI3K. The incubation of cells with either GM-CSF or insulin increased the rate of pseudopod extension by 50% when the cells were stimulated with IL-8 but not with fMLP. The stimulation with IL-8 phosphorylated the PI3K regulatory subunit. This phosphorylation was enhanced by GM-CSF, which increased PI3K activity and total phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) production. The effect of GM-CSF was blocked with wortmannin. In contrast, insulin did not increase p85 phosphorylation and did not enhance PI3K activity or PtdIns(3,4,5)P3 production. The effect of insulin was insensitive to wortmannin; however, it was blocked by an Src homology 2 (SH2)–binding peptide. These data indicate that priming of IL-8 activation with GM-CSF was mediated via the PI3Ks of class IA, while priming with insulin used a PI3K-independent pathway.
High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis
Authors: Nash Richard A. , Bowen James D. , McSweeney Peter A. , Pavletic Steven Z. , Maravilla Kenneth R. , Park Man-soo , Storek Jan , Sullivan Keith M. , Al-Omaishi Jinan , Corboy John R. , DiPersio John , Georges George E. , Gooley Theodore A. , Holmberg Leona A. , LeMaistre C. Fred , Ryan Kate , Openshaw Harry , Sunderhaus Julie , Storb Rainer , Zunt Joseph , Kraft George H. 
Published: May 2003

AbstractThere were 26 patients enrolled in a pilot study of high-dose immunosuppressive therapy (HDIT) for severe multiple sclerosis (MS). Median baseline expanded disability status scale (EDSS) was 7.0 (range, 5.0-8.0). HDIT consisted of total body irradiation, cyclophosphamide, and antithymocyte globulin (ATG) and was followed by transplantation of autologous, granulocyte colony-stimulating factor (G-CSF)-mobilized CD34-selected stem cells. Regimen-related toxicities were mild. Because of bladder dysfunction, there were 8 infectious events of the lower urinary tract. One patient died from Epstein-Barr virus (EBV)-related posttransplantation lymphoproliferative disorder (PTLD) associated with a change from horse-derived to rabbit-derived ATG in the HDIT regimen. An engraftment syndrome characterized by noninfectious fever with or without rash developed in 13 of the first 18 patients and was associated in some cases with transient worsening of neurologic symptoms. There were 2 significant adverse neurologic events that occurred, including a flare of MS during mobilization and an episode of irreversible neurologic deterioration after HDIT associated with fever. With a median follow-up of 24 (range, 3-36) months, the Kaplan-Meier estimate of progression (≥ 1.0 point EDSS) at 3 years was 27%. Of 12 patients who had oligoclonal bands in the cerebrospinal fluid at baseline, 9 had persistence after HDIT. After HDIT, 4 patients developed new enhancing lesions on magnetic resonance imaging of the brain. The estimate of survival at 3 years was 91%. Important clinical issues in the use of HDIT and stem cell transplantation for MS were identified; however, modifications of the initial approaches appear to reduce treatment risks. This was a heterogeneous high-risk group, and a phase 3 study is planned to fully assess efficacy. (Blood. 2003;102:2364-2372)
Proliferation kinetics of subpopulations of human marrow cells determined by quantifying in vivo incorporation of [2H2]-glucose into DNA of S-phase cells
Authors: Schwartz Gretchen N. , Vance Barbara A. , Levine Benjamin M. , Fukazawa Motoharu , Telford William G. , Cesar Denise , Hellerstein Marc , Gress Ronald E. 
Published: May 2003

Abstract
This report investigated in vivo turnover kinetics of marrow hematopoietic progenitors and precursors using a recently developed stable isotope–mass spectrometric technique (SIMST). Human subjects were administered a 2-day infusion of 6,6-[2H2]-glucose, a nontoxic stable isotope-labeled form of glucose, which becomes incorporated into DNA of all S-phase cells. The percent [2H2]-glucose incorporated into DNA in the form of [2H2]-deoxyadenosine (%[2H2]-dA enrichment) was determined by gas chromatography–mass spectrometry. The rate constant of replacement of unlabeled by labeled DNA strands (labeling kinetics) was used to calculate population turnover kinetics of CD34+ cells, CD133+ cells, and CD133–CD34+ cells. The observed mean replacement half-life (t1/2) was 2.6 days for CD34+ cells, 2.5 days for CD133–CD34+ cells, and 6.2 days for CD133+ cells. Results from the estimated rate constant of replacement of labeled by unlabeled DNA (delabeling kinetics) also demonstrated slower turnover rates for CD133+ cells than for CD133–CD34+ cells. Although there was a relatively rapid initial decrease in the %[2H2]-dA enrichment, low levels of labeled DNA persisted in CD34+ cells for at least 4 weeks. The results indicate the presence of subpopulations of CD34+ cells with relatively rapid turnover rates and subpopulations with a slower t1/2 of 28 days. Results also demonstrate that in vivo [2H2]-glucose-SIMST is sensitive enough to detect differences in turnover kinetics between erythroid and megakaryocyte lineage cells. These studies are the first to demonstrate the use of in vivo [2H2]-glucose-SIMST to measure in vivo turnover kinetics of subpopulations of CD34+ cells and precursors in healthy human subjects.
Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion
Authors: Powell Jerry S. , Ragni Margaret V. , White Gilbert C. , Lusher Jeanne M. , Hillman-Wiseman Carol , Moon Tom E. , Cole Veronica , Ramanathan-Girish Sandhya , Roehl Holger , Sajjadi Nancy , Jolly Douglas J. , Hurst Deborah 
Published: May 2003

Abstract
In a phase 1 dose escalation study, 13 subjects with hemophilia A received by peripheral intravenous infusion a retroviral vector carrying a B-domain–deleted human factor VIII (hFVIII) gene. Infusions were well tolerated. Tests for replication competent retrovirus have been negative. Polymerase chain reaction (PCR) analyses demonstrate the persistence of vector gene sequences in peripheral blood mononuclear cells in 3 of 3 subjects tested. Factor VIII was measured in serial samples using both a one-stage clotting assay and a chromogenic assay. While no subject had sustained FVIII increases, 9 subjects had FVIII higher than 1% on at least 2 occasions 5 or more days after infusion of exogenous FVIII, with isolated levels that ranged from 2.3% to 19%. Pharmacokinetic parameters of exogenous FVIII infused into subjects 13 weeks after vector infusion showed an increased half-life (T1/2; P &lt; .02) and area under the curve (AUC, P &lt; .04) compared with prestudy values. Bleeding frequency decreased in 5 subjects compared with historical rates. These results demonstrate that this retroviral vector (hFVIII(V)) is safe and, in some subjects, persists more than a year in peripheral blood mononuclear cells, with measurable factor VIII levels and with increased available FVIII activity (increased T1/2 and AUC) after infusion of exogenous FVIII concentrate.
CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells
Authors: Deaglio Silvia , Capobianco Andrea , Bergui Luciana , Dürig Jan , Morabito Fortunato , Dührsen Ulrich , Malavasi Fabio 
Published: May 2003

AbstractThe prognosis for patients with B-cell chronic lymphocytic leukemia (B-CLL) is generally less favorable for those expressing CD38. Our working hypothesis is that CD38 is not merely a marker in B-CLL, but that it plays a receptor role with pathogenetic potential ruling the proliferation of the malignant clone. CD38 levels were generally low in the patients examined and monoclonal antibody (mAb) ligation was inefficient in signaling. Other cellular models indicated that molecular density and surface organization are critical for CD38 functionality. Interleukin 2 (IL-2) induced a marked up-modulation and surface rearrangement of CD38 in all the patients studied. On reaching a specific expression threshold, CD38 becomes an efficient receptor in purified B-CLL cells. Indeed, mAb ligation is followed by Ca2+ fluxes and by a markedly increased proliferation. The unsuitability of CD38 to perform as a receptor is obviated through close interaction with the B-cell–receptor (BCR) complex and CD19. On mAb binding, CD38 translocates to the membrane lipid microdomains, as shown by a colocalization with the GM1 ganglioside and with CD81, a raft-resident protein. Finally, CD38 signaling in IL-2–treated B-CLL cells prolonged survival and induced the appearance of plasmablasts, providing a pathogenetic hypothesis for the occurrence of Richter syndrome.
Oligomerization of RANTES is required for CCR1-mediated arrest but not CCR5-mediated transmigration of leukocytes on inflamed endothelium
Authors: Baltus Thomas , Weber Kim S. C. , Johnson Zoë , Proudfoot Amanda E. I. , Weber Christian 
Published: May 2003

AbstractChemokines control inflammatory leukocyte recruitment. The propensity of chemokines such as CC chemokine ligand 5 (CCL5)/RANTES (regulated on activation, normal T cell expressed and secreted) to bind to glycosaminoglycans and to form higher order oligomers has been shown to be essential for its in vivo activity. However, the specific functional relevance of RANTES oligomerization for distinct steps of leukocyte recruitment on inflamed endothelium mediated by the RANTES receptors CC chemokine receptor 1 (CCR1) and CCR5 remains undefined. We studied RANTES mutants with deficient oligomerization in an assay in which recruitment of monocytes and CD45RO+ CD4+ T cells is triggered by RANTES immobilized on activated endothelium under flow conditions. Notably, the formation of higher order RANTES oligomers was crucial for CCR1-mediated arrest but not for CCR5-mediated spreading/transmigration in flow or transendothelial chemotaxis of leukocytes. Efficient leukocyte arrest in flow but not transmigration may thus require the presentation of RANTES oligomers to bridge surface-bound RANTES and CCR1.
PSGL-1 participates in E-selectin–mediated progenitor homing to bone marrow: evidence for cooperation between E-selectin ligands and α4 integrin
Authors: Katayama Yoshio , Hidalgo Andrés , Furie Barbara C. , Vestweber Dietmar , Furie Bruce , Frenette Paul S. 
Published: May 2003

AbstractThe nature and exact function of selectin ligands involved in hematopoietic progenitor cell (HPC) homing to the bone marrow (BM) are unclear. Using murine progenitor homing assays in lethally irradiated recipients, we found that the P-selectin glycoprotein ligand-1 (PSGL-1) plays a partial role in HPC homing to the BM (a reduction of about 35% when the P-selectin binding region is blocked). Blockade of both PSGL-1 and α4 integrin did not further enhance the effect of anti-α4 integrin (a reduction of about 55%). We suspected that E-selectin ligands might contribute to the remaining homing activity. To test this hypothesis, HPC homing assays were carried out in E-selectin–deficient recipients and revealed a profound alteration in HPC homing when E-selectin and α4 integrin were inactivated (&gt; 90% reduction). Competitive assays to test homing of long-term repopulating stem cells revealed a drastic reduction (&gt; 99%) of the homed stem cell activity when both α4 integrin and E-selectin functions were absent. Further homing studies with PSGL-1–deficient HPCs pretreated with anti-α4 integrin antibody revealed that PSGL-1 contributes to approximately 60% of E-selectin ligand–mediated homing activity. Our results thus underscore a major difference between mature myeloid cells and immature stem/progenitor cells in that E-selectin ligands cooperate with α4 integrin rather than P-selectin ligands.
A Constitutively Active Somatic Mutation of the Human Lutropin Receptor Found in Leydig Cell Tumors Activates the Same Families of G Proteins as Germ Line Mutations Associated with Leydig Cell Hyperplasia
Authors: Hirakawa Takashi , Ascoli Mario 
Published: May 2003

AbstractUsing a Leydig tumor cell line (MA-10) transiently transfected with the human lutropin receptor (hLHR) and mutants thereof, we examined the identity of the G proteins activated by the agonist-engaged hLHR-wild type (wt) and by three of its naturally occurring constitutively active mutants. Two of the mutants examined, L457R in transmembrane helix 3 and D578Y in transmembrane helix 6, are germ-line mutations found in boys with Leydig cell hyperplasia and precocious puberty. The third, D578H, is a somatic mutation found in Leydig cell tumors in boys with precocious puberty. We show that the hLHR-wt and the three mutants activate the Gs, Gi/o, and Gq/11, but not the G12/13, families of G proteins. The activation of these G proteins by the hLHR-wt occurs only when engaged by agonist, but their activation by the L457R, D578Y, and D578H mutants occurs independently of agonist stimulation. We conclude that the G proteins activated by constitutively active mutants of the hLHR associated with Leydig cell hyperplasia or tumors are identical and are the same as those activated by the agonist-engaged hLHR-wt. If there was preferential activation of some G protein families by the somatic D578H mutation found in Leydig cell tumors as opposed to the germ line mutations found in Leydig cell hyperplasia, then one could envision mechanisms by which the D578H mutant would be oncogenic. The data presented here suggest that such mechanisms do not need to be considered.
Pre- and Postnatal Propylthiouracil-Induced Hypothyroidism Impairs Synaptic Transmission and Plasticity in Area CA1 of the Neonatal Rat Hippocampus
Authors: Sui Li , Gilbert M. E. 
Published: May 2003

Abstract
Thyroid hormones are essential for neonatal brain development. It is well established that insufficiency of thyroid hormone during critical periods of development can impair cognitive functions. The mechanisms that underlie learning deficits in hypothyroid animals, however, are not well understood. As impairments in synaptic function are likely to contribute to cognitive deficits, the current study tested whether thyroid hormone insufficiency during development would alter quantitative characteristics of synaptic function in the hippocampus. Developing rats were exposed in utero and postnatally to 0, 3, or 10 ppm propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, administered in the drinking water of dams from gestation d 6 until postnatal day (PN) 30. Excitatory postsynaptic potentials and population spikes were recorded from the stratum radiatum and the pyramidal cell layer, respectively, in area CA1 of hippocampal slices from offspring between PN21 and PN30. Baseline synaptic transmission was evaluated by comparing input-output relationships between groups. Paired-pulse facilitation, paired-pulse depression, long-term potentiation, and long-term depression were recorded to examine short- and long-term synaptic plasticity. PTU reduced thyroid hormones, reduced body weight gain, and delayed eye-opening in a dose-dependent manner. Excitatory synaptic transmission was increased by developmental exposure to PTU. Thyroid hormone insufficiency was also dose-dependently associated with a reduction paired-pulse facilitation and long-term potentiation of the excitatory postsynaptic potential and elimination of paired-pulse depression of the population spike. The results indicate that thyroid hormone insufficiency compromises the functional integrity of synaptic communication in area CA1 of developing rat hippocampus and suggest that these changes may contribute to learning deficits associated with developmental hypothyroidism.
Differential Control of Adrenal and Sympathetic Catecholamine Release by α2-Adrenoceptor Subtypes
Authors: Brede Marc , Nagy Gábor , Philipp Melanie , Sørensen Jakob B. , Lohse Martin J. , Hein Lutz 
Published: May 2003

Abstract
In the adrenergic system, release of the neurotransmitter norepinephrine from sympathetic nerves is regulated by presynaptic inhibitory α2-adrenoceptors, but it is unknown whether release of epinephrine from the adrenal gland is controlled by a similar short feedback loop. Using gene-targeted mice we demonstrate that two distinct subtypes of α2-adrenoceptors control release of catecholamines from sympathetic nerves (α2A) and from the adrenal medulla (α2C). In isolated mouse chromaffin cells, α2-receptor activation inhibited the electrically stimulated increase in cell capacitance (a correlate of exocytosis), voltage-activated Ca2+ current, as well as secretion of epinephrine and norepinephrine. The inhibitory effects of α2-agonists on cell capacitance, voltage-activated Ca2+ currents, and on catecholamine secretion were completely abolished in chromaffin cells isolated from α2C-receptor-deficient mice. In vivo, deletion of sympathetic or adrenal feedback control led to increased plasma and urine norepinephrine (α2A-knockout) and epinephrine levels (α2C-knockout), respectively. Loss of feedback inhibition was compensated by increased tyrosine hydroxylase activity, as detected by elevated tissue dihydroxyphenylalanine levels. Thus, receptor subtype diversity in the adrenergic system has emerged to selectively control sympathetic and adrenal catecholamine secretion via distinct α2-adrenoceptor subtypes. Short-loop feedback inhibition of epinephrine release from the adrenal gland may represent a novel therapeutic target for diseases that arise from enhanced adrenergic stimulation.
Associative learning and memory inLymnaea stagnalis: how well do they remember?
Authors: Lukowiak Ken , Sangha Susan , McComb Chloe , Varshney Nishi , Rosenegger David , Sadamoto Hisayo , Scheibenstock Andi 
Published: May 2003

SUMMARYThe search for `the how and the where' of memory formation in the brain,the engram, is still one of the unattained `Holy Grails' of neuroscience. Over the years, various paths have been trodden in attempts to attain this goal,and while tantalizing glimpses appear now and then on the scientific horizon,the Grail still has not been grasped. One of the paths that investigators have walked is the invertebrate `model system' approach. Some invertebrates possess relatively simple nervous systems that mediate relatively simple behaviours that are both interesting and trainable. In this commentary, we would like to shed light on a relatively new player, the pond snail Lymnaea stagnalis L., that is being used in the quest to illuminate `the how and the where' the nervous systems encode and store memory. We will show that it is possible to demonstrate that a single neuron is a site of memory formation and storage for a form of associative learning in this lowly snail. It may be that the Grail is a little closer to being grasped.
The effects of gape angle and bite point on bite force in bats
Authors: Dumont Elizabeth R. , Herrel Anthony 
Published: May 2003

SUMMARY
Models of mammalian mastication predict that bite force is affected by both the degree of mouth opening (gape angle) and the point along the tooth row at which force is transferred to a food item (bite point). Despite the widespread use of these models in comparative analyses, experimental data documenting bite force in non-human mammals are extremely limited. The goal of this study is to document variation in non-stimulated bite force associated with change in gape angle and bite point in a broad range of species. We focus on plant-visiting bats because they exhibit a relatively primitive cranial morphology and are good models for generalized mammals. Assessments of the relationship between gape angle and bite force within and among species demonstrate that bite force decreases significantly as gape angle increases. The relationship between bite force and bite point within each of seven species demonstrates that unilateral molar biting universally generates the highest forces while the unilateral canine biting produces the lowest forces. Bilateral canine biting is intermediate. Beyond these general patterns,differences among species suggest that bite force reflects variation in craniofacial architecture. Finally, these data suggest that behavioral variation in gape angle and bite point may be important variables in comparative, functional analyses of feeding.