bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurosteroid pregnenolone sulfate enhances glutamatergic synaptic transmission by facilitating presynaptic calcium currents at the calyx of Held of immature rats
Authors: Hige Toshihide , Fujiyoshi Yoshinori , Takahashi Tomoyuki 
Published: October 2006

AbstractPregnenolone sulfate (PREGS) is an endogenous neurosteroid widely released from neurons in the brain, and is thought to play a memory‐enhancing role. At excitatory synapses PREGS facilitates transmitter release, but the underlying mechanism is not known. We addressed this issue at the calyx of Held in rat brainstem slices, where direct whole‐cell recordings from giant nerve terminals are feasible. PREGS potentiated nerve‐evoked excitatory postsynaptic currents (EPSCs) without affecting the amplitude of miniature EPSCs, suggesting that its site of action is presynaptic. In whole‐cell recordings from calyceal nerve terminals, PREGS facilitated Ca2+ currents, by accelerating their activation kinetics and shifting the half‐activation voltage toward negative potentials. PREGS had no effect on presynaptic K+ currents, resting conductance or action potential waveforms. In simultaneous pre‐ and postsynaptic recordings, PREGS did not change the relationship between presynaptic Ca2+ influx and EPSCs, suggesting that exocytotic machinery downstream of Ca2+ influx is not involved in its effect. PREGS facilitated Ba2+ currents recorded from nerve terminals and also from HEK 293 cells expressed with recombinant N‐ or P/Q‐type Ca2+ channels, suggesting that PREGS‐induced facilitation of voltage‐gated Ca2+ channels (VGCCs) is neither Ca2+ dependent nor VGCC‐type specific. The PREGS‐induced VGCC facilitation was blocked by the PREGS scavenger (2‐hydroxypropyl)‐β‐cyclodextrin applied from outside, but not from inside, of nerve terminals. We conclude that PREGS facilitates VGCCs in presynaptic terminals by acting from outside, thereby enhancing transmitter release. We propose that PREGS may directly modulate VGCCs acting on their extracellular domain.
Key role of selective viral‐induced mortality in determining marine bacterial community composition
Authors: Bouvier T. , Del Giorgio P. A. 
Published: October 2006

SummaryViral infection is thought to play an important role in shaping bacterial community composition and diversity in aquatic ecosystems, but the strength of this interaction and the mechanisms underlying this regulation are still not well understood. The consensus is that viruses may impact the dominant bacterial strains, but there is little information as to how viruses may affect the less abundant taxa, which often comprise the bulk of the total bacterial diversity. The potential effect of viruses on the phylogenetic composition of marine bacterioplankton was assessed by incubating marine bacteria collected along a North Pacific coastal‐open ocean transect in seawater that was greatly depleted of ambient viruses. The ambient communities were dominated by typical marine groups, including alphaproteobacteria and the Bacteroidetes. Incubation of these communities in virus‐depleted ambient water yielded an unexpected and dramatic increase in the relative abundance of bacterial groups that are generally undetectable in the in situ assemblages, such as betaproteobacteria and Actinobacteria. Our results suggest that host susceptibility is not necessarily only proportional to its density but to other characteristics of the host, that rare marine bacterial groups may be more susceptible to viral‐induced mortality, and that these rare groups may actually be the winners of competition for resources. These observations are not inconsistent with the ‘phage kills the winner’ hypothesis but represent an extreme and yet undocumented case of this paradigm, where the potential winners apparently never actually develop beyond a very low abundance threshold in situ. We further suggest that this mode of regulation may influence not just the distribution of single strains but of entire phylogenetic groups.
Critical Issues in Participatory GIS: Deconstructions, Reconstructions, and New Research Directions
Authors: Elwood Sarah 
Published: October 2006

AbstractIn the mid‐1990s, several critical texts raised concerns about the social, political, and epistemological implications of GIS. Subsequent responses to these critiques have fundamentally altered the technological, political, and intellectual practices of GIScience. Participatory GIS, for instance, has intervened in multiple ways to try to ameliorate uneven access to GIS and digital spatial data and diversify the forms of spatial knowledge and spatial logic that may be incorporated in a GIS. While directly addressing core elements of the ‘GIS & Society’ critique, these reconstructions of a critical GIScience introduce their own ambiguities with respect to access, equity, digital representation of spatial knowledge, and epistemologies of new GIS research practices. In this paper, I examine some of the new and persistent ambiguities of participatory GIS that bear inclusion in future critical GIScience research.
Cell death: regulation by the Bcl‐2 protein family
Authors: TSUJIMOTO Yoshihide 
Published: October 2006

AbstractAn increase in mitochondrial membrane permeability is central to cell death including apoptosis and necrosis. During apoptosis, permeabilization of outer mitochondrial membrane leads to the release of several apoptogenic factors, such as cytochrome c and Smac/Diablo, into the cytoplasm that activate downstream death programs, including apoptotic proteases called caspases, although the detailed mechanism of outer mitochondrial membrane permeabilization remains elusive. Although the mitochondrial membrane permeability transition (MPT), resulting in Δψ loss, mitochondrial swelling and rupture of the outer membrane has initially been proposed as a general mechanism for apoptotic permeabilization of outer mitochondrial membrane, the recent studies with cyclophilin D‐deficient mice indicate that MPT regulates some forms of necrotic death, but not apoptotic death, and that MPT is involved in ischemia–reperfusion injury in heart and brain. Anti‐apoptotic proteins, Bcl‐2 and Bcl‐xL, efficiently block not only apoptotic mitochondrial permeabilization but also MPT. The present paper focuses on the mechanisms by which Bcl‐2 family members control the permeability of mitochondrial membrane during apoptosis and necrosis.
Petrogenesis of Maobei rutile eclogites from the southern Sulu ultrahigh‐pressure metamorphic belt, eastern China
Authors: ZHANG Z. M. , LIOU J. G. , ZHAO X. D. , SHI C. 
Published: October 2006

AbstractThe Maobei complex in the southern Sulu ultrahigh‐pressure (UHP) metamorphic belt, eastern China, mainly consists of layered eclogites, garnet peridotites and orthogneisses. Based on the modal mineral and whole‐rock compositions, eclogites from the Maobei complex are divided into quartz eclogite, quartz‐rich eclogite, rutile eclogite, rutile‐rich eclogite and eclogite. The distinct spatial changes in the lithology and related chemical compositions indicate that this complex includes 10 rhythmic layers. The rutile eclogites have high TiO2(2.4–5.9 wt%), commonly coupled with high P2O5(up to 4.1 wt%) contents; most show fractionated REE patterns with slight positive Eu anomalies. The rutile‐rich eclogites have very high TiO2(3.3–5.7 wt%), FeOT(17.5–25.3 wt%), V (126–1163 ppm) and Co (14–132 ppm), and very low SiO2(38.0–42.3 wt%), Zr (24–85 ppm), Nb (0.3–6.9 ppm), Ta (<0.1–0.6 ppm) and total REE (10.7–334.0 ppm) contents, variable degree of LREE depletion, and positive Eu anomalies (Eu/Eu* = 1.1–2.9), and the Ti is decoupled from other high‐field‐strength elements. These characteristics are consistent with Fe‐Ti gabbros of typical layered intrusions, implying a cumulate of plagioclase, clinopyroxene and abundant accessory magnetite in an evolved basaltic magmatic chamber. Based on a normal stratigraphic sequence, the Maobei complex shows an iron‐enrichment trend, followed by alkaline enrichment with increasing fractionated crystallization and stratigraphic height. These facts, together with SHRIMP U‐Pb zircon ages of 773.7 ± 8.0 Ma, indicate that the protolith of the Maobei complex is a Neoproterozoic layered intrusion consisting of a base of peridogabbro, a main body of gabbro and minor granodiorite. Unusually high Ti, V and P contents in three rutile eclogite layers suggest that they are potential economic ore deposits.
Accident Year Development, Bonus Banks, and Insurance Incentive Compensation
Authors: Calandro Joseph 
Published: October 2006

AbstractInsurance claims can take years to resolve, which makes insurance performance measurement—and incentive compensation based on such measurement— challenging. The insurance industry utilizes a method of analysis called accident year analysis to manage the temporal challenge inherent in insurance claims. Despite the managerial and economic utility of this method of analysis, it has generally not been applied to incentive compensation programs for insurance company executives and employees. This article will explain accident year analysis, and will show how it can be merged with the bonus bank concept and the Insurance Performance Measure, which is an insurance economic profit metric, to construct an economically consistent insurance incentive compensation program.
Pacemaker Longevity: Are We Getting What We Are Promised?
Authors: SENARATNE JANEK , IRWIN MARLEEN E. , SENARATNE MANOHARA P. J. 
Published: October 2006

Background: Although pacemaker manufacturers provide projections on longevity, these projections cannot be relied upon due to the assumptions of output parameters being far in excess of those programmed in clinical practice.
Objective: The purpose of this review was to compare the actual longevity to the calculated longevity of pacemakers based on battery cell characteristics taking into account individual programmed parameters, mode, degree of usage, and percent pacing. This was also compared to the manufacturers' own projected longevities.
Methods: Patients who had a pacemaker replaced between 1998 and 2003 were included (n = 124). Cell characteristics were obtained from manufacturers and programmed parameters were obtained at each visit. Stepwise calculations were done for each visit to find current drain during each interval, and then were used in a weighted average to find the total average lifetime current drain. This was subsequently used to find a calculated longevity for each pacemaker to be compared to the actual longevity observed.
Results: The pacemakers lasted 491±92 days (mean±SEM) less than calculated. There was also a difference between dual‐ and single‐chamber devices (though not statistically significant). Moreover, it was found that there were significant differences between manufacturers.
Conclusions: There appears to be a significant discrepancy between calculated and actual longevities, confirming that battery depletion occurs earlier than expected. This suggests that current drain expended for ancillary functions may be considerable. Another factor may be pre‐implantation drain. Vigilance with programming of outputs, modes, sensors, heart rates, and ancillary functions could potentially extend longevity and postpone/obviate the need for costly repeat surgery with its attended risk of complications. Furthermore, the differences between manufacturers seem to parallel the clinical impressions.
Optimization Modeling in Acquisitions: A Case Study from the Motor Carrier Industry
Authors: Bhadury Joyendu , Khurana S. , Peng H.S. , Zong Helen 
Published: October 2006

SUMMARYThis paper develops a comprehensive methodology to optimize the planning of acquiring motor carriers in transportation companies. A conceptual framework describing the nature of the asset acquisition planning problem is posited, followed by the detailed development of a network flows–based optimization model. A study is undertaken at a Canadian transportation company that examines current acquisition planning for heavy trucking equipment. This is followed by a discussion of findings, managerial implications and directions for future research.
Induction of apoptosis by monastrol, an inhibitor of the mitotic kinesin Eg5, is independent of the spindle checkpoint
Authors: Chin Gregory M. , Herbst Ronald 
Published: October 2006

AbstractSpindle poisons such as paclitaxel are widely used as cancer therapeutics. By interfering with microtubule dynamics, paclitaxel induces mitotic arrest and apoptosis. Targeting the kinesin Eg5, which is required for the formation of a bipolar spindle, is a promising therapeutic alternative to drugs that interfere with microtubule dynamics. Recent data suggest that the spindle checkpoint can determine the response of tumor cells to microtubule poisons. The relationship between checkpoint function and Eg5 inhibition, however, has not yet been fully investigated. Here, we used time-lapse video microscopy and biochemical analysis to study the effect of spindle checkpoint abrogation on the response of HeLa cells to monastrol, a selective Eg5 inhibitor. In HeLa cells, monastrol activated the spindle checkpoint, leading to mitotic arrest and apoptosis. Small interfering RNA–mediated depletion of the spindle checkpoint proteins BubR1 or Mad2 significantly shortened drug-induced arrest, causing premature mitotic exit without cell division. Time-lapse microscopy as well as analysis of caspase activation shows that these checkpoint-deficient cells initiate apoptosis after mitotic exit in response to monastrol. Checkpoint-deficient cells treated with paclitaxel, on the other hand, yielded a higher frequency of cells with &gt;4N DNA content and a decreased incidence of apoptotic events, particularly in Mad2-depleted cells. These results indicate that the immediate fate of postmitotic cells is influenced by both the nature of the checkpoint defect and the type of drug used. Furthermore, these results show that inactivation of the kinesin Eg5 can induce apoptosis in tumor cells in the absence of critical spindle checkpoint components. [Mol Cancer Ther 2006;5(10):2580–91]
The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity
Authors: Chattopadhyay Shrikanta , Zhao Rongbao , Tsai Eugenia , Schramm Vern L. , Goldman I. David 
Published: October 2006

AbstractPemetrexed is a new-generation antifolate inhibitor of thymidylate synthase (TS) and a weaker inhibitor of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis. Methylthioadenosine phosphorylase (MTAP) salvages purines by releasing adenine from methylthioadenosine and is often deleted in mesothelioma. The current study addresses the effect of MTAP on pemetrexed activity using a highly potent transition state inhibitor of MTAP, MT-DADMe-Immucillin A (ImmA; Ki = 86 pmol/L) in the MTAP(+) NCI-H28 and MTAP(−) NCI-H2052 mesothelioma cell lines. Based on selective nucleoside protection, TS was found to be the primary pemetrexed target in both cell lines with GARFT inhibition requiring 20- to 30-fold higher pemetrexed concentrations. ImmA had no effect on pemetrexed activity but, when thymidine was added, the pemetrexed IC50 decreased by a factor of ∼3 in MTAP(+) H28 cells with no effect in MTAP(−) H2052 cells. Conversely, the transfection of MTAP into H2052 cells increased the pemetrexed IC50 by nearly 3-fold but only in the presence of thymidine; this was reversed by ImmA. An MTAP-specific short interfering RNA produced a 2-fold decrease in pemetrexed IC50 in MTAP(+) HeLa cells in the presence of thymidine. These data indicate that suppression of constitutive MTAP has no effect on pemetrexed activity when the primary target is TS. There is a modest salutary effect when the pemetrexed target is GARFT alone. [Mol Cancer Ther 2006;5(10):2549–55]
Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor
Authors: Seamon Jennifer A. , Rugg Catherine A. , Emanuel Stuart , Calcagno Anna Maria , Ambudkar Suresh V. , Middleton Steven A. , Butler Jeannene , Borowski Virna , Greenberger Lee M. 
Published: October 2006

Abstract
Cell cycle kinase inhibitors have advanced into clinical trials in oncology. One such molecule, JNJ-7706621, is a broad-spectrum inhibitor of the cyclin-dependent kinases and Aurora kinases that mediate G2-M arrest and inhibits tumor growth in xenograft models. To determine the putative mechanisms of resistance to JNJ-7706621 that might be encountered in the clinic, the human epithelial cervical carcinoma cell line (HeLa) was exposed to incrementally increasing concentrations of JNJ-7706621. The resulting resistant cell population, designated HeLa-6621, was 16-fold resistant to JNJ-7706621, cross-resistant to mitoxantrone (15-fold) and topotecan (6-fold), and exhibited reduced intracellular drug accumulation of JNJ-7706621. ABCG2 was highly overexpressed at both the mRNA (∼163-fold) and protein levels. The functional role of ABCG2 in mediating resistance to JNJ-7706621 was consistent with the following findings: (a) an ABCG2 inhibitor, fumitremorgin C, restored the sensitivity of HeLa-6621 cells to JNJ-7706621 and to mitoxantrone; (b) human embryonic kidney-293 cells transfected with ABCG2 were resistant to both JNJ-7706621 and mitoxantrone; and (c) resistant cells that were removed from the drug for 12 weeks and reverted to susceptibility to JNJ-7706621 showed near-normal ABCG2 RNA levels. ABCG2 is likely to limit the bioavailability of JNJ-7706621 because oral administration of JNJ-7706621 to Bcrp (the murine homologue of ABCG2) knockout mice resulted in an increase in the plasma concentration of JNJ-7706621 compared with wild-type mice. These findings indicate that ABCG2 mediates the resistance to JNJ-7706621 and alters the absorption of the compound following administration. [Mol Cancer Ther 2006;5(10):2459–67]
Developing gene expression signatures of pathway deregulation in tumors
Authors: Watters James W. , Roberts Christopher J. 
Published: October 2006

Abstract
Recent advances in our understanding of cancer biology have led to the development of therapies targeting specific signaling pathways. Molecular targeting promises to improve our ability to predict who will respond by assessing the state of these targeted pathways in patients. However, a single pathway can be deregulated by multiple mechanisms, and for some pathways it may be difficult to assess activation state by analyzing a single oncogene or tumor suppressor. Therefore, developing gene expression signatures of pathway activation status using model systems or human tumor samples may enable a more reliable measurement of pathway activity. This review discusses recent advances in the identification of gene expression–based signatures of pathway deregulation and how this information may lead to improved therapeutic response prediction. [Mol Cancer Ther 2006;5(10):2444–9]
Dissecting the role of endothelial SURVIVIN ΔEx3 in angiogenesis
Authors: Caldas Hugo , Fangusaro Jason R. , Boué Daniel R. , Holloway Michael P. , Altura Rachel A. 
Published: October 2006

AbstractThe identification of alternative splice variants of Survivin that possess distinct functions from those originally identified for the main Survivin isoform has greatly increased the complexity of our understanding of the role of Survivin in different cells. Previous functional studies of the Survivin splice variants have been performed almost exclusively in cancer cells. However, Survivin has increasingly been implicated in other normal physiologic and pathophysiologic processes, including angiogenesis. In this study, we dissect the involvement of Survivin ΔEx3 in angiogenesis. We show by confocal microscopy that a pool of endothelial Survivin ΔEx3 is localized to membrane ruffles. We also demonstrate that Survivin ΔEx3 is the Survivin splice variant responsible for modulating angiogenesis in vitro, in tube formation assays, and in vivo, in an in vivo angiogenesis assay. Our data indicate that Survivin ΔEx3 may regulate angiogenesis via several mechanisms including cell invasion, migration, and Rac1 activation. Our findings identify a novel pathway regulating angiogenesis through Survivin ΔEx3 and a novel mechanism for Rac1 activation during angiogenesis. In conclusion, our results provide new insights into the regulation of endothelial cell homeostasis and angiogenesis by the Survivin proteins.
Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem-cell transplants from related donors in adult patients with hematologic malignancies after myeloablative conditioning regimen
Authors: Takahashi Satoshi , Ooi Jun , Tomonari Akira , Konuma Takaaki , Tsukada Nobuhiro , Oiwa-Monna Maki , Fukuno Kenji , Uchiyama Michihiro , Takasugi Kashiya , Iseki Tohru , Tojo Arinobu , Yamaguchi Takuhiro , Asano Shigetaka 
Published: October 2006

Abstract
We studied the clinical outcomes of 171 adults with hematologic malignancies who received unrelated cord blood transplantation (CBT) as a primary unrelated stem-cell source (n = 100), or bone marrow transplant (BMT) or peripheral blood stem-cell transplant (PBSCT) from related donors (n = 71, 55 BMT and 16 PBSCT). All patients received myeloablative regimens including 12 Gy total body irradiation. We analyzed the hematologic recovery, and risks of graft-versus-host disease (GVHD), transplantation-related mortality (TRM) and relapse, and disease-free survival (DFS) using Cox proportional hazards models. Significant delays in engraftment occurred after cord blood transplantation; however, overall engraftment rates were almost the same for both grafts. The cumulative incidences of grades III to IV acute and extensive-type chronic GVHDs among CBT recipients were significantly lower than those among BMT/PBSCT recipients. Multivariate analysis demonstrated no apparent differences in TRM (9% in CBT and 13% in BMT/PBSCT recipients), relapse (17% in CBT and 26% in BMT/PBSCT recipients), and DFS (70% in CBT and 60% in BMT/PBSCT recipients) between both groups. These data suggest that unrelated cord blood could be as safe and effective a stem-cell source as related bone marrow or mobilized peripheral blood for adult patients when it is used as a primary unrelated stem-cell source.
The hypomorphic Gata1low mutation alters the proliferation/differentiation potential of the common megakaryocytic-erythroid progenitor
Authors: Ghinassi Barbara , Sanchez Massimo , Martelli Fabrizio , Amabile Giovanni , Vannucchi Alessandro Maria , Migliaccio Giovanni , Orkin Stuart H. , Migliaccio Anna Rita 
Published: October 2006

AbstractRecent evidence suggests that mutations in the Gata1 gene may alter the proliferation/differentiation potential of hemopoietic progenitors. By single-cell cloning and sequential replating experiments of prospectively isolated progenitor cells, we demonstrate here that the hypomorphic Gata1low mutation increases the proliferation potential of a unique class of progenitor cells, similar in phenotype to adult common erythroid/megakaryocytic progenitors (MEPs), but with the “unique” capacity to generate erythroblasts, megakaryocytes, and mast cells in vitro. Conversely, progenitor cells phenotypically similar to mast cell progenitors (MCPs) are not detectable in the marrow from these mutants. At the single-cell level, about 11% of Gata1low progenitor cells, including MEPs, generate cells that will continue to proliferate in cultures for up to 4 months. In agreement with these results, trilineage (erythroid, megakaryocytic, and mastocytic) cell lines are consistently isolated from bone marrow and spleen cells of Gata1low mice. These results confirm the crucial role played by Gata1 in hematopoietic commitment and identify, as a new target for the Gata1 action, the restriction point at which common myeloid progenitors become either MEPs or MCPs.