bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell death: regulation by the Bcl‐2 protein family
Authors: TSUJIMOTO Yoshihide
Published: October 2006

An 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

The 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.
Hormonal Changes Throughout Life in Women
Authors: Zacur Howard A.
Published: October 2006

The changes in hormonal milieu associated with menarche, pregnancy, lactation, and menopause are frequently accompanied by changes in the patterns and frequency of migraine. Migraine headache is more common in females and, for many women, the onset of this condition occurs at menarche. As many as 60% of women migraineurs report an association between migraine and menstruation, and evidence suggests that estrogen withdrawal may be a trigger for menstrual migraine in susceptible women. Moreover, in the majority of women, migraine frequency increases during the pill‐free interval with oral contraceptive use and during the postpartum period, which are other times of decreasing estrogen levels. Migraine frequency tends to decrease during periods of increasing or stable estrogen levels. For these reasons, the numerous neuroendocrine effects elicited by estrogen have been evaluated to explain its role in migraine. Overall, estrogen appears to be a key factor in menstrual migraine, but it is likely to be only one of several factors that act in concert to trigger migraine in susceptible women. Understanding the relationship of the different hormonal milieus through the natural course of women's lives can guide diagnosis and treatment.
Accident Year Development, Bonus Banks, and Insurance Incentive Compensation
Authors: Calandro Joseph
Published: October 2006

Abstract

Insurance 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.
Wide QRS Tachycardia: What Is the Rhythm?
Authors: Rosman Jonathan , Tawil Joseph , Hanon Sam , Schweitzer Paul
Published: October 2006

We report a case of an elderly man who presented to the emergency room complaining of palpitations. Electrocardiogram revealed wide QRS tachycardia with a narrow beat within the tachycardia. Most commonly, a narrow complex beat during a wide complex tachycardia suggests a capture or fusion beat in the setting of ventricular tachycardia. However, there are situations where supraventricular tachycardia can also manifest this way. In our patient a pacemaker interrogation clarified the diagnosis.
Difficulties encountered at the beginning of professional life: results of a 2003 pilot survey among undergraduate students in Paris Rene Descartes University (France)
Authors: Benbelaïd R. , Dot D. , Levy G. , Eid N.
Published: October 2006

Abstract  In addition to dental hospital clinical activity, dental students at Paris Rene Descartes University have the opportunity in their final year of study to practise clinically in a dental office, as associates. This paper outlines a pilot, experimental study designed to assess student reaction to this Vocational Clinical Activity (VCA) in order to identify relevant weaknesses of the undergraduate programme. Using questionnaires, data were collected for each of the following clinical or management skills: clinical difficulty, therapeutic decision‐making, patient/practitioner relationship, time management, administrative matters and technical problems. Students were asked to rank each item in order of difficulty (1, high level to 6, low level). A high response rate was observed (90%) among the 50 undergraduate VCA students. The results pointed out three main difficulties encountered by undergraduate students during the VCA: time management (90% of the students), administrative matters (85% of the students) and clinical decision‐making (80% of the students). These preliminary results need further investigation. However, they give us the incentive to carry on with this type of assessment and to extend it to young, qualified colleagues’ perceptions and to other French Universities.
Division of Labor in German Dual‐Earner Families: Testing Equity Theoretical Hypotheses
Authors: Klumb Petra , Hoppmann Christiane , Staats Melanie
Published: October 2006

On the basis of 52 German dual‐earner couples with at least 1 child younger than 5 years, we tested the effects of an unequal division of labor on relationship satisfaction. We analyzed diary reports of time allocated to productive activities according to the actor‐partner‐interdependence model. Hierarchical linear models showed that rather than individual time allocated to household work, the absolute difference in partners’ contribution to productive activities influenced relationship satisfaction. This reduction in satisfaction disappeared after accounting for perceived social appreciation of individual contributions. Models with gender‐specific slopes showed the effect of input and output to be different for women and men. The findings indicate that a relative equity model best explains the effects of an unequal division of labor.
“The Guilt Thing”: Balancing Domestic and Professional Roles
Authors: Guendouzi Jackie
Published: October 2006

Women’s representation in the workforce has increased dramatically over the past 30 years; yet, women “take a greater responsibility for the care of children” (Equal Opportunities Commission, 2006). Research has suggested working mothers may experience guilt resulting from the social constrictions of a traditional model of intensive mothering (B. Holcomb, 1998). Forty‐two audiotaped conversations of female teachers (n = 8) were collected in a British high school. Qualitative analyses of 3 conversations, in which 5 of the teachers discussed their professional and domestic responsibilities, demonstrated that the participants discursively aligned to 3 dominant interactional positions, accessibility, happiness, and separate spheres (Y. Elvin‐Novak & H. Thomsson, 2001). The analyses also revealed the use of supportive conversational strategies such as co‐complaining and matching accounts.
The Noncustodial Father–Child Relationship From Adolescence Into Young Adulthood
Authors: Aquilino William S.
Published: October 2006

The relationship between adult children aged 18 – 24 and noncustodial fathers was explored with longitudinal data from the National Survey of Families and Households (n = 359). Noncustodial fathers’ commitment to their adolescent children (contact, involvement in childrearing decisions) was strongly associated with father‐child relations in early adulthood. Father–adult child relations were weaker when children were born to an unmarried mother and when children had no memory of living with the father. Contrary to expectations, both mothers’ and fathers’ remarriage was associated with stronger father‐child relationships in early adulthood. The results show continuity in the father‐child relationship from adolescence into young adulthood and suggest that the life course transitions of family members influence the father‐child bond.
Solidarity and Conflict Between Adult Children and Parents: A Latent Class Analysis
Authors: Van Gaalen Ruben I. , Dykstra Pearl A.
Published: October 2006

Using multiple dimensions of solidarity and conflict in a latent class analysis, we develop a typology of adult child–parent relationships. The data (N= 4,990) are from the first wave of the Netherlands Kinship Panel Study. In descending order of relationship quality, the 5 types are harmonious (akin to relationships with friends), ambivalent (intensive exchange of material support accompanied by strain), obligatory (just keeping in touch), affective (emotionally supportive with few other meaningful exchanges), and discordant (predominantly negative engagement). The types are differentiated by gender, age, family size, geographic distance, and parental marital history, indicating that they are not fixed but are shaped by social‐structural conditions.
Functional characterization and Me2+ ion specificity of a Ca2+–citrate transporter from Enterococcus faecalis
Authors: Blancato Victor S. , Magni Christian , Lolkema Juke S.
Published: October 2006

Secondary transporters of the bacterial CitMHS family transport citrate in complex with a metal ion. Different members of the family are specific for the metal ion in the complex and have been shown to transport Mg2+–citrate, Ca2+–citrate or Fe3+–citrate. The Fe3+–citrate transporter of Streptococcus mutans clusters on the phylogenetic tree on a separate branch with a group of transporters found in the phylum Firmicutes which are believed to be involved in anaerobic citrate degradation. We have cloned and characterized the transporter from Enterococcus faecalis EfCitH in this cluster. The gene was functionally expressed in Escherichia coli and studied using right‐side‐out membrane vesicles. The transporter catalyzes proton‐motive‐force‐driven uptake of the Ca2+–citrate complex with an affinity constant of 3.5 µm. Homologous exchange is catalyzed with a higher efficiency than efflux down a concentration gradient. Analysis of the metal ion specificity of EfCitH activity in right‐side‐out membrane vesicles revealed a specificity that was highly similar to that of the Bacillus subtilis Ca2+–citrate transporter in the same family. In spite of the high sequence identity with the S. mutans Fe3+–citrate transporter, no transport activity with Fe3+ (or Fe2+) could be detected. The transporter of E. faecalis catalyzes translocation of citrate in complex with Ca2+, Sr2+, Mn2+, Cd2+ and Pb2+ and not with Mg2+, Zn2+, Ni2+ and Co2+. The specificity appears to correlate with the size of the metal ion in the complex.
Ranitidine in Acute High‐Dose Organophosphate Exposure in Rats: Effect of the Time‐Point of Administration and Comparison with Pyridostigmine
Authors: Petroianu Georg A. , Hasan Mohamed Y. , Nurulain Syed M. , Shafiullah Mohamed , Sheen Rajan , Nagelkerke Nicolas
Published: October 2006

Abstract: Weak and reversible inhibitors of cholinesterase, when co‐administered in large doses, can act in a protective manner against more potent inhibitors such as organophosphates. The clinically widely used histamine type 2 (H2) receptor blocker ranitidine is among H2 blockers the most potent inhibitor of acetylcholinesterase but roughly three to four orders of magnitude less potent than paraoxon (an irreversible organophosphate esterase inhibitor) or pyridostigmine (a reversible carbamate esterase inhibitor). We have previously shown that in vitro ranitidine confers some protection against inhibition of cholinesterases by paraoxon and that in vivo it both increases the number of rats surviving an acute paraoxon exposure and also protects to some degree the cholinesterases from organophosphate inhibition. The purpose of the study was to compare in a prospective non‐blinded study, in a rat model of acute high‐dose paraoxon exposure, ranitidine with pyridostigmine either administered simultaneously or 30 min. before exposure. There were 36 rats in each of the 5 groups. All substances were applied intraperitoneally. Additional analysis included data from a similar experiment carried out in 2005, in which 54 rats were exposed to paraoxon only (G1) and 54 to paraoxon+ranitidine simultaneously (G2). All groups (except controls; G6 & G7) received 1 μMol paraoxon (≈LD75); groups 2–5 received in addition to paraoxon: G2: 50 μMol ranitidine within 1 min. of paraoxon, G3: 1 μMol pyridostigmine within 1 min. of paraoxon, G4: 50 μMol ranitidine 30 min. before paraoxon, G5: 1 μMol pyridostigmine 30 min. before paraoxon. Groups 6 & 7 received only ranitidine and pyridostigmine respectively, group G1 received only paraoxon. Mortality was recorded at 30 min., 1, 2, 3, 4, 24 and 48 hr. Mortality data were compared using Kaplan‐Meier plots and logrank tests. No Bonferroni correction for multiple comparisons was applied and an α≤0.05 was considered significant. All statistical analysis was performed by using SPSS 12.0 statistical software (SPSS Inc., Chicago, IL, USA). Simultaneous administration of ranitidine or pyridostigmine with paraoxon does not significantly affect mortality. Pretreatment (30 min. before) with both ranitidine or pyridostigmine statistically and significantly reduced mortality. When administered before paraoxon, pyridostigmine is statistically significantly superior to ranitidine. Both ranitidine and pyridostigmine are protective against acute paraoxon toxicity provided they are administered before paraoxon. Pyridostigmine results are statistically significantly superior to ranitidine (≤0.05).
Mitochondrial Uncoupling by the Sulindac Metabolite, Sulindac Sulfide
Authors: Leite Samara , Martins Nádia Maria , Dorta Daniel Junqueira , Curti Carlos , Uyemura Sérgio Akira , Cardozo dos Santos Antonio
Published: October 2006

Abstract: Sulindac is a non‐steroidal antiinflammatory drug (NSAID) known to inhibit cyclooxygenases (COX) 1 and 2, and at present of interest for cancer prevention. However, its therapeutic use has been limited by its toxicity to the gastrointestinal tract and liver. We address the effects of sulindac, of the pharmacologically inactive metabolite, sulindac sulfone, and of the pharmacologically active metabolite, sudindac sulfide, on isolated rat liver mitochondria and HepG2 cells. Sulindac sulfide, but not sulindac sulfone or sulindac itself, caused mitochondrial uncoupling, released preaccumulated Ca2+ from the organelle, and decreased Hep‐G2 cell viability in apparent association with cell ATP depletion resulting from mitochondrial uncoupling‐associated membrane potential dissipation.
Effect of Caffeine Intake 12 or 24 Hours Prior to Melatonin Intake and CYP1A2*1F Polymorphism on CYP1A2 Phenotyping by Melatonin
Authors: Härtter Sebastian , Korhonen Tuomas , Lundgren Stefan , Rane Anders , Tolonen Ari , Turpeinen Miia , Laine Kari
Published: October 2006

Abstract: Earlier evidence suggests that melatonin is almost exclusively metabolised by CYP1A2 and could serve as a probe drug for CYP1A2 phenotyping. However, caffeine inhibits the metabolism of melatonin by CYP1A2 and dietary caffeine could be a potential confounder for the measurement of CYP1A2 activity with melatonin. We undertook a 3‐phase cross‐over study in 12 healthy volunteers to examine whether caffeine (200 mg single dose), taken 12 hr or 24 hr prior to melatonin intake, would affect the results of CYP1A2 phenotyping results as assessed by a spot sample melatonin concentration 1.5 hr after intake of 6 mg of melatonin orally. In addition we examined the influence of the CYP1A2*1F polymorphism on the phenotyping results by combining the present material with another 12 persons from a previous study. Caffeine, co‐administered 12 or 24 hr prior to melatonin intake, did not have any significant effect on the 1.5 hr melatonin concentration (P=0.086 for ANOVA), but in two volunteers about 4 times increase in melatonin concentration was observed after caffeine intake 12 hr (but not 24 hr) before phenotyping with melatonin. Also, individuals homozygous for the CYP1A2*1A allele had clearly higher 1.5 hr melatonin concentration compared with the *1F/*1F or the *1F/*1A genotypes. Abstinence from caffeine for 24 hr prior to melatonin intake should be enough to overcome the possible confounding effect of caffeine on the CYP1A2 phenotyping with melatonin. Also, melatonin may be a sensitive probe to detect phenotypic differences with regard to CYP1A2*1F polymorphism. Melatonin might be, thus, advantageous for CYP1A2 phenotyping compared to the standard probe caffeine.
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

This 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.
The effects of green tree retention and subsequent prescribed burning on ground beetles (Coleoptera: Carabidae) in boreal pine‐dominated forests
Authors: Martikainen Petri , Kouki Jari , Heikkala Osmo
Published: October 2006

We studied how two methods to promote biodiversity in managed forests, i.e. green tree retention and prescribed fire, affect the assemblages of carabid beetles. Our experiment consisted of 24 study sites, each 3–5 ha in size, which had been prepared according to factorial design. Each of the eight treatment combinations determined by the two factors explored – tree retention level (0, 10, 50 m3/ha−1 and uncut controls) and prescribed use of fire (yes/no) – was replicated three times. We sampled carabids using pitfall traps one year after the treatments. Significantly more individuals were caught in most of the burned sites, but this difference was partially reflective of the trap‐catches of Pterostichus adstrictus. The fire did not increase no. of P. adstrictus in the uncut sites as much as in the other sites. Species richness was significantly affected by both factors, being higher in the burned than in the unburned sites and in the harvested than in the unharvested sites. Many species were concentrated in the groups of retention trees in the burned sites, but only a few were in the unburned sites. The species turnover was greater in the burned than in the unburned sites, as indicated by the NMDS ordinations. Greater numbers of smaller sized species and proportion of brachypterous species were present in the burned sites. Fire‐favored species, and also the majority of other species that prefer open habitats were more abundantly caught in the burned sites than in the unburned sites. Dead wood or logging waste around the traps did not correlate with the occurrence of species. We conclude that carabids are well adapted to disturbances, and that frequent use of prescribed fire is essential for the maintenance of natural assemblages of carabid beetles in the boreal forest. Small retention tree groups can not maintain assemblages of uncut forest, but they can be important by providing food, shelter and breeding sites for many species, particularly in the burned sites.
Spatial patterns and competition of tree species in a Douglas‐fir chronosequence on Vancouver Island
Authors: Getzin Stephan , Dean Charmaine , He Fangliang , A. Trofymow John , Wiegand Kerstin , Wiegand Thorsten
Published: October 2006

While the successional dynamics and large‐scale structure of Douglas‐fir forest in the Pacific Northwest region is well studied, the fine‐scale spatial characteristics at the stand level are still poorly understood. Here we investigated the fine‐scale spatial structure of forest on Vancouver Island, in order to understand how the three dominant species, Douglas‐fir, western hemlock, and western redcedar, coexist and partition space along a chronosequence comprised of immature, mature, and old‐growth stands. We quantified the changes in spatial distribution and association of the species along the chronosequence using the scale‐dependent point pattern analyses pair‐correlation function g(r) and Ripley's L‐function. Evidence on intra‐ and inter‐specific competition was also inferred from correlations between nearest‐neighbor distances and tree size. Our results show that 1) the aggregation of Douglas‐fir in old‐growth was primarily caused by variation in local site characteristics, 2) only surviving hemlock were more regular than their pre‐mortality patterns, a result consistent with strong intra‐specific competition, 3) inter‐specific competition declined rapidly with stand age due to spatial resource partitioning, and (4) tree death was spatially randomly distributed among larger overstory trees. The study highlights the importance of spatial heterogeneity for the long‐term coexistence of shade‐intolerant pioneer Douglas‐fir and shade‐tolerant western hemlock and western redcedar.
Mouse models of long QT syndrome
Authors: Salama Guy , London Barry
Published: October 2006

Congenital long QT syndrome is a rare inherited condition characterized by prolongation of action potential duration (APD) in cardiac myocytes, prolongation of the QT interval on the surface electrocardiogram (ECG), and an increased risk of syncope and sudden death due to ventricular tachyarrhythmias. Mutations of cardiac ion channel genes that affect repolarization cause the majority of the congenital cases. Despite detailed characterizations of the mutated ion channels at the molecular level, a complete understanding of the mechanisms by which individual mutations may lead to arrhythmias and sudden death requires study of the intact heart and its modulation by the autonomic nervous system. Here, we will review studies of molecularly engineered mice with mutations in the genes (a) known to cause long QT syndrome in humans and (b) specific to cardiac repolarization in the mouse. Our goal is to provide the reader with a comprehensive overview of mouse models with long QT syndrome and to emphasize the advantages and limitations of these models.
Protection conferred by myocardial ATP‐sensitive K+ channels in pressure overload‐induced congestive heart failure revealed in KCNJ11 Kir6.2‐null mutant
Authors: Yamada Satsuki , Kane Garvan C. , Behfar Atta , Liu Xiao‐Ke , Dyer Roy B. , Faustino Randolph S. , Miki Takashi , Seino Susumu , Terzic Andre
Published: October 2006

Ventricular load can precipitate development of the heart failure syndrome, yet the molecular components that control the cardiac adaptive response to imposed demand remain partly understood. Compromised ATP‐sensitive K+ (KATP) channel function renders the heart vulnerable to stress, implicating this metabolic sensor in the homeostatic response that would normally prevent progression of cardiac disease. Here, pressure overload was imposed on the left ventricle by transverse aortic constriction in the wild‐type and in mice lacking sarcolemmal KATP channels through Kir6.2 pore knockout (Kir6.2‐KO). Despite equivalent haemodynamic loads, within 30 min of aortic constriction, Kir6.2‐KO showed an aberrant prolongation of action potentials with intracellular calcium overload and ATP depletion, whereas wild‐type maintained ionic and energetic handling. On catheterization, constricted Kir6.2‐KO displayed compromised myocardial performance with elevated left ventricular end‐diastolic pressure, not seen in the wild‐type. Glyburide, a KATP channel inhibitor, reproduced the knockout phenotype in the wild‐type, whereas the calcium channel antagonist, verapamil, prevented abnormal outcome in Kir6.2‐KO. Within 48 h following aortic constriction, fulminant biventricular congestive heart failure, characterized by exercise intolerance, cardiac contractile dysfunction, hepatopulmonary congestion and ascites, halved the Kir6.2‐KO cohort, while no signs of organ failure or mortality were seen in wild‐type. Surviving Kir6.2‐KO developed premature and exaggerated fibrotic myocardial hypertrophy associated with nuclear up‐regulation of calcium‐dependent pro‐remodelling MEF2 and NF‐AT pathways, precipitating chamber dilatation within 3 weeks. Thus, KATP channels appear mandatory in acute and chronic cardiac adaptation to imposed haemodynamic load, protecting against congestive heart failure and death.
5'-Triphosphate RNA Is the Ligand for RIG-I
Authors: Hornung Veit , Ellegast Jana , Kim Sarah , Brzózka Krzysztof , Jung Andreas , Kato Hiroki , Poeck Hendrik , Akira Shizuo , Conzelmann Karl-Klaus , Schlee Martin , Endres Stefan , Hartmann Gunther
Published: October 2006

The structural basis for the distinction of viral RNA from abundant self RNA in the cytoplasm of virally infected cells is largely unknown. We demonstrated that the 5′-triphosphate end of RNA generated by viral polymerases is responsible for retinoic acid–inducible protein I (RIG-I)–mediated detection of RNA molecules. Detection of 5′-triphosphate RNA is abrogated by capping of the 5′-triphosphate end or by nucleoside modification of RNA, both occurring during posttranscriptional RNA processing in eukaryotes. Genomic RNA prepared from a negative-strand RNA virus and RNA prepared from virus-infected cells (but not from noninfected cells) triggered a potent interferon-α response in a phosphatase-sensitive manner. 5′-triphosphate RNA directly binds to RIG-I. Thus, uncapped 5′-triphosphate RNA (now termed 3pRNA) present in viruses known to be recognized by RIG-I, but absent in viruses known to be detected by MDA-5 such as the picornaviruses, serves as the molecular signature for the detection of viral infection by RIG-I.
TESTING THE STABILITY OF THE SOLAR NEUTRINO LMA SOLUTION WITH A BAYESIAN ANALYSIS
Authors: CHEN B. L. , GE H. L. , GIUNTI C. , LIU Q. Y.
Published: October 2006

We analyze with the Bayesian method the solar and KamLAND neutrino data in terms of neutrino oscillations. We show that Bayesian credible regions with a flat prior in the [Formula: see text] plane strongly support the LMA solution, in agreement with the usual chi-square analysis. Other reasonable priors are considered in order to test the stability of the LMA solution. We show that priors which favor small or large values of the mixing angle lead to minor changes of the allowed LMA region, affecting mainly its large- tan 2θ12 part.
UV/IR MIXING IN NONCOMMUTATIVE FIELD THEORIES AND OPEN–CLOSED STRING DUALITY
Authors: SARKAR SWARNENDU
Published: October 2006

In this paper we study the phenomenon of UV/IR mixing in noncommutative field theories from the point of view of worldsheet open–closed duality in string theory. New infrared divergences in noncommutative field theories arise as a result of integrating over high momentum modes in the loops. These are believed to come from integrating out additional bulk closed string modes. We analyze this issue in detail for the bosonic theory and further for the supersymmetric theory on the C2/Z2 orbifold. We elucidate on the exact role played by the constant background B-field in this correspondence.
STUDIES ON CHEMICALLY SYNTHESIZED DOPED POLY(O-ANISIDINE) AND COPOLY{ANILINE-(O-ANISIDINE)}
Authors: KONDAWAR S. B. , HEDAU M. J. , TABHANE V. A. , DONGRE S. P. , MAHATME U. B. , MONDAL R. A.
Published: October 2006

Substituted polyaniline poly(o-anisidine) and copoly{aniline-(o-anisidine)} were synthesized by the oxidative chemical polymerization method. Sulfuric acid was used as the dopant during the polymerization process. Synthesized polymers were subjected to the spectroscopic, X-ray and thermal analysis. Formation of different oxidation states of the polymer were confirmed by the spectroscopic (UV-VIS and FTIR) analysis. Polymers reveal polycrystalline nature and orthorhombic crystal structure. Three step decomposition patterns similar to that of polyaniline are observed in the thermogram. The conductivity is found to be higher in copoly{aniline-(o-anisidine)} than poly(o-anisidine). Increase in conductivity with increasing temperature was observed in both of the polymers.
ONLINE TRAINING IN ENTREPRENEURSHIP IN LDC'S: A CASE STUDY
Authors: LEIGH LAURENCE
Published: October 2006

The use of online learning techniques is a rapidly growing feature of management education globally. Training entrepreneurs in developing countries using this approach is still in its infancy, however. This paper reports on an early effort at using this approach using a web-based 'learning platform' developed by the International Labor Organization (ILO) for use with entrepreneurs in Ethiopia. It discusses some of the difficulties encountered and draws conclusions for future training initiatives of this type. In particular, it recommends simplification of the web-based tools used and the provision of more onsite assistance to help participants in this type of training use them more effectively.
Hemodynamic analysis of Hyrtl anastomosis in human placenta
Authors: Gordon Zoya , Eytan Osnat , Jaffa Ariel J. , Elad David
Published: October 2006

The Hyrtl anastomosis is a common connection between the umbilical arteries near the cord insertion in most human placentas. It has been speculated that it equalizes the blood pressure between the territories supplied by the umbilical arteries. However, its functional role in the regulation and distribution of fetal blood flow to the placenta has not yet been explored. A computational model has been developed for quantitative analysis of hemodynamic characteristic of the Hyrtl anastomosis in cases of discordant blood flow in the umbilical arteries. Simulations were performed for cases of either increased placental resistance at the downstream end or reduced arterial blood flow due to some pathologies upstream of one of the arteries. The results indicate that when placental territories of one artery impose increased resistance to fetal blood flow, the Hyrtl anastomosis redistributes the blood flow into the second artery to reduce the large pressure gradients that are developed in the affected artery. When one of the arteries conducts a smaller blood flow into the placenta and a relatively smaller pressure gradient is developed, the Hyrtl anastomosis rebuilds the pressure gradients in the affected artery and redistributes blood flow from the unaffected artery to the affected one to improve placental perfusion. In conclusion, the Hyrtl anastomosis plays the role of either a safety valve or a pressure stabilizer between the umbilical arteries at the placental insertion.
ANP signaling inhibits TGF-β-induced Smad2 and Smad3 nuclear translocation and extracellular matrix expression in rat pulmonary arterial smooth muscle cells
Authors: Li Peng , Oparil Suzanne , Novak Lea , Cao Xu , Shi Weibin , Lucas Jason , Chen Yiu-Fai
Published: October 2006

Atrial natriuretic peptide (ANP) and transforming growth factor (TGF)-β play important counterregulatory roles in pulmonary vascular adaptation to chronic hypoxia. To define the molecular mechanism of this important interaction, we tested whether ANP-cGMP-protein kinase G (PKG) signaling inhibits TGF-β1-induced extracellular matrix (ECM) expression and defined the specific site(s) at which this molecular merging of signaling pathways occurs. Rat pulmonary arterial smooth muscle cells (PASMCs) were treated with ANP (1 μM) or cGMP (1 mM) with or without pretreatment with PKG inhibitors KT-5823 (1 μM) or Rp-8-bromo-cGMP (Rp-8-Br-cGMP 50 μM), then exposed to TGF-β1 (1 ng/ml) for 5–360 min (for pSmad nuclear translocation and protein analysis) or 24 h (for ECM mRNA expression). Nuclear translocation of pSmad2 and pSmad3 was assessed by fluorescent confocal microscopy. ANP and cGMP inhibited TGF-β1-induced pSmad2 and pSmad3 nuclear translocation and expression of periostin, osteopontin, and plasminogen activator inhibitor-1 mRNA and protein, but not TGF-β1-induced phosphorylation of Smad2 and Smad3. KT-5823 and Rp-8-Br-cGMP blocked ANP/cGMP-induced activation of PKG and inhibition of TGF-β1-stimulated nuclear translocation of pSmad2 and pSmad3 in PASMCs. These results reveal for the first time a precise site at which ANP-cGMP-PKG signaling exerts its antifibrogenic effect on the profibrogenic TGF-β1 signaling pathway: by blocking TGF-β1-induced pSmad2 and pSmad3 nuclear translocation and ECM expression in PASMCs. Blocking nuclear translocation and subsequent binding of pSmad2 and pSmad3 to TGF-β-Smad response elements in ECM genes may be responsible for the inhibitory effects of ANP on TGF-β-induced expression of ECM molecules.
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

Spindle 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 >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

Pemetrexed 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

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

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]
Coxsackievirus B3 Induces T Regulatory Cells, Which Inhibit Cardiomyopathy in Tumor Necrosis Factor-α Transgenic Mice
Authors: Huber Sally A. , Feldman Arthur M. , Sartini Danielle
Published: October 2006

Innate immunity promotes both the generation of autoimmunity and immunoregulation of adaptive immunity. Transgenic mice expressing the tumor necrosis factor-α (TNF-α) gene under the cardiac myosin promoter (TNF1.6 mice) develop dilated cardiomyopathy. Transgenic mice show extensive cardiac inflammation, suggesting that immunopathogenic mechanisms may promote cardiomyopathy. Two coxsackievirus B3 (CVB3) variants infect and replicate in the heart. H3 variant is highly myocarditic, but H310A1 variant activates CD4
+
T regulatory cells, which protect against viral myocarditis. T-cell depletion of TNF1.6 mice using monoclonal anti-CD3 or anti-CD4 antibody significantly reduced heart size and plasma troponin I concentrations compared with control TNF1.6 mice. Cardiomyopathy in TNF1.6 mice correlates to a CD4
+
Th1 response and autoimmune IgG2a antibodies. TNF1.6 mice infected with H310A1 virus reduced heart size and cardiac inflammation corresponding to the activation of CD4
+
CD25
+
FoxP3
+
(T regulatory cells). Immunosuppression is dependent on IL-10 but not TGFβ. Adoptive transfer of the CD4
+
CD25
+
cells from H310A1-infected mice into uninfected TNF1.6 recipients abrogated cardiomyopathy. Exogenous administration of recombinant TNF-α to H310A1-infected mice for 4 days abrogated immunosuppression. Cardiac enlargement in TNF1.6 mice is partly attributable to T-cell activation and humoral autoimmunity caused by cytokine expression. T regulatory cells induced by H310A1 virus abrogate autoimmunity caused by TNF-α overexpression. H3 virus infection induces high levels of systemic TNF-α, whereas H310A1 virus does not. The low TNF-α response during H310A1 infections is likely responsible for the T regulatory cell response in these animals.
Michigan Gambling
Authors: Wacker R. Fred
Published: October 2006

Michigan is the most prominent gambling destination between Atlantic City and Nevada. Since the mid-1990s, there has been competition between casinos in Ontario, Detroit, and those on Native American reservations. The Ontario, Detroit, and Chippewa casinos in Mount Pleasant and Sault Saint Marie are full-scale, land-based, Las Vegas-style gaming venues. Other smaller Native American casinos that rely largely on machine gaming revenues are scattered throughout the state (in a manner similar to other midwestern and Northern Plains states).
Indian Gaming
Authors: Fenelon James V.
Published: October 2006

This article discusses Indian gaming issues from the perspectives of “traditional” Lakota and Dakota people through the lens of cultural sovereignty. The author reviews the sociopolitical background of gambling on Indian reservations, compares mainstream and Indian gaming, observes historical locations of tribal sovereignty, identifies traditional views through direct interviews, and illustrates economic development and social change issues, all considered through the lens of modernity. Findings include positive effects in each of these social realms, comparatively few and quite small negative results, and internal conflicts arising from fast-acting shifts in social location for many Indian nations and tribes.