bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-Wide Screen Identifies Drug-Induced Regulation of the Gene Giant Axonal Neuropathy (Gan) in a Mouse Model of Antiretroviral-Induced Painful Peripheral Neuropathy
Authors: Dorsey Susan G. , Leitch Carmen C. , Renn Cynthia L. , Lessans Sherrie , Smith Barbara A. , Wang Xiao M. , Dionne Raymond A.
Published: April 2009

Painful peripheral neuropathy is a debilitating complication of the treatment of HIV with nucleoside reverse transcriptase inhibitors (NRTIs). Patients are living longer with these drugs; however many develop excruciating, unremitting, and often treatment-limiting neuropathy that is resistant to conventional pain management therapies. Improving patient comfort and quality of life is paramount and depends on a clearer understanding of this devastating side effect. The mechanisms underlying the development of NRTI-induced neuropathy, however, remain unclear. Using a mouse model of NRTI-induced neuropathy, the authors conducted an unbiased whole-genome microarray screen to identify molecular targets in the spinal dorsal horn, which is the location where integration of ascending sensory transmission and descending modulatory effects occur. Analysis of the microarray data identified a change in the gene giant axonal neuropathy 1 (Gan1). Mutation of this gene has been linked to the development of giant axonal neuropathy (GAN), a rare autosomal recessive condition characterized by a progressive sensorimotor neuropathy. Gan1 has not been previously linked to nerve pathologies in other populations. In this study, downregulation of the Gan1 gene and the gene protein product, gigaxonin, was validated via quantitative polymerase chain reaction ([qPCR] gene expression) and Western blot analyses (protein level). Our report is the first to suggest that Gan1 might be a novel molecular target in the development of NRTI-induced peripheral neuropathy with implications for new therapeutic approaches to preventing or reducing a significant side effect of HIV treatment.
Genetic Characterization of Familial CPVT After 30 Years
Authors: Beery Theresa A. , Shah Maully J. , Benson D. Woodrow
Published: April 2009

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-related, bidirectional ventricular tachycardia and atrial tachyarrhythmia in the absence of either structural heart disease or prolonged QT interval. Autosomal dominant and recessive forms of CPVT because of mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin 2 (CASQ2) have been reported. The objective of this study was the clinical and genetic characterization of the family of an individual initially diagnosed as a child in 1978. Method: We collected family medical history and recorded a four-generation pedigree. We performed mutation analysis of RyR2 ``critical regions'' in the N-terminus, FKBP12.6 binding domain, Ca2+ binding domain, and transmembrane domains of the C-terminus by direct sequencing. Results: CPVT was diagnosed in two of the nine family members evaluated. Pedigree analysis suggested autosomal dominant disease transmission. There were no additional reports of seizures, pregnancy loss, neonatal death, or sudden cardiac death in family members. A novel RyR2 gene variant (W4645R) was found in four family members including two without symptoms. RyR2-W4645R segregates with disease in this family with incomplete penetrance. The W4645 residue is evolutionarily conserved in the transmembrane region adjacent to previously reported disease-causing mutations. Based on sorting intolerant from tolerant analysis of protein structure, RyR2-W4645R is predicted to be deleterious. Conclusions: All current evidence supports RyR2-W4645R as a disease-causing variant, which was silent in persons for two generations before causing symptoms in persons for the next two generations, beginning in 1978.
Recipes for cookies: how institutions shape communication technologies
Authors: Shah Rajiv C. , Kesan Jay P.
Published: April 2009

The ability of communication technologies to favor certain societal concerns, such as privacy, is widely recognized. This article argues that an institutional analysis is central to understanding how a technology affects a societal concern. This is demonstrated with a case study of cookie technology, which has been shaped in differing ways by universities, firms and consortia. A comparative institutional analysis finds that each of these institutions act according to their own norms and processes in influencing the recipe for cookies. It is these institutional tendencies that shape cookie technology. By understanding these tendencies, policymakers can better assess, predict and proactively influence the development of communication technologies to improve societal welfare.
'Egoboo' vs. altruism: the role of reputation in online consumer communities
Authors: Utz Sonja
Published: April 2009

This article focuses on the role of reputation in consumer communities. Reputation systems can have a sanctioning function (incentive for good conduct) or a signalling function (e.g. signalling competence or trustworthiness). If the sanctioning function is dominant, striving for reputation should be the major motivation for contribution. However, contributions also can be motivated by altruism, the pleasure of interaction, earning money or generalized reciprocity. An online study of members of a German consumer community assessed the motivations for contribution and the evaluation of various features of the site. Overall, reputation turned out to be the least important motivation. Five types of users could be distinguished, but only the multiple motive consumers scored high on reputation. However, all community members perceived the quality ratings of the reviews as very important. The findings suggest that reputation has mainly a signalling function, but not so much of a sanctioning function in consumer communities.
E-commerce use among digital TV subscribers: audiovisual abundance and virtual purchase — predictors of e-commerce use among digital television subscribers in Spain
Authors: Garitaonandía Carmelo , Garmendia Maialen
Published: April 2009

Assuming that internet purchasing is related to the amount and quality of technological equipment in a household, the aim of this study was to find some predictors which would help to explain the use of e-commerce in Spain. However, instead of discovering people's reasons for using internet shopping services, it discovered their reasons for not doing so. The use of e-commerce was low in digital households, as only 7.7 percent of those polled had used an internet shopping service on occasion, and only 6.8 percent had done so during the month prior to the poll. Users of e-commerce have a large amount of computer equipment at home and other equipment for leisure activities which is compatible with the former. The results of this study are based on a survey involving personal interviews with members of 560 households in five Spanish cities who subscribe to a TV digital package, by cable or satellite.
Initial Treatment Success Followed By Failure
Authors: Prisciandaro James J. , Roberts John E.
Published: April 2009

This article presents a diagnostically complicated case involving comorbid major depressive disorder with psychotic features, social phobia and personality pathology (including avoidant, paranoid, and obsessive compulsive traits). “Mr. X” was a 45-year-old single White male who was unemployed and living with his parents at the time of treatment. He presented with severe anxiety (Beck Anxiety Inventory = 43) and depression (Beck Depression Inventory = 41) as well as active psychotic symptoms (e.g., self-depreciating auditory hallucinations). Although a cognitive case formulation and treatment plan led to initial success in terms of improvements in symptomatology and functional impairment, we speculate that failure to adequately address core toxic beliefs (e.g., “I am inadequate”) ultimately contributed to a precipitous return of symptomatology, followed by a suicide attempt and premature treatment termination. We discuss the challenges of working within a cognitive framework with this client and suggest alternative approaches that might have proven more successful.
Habit Reversal Treatment of Repetitive Hand Writing in a 7-Year-Old Child with a Learning Disability
Authors: Shumaker David M.
Published: April 2009

Habit reversal (HR) is a cognitive—behavioral treatment for tic disorders, Tourette syndrome, stereotypic movements, and habit disorders. This case study utilizes aspects of habit reversal, including awareness training, self-monitoring, and competing response training, as an intervention for obsessive—compulsive repetitive air handwriting in a 7-year-old girl with a significant learning disability. Therapy is provided on an outpatient basis in a private practice setting. Analysis of in-home, at-school, and in-session data collected by the parents, teacher, and therapist show decreased frequency in repetitive handwriting. Supplemental and cojoint administration of antianxiety medication extinguishes all obsessive handwriting within a 6-month period. These results support previous research demonstrating the efficacy of cojoint cognitive—behavioral and medication treatment of acute obsessive—compulsive symptomatology in children.
Nurse teacherhood and the categories influencing it
Authors: Holopainen Arja , Tossavainen Kerttu , Kärnä-Lin Eija
Published: April 2009

Abstract

Nurse teacherhood is composed of many factors. It includes nurse teachers’ tasks and different multidimensional roles and also nurse teachers’ individual experiences of being a nurse teacher. Nurse teachers’ experiences of nurse teacherhood depend on the meanings they give to the different factors. In other words, there are not only one but also several interpretations of what nurse teacherhood is. These interpretations affect what is important for each nurse teacher in their own nurse teacherhood and how satisfied they are with their profession. This paper is part of a larger study examining how Finnish nurse teachers experience their nurse teacherhood in polytechnics. The purpose of this paper was to describe nurse teacherhood during the years 2003 and 2004, when polytechnics and thus also nurse education were actively being developed in Finland. Nurse teachers ( N = 34) were interviewed and the data were analysed using the grounded theory method. The categories describing nurse teacherhood were: process of change in the organisation, operating culture of the health care working community, professional self-esteem, focus of competence, relationship with students, the future in one’s profession and requirements for staying in the profession. The core category was commitment to nurse teacherhood. Nurse teachers’ individual experiences of the significance of the categories describing teacherhood were reflected by their level of commitment to teacherhood. Nurse teachers, whose commitment to nurse teacherhood was weak, were especially unsatisfied with changes related to their teacherhood. Nurse teachers’ conceptions of their future as nurse teachers were significant in terms of the direction in which they were developing their own teacherhood. Some nurse teachers who were weakly committed to nurse teacherhood considered it unlikely that they would continue in the profession in the future.
Cardiac rehabilitation: Adding years to life and life to years
Authors: Thompson David R
Published: April 2009

Abstract

Cardiac rehabilitation is an integral component of comprehensive cardiac care and is effective in reducing morbidity and mortality and improving quality of life. However, despite a 50-year-history and extensive evidence base attesting to its clinical and cost-effectiveness, including adding years to life and life to years, and exhortations that its implementation should be a key priority, the majority of cardiac patients do not receive rehabilitation. There is a comparative dearth of funding and wide variation in service provision, with a health care system that often fails to address issues such as sub-optimal referral, enrolment and completion, particularly amongst certain potential user groups that could benefit. This paper reviews these issues and suggests ways of overcoming the obstacles identified. It also highlights some of the knowledge gaps and areas that warrant further research.
Cardiac rehabilitation – Past to Present
Authors: Evans Lynda , Probert Heather , Shuldham Caroline
Published: April 2009

Abstract

Cardiac rehabilitation and secondary prevention can promote recovery, reduce coronary events and improve quality of life in many people with heart disease. Traditionally provided for people with coronary heart disease, there is scope to have provision for a range of people, both young and old, and including those with heart failure, valve disease or with an internal cardiac defibrillator. At its best, cardiac rehabilitation spans the whole pathway of care, beginning before admission to hospital and continuing long after, with ongoing management of lifestyle changes. Guidelines are available based on best evidence, and programmes focus on the whole person and address physical, psychological and social well-being. They incorporate health education, risk factor modification, social support and exercise. Programmes can be run in the community, home or hospital. To ensure effective cardiac rehabilitation for each patient, members of the multi-disciplinary team are challenged to work together to meet the individual needs of patients and their family. The standard of care should be monitored through audit so that improvements can be made.
Effective treatment of chronic radiation proctitis using radiofrequency ablation
Authors: Chao Zhou  , Adler Desmond C. , Becker Laren , Yu Chen  , Tsai Tsung-Han , Figueiredo Marisa , Schmitt Joseph M. , Fujimoto James G. , Mashimo Hiroshi
Published: April 2009

Endoscopic argon plasma coagulation and bipolar electrocautery are currently preferred treatments for chronic radiation proctitis, but ulcerations and strictures frequently occur. Radiofrequency ablation (RFA) has been successful for mucosal ablation in the esophagus. Here we report the efficacy of RFA with the BarRx Halo90 system in three patients with bleeding from chronic radiation proctitis. In all cases, the procedure was well tolerated and hemostasis was achieved after 1 or 2 RFA sessions. Re-epithelialization of squamous mucosa was observed over areas of prior hemorrhage. No stricturing or ulceration was seen on follow-up up to 19 months after RFA treatment. Real-time endoscopic optical coherence tomography (EOCT) visualized epithelialization and subsurface tissue microvasculature pre- and post-treatment, demonstrating its potential for follow-up assessment of endoscopic therapies.
Theoretical study on behaviour of superplastic forming/diffusion bonding of bulk metallic glasses
Authors: Lin J. G. , Wang X. F. , Wen C.
Published: April 2009

Based on the behaviour of the superplastic deformation of metallic glasses and Pilling's model, a diffusion bonding model suitable for metallic glasses is proposed in the present study. In the current model, the diffusion bonding processes consists of two stages: one is the plastic deformation stage and the other is the void shrinkage stage, in which, the atom diffusion and superplastic deformation are responsible for the void shrinkage. Applying this model to the diffusion bonding of a Zr based metallic glass, the predicted bonding time is in good agreement with the experimental result. A map for determining the bonding temperature and time to achieve high quality bonding in a Zr based metallic glass is suggested.
Brumadoite, a new copper tellurate hydrate, from Brumado, Bahia, Brazil
Authors: Atencio D. , Roberts A. C. , Matioli P. A. , Stirling J. A. R. , Venance K. E. , Doherty W. , Stanley C. J. , Rowe R. , Carpenter G. J. C. , Coutinho J. M. V.
Published: April 2009

Brumadoite, ideally Cu3Te6+O4(OH)4-5H2O, is a new mineral from Pedra Preta mine, Serra das Eguas. Brumado, Bahia, Brazil. It occurs as microcrystalline aggregates both on and, rarely, pseudomorphous after coarse-grained magnesite, associated with mottramite and quartz. Crystals are platy, subhedral. 1—2 μm in size. Brumadoite is blue (near RHS 114B), has a pale blue streak and a vitreous lustre. It is transparent to translucent and does not fluoresce. The empirical formula is (Cu2.90Pb0.04Ca0.01)Σ2.95 (Te0.936+Si0.05)Σ0.98O3.92(OH)3.84.5.24H2O. Infrared spectra clearly show both (OH) and H2O. Microchemical spot tests using a KI solution show that brumadoite has tellurium in the 6+ state. The mineral is monoclinic, P2/m or P21. Unit-cell parameters refined from X-ray powder data are a 8.629(2) Å, b 5.805(2) Å, c 7.654(2) Å,β 0 103.17(2)°, F 373.3(2) Å3, Z= 2. The eight strongest X-ray powder-diffraction lines [d in Å,(I),(hkl)] are: 8.432,(100),(100); 3.162,(66),(2̄02); 2.385,(27),(220); 2.291,(12),(l̄22); 1.916,(11),(312); 1.666,(14),(4̄22,114); 1.452,(10),(323,040); 1.450,(10),(422,403). The name is for the type locality, Brumado, Bahia, Brazil. The new mineral species has been approved by the CNMNC (IMA 2008-028).
Polyhedral serpentine: a spherical analogue of polygonal serpentine?
Authors: Cressey G. , Cressey B. A. , Wicks F. J.
Published: April 2009

Vugs in late hydrothermal veins in the serpentinite at Gew-graze, Lizard, Cornwall, UK, contain serpentine spheres ≤0.7 mm in diameter composed of a crystallographically controlled radial array of well crystallized lizardite-1T crystals. Examinations with optical and scanning electron microscopy reveal that the spheres actually have polyhedral morphology. The polyhedral facets at the sphere surface are the (0001) terminations of individual single crystals of lizardite. Each lizardite crystal is a hexagonal prism and tapers inwards to the core. The angle from prism axis to prism axis is always ∼24°, and this angle is consistent even though individual prisms have not maintained contact during growth. The space between prisms is filled by smaller crystals of lizardite in more random orientations, forming a solid sphere. Collectively, the tapering prisms form a growth array that produces a surface tessellation consisting of mainly 6-fold neighbours, but with some 5-fold arrangements to accommodate a closed spherical structure. A ‘buckybalF, modified by adding face-centring points to each hexagon and pentagon, provides a useful model to describe the space filling adopted by the polyhedral lizardite spheres. Cross sections (close to an equatorial plane) through these polyhedral spheres resemble cross sections of polygonal serpentine, with 15 sectors at 24° to each other, though very much larger in diameter.
Peripheral mural cell recruitment requires cell-autonomous heparan sulfate
Authors: Stenzel Denise , Nye Emma , Nisancioglu Maya , Adams Ralf H. , Yamaguchi Yu , Gerhardt Holger
Published: April 2009

Blood vessel maturation and stability require recruitment of mural cells (MCs) to the nascent vessel. Loss or detachment of MCs causes vascular dysfunction in diseases. N-sulfation of heparan sulfate (HS) is required for platelet-derived growth factor B (PDGF-B) retention and platelet-derived growth factor receptor-β (PDGFR-β) signaling during MC recruitment. To analyze the specific role of MC-derived HS in this process, we inactivated HS synthesis in MCs. MC-specific loss of HS causes embryonic lethality associated with vascular patterning defects, edema, and hemorrhages during late gestation. MC recruitment in the skin is impaired, correlating with defective PDGFR-β and transforming growth factor-β (TGF-β)–SMAD signaling. Accumulation of rounded cells positive for MC markers close to the vessels indicates defective polarization and migration of local MC progenitors. In contrast, MC recruitment and signaling in the central nervous system (CNS) are unaffected by MC HS loss. Our results suggest that HS is selectively required in a cell-autonomous manner, acting in cis with PDGFR-β and TGF-β receptors during induction/polarization and migration of local progenitor cells to the nascent vessel. Once MCs are in contact with the vessel, as during CNS vascularization, endothelial HS appears sufficient to facilitate PDGFR-β activation in trans.
Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome
Authors: Raza Azra , Galili Naomi , Smith Scott , Godwin John , Lancet Jeffrey , Melchert Magda , Jones Marsha , Keck James G. , Meng Lisa , Brown Gail L. , List Alan
Published: April 2009

Phase 1 testing of ezatiostat, a glutathione S-transferase P1-1 inhibitor, for the treatment of myelodysplastic syndrome was conducted in a multidose-escalation study. Patients received 10 dose levels (200, 400, 1000, 1400, 2000, 2400, 3000, 4000, 5000, and 6000 mg) of ezatiostat tablets in divided doses on days 1 to 7 of a 21-day cycle for a maximum of 8 cycles. The safety and pharmacokinetics of ezatiostat were evaluated. Forty-five patients with low to intermediate-2 International Prognostic Scoring System risk myelodysplastic syndrome were enrolled. No dose-limiting toxicities were observed. The most common grade 1 or 2, respectively, treatment-related adverse events were nonhematologic: nausea (56%, 9%), diarrhea (36%, 7%), vomiting (24%, 7%), abdominal pain (9%, 0%), constipation (4%, 9%), anorexia (3%, 7%), and dyspepsia (3%, 7%). Concentration of the primary active metabolite, TLK236, increased proportionate to ezatiostat dosage. Seventeen hematologic improvement (HI) responses by International Working Group criteria were observed at dose levels of 200 to 6000 mg/day with 11 HI responses at doses of 4000 to 6000 mg/day. HI responses occurred in all lineages including 3 bilineage and 1 complete cytogenetic response. Decreased number of red blood cell and platelet transfusions and in some cases transfusion independence were attained. Extended dose schedules of ezatiostat tablets are under investigation. This study was registered at http://www.clinicaltrials.gov as NCT00280631.
Molecular profiles of Quadriceps muscle in myostatin-null mice reveal PI3K and apoptotic pathways as myostatin targets
Authors: Chelh Ilham , Meunier Bruno , Picard Brigitte , Reecy Mark James , Chevalier Catherine , Hocquette Jean-François , Cassar-Malek Isabelle
Published: April 2009

Background

Myostatin (MSTN), a member of the TGF-β superfamily, has been identified as a negative regulator of skeletal muscle mass. Inactivating mutations in the MSTN gene are responsible for the development of a hypermuscular phenotype. In this study, we performed transcriptomic and proteomic analyses to detect altered expression/abundance of genes and proteins. These differentially expressed genes and proteins may represent new molecular targets of MSTN and could be involved in the regulation of skeletal muscle mass.

Results

Transcriptomic analysis of the Quadriceps muscles of 5-week-old MSTN-null mice (n = 4) and their controls (n = 4) was carried out using microarray (human and murine oligonucleotide sequences) of 6,473 genes expressed in muscle. Proteomic profiles were analysed using two-dimensional gel electrophoresis coupled with mass spectrometry. Comparison of the transcriptomic profiles revealed 192 up- and 245 down- regulated genes. Genes involved in the PI3K pathway, insulin/IGF pathway, carbohydrate metabolism and apoptosis regulation were up-regulated. Genes belonging to canonical Wnt, calcium signalling pathways and cytokine-receptor cytokine interaction were down-regulated. Comparison of the protein profiles revealed 20 up- and 18 down-regulated proteins spots. Knockout of the MSTN gene was associated with up-regulation of proteins involved in glycolytic shift of the muscles and down-regulation of proteins involved in oxidative energy metabolism. In addition, an increased abundance of survival/anti-apoptotic factors were observed.

Conclusion

All together, these results showed a differential expression of genes and proteins related to the muscle energy metabolism and cell survival/anti-apoptotic pathway (e.g. DJ-1, PINK1, 14-3-3ε protein, TCTP/GSK-3β). They revealed the PI3K and apoptotic pathways as MSTN targets and are in favour of a role of MSTN as a modulator of cell survival in vivo.
Induction of mast cell accumulation, histamine release and skin edema by N49 phospholipase A2
Authors: Wei Ji-Fu , Wei Xiao-Long , Mo Ya-Zhen , He Shao-Heng
Published: April 2009

Background

It has been recognized that phospholipase A2(PLA2) is a crucial component of snake venom, which contributes greatly to snake venom induced inflammation in man. However, the mechanisms through which N49 PLA2provoke inflammation remain unclear. Recently, a N49 PLA2, TM-N49 fromProtobothrops mucrosquamatuscrude venom was characterized in our laboratory. Since the purification procedure developed is able to supply us with relatively large quantity of highly purified TM-N49, we investigated the ability of TM-N49 in induction of inflammation.

Results

The results showed that TM-N49 provoked a dose dependent increase in microvascular leakage in the skin of rats. The potency of TM-N49 in induction of skin edema appeared similar potency of bradykinin and histamine. Pretreatment of rats with compound 48/80 diminished TM-N49 induced skin reaction and reduced mast cell numbers in rats. Ginkgolide B and cyproheptadine, but not terfenadine and quinacrine, inhibited TM-N49 elicited microvascular leakage when they were co-injected with the stimulus to rat skin. Moreover, TM-N49 was found to induce histamine release from human colon, lung and tonsil mast cells, and both metabolic inhibitors and pertussis toxin were capable of inhibiting TM-N49 elicited histamine release. TM-N49 induced mast cell accumulation in the peritoneum of mice, which was inhibited by co-injection of ginkgolide B, cyproheptadine and terfenadine. Intravenous injection of monoclonal antibodies against CD18, ICAM-1 and CD11a also blocked TM-N49 induced mast cell accumulation.

Conclusion

TM-N49 is a potent stimulus for skin edema, mast cell activation and accumulation.
The mitochondrial DNA T16189C polymorphism and HIV-associated cardiomyopathy: a genotype-phenotype association study
Authors: Shaboodien Gasnat , Engel Mark E , Syed Faisal F , Poulton Joanna , Badri Motasim , Mayosi Bongani M
Published: April 2009

Background

The mitochondrial DNA (mtDNA) T16189C polymorphism, with a homopolymeric C-tract of 10–12 cytosines, is a putative genetic risk factor for idiopathic dilated cardiomyopathy in the African and British populations. We hypothesized that this variant may predispose to dilated cardiomyopathy in people who are infected with the human immunodeficiency virus (HIV).

Methods

A case-control study of 30 HIV-positive cases with dilated cardiomyopathy and 37 HIV-positive controls without dilated cardiomyopathy was conducted. The study was confined to persons of black African ancestry to minimize confounding of results by population admixture. HIV-positive patients with an echocardiographically confirmed diagnosis of dilated cardiomyopathy and HIV-positive controls with echocardiographically normal hearts were studied. Patients with secondary causes of cardiomyopathy (such as hypertension, diabetes, pregnancy, alcoholism, valvular heart disease, and opportunistic infection) were excluded from the study. DNA samples were sequenced for the mtDNA T16189C polymorphism with a homopolymeric C-tract in the forward and reverse directions on an ABI3100 sequencer.

Results

The cases and controls were well matched for age (median 35 years versus 34 years, P = 0.93), gender (males 60% vs 53%, P = 0.54), and stage of HIV disease (mean CD4 T cell count 260.7/μL vs. 176/μL, P = 0.21). The mtDNA T16189C variant with a homopolymeric C-tract was detected at a frequency of 26.7% (8/30) in the HIV-associated cardiomyopathy cases and 13.5% (5/37) in the HIV-positive controls. There was no significant difference between cases and controls (Odds Ratio 2.33, 95% Confidence Interval 0.67–8.06, p = 0.11).

Conclusion

The mtDNA T16189C variant with a homopolymeric C-tract is not associated with dilated cardiomyopathy in black African people infected with HIV.
Clinical relevance of heparin-PF4 complex antibody in DVT after total joint replacement
Authors: Torigoshi Takafumi , Motokawa Satoru , Maeda Yumi , Maeda Kazushige , Hiura Takeshi , Takayama Gou , Taguchi Kenji , Shindo Hiroyuki , Migita Kiyoshi
Published: April 2009

Background

Antibodies to the heparin-platelet factor-4 (HPF-4) complex (HIT antibodies) have been observed in patients with heparin-induced thrombocytopenia (HIT). These antibodies are thought to be involved in thrombosis through activation of platelet/endothelial cells. This prospective study was conducted to determine the incidence of post-operative HIT antibodies to assess the associated risk of deep vein thrombosis (DVT) in patients undergoing total knee arthroplasty (TKA) or total hip arthroplasty (THA).

Methods

We studied 104 patients who underwent unilateral primary TKA (n = 44) and primary THA (n = 60) with short-duration prophylaxis (1–2 days of a fixed dose of unfractionated heparin). HIT antibodies were assayed using a sandwich-type ELISA before the operation and after heparin treatment (post-operative day 7).

Results

In the clinical outcome, the incidence of symptomatic DVT was 15.4% (16/104, TKA; 10, THA 6) and pulmonary embolism (PE) was not observed. The total seroconversion rate of HIT antibodies at post-operative day 7 was 34.6% (36/104). Among 36 seroconverted patients, 11 (30.6%) developed symptomatic DVT and 5 out of 68 of the non-seroconverted patients (7.4%) developed symptomatic DVT. The incidence for DVT was significantly higher in the seroconverted patients compared with that of the non-seroconverted patients (odds ratio 5.5, 95%CI: 1.7–17.6 p = 0.0028). Furthermore, in the patients with symptomatic DVT, the titer of HIT antibodies at post-operative day 7 was significantly higher compared with those without symptomatic DVT.

Conclusion

Our data therefore suggest that seroconversion for HIT antibodies generated by heparin is associated with a risk of DVT in patients undergoing total joint replacement.
Identification of potentially safe promising fungal cell factories for the production of polyketide natural food colorants using chemotaxonomic rationale
Authors: Mapari Sameer AS , Meyer Anne S , Thrane Ulf , Frisvad Jens C
Published: April 2009

Background

Colorants derived from natural sources look set to overtake synthetic colorants in market value as manufacturers continue to meet the rising demand for clean label ingredients – particularly in food applications. Many ascomycetous fungi naturally synthesize and secrete pigments and thus provide readily available additional and/or alternative sources of natural colorants that are independent of agro-climatic conditions. With an appropriately selected fungus; using in particular chemotaxonomy as a guide, the fungal natural colorants could be produced in high yields by using the optimized cultivation technology. This approach could secure efficient production of pigments avoiding use of genetic manipulation.

Results

Polyketide pigment producing ascomycetous fungi were evaluated for their potential as production organisms based on a priori knowledge on species-specific pigment and potential mycotoxin production and BioSafety level (BSL) classification. Based on taxonomic knowledge, we pre-selected ascomycetous fungi belonging to Penicillium subgenus Biverticillium that produced yellow, orange or red pigments while deselecting Penicillium marneffei; a well known human pathogen in addition to other mycotoxigenic fungi belonging to the same group. We identified 10 strains belonging to 4 species; viz. P. purpurogenum, P. aculeatum, P. funiculosum, and P. pinophilum as potential pigment producers that produced Monascus-like pigments but no known mycotoxins. The selection/deselection protocol was illustrated in the pigment extracts of P. aculeatum IBT 14259 and P. crateriforme IBT 5015 analysed by HPLC-DAD-MS. In addition, extracellular pigment producing ability of some of the potential pigment producers was evaluated in liquid media with a solid support and N-glutarylmonascorubramine was discovered in the partially purified pigment extract of P. purpurogenum IBT 11181 and IBT 3645.

Conclusion

The present work brought out that the use of chemotaxonomic tools and a priori knowledge of fungal extrolites is a rational approach towards selection of fungal polyketide pigment producers considering the enormous chemical diversity and biodiversity of ascomycetous fungi. This rationale could be very handy for the selection of potentially safe fungal cell factories not only for polyketide pigments but also for the other industrially important polyketides; the molecular and genetic basis for the biosynthesis of which has not yet been examined in detail. In addition, 4 out of the 10 chemotaxonomically selected promising Penicillium strains were shown to produce extracellular pigments in the liquid media using a solid support indicating future cell factory possibilities for polyketide natural food colorants.
The calcium-sensing receptor regulates parathyroid hormone gene expression in transfected HEK293 cells
Authors: Galitzer Hillel , Lavi-Moshayoff Vardit , Nechama Morris , Meir Tomer , Silver Justin , Naveh-Many Tally
Published: April 2009

Background

The parathyroid calcium receptor determines parathyroid hormone secretion and the response of parathyroid hormone gene expression to serum Ca2+ in the parathyroid gland. Serum Ca2+ regulates parathyroid hormone gene expression in vivo post-transcriptionally affecting parathyroid hormone mRNA stability through the interaction of trans-acting proteins to a defined cis element in the parathyroid hormone mRNA 3'-untranslated region. These parathyroid hormone mRNA binding proteins include AUF1 which stabilizes and KSRP which destabilizes the parathyroid hormone mRNA. There is no parathyroid cell line; therefore, we developed a parathyroid engineered cell using expression vectors for the full-length human parathyroid hormone gene and the human calcium receptor.

Results

Co-transfection of the human calcium receptor and the human parathyroid hormone plasmid into HEK293 cells decreased parathyroid hormone mRNA levels and secreted parathyroid hormone compared with cells that do not express the calcium receptor. The decreased parathyroid hormone mRNA correlated with decreased parathyroid hormone mRNA stability in vitro, which was dependent upon the 3'-UTR cis element. Moreover, parathyroid hormone gene expression was regulated by Ca2+ and the calcimimetic R568, in cells co-transfected with the calcium receptor but not in cells without the calcium receptor. RNA immunoprecipitation analysis in calcium receptor-transfected cells showed increased KSRP-parathyroid hormone mRNA binding and decreased binding to AUF1. The calcium receptor led to post-translational modifications in AUF1 as occurs in the parathyroid in vivo after activation of the calcium receptor.

Conclusion

The expression of the calcium receptor is sufficient to confer the regulation of parathyroid hormone gene expression to these heterologous cells. The calcium receptor decreases parathyroid hormone gene expression in these engineered cells through the parathyroid hormone mRNA 3'-UTR cis element and the balanced interactions of the trans-acting factors KSRP and AUF1 with parathyroid hormone mRNA, as in vivo in the parathyroid. This is the first demonstration that the calcium receptor can regulate parathyroid hormone gene expression in heterologous cells.
Short hairpin-loop-structured oligodeoxynucleotides reduce HSV-1 replication
Authors: Falkenhagen Alexander , Heinrich Jochen , Moelling Karin
Published: April 2009

The Herpes simplex virus (HSV) is known as an infectious agent and widespread in the human population. The symptoms of HSV infections can range from mild to life threatening, especially in immune-compromised individuals. HSV infections are commonly treated with the guanosine analogue Aciclovir, but reports of resistance are increasing. Efforts are made to establish single-stranded antisense oligodeoxynucleotides (as) and small interfering ribonucleic acids (siRNAs) for antiviral treatment. Recently, another class of short interfering nucleic acids, partially double-stranded hairpin loop-structured 54 mer oligodeoxynucleotides (ODNs), was shown to allow hydrolysis of HIV RNA by binding to the viral RNA. This leads to a substrate for the viral RNase H. To assess the potential of such ODNs for inhibition of HSV-1 replication, five partially double-stranded ODNs were designed based on the sequences of known siRNAs against HSV-1 with antiviral activity. Three of them are directed against early and two against leaky late genes. Primary human lung fibroblasts, MRC-5, and African green monkey kidney cells, Vero, were transfected with ODNs and subsequently infected. The effect on HSV-1 replication was determined by analyzing the virus titer in cell culture supernatants by quantitative PCR and plaque assays. An inhibitory effect was observed with all five selected ODNs, with two cases showing statistical significance in both cell types. The observed effect was sequence-specific and dose dependent. In one case the ODN was more efficient than a previously described siRNA directed against the same target site in the mRNA of UL5, a component of the helicase/primase complex. HSV-1 virions and ODNs can be applied simultaneously without transfection reagent, but at a 50-fold higher concentration to Vero cells with similar efficiencies. The results underline the potential of partially double-stranded hairpin loop-structured ODNs as antiviral agents.
Vaccinia virus p37 interacts with host proteins associated with LE-derived transport vesicle biogenesis
Authors: Chen Yali , Honeychurch Kady M , Yang Guang , Byrd Chelsea M , Harver Chris , Hruby Dennis E , Jordan Robert
Published: April 2009

Background

Proteins associated with the late endosome (LE) appear to play a central role in the envelopment of a number of taxonomically diverse viruses. How viral proteins interact with LE-associated proteins to facilitate envelopment is not well understood. LE-derived transport vesicles form through the interaction of Rab9 GTPase with cargo proteins, and TIP47, a Rab9-specific effector protein. Vaccinia virus (VV) induces a wrapping complex derived from intracellular host membranes to envelope intracellular mature virus particles producing egress-competent forms of virus.

Results

We show that VV p37 protein associates with TIP47-, Rab9-, and CI-MPR-containing membranes. Mutation of a di-aromatic motif in p37 blocks association with TIP47 and inhibits plaque formation. ST-246, a specific inhibitor of p37 function, inhibits these interactions and also blocks wrapped virus particle formation. Vaccinia virus expressing p37 variants with reduced ST-246 susceptibility associates with Rab9 and co-localizes with CI-MPR in the presence and absence of compound.

Conclusion

These results suggest that p37 localizes to the LE and interacts with proteins associated with LE-derived transport vesicle biogenesis to facilitate assembly of extracellular forms of virus.
Simulation-based model checking approach to cell fate specification during Caenorhabditis elegans vulval development by hybrid functional Petri net with extension
Authors: Li Chen , Nagasaki Masao , Ueno Kazuko , Miyano Satoru
Published: April 2009

Background

Model checking approaches were applied to biological pathway validations around 2003. Recently, Fisheret al. have proved the importance of model checking approach by inferring new regulation of signaling crosstalk inC. elegansand confirming the regulation with biological experiments. They took a discrete and state-based approach to explore all possible states of the system underlying vulval precursor cell (VPC) fate specification for desired properties. However, since both discrete and continuous features appear to be an indispensable part of biological processes, it is more appropriate to use quantitative models to capture the dynamics of biological systems. Our key motivation of this paper is to establish a quantitative methodology to model and analyzein silicomodels incorporating the use of model checking approach.

Results

A novel method of modeling and simulating biological systems with the use of model checking approach is proposed based on hybrid functional Petri net with extension (HFPNe) as the framework dealing with both discrete and continuous events. Firstly, we construct a quantitative VPC fate model with 1761 components by using HFPNe. Secondly, we employ two major biological fate determination rules – Rule I and Rule II – to VPC fate model. We then conduct 10,000 simulations for each of 48 sets of different genotypes, investigate variations of cell fate patterns under each genotype, and validate the two rules by comparing three simulation targets consisting of fate patterns obtained fromin silicoandin vivoexperiments. In particular, an evaluation was successfully done by using our VPC fate model to investigate one target derived from biological experiments involving hybrid lineage observations. However, the understandings of hybrid lineages are hard to make on a discrete model because the hybrid lineage occurs when the system comes close to certain thresholds as discussed by Sternberg and Horvitz in 1986. Our simulation results suggest that: Rule I that cannot be applied with qualitative based model checking, is more reasonable than Rule II owing to the high coverage of predicted fate patterns (except for the genotype oflin-15ko; lin-12kodouble mutants). More insights are also suggested.

Conclusion

The quantitative simulation-based model checking approach is a useful means to provide us valuable biological insights and better understandings of biological systems and observation data that may be hard to capture with the qualitative one.
Tamoxifen-elicited uterotrophy: cross-species and cross-ligand analysis of the gene expression program
Authors: Kwekel Joshua C , Forgacs Agnes L , Burgoon Lyle D , Williams Kurt J , Zacharewski Timothy R
Published: April 2009

Background

Tamoxifen (TAM) is a well characterized breast cancer drug and selective estrogen receptor modulator (SERM) which also has been associated with a small increase in risk for uterine cancers. TAM's partial agonist activation of estrogen receptor has been characterized for specific gene promoters but not at the genomic levelin vivo.Furthermore, reducing uncertainties associated with cross-species extrapolations of pharmaco- and toxicogenomic data remains a formidable challenge.

Results

A comparative ligand and species analysis approach was conducted to systematically assess the physiological, morphological and uterine gene expression alterations elicited across time by TAM and ethynylestradiol (EE) in immature ovariectomized Sprague-Dawley rats and C57BL/6 mice. Differential gene expression was evaluated using custom cDNA microarrays, and the data was compared to identify conserved and divergent responses. 902 genes were differentially regulated in all four studies, 398 of which exhibit identical temporal expression patterns.

Conclusion

Comparative analysis of EE and TAM differentially expressed gene lists suggest TAM regulates no unique uterine genes that are conserved in the rat and mouse. This demonstrates that the partial agonist activities of TAM extend to molecular targets in regulating only a subset of EE-responsive genes. Ligand-conserved, species-divergent expression of carbonic anhydrase 2 was observed in the microarray data and confirmed by real time PCR. The identification of comparable temporal phenotypic responses linked to related gene expression profiles demonstrates that systematic comparative genomic assessments can elucidate important conserved and divergent mechanisms in rodent estrogen signalling during uterine proliferation.
Altered gene expression and miRNA expression associated with cancerous IEC-6 cell transformed by MNNG
Authors: Zhang Bo , Wang Xukai , Wang Yan
Published: April 2009

Background

Tumorigenesis is thought to be the consequence of gene mutation and disordered gene expression. However, the detailed molecular mechanism underlying the development and progress of colon cancer have not been elucidate completely. This study aimed to find out the genes associated with cancer biological pathways involved in transformation and tumorigenesis.

Methods

Normal intestinal cell line 6 (IEC-6) cells were transformed to cancer cells by treatment with cancerogenic agent of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and Phorbol 12-myristate 13 acetate (PMA). Then we investigated the altered gene expression of transformed IEC-6 cells by the microarray containing 113 genes associated with cancer pathway. Also the altered miRNAs of transformed IEC-6 cells were analyzed by array hybridization (miRCURY Array v9.2, Exiqon). The levels of acetylated histone H3 in transformed IEC-6 cells was evaluated by western blot.

Results

Cell proliferation was significantly increased as IEC-6 cells were transformed and tumor xenografts could be detected in animals as transformed IEC-6 cells were inoculated subcutaneously in nude mice. Result of microarray showed nine genes were increased and two decreased, as well as 13 miRNA were increased and 97 decreased. Verification by real-time PCR implies that the data obtained from microarray analysis were reliable. Western blot showed the levels of acetylated histone H3 were increased dramatically after MNNG/PMA treatment.

Conclusion

Our results showed many important biological pathways and miRNAs were involved in transformation and tumorigenesis of IEC-6 cells, which suggested the transformation of normal cells was involved with large mount of genetic and epigenetic variation.
Claims of Stable Identity and (Un)reliability in Dissonant Narration
Authors: McCormick Paul
Published: April 2009

Self-conscious character narration provides special opportunities for authors to signal (un)reliability. This article focuses on one such opportunity. When narrators like John Dowell in Ford Madox Ford's The Good Soldier consistently assert moral and cognitive distance from their existences as characters in a story world, they create a pattern that Dorrit Cohn calls dissonant narration. But otherwise dissonant narrators close this distance and deviate from their pattern if they link a character trait to both their narrating- and their experiencing-self, thereby asserting that their claimed character trait is temporally continuous. I refer to these kinds of exceptions within dissonant narration as claims of stable identity and argue for their importance for judgments of (un)reliable narration. After defining the concept in relation to contemporary models of unreliability, the article analyzes particular claims of stable identity made by John Dowell and other narrators to show that authors can use them in different ways to guide readers' understandings in character narration.
Biological Activity of Some Cyanobiphenyl Derivatives
Authors: Yoshizawa Atsushi , Takahashi Yuuka , Nishizawa Ayumi , Takeuchi Kazuhito , Sagisaka Masanobu , Takahashi Kenji , Hazawa Masaharu , Kashiwakura Ikuo
Published: April 2009

We investigated biological activity of a homologous series of 4-cyano-4′-(ω-hydroxyalkyloxy)biphenyl. The amphiphilic compounds with a nematic phase were found to exhibit marked inhibition of cell proliferation of A549 human lung carcinoma cell lines, although they showed no such inhibition against WI-38 normal fibroblast cell lines under identical conditions.
Pulsed Ultrasound Effect on DNA Polymerase Reaction Monitored on a QCM
Authors: Kawasaki Takayoshi , Toyoda Momoko , Hoshino Yu , Okahata Yoshio
Published: April 2009

DNA polymerase reaction under pulsed ultrasound irradiation was investigated on a DNA-immobilized quartz-crystal microbalance (QCM), and the 240-kHz ultrasound irradiation pulsed at 20 s−1 increased the polymerization reactivity owing to the increase of the stability of the DNA/polymerase/monomer complex, although the continuous irradiation decreases the stability.