bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of a Speed-Based Classification System Using Quantitative Measures of Walking Performance Poststroke
Authors: Bowden Mark G. , Balasubramanian Chitralakshmi K. , Behrman Andrea L. , Kautz Steven A.
Published: October 2008

Background. For clinical trials in stroke rehabilitation, self-selected walking speed has been used to stratify persons to predict functional walking status and to define clinical meaningfulness of changes. However, this stratification was validated primarily using self-report questionnaires. Objective. This study aims to validate the speed-based classification system with quantitative measures of walking performance. Methods. A total of 59 individuals who had hemiparesis for more than 6 months after stroke participated in this study. Spatiotemporal and kinetic measures included the percentage of total propulsion generated by the paretic leg (Pp), the percentage of the stride length accounted for by the paretic leg step length (PSR), and the percentage of the gait cycle spent in paretic preswing (PPS). Additional measures included the synergy portion of the Fugl-Meyer Assessment and the average number of steps/day in the home and community measured with a step activity monitor. Participants were stratified by self-selected gait speed into 3 groups: household (<0.4 m/s), limited community (0.4-0.8 m/s), and community (>0.8 m/s) ambulators. Group differences were analyzed using a Kruskal—Wallis H test with rank sums test post hoc analyses. Results. Analyses demonstrated a main effect in all measures, but only steps/day and PPS demonstrated a significant difference between all 3 groups. Conclusions. Classifying individuals poststroke by self-selected walking speed is associated with home and community-based walking behavior as quantified by daily step counts. In addition, PPS distinguishes all 3 groups. Pp differentiates the moderate from the fast groups and may represent a contribution to mechanisms of increasing walking speed. Speed classification presents a useful yet simple mechanism to stratify subjects poststroke and may be mechanically linked to changes in PPS.
Successful Aging: The Role of Physical Activity
Authors: Chodzko-Zajko Wojtek , Schwingel Andiara , Chae Hee Park
Published: October 2008

Although no amount of physical activity can stop the aging process, a moderate amount of regular exercise can minimize the physiological effects of an otherwise sedentary lifestyle and increase active life expectancy by limiting the development and progression of chronic disease and disabling conditions. Ideally, exercise prescription for older adults should include aerobic, muscle strengthening, and flexibility exercises. In addition, individuals at risk for falling or mobility impairment should also perform specific exercises to improve balance. The intensity and duration of physical activity should be low at the outset for those who are highly deconditioned, are functionally limited, or have chronic conditions affecting their ability to perform physical tasks. Furthermore, the progression of activities should be individualized and tailored to tolerance and preference. Incorporating principles of behavioral change into the design and application of exercise and physical activity programs will increase the likelihood of an individual initiating and maintaining a regular program of exercise and/ or physical activity. Strategies for maintaining physical function and improving overall health of older adults with chronic conditions and disability are discussed. All older adults with and without disabilities should be encouraged to develop a personalized physical activity plan that meets their needs and personal preferences.
The Role of Gender in `Expressive' Abuse at Abu Ghraib
Authors: Caldwell Ryan Ashley , Mestrovic Stjepan G.
Published: October 2008

We analyze the court-martial of Sabrina Harman, one of the alleged `seven rotten apples' associated with specific incidents of abuse at Abu Ghraib prison in Iraq, vis-a-vis the Parsonian distinction between `instrumental' and `expressive' pattern-variables. The Parsonian distinction between instrumental and expressive roles served a multitude of functions simultaneously, and especially given the masculine code of the military. We move beyond Parsons to introduce the new concepts of `expressive abuse', `expressive torture', and `instrumental misuse of expressive functions' to capture the overall thrust of the courts-martial as well as important aspects of the abuse at Abu Ghraib as revealed through testimony, government reports, interviews, and other sources of data. Both co-authors were participant-observers at the courts-martial of Sabrina Harman and Lynndie England, and draw upon the testimony and data from those trials in addition to the documents that are cited.
Common Sense and the Collaborative Production of Class
Authors: Pascale Celine-Marie
Published: October 2008

In the USA, economic inequality, while arguably one of the most material sites of `difference', is often one of the least visible. The presence and meaning of class in daily life may be more vague than at any other time in US history. This article examines how commonsense knowledge about class leads people to engage in practices that systematically disorganize the presence of social and economic capital. The over-arching analytical framework builds a performative analysis of class by situating the personal agency of talk within broader cultural discourses that shape and constrain possibilities for talk. I draw from ethnomethodology and post-structural discourse analysis to analyze talk about class in 1600 pages of transcript from interviews with 23 people. By linking the interpretive practices of talk in interviews to the circulation and repetition of cultural knowledge in discourses, I demonstrate how class identities are constituted through conditions not generally associated with economic processes.
Thermal cycle properties of plasma sprayed YSZ/Al2O3 thermal barrier coatings
Authors: Saral U. , Toplan N.
Published: October 2008

In the present study, yttria partially stabilised zirconia (YSZ)/Al2O3 coatings, which are used for jet engines, gas turbines and diesel engines were coated with thermal barrier coatings to provide high thermal resistance, reduce the metal surface temperatures and increase component durability. The effect of alumina addition from 0 to 80 wt-% on the properties of plasma sprayed YSZ coatings was investigated. The coating comprised of YSZ–Al2O3 (0, 20, 50 and 80 wt- %Al2O3); NiCrAlY bond coat; and AISI 304L stainless steels substrates. Scanning electron microscopy was used to analyse the microstructures of the coated samples. Thermal shock tests were performed over the specimens, at 1000 and 1200°C for 5 min and then forced air quenching for 2 min. The microhardness was investigated depending on the alumina contents. Vickers hardness on cross-section of coatings was observed to increase with the increase in alumina mixing ratio. It was noticed that with increase in Al2O3 content the thermal shock life of the specimens decreased.
Advanced composite coating by electrodeposition technique
Authors: Aal A. Abdel , Gobran H. A. , Muecklich F.
Published: October 2008

This work aims to prepare Ni–RuAl composite coatings from Watts’ solution containing suspension of the single phase powder of the intermetallic compound RuAl. The chemical composition, phase structure and surface morphology of pure Ni and Ni–RuAl composite coatings are investigated using energy dispersive analyser system (EDX), X-ray diffraction (XRD) and scanning electron microscopy (SEM) respectively. The microhardness and oxidation resistance of Ni–RuAl composite coatings in comparison with pure Ni are evaluated. The corrosion behaviour for both of Ni and Ni–RuAl deposits is evaluated by polarisation curves in 3·5% NaCl solution. The results reveal that the content of RuAl in the Ni matrix is a function of applied current density and concentration of RuAl powder in the plating bath. Moreover, the presence of RuAl improves the oxidation and corrosion resistance of Ni coatings. The microhardness of composite coatings increases with the increasing content of the RuAl particles in the deposit.
Thin film silicon substrate formation using electrochemical anodic etching method
Authors: Kwon J.-H. , Lee S.-H. , Ju B.-K.
Published: October 2008

The production of detached porous silicon (PS) layers for layer transfer (LT) has been investigated. Electrochemical anodisation (ECA) studies of monocrystalline silicon (mono-Si) wafers in a hydrofluoric acid/ethanol/deionised (DI) water solution showed that porosity can be controlled by controlling current density during ECA. Double layered PS layers consisting of low (26·5%) and high (86·3%) porosity layers were formed by ECA at 1·5 mA cm–2 and 100 mA cm–2 for etching times of 10 min and 10 sec respectively. These PS layers are considered viable for LT substrate technology.
Two distinct roles of mitogen-activated protein kinases in platelets and a novel Rac1-MAPK–dependent integrin outside-in retractile signaling pathway
Authors: Flevaris Panagiotis , Li Zhenyu , Zhang Guoying , Zheng Yi , Liu Junling , Du Xiaoping
Published: October 2008

Mitogen-activated protein kinases (MAPK), p38, and extracellular stimuli-responsive kinase (ERK), are acutely but transiently activated in platelets by platelet agonists, and the agonist-induced platelet MAPK activation is inhibited by ligand binding to the integrin αIIbβ3. Here we show that, although the activation of MAPK, as indicated by MAPK phosphorylation, is initially inhibited after ligand binding to integrin αIIbβ3, integrin outside-insignaling results in a late but sustained activation of MAPKs in platelets. Furthermore, we show that the early agonist-induced MAPK activation and the late integrin-mediated MAPK activation play distinct roles in different stages of platelet activation. Agonist-induced MAPK activation primarily plays an important role in stimulating secretion of platelet granules, while integrin-mediated MAPK activation is important in facilitating clot retraction. The stimulatory role of MAPK in clot retraction is mediated by stimulating myosin light chain (MLC) phosphorylation. Importantly, integrin-dependent MAPK activation, MAPK-dependent MLC phosphorylation, and clot retraction are inhibited by a Rac1 inhibitor and in Rac1 knockout platelets, indicating that integrin-induced activation of MAPK and MLC and subsequent clot retraction is Rac1-dependent. Thus, our results reveal 2 different activation mechanisms of MAPKs that are involved in distinct aspects of platelet function and a novel Rac1-MAPK–dependent cell retractile signaling pathway.
In vitro–differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations
Authors: Carlson Michael J. , West Michelle L. , Coghill James M. , Panoskaltsis-Mortari Angela , Blazar Bruce R. , Serody Jonathan S.
Published: October 2008

The morbidity and mortality associated with graft-host-disease (GVHD) is a significant obstacle to the greater use of allogeneic stem cell transplantation. Donor T cells that predominantly differentiate into TH1/Tc1 T cells and generate pro-inflammatory cytokines such as interferon-γ (IFN-γ) mediate GVHD. Although numerous studies have described a pathogenic role for IFN-γ, multiple reports have demonstrated that the lack of IFN-γ paradoxically exacerbated GVHD lethality. This has led to speculation that another subset of T cells may significantly contribute to GVHD mortality. Several groups have demonstrated a new lineage of CD4+ T helper cell development distinct from TH1 or TH2 differentiation. This lineage is characterized by production of interleukin (IL)–17A, IL-17F, IL-22, and IL-21 and has been termed TH17 cells. Here, we demonstrate that a highly purified population of TH17 cells is capable of inducing lethal GVHD, hallmarked by extensive pathologic cutaneous and pulmonary lesions. Upon transfer, these cells migrate to and expand in GVHD target organs and secondary lymphoid tissues. Finally, we demonstrate differential roles for tumor necrosis factor-α (TNF-α) and IL-17A in the clinical manifestations of GVHD induced by TH17 cells. Our studies demonstrate that cells other than TH1/Tc1 can mediate acute GVHD.
Knowledge-guided multi-scale independent component analysis for biomarker identification
Authors: Chen Li , Xuan Jianhua , Wang Chen , Shih Ie-Ming , Wang Yue , Zhang Zhen , Hoffman Eric , Clarke Robert
Published: October 2008

Background

Many statistical methods have been proposed to identify disease biomarkers from gene expression profiles. However, from gene expression profile data alone, statistical methods often fail to identify biologically meaningful biomarkers related to a specific disease under study. In this paper, we develop a novel strategy, namely knowledge-guided multi-scale independent component analysis (ICA), to first infer regulatory signals and then identify biologically relevant biomarkers from microarray data.

Results

Since gene expression levels reflect the joint effect of several underlying biological functions, disease-specific biomarkers may be involved in several distinct biological functions. To identify disease-specific biomarkers that provide unique mechanistic insights, a meta-data "knowledge gene pool" (KGP) is first constructed from multiple data sources to provide important information on the likely functions (such as gene ontology information) and regulatory events (such as promoter responsive elements) associated with potential genes of interest. The gene expression and biological meta data associated with the members of the KGP can then be used to guide subsequent analysis. ICA is then applied to multi-scale gene clusters to reveal regulatory modes reflecting the underlying biological mechanisms. Finally disease-specific biomarkers are extracted by their weighted connectivity scores associated with the extracted regulatory modes. A statistical significance test is used to evaluate the significance of transcription factor enrichment for the extracted gene set based on motif information. We applied the proposed method to yeast cell cycle microarray data and Rsf-1-induced ovarian cancer microarray data. The results show that our knowledge-guided ICA approach can extract biologically meaningful regulatory modes and outperform several baseline methods for biomarker identification.

Conclusion

We have proposed a novel method, namely knowledge-guided multi-scale ICA, to identify disease-specific biomarkers. The goal is to infer knowledge-relevant regulatory signals and then identify corresponding biomarkers through a multi-scale strategy. The approach has been successfully applied to two expression profiling experiments to demonstrate its improved performance in extracting biologically meaningful and disease-related biomarkers. More importantly, the proposed approach shows promising results to infer novel biomarkers for ovarian cancer and extend current knowledge.
Protocol for German trial of Acyclovir and corticosteroids in Herpes-simplex-virus-encephalitis (GACHE): a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial [ISRCTN45122933]
Authors: Martinez-Torres Francisco , Menon Sanjay , Pritsch Maria , Victor Norbert , Jenetzky Ekkehart , Jensen Katrin , Schielke Eva , Schmutzhard Erich , de Gans Jan , Chung Chin-Hee , Luntz Steffen , Hacke Werner , Meyding-Lamadé Uta ,   the GACHE Investigators
Published: October 2008

Background

The treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major unsolved problem in Neurology. Current gold standard for therapy is acyclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains up to 15%, less than 20% of patients are able to go back to work, and the majority of patients suffer from severe disability. This is a discouraging, unsatisfactory situation for treating physicians, the disabled patients and their families, and constitutes an enormous burden to the public health services. The information obtained from experimental animal research and from recent retrospective clinical observations, indicates that a substantial benefit in outcome can be expected in patients with HSVE who are treated with adjuvant dexamethasone. But currently there is no available evidence to support the routine use of adjuvant corticosteroid treatment in HSVE. A randomized multicenter trial is the only useful instrument to address this question.

Design

GACHE is a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial of treatment with acyclovir and adjuvant dexamethasone, as compared with acyclovir and placebo in adults with HSVE. The statistical design will be that of a 3-stage-group sequential trial with potential sample size adaptation in the last stage.

Conclusion

372 patients with proven HSVE (positive HSV-DNA-PCR), aged 18 up to 85 years; with focal neurological signs no longer than 5 days prior to admission, and who give informed consent will be recruited from Departments of Neurology of academic medical centers in Germany, Austria and The Netherlands. Sample size will potentially be extended after the second interim analysis up to a maximum of 450 patients.

Trial Registration

Current Controlled Trials

ISRCTN45122933
Heterogeneous in vitro effects of doxorubicin on gene expression in primary human liposarcoma cultures
Authors: Daigeler Adrien , Klein-Hitpass Ludger , Chromik Ansgar Michael , Müller Oliver , Hauser Jörg , Homann Heinz-Herbert , Steinau Hans-Ulrich , Lehnhardt Marcus
Published: October 2008

Background

Doxorubicin is considered one of the most potent established chemotherapeutics in the treatment of liposarcoma; however, the response rates usually below 30%, are still disappointing. This study was performed to identify gene expression changes in liposarcoma after doxorubicin treatment.

Methods

Cells of 19 primary human liposarcoma were harvested intraoperatively and brought into cell culture. Cells were incubated with doxorubicin for 24 h, RNA was isolated and differential gene expression was analysed by the microarray technique.

Results

A variety of genes involved in apoptosis were up and down regulated in different samples revealing a heterogeneous expression pattern of the 19 primary tumor cell cultures in response to doxorubicin treatment. However, more than 50% of the samples showed up-regulation of pro-apoptotic genes such as TRAIL Receptor2, CDKN1A, GADD45A, FAS, CD40, PAWR, NFKBIA, IER3, PSEN1, RIPK2, and CD44. The anti-apoptotic genes TNFAIP3, PEA15, Bcl2A1, NGFB, and BIRC3 were also up-regulated. The pro-apoptotic CD14, TIA1, and ITGB2 were down-regulated in more than 50% of the tumor cultures after treatment with doxorubicin, as was the antiapoptotic YWHAH.

Conclusion

Despite a correlation of the number of differentially regulated genes to the tumor grading and to a lesser extent histological subtype, the expression patterns varied strongly; however, especially among high grade tumors the responses of selected apoptosis genes were similar. The predescribed low clinical response rates of low grade liposarcoma to doxorubicin correspond to our results with only little changes on gene expression level and also divergent findings concerning the up- and down-regulation of single genes in the different sarcoma samples.
A general SNP-based molecular barcode for Plasmodium falciparum identification and tracking
Authors: Daniels Rachel , Volkman Sarah K , Milner Danny A , Mahesh Nira , Neafsey Daniel E , Park Daniel J , Rosen David , Angelino Elaine , Sabeti Pardis C , Wirth Dyann F , Wiegand Roger C
Published: October 2008

Background

Single nucleotide polymorphism (SNP) genotyping provides the means to develop a practical, rapid, inexpensive assay that will uniquely identify any Plasmodium falciparum parasite using a small amount of DNA. Such an assay could be used to distinguish recrudescence from re-infection in drug trials, to monitor the frequency and distribution of specific parasites in a patient population undergoing drug treatment or vaccine challenge, or for tracking samples and determining purity of isolates in the laboratory during culture adaptation and sub-cloning, as well as routine passage.

Methods

A panel of twenty-four SNP markers has been identified that exhibit a high minor allele frequency (average MAF > 35%), for which robust TaqMan genotyping assays were constructed. All SNPs were identified through whole genome sequencing and MAF was estimated through Affymetrix array-based genotyping of a worldwide collection of parasites. These assays create a "molecular barcode" to uniquely identify a parasite genome.

Results

Using 24 such markers no two parasites known to be of independent origin have yet been found to have the same allele signature. The TaqMan genotyping assays can be performed on a variety of samples including cultured parasites, frozen whole blood, or whole blood spotted onto filter paper with a success rate > 99%. Less than 5 ng of parasite DNA is needed to complete a panel of 24 markers. The ability of this SNP panel to detect and identify parasites was compared to the standard molecular methods, MSP-1 and MSP-2 typing.

Conclusion

This work provides a facile field-deployable genotyping tool that can be used without special skills with standard lab equipment, and at reasonable cost that will unambiguously identify and track P. falciparum parasites both from patient samples and in the laboratory.
Development of selective blockers for Ca2+-activated Cl- channel using Xenopus laevis oocytes with an improved drug screening strategy
Authors: Oh Soo-Jin , Park Jung Hwan , Han Sungyu , Lee Jae Kyun , Roh Eun Joo , Lee C Justin
Published: October 2008

Background

Ca2+-activated Cl-channels (CaCCs) participate in many important physiological processes. However, the lack of effective and selective blockers has hindered the study of these channels, mostly due to the lack of good assay system. Here, we have developed a reliable drug screening method for better blockers of CaCCs, using the endogeneous CaCCs inXenopus laevisoocytes and two-electrode voltage-clamp (TEVC) technique.

Results

Oocytes were prepared with a treatment of Ca2+ionophore, which was followed by a treatment of thapsigargin which depletes Ca2+stores to eliminate any contribution of Ca2+release. TEVC was performed with micropipette containing chelerythrine to prevent PKC dependent run-up or run-down. Under these conditions, Ca2+-activated Cl-currents induced by bath application of Ca2+to oocytes showed stable peak amplitude when repetitively activated, allowing us to test several concentrations of a test compound from one oocyte. Inhibitory activities of commercially available blockers and synthesized anthranilic acid derivatives were tested using this method. As a result, newly synthesizedN-(4-trifluoromethylphenyl)anthranilic acid with trifluoromethyl group (-CF3) atparaposition on the benzene ring showed the lowest IC50.

Conclusion

Our results provide an optimal drug screening strategy suitable for high throughput screening, and proposeN-(4-trifluoromethylphenyl)anthranilic acid as an improved CaCC blocker.
Changes in protein expression during honey bee larval development
Authors: Chan Queenie WT , Foster Leonard J
Published: October 2008

Background

The honey bee (Apis mellifera), besides its role in pollination and honey production, serves as a model for studying the biochemistry of development, metabolism, and immunity in a social organism. Here we use mass spectrometry-based quantitative proteomics to quantify nearly 800 proteins during the 5- to 6-day larval developmental stage, tracking their expression profiles.

Results

We report that honey bee larval growth is marked by an age-correlated increase of protein transporters and receptors, as well as protein nutrient stores, while opposite trends in protein translation activity and turnover were observed. Levels of the immunity factors prophenoloxidase and apismin are positively correlated with development, while others surprisingly were not significantly age-regulated, suggesting a molecular explanation for why bees are susceptible to major age-associated bee bacterial infections such as American Foulbrood or fungal diseases such as chalkbrood. Previously unreported findings include the reduction of antioxidant and G proteins in aging larvae.

Conclusion

These data have allowed us to integrate disparate findings in previous studies to build a model of metabolism and maturity of the immune system during larval development. This publicly accessible resource for protein expression trends will help generate new hypotheses in the increasingly important field of honey bee research.
Treatment of Pituitary-Dependent Cushing’s Disease with the Multireceptor Ligand Somatostatin Analog Pasireotide (SOM230): A Multicenter, Phase II Trial
Authors: Boscaro M. , Ludlam W. H. , Atkinson B. , Glusman J. E. , Petersenn S. , Reincke M. , Snyder P. , Tabarin A. , Biller B. M. K. , Findling J. , Melmed S. , Darby C. H. , Hu K. , Wang Y. , Freda P. U. , Grossman A. B. , Frohman L. A. , Bertherat J.
Published: October 2008

Context: There is currently no medical therapy for Cushing’s disease that targets the pituitary adenoma. Availability of such a medical therapy would be a valuable therapeutic option for the management of this disorder.

Objective: Our objective was to evaluate the short-term efficacy of the novel multireceptor ligand somatostatin analog pasireotide in patients with de novo, persistent, or recurrent Cushing’s disease.

Design: We conducted a phase II, proof-of-concept, open-label, single-arm, 15-d multicenter study.

Patients: Thirty-nine patients with either de novo Cushing’s disease who were candidates for pituitary surgery or with persistent or recurrent Cushing’s disease after surgery without having received prior pituitary irradiation.

Intervention: Patients self-administered sc pasireotide 600 μg twice daily for 15 d.

Main Outcome Measure: Normalization of urinary free cortisol (UFC) levels after 15 d treatment was the main outcome measure.

Results: Of the 29 patients in the primary efficacy analysis, 22 (76%) showed a reduction in UFC levels, of whom five (17%) had normal UFC levels (responders), after 15 d of treatment with pasireotide. Serum cortisol levels and plasma ACTH levels were also reduced. Steady-state plasma concentrations of pasireotide were achieved within 5 d of treatment. Responders appeared to have higher pasireotide exposure than nonresponders.

Conclusions: Pasireotide produced a decrease in UFC levels in 76% of patients with Cushing’s disease during the treatment period of 15 d, with direct effects on ACTH release. These results suggest that pasireotide holds promise as an effective medical treatment for this disorder.
Treatment with the Dipeptidyl Peptidase-4 Inhibitor Vildagliptin Improves Fasting Islet-Cell Function in Subjects with Type 2 Diabetes
Authors: D'Alessio David A. , Denney Amanda M. , Hermiller Linda M. , Prigeon Ronald L. , Martin Julie M. , Tharp William G. , Saylan Monica Liqueros , He YanLing , Dunning Beth E. , Foley James E. , Pratley Richard E.
Published: October 2008

Context: Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes mellitus (T2DM) by prolonging the activity of the circulating incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Consistent with this mechanism of action, DPP-4 inhibitors improve glucose tolerance after meals by increasing insulin and reducing glucagon levels in the plasma. However, DPP-4 inhibitors also reduce fasting blood glucose, an unexpected effect because circulating levels of active GIP and GLP-1 are low in the postabsorptive state.

Objective: The objective of the study was to examine the effects of DPP-4 inhibition on fasting islet function.

Design: We conducted a randomized, double-blind, placebo-controlled trial.

Setting: The study was performed in General Clinical Research Centers at two University Hospitals.

Subjects: Forty-one subjects with T2DM were treated with metformin or diet, having good glycemic control with glycosylated hemoglobin values of 6.2–7.5%.

Intervention: Subjects were treated with vildagliptin (50 mg twice daily) or placebo for 3 months, followed by a 2-wk washout.

Major Outcome Measure: We measured insulin secretion in response to iv glucose and arginine before and after treatment and after drug washout.

Results: There were small and comparable reductions in glycosylated hemoglobin in both groups over 3 months. Vildagliptin increased fasting GLP-1 levels in subjects taking metformin, but not those managed with diet, and raised active GIP levels slightly. DPP-4 inhibitor treatment improved the acute insulin and C-peptide responses to glucose (50 and 100% respectively; P < 0.05) and increased the slope of the C-peptide response to glucose (33%; P = 0.023).

Conclusion: Vildagliptin improves islet function in T2DM under fasting conditions. This suggests that DPP-4 inhibition has metabolic benefits in addition to enhancing meal-induced GLP-1 and GIP activity.
Lethal Respiratory Failure and Mild Primary Hypothyroidism in a Term Girl with a de Novo Heterozygous Mutation in the TITF1/NKX2.1 Gene
Authors: Maquet Emilie , Costagliola Sabine , Parma Jasmine , Christophe-Hobertus Christiane , Oligny Luc L. , Fournet Jean-Christophe , Robitaille Yves , Vuissoz Jean-Marc , Payot Antoine , Laberge Sophie , Vassart Gilbert , Van Vliet Guy , Deladoëy Johnny
Published: October 2008

Context: Thyroid transcription factor 1 (TITF1/NKX2.1) is expressed in the thyroid, lung, ventral forebrain, and pituitary. In the lung, TITF1/NKX2.1 activates the expression of genes critical for lung development and function. Titf/Nkx2.1−/− mice have pituitary and thyroid aplasia but also impairment of pulmonary branching. Humans with heterozygous TITF1/NKX2.1 mutations present with various combinations of primary hypothyroidism, respiratory distress, and neurological disorders.

Objective: The objective of the study was to report clinical and molecular studies of the first patient with lethal neonatal respiratory distress from a novel heterozygous TITF1/NKX2.1 mutation.

Participant: This girl, the first child of healthy nonconsanguineous French-Canadian parents, was born at 41 wk. Birth weight was 3460 g and Apgar scores were normal. Soon after birth, she developed acute respiratory failure with pulmonary hypertension. At neonatal screening on the second day of life, TSH was 31 mU/liter (N <15) and total T4 245 nmol/liter (N = 120–350). Despite mechanical ventilation, thyroxine, surfactant, and pulmonary vasodilators, the patient died on the 40th day.

Results: Histopathology revealed pulmonary tissue with low alveolar counts. The thyroid was normal. Sequencing of the patient’s lymphocyte DNA revealed a novel heterozygous TITF1/NKX2.1 mutation (I207F). This mutation was not found in either parent. In vitro, the mutant TITF-1 had reduced DNA binding and transactivation capacity.

Conclusion: This is the first reported case of a heterozygous TITF1/NKX2.1 mutation leading to neonatal death from respiratory failure. The association of severe unexplained respiratory distress in a term neonate with mild primary hypothyroidism is the clue that led to the diagnosis.
A non-apoptotic role for caspase-9 in muscle differentiation
Authors: Murray Thomas V. A. , McMahon Jill M. , Howley Breege A. , Stanley Alanna , Ritter Thomas , Mohr Andrea , Zwacka Ralf , Fearnhead Howard O.
Published: October 2008

Caspases, a family of cysteine proteases most often investigated for their roles in apoptosis, have also been demonstrated to have functions that are vital for the efficient execution of cell differentiation. One such role that has been described is the requirement of caspase-3 for the differentiation of skeletal myoblasts into myotubes but, as yet, the mechanism leading to caspase-3 activation in this case remains elusive. Here, we demonstrate that caspase-9, an initiator caspase in the mitochondrial death pathway, is responsible for the activation of caspase-3 in differentiating C2C12 cells. Reduction of caspase-9 levels, using an shRNA construct, prevented caspase-3 activation and inhibited myoblast fusion. Myosin-heavy-chain expression, which accompanies myoblastic differentiation, was not caspase-dependent. Overexpression of Bcl-xL, a protein that inhibits caspase-9 activation, had the same effect on muscle differentiation as knockdown of caspase-9. These data suggest that the mitochondrial pathway is required for differentiation; however, the release of cytochrome c or Smac (Diablo) could not be detected, raising the possibility of a novel mechanism of caspase-9 activation during muscle differentiation.
Regulation of PLCβ1a membrane anchoring by its substrate phosphatidylinositol (4,5)-bisphosphate
Authors: Adjobo-Hermans Merel J. W. , Goedhart Joachim , Gadella Theodorus W. J.
Published: October 2008

Basic knowledge as to the subcellular location and dynamics of PLCβ isozymes is scant. Here, we report on the subcellular location of GFP-PLCβ1a and the use of total internal reflection fluorescence (TIRF) microscopy to examine the dynamics of GFP-PLCβ1a at the plasma membrane upon stimulation of Gq-coupled receptors. Using this technique, we observed PLCβ1a dissociation from the plasma membrane upon addition of agonist. An increase in intracellular calcium and a decrease in PtdIns(4,5)P2 both coincided with a translocation of PLCβ1a from the plasma membrane into the cytosol. In order to differentiate between calcium and PtdIns(4,5)P2, rapamycin-induced heterodimerization of FRB and FKBP12 fused to 5-phosphatase IV was used to instantaneously convert PtdIns(4,5)P2 into PtdIns(4)P. Addition of rapamycin caused PLCβ1a to dissociate from the plasma membrane, indicating that removal of PtdIns(4,5)P2 is sufficient to cause translocation of PLCβ1a from the plasma membrane. In conclusion, PLCβ1a localization is regulated by its own substrate.
The Rip11/Rab11-FIP5 and kinesin II complex regulates endocytic protein recycling
Authors: Schonteich Eric , Wilson Gayle M. , Burden Jemima , Hopkins Colin R. , Anderson Keith , Goldenring James R. , Prekeris Rytis
Published: October 2008

Sorting and recycling of endocytosed proteins are required for proper cellular function and growth. Internalized receptors either follow a fast constitutive recycling pathway, returning to the cell surface directly from the early endosomes, or a slow pathway that involves transport via perinuclear recycling endosomes. Slow recycling pathways are thought to play a key role in directing recycling proteins to specific locations on cell surfaces, such as the leading edges of motile cells. These pathways are regulated by various Rab GTPases, such as Rab4 and Rab11. Here we characterize the role of Rip11/FIP5, a known Rab11-binding protein, in regulating endocytic recycling. We use a combination of electron and fluorescent microscopy with siRNA-based protein knockdown to show that Rip11/FIP5 is present at the peripheral endosomes, where it regulates the sorting of internalized receptors to a slow recycling pathway. We also identify kinesin II as a Rip11/FIP5-binding protein and show that it is required for directing endocytosed proteins into the same recycling pathway. Thus, we propose that the Rip11/FIP5-kinesin-II complex has a key role in the routing of internalized receptors through the perinuclear recycling endosomes.
Dissecting the involvement of formins in Bud6p-mediated cortical capture of microtubules in S. cerevisiae
Authors: Delgehyr Nathalie , Lopes Cláudia S. J. , Moir Catherine A. , Huisman Stephen M. , Segal Marisa
Published: October 2008

In S. cerevisiae, spindle orientation is linked to the inheritance of the `old' spindle pole by the bud. A player in this asymmetric commitment, Bud6p, promotes cortical capture of astral microtubules. Additionally, Bud6p stimulates actin cable formation though the formin Bni1p. A relationship with the second formin, Bnr1p, is unclear. Another player is Kar9p, a protein that guides microtubules along actin cables organised by formins. Here, we ask whether formins mediate Bud6p-dependent microtubule capture beyond any links to Kar9p and actin. We found that both formins control Bud6p localisation. bni1 mutations advanced recruitment of Bud6p at the bud neck, ahead of spindle assembly, whereas bnr1Δ reduced Bud6p association with the bud neck. Accordingly, bni1 or bnr1 mutations redirected microtubule capture to or away from the bud neck, respectively. Furthermore, a Bni1p truncation that can form actin cables independently of Bud6p could not bypass a bud6Δ for microtubule capture. Conversely, Bud61-565p, a truncation insufficient for correct actin organisation via formins, supported microtubule capture. Finally, Bud6p or Bud61-565p associated with microtubules in vitro. Thus, surprisingly, Bud6p may promote microtubule capture independently of its links to actin organisation, whereas formins would contribute to the program of Bud6p-dependent microtubule-cortex interactions by controlling Bud6p localisation.
Structural determinants of the cellular localization and shuttling of TDP-43
Authors: Ayala Youhna M. , Zago Paola , D'Ambrogio Andrea , Xu Ya-Fei , Petrucelli Leonard , Buratti Emanuele , Baralle Francisco E.
Published: October 2008

TDP-43 (also known as TARDBP) regulates different processes of gene expression, including transcription and splicing, through RNA and DNA binding. Moreover, recent reports have shown that the protein interacts with the 3′UTRs of specific mRNAs. The aberrant cellular distribution and aggregation of TDP-43 were recently reported in neurodegenerative diseases, namely frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A detailed description of the determinants for cellular localization has yet to emerge, including information on how the known functions of TDP-43 and cellular targeting affect each other. We provide the first experimental evidence that TDP-43 continuously shuttles between nucleus and cytoplasm in a transcription-dependent manner. Furthermore, we investigate the role of the functional TDP-43 domains in determining cellular targeting through a combination of immunofluorescence and biochemical fractionation methods. Our analyses indicate that the C-terminus is essential for solubility and cellular localization, because its deletion results in the formation of large nuclear and cytoplasmic aggregates. Disruption of the RNA-recognition domain required for RNA and DNA binding, however, alters nuclear distribution by decreasing TDP-43 presence in the nucleoplasm. Our findings suggest that TDP-43 solubility and localization are particularly sensitive to disruptions that extend beyond the newly found nuclear localization signal and depend on a combination of factors that are closely connected to the functional properties of this protein.
Automated motif extraction and classification in RNA tertiary structures
Authors: Djelloul Mahassine , Denise Alain
Published: October 2008

We used a novel graph-based approach to extract RNA tertiary motifs. We cataloged them all and clustered them using an innovative graph similarity measure. We applied our method to three widely studied structures: Haloarcula marismortui 50S (H.m 50S), Escherichia coli 50S (E. coli 50S), and Thermus thermophilus 16S (T.th 16S) RNAs. We identified 10 known motifs without any prior knowledge of their shapes or positions. We additionally identified four putative new motifs.
Annotation of tertiary interactions in RNA structures reveals variations and correlations
Authors: Xin Yurong , Laing Christian , Leontis Neocles B. , Schlick Tamar
Published: October 2008

RNA tertiary motifs play an important role in RNA folding and biochemical functions. To help interpret the complex organization of RNA tertiary interactions, we comprehensively analyze a data set of 54 high-resolution RNA crystal structures for motif occurrence and correlations. Specifically, we search seven recognized categories of RNA tertiary motifs (coaxial helix, A-minor, ribose zipper, pseudoknot, kissing hairpin, tRNA D-loop/T-loop, and tetraloop–tetraloop receptor) by various computer programs. For the nonredundant RNA data set, we find 613 RNA tertiary interactions, most of which occur in the 16S and 23S rRNAs. An analysis of these motifs reveals the diversity and variety of A-minor motif interactions and the various possible loop–loop receptor interactions that expand upon the tetraloop–tetraloop receptor. Correlations between motifs, such as pseudoknot or coaxial helix with A-minor, reveal higher-order patterns. These findings may ultimately help define tertiary structure restraints for RNA tertiary structure prediction. A complete annotation of the RNA diagrams for our data set is available at http://www.biomath.nyu.edu/motifs/.
These Lives Will Not Be Lost in Vain: Organizational Learning from Disaster in U.S. Coal Mining
Authors: Madsen Peter M.
Published: October 2008

The stated purpose of the investigations that invariably follow industrial, transportation, and mining disasters is to learn from those tragedies to prevent future tragedies. But does prior experience with disaster make organizations more capable of preventing future disasters? Do organizations learn from disasters experienced by other organizations? Do organizations learn differently from rare disasters than they do from common minor accidents? In its present state, the organizational safety literature is poorly equipped to answer these questions.

The present work begins to address this gap by empirically examining how prior organizational experience with disaster affects the likelihood that organizations will experience future disasters. It approaches the issue in the context of fatal U.S. coal mining accidents from 1983 to 2006. The analysis demonstrates that organizations do learn to prevent future disasters through both direct and vicarious experience with disaster. It also indicates that the mechanisms through which organizations learn from disasters differ from those through which they learn from minor accidents.
Role of Domain-Specific Facets of Perceived Organizational Support During Expatriation and Implications for Performance
Authors: Takeuchi Riki , Wang Mo , Marinova Sophia V. , Yao Xin
Published: October 2008

In this study, we integrated social exchange theory with a spillover perspective to examine the relationships between two facets of perceived organizational support (POS) among expatriated managers (at Time 1), their work and general adjustment (at Time 2), affective commitment (at Time 2), and job performance (at Time 3). A longitudinal survey sampled 165 expatriate managers in China across three time periods. POS in the current assignment and in off-the-job life were found to interact with each other to predict work and general adjustment. Work and general adjustment were related to higher affective commitment by the expatriate employees, which, in turn, led to better job performance. The theoretical and practical implications of these results are discussed.
Role of Ambrisentan in the Management of Pulmonary Hypertension
Authors: Hrometz Sandra L , Shields Kelly M
Published: October 2008

Objective:

To review the role of ambrisentan in the treatment of pulmonary arterial hypertension (PAH).

Data Sources:

Literature was accessed through MEDLINE (1950-June 2008), Iowa Drug Information Service (1966–March 2008), EMBASE (1966-June 2008), bibliographies of pertinent articles, and unpublished data provided by the manufacturer and the Food and Drug Administration (FDA). Search terms included ambrisentan, endothelin antagonist, pulmonary hypertension, and pulmonary arterial hypertension. Due to limited literature available, additional criteria to limit searches were not used.

Study Selection and Data Extraction:

Abstracts and original preclinical and clinical research reports available in the English language were Identified for review. All manufacturer-provided data were also evaluated. Literature related to ambrisentan, endothelin antagonists, pulmonary hypertension, and pulmonary arterial hypertension were included. Four clinical trials evaluated the efficacy of ambrisentan in adults with symptomatic PAH.

Data Synthesis:

Ambrisentan is the latest endothelin-receptor antagonist (ERA) to obtain FDA approval for the treatment of PAH. It joins the first FDA-approved ERA, bosentan. Like bosentan, ambrisentan is available orally (with once-daily dosing compared with bosentan's twice-daily dosing) and has been shown to improve exercise capacity and delay clinical worsening. As with bosentan, the most significant safety concerns with ambrisentan relate to potential liver injury and a contraindication in pregnancy. Although ambrisentan has higher affinity for the endothelin type A receptor than for the endothelin type B receptor, specific advantages of this selectivity, in terms of efficacy compared with bosentan, a nonselective agent, have not been demonstrated.

Conclusions:

Ambrisentan has been shown to be an effective ERA in patients with PAH. A significant advantage of ambrisentan is the lack of any clinically important drug interactions with warfarin and sildenafil, which are frequently used by patients being treated for PAH.
Adverse Effects of Tenofovir Use in HIV-infected Pregnant Women and their Infants
Authors: Nurutdinova Diana , Onen Nur F , Hayes Ericka , Mondy Kristin , Overton E Turner
Published: October 2008

Background:

Data regarding use of tenofovir disopraxil fumarate in HIV-infected pregnant women are limited.

Objective:

To identify adverse effects of tenofovir use during pregnancy in HIV-infected women and their infants.

Methods:

In a retrospective case series, the charts of 127 pregnant HIV-infected women who received highly active antiretroviral therapy (HAART) between 2001 and 2005 were reviewed. Those who received tenofovir during pregnancy were selected for this study. Each woman's chart was reviewed for clinical data and adverse events during the pregnancy; each infant's chart was reviewed for growth parameters from birth to 12 months.

Results:

Fifteen HIV-infected women with limited treatment options were prescribed HAART containing tenofovir during 16 pregnancies. In utero tenofovir exposure was a median of 127 days (range 6–259). Tenofovir was well tolerated by all women throughout pregnancy. There were 15 successful deliveries occurring at a median (range) of 36 weeks (30–40), with a median birth weight of 3255 g (1135–3610). Complications, including 1 spontaneous abortion, occurred in 9 pregnancies and were not attributed to tenofovir. Eleven (73%) women had abnormal laboratory results, including 6 who experienced grade 1 hemoglobin abnormalities; 4 of these women had preexisting anemia. Calculated glomerular filtration rate (calculated by Modification of Diet in Renal Disease equation) remained above 90 mL/min/1.73 m2 in all women, except one who had a transient decline. Fourteen infants demonstrated normal growth and development for weight and height at birth, as well as during the 12-month follow-up period; no congenital malformations were documented. Mother-to-child transmission of HIV was not observed in this cohort.

Conclusions:

Tenofovir was found to be a well-tote rated component of HAART in this small cohort. Longer-term assessment of tenofovir effects on childhood growth and larger prospective studies of tenofovir use in pregnant women are warranted.