bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential response of skeletal muscles to mTORC1 signaling during atrophy and hypertrophy
Authors: Bentzinger C Florian , Lin Shuo , Romanino Klaas , Castets Perrine , Guridi Maitea , Summermatter Serge , Handschin Christoph , Tintignac Lionel A , Hall Michael N , Rüegg Markus A 
Published: March 2013

Abstract

Background
Skeletal muscle mass is determined by the balance between protein synthesis and degradation. Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of protein translation and has been implicated in the control of muscle mass. Inactivation of mTORC1 by skeletal muscle-specific deletion of its obligatory component raptor results in smaller muscles and a lethal dystrophy. Moreover, raptor-deficient muscles are less oxidative through changes in the expression PGC-1α, a critical determinant of mitochondrial biogenesis. These results suggest that activation of mTORC1 might be beneficial to skeletal muscle by providing resistance to muscle atrophy and increasing oxidative function. Here, we tested this hypothesis by deletion of the mTORC1 inhibitor tuberous sclerosis complex (TSC) in muscle fibers.

Method
Skeletal muscles of mice with an acute or a permanent deletion of raptor or TSC1 were examined using histological, biochemical and molecular biological methods. Response of the muscles to changes in mechanical load and nerve input was investigated by ablation of synergistic muscles or by denervation .

Results
Genetic deletion or knockdown of raptor, causing inactivation of mTORC1, was sufficient to prevent muscle growth and enhance muscle atrophy. Conversely, short-term activation of mTORC1 by knockdown of TSC induced muscle fiber hypertrophy and atrophy-resistance upon denervation, in both fast tibialis anterior (TA) and slow soleus muscles. Surprisingly, however, sustained activation of mTORC1 by genetic deletion of Tsc1 caused muscle atrophy in all but soleus muscles. In contrast, oxidative capacity was increased in all muscles examined. Consistently, TSC1-deficient soleus muscle was atrophy-resistant whereas TA underwent normal atrophy upon denervation. Moreover, upon overloading, plantaris muscle did not display enhanced hypertrophy compared to controls. Biochemical analysis indicated that the atrophy response of muscles was based on the suppressed phosphorylation of PKB/Akt via feedback inhibition by mTORC1 and subsequent increased expression of the E3 ubiquitin ligases MuRF1 and atrogin-1/MAFbx. In contrast, expression of both E3 ligases was not increased in soleus muscle suggesting the presence of compensatory mechanisms in this muscle.

Conclusions
Our study shows that the mTORC1- and the PKB/Akt-FoxO pathways are tightly interconnected and differentially regulated depending on the muscle type. These results indicate that long-term activation of the mTORC1 signaling axis is not a therapeutic option to promote muscle growth because of its strong feedback induction of the E3 ubiquitin ligases involved in protein degradation.
A standardized microarray assay for the independent gene expression markers in AML: EVI1 and BAALC
Authors: Brand Jaap , van Vliet Martin H , de Best Leonie , Valk Peter JM , Viëtor Henk E , Löwenberg Bob , van Beers Erik H 
Published: March 2013

Abstract
High levels of BAALC, ERG, EVI1 and MN1 expression have been associated with shorter overall survival in AML but standardized and clinically validated assays are lacking. We have therefore developed and optimized an assay for standardized detection of these prognostic genes for patients with intermediate cytogenetic risk AML. In a training set of 147 intermediate cytogenetic risk cases we performed cross validations at 5 percentile steps of expression level and observed a bimodal significance profile for BAALC expression level and unimodal significance profiles for ERG and MN1 levels with no statistically significant cutoff points near the median expression level of BAALC, ERG or MN1. Of the possible cutoff points for expression levels of BAALC, ERG and MN1, just the 30th and 75th percentile of BAALC expression level and the 30th percentile of MN1 expression level cutoff points showed clinical significance. Of these only the 30th percentile of BAALC expression level reproduced in an independent verification (extended training) data set of 242 cytogenetically normal AML cases and successfully validated in an external cohort of 215 intermediate cytogenetic risk AML cases. Finally, we show independent prognostic value for high EVI1 and low BAALC in multivariate analysis with other clinically relevant molecular AML markers. We have developed a highly standardized molecular assay for the independent gene expression markers EVI1 and BAALC.
Does aid induce brain drain? A panel data analysis
Authors: Ugarte Ontiveros Darwin , Verardi Vincenzo 
Published: March 2013

Abstract

Abstract
Recent evidence suggests that aid induces migration. This result is nevertheless not very informative from a policy perspective since what counts in terms of welfare consequences is the composition of migration. In this paper we focus on education and study which of skilled or unskilled migration is more sensitive to aid. More specifically we investigate the possible channels through which aid might affect self-selection among international emigrants and find that aid induces positive selection by easing the movement of highly qualified workers. Interestingly, we find that technical cooperation and bilateral aid have a significant influence on skilled migration but do not seem to affect unskilled migration significantly. On the other hand, aid targeted to development enhancement affects both categories but seems to have a larger effect on the former.

JEL codes
F35, F22, C23
Computational pharmacokinetics at a crossroads
Authors: Bois Frédéric Y 
Published: March 2013

AbstractThis first special issue of In Silico Pharmacology focuses on computational pharmacokinetics since they are an important part of integrated applications in computational pharmacology. The important topics of model structure, model parameterization, improved organ description, and modeling of drug-drug interactions are covered. They are actually at the crossroads between several emerging disciplines which will shape the future of therapeutic treatments and public health.
Zebrafish as a model for the study of neutrophil biology
Authors: Henry Katherine M , Loynes Catherine A , Whyte Moira K B , Renshaw Stephen A 
Published: March 2013

ABSTRACTTo understand inflammation and immunity, we need to understand the biology of the neutrophil. Whereas these cells can readily be extracted from peripheral blood, their short lifespan makes genetic manipulations impractical. Murine knockout models have been highly informative, and new imaging techniques are allowing neutrophils to be seen during inflammation in vivo for the first time. However, there is a place for a new model of neutrophil biology, which readily permits imaging of individual neutrophils during inflammation in vivo, combined with the ease of genetic and chemical manipulation. The zebrafish has long been the model of choice for the developmental biology community, and the availability of genomic resources and tools for gene manipulation makes this an attractive model. Zebrafish innate immunity shares many features with mammalian systems, including neutrophils with morphological, biochemical, and functional features, also shared with mammalian neutrophils. Transgenic zebrafish with neutrophils specifically labeled with fluorescent proteins have been generated, and this advance has led to the adoption of zebrafish, alongside existing models, by a number of groups around the world. The use of these models has underpinned a number of key advances in the field, including the identification of a tissue gradient of hydrogen peroxide for neutrophil recruitment following tissue injury and direct evidence for reverse migration as a regulatable mechanism of inflammation resolution. In this review, we discuss the importance of zebrafish models in neutrophil biology and describe how the understanding of neutrophil biology has been advanced by the use of these models.
cAMP Response Element-Binding Protein Interacts With and Stimulates the Proteasomal Degradation of the Nuclear Receptor Coactivator GRIP1
Authors: Hoang Tuyen , Fenne Ingvild S. , Madsen Andre , Bozickovic Olivera , Johannessen Mona , Bergsvåg Mari , Lien Ernst Asbjørn , Stallcup Michael R. , Sagen Jørn V. , Moens Ugo , Mellgren Gunnar 
Published: March 2013

AbstractThe glucocorticoid receptor interacting protein (GRIP1) belongs to the p160 steroid receptor coactivator family that plays essential roles in nuclear receptor-dependent transcriptional regulation. Previously, we reported that the cAMP-dependent protein kinase (PKA) induces ubiquitination leading to degradation of GRIP1. Here we show that the cAMP response element-binding protein (CREB) downregulates GRIP1 and is necessary for the PKA-stimulated degradation of GRIP1, which leads to changes in the expression of a subset of genes regulated by estrogen receptor-α in MCF-7 breast cancer cells. Our data of domain-mapping and ubiquitination analyses suggest that CREB promotes the proteasomal breakdown of ubiquitinated GRIP1 through 2 functionally independent protein domains containing amino acids 347 to 758 and 1121 to 1462. We provide evidence that CREB interacts directly with GRIP1 and that CREB Ser-133 phosphorylation or transcriptional activity is not required for GRIP1 interaction and degradation. The basic leucine zipper domain (bZIP) of CREB is important for the interaction with GRIP1, and deletion of this domain led to an inability to downregulate GRIP1. We propose that CREB mediates the PKA-stimulated degradation of GRIP1 through protein-protein interaction and stimulation of proteasomal degradation of ubiquitinated GRIP1.
Alteplase for the Treatment of Catheter Occlusion in Pediatric Patients
Authors: Anderson Debra M , Pesaturo Kimberly A , Casavant Jonathan , Ramsey E Zachary 
Published: March 2013

OBJECTIVE To review the literature pertaining to the efficacy of alteplase for restoration of patency of occluded venous and dialysis catheters in pediatric patients. DATA SOURCES A MEDLINE search was conducted and cross-referenced with an EMBASE search through November 2012. Search terms included alteplase, tissue plasminogen activator, and catheter. STUDY SELECTION AND DATA EXTRACTION Search results were limited to humans, English language, and ages from neonates to 18 years. Pertinent studies discussing efficacy of alteplase for restoration of occluded venous or dialysis catheter function were included. Case reports, review articles, and studies that specified inclusion of hemophilia patients or more than 75% of children with malignancy were excluded. DATA SYNTHESIS Fibrinolytics are the drug class of choice for restoration of patency (defined as the ability to withdraw a blood sample) of thrombus-occluded catheters. The trials used to support Food and Drug Administration approval of alteplase for central venous catheter (CVC) occlusions generally had low pediatric enrollment; however, additional small studies are available that support use of alteplase for this indication in children. Alteplase doses of 0.5–2 mg instilled into the lumen of a CVC with dwell times ranging from 30 to more than 240 minutes plus the potential for repeat dosing were reported. Overall efficacy ranged from approximately 50% to 90%, with greater efficacy generally reported with larger doses and longer dwell times. Alteplase doses of 2–2.5 mg with dwell times of 60–120 minutes were observed in 2 studies of occluded peritoneal or hemodialysis catheters, in which efficacy was reported in 57–100% of cases. Limitations of current studies of alteplase for catheter occlusion in children include small study populations and relative lack of pediatric-specific prospective trials. CONCLUSIONS Alteplase appears to show efficacy for treatment of thrombus-related venous catheter occlusion in pediatric patients; however, data regarding its use in occluded dialysis catheters are limited.
Pharmacogenetics of Risperidone: A Systematic Review of the Clinical Effects of CYP2D6 Polymorphisms
Authors: Cartwright Andrea L , Wilby Kyle J , Corrigan Susan , Ensom Mary HH 
Published: March 2013

OBJECTIVE To summarize and evaluate the pharmacogenetic literature pertaining to the effects of CYP2D6 polymorphism on clinical outcomes of risperidone therapy. DATA SOURCES A systematic literature search was performed using the search terms risperidone, pharmacogenetics, cytochrome P-450 enzyme system, cytochrome P-450 CYP2D6, and polymorphism (genetic) in MEDLINE (1946-October 2012), EMBASE (1980-October 2012), PubMed (1947-October 2012), International Pharmaceutical Abstracts (1970-October 2012), and Google Scholar. STUDY SELECTION AND DATA EXTRACTION Identified articles were included if they measured the association between CYP2D6 genetic polymorphisms and clinical outcomes in at least 2 patients taking risperidone. The data elements extracted from these articles consisted of study design, number of subjects, indication for risperidone therapy, CYP2D6 phenotype status, mean daily dose of risperidone, and effects on clinical outcomes. DATA SYNTHESIS The identified citations consisted of 10 prospective nonrandomized, uncontrolled cohort studies, 1 retrospective cohort study, 1 prospective case-control study, and 1 retrospective case series. Studies were of variable quality and none provided high-quality evidence; they included heterogeneous patient populations with varying clinical diagnoses and drug therapy regimens. Most studies reported nonsignificant trends but were limited by power to detect statistical significance and short trial duration. However, increased risk of adverse effects (including QT interval prolongation) was observed in patients with inactive alleles. CONCLUSIONS While there were trends toward increased adverse effects in poor metabolizers, most outcomes were not significant. As such, routine genotyping should not be used for screening. Future usefulness cannot be ruled out, as many studies had significant limitations that preclude determination of clinical relevance. Adequately powered clinical and epidemiologic studies are warranted to clarify the role of CYP2D6 genotyping in practice.
Use of Number Needed to Treat in Cost-Effectiveness Analyses
Authors: Garg Vishvas , Shen Xian , Cheng Yan , Nawarskas James J , Raisch Dennis W 
Published: March 2013

OBJECTIVE To review the use of number needed to treat (NNT) and/or number needed to harm (NNH) values to determine their relevance in helping clinicians evaluate cost-effectiveness analyses (CEAs). DATA SOURCES PubMed and EconLit were searched from 1966 to September 2012. STUDY SELECTION AND DATA EXTRACTION Reviews, editorials, non–English-language articles, and articles that did not report NNT/NNH or cost-effectiveness ratios were excluded. CEA studies reporting cost per life-year gained, per quality-adjusted life-year (QALY), or other cost per effectiveness measure were included. Full texts of all included articles were reviewed for study information, including type of journal, impact factor of the journal, focus of study, data source, publication year, how NNT/NNH values were reported, and outcome measures. DATA SYNTHESIS A total of 188 studies were initially identified, with 69 meeting our inclusion criteria. Most were published in clinician-practice–focused journals (78.3%) while 5.8% were in policy-focused journals, and 15.9% in health-economics–focused journals. The majority (72.4%) of the articles were published in high-impact journals (impact factor >3.0). Many articles focused on either disease treatment (40.5%) or disease prevention (40.5%). Forty-eight percent reported NNT as a part of the CEA ratio per event. Most (53.6%) articles used data from literature reviews, while 24.6% used data from randomized clinical trials, and 20.3% used data from observational studies. In addition, 10% of the studies implemented modeling to perform CEA. CONCLUSIONS CEA studies sometimes include NNT ratios. Although it has several limitations, clinicians often use NNT for decision-making, so including NNT information alongside CEA findings may help clinicians better understand and apply CEA results. Further research is needed to assess how NNT/NNH might meaningfully be incorporated into CEA publications.
Longitudinal Perspectives of Child Positive Impact on Families: Relationship to Disability and Culture
Authors: Blacher Jan , Begum Gazi F. , Marcoulides George A. , Baker Bruce L. 
Published: March 2013

AbstractThis study examined mothers' perceptions of the positive impact of having a child with an intellectual disability. Trajectories of positive impact from 7 time points were developed using latent growth modeling and 2 predictors: culture (Anglo, Latino) and child disability status (intellectual disability, typical development). Data were from 219 mothers of children from age 3 to 9 years. Growth trajectories reflected a general decline in positive impact on Anglo mothers. On average, at age 3, Anglo mothers reported significantly lower initial values on positive impact when their children had an intellectual disability, but Latino mothers did not. Across all time points, Latino mothers had higher scores on the positive impact, regardless of whether they had a child with an intellectual disability or a typically developing child.
Prenatal and Perinatal Factors Associated with Intellectual Disability
Authors: Bilder Deborah A. , Pinborough-Zimmerman Judith , Bakian Amanda V. , Miller Judith S. , Dorius Josette T. , Nangle Barry , McMahon William M. 
Published: March 2013

AbstractPrenatal and perinatal risk factors associated with intellectual disability (ID) were studied in 8-year-old Utah children from a 1994 birth cohort (N  =  26,108) using broad ascertainment methods and birth records following the most current recording guidelines. Risk factor analyses were performed inclusive and exclusive of children with a known or suspected underlying genetic disorder. Risk factors identified were poly/oligohydramnios, advanced paternal/maternal age, prematurity, fetal distress, premature rupture of membranes, primary/repeat cesarean sections, low birth weight, assisted ventilation greater than 30 min, small-for-gestational age, low Apgar scores, and congenital infection. Although several risk factors lost significance once children with underlying genetic disorders were excluded, socioeconomic variables were among those that maintained a prominent association with increased ID risk.
An Investigation of Narrative Ability in Boys with Autism and Fragile X Syndrome
Authors: Hogan-Brown Abigail L. , Losh Molly , Martin Gary E. , Mueffelmann Deborah J. 
Published: March 2013

AbstractWhereas pragmatic language difficulties are characteristic of both autism and Fragile X syndrome, it is unclear whether such deficits are qualitatively similar or whether certain skills are differentially affected. This study compared narrative competence in boys with autism, Fragile X syndrome, Down syndrome, and typical development. Results revealed that an interaction between diagnosis and nonverbal mental age predicted narrative microstructure (e.g., complex syntax) but not macrostructure (e.g., thematic maintenance). Correlations with FMR1-related variation were investigated in children with Fragile X syndrome. While CGG repeat length was associated with many language characteristics, nonverbal IQ appeared to mediate these relationships. These findings are an important step toward understanding narrative abilities in boys with and without the FMR1 mutation.
Interaction of uranium(VI) with bioligands present in human biological fluids: the case study of urea and uric acid
Authors: Osman Alfatih A. A. , Geipel Gerhard , Bernhard Gert 
Published: March 2013

Abstract
The complexation of uranium(VI) with bioligands found in human biological fluids, viz, urea and uric acid in aqueous solutions, has been investigated using time-resolved laser-induced fluorescence spectroscopy (TRLFS) at room temperature, I = 0.1 M (NaClO4) and pH (3 for uric acid; 4 for urea). In both complex systems a static quench effect with increasing ligand concentration and no peaks shift upon complexation were observed. With uranium(VI) both ligands formed a fairly weak 1:1 complex with average stability constants of log β110 = 4.67 ± 0.29 for uric acid and log β110 = 3.79 ± 0.15 and 2.12 ± 0.18 for relatively low and relatively high urea concentrations, respectively. Application of the newly generated data on the U(VI) speciation modelling in biofluids, e.g., human urine was also discussed.
A functional conditional symmetry test for a GARCH-SM model: Power asymptotic properties
Authors: Laïb Naâmane , Lemdani Mohamed , Ould Saïd Elias 
Published: March 2013

AbstractIn this paper we consider the empirical process of the errors appearing in a generalized autoregressive conditional heteroskedastic with stochastic mean (GARCH-SM) model. Various functional tests of conditional symmetry can be built on the basis of the limiting distribution of this process. In particular, a Cramér–von Mises-type test is considered. Its theoretical power is studied under fixed and local alternatives. Using the Karhunen–Loève decomposition, the limiting law of the latter is approximated by a chi-square distribution under both null and alternative hypotheses. The local power under a sequence of alternatives is also computed.
Properties of hierarchical Archimedean copulas
Authors: Okhrin Ostap , Okhrin Yarema , Schmid Wolfgang 
Published: March 2013

Abstract
In this paper we analyse the properties of hierarchical Archimedean copulas. This class is a generalisation of the Archimedean copulas and allows for general non-exchangeable dependency structures. We show that the structure of the copula can be uniquely recovered from all bivariate margins. We derive the distribution of the copula values, which is particularly useful for tests and constructing confidence intervals. Furthermore, we analyse dependence orderings, multivariate dependence measures, and extreme value copulas. We pay special attention to the tail dependencies and derive several tail dependence indices for general hierarchical Archimedean copulas.
Inverse processing-structure relation for the nucleation and growth mechanism
Authors: Jhon Mark , Lau Yang Hao , Quek Siu Sin , Wu David T. 
Published: March 2013

ABSTRACTThe formation of realistic, polycrystalline microstructures can be simulated by modeling the kinetics of nucleation and growth. However, it is difficult to perform the inverse simulation, where details of the nucleation and growth process are inferred from geometric properties of the final microstructure. In the present study, we develop a methodology for solving the inverse problem for interface-limited growth in 1D, utilizing a reverse Monte Carlo (RMC) algorithm. The algorithm produces a time dependent nucleation rate that gives a grain size distribution closest to a target distribution. Its results may be used to understand the limitations of manipulating the grain boundary distributions through temperature alone.