bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection, Validation, and Downstream Analysis of Allelic Variation in Gene Expression
Authors: Ciobanu Daniel C , Lu Lu , Mozhui Khyobeni , Wang Xusheng , Jagalur Manjunatha , Morris John A , Taylor William L , Dietz Klaus , Simon Perikles , Williams Robert W 
Published: November 2009

AbstractCommon sequence variants within a gene often generate important differences in expression of corresponding mRNAs. This high level of local (allelic) control—or cis modulation—rivals that produced by gene targeting, but expression is titrated finely over a range of levels. We are interested in exploiting this allelic variation to study gene function and downstream consequences of differences in expression dosage. We have used several bioinformatics and molecular approaches to estimate error rates in the discovery of cis modulation and to analyze some of the biological and technical confounds that contribute to the variation in gene expression profiling. Our analysis of SNPs and alternative transcripts, combined with eQTL maps and selective gene resequencing, revealed that between 17 and 25% of apparent cis modulation is caused by SNPs that overlap probes rather than by genuine quantitative differences in mRNA levels. This estimate climbs to 40–50% when qualitative differences between isoform variants are included. We have developed an analytical approach to filter differences in expression and improve the yield of genuine cis-modulated transcripts to ∼80%. This improvement is important because the resulting variation can be successfully used to study downstream consequences of altered expression on higher-order phenotypes. Using a systems genetics approach we show that two validated cis-modulated genes, Stk25 and Rasd2, are likely to control expression of downstream targets and affect disease susceptibility.
Seizure Sensitivity Is Ameliorated by Targeted Expression of K+–Cl− Cotransporter Function in the Mushroom Body of the Drosophila Brain
Authors: Hekmat-Scafe Daria S , Mercado Adriana , Fajilan Adriel A , Lee Ann W , Hsu Richard , Mount David B , Tanouye Mark A 
Published: November 2009

AbstractThe kccDHS1 allele of kazachoc (kcc) was identified as a seizure-enhancer mutation exacerbating the bang-sensitive (BS) paralytic behavioral phenotypes of several seizure-sensitive Drosophila mutants. On their own, young kccDHS1 flies also display seizure-like behavior and demonstrate a reduced threshold for seizures induced by electroconvulsive shock. The product of kcc shows substantial homology to KCC2, the mammalian neuronal K+–Cl− cotransporter. The kccDHS1 allele is a hypomorph, and its seizure-like phenotype reflects reduced expression of the kcc gene. We report here that kcc functions as a K+–Cl− cotransporter when expressed heterologously in Xenopus laevis oocytes: under hypotonic conditions that induce oocyte swelling, oocytes that express Drosophila kcc display robust ion transport activity observed as a Cl−-dependent uptake of the K+ congener 86Rb+. Ectopic, spatially restricted expression of a UAS-kcc+ transgene was used to determine where cotransporter function is required in order to rescue the kccDHS1 BS paralytic phenotype. Interestingly, phenotypic rescue is largely accounted for by targeted, circumscribed expression in the mushroom bodies (MBs) and the ellipsoid body (EB) of the central complex. Intriguingly, we observed that MB induction of kcc+ functioned as a general seizure suppressor in Drosophila. Drosophila MBs have generated considerable interest especially for their role as the neural substrate for olfactory learning and memory; they have not been previously implicated in seizure susceptibility. We show that kccDHS1 seizure sensitivity in MB neurons acts via a weakening of chemical synaptic inhibition by GABAergic transmission and suggest that this is due to disruption of intracellular Cl− gradients in MB neurons.
Sen1p Performs Two Genetically Separable Functions in Transcription and Processing of U5 Small Nuclear RNA inSaccharomyces cerevisiae
Authors: Finkel Jonathan S , Chinchilla Karen , Ursic Doris , Culbertson Michael R 
Published: November 2009

AbstractThe Saccharomyces cerevisiae SEN1 gene codes for a nuclear-localized superfamily I helicase. SEN1 is an ortholog of human SETX (senataxin), which has been implicated in the neurological disorders ataxia-ocular apraxia type 2 and juvenile amyotrophic lateral sclerosis. Pleiotropic phenotypes conferred by sen1 mutations suggest that Sen1p affects multiple steps in gene expression. Sen1p is embedded in a protein–protein interaction network involving direct binding to multiple partners. To test whether the interactions occur independently or in a dependent sequence, we examined interactions with the RNA polymerase II subunit Rpb1p, which is required for transcription, and Rnt1p, which is required for 3′-end maturation of many noncoding RNAs. Mutations were identified that impair one of the two interactions without impairing the other interaction. The effects of the mutants on the synthesis of U5 small nuclear RNA were analyzed. Two defects were observed, one in transcription termination and one in 3′-end maturation. Impairment of the Sen1p–Rpb1p interaction resulted in a termination defect. Impairment of the Sen1p–Rnt1p interaction resulted in a processing defect. The results suggest that the Sen1p–Rpb1p and Sen1p–Rnt1p interactions occur independently of each other and serve genetically separable purposes in targeting Sen1p to function in two temporally overlapping steps in gene expression.
Genetic Screen inDrosophila melanogasterUncovers a Novel Set of Genes Required for Embryonic Epithelial Repair
Authors: Campos Isabel , Geiger Jennifer A , Santos Ana Catarina , Carlos Vanessa , Jacinto Antonio 
Published: November 2009

AbstractThe wound healing response is an essential mechanism to maintain the integrity of epithelia and protect all organisms from the surrounding milieu. In the “purse-string” mechanism of wound closure, an injured epithelial sheet cinches its hole closed via an intercellular contractile actomyosin cable. This process is conserved across species and utilized by both embryonic as well as adult tissues, but remains poorly understood at the cellular level. In an effort to identify new players involved in purse-string wound closure we developed a wounding strategy suitable for screening large numbers of Drosophila embryos. Using this methodology, we observe wound healing defects in Jun-related antigen (encoding DJUN) and scab (encoding Drosophila αPS3 integrin) mutants and performed a forward genetics screen on the basis of insertional mutagenesis by transposons that led to the identification of 30 lethal insertional mutants with defects in embryonic epithelia repair. One of the mutants identified is an insertion in the karst locus, which encodes Drosophila βHeavy-spectrin. We show βHeavy-spectrin (βH) localization to the wound edges where it presumably exerts an essential function to bring the wound to normal closure.
Synthesis and Characterization of Highly Transparent Sol-Gel Glass for Photovoltaic Applications
Authors: Shanmugam Mariyappan , Baroughi Mahdi Farrokh , Yan XingZhong , Galipeau David 
Published: November 2009

ABSTRACTRoom temperature sol-gel synthesis and optical characterization of highly transparent silica glass for photovoltaic (PV) applications is presented in this paper. Tetraethyl orthosilicate (TEOS), Ethanol, Hydrochloric acid (HCl) and deionized water were used as precursors in the volumetric ratio of 4:4.3:0.1:3.2 ml. Silica glass of thickness in the range of 0.5-1 cm were obtained with an average transmittance of 93% and absorption coefficient (α) of 0.08 cm−1 in a wide wavelength window of 350-1100 nm. Application of the developed sol-gel silica glass on solar ray concentration, anti-reflective coating (ARC) and effect of surface passivation on silicon wafers were examined. Carrier lifetime of the sol-gel silica passivated silicon substrate was 16 s and the calculated surface recombination velocity of the was 2200 cm/sec. Very low value of α, high transparency in a wide spectral window and effective surface passivation on silicon suggest that sol-gel processed silica glass can be a potential cost effective candidate for different PV applications.
Hepatic Toxicities Associated with the Use of Preoperative Systemic Therapy in Patients with Metastatic Colorectal Adenocarcinoma to the Liver
Authors: Cleary James M. , Tanabe Kenneth T. , Lauwers Gregory Y. , Zhu Andrew X. 
Published: October 2009

Abstract
Colorectal cancer patients with isolated liver metastasis are potentially cured with surgical resection. Recent advances in systemic chemotherapy have increased the ability to convert unresectable metastatic liver lesions to resectable lesions. The cost in toxicity of these therapeutic advances is increasingly being recognized. Numerous reports have demonstrated an association between irinotecan and steatohepatitis as well as between oxaliplatin and sinusoidal dilation. In this review, we summarize the current clinical experience with these hepatic toxicities and discuss the role they play in determining postoperative morbidity. We also review emerging safety data regarding the use of bevacizumab and cetuximab. Finally, we give specific clinical examples of how multidisciplinary teams can best manage patients receiving preoperative chemotherapy for potentially resectable liver metastases.
Environmental risk assessment of human pharmaceuticals in the European Union: A case study with the β-blocker atenolol
Authors: Küster Anette , Alder Alfredo C , Escher Beate I , Duis Karen , Fenner Kathrin , Garric Jeanne , Hutchinson Thomas H , Lapen David R , Péry Alexandre , Römbke Jörg , Snape Jason , Ternes Thomas , Topp Ed , Wehrhan Anne , Knacker Thomas 
Published: November 2009

Abstract
β-Adrenergic receptor blockers (β-blockers) are applied to treat high blood pressure, ischemic heart disease, and heart rhythm disturbances. Due to their widespread use and limited human metabolism, β-blockers are widely detected in sewage effluents and surface waters. β-Adrenergic receptors have been characterized in fish and other aquatic animals, so it can be expected that physiological processes regulated by these receptors in wild animals may be affected by the presence of β-blockers. Because ecotoxicological data on β-blockers are scarce, it was decided to choose the β-blocker atenolol as a case study pharmaceutical within the project ERAPharm. A starting point for the assessment of potential environmental risks was the European guideline on the environmental risk assessment of medicinal products for human use. In Phase I of the risk assessment, the initial predicted environmental concentration (PEC) of atenolol in surface water (500 ng L−1) exceeded the action limit of 10 ng L−1. Thus, a Phase II risk assessment was conducted showing acceptable risks for surface water, for groundwater, and for aquatic microorganisms. Furthermore, atenolol showed a low potential for bioaccumulation as indicated by its low lipophilicity (log KOW = 0.16), a low potential for exposure of the terrestrial compartment via sludge (log KOC = 2.17), and a low affinity for sorption to the sediment. Thus, the risk assessment according to Phase II-Tier A did not reveal any unacceptable risk for atenolol. Beyond the requirements of the guideline, additional data on effects and fate were generated within ERAPharm. A 2-generation reproduction test with the waterflea Daphnia magna resulted in the most sensitive no-observed-effect concentration (NOEC) of 1.8 mg L−1. However, even with this NOEC, a risk quotient of 0.003 was calculated, which is still well below the risk threshold limit of 1. Additional studies confirm the outcome of the environmental risk assessment according to EMEA/CHMP (2006). However, atenolol should not be considered as representative for other β-blockers, such as metoprolol, oxprenolol, and propranolol, some of which show significantly different physicochemical characteristics and varying toxicological profiles in mammalian studies. Integr Environ Assess Manag 2010;6:514–523. © 2009 SETAC
The chironomid acute toxicity test: Development of a new test system
Authors: Weltje Lennart , Rufli Hans , Heimbach Fred , Wheeler James , Vervliet-Scheebaum Marco , Hamer Michael 
Published: November 2009

Abstract
This paper describes the basis for a water-only acute chironomid toxicity test guideline using first-instar larvae. The method is based on the OECD test guidelines for the acute Daphnia sp. immobilization test and the long-term tests with Chironomus sp., reflecting the common test procedures currently used by the European agrochemical industry. Development of this guideline proposal is important under the European Plant Protection Products Directive (91/414/EEC), under which an insect species may be required to be tested, particularly for certain insecticides, for which Daphnia sp. may not be representative of the sensitivity of nontarget aquatic invertebrates. Chironomus sp. is a freshwater insect currently used in different international test guidelines. Because their ready availability as a test organism, with culturing conditions and certain test methods already established, Chironomus sp. is regarded as a suitable additional freshwater invertebrate species for regulatory testing. Integr Environ Assess Manag 2010;6:301–307. © 2009 SETAC
Effects of Walnut Consumption on Endothelial Function in Type 2 Diabetic Subjects
Authors: Ma Yingying , Njike Valentine Yanchou , Millet John , Dutta Suparna , Doughty Kim , Treu Judith A. , Katz David L. 
Published: October 2009

OBJECTIVE
To determine the effects of daily walnut consumption on endothelial function, cardiovascular biomarkers, and anthropometric measures in type 2 diabetic individuals.

RESEARCH DESIGN AND METHODS
This study was a randomized, controlled, single-blind, crossover trial. Twenty-four participants with type 2 diabetes (mean age 58 years; 14 women and 10 men) were randomly assigned to one of the two possible sequence permutations to receive an ad libitum diet enriched with 56 g (366 kcal) walnuts/day and an ad libitum diet without walnuts for 8 weeks. Subjects underwent endothelial function testing (measured as flow-mediated dilatation [FMD]) and assessment of cardiovascular biomarkers before and after each 8-week treatment phase. The primary outcome measure was the change in FMD after 8 weeks. Secondary outcome measures included changes in plasma lipids, A1C, fasting glucose, insulin sensitivity, and anthropometric measures.

RESULTS
Endothelial function significantly improved after consumption of a walnut-enriched ad libitum diet compared with that after consumption of an ad libitum diet without walnuts (2.2 ± 1.7 vs. 1.2 ± 1.6%; P = 0.04). The walnut-enriched diet increased fasting serum glucose and lowered serum total cholesterol and LDL cholesterol from baseline (10.0 ± 20.5 mg/dl, P = 0.04; −9.7 ± 14.5 mg/dl, P &lt; 0.01; and −7.7 ± 10 mg/dl, P &lt; 0.01, respectively), although these changes were not significant compared with those for an ad libitum diet without walnuts. There were no significant changes in anthropometric measures, plasma A1C, and insulin sensitivity.

CONCLUSIONS
A walnut-enriched ad libitum diet improves endothelium-dependent vasodilatation in type 2 diabetic individuals, suggesting a potential reduction in overall cardiac risk.
Adaptation of Human CD4+ T Cells to Pathophysiological Hypoxia: A Transcriptome Analysis
Authors: GABER TIMO , HÄUPL THOMAS , SANDIG GRIT , TYKWINSKA KAROLINA , FANGRADT MONIQUE , TSCHIRSCHMANN MIRIAM , HAHNE MARTIN , DZIURLA RENÉ , EREKUL KEREM , LAUTENBACH MARTIN , KOLAR PAULA , BURMESTER GERD-RÜDIGER , BUTTGEREIT FRANK 
Published: November 2009

Objective.Inflamed tissues are usually characterized by low oxygen levels. We investigated whether pathophysiological hypoxia (pO2< 1%) as found in the rheumatoid synovium modulates the transcriptome of human CD4+ T cells.Methods.We analyzed the extent to which hypoxia influences the transcriptome in the rheumatoid synovium according to a gene cluster reflecting adaptation to low oxygen levels. Hypoxia-inducible factor-1α (HIF-1α) was detected in the rheumatoid synovium using immunohistochemistry. Isolated human CD4+ T cells were exposed to hypoxia and analyzed using microarray analysis, quantitative polymerase chain reaction, and immunoblot detection.Results.In rheumatoid arthritis (RA) synovial tissue samples, hypoxia modulates the transcription profile. This profile is similar, but not identical, to that found in isolated CD4+ T cells incubated under hypoxic conditions. We show that HIF-1α is expressed in synovial tissue samples and in hypoxic CD4+ cells; and that hypoxia directly affects differential gene expression in human T cells with up to 4.8% modulation of the transcriptome. Functional genome analysis revealed substantial effects of hypoxia on immune response, transcriptional regulation, protein modification, cell growth and proliferation, and cell metabolism.Conclusion.Severe hypoxia, a feature of joint inflammation, considerably modulates the transcriptome of cells found in the rheumatoid synovium. Human CD4+ T cells adapt to hypoxic conditions mainly by HIF-1-driven effects on the transcriptome reflecting a profound influence on immune functions. Thus, hypoxia must be taken into account when therapeutically targeting inflammation.
Assessment of the Methodologic Quality of Medical and Surgical Clinical Trials in Patients with Arthroplasty
Authors: SINGH JASVINDER A. , MURPHY STEPHEN , BHANDARI MOHIT 
Published: November 2009

Objective.To assess the methodological quality of randomized controlled trials (RCT) of medical and surgical therapy in patients with arthroplasty.Methods.We conducted a Medline database search for all arthroplasty RCT from 1997 and 2006. The quality of the methods of all eligible RCT was assessed by a trained abstractor. We used a checklist of trial quality characteristics, and the overall trial quality was assessed by 3 scales: Jadad (range 0–5), Delphi list (range 0–9), and numeric rating scale (NRS; range 1–10), based on User’s Guides to the Medical Literature.Results.A total of 196 articles were included in the analysis; most included hip (n = 81) or knee (n = 80) or both hip/knee arthroplasty (n = 19); 66 (34%) assessed pharmacological treatments, 117 (60%) nonpharmacological treatments, and 13 (7%) both. Mean (SEM) overall quality scores of arthroplasty RCT were low: Jadad score 2.36 (1.4), Delphi list 5.33 (1.6), and NRS score 4.30 (2.6). Multivariable analyses revealed that nonpharmacological intervention RCT had lower odds (odds ratio 0.28–0.39; p = 0.008–0.033) and those with no funding had lower odds (OR 0.28–0.50; p = 0.014–0.119) of being in the highest quartiles of the 3 overall quality scores. In contrast, multicenter RCT had 1.8–4.7 times higher odds of being in highest tertiles of quality scores (p = 0.017–0.185).Conclusion.Methodological deficiencies in reporting of hip/knee arthroplasty RCT offer an opportunity for improvement. Type of intervention, number of trial centers, and presence of funding were independently associated with overall trial quality. In future, multicenter RCT (rather than single-center) and modeling protocols of single-center RCT similar in rigor to multicenter RCT may improve the quality of arthroplasty RCT.
Osteonecrosis of the Jaw Correlated to Bisphosphonate Therapy in Non-oncologic Patients: Clinicopathological Features of 24 Patients
Authors: FAVIA GIANFRANCO , PILOLLI GIOVANNI PIETRO , MAIORANO EUGENIO 
Published: November 2009

Objective.Osteonecrosis of the jaws (ONJ) is a well known side effect of bisphosphonate therapies in patients with multiple myeloma or other malignancies. Its real incidence is still undetermined, and only few cases of ONJ in patients taking bisphosphonates for non-oncologic diseases have been reported. It was postulated that the clinical features, predisposing factors, and treatment outcome of this subset of patients might be different from those of oncologic patients.Methods.Over a 4 year period, a total of 102 bisphosphonate-treated patients affected by ONJ were identified. Among these, 24 patients underwent bisphosphonate therapy for non-neoplastic disease and their profile was analyzed.Results.In this study cohort, bisphosphonates had been administered mainly for postmenopausal osteoporosis (20/24 patients, 83.3%), the duration of therapy until presentation of ONJ ranging from 11 to 40 months and the most common triggering event being dentoalveolar surgery. All patients were nonsmokers; 6 manifested multiple ONJ lesions and only 3 of them had possible comorbidities. Surgical debridement was performed in 19 patients for a total of 22 lesions, which were individually considered in the followup. The latter showed complete remission of ONJ in 21/22 lesions.Conclusion.Although it might be considered a rare condition in non-oncologic patients, ONJ is a harmful side effect of bisphosphonate therapies. Clinicians must be aware of this entity, inform patients of the risks related to dental surgery, and possibly undertake adequate preventive measures.
Dec2 Promotes Th2 Cell Differentiation by Enhancing IL-2R Signaling
Authors: Liu Zhiduo , Li Zhenhu , Mao Kairui , Zou Jia , Wang Yuan , Tao Zhiyun , Lin Guomei , Tian Lin , Ji Yongyong , Wu Xiaodong , Zhu Xueliang , Sun Shuhui , Chen Weiguang , Xiang Charlie , Sun Bing 
Published: October 2009

Abstract
Th cell differentiation is precisely regulated by thousands of genes at different stages. In the present study, we demonstrate that Dec2, a transcription factor belonging to the bHLH (basic helix-loop-helix) superfamily, is progressively induced during the course of Th2 differentiation, especially at the late stage. The up-regulated Dec2 can strongly promote Th2 development under Th2-inducing conditions, as evidenced by retrovirus-mediated gene transfer or transgenic manipulation. In addition, an enhancement of Th2 responses is also detectable in Dec2 transgenic mice in vivo. Conversely, RNA interference-mediated suppression of endogenous Dec2 could attenuate Th2 differentiation. Finally, we show that the enhanced Th2 development is at least in part due to substantial up-regulation of CD25 expression elicited by Dec2, thereby resulting in hyperresponsiveness to IL-2 stimulation.
The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis
Authors: Mencarelli Andrea , Renga Barbara , Migliorati Marco , Cipriani Sabrina , Distrutti Eleonora , Santucci Luca , Fiorucci Stefano 
Published: October 2009

Abstract
Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. In this study, we report that activation of the farnesoid X receptor (FXR), a member of the ligand-activated nuclear receptor superfamily and bile sensor highly expressed in the liver, attenuates liver injury in a model of autoimmune hepatitis induced by Con A. We found that FXR gene ablation results in a time-dependent increase of liver expression (up to 20-fold in a 9-mo-old mouse) of osteopontin, a NKT cell-derived extracellular matrix protein and immunoregulatory cytokine. In comparison to wild-type, FXR−/− mice are more susceptible to Con A-induced hepatitis and react to Con A administration by an unregulated production of osteopontin. Administering wild-type mice with a synthetic FXR agonist attenuated Con A-induced liver damage and liver expression of the osteopontin gene. By in vitro studies, we found that FXR is expressed by primarily isolated NKT cells and its ablation favors ostepontin production in response to Con A. Chromatin immunoprecipitation assay and coimmunoprecipitation experiments demonstrate that the short heterodimer partner (SHP), a nuclear receptor and FXR target, was expressed by NKT cell hybridomas and increased in response to FXR activation. FXR activates SHP that interacts with and inhibits c-Jun binding to the osteopontin promoter. These data indicate that in NKT cells, FXR activation causes a SHP-mediated inhibition of osteopontin production. These data support the notion that the bile acid sensor FXR regulates the activation of liver NKT cells.