cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5104579
title: Supplementary Material for: Statistical Models for Haplotype Sharing in Case-Parent Trio Data

description: <i>Background:</i> Haplotype sharing statistics have been introduced in an ad-hoc way, often relying heavily on permutation testing. As a result, applying these approaches to whole genome association studies or to evaluate their properties in extensive simulation experiments is problematic. Further, permutation testing may be inappropriate in the presence of phase ambiguity and population stratification. <i>Aims:</i> To present a simple framework for a class of haplotype sharing statistics useful for association mapping in case-parent trio data. This framework allows derivation of novel haplotype sharing tests as well as simple variance estimators and asymptotic distributions for haplotype sharing tests. <i>Results and Conclusions:</i> We validated that our approach is appropriately sized using simulated data, and illustrate the methodology by analyzing a Crohn’s disease dataset. We find that haplotype-based analyses are much more powerful than single-locus analyses for these data.
DOI: 10.6084/m9.figshare.5104588.v1
title: Supplementary Material for: <i>DTNBP1 (Dystrobrevin Binding Protein 1)</i> and Schizophrenia: Association Evidence in the 3′ End of the Gene

description: <i>Objectives:</i><i>Dysbindin</i> (<i>DTNBP1</i>) has been identified as a susceptibility gene for schizophrenia (SZ) through a positional approach. However, a variety of single nucleotide polymorphisms (SNPs) and haplotypes, in different parts of the gene, have been reported to be associated in different samples, and a precise molecular mechanism of disease remains to be defined. We have performed an association study with two well-characterized family samples not previously investigated at the <i>DTNBP1</i> locus. <i>Methods:</i> We examined 646 subjects in 136 families with SZ, largely of European ancestry (EA), genotyping 26 SNPs in <i>DTNBP1</i>. <i>Results:</i> Three correlated markers (rs875462, rs760666, and rs7758659) at the 3′ region of <i>DTNBP1 </i>showed evidence for association to SZ (p = 0.004), observed in both the EA (p = 0.031) and the African American (AA) subset (p = 0.045) with the same over-transmitted allele. The most significant haplotype in our study was rs7758659-rs3213207 (global p = 0.0015), with rs3213207 being the most frequently reported associated marker in previous studies. A non-conservative missense variant (Pro272Ser) in the 3′ region of <i>DTNBP1</i> that may impair <i>DTNBP1</i> function was more common in SZ probands (8.2%) than in founders (5%) and in dbSNP (2.1%), but did not reach statistical significance. <i>Conclusion: </i>Our results provide evidence for an association of SZ with SNPs at the 3′ end of <i>DTNBP1</i> in the samples studied.
DOI: 10.6084/m9.figshare.5104567
title: Supplementary Material for: Rationale, Design and Baseline Data of a Randomized, Double-Blind, Controlled Trial Comparing Two Antithrombotic Regimens (a Fixed-Dose Combination of Extended-Release Dipyridamole plus ASA with Clopidogrel) and Telmisartan versus Placebo in Patients with Strokes: The Prevention Regimen for Effectively Avoiding Second Strokes Trial (PRoFESS)

description: <i>Background:</i> Individuals with transient ischemic attack and ischemic stroke have a high risk of recurrent stroke and death. While acetylsalicylic acid (ASA, aspirin) is proven and accepted as standard therapy in these patients, recent trials demonstrate that a combination of ASA and dipyridamole (DP) or clopidogrel may be superior to ASA. Blocking the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may also reduce recurrent stroke. The ongoing PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) trial is designed to evaluate whether ASA + extended-release DP compared to clopidogrel, and whether telmisartan in addition to usual care in individuals after a stroke, will reduce the risk of further strokes. <i>Methods:</i> PRoFESS is a multicenter, randomized, double-blind trial involving 695 sites from 35 countries or regions. Patients ≧50 years presenting with an ischemic stroke &lt;120 days who were stable were randomized. The primary outcome for the trial is recurrent stroke, using a time-to-event analysis. The most important secondary outcome is the composite of stroke, myocardial infarction or vascular death. Other secondary outcomes include this composite + congestive heart failure, new-onset diabetes, other designated occlusive vascular events (pulmonary embolism, deep-vein thrombosis, peripheral arterial occlusion, transient ischemic attack, cerebral venous thrombosis or retinal vascular accident not classified as stroke), any death, stroke subtype by TOAST criteria and Mini Mental State Examination score. Safety is evaluated by assessing the risk of major hemorrhagic events. The comparison between ASA + DP and clopidogrel is based on an initial assessment of noninferiority, followed by evaluation of superiority, while for telmisartan, we will assess its superiority over placebo. <i>Results:</i> With over 20,000 patients randomized, and utilizing a 2 × 2 factorial design, PRoFESS is the largest stroke trial to investigate the prevention of recurrent stroke. The mean age was 66.1 ± 8.6 years, and 36.0% of the patients were females. The median time from qualifying event to randomization was 15 days with 39.9% of patients randomized within 10 days. According to the TOAST criteria, 28.5% of the strokes were due to large-vessel disease, 52.1% to small-vessel disease, 1.8% to cardioembolism, and 2.0% to other determined etiologies and 15.5% were of undetermined etiology. <i>Conclusions:</i> PRoFESS is the largest secondary stroke prevention trial to date and will directly compare two antiplatelet regimens as well as the benefit of telmisartan versus placebo.
DOI: 10.6084/m9.figshare.5104579.v1
title: Supplementary Material for: Statistical Models for Haplotype Sharing in Case-Parent Trio Data

description: <i>Background:</i> Haplotype sharing statistics have been introduced in an ad-hoc way, often relying heavily on permutation testing. As a result, applying these approaches to whole genome association studies or to evaluate their properties in extensive simulation experiments is problematic. Further, permutation testing may be inappropriate in the presence of phase ambiguity and population stratification. <i>Aims:</i> To present a simple framework for a class of haplotype sharing statistics useful for association mapping in case-parent trio data. This framework allows derivation of novel haplotype sharing tests as well as simple variance estimators and asymptotic distributions for haplotype sharing tests. <i>Results and Conclusions:</i> We validated that our approach is appropriately sized using simulated data, and illustrate the methodology by analyzing a Crohn’s disease dataset. We find that haplotype-based analyses are much more powerful than single-locus analyses for these data.
DOI: 10.6084/m9.figshare.5104561
title: Supplementary Material for: Contribution of Extracytoplasmic Function Sigma Factors to Transition Metal Homeostasis in <i>Cupriavidus metallidurans</i> Strain CH34

description: <i>Cupriavidus metallidurans</i> strain CH34 is a highly metal-resistant bacterium that contains 11 sigma factors of the extracytoplasmic function (ECF) protein family, which can be subgrouped into the ECF:FecI 1, ECF:FecI 2, ECF:RpoE and ‘(ECF)’ clusters. To analyze the contribution of these 11 sigma factors to metal resistance, upregulation of the respective genes was measured by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR). As determined by RT-PCR, the ECF sigma factor genes were part of two- to tetra-cistronic operons, each containing genes for the sigma factor plus one or two antisigma factors. The three sigma factors RpoJ, RpoK and RpoI (ECF:FecI 1 cluster) were upregulated by Cu(II) and Ni(II), and under conditions of iron depletion. The other 8 ECF sigma factor genes were not induced by iron depletion. Strong upregulation of <i>rpoJ</i> and <i>rpoK</i> under iron depletion in a Δ<i>rpoI</i> mutant strain and close vicinity of <i>rpoI</i> to genes involved in iron siderophore metabolism marked RpoI as the primary ECF sigma factor for siderophore-mediated iron uptake. Genes for RpoO, RpoL and RpoM (ECF:FecI 2 cluster) were not upregulated by transition metal cations and influenced metal resistance only weakly. Concerning the two ‘(ECF)’ group proteins, <i>rpoQ</i> was strongly upregulated by Cu(II) and deletion of <i>rpoR</i> led to a small decrease in copper resistance. Of the three ECF:RpoE-encoding genes, <i>rpoP</i> was not transcribed under the conditions tested, <i>cnrH</i> was upregulated by Ni(II) and essential for nickel resistance as known before. RpoE was required for full metal resistance of <i>C. metallidurans</i>. None of these 11 sigma factors was essential for metal resistance mediated by the cobalt, zinc and cadmium resistance determinant <i>czc</i>, or for its expression. However, RpoI was essential for siderophore production in <i>C. metallidurans</i>, and, in addition to the known role of CnrH in nickel resistance, RpoE, RpoI, RpoJ, RpoK and maybe also RpoQ are required for the outstanding transition metal resistance of this bacterium.
DOI: 10.6084/m9.figshare.5104564
title: Supplementary Material for: Phospholipid Transfer Protein in Hemodialysis Patients

description: <i>Introduction:</i> Phospholipid transfer protein (PLTP) is mainly involved in high-density lipoprotein (HDL) metabolism. The role of PLTP in atherogenesis is still controversial. We aimed to investigate PLTP activity in hemodialysis (HD) patients, a population which has an increased risk for the development of atherosclerosis. <i>Methods:</i> PLTP activity and other markers were analyzed in blood samples from 68 HD patients and in a matched group of 68 healthy controls. <i>Results:</i> Serum PLTP activity was nearly doubled in HD patients in comparison to healthy controls (median 43.0 vs. 22.4 pmol/µl/h, p &lt; 0.001). In HD patients, PLTP activity correlated with HDL-C (r = 0.342, p = 0.004), but not with CRP (r = –0.057, p = 0.644) or leukocyte count (r = 0.116, p = 0.345). After a follow-up of 2 years, 26 HD patients had died. Kaplan-Meier analyses showed that low CRP (p = 0.047) but neither high HDL-C (p = 0.071) nor low PLTP activity (p = 0.853) were relevantly related to survival of HD patients. <i>Conclusion:</i> An elevated PLTP activity in HD patients may be considered as a further aspect of uremic dyslipidemia in HD patients. However, PLTP activity was not related to markers of inflammation or to survival of HD patients, even though it correlated with HDL-C. Thus, we conclude that PLTP does not influence the prognostically relevant inflammatory process in HD patients although it does influence the composition of HDL particles.
DOI: 10.6084/m9.figshare.5104558
title: Supplementary Material for: Accounting for Epistasis in Linkage Analysis of General Pedigrees

description: Complex traits are generally believed to be influenced by multiple loci. Identification of loci involved in complex traits is more difficult for interacting than for additive loci. Here we describe an extension of the program lm_twoqtl in the package MORGAN to handle two quantitative trait loci (QTLs) with gene-gene interaction. We investigate whether parametric linkage analysis that accounts for such epistasis improves prospects for linkage detection and accuracy of localization of QTLs. Through use of simulated data we show that analysis that accounts for epistasis provides higher lod scores and better localization than does analysis without epistasis. In addition, we demonstrate that the difference between lod scores in the presence vs. absence of use of an interaction model in analysis is greater in extended than in nuclear pedigrees.
DOI: 10.6084/m9.figshare.5104570.v1
title: Supplementary Material for: A model for genetic complementation controlling the chromosomal abnormalities and loss of heterozygosity formation in cancer

description: The relationship between the apparently random chromosomal changes found in aneuploidy and the genetic instability driving the progression of cancer is not clear. We report a test of the hypothesis that aneuploid chromosomal abnormalities might be selected to preserve cell-survival genes during loss of heterozygosity (LOH) formations which eliminate tumor suppressor genes. The LOHs and structurally abnormal chromosomes present in the aneuploid LoVo (colon), A549 (lung), SUIT-2 (pancreas), and LN-18 (glioma) cancer cell lines were identified by single nucleotide polymorphisms (SNPs) and Spectral Karyotyping (SKY). The Mann-Whitney U and chi square tests were used to evaluate possible differences in chromosome numbers and abnormalities between the cell lines, with two-tailed <i>P</i> values of &lt;0.01 being considered significant. The cell lines differed significantly in chromosome numbers and frequency of structurally abnormal chromosomes. The SNP analysis revealed that each cell line contained at least a haploid set of somatic chromosomes, consistent with our hypothesis that cell-survival genes are widely scattered throughout the genome. Further, over 90% of the chromosomal abnormalities seemed to be selected, often after LOH formation, for gene-dosage compensation or to provide heterozygosity for specific chromosomal regions. These results suggest that the chromosomal changes of aneuploidy are not random, but may be selected to provide gene-dosage compensation and/or retain functional alleles of cell-survival genes during LOH formation.
DOI: 10.6084/m9.figshare.5104555
title: Supplementary Material for: Novel Electrical Stimulation Sets the Cultured Myoblast Contractile Function to ‘On’

description: <i>Objective: </i>In the present study, the effect of electrical stimulation was examined for the ability to induce morphological, physiological, and molecular biological effects on myoblasts during cell differentiation. <i>Methods:</i> L6 rat myoblasts were electrically stimulated by newly developed methods on culture days 6, 8, 10 and 12. <i>Results: </i>This electrical stimulation accelerated the appearance of myotubes, and subsequently produced spontaneously contracting muscle fibers. Measurement of membrane potential showed that the contracting cell had functional ion channels and gap junctional intercellular communication. In the electrically stimulated cells, an enhanced expression of MyoD family and M-cadherin was also observed. Expression of connexin 43 was increased and maintained at a high level in the electrically stimulated cells. <i>Conclusion:</i> This is the first demonstration of in vitro induction of myoblasts in spontaneously contractile muscle fibers by intermittent stimulation. This novel method for induction of myoblast differentiation represents an important advance in cell therapy.
DOI: 10.6084/m9.figshare.5104558.v1
title: Supplementary Material for: Accounting for Epistasis in Linkage Analysis of General Pedigrees

description: Complex traits are generally believed to be influenced by multiple loci. Identification of loci involved in complex traits is more difficult for interacting than for additive loci. Here we describe an extension of the program lm_twoqtl in the package MORGAN to handle two quantitative trait loci (QTLs) with gene-gene interaction. We investigate whether parametric linkage analysis that accounts for such epistasis improves prospects for linkage detection and accuracy of localization of QTLs. Through use of simulated data we show that analysis that accounts for epistasis provides higher lod scores and better localization than does analysis without epistasis. In addition, we demonstrate that the difference between lod scores in the presence vs. absence of use of an interaction model in analysis is greater in extended than in nuclear pedigrees.
DOI: 10.6084/m9.figshare.5104561.v1
title: Supplementary Material for: Contribution of Extracytoplasmic Function Sigma Factors to Transition Metal Homeostasis in <i>Cupriavidus metallidurans</i> Strain CH34

description: <i>Cupriavidus metallidurans</i> strain CH34 is a highly metal-resistant bacterium that contains 11 sigma factors of the extracytoplasmic function (ECF) protein family, which can be subgrouped into the ECF:FecI 1, ECF:FecI 2, ECF:RpoE and ‘(ECF)’ clusters. To analyze the contribution of these 11 sigma factors to metal resistance, upregulation of the respective genes was measured by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR). As determined by RT-PCR, the ECF sigma factor genes were part of two- to tetra-cistronic operons, each containing genes for the sigma factor plus one or two antisigma factors. The three sigma factors RpoJ, RpoK and RpoI (ECF:FecI 1 cluster) were upregulated by Cu(II) and Ni(II), and under conditions of iron depletion. The other 8 ECF sigma factor genes were not induced by iron depletion. Strong upregulation of <i>rpoJ</i> and <i>rpoK</i> under iron depletion in a Δ<i>rpoI</i> mutant strain and close vicinity of <i>rpoI</i> to genes involved in iron siderophore metabolism marked RpoI as the primary ECF sigma factor for siderophore-mediated iron uptake. Genes for RpoO, RpoL and RpoM (ECF:FecI 2 cluster) were not upregulated by transition metal cations and influenced metal resistance only weakly. Concerning the two ‘(ECF)’ group proteins, <i>rpoQ</i> was strongly upregulated by Cu(II) and deletion of <i>rpoR</i> led to a small decrease in copper resistance. Of the three ECF:RpoE-encoding genes, <i>rpoP</i> was not transcribed under the conditions tested, <i>cnrH</i> was upregulated by Ni(II) and essential for nickel resistance as known before. RpoE was required for full metal resistance of <i>C. metallidurans</i>. None of these 11 sigma factors was essential for metal resistance mediated by the cobalt, zinc and cadmium resistance determinant <i>czc</i>, or for its expression. However, RpoI was essential for siderophore production in <i>C. metallidurans</i>, and, in addition to the known role of CnrH in nickel resistance, RpoE, RpoI, RpoJ, RpoK and maybe also RpoQ are required for the outstanding transition metal resistance of this bacterium.
DOI: 10.6084/m9.figshare.5104567.v1
title: Supplementary Material for: Rationale, Design and Baseline Data of a Randomized, Double-Blind, Controlled Trial Comparing Two Antithrombotic Regimens (a Fixed-Dose Combination of Extended-Release Dipyridamole plus ASA with Clopidogrel) and Telmisartan versus Placebo in Patients with Strokes: The Prevention Regimen for Effectively Avoiding Second Strokes Trial (PRoFESS)

description: <i>Background:</i> Individuals with transient ischemic attack and ischemic stroke have a high risk of recurrent stroke and death. While acetylsalicylic acid (ASA, aspirin) is proven and accepted as standard therapy in these patients, recent trials demonstrate that a combination of ASA and dipyridamole (DP) or clopidogrel may be superior to ASA. Blocking the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may also reduce recurrent stroke. The ongoing PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) trial is designed to evaluate whether ASA + extended-release DP compared to clopidogrel, and whether telmisartan in addition to usual care in individuals after a stroke, will reduce the risk of further strokes. <i>Methods:</i> PRoFESS is a multicenter, randomized, double-blind trial involving 695 sites from 35 countries or regions. Patients ≧50 years presenting with an ischemic stroke &lt;120 days who were stable were randomized. The primary outcome for the trial is recurrent stroke, using a time-to-event analysis. The most important secondary outcome is the composite of stroke, myocardial infarction or vascular death. Other secondary outcomes include this composite + congestive heart failure, new-onset diabetes, other designated occlusive vascular events (pulmonary embolism, deep-vein thrombosis, peripheral arterial occlusion, transient ischemic attack, cerebral venous thrombosis or retinal vascular accident not classified as stroke), any death, stroke subtype by TOAST criteria and Mini Mental State Examination score. Safety is evaluated by assessing the risk of major hemorrhagic events. The comparison between ASA + DP and clopidogrel is based on an initial assessment of noninferiority, followed by evaluation of superiority, while for telmisartan, we will assess its superiority over placebo. <i>Results:</i> With over 20,000 patients randomized, and utilizing a 2 × 2 factorial design, PRoFESS is the largest stroke trial to investigate the prevention of recurrent stroke. The mean age was 66.1 ± 8.6 years, and 36.0% of the patients were females. The median time from qualifying event to randomization was 15 days with 39.9% of patients randomized within 10 days. According to the TOAST criteria, 28.5% of the strokes were due to large-vessel disease, 52.1% to small-vessel disease, 1.8% to cardioembolism, and 2.0% to other determined etiologies and 15.5% were of undetermined etiology. <i>Conclusions:</i> PRoFESS is the largest secondary stroke prevention trial to date and will directly compare two antiplatelet regimens as well as the benefit of telmisartan versus placebo.
DOI: 10.6084/m9.figshare.5104546
title: Supplementary Material for: Subsets of Finns with High HDL to Total Cholesterol Ratio Show Evidence for Linkage to Type 2 Diabetes on Chromosome 6q

description: <i>Objectives:</i> The purpose of this study was to examine carefully heterogeneity underlying evidence for linkage to type 2 diabetes (T2DM) on chromosome 6q from two sets of FUSION families. <i>Methods:</i> Ordered subsets analysis (OSA) was performed on two sets of FUSION families. For OSA results showing significant improvement in evidence for linkage, T2DM-related phenotypes were compared between individuals with T2DM within the subset versus the complement. <i>Results:</i> OSA analysis revealed 105 families with the highest average HDL to total cholesterol ratio (HDL ratio) that had strongly increased evidence for linkage (MLS = 7.91 at 78.0 cM; uncorrected p = 0.00002). Subjects with T2DM within this subset were significantly leaner, had lower fasting glucose, insulin, and C-peptide, and more favorable cardiovascular risk profile compared to the complement set of subjects with T2DM. OSA also revealed 33 families with the lowest average fasting insulin that had increased evidence for linkage at a second locus (MLS = 3.45 at 128 cM; uncorrected p = 0.017) coincident with quantitative trait locus linkage analysis results for fasting and 2-hour insulin in subjects without T2DM. <i>Conclusions:</i> These results suggest two diabetes susceptibility loci on chromosome 6q that may affect subsets of individuals with a milder form of T2DM.
DOI: 10.6084/m9.figshare.5104555.v1
title: Supplementary Material for: Novel Electrical Stimulation Sets the Cultured Myoblast Contractile Function to ‘On’

description: <i>Objective: </i>In the present study, the effect of electrical stimulation was examined for the ability to induce morphological, physiological, and molecular biological effects on myoblasts during cell differentiation. <i>Methods:</i> L6 rat myoblasts were electrically stimulated by newly developed methods on culture days 6, 8, 10 and 12. <i>Results: </i>This electrical stimulation accelerated the appearance of myotubes, and subsequently produced spontaneously contracting muscle fibers. Measurement of membrane potential showed that the contracting cell had functional ion channels and gap junctional intercellular communication. In the electrically stimulated cells, an enhanced expression of MyoD family and M-cadherin was also observed. Expression of connexin 43 was increased and maintained at a high level in the electrically stimulated cells. <i>Conclusion:</i> This is the first demonstration of in vitro induction of myoblasts in spontaneously contractile muscle fibers by intermittent stimulation. This novel method for induction of myoblast differentiation represents an important advance in cell therapy.