cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5123815
title: Supplementary Material for: Detection of Phenotype Modifier Genes Using Two-Locus Linkage Analysis in Complex Disorders Such as Major Psychosis

description: <b><i>Objective:</i></b> To increase power to detect modifier loci conferring susceptibility to specific phenotypes such as disease diagnoses which are part of a broader disorder spectrum by jointly modeling a modifier and a broad susceptibility gene and to identify modifier loci conferring specific susceptibility to schizophrenia (SZ) or to bipolar disorder (BP) using the approach. <b><i>Methods:</i></b> We implemented a two-locus linkage analysis model where a gene 1 genotype increases the risk of a broad phenotype and a gene 2 genotype modifies the expression of gene 1 by conferring susceptibility to a specific phenotype. <b><i>Results:</i></b> Compared to a single-locus analysis within the broad phenotype, the proposed approach had greater power to detect the modifier gene 2 (0.96 vs. 0.54 under a simulation scenario including heterogeneity). In a sample of 12 mixed SZ and BP Eastern Quebec kindreds, D8S1110 at 8p22 showed the strongest evidence of linkage to a gene determining a specific phenotype (SZ or BP) among subjects susceptible to major psychosis because of putative genes at 10p13 (D10S245, conditional maximized LOD (cMOD) = 4.20, p = 0.0003) and 3q21–q23 (D3S2418, cMOD = 4.09, p = 0.0005). <b><i>Conclusion:</i></b> The proposed strategy is useful to detect modifier loci conferring susceptibility to a specific phenotype within a broader phenotype.
DOI: 10.6084/m9.figshare.5123827.v1
title: Supplementary Material for: A Short Introduction to Cytogenetic Studies in Mammals with Reference to the Present Volume

description: Genome diversity has long been studied from the comparative cytogenetic perspective. Early workers documented differences between species in diploid chromosome number and fundamental number. Banding methods allowed more detailed descriptions of between-species rearrangements and classes of differentially staining chromosome material. The infusion of molecular methods into cytogenetics provided a third revolution, which is still not exhausted. Chromosome painting has provided a global view of the translocation history of mammalian genome evolution, well summarized in the contributions to this special volume. More recently, FISH of cloned DNA has provided details on defining breakpoint and intrachromosomal marker order, which have helped to document inversions and centromere repositioning. The most recent trend in comparative molecular cytogenetics is to integrate sequencing information in order to formulate and test reconstructions of ancestral genomes and phylogenomic hypotheses derived from comparative cytogenetics. The integration of comparative cytogenetics and sequencing promises to provide an understanding of what drives chromosome rearrangements and genome evolution in general. We believe that the contributions in this volume, in no small way, point the way to the next phase in cytogenetic studies.
DOI: 10.6084/m9.figshare.5123809
title: Supplementary Material for: Unusual Aortic Valve Anomaly in the Fetus: A Case Report

description: Aortic valve anomalies in fetal life usually concern aortic valve stenosis, in severe forms associated to left ventricular impairment – endocardial fibroelastosis and mitral valve insufficiency. Isolated aortic regurgitation in utero is infrequent and is usually considered to be due to a rare anomaly: aorto-left ventricular tunnel. We describe an unusual case of fetal aortic valve anomaly with severe dysplasia, with a marked regurgitant flow through the aortic valve, passing in a retrograde way from the duct, associated with a marked left ventricular endocardial fibroelastosis and dysfunction, resulting in the fatal outcome of the case.
DOI: 10.6084/m9.figshare.5123812.v1
title: Supplementary Material for: Sex-Biased miRNA Expression in Atlantic Halibut <b><i>(Hippoglossus hippoglossus)</i></b> Brain and Gonads

description: The role of miRNA in fish sexual development is not elucidated yet. We profiled miRNAs in gonads and brains of Atlantic halibut using SOLiD sequencing technology. We found tissue- and sexually dimorphic expression of several miRNAs, including miR-29a, miR-34, miR-143, miR-145, miR-202-3p, miR-451, and miR-2188. miR-9 and miR-202 were abundant in brain and gonads, respectively. In the next step, we selected some miRNAs showing differential expression patterns between sexes and performed RT-qPCR on 3 age groups: juveniles, 3-year-, and 5-year-olds. In brains, miR-451 was significantly down-regulated in juveniles compared to adults. let-7a, miR-143, and miR-202-3p were up-regulated in gonads of mature males compared to immature females at the same age. We investigated the effect of suppressing aromatase cytochrome P450 enzyme on miRNA expression at the onset of sex differentiation through masculinization with Fadrozole or 17-α-methyltestosterone. We found significant differences in miRNA expression between masculinized individuals and untreated controls. miR-202-3p was significantly down-regulated in female juveniles compared to male juveniles. The expression levels of let-7a and miR-451 were restored after termination of the masculinization treatment. Our data give a first insight into miRNA involvement in sexual development in teleosts.
DOI: 10.6084/m9.figshare.5123806
title: Supplementary Material for: The <b><i>P</i></b>x<b><i>DLLC</i></b>x<b><i>E</i></b> Sequence in Conserved Region 2 of Human Papilloma Virus 18 Protein E7 Is Required for E7 Binding to Centromere Protein C

description: High-risk human papillomaviruses (HPVs) are etiologically linked to human cervical and oral cancers. HPV infection leads to aneuploidy, a numerical chromosomal aberration caused by dysregulation of chromosomal segregation. We found that high-risk HPV18 and HPV58 E7 proteins bind to centromere protein C (CENP-C), a component of the kinetochore that is essential for proper chromosomal segregation. Low-risk HPV4, HPV6, and HPV11 E7s do not bind to CENP-C. The <i>P</i>x<i>DLLC</i>x<i>E</i> sequence in conserved region 2 (CR2) of HPV18 E7 is required for E7 binding to CENP-C. Our results indicate that differences in the ability of high- and low-risk HPV E7s to bind to CENP-C reflect the different oncogenic potentials of high- and low-risk type HPVs.
DOI: 10.6084/m9.figshare.5123815.v1
title: Supplementary Material for: Detection of Phenotype Modifier Genes Using Two-Locus Linkage Analysis in Complex Disorders Such as Major Psychosis

description: <b><i>Objective:</i></b> To increase power to detect modifier loci conferring susceptibility to specific phenotypes such as disease diagnoses which are part of a broader disorder spectrum by jointly modeling a modifier and a broad susceptibility gene and to identify modifier loci conferring specific susceptibility to schizophrenia (SZ) or to bipolar disorder (BP) using the approach. <b><i>Methods:</i></b> We implemented a two-locus linkage analysis model where a gene 1 genotype increases the risk of a broad phenotype and a gene 2 genotype modifies the expression of gene 1 by conferring susceptibility to a specific phenotype. <b><i>Results:</i></b> Compared to a single-locus analysis within the broad phenotype, the proposed approach had greater power to detect the modifier gene 2 (0.96 vs. 0.54 under a simulation scenario including heterogeneity). In a sample of 12 mixed SZ and BP Eastern Quebec kindreds, D8S1110 at 8p22 showed the strongest evidence of linkage to a gene determining a specific phenotype (SZ or BP) among subjects susceptible to major psychosis because of putative genes at 10p13 (D10S245, conditional maximized LOD (cMOD) = 4.20, p = 0.0003) and 3q21–q23 (D3S2418, cMOD = 4.09, p = 0.0005). <b><i>Conclusion:</i></b> The proposed strategy is useful to detect modifier loci conferring susceptibility to a specific phenotype within a broader phenotype.
DOI: 10.6084/m9.figshare.5123803
title: Supplementary Material for: Predicting Survival of Patients with Amyotrophic Lateral Sclerosis at Presentation: A 15-Year Experience

description: <b><i>Objective:</i></b> To describe the clinical features at first evaluation that best predict survival of the amyotrophic lateral sclerosis (ALS) population from the Salpêtrière Hospital between 1995 and 2009. <b><i>Methods:</i></b> Data are collected and entered into a clinical database from all patients seen at the Paris ALS Center. Variables analyzed were demographic and baseline information, strength testing (manual muscle testing; 1995-2009), the revised ALS Functional Rating Scale (ALSFRS-R; 2002-2009) and survival status. The χ<sup>2</sup> test and ANOVA assessed differences in variables by region and across time period. Univariate and multivariate Cox proportional hazards models determined which variables best predicted survival. Flexible modeling of continuous predictors (splines) assessed trends in survival for different variables. <b><i>Results:</i></b> 3,885 patients with ALS were seen in 1995-2009, of whom 2,037 had ALSFRS-R scores. Age, weight, strength, and site of onset varied by region of residence. The proportion of patients living outside Paris, the time to first visit, patient age, and motor function differed across time periods. In Cox models, site of onset, time to first visit greater than 18 months, strength and the year of visit after 2006 predicted survival (all p values &lt;0.0001). Compared to patients first seen between 1999 and 2002, the hazard ratio of death was 1.04 (95% CI = 0.95-1.14) for 2003-2006, and 0.76 (95% CI = 0.66-0.87) after 2006, while adjusting for other predictors of survival. The use of noninvasive ventilation increased during 2004-2008 from 16 to 51% of patients. <b><i>Conclusions:</i></b> Older age, bulbar onset, shorter delay to first visit and poor motor function at first visit predicted shorter survival rates in this large center-based sample from France, showing marked consistency across time and region of residence. Survival improved after 2006, concurrent with increasing rates of noninvasive ventilation use. Clinicopathologic correlation could better define subgroups, but identification of etiologies may be needed to elucidate individual forms of ALS with unique survival patterns.
DOI: 10.6084/m9.figshare.5123809.v1
title: Supplementary Material for: Unusual Aortic Valve Anomaly in the Fetus: A Case Report

description: Aortic valve anomalies in fetal life usually concern aortic valve stenosis, in severe forms associated to left ventricular impairment – endocardial fibroelastosis and mitral valve insufficiency. Isolated aortic regurgitation in utero is infrequent and is usually considered to be due to a rare anomaly: aorto-left ventricular tunnel. We describe an unusual case of fetal aortic valve anomaly with severe dysplasia, with a marked regurgitant flow through the aortic valve, passing in a retrograde way from the duct, associated with a marked left ventricular endocardial fibroelastosis and dysfunction, resulting in the fatal outcome of the case.
DOI: 10.6084/m9.figshare.5123797
title: Supplementary Material for: Different Effect of Rho Kinase Inhibition on Calcium Signaling in Rat Isolated Large and Small Arteries

description: In addition to its role in the regulation of artery contraction, Rho kinase (ROCK) was reported to be involved in the cytosolic calcium response to vasoconstrictor agonists in rat aorta and superior mesenteric artery (SMA). However, it remains to be determined whether ROCK also contributes to calcium signaling in resistance arteries, which play a major role in blood pressure regulation. The investigation of the effect of ROCK inhibition on the calcium and contractile responses of rat resistance mesenteric artery (RMA), in comparison with aorta and SMA, indicated that the calcium response to noradrenaline was inhibited by the ROCK inhibitor Y-27632 in aorta and SMA but not in RMA. The effect of Y-27632 on the calcium signal was unaffected by cytochalasin-D. ROCK activation in noradrenaline-stimulated arteries was confirmed by the inhibition of myosin light chain phosphorylation by Y-27632. Moreover, noradrenaline-induced calcium signaling was similarly inhibited by nimodipine in aorta, SMA and RMA, but nimodipine sensitivity of the contraction increased from the aorta to the RMA, suggesting that the contraction was controlled by different sources of calcium. In pressurized RMA, Y-27632 and H-1152 depressed pressure-induced calcium responses and abolished myogenic contraction. These results stress the important differences in calcium signaling between conductance and resistance arteries.
DOI: 10.6084/m9.figshare.5123800
title: Supplementary Material for: Nutrient-Based Therapies for Bipolar Disorder: A Systematic Review

description: <b><i>Background:</i></b> Pharmacotherapy is the first line of treatment for bipolar disorder, but many patients continue to experience persistent subthreshold symptoms. Alternative adjunct treatments, including nutritional therapies, may have the potential to alleviate residual symptoms and improve the outcomes of standard pharmacotherapy. The aim of this paper is to critically review the current clinical evidence and mechanisms of action of nutrient-based therapies alone or in combination with commonly used pharmacotherapies for mania and bipolar depression. <b><i>Methods:</i></b> We conducted a Medline search for clinical trials conducted with humans, published in English from 1960 to 2012 using nutritional supplements such as n–3, chromium, inositol, choline, magnesium, folate and tryptophan alone or in combination with pharmacotherapies for the treatment of bipolar disorder. <b><i>Results:</i></b> Preliminary data yields conflicting but mainly positive evidence for the use of n–3 fatty acids and chromium in the treatment of bipolar depression. Limited evidence found that inositol may be helpful for bipolar depression, but larger sample sizes are needed. Preliminary randomized, controlled trials suggest that choline, magnesium, folate and tryptophan may be beneficial for reducing symptoms of mania. <b><i>Conclusions:</i></b> Given the potential public health impact of identifying adjunct treatments that improve psychiatric as well as physical health outcomes, nutritional treatments appear promising for the management of bipolar disorder but require further study.
DOI: 10.6084/m9.figshare.5123791
title: Supplementary Material for: What Is the Best Sequential Treatment Strategy in the Treatment of Depression? Adding Pharmacotherapy to Psychotherapy or Vice Versa?

description: <b><i>Background:</i></b> Insufficient response to monotreatment for depression is a common phenomenon in clinical practice. Even so, evidence indicating how to proceed in such cases is sparse. <b><i>Methods:</i></b> This study looks at the second phase of a sequential treatment algorithm, in which 103 outpatients with moderately severe depression were initially randomized to either short-term supportive psychodynamic therapy (PDT) or antidepressants. Patients who reported less than 30% symptom improvement after 8 weeks were offered combined treatment. Outcome measures were the Hamilton Depression Rating Scale (HAM-D), the Clinical Global Impression of Severity and Improvement, the SCL-90 depression subscale and the EuroQOL questionnaire. <b><i>Results:</i></b> Despite being nonresponsive, about 40% of patients preferred to continue with monotherapy. At treatment termination, patients initially randomized to PDT had improved more than those initially receiving antidepressants, as indicated by the HAM-D and the EuroQOL, independently of whether the addition was accepted or not. <b><i>Conclusions:</i></b> Starting with psychotherapy may be preferable in mildly and moderately depressed outpatients. For patients who receive either PDT or antidepressants, combined therapy after early nonresponse seems to be helpful. Nevertheless, this sequential strategy is not always preferred by patients.
DOI: 10.6084/m9.figshare.5123794
title: Supplementary Material for: Cerebrospinal Fluid β-Amyloid Turnover in the Mouse, Dog, Monkey and Human Evaluated by Systematic Quantitative Analyses

description: <b><i>Background:</i></b> Reducing brain β-amyloid (Aβ) via inhibition of β-secretase, or inhibition/modulation of γ-secretase, has been widely pursued as a potential disease-modifying treatment for Alzheimer's disease. Compounds that act through these mechanisms have been screened and characterized with Aβ lowering in the brain and/or cerebrospinal fluid (CSF) as the primary pharmacological end point. Interpretation and translation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship for these compounds is complicated by the relatively slow Aβ turnover process in these compartments. <b><i>Objective:</i></b> To understand Aβ turnover kinetics in preclinical species and humans. <b><i>Methods:</i></b> We collected CSF Aβ dynamic data after β- or γ-secretase inhibitor treatment from in-house experiments and the public domain, and analyzed the data using PK/PD modeling to obtain CSF Aβ turnover rates (k<sub>out</sub>) in the mouse, dog, monkey and human. <b><i>Results:</i></b> The k<sub>out</sub> for CSF Aβ40 follows allometry (k<sub>out</sub> = 0.395 × body weight<sup>-0.351</sup>). The k<sub>out</sub> for CSF Aβ40 is approximately 2-fold higher than the turnover of CSF in rodents, but in higher species, the two are comparable. <b><i>Conclusion:</i></b> The turnover of CSF Aβ40 was systematically examined, for the first time, in multiple species through quantitative modeling of multiple data sets. Our result suggests that the clearance mechanisms for CSF Aβ in rodents may be different from those in the higher species. The understanding of Aβ turnover has considerable implications for the discovery and development of Aβ-lowering therapeutics, as illustrated from the perspectives of preclinical PK/PD characterization and preclinical-to-clinical translation.
DOI: 10.6084/m9.figshare.5123797.v1
title: Supplementary Material for: Different Effect of Rho Kinase Inhibition on Calcium Signaling in Rat Isolated Large and Small Arteries

description: In addition to its role in the regulation of artery contraction, Rho kinase (ROCK) was reported to be involved in the cytosolic calcium response to vasoconstrictor agonists in rat aorta and superior mesenteric artery (SMA). However, it remains to be determined whether ROCK also contributes to calcium signaling in resistance arteries, which play a major role in blood pressure regulation. The investigation of the effect of ROCK inhibition on the calcium and contractile responses of rat resistance mesenteric artery (RMA), in comparison with aorta and SMA, indicated that the calcium response to noradrenaline was inhibited by the ROCK inhibitor Y-27632 in aorta and SMA but not in RMA. The effect of Y-27632 on the calcium signal was unaffected by cytochalasin-D. ROCK activation in noradrenaline-stimulated arteries was confirmed by the inhibition of myosin light chain phosphorylation by Y-27632. Moreover, noradrenaline-induced calcium signaling was similarly inhibited by nimodipine in aorta, SMA and RMA, but nimodipine sensitivity of the contraction increased from the aorta to the RMA, suggesting that the contraction was controlled by different sources of calcium. In pressurized RMA, Y-27632 and H-1152 depressed pressure-induced calcium responses and abolished myogenic contraction. These results stress the important differences in calcium signaling between conductance and resistance arteries.
DOI: 10.6084/m9.figshare.5123800.v1
title: Supplementary Material for: Nutrient-Based Therapies for Bipolar Disorder: A Systematic Review

description: <b><i>Background:</i></b> Pharmacotherapy is the first line of treatment for bipolar disorder, but many patients continue to experience persistent subthreshold symptoms. Alternative adjunct treatments, including nutritional therapies, may have the potential to alleviate residual symptoms and improve the outcomes of standard pharmacotherapy. The aim of this paper is to critically review the current clinical evidence and mechanisms of action of nutrient-based therapies alone or in combination with commonly used pharmacotherapies for mania and bipolar depression. <b><i>Methods:</i></b> We conducted a Medline search for clinical trials conducted with humans, published in English from 1960 to 2012 using nutritional supplements such as n–3, chromium, inositol, choline, magnesium, folate and tryptophan alone or in combination with pharmacotherapies for the treatment of bipolar disorder. <b><i>Results:</i></b> Preliminary data yields conflicting but mainly positive evidence for the use of n–3 fatty acids and chromium in the treatment of bipolar depression. Limited evidence found that inositol may be helpful for bipolar depression, but larger sample sizes are needed. Preliminary randomized, controlled trials suggest that choline, magnesium, folate and tryptophan may be beneficial for reducing symptoms of mania. <b><i>Conclusions:</i></b> Given the potential public health impact of identifying adjunct treatments that improve psychiatric as well as physical health outcomes, nutritional treatments appear promising for the management of bipolar disorder but require further study.
DOI: 10.6084/m9.figshare.5123803.v1
title: Supplementary Material for: Predicting Survival of Patients with Amyotrophic Lateral Sclerosis at Presentation: A 15-Year Experience

description: <b><i>Objective:</i></b> To describe the clinical features at first evaluation that best predict survival of the amyotrophic lateral sclerosis (ALS) population from the Salpêtrière Hospital between 1995 and 2009. <b><i>Methods:</i></b> Data are collected and entered into a clinical database from all patients seen at the Paris ALS Center. Variables analyzed were demographic and baseline information, strength testing (manual muscle testing; 1995-2009), the revised ALS Functional Rating Scale (ALSFRS-R; 2002-2009) and survival status. The χ<sup>2</sup> test and ANOVA assessed differences in variables by region and across time period. Univariate and multivariate Cox proportional hazards models determined which variables best predicted survival. Flexible modeling of continuous predictors (splines) assessed trends in survival for different variables. <b><i>Results:</i></b> 3,885 patients with ALS were seen in 1995-2009, of whom 2,037 had ALSFRS-R scores. Age, weight, strength, and site of onset varied by region of residence. The proportion of patients living outside Paris, the time to first visit, patient age, and motor function differed across time periods. In Cox models, site of onset, time to first visit greater than 18 months, strength and the year of visit after 2006 predicted survival (all p values &lt;0.0001). Compared to patients first seen between 1999 and 2002, the hazard ratio of death was 1.04 (95% CI = 0.95-1.14) for 2003-2006, and 0.76 (95% CI = 0.66-0.87) after 2006, while adjusting for other predictors of survival. The use of noninvasive ventilation increased during 2004-2008 from 16 to 51% of patients. <b><i>Conclusions:</i></b> Older age, bulbar onset, shorter delay to first visit and poor motor function at first visit predicted shorter survival rates in this large center-based sample from France, showing marked consistency across time and region of residence. Survival improved after 2006, concurrent with increasing rates of noninvasive ventilation use. Clinicopathologic correlation could better define subgroups, but identification of etiologies may be needed to elucidate individual forms of ALS with unique survival patterns.