cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5126539
title: Supplementary Material for: Circulating Matrix Metalloproteinase-9 Level Is Associated with Cerebral White Matter Hyperintensities in Non-Stroke Individuals

description: <b><i>Backgrounds:</i></b> The pathogenesis of cerebral white matter hyperintensities (WMH) has been poorly understood. Our aim was to investigate the association of circulating proteins, the biomarkers of inflammation, blood-brain barrier (BBB) dysfunction, and thrombosis with WMH in non-stroke individuals. <b><i>Methods:</i></b> Demographic, laboratory, and brain magnetic resonance imaging parameters were prospectively analyzed in 137 subjects. The relationship between plasma interleukin-6, tumor necrosis factor-α, matrx-metalloproteinase-9 (MMP-9), plasminogen activator inhibitor-1 and overt WMH (Fazekas grading score ≥2) was analyzed. <b><i>Results:</i></b> In univariate analysis, old age, high blood pressure, history of hypertension, and elevated plasma MMP-9 level were associated with overt WMH. In multivariate analysis, plasma MMP-9 still maintained a significant association with WMH. Plasma MMP-9 level was weakly but significantly associated with WMH volume (r = 0.232, p = 0.006). All the other circulating proteins examined failed to demonstrate a significant relationship with WMH. <b><i>Conclusions:</i></b> Plasma MMP-9 is associated with pathophysiology of WMH development.
DOI: 10.6084/m9.figshare.5126542
title: Supplementary Material for: A Candidate Gene Association Study Further Corroborates Involvement of Contactin Genes in Autism

description: Although autism spectrum disorder (ASD) shows a high degree of heritability, only a few mutated genes and mostly de novo copy number variations (CNVs) with a high phenotypic impact have as yet been identified. In families with multiple ASD patients, transmitted CNVs often do not appear to cosegregate with disease. Therefore, also transmitted single nucleotide variants which escape detection if genetic analyses were limited to CNVs may contribute to disease risk. In several studies of ASD patients, CNVs covering at least one gene of the contactin gene family were found. To determine whether there is evidence for a contribution of transmitted variants in contactin genes, a cohort of 67 ASD patients and a population-based reference of 117 healthy individuals, who were not related to the ASD families, were compared. In total, 1,648 SNPs, spanning 12.1 Mb of genomic DNA, were examined. After Bonferroni correction for multiple testing, the strongest signal was found for a SNP located within the <i>CNTN5</i> gene (rs6590473 [G], p = 4.09 × 10<sup>-7</sup>; OR = 3.117; 95% CI = 1.603-6.151). In the ASD cohort, a combination of risk alleles of SNPs in <i>CNTN6 </i>(rs9878022 [A]; OR = 3.749) and in <i>CNTNAP2 </i>(rs7804520 [G]; OR = 2.437) was found more frequently than would be expected under random segregation, albeit this association was not statistically significant. The latter finding is consistent with a polygenic disease model in which multiple mutagenic mechanisms, operating<b> </b>concomitantly, elicit the ASD phenotype. Altogether, this study corroborates the possible involvement of contactins in ASD, which has been indicated by earlier studies of CNVs.
DOI: 10.6084/m9.figshare.5126536
title: Supplementary Material for: Using Gene Expression to Improve the Power of Genome-Wide Association Analysis

description: <b><i>Background/Aims:</i></b> Genome-wide association (GWA) studies have reported susceptible regions in the human genome for many common diseases and traits; however, these loci only explain a minority of trait heritability. To boost the power of a GWA study, substantial research endeavors have been focused on integrating other available genomic information in the analysis. Advances in high through-put technologies have generated a wealth of genomic data and made combining SNP and gene expression data become feasible. <b><i>Results:</i></b> In this paper, we propose a novel procedure to incorporate gene expression information into GWA analysis. This procedure utilizes weights constructed by gene expression measurements to adjust p values from a GWA analysis. Results from simulation analyses indicate that the proposed procedures may achieve substantial power gains, while controlling family-wise type I error rates at the nominal level. To demonstrate the implementation of our proposed approach, we apply the weight adjustment procedure to a GWA study on serum interferon-regulated chemokine levels in systemic lupus erythematosus patients. The study results can provide valuable insights for the functional interpretation of GWA signals. <b><i>Availability:</i></b> The R source code for implementing the proposed weighting procedure is available at http://www.biostat.umn.edu/∼yho/research.html.
DOI: 10.6084/m9.figshare.5126539.v1
title: Supplementary Material for: Circulating Matrix Metalloproteinase-9 Level Is Associated with Cerebral White Matter Hyperintensities in Non-Stroke Individuals

description: <b><i>Backgrounds:</i></b> The pathogenesis of cerebral white matter hyperintensities (WMH) has been poorly understood. Our aim was to investigate the association of circulating proteins, the biomarkers of inflammation, blood-brain barrier (BBB) dysfunction, and thrombosis with WMH in non-stroke individuals. <b><i>Methods:</i></b> Demographic, laboratory, and brain magnetic resonance imaging parameters were prospectively analyzed in 137 subjects. The relationship between plasma interleukin-6, tumor necrosis factor-α, matrx-metalloproteinase-9 (MMP-9), plasminogen activator inhibitor-1 and overt WMH (Fazekas grading score ≥2) was analyzed. <b><i>Results:</i></b> In univariate analysis, old age, high blood pressure, history of hypertension, and elevated plasma MMP-9 level were associated with overt WMH. In multivariate analysis, plasma MMP-9 still maintained a significant association with WMH. Plasma MMP-9 level was weakly but significantly associated with WMH volume (r = 0.232, p = 0.006). All the other circulating proteins examined failed to demonstrate a significant relationship with WMH. <b><i>Conclusions:</i></b> Plasma MMP-9 is associated with pathophysiology of WMH development.
DOI: 10.6084/m9.figshare.5126542.v1
title: Supplementary Material for: A Candidate Gene Association Study Further Corroborates Involvement of Contactin Genes in Autism

description: Although autism spectrum disorder (ASD) shows a high degree of heritability, only a few mutated genes and mostly de novo copy number variations (CNVs) with a high phenotypic impact have as yet been identified. In families with multiple ASD patients, transmitted CNVs often do not appear to cosegregate with disease. Therefore, also transmitted single nucleotide variants which escape detection if genetic analyses were limited to CNVs may contribute to disease risk. In several studies of ASD patients, CNVs covering at least one gene of the contactin gene family were found. To determine whether there is evidence for a contribution of transmitted variants in contactin genes, a cohort of 67 ASD patients and a population-based reference of 117 healthy individuals, who were not related to the ASD families, were compared. In total, 1,648 SNPs, spanning 12.1 Mb of genomic DNA, were examined. After Bonferroni correction for multiple testing, the strongest signal was found for a SNP located within the <i>CNTN5</i> gene (rs6590473 [G], p = 4.09 × 10<sup>-7</sup>; OR = 3.117; 95% CI = 1.603-6.151). In the ASD cohort, a combination of risk alleles of SNPs in <i>CNTN6 </i>(rs9878022 [A]; OR = 3.749) and in <i>CNTNAP2 </i>(rs7804520 [G]; OR = 2.437) was found more frequently than would be expected under random segregation, albeit this association was not statistically significant. The latter finding is consistent with a polygenic disease model in which multiple mutagenic mechanisms, operating<b> </b>concomitantly, elicit the ASD phenotype. Altogether, this study corroborates the possible involvement of contactins in ASD, which has been indicated by earlier studies of CNVs.
DOI: 10.6084/m9.figshare.5126548.v1
title: Supplementary Material for: The Silencing of N-myc Downstream-Regulated Gene-1 in an Orthotopic Pancreatic Cancer Model Leads to More Aggressive Tumor Growth and Metastases

description: <b><i>Background:</i></b> The understanding of molecular mechanisms leading to poor prognosis in pancreatic cancer may help develop treatment options. N-myc downstream-regulated gene-1 (NDRG1) has been correlated to better prognosis in pancreatic cancer. Therefore, we thought to analyze how the loss of NDRG1 affects progression in an orthotopic xenograft animal model of recurrence. <b><i>Methods:</i></b> Capan-1 cells were silenced for NDRG1 (C<sup>sil</sup>) or transfected with scrambled shRNA (C<sup>scr</sup>) and compared for anchorage-dependent and anchorage-independent growth, invasion and tube formation in vitro. In an orthotopic xenograft model of recurrence tumors were grown in the pancreatic tail. The effect of NDRG1 silencing was evaluated on tumor size and metastasis. <b><i>Results:</i></b> The silencing of NDRG1 in Capan-1 cells leads to more aggressive tumor growth and metastasis. We found faster cell growth, double count of invaded cells and 1.8-fold increase in tube formation in vitro. In vivo local tumors were 5.9-fold larger (p = 0.006) and the number of metastases was higher in animals with tumors silenced for NDRG1 primarily (3 vs. 1.1; p = 0.005) and at recurrence (3.3 vs. 0.9; p = 0.015). <b><i>Conclusion:</i></b> NDRG1 may be an interesting therapeutic target as its silencing in human pancreatic cancer cells leads to a phenotype with more aggressive tumor growth and metastasis.
DOI: 10.6084/m9.figshare.5126533
title: Supplementary Material for: (Epi)Genetic Analyses of Age-Related Macular Degeneration: Case-Control and Discordant Twin Studies

description: <b><i>Background/Aims:</i></b> Phenotypic discordance in monozygotic (MZ) twin pairs can have an epigenetic or genetic basis. Although age-related macular degeneration (AMD) has a strong genetic component, few studies have addressed its epigenetic basis. <b><i>Methods:</i></b> Using SNP arrays, we evaluated differences in copy number variation (CNV) and allele-specific methylation (ASM) patterns (via methyl-sensitive restriction enzyme digestion of DNA) in MZ twin pairs from the US Twin Study of AMD. Further analyses examined the relationship between ASM and CNVs with AMD by both case/control analysis of ASM at candidate regions and by analysis of ASM and CNVs in twins discordant for AMD. <b><i>Results:</i></b> The frequency of ASM sites differs between cases and controls in regions surrounding the AMD candidate genes <i>CFH</i>, <i>C2 </i>and <i>CFB</i>. While ASM patterns show a substantial dependence on local sequence polymorphisms, we observed dissimilar patterns of ASM between MZ twins. The genes closest to the sites where discordant MZ twins have dissimilar patterns of ASM are enriched for genes implicated in gliosis, a process associated with neovascular AMD. Similar twin-based analyses revealed no AMD-associated CNVs. <b><i>Conclusions:</i></b> Our results provide evidence of epigenetic influences beyond the known genetic susceptibility and implicate inflammatory responses and gliosis in the etiology of AMD.
DOI: 10.6084/m9.figshare.5126545.v1
title: Supplementary Material for: Infarct Patterns, Collaterals and Likely Causative Mechanisms of Stroke in Symptomatic Intracranial Atherosclerosis

description: <b><i>Background:</i></b> There are limited data on the specific mechanisms of stroke in patients with intracranial atherosclerotic stenosis (ICAS). We undertook this study to describe infarct patterns and likely mechanisms of stroke in a large cohort of patients with ICAS, and to evaluate the relationship of these infarct patterns to angiographic features (collaterals, stenosis location and stenosis severity). <b><i>Methods:</i></b> We evaluated infarct patterns in the territory of a stenotic intracranial artery on neuroimaging performed at baseline and during follow-up if a recurrent stroke occurred in patients enrolled in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial. We defined the likely mechanism of stroke (artery-to-artery embolism, perforator occlusion, hypoperfusion or mixed) according to the site of ICAS and based on the infarct patterns on neuroimaging. Collaterals were assessed using American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grades, and stenosis severity using the WASID trial's measurement technique. We evaluated the association of infarct patterns with angiographic features using χ<sup>2</sup> tests. <b><i>Results:</i></b> The likely mechanisms of stroke based on the infarct patterns at baseline in the 136 patients included in the study were artery-to-artery embolism (n = 69; 50.7%), perforator occlusion (n = 34; 25%), hypoperfusion (n = 12; 8.8%) and mixed (n = 21; 15.5%). Perforator-occlusive infarcts were more frequent in the posterior circulation, and mixed patterns were more prevalent in the anterior circulation (both p &lt; 0.01). Most of the mixed patterns in the anterior circulation combined small pial or scattered multiple cortical infarcts with infarcts in border-zone regions, especially the cortical ones. Isolated border-zone infarcts were not significantly associated with a poor grading for collaterals or the severity of stenosis. Among 47 patients with a recurrent infarct during follow-up, the infarct patterns suggested an artery-to-artery embolic mechanism in 29 (61.7%). <b><i>Conclusions:</i></b> Artery-to-artery embolism is probably the most common mechanism of stroke in both the anterior and the posterior circulations in patients with ICAS. An extension of intracranial atherosclerosis at the site of stenosis into adjacent perforators also appears to be a common mechanism of stroke, particularly in the posterior circulation, whereas hypoperfusion as the sole mechanism is relatively uncommon. Further research is important to accurately establish the specific mechanisms of stroke in patients with ICAS, since preliminary data suggest that the underlying mechanism of stroke is an important determinant of prognosis.
DOI: 10.6084/m9.figshare.5126521
title: Supplementary Material for: Hypoxic/Ischemic and Infectious Events Have Cumulative Effects on the Risk of Cerebral Palsy in Very-Low-Birth-Weight Preterm Infants

description: <b><i>Background:</i></b> Hypoxia/ischemia and inflammation are two major mechanisms for cerebral palsy (CP) in preterm infants. <b><i>Objective:</i></b> To investigate whether hypoxia/ischemia- and infection-related events in the perinatal and neonatal periods had cumulative effects on CP risk in very-low-birth-weight (VLBW) premature infants. <b><i>Methods:</i></b> From 1995 to 2005, 5,807 VLBW preterm infants admitted to Taiwan hospitals were enrolled.<b> </b>The cumulative effects of hypoxic/ischemic and infectious events during the perinatal and neonatal periods on CP risk at corrected age 24 months were analyzed. <b><i>Results:</i></b> Of the 4,355 infants with 24-month follow-up, 457 (10.5%) had CP. The CP group had significantly higher incidences of hypoxia/ischemia-related events in the perinatal and neonatal periods, and sepsis in the neonatal period than the normal group. Three hypoxic/ischemic events, including birth cardiopulmonary resuscitation (OR 2.25; 95% CI 1.81-2.82), patent ductus arteriosus (PDA) ligation (2.94; 1.35-5.75) and chronic lung disease (3.14; 2.61-3.85) had the most significant contribution to CP. Relative to CP risk for infants with neither the three hypoxic/ischemic events nor sepsis, the CP odds increased 1.98-, 2.26- and 2.15-fold for infants with birth cardiopulmonary resuscitation, PDA ligation and chronic lung disease, respectively; while the combination with sepsis further increased the odds to 3.18-, 3.83- and 3.25-fold, respectively. Using the three hypoxic/ischemic events plus sepsis, CP rates were 10.0, 16.7, 26.7, 40.0 and 54.7% for infants with none, one, two, three and four events, respectively. <b><i>Conclusions:</i></b> Hypoxic/ischemic and infectious events across the perinatal and neonatal periods exerted cumulative effects on CP risk in VLBW premature infants.
DOI: 10.6084/m9.figshare.5126524
title: Supplementary Material for: The Human Cathelicidin LL-37 Host Defense Peptide Upregulates Tight Junction-Related Proteins and Increases Human Epidermal Keratinocyte Barrier Function

description: Both psoriasis and atopic dermatitis (AD) are not only associated with an impaired stratum corneum barrier, but also with abnormal expression of the tight junction (TJ) proteins. Because host defense peptides, including LL-37, are overexpressed in lesional psoriatic skin but are downregulated in lesional AD skin, we hypothesized that LL-37 might regulate the TJ function in keratinocytes. We demonstrated that LL-37 selectively increased the expression of several claudins and occludin, and enhanced their membrane distribution. Furthermore, LL-37 elevated the transepithelial electrical resistance while reducing the paracellular permeability of keratinocyte layers, and this activity was weakened by the claudin inhibitor ochratoxin A. A characterization of the molecular mechanism underlying the regulation of the TJ barrier by LL-37 revealed that LL-37 induced the activation of the Rac1, atypical PKC, glycogen synthase kinase-3 and PI3K pathways, and the specific inhibition of these pathways reversed the LL-37-mediated regulation of TJ function. In addition, LL-37 enhanced the expression of differentiation markers under the control of ochratoxin A, suggesting an association between LL-37-induced TJ function and keratinocyte differentiation. These data provide novel evidence that, in addition to its antimicrobial and other immunoregulatory functions, LL-37 contributes to cutaneous immunity by strengthening the skin's barrier function.
DOI: 10.6084/m9.figshare.5126527
title: Supplementary Material for: Detection of <b><i>Dehalococcoides</i></b> spp. by Peptide Nucleic Acid Fluorescent in situ Hybridization

description: Chlorinated solvents including tetrachloroethene (perchloroethene and trichloroethene), are widely used industrial solvents. Improper use and disposal of these chemicals has led to a widespread contamination. Anaerobic treatment technologies that utilize <i>Dehalococcoides</i> spp. can be an effective tool to remediate these contaminated sites. Therefore, the aim of this study was to develop, optimize and validate peptide nucleic acid (PNA) probes for the detection of <i>Dehalococcoides</i> spp. in both pure and mixed cultures. PNA probes were designed by adapting previously published DNA probes targeting the region of the point mutations described for discriminating between the <i>Dehalococcoides</i> spp. strain CBDB1 and strain 195 lineages. Different fixation, hybridization and washing procedures were tested. The results indicated that the PNA probes hybridized specifically and with a high sensitivity to their corresponding lineages, and that the PNA probes developed during this work can be used in a duplex assay to distinguish between strain CBDB1 and strain 195 lineages, even in complex mixed cultures. This work demonstrates the effectiveness of using PNA fluorescence in situ hybridization to distinguish between two metabolically and genetically distinct <i>Dehalococcoides</i> strains, and they can have strong implications in the monitoring and differentiation of <i>Dehalococcoides</i> populations in laboratory cultures and at contaminated sites.
DOI: 10.6084/m9.figshare.5126530
title: Supplementary Material for: Implementation of a Cost-Accounting Model in a Biobank: Practical Implications

description: Given the state of global economy, cost measurement and control have become increasingly relevant over the past years. The scarcity of resources and the need to use these resources more efficiently is making cost information essential in management, even in non-profit public institutions. Biobanks are no exception. However, no empirical experiences on the implementation of cost accounting in biobanks have been published to date. The aim of this paper is to present a step-by-step implementation of a cost-accounting tool for the main production and distribution activities of a real/active biobank, including a comprehensive explanation on how to perform the calculations carried out in this model. Two mathematical models for the analysis of (1) production costs and (2) request costs (order management and sample distribution) have stemmed from the analysis of the results of this implementation, and different theoretical scenarios have been prepared. Global analysis and discussion provides valuable information for internal biobank management and even for strategic decisions at the research and development governmental policies level.
DOI: 10.6084/m9.figshare.5126518
title: Supplementary Material for: Quantifying the Vestibulo-Ocular Reflex with Video-Oculography: Nature and Frequency of Artifacts

description: Video-oculography devices are now used to quantify the vestibulo-ocular reflex (VOR) at the bedside using the head impulse test (HIT). Little is known about the impact of disruptive phenomena (e.g. corrective saccades, nystagmus, fixation losses, eye-blink artifacts) on quantitative VOR assessment in acute vertigo. This study systematically characterized the frequency, nature, and impact of artifacts on HIT VOR measures.<b> </b>From a prospective study of 26 patients with acute vestibular syndrome (16 vestibular neuritis, 10 stroke), we classified findings using a structured coding manual. Of 1,358 individual HIT traces, 72% had abnormal disruptive saccades, 44% had at least one artifact, and 42% were uninterpretable. Physicians using quantitative recording devices to measure head impulse VOR responses for clinical diagnosis should be aware of the potential impact of disruptive eye movements and measurement artifacts. i 2014 S. Karger AG, Basel
DOI: 10.6084/m9.figshare.5126530.v1
title: Supplementary Material for: Implementation of a Cost-Accounting Model in a Biobank: Practical Implications

description: Given the state of global economy, cost measurement and control have become increasingly relevant over the past years. The scarcity of resources and the need to use these resources more efficiently is making cost information essential in management, even in non-profit public institutions. Biobanks are no exception. However, no empirical experiences on the implementation of cost accounting in biobanks have been published to date. The aim of this paper is to present a step-by-step implementation of a cost-accounting tool for the main production and distribution activities of a real/active biobank, including a comprehensive explanation on how to perform the calculations carried out in this model. Two mathematical models for the analysis of (1) production costs and (2) request costs (order management and sample distribution) have stemmed from the analysis of the results of this implementation, and different theoretical scenarios have been prepared. Global analysis and discussion provides valuable information for internal biobank management and even for strategic decisions at the research and development governmental policies level.