cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5122666
title: Supplementary Material for: Developmental Activation of the Proteolipid Protein Promoter Transgene in Neuronal and Oligodendroglial Cells of Neostriatum in Mice

description: Prior studies suggest that non-canonical proteolipid protein <i>(PLP)</i> gene expression occurs during development in non-myelinating neurons as well as myelinating oligodendroglia in mammalian brain. To assess this possibility in neostriatum, a region of uncertain <i>PLP</i> gene expression in neurons, morphological and electrophysiological tools were used to determine phenotypes of cells with activation of a <i>PLP</i> promoter transgene during the early postnatal period in mice. <i>PLP</i> gene expression is evident in both neuronal and oligodendroglial phenotypes in developing neostriatum, a conclusion based on three novel observations: (1) An enhanced green fluorescent protein (EGFP) reporter of <i>PLP</i> promoter activation was localized in two distinct populations of cells, which exhibit collective, developmental differences of morphological and electrophysiological characteristics in accord with neuronal and oligodendroglial phenotypes of neostriatal cells found during the early postnatal period in both transgenic and wild-type mice. (2) The EGFP reporter of <i>PLP</i> promoter activation was appropriately positioned to serve as a regulator of <i>PLP</i> gene expression. It colocalized with native PLP proteins in both neuronal and oligodendroglial phenotypes; however, only soma-restricted PLP protein isoforms were found in the neuronal phenotype, while classic and soma-restricted PLP protein isoforms were found in the oligodendroglial phenotype. (3) As shown by EGFP reporter, <i>PLP</i> promoter activation was placed to regulate <i>PLP</i> gene expression in only one neuronal phenotype among the several that constitute neostriatum. It was localized in medium spiny neurons, but not large aspiny neurons. These outcomes have significant implications for the non-canonical functional roles of <i>PLP</i> gene expression in addition to myelinogenesis in mammalian brain, and are consistent with potentially independent pathologic loci in neurons during the course of human mutational disorders of <i>PLP</i> gene expression.
DOI: 10.6084/m9.figshare.5122663
title: Supplementary Material for: Dynamic ‘Spot Sign’ Resolution following INR Correction in a Patient with Warfarin-Associated Intracerebral Hemorrhage

description: Hematoma expansion in intracerebral hemorrhage is associated with poor clinical outcome. The ‘spot sign’ is a radiological marker that is associated with hematoma expansion, and thought to represent active extravasation of contrast. This case demonstrates the use of dynamic CT angiography in identifying the time-dependent appearance of a spot sign in a patient with warfarin-associated intracerebral hemorrhage. Repeat imaging is also presented which verified cessation of the spot sign after INR correction.
DOI: 10.6084/m9.figshare.5122675.v1
title: Supplementary Material for: Inhibition of Microglial Activation Protects Hippocampal Neurogenesis and Improves Cognitive Deficits in a Transgenic Mouse Model for Alzheimer’s Disease

description: <b><i>Background:</i></b> Activated microglia with macrophage-like functions invade and surround β-amyloid (Aβ) plaques in Alzheimer’s disease (AD), possibly contributing to the turnover of Aβ, but they can also secrete proinflammatory factors that may be involved in the pathogenesis of AD. Microglia are known to modulate adult hippocampal neurogenesis. <b><i>Objectives/Methods:</i></b> To determine the role of microglia on neurogenesis in brains with Aβ pathology, we inhibited microglial activation with the tetracycline derivative minocycline in doubly transgenic mice expressing mutant human amyloid precursor protein (APP) and mutant human presenilin-1 (PS1). <b><i>Results:</i></b> Minocycline increased the survival of new dentate granule cells in APP/PS1 mice indicated by more BrdU+/NeuN+ cells as compared to vehicle-treated transgenic littermates, accompanied by improved behavioral performance in a hippocampus-dependent learning task. Both brain levels of Aβ and Aβ-related morphological deficits in the new neurons labeled with GFP-expressing retrovirus were unaffected in minocycline-treated mice. <b><i>Conclusions:</i></b> These results suggest a role for microglia in Aβ-related functional deficits and in suppressing the survival of new neurons, and show that modulation of microglial function with minocycline can protect hippocampal neurogenesis in the presence of Aβ pathology.
DOI: 10.6084/m9.figshare.5122660
title: Supplementary Material for: Changes in Fetal Circulation Associated with Congenital Heart Disease and Their Effects on Fetal Growth

description: <i>Objective:</i> Our aim was to investigate the association between fetal growth and cerebrovascular resistance in fetuses with congenital heart disease (CHD). <i>Methods:</i> Fetal echocardiography was performed to measure the biparietal diameter, abdominal circumference, femur length, estimated fetal body weight, middle cerebral artery (MCA) resistance index (RI) and umbilical artery (UA) RI in 44 fetuses with CHD and 140 normal fetuses at a gestational age of 28–34 weeks. <i>Results:</i> Fetuses with CHD exhibited significantly lower values for femur length, estimated fetal body weight at the third trimester, body weight, length, and chest circumference at birth than normal controls. The percentages of fetuses showing MCA RI values &lt;10th percentile and UA RI values &gt;90th percentile were significantly higher in the CHD group than in the control group. However, there were no significant differences in any biometric parameters measured between cases with MCA RI values ≧10th percentile and values &lt;10th percentile. <i>Conclusions:</i> Growth restriction and blood flow changes were observed significantly more frequently in fetuses with CHD than in those without CHD. Further studies are necessary to clarify the association between fetal growth and dynamic changes in fetal circulation.
DOI: 10.6084/m9.figshare.5122666.v1
title: Supplementary Material for: Developmental Activation of the Proteolipid Protein Promoter Transgene in Neuronal and Oligodendroglial Cells of Neostriatum in Mice

description: Prior studies suggest that non-canonical proteolipid protein <i>(PLP)</i> gene expression occurs during development in non-myelinating neurons as well as myelinating oligodendroglia in mammalian brain. To assess this possibility in neostriatum, a region of uncertain <i>PLP</i> gene expression in neurons, morphological and electrophysiological tools were used to determine phenotypes of cells with activation of a <i>PLP</i> promoter transgene during the early postnatal period in mice. <i>PLP</i> gene expression is evident in both neuronal and oligodendroglial phenotypes in developing neostriatum, a conclusion based on three novel observations: (1) An enhanced green fluorescent protein (EGFP) reporter of <i>PLP</i> promoter activation was localized in two distinct populations of cells, which exhibit collective, developmental differences of morphological and electrophysiological characteristics in accord with neuronal and oligodendroglial phenotypes of neostriatal cells found during the early postnatal period in both transgenic and wild-type mice. (2) The EGFP reporter of <i>PLP</i> promoter activation was appropriately positioned to serve as a regulator of <i>PLP</i> gene expression. It colocalized with native PLP proteins in both neuronal and oligodendroglial phenotypes; however, only soma-restricted PLP protein isoforms were found in the neuronal phenotype, while classic and soma-restricted PLP protein isoforms were found in the oligodendroglial phenotype. (3) As shown by EGFP reporter, <i>PLP</i> promoter activation was placed to regulate <i>PLP</i> gene expression in only one neuronal phenotype among the several that constitute neostriatum. It was localized in medium spiny neurons, but not large aspiny neurons. These outcomes have significant implications for the non-canonical functional roles of <i>PLP</i> gene expression in addition to myelinogenesis in mammalian brain, and are consistent with potentially independent pathologic loci in neurons during the course of human mutational disorders of <i>PLP</i> gene expression.
DOI: 10.6084/m9.figshare.5122669.v1
title: Supplementary Material for: Prothrombotic Gene Variants and Mortality after Cerebral Ischemia of Arterial Origin

description: <i>Background:</i> Several functional prothrombotic gene variants have been associated with cerebral ischemia and myocardial infarction. We hypothesized that such gene variants may also be associated with mortality after cerebral ischemia of arterial origin because of an increased risk of fatal vascular events. <i>Methods:</i> We performed a case-control study in 316 long-term survivors and 887 patients with recent cerebral ischemia of arterial origin. False discovery rate q values were calculated to account for multiple testing. The mean duration between occurrence of cerebral ischemia and DNA collection was 16.8 years in long-term survivors and 3.2 months in recent patients. <i>Results:</i> Two of 23 variants were associated with mortality: the 95Arg allele of the coagulation factor XIII subunit B (F13B) His95Arg variant (OR, 1.5 for Arg/Arg and His/Arg vs. His/His genotype; 95% CI, 1.1–2.2, q = 0.29) and the 4G allele of the plasminogen activator inhibitor-1 (PAI-1) 4G/5G variant (OR, 1.5 for 4G/4G and 5G/4G vs. 5G/5G genotype; 95% CI, 1.1–2.0, q = 0.29). Both associations disappeared after accounting for multiple testing. Data analysis restricted to recently deceased patients (n = 133) yielded similar results. <i>Conclusions:</i> In this hospital-based study none of 23 prothrombotic gene variants were associated with long-term mortality after cerebral ischemia of arterial origin. Prothrombotic gene variants do not appear to play an important role in long-term mortality after cerebral ischemia.
DOI: 10.6084/m9.figshare.5122654
title: Supplementary Material for: A Geographic Cline of Skull and Brain Morphology among Individuals of European Ancestry

description: <i>Background:</i> Human skull and brain morphology are strongly influenced by genetic factors, and skull size and shape vary worldwide. However, the relationship between specific brain morphology and genetically-determined ancestry is largely unknown. <i>Methods:</i> We used two independent data sets to characterize variation in skull and brain morphology among individuals of European ancestry. The first data set is a historical sample of 1,170 male skulls with 37 shape measurements drawn from 27 European populations. The second data set includes 626 North American individuals of European ancestry participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with magnetic resonance imaging, height and weight, neurological diagnosis, and genome-wide single nucleotide polymorphism (SNP) data. <i>Results:</i> We found that both skull and brain morphological variation exhibit a population-genetic fingerprint among individuals of European ancestry. This fingerprint shows a Northwest to Southeast gradient, is independent of body size, and involves frontotemporal cortical regions. <i>Conclusion:</i> Our findings are consistent with prior evidence for gene flow in Europe due to historical population movements and indicate that genetic background should be considered in studies seeking to identify genes involved in human cortical development and neuropsychiatric disease.
DOI: 10.6084/m9.figshare.5122657
title: Supplementary Material for: Focal Adhesion Kinase Regulates Neuronal Growth, Synaptic Plasticity and Hippocampus-Dependent Spatial Learning and Memory

description: The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase abundantly expressed in the mammalian brain and highly enriched in neuronal growth cones. Inhibitory and facilitatory activities of FAK on neuronal growth have been reported and its role in neuritic outgrowth remains controversial. Unlike other tyrosine kinases, such as the neurotrophin receptors regulating neuronal growth and plasticity, the relevance of FAK for learning and memory in vivo has not been clearly defined yet. A comprehensive study aimed at determining the role of FAK in neuronal growth, neurotransmitter release and synaptic plasticity in hippocampal neurons and in hippocampus-dependent learning and memory was therefore undertaken using the mouse model. Gain- and loss-of-function experiments indicated that FAK is a critical regulator of hippocampal cell morphology. FAK mediated neurotrophin-induced neuritic outgrowth and FAK inhibition affected both miniature excitatory postsynaptic potentials and activity-dependent hippocampal long-term potentiation prompting us to explore the possible role of FAK in spatial learning and memory in vivo. Our data indicate that FAK has a growth-promoting effect, is importantly involved in the regulation of the synaptic function and mediates in vivo hippocampus-dependent spatial learning and memory.
DOI: 10.6084/m9.figshare.5122648
title: Supplementary Material for: EX-HOM (EXome HOMozygosity): A Proof of Principle

description: <i>Objective:</i> We provide the proof of principle that exome sequencing of only two affected siblings born to first-cousin parents is capable of directly identifying a single candidate gene for an autosomal recessive disorder. This strategy, which we call EX-HOM (EXome HOMozygosity), combines in a single step the capacity of exome sequencing to identify all the coding variants present in a genome with the property of homozygosity mapping to limit the search for candidate genes to specific chromosomal regions. <i>Methods:</i> We sequenced the exomes of two siblings born to first-cousin parents affected with dysmyelinating leukodystrophy and spastic paraparesis caused by a mutation in <i>FA2H</i>. We used exome sequencing data to identify homozygous regions shared by the two affected siblings (EX-HOM regions), compared them with the regions of maximum LOD score obtained with SNP genotyping, and selected the candidate variants within. <i>Results:</i> We identified regions of shared homozygosity (&gt;1 Mb) accounting for about 290 Mb, containing only 3 candidate variants. Among these, the <i>FA2H</i> mutation remained the only plausible one. <i>Conclusion:</i> In single consanguineous pedigrees with a few affected sibs, EX-HOM can be a one-step approach to identify the candidate genetic defect, bypassing obstacles such as genetic heterogeneity and the need for large pedigrees.
DOI: 10.6084/m9.figshare.5122651
title: Supplementary Material for: Discordant Patterns of mtDNA and Ethno-Linguistic Variation in 14 Iranian Ethnic Groups

description: <i>Background/Aims:</i> Present-day Iran has long represented a natural hub for the expansion of human genes and cultures. That being so, the overlapping of prehistoric and more recent demographic events interacting at different time scales with geographical and cultural barriers has yielded a tangled patchwork of anthropological types within this narrow area. This study aims to comprehensively evaluate this ethnic mosaic by depicting a fine-grained picture of the Iranian mitochondrial landscape. <i>Methods:</i> mtDNA variability at both HVS-I and coding regions was surveyed in 718 unrelated individuals belonging to 14 Iranian ethnic groups characterized by different languages, religions and patterns of subsistence. <i>Results:</i> A discordant pattern of high ethno-linguistic and low mtDNA heterogeneity was observed for the whole examined Iranian sample. Geographical factors and cultural/linguistic differences actually represented barriers to matrilineal gene flow only for the Baloch, Lur from Yasouj, Zoroastrian and Jewish groups, for which unusual reduced levels of mtDNA variability and high inter-population distances were found. <i>Conclusion:</i> Deep rooting genealogies and endogamy in a few of the examined ethnic groups might have preserved ancestral lineages that can be representative of Proto-Indo-Iranian or prehistoric mitochondrial profiles which survived relatively recent external contributions to the Iranian gene pool.
DOI: 10.6084/m9.figshare.5122654.v1
title: Supplementary Material for: A Geographic Cline of Skull and Brain Morphology among Individuals of European Ancestry

description: <i>Background:</i> Human skull and brain morphology are strongly influenced by genetic factors, and skull size and shape vary worldwide. However, the relationship between specific brain morphology and genetically-determined ancestry is largely unknown. <i>Methods:</i> We used two independent data sets to characterize variation in skull and brain morphology among individuals of European ancestry. The first data set is a historical sample of 1,170 male skulls with 37 shape measurements drawn from 27 European populations. The second data set includes 626 North American individuals of European ancestry participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with magnetic resonance imaging, height and weight, neurological diagnosis, and genome-wide single nucleotide polymorphism (SNP) data. <i>Results:</i> We found that both skull and brain morphological variation exhibit a population-genetic fingerprint among individuals of European ancestry. This fingerprint shows a Northwest to Southeast gradient, is independent of body size, and involves frontotemporal cortical regions. <i>Conclusion:</i> Our findings are consistent with prior evidence for gene flow in Europe due to historical population movements and indicate that genetic background should be considered in studies seeking to identify genes involved in human cortical development and neuropsychiatric disease.
DOI: 10.6084/m9.figshare.5122645
title: Supplementary Material for: Including Additional Controls from Public Databases Improves the Power of a Genome-Wide Association Study

description: Though genome-wide association studies (GWAS) have identified numerous susceptibility loci for common diseases, their use is limited due to the expense of genotyping large cohorts of individuals. One potential solution is to use ‘additional controls’, or genotype data from control individuals deposited in public repositories. While this approach has been used by several groups, the genetically heterogeneous nature of the population of the United States makes this approach potentially problematic. We empirically investigated the utility of this approach in a US-based GWAS. In a small GWAS of pancreatic cancer in New York, we observed clear population structure differences relative to controls from the database of Genotypes and Phenotypes (dbGaP). When we conduct the GWAS using these additional controls, we find large inflation of the test statistic that is properly corrected by using eigenvectors from principal components analysis as covariates. To deal with errors introduced due to different sources, we propose simultaneously genotyping a small number of controls along with cases and then comparing this group to the additional controls. We show that removing SNPs that show differences between these control groups reduces false-positive findings. Thus, through an empirical approach, this report provides practical guidance for using additional controls from publicly available datasets.
DOI: 10.6084/m9.figshare.5122660.v1
title: Supplementary Material for: Changes in Fetal Circulation Associated with Congenital Heart Disease and Their Effects on Fetal Growth

description: <i>Objective:</i> Our aim was to investigate the association between fetal growth and cerebrovascular resistance in fetuses with congenital heart disease (CHD). <i>Methods:</i> Fetal echocardiography was performed to measure the biparietal diameter, abdominal circumference, femur length, estimated fetal body weight, middle cerebral artery (MCA) resistance index (RI) and umbilical artery (UA) RI in 44 fetuses with CHD and 140 normal fetuses at a gestational age of 28–34 weeks. <i>Results:</i> Fetuses with CHD exhibited significantly lower values for femur length, estimated fetal body weight at the third trimester, body weight, length, and chest circumference at birth than normal controls. The percentages of fetuses showing MCA RI values &lt;10th percentile and UA RI values &gt;90th percentile were significantly higher in the CHD group than in the control group. However, there were no significant differences in any biometric parameters measured between cases with MCA RI values ≧10th percentile and values &lt;10th percentile. <i>Conclusions:</i> Growth restriction and blood flow changes were observed significantly more frequently in fetuses with CHD than in those without CHD. Further studies are necessary to clarify the association between fetal growth and dynamic changes in fetal circulation.
DOI: 10.6084/m9.figshare.5122639
title: Supplementary Material for: Association of Primary Ovarian Insufficiency with a Specific Human Leukocyte Antigen Haplotype (A*24:02-C*03:03-B*35:01) in Japanese Women

description: Primary ovarian insufficiency (POI) is a heterogeneous condition defined by the triad of oligo/amenorrhea, elevated gonadotropins and estrogen deficiency in women under the age of 40 years. Although autoimmune abnormalities appear to be involved in the development of POI, there are only a few studies with respect to human leukocyte antigen (HLA). The objective of this study was to identify an HLA allele(s) and/or haplotype(s) constituting a susceptibility factor(s) for POI. We examined 83 Japanese women with apparently idiopathic isolated POI. For controls, Japanese HLA reference data registered in the HLA Laboratory were utilized. No significant association was found for a total of 94 alleles for HLA-A, B, C, DRB1, and DQB1 loci, after both stringent Bonferroni correction and less stringent Benjamini- Hochberg (B-H) correction for multiple comparisons. By contrast, of 86 haplotypes identified for MHC class I (HLA-A, B, and C) and 31 haplotypes detected for MHC class II (HLA-DRB1 and DQB1), a single haplotype (A*24:02-C*03:03-B*35:01) remained significant after Bonferroni and B-H corrections (frequency: 4.82% in women with POI and 1.06% in the control data; p = 0.00049). The results imply that a specific HLA haplotype (A*24:02-C*03:03-B*35:01) constitutes a susceptibility factor for apparently isolated POI in Japanese women.
DOI: 10.6084/m9.figshare.5122642
title: Supplementary Material for: A Method for Generating Selective DNA Probes for the Analysis of C-Negative Regions in Human Chromosomes

description: Linker-adapter polymerase chain reaction (LA-PCR) is among the most efficient techniques for whole genome DNA amplification. The key stage in LA-PCR is the hydrolysis of a DNA sample with restriction endonucleases, and the choice of a restriction endonuclease (or several endonucleases) determines the composition of DNA probes generated in LA-PCR. Computer analysis of the localization of the restriction sites in human genome has allowed us to propose an efficient technique for generating DNA probes by LA-PCR using the restriction endonucleases <i>Hae</i>III and <i>Rsa</i>I. In silico hydrolysis of human genomic DNA with endonucleases <i>Hae</i>III and <i>Rsa</i>I demonstrate that 100- to 1,000-bp DNA fragments are more abundant in the gene-rich regions. Applying in situ hybridization to metaphase chromosomes, we demonstrated that the produced DNA probes predominantly hybridized to the C-negative chromosomal regions, whereas the FISH signal was almost absent in the C-positive regions. The described protocol for generating DNA probes may be successfully used in subsequent cytogenetic analysis of the C-negative chromosomal regions.