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Search Results: 1 - 10 of 285848 matches for " Caroline C. W. Klaver "
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Analysis of Rare Variants in the C3 Gene in Patients with Age-Related Macular Degeneration
Maheswara R. Duvvari, Codrut C. Paun, Gabri?lle H. S. Buitendijk, Nicole T. M. Saksens, Elena B. Volokhina, Tina Ristau, Frederieke E. Schoenmaker-Koller, Johannes P. H. van de Ven, Joannes M. M. Groenewoud, Lambertus P. W. J. van den Heuvel, Albert Hofman, Sascha Fauser, André G. Uitterlinden, Caroline C. W. Klaver, Carel B. Hoyng, Eiko K. de Jong, Anneke I. den Hollander
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094165
Abstract: Age-related macular degeneration (AMD) is a progressive retinal disorder affecting over 33 million people worldwide. Genome-wide association studies (GWASs) for AMD identified common variants at 19 loci accounting for 15–65% of the heritability and it has been hypothesized that the missing heritability may be attributed to rare variants with large effect sizes. Common variants in the complement component 3 (C3) gene have been associated with AMD and recently a rare C3 variant (Lys155Gln) was identified which exerts a large effect on AMD susceptibility independent of the common variants. To explore whether additional rare variants in the C3 gene are associated with AMD, we sequenced all coding exons in 84 unrelated AMD cases. Subsequently, we genotyped all identified variants in 1474 AMD cases and 2258 controls. Additionally, because of the known genetic overlap between AMD and atypical hemolytic uremic syndrome (aHUS), we genotyped two recurrent aHUS-associated C3 mutations in the entire cohort. Overall, we identified three rare variants (Lys65Gln (P = 0.04), Arg735Trp (OR = 17.4, 95% CI = 2.2–136; P = 0.0003), and Ser1619Arg (OR = 5.2, 95% CI = 1.0–25; P = 0.05) at the C3 locus that are associated with AMD in our EUGENDA cohort. However, the Arg735Trp and Ser1619Arg variants were not found to be associated with AMD in the Rotterdam Study. The Lys65Gln variant was only identified in patients from Nijmegen, the Netherlands, and thus may represent a region-specific AMD risk variant.
The ERCC6 Gene and Age-Related Macular Degeneration
Dominique C. Baas,Dominiek D. Despriet,Theo G. M. F. Gorgels,Julie Bergeron-Sawitzke,André G. Uitterlinden,Albert Hofman,Cornelia M. van Duijn,Joanna E. Merriam,R. Theodore Smith,Gaetano R. Barile,Jacoline B. ten Brink,Johannes R. Vingerling,Caroline C. W. Klaver,Rando Allikmets,Michael Dean,Arthur A. B. Bergen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013786
Abstract: Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the developed countries and is caused by both environmental and genetic factors. A recent study (Tuo et al., PNAS) reported an association between AMD and a single nucleotide polymorphism (SNP) (rs3793784) in the ERCC6 (NM_000124) gene. The risk allele also increased ERCC6 expression. ERCC6 is involved in DNA repair and mutations in ERCC6 cause Cockayne syndrome (CS). Amongst others, photosensitivity and pigmentary retinopathy are hallmarks of CS.
A Genome-Wide Association Study of Optic Disc Parameters
Wishal D. Ramdas equal contributor,Leonieke M. E. van Koolwijk equal contributor,M. Kamran Ikram equal contributor,Nomdo M. Jansonius,Paulus T. V. M. de Jong,Arthur A. B. Bergen,Aaron Isaacs,Najaf Amin,Yurii S. Aulchenko,Roger C. W. Wolfs,Albert Hofman,Fernando Rivadeneira,Ben A. Oostra,Andre G. Uitterlinden,Pirro Hysi,Christopher J. Hammond,Hans G. Lemij,Johannes R. Vingerling ,Caroline C. W. Klaver equal contributor,Cornelia M. van Duijn equal contributor
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000978
Abstract: The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72×10?19) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67×10?33) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15×10?11) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93×10?10) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.
Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma
Leonieke M. E. van Koolwijk equal contributor,Wishal D. Ramdas equal contributor,M. Kamran Ikram,Nomdo M. Jansonius,Francesca Pasutto,Pirro G. Hysi,Stuart Macgregor,Sarah F. Janssen,Alex W. Hewitt,Ananth C. Viswanathan,Jacoline B. ten Brink,S. Mohsen Hosseini,Najaf Amin,Dominiek D. G. Despriet,Jacqueline J. M. Willemse-Assink,Rogier Kramer,Fernando Rivadeneira,Maksim Struchalin,Yurii S. Aulchenko,Nicole Weisschuh,Matthias Zenkel,Christian Y. Mardin,Eugen Gramer,Ulrich Welge-Lüssen,Grant W. Montgomery,Francis Carbonaro,Terri L. Young,The DCCT/EDIC Research Group,Céline Bellenguez,Peter McGuffin,Paul J. Foster,Fotis Topouzis,Paul Mitchell,Jie Jin Wang,Tien Y. Wong,Monika A. Czudowska,Albert Hofman,Andre G. Uitterlinden,Roger C. W. Wolfs,Paulus T. V. M. de Jong,Ben A. Oostra,Andrew D. Paterson,Wellcome Trust Case Control Consortium 2,David A. Mackey,Arthur A. B. Bergen,André Reis,Christopher J. Hammond,Johannes R. Vingerling,Hans G. Lemij,Caroline C. W. Klaver,Cornelia M. van Duijn
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002611
Abstract: Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4×10?8), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6×10?8). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4×10?2 for rs11656696 and p = 9.1×10?4 for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.
Effects of Heparin and Enoxaparin on APP Processing and Aβ Production in Primary Cortical Neurons from Tg2576 Mice
Hao Cui, Amos C. Hung, David W. Klaver, Toshiharu Suzuki, Craig Freeman, Christian Narkowicz, Glenn A. Jacobson, David H. Small
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023007
Abstract: Background Alzheimer's disease (AD) is caused by accumulation of Aβ, which is produced through sequential cleavage of β-amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE1) and γ-secretase. Enoxaparin, a low molecular weight form of the glycosaminoglycan (GAG) heparin, has been reported to lower Aβ plaque deposition and improve cognitive function in AD transgenic mice. Methodology/Principal Findings We examined whether heparin and enoxaparin influence APP processing and inhibit Aβ production in primary cortical cell cultures. Heparin and enoxaparin were incubated with primary cortical cells derived from Tg2576 mice, and the level of APP and proteolytic products of APP (sAPPα, C99, C83 and Aβ) was measured by western blotting. Treatment of the cells with heparin or enoxaparin had no significant effect on the level of total APP. However, both GAGs decreased the level of C99 and C83, and inhibited sAPPα and Aβ secretion. Heparin also decreased the level of β-secretase (BACE1) and α-secretase (ADAM10). In contrast, heparin had no effect on the level of ADAM17. Conclusions/Significance The data indicate that heparin and enoxaparin decrease APP processing via both α- and β-secretase pathways. The possibility that GAGs may be beneficial for the treatment of AD needs further study.
Mine Spoil Prairies Expand Critical Habitat for Endangered and Threatened Amphibian and Reptile Species
Michael J. Lannoo,Vanessa C. Kinney,Jennifer L. Heemeyer,Nathan J. Engbrecht,Alisa L. Gallant,Robert W. Klaver
Diversity , 2009, DOI: 10.3390/d1020118
Abstract: Coal extraction has been occurring in the Midwestern United States for over a century. Despite the pre-mining history of the landscape as woodlands, spent surface coalfields are often reclaimed to grasslands. We assessed amphibian and reptile species on a large tract of coal spoil prairie and found 13 species of amphibians (nine frog and four salamander species) and 19 species of reptiles (one lizard, five turtle, and 13 snake species). Two state-endangered and three state species of special concern were documented. The amphibian diversity at our study site was comparable to the diversity found at a large restored prairie situated 175 km north, within the historic prairie peninsula.
Transdifferentiation from cornea to lens in Xenopus laevis depends on BMP signalling and involves upregulation of Wnt signalling
Robert C Day, Caroline W Beck
BMC Developmental Biology , 2011, DOI: 10.1186/1471-213x-11-54
Abstract: Here, we have used a functional transgenic approach to show that BMP signalling is required for lens regeneration and a microarray approach to identify genes that are upregulated specifically during this process. Analysis of the array data strongly implicates Wnt signalling and the Pitx family of transcription factors in the process of cornea to lens transdifferentiation. Our analysis also captured several genes associated with congenital cataract in humans. Pluripotency genes, in contrast, were not upregulated, supporting the idea that corneal cells transdifferentiate without returning to a stem cell state. Several genes from the array were expressed in the forming lens during embryogenesis. One of these, Nipsnap1, is a known direct target of BMP signalling.Our results strongly implicate the developmental Wnt and BMP signalling pathways in the process of cornea to lens transdifferentiation (CLT) in Xenopus, and suggest direct transdifferentiation between these two anterior eye tissues.Urodele amphibians, for example the axolotl, are well known for their incredible ability to regenerate appendages, such as the limb. However, axolotls are unable to regenerate the lens of the eye following its removal (lentectomy). In contrast, the anuran amphibian Xenopus laevis, in which limb regeneration is subject to an ontogenic decline leading up to metamorphosis, is able to regenerate a new lens from the overlying central corneal cells (for review see [1,2]). This process was first described by Freeman in 1963, and involves a transdifferentiation of one cell type (corneal epithelium) to another (lens) [3]. It differs from the better-known Wolffian regeneration in adult newts, where a new lens is formed from cells of the pigmented dorsal iris epithelium and is known as cornea to lens transdifferentiation, or CLT [2].The trigger for CLT in vivo is exposure of the outer corneal cells to an unidentified factor present in the vitreous of the eye, most likely originating from the neu
TRPM8 and Nav1.8 sodium channels are required for transthyretin-induced calcium influx in growth cones of small-diameter TrkA-positive sensory neurons
Robert J Gasperini, Xu Hou, Helena Parkington, Harry Coleman, David W Klaver, Adele J Vincent, Lisa C Foa, David H Small
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-19
Abstract: Levels of intracellular cytosolic calcium were monitored in dorsal root ganglion (DRG) neurons isolated from embryonic rats using the calcium-sensitive fluorescent indicator Fluo4. An amyloidogenic mutant form of TTR, L55P, induced calcium influx into the growth cones of DRG neurons, whereas wild-type TTR had no significant effect. Atomic force microscopy and dynamic light scattering studies confirmed that the L55P TTR contained oligomeric species of TTR. The effect of L55P TTR was decreased by blockers of voltage-gated calcium channels (VGCC), as well as by blockers of Nav1.8 voltage-gated sodium channels and transient receptor potential M8 (TRPM8) channels. siRNA knockdown of TRPM8 channels using three different TRPM8 siRNAs strongly inhibited calcium influx in DRG growth cones.These data suggest that activation of TRPM8 channels triggers the activation of Nav1.8 channels which leads to calcium influx through VGCC. We suggest that TTR-induced calcium influx into DRG neurons may contribute to the pathophysiology of FAP. Furthermore, we speculate that similar mechanisms may mediate the toxic effects of other amyloidogenic proteins such as the β-amyloid protein of Alzheimer's disease.Protein misfolding is a common feature of many neurodegenerative diseases. In some of these diseases, such as the synucleinopathies and the tauopathies, cytoplasmic proteins aggregate to form intracellular deposits. However, in the amyloidoses, which include Alzheimer's disease (AD), prion diseases and the British and Danish familial dementias, proteinaceous aggregates are observed extracellularly [1-4]. There is increasing evidence that the mechanism of neurotoxicity in these amyloidoses is similar and that it is the conformation of the aggregated protein, rather than its specific amino acid sequence which results in altered membrane permeability to calcium [5]. Therefore, studies on the mechanism of neurotoxicity in one disease may provide insights into the mechanisms involved in other
The Class of Language: Examining Rhetoric, Children’s Social Education, and Pedagogy in Economically Distinct Classrooms  [PDF]
Caroline C.
Creative Education (CE) , 2018, DOI: 10.4236/ce.2018.93024
Abstract: My paper examines the uses of language in a Rochester city public elementary school compared to the uses of language in a suburban, accelerated after school program. The goal of this research was to address how language is employed in these two classrooms and if rhetorical variations between the two are indicative of their community’s economic, social, and racial differences. From my experience working at each facility, I was able to observe how specific language operates and in what context over the course of three weeks. I consulted visual, auditory, and carefully written recordings of structured classes and of free time at each facility. As a result, I have located salient differences in the way two institutions of disparate levels of income negotiate language and how that “class-coded” language affects the students. Namely, these differences delineate the following: what are considered appropriate and forbidden words around children, disciplinary tactics believed to be most effective, strategies in executing effective lesson plans, and types of social bonding within the classroom. Depending on how teachers use language in the classroom, children receive starkly different structural education as well as social education. Thus, examining different classrooms’ language choices and their effects on students allows us to adapt our language and elevate children’s education in any classroom, regardless of economic status.
Self-reported drunkenness among adolescents in four sub-Saharan African countries: associations with adverse childhood experiences
Kabiru Caroline W,Beguy Donatien,Crichton Joanna,Ezeh Alex C
Child and Adolescent Psychiatry and Mental Health , 2010, DOI: 10.1186/1753-2000-4-17
Abstract: Background Consumption of alcohol is associated with acute and chronic adverse health outcomes. There is a paucity of studies that explore the determinants of alcohol use among adolescents in sub-Saharan Africa and, in particular, that examine the effects of adverse childhood experiences on alcohol use. Methods The paper draws on nationally-representative data from 9,819 adolescents aged 12-19 years from Burkina Faso, Ghana, Malawi, and Uganda. Logistic regression models were employed to identify correlates of self-reported past-year drunkenness. Exposure to four adverse childhood experiences comprised the primary independent variables: living in a food-insecure household, living with a problem drinker, having been physically abused, and having been coerced into having sex. We controlled for age, religiosity, current schooling status, the household head's sex, living arrangements, place of residence, marital status, and country of survey. All analyses were conducted separately for males and females. Results At the bivariate level, all independent variables (except for coerced sex among males) were associated with the outcome variable. Overall, 9% of adolescents reported that they had been drunk in the 12 months preceding the survey. In general, respondents who had experienced an adverse event during childhood were more likely to report drunkenness. In the multivariate analysis, only two adverse childhood events emerged as significant predictors of self-reported past-year drunkenness among males: living in a household with a problem drinker before age 10, and being physically abused before age 10. For females, exposure to family-alcoholism, experience of physical abuse, and coerced sex increased the likelihood of reporting drunkenness in the last 12 months. The association between adverse events and reported drunkenness was more pronounced for females. For both males and females there was a graded relationship between the number of adverse events experienced and the proportion reporting drunkenness. Conclusions We find an association between experience of adverse childhood events and drunkenness among adolescents in four sub-Saharan African countries. The complex impacts of adverse childhood experiences on young people's development and behavior may have an important bearing on the effectiveness of interventions geared at reducing alcohol dependence among the youth.
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