1,721,125 research outputs found
Investigation of association between PFO complicated by cryptogenic stroke and a common variant of the cardiac transcription factor GATA4
Get PDFPatent foramen ovale (PFO) is associated with clinical conditions including cryptogenic stroke, migraine and varicose veins. Data from studies in humans and mouse suggest that PFO and the secundum form of atrial septal defect (ASDII) exist in an anatomical continuum of septal dysmorphogenesis with a common genetic basis. Mutations in multiple members of the evolutionarily conserved cardiac transcription factor network, including GATA4, cause or predispose to ASDII and PFO. Here, we assessed whether the most prevalent variant of the GATA4 gene, S377G, was significantly associated with PFO or ASD. Our analysis of world indigenous populations showed that GATA4 S377G was largely Caucasian-specific, and so subjects were restricted to those of Caucasian descent. To select for patients with larger PFO, we limited our analysis to those with cryptogenic stroke in which PFO was a subsequent finding. In an initial study of Australian subjects, we observed a weak association between GATA4 S377G and PFO/Stroke relative to Caucasian controls in whom ASD and PFO had been excluded (OR = 2.16; p = 0.02). However, in a follow up study of German Caucasians no association was found with either PFO or ASD. Analysis of combined Australian and German data confirmed the lack of a significant association. Thus, the common GATA4 variant S377G is likely to be relatively benign in terms of its participation in CHD and PFO/Stroke. © 2011 Moradi Marjaneh et al
Nkx2.7 and Nkx2.5 Function Redundantly and Are Required for Cardiac Morphogenesis of Zebrafish Embryos
No full textReproductive differences among species, and between individuals and cohorts, in the leech genus <i>Helobdella</i> (Lophotrochozoa; Annelida; Clitellata; Hirudinida; Glossiphoniidae), with implications for reproductive resource allocation in hermaphrodites
Get PDFLeeches and oligochaetes comprise a monophyletic group of annelids, the Clitellata, whose reproduction is characterized by simultaneous hermaphroditism. While most clitellate species reproduce by cross-fertilization, self-fertilization has been described within the speciose genus Helobdella. Here we document the reproductive life histories and reproductive capacities for three other Helobdella species. Under laboratory conditions, both H. robusta and H. octatestisaca exhibit uniparental reproduction, apparently reflecting self-fertility, and suggesting that this trait is ancestral for the genus. However, the third species, H. austinensis, seems incapable of reproduction by self-fertilization, so we inferred its reproductive life history by analyzing reproduction in breeding cohorts. Comparing the reproductive parameters for H. robusta reproducing in isolation and in cohorts revealed that reproduction in cohorts is dramatically delayed with respect to that of isolated individuals, and that cohorts of leeches coordinate their cocoon deposition in a manner that is not predicted from the reproductive parameters of individuals reproducing in isolation. Finally, our comparisons of reproductive capacity for individuals versus cohorts for H. robusta, and between different sizes of cohorts for H. austinensis, reveal differences in resource allocation between male and female reproductive roles that are consistent with evolutionary theory.</div
Karakterisatie van genetische determinanten die de respons op stemmingsstabilisatoren reguleren
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Levels and patterns of nucleotide variation in domestication QTL regions on rice chromosome 3 suggest lineage-specific selection.
Get PDFOryza sativa or Asian cultivated rice is one of the major cereal grass species domesticated for human food use during the Neolithic. Domestication of this species from the wild grass Oryza rufipogon was accompanied by changes in several traits, including seed shattering, percent seed set, tillering, grain weight, and flowering time. Quantitative trait locus (QTL) mapping has identified three genomic regions in chromosome 3 that appear to be associated with these traits. We would like to study whether these regions show signatures of selection and whether the same genetic basis underlies the domestication of different rice varieties. Fragments of 88 genes spanning these three genomic regions were sequenced from multiple accessions of two major varietal groups in O. sativa--indica and tropical japonica--as well as the ancestral wild rice species O. rufipogon. In tropical japonica, the levels of nucleotide variation in these three QTL regions are significantly lower compared to genome-wide levels, and coalescent simulations based on a complex demographic model of rice domestication indicate that these patterns are consistent with selection. In contrast, there is no significant reduction in nucleotide diversity in the homologous regions in indica rice. These results suggest that there are differences in the genetic and selective basis for domestication between these two Asian rice varietal groups
Deterioration of the G alpha o vomeronasal pathway in sexually dimorphic mammals
No full textIn mammals, social and sexual behaviours are largely mediated by the vomeronasal system (VNS). The accessory olfactory bulb (AOB) is the first synaptic locus of the VNS and ranges from very large in Caviomorph rodents, small in carnivores and ungulates, to its complete absence in apes, elephants, most bats and aquatic species. Two pathways have been described in the VNS of mammals. In mice, vomeronasal neurons expressing Gαi2 protein project to the rostral portion of the AOB and respond mostly to small volatile molecules, whereas neurons expressing Gαo project to the caudal AOB and respond mostly to large non-volatile molecules. However, the Gαo-expressing pathway is absent in several species (horses, dogs, musk shrews, goats and marmosets) but no hypotheses have been proposed to date to explain the loss of that pathway. We noted that the species that lost the Gαo pathway belong to Laurasiatheria and Primates lineages, both clades with ubiquitous sexual dimorphisms across species. To assess whether similar events of Gαo pathway loss could have occurred convergently in dimorphic species we studied G-protein expression in the AOB of two species that independently evolved sexually dimorphic traits: the California ground squirrel Spermophilus beecheyi (Rodentia; Sciurognathi) and the cape hyrax Procavia capensis (Afrotheria; Hyracoidea). We found that both species show uniform expression of Gαi2-protein throughout AOB glomeruli, while Gαo expression is restricted to main olfactory glomeruli only. Our results suggest that the degeneration of the Gαo-expressing vomeronasal pathway has occurred independently at least four times in Eutheria, possibly related to the emergence of sexual dimorphisms and the ability of detecting the gender of conspecifics at distance
Zebrafish Bioassay-Guided Natural Product Discovery: Isolation of Angiogenesis Inhibitors from East African Medicinal Plants
No full textNatural products represent a significant reservoir of unexplored chemical diversity for early-stage drug discovery. The identification of lead compounds of natural origin would benefit from therapeutically relevant bioassays capable of facilitating the isolation of bioactive molecules from multi-constituent extracts. Towards this end, we developed an in vivo bioassay-guided isolation approach for natural product discovery that combines bioactivity screening in zebrafish embryos with rapid fractionation by analytical thin-layer chromatography (TLC) and initial structural elucidation by high-resolution electrospray mass spectrometry (HRESIMS). Bioactivity screening of East African medicinal plant extracts using fli-1:EGFP transgenic zebrafish embryos identified Oxygonum sinuatum and Plectranthus barbatus as inhibiting vascular development. Zebrafish bioassay-guided fractionation identified the active components of these plants as emodin, an inhibitor of the protein kinase CK2, and coleon A lactone, a rare abietane diterpenoid with no previously described bioactivity. Both emodin and coleon A lactone inhibited mammalian endothelial cell proliferation, migration, and tube formation in vitro, as well as angiogenesis in the chick chorioallantoic membrane (CAM) assay. These results suggest that the combination of zebrafish bioassays with analytical chromatography methods is an effective strategy for the rapid identification of bioactive natural products.sponsorship: This work was funded in part by the Industrieel Onderzoeksfonds (IOF-HB/06/018) of K. U. Leuven, the Centers of Excellence of the K. U. Leuven (EF-05/15) and the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (G. 0486.08). Sandra Liekens is a postdoctoral researcher of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. (Industrieel Onderzoeksfonds|IOF-HB/06/018, Centers of Excellence of the K. U. Leuven|EF-05/15, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen|G. 0486.08)status: Publishe
Hippocampal gene expression analysis highlights Ly6a/Sca-1 as candidate gene for previously mapped novelty induced behaviors in mice.
Get PDFIn this study, we show that the covariance between behavior and gene expression in the brain can help further unravel the determinants of neurobehavioral traits. Previously, a QTL for novelty induced motor activity levels was identified on murine chromosome 15 using consomic strains. With the goal of narrowing down the linked region and possibly identifying the gene underlying the quantitative trait, gene expression data from this F(2)-population was collected and used for expression QTL analysis. While genetic variation in these mice was limited to chromosome 15, eQTL analysis of gene expression showed strong cis-effects as well as trans-effects elsewhere in the genome. Using weighted gene co-expression network analysis, we were able to identify modules of co-expressed genes related to novelty induced motor activity levels. In eQTL analyses, the expression of Ly6a (a.k.a. Sca-1) was found to be cis-regulated by chromosome 15. Ly6a also surfaced in a group of genes resulting from the network analysis that was correlated with behavior. Behavioral analysis of Ly6a knock-out mice revealed reduced novelty induced motor activity levels when compared to wild type controls, confirming functional importance of Ly6a in this behavior, possibly through regulating other genes in a pathway. This study shows that gene expression profiling can be used to narrow down a previously identified behavioral QTL in mice, providing support for Ly6a as a candidate gene for functional involvement in novelty responsiveness
Identificatie van genetische modifiers van axonaal transport afhankelijke neurodegeneratie in Drosophila
No full textNeurodegenerative diseases, like Alzheimer disease and amyotrophic lateral sclerosis (ALS), are serious illnesses affecting selectively neuronal populations in the central or peripheral nervous system. These diseases lead to a variety of clinical phenotypes including mental retardation, physical impairment and behavioral problems. Although over the last years major efforts have gone towards studying the mechanisms leading to this selective neuronal death, these diseases still remain untreatable and incurable. Additionally, since the majority of these diseases affect elder people and because of the growing life expectancy, they are becoming more costly and help-demanding to society. Therefore, understanding the pathogenic mechanisms of neurodegenerative diseases is a pressing issue. Coupling genetic findings in human patients to model systems like cell-based systems or animal models like Drosophila melanogaster or mice will contribute greatly to this research area.Motor neuron diseases are considered a subtype of neurodegenerative diseases, characterized by the specific involvement of motor neurons. In general, the pathology of these diseases is caused by selective degeneration of motor neurons residing in the motor cortex, brain stem or spinal cord followed by progressive weakness and wasting of specific muscles, depending on the motor output pathway that is targeted. Recently, more than 30 disease-causing genes have been identified for motor neuron diseases. These genes suggest the involvement of pathways like RNA processing, mitochondrial function, membrane trafficking and axonal transport. The identification of pathogenic mutations in motor proteins, which are important in axonal transport, identifies the transport machinery as one of the key players in the mechanisms underlying motor neurodegeneration. In this project, I took advantage of the fly model Drosophila melanogaster to study the pathogenic mechanisms leading to motor neuron disease. Specifically, I used the Drosophila DCTN1 homolog, Gl, to characterize a possible role in (motor) neurodegeneration of Gl-interacting genes. Given that mutations in human DCTN1 have been linked to different forms of neurodegeneration like ALS (with fronto-temporal dementia (FTD)), distal hereditary motor neuropathy (dHMN) type VII and Perry Syndrome, I anticipate that my newly generated results will provide additional insights in the genetics of these disorders.First, I established a model allowing easy quantification of behavioral and cellular problems with respect to identifying modifiers and validating them. I found that the dominant Gl mutation, Gl1 can serve as a genetic model with defects in axonal function. These mutants showed a progressive decline in motor performance caused by motor neuron dysfunction. The latter problem was caused by an age-dependent increase in axonal mitochondrial density.Next, I validated the genetic Gl1 model by using DLis1, the Drosophila homolog of LIS1. Mutations in the human LIS1 gene have previously been shown to cause classical lissencephaly, which is a neuronal migration disorder and results in brain developmental defects. The function of LIS1 has been linked to dynein and kinesin-mediated intracellular transport. Although DLis1 is a known Gl-interacting gene, no direct evidence has yet been found concerning its involvement in motor neurodegeneration. I found that altered levels of Lis1 affected the onset of the progressive decline in motor performance caused by Gl1 mutants. Furthermore, reduced Lis1 levels had a beneficial effect on motor neuron dysfunction. Results from this part of the study suggested that a stoichiometric balance between dynactin and Lis1 is important for proper function of axonal transport and that disturbing this balance might accelerate degenerative phenotypes.Finally I used the Gl1 model to perform a genetic modifier screen based on the rough-eye phenotype of Gl1 mutants. By screening for enhancement or suppression of the rough-eye phenotype I identified several interacting genes: Hel25E, CSN6, Atg1, Ptp69D, mRpL45, Klc, CG6907, CG5326 and CG32113. Interestingly, all these identified genes seemed to play a role in pathways that have already been linked to (motor) neurodegeneration and therefore provided a link between different pathogenic mechanisms in motor neuron disease pathology. I validated the modifier effects in the Gl1 motor performance phenotype, which clearly showed that the eye read-out system is an easy and quick way to find modifiers that can be translated to motor performance based on the fact that both depend on the same microtubule-regulated transport.I also identified an important role for lipid metabolism as a modifier of motor performance progression. I validated lipid metabolism as a genetic risk factor but also demonstrated potential therapeutic options by providing exogenous fatty acids.I conclude that, by using the Gl1 mutant as a genetic model with mitochondrial dysfunction correlated with axonal transport and a rough-eye phenotype, I was able to identify new modifier genes with a potential role in axonal transport and neurodegeneration of (motor) neurons. Linking the identification of these genes in the Drosophila model with human genetics, and screening disease-causing loci for these genetic variants of these genes, will help to uncover the disease-causing mechanisms. Further experiments in Drosophila concerning potential drug targets and interpretation of these results in the human situation will be an important step in discovering new therapeutics for (motor) neurodegeneration.status: Publishe
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