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Plausible Candidates (plausible + candidate)
Selected AbstractsIdentification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2,HUMAN MUTATION, Issue 6 2005Patrick G. Buckley Abstract Schwannomatosis is characterized by multiple peripheral and cranial nerve schwannomas that occur in the absence of bilateral 8th cranial nerve schwannomas. The latter is the main diagnostic criterion of neurofibromatosis type 2 (NF2), which is a related but distinct disorder. The genetic factors underlying the differences between schwannomatosis and NF2 are poorly understood, although available evidence implicates chromosome 22 as the primary location of the gene(s) of interest. To investigate this, we comprehensively profiled the DNA copy number in samples from sporadic and familial schwannomatosis, NF2, and a large cohort of normal controls. Using a tiling-path chromosome 22 genomic array, we identified two candidate regions of copy number variation, which were further characterized by a PCR-based array with higher resolution. The latter approach allows the detection of minute alterations in total genomic DNA, with as little as 1.5,kb per measurement point of nonredundant sequence on the array. In DNA derived from peripheral blood from a schwannomatosis patient and a sporadic schwannoma sample, we detected rearrangements of the immunoglobulin lambda (IGL) locus, which is unlikely to be due to a B-cell specific somatic recombination of IGL. Analysis of normal controls indicated that these IGL rearrangements were restricted to schwannomatosis/schwannoma samples. In the second candidate region spanning GSTT1 and CABIN1 genes, we observed a frequent copy number polymorphism at the GSTT1 locus. We further describe missense mutations in the CABIN1 gene that are specific to samples from schwannomatosis and NF2 and make this gene a plausible candidate for contributing to the pathogenesis of these disorders. Hum Mutat 26(6), 540,549, 2005. © 2005 Wiley-Liss, Inc. [source] Hypercholesterolemia and inflammation in atherogenesis: Two sides of the same coinMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 11 2005Daniel SteinbergArticle first published online: 3 NOV 200 Abstract An abundance of experimental, clinical, and epidemiologic data capped by stunning interventional results with the statins has established hypercholesterolemia as a major causative factor in atherogenesis. In familial hypercholesterolemia and in animal models it is a sufficient cause. Some degree of hypercholesterolemia, perhaps 30,50 mg/dL, may even be a necessary cause. It is equally clear that from the very beginning atherogenesis has a strong inflammatory component, i. e., it is characterized by penetration of monocytes and of T-cells into the developing lesion. These cells, through the secretion of cytokines and growth factors, through immune responses, and through complex cross-talk with elements of the artery wall modulate the growth of the lesion and affect its stability. But inflammation has to occur in response to something. What is that something? What is the "injury" in "response-to-injury"? The case will be made that oxidized lipids in oxidized LDL or generated in response to prooxidative changes in the cells of the artery wall should be considered a plausible candidate. There is no need to consider hypercholesterolemia and inflammation as alternative hypotheses. Both are very much involved. Optimal intervention and prevention will probably require attention to both. [source] Expression, functional, and structural analysis of proteins critical for otoconia developmentDEVELOPMENTAL DYNAMICS, Issue 10 2010Yinfang Xu Abstract Otoconia, developed during late gestation and perinatal stages, couple mechanic force to the sensory hair cells in the vestibule for motion detection and bodily balance. In the present work, we have investigated whether compensatory deposition of another protein(s) may have taken place to partially alleviate the detrimental effects of Oc90 deletion by analyzing a comprehensive list of plausible candidates, and have found a drastic increase in the deposition of Sparc-like 1 (aka Sc1 or hevin) in Oc90 null versus wt otoconia. We show that such up-regulation is specific to Sc1, and that stable transfection of Oc90 and Sc1 full-length expression constructs in NIH/3T3 cells indeed promotes matrix calcification. Analysis and modeling of Oc90 and Sc1 protein structures show common features that may be critical requirements for the otoconial matrix backbone protein. Such information will serve as the foundation for future regenerative purposes. Developmental Dynamics 239:2659,2673, 2010. © 2010 Wiley-Liss, Inc. [source] Common genetic influences underlie comorbidity of migraine and endometriosisGENETIC EPIDEMIOLOGY, Issue 2 2009Dale R. Nyholt Abstract We examined the co-occurrence of migraine and endometriosis within the largest known collection of families containing multiple women with surgically confirmed endometriosis and in an independent sample of 815 monozygotic and 457 dizygotic female twin pairs. Within the endometriosis families, a significantly increased risk of migrainous headache was observed in women with endometriosis compared to women without endometriosis (odds ratio [OR] 1.57, 95% confidence interval [CI]: 1.12,2.21, P=0.009). Bivariate heritability analyses indicated no evidence for common environmental factors influencing either migraine or endometriosis but significant genetic components for both traits, with heritability estimates of 69 and 49%, respectively. Importantly, a significant additive genetic correlation (rG = 0.27, 95% CI: 0.06,0.47) and bivariate heritability (h2=0.17, 95% CI: 0.08,0.27) was observed between migraine and endometriosis. Controlling for the personality trait neuroticism made little impact on this association. These results confirm the previously reported comorbidity between migraine and endometriosis and indicate common genetic influences completely explain their co-occurrence within individuals. Given pharmacological treatments for endometriosis typically target hormonal pathways and a number of findings provide support for a relationship between hormonal variations and migraine, hormone-related genes and pathways are highly plausible candidates for both migraine and endometriosis. Therefore, taking into account the status of both migraine and endometriosis may provide a novel opportunity to identify the genes underlying them. Finally, we propose that the analysis of such genetically correlated comorbid traits can increase power to detect genetic risk loci through the use of more specific, homogenous and heritable phenotypes. Genet. Epidemiol. 2008. © 2008 Wiley-Liss, Inc. [source] An aging Interventions Testing Program: study design and interim reportAGING CELL, Issue 4 2007Richard A. Miller Summary The National Institute on Aging's Interventions Testing Program (ITP) has developed a plan to evaluate agents that are considered plausible candidates for delaying rates of aging. Key features include: (i) use of genetically heterogeneous mice (a standardized four-way cross), (ii) replication at three test sites (the Jackson Laboratory, TJL; University of Michigan, UM; and University of Texas, UT), (iii) sufficient statistical power to detect 10% changes in lifespan, (iv) tests for age-dependent changes in T cell subsets and physical activity, and (v) an annual solicitation for collaborators who wish to suggest new interventions for evaluation. Mice in the first cohort were exposed to one of four agents: aspirin, nitroflurbiprofen (NFP), 4-OH-,-phenyl-N-tert-butyl nitrone (4-OH-PBN), or nordihydroguiaretic acid (NDGA). An interim analysis was conducted using survival data available on the date at which at least 50% of the male control mice had died at each test site. Survival of control males was significantly higher, at the interim time-point, at UM than at UT or TJL; all three sites had similar survival of control females. Males in the NDGA group had significantly improved survival (P = 0.0004), with significant effects noted at TJL (P < 0.01) and UT (P < 0.04). None of the other agents altered survival, although there was a suggestion (P = 0.07) of a beneficial effect of aspirin in males. More data will be needed to determine if any of these compounds can extend maximal lifespan, but the current data show that NDGA reduces early life mortality risks in genetically heterogeneous mice at multiple test sites. [source] Rational Ignorance and Political Morality,PHILOSOPHY AND PHENOMENOLOGICAL RESEARCH, Issue 1 2006Guido Pincione People frequently advance political proposals in the name of a goal while remaining apparently indifferent to the fact that those proposals, if implemented, would frustrate that goal. Theorists of "deliberative democracy" purport to avoid this difficulty by arguing that deliberation is primarily about moral not empirical issues. We reject this view (the moral turn) and propose a method (The Display Test) to check whether a political utterance is best explained by the rational ignorance hypothesis or by the moral turn: the speaker must be prepared to openly acknowledge the bad consequences of his political position. If he is, the position is genuinely moral; if he is not, the position evinces either rational ignorance or posturing. We introduce deontological notions to explain when the moral turn works and when it does not. We discuss and reject possible replies, in particular the view that a moral-political stance insensitive to consequences relies on a distribution of moral responsibility in evildoing. Finally, we show that even the most plausible candidates for the category of purely moral political proposals are best explained by the rational ignorance/posturing hypothesis, if only because enforcing morality gives rise to complex causal issues. [source] Screening South Indian medicinal plants for antifungal activity against cutaneous pathogensPHYTOTHERAPY RESEARCH, Issue 9 2003A. Vonshak Abstract In this study, twenty-eight South Indian medicinal plants were screened for their anti-fungal activity against six species of fungi (Trichophyton mentagrophytes, T. rubrum, T. soudanense, Candida albicans, Torulopsis glabrata, and C. krusei). Three plant species extracts, Celastrus paniculatus, Eriodendron anfractuosum and Ficus glomerata showed inhibitory activity. An aqueous extract of galls of Terminalia chebula showed inhibitory effects on three dermatophytes (Trichophyton spp.) and three yeasts (Candida spp.). Seeds extract of T. chebula inhibited only the growth of T. glabrata. An aqueous extract of T. chebula showed inhibitory effects higher than those measured in ethanol extracts. It is therefore suggested that tannins are plausible candidates for the anti-dermatophytic effects of T. chebula. Chebulinic acid, a known tannin of T. chebula was tested and found not inhibitory, thus a search for the active compound is needed. Copyright © 2003 John Wiley & Sons, Ltd. [source] Evidence by Expression Analysis of Candidate Genes for Congenital Heart Defects in the NF1 Microdeletion IntervalANNALS OF HUMAN GENETICS, Issue 5 2005M. Venturin Summary It was recently reported that congenital heart disease is significantly more frequent in patients with NF1 microdeletion syndrome than in those with classical NF1. The outcome of congenital heart disease in this subset of patients is likely caused by the haploinsufficiency of gene/s in the deletion interval. Following in silico analysis of the deleted region, we found two genes known to be expressed in adult heart, the Joined to JAZF1 (SUZ12) and the Centaurin-alpha 2 (CENTA2) genes, and seven other genes with poorly defined patterns of expression and function. With the aim of defining their expression profiles in human fetal tissues (15th,21st weeks of gestation), expression analysis by RT-PCR and Northern blotting was performed. C17orf40, SUZ12 and CENTA2 were found to be mainly expressed in fetal heart, and following RT-PCR on mouse embryos and embryonic heart and brain at different stages of development, we found that the orthologous genes C17orf40, Suz12 and Centa2 are also expressed in early stages of development, before and during the formation of the four heart chambers. The presence of binding sites for Nkx2-5, a transcription factor expressed early in heart development, in all three mouse orthologous genes was predicted by bioinformatics, thus reinforcing the hypothesis that these genes might be involved in heart development and may be plausible candidates for congenital heart disease. [source] Role of inflammation-related gene polymorphisms in branch retinal vein occlusionACTA OPHTHALMOLOGICA, Issue 2009M WEGER Purpose Branch retinal vein occlusion (BRVO) is a common vision-threatening disease. Some cytokines have previously been shown to exert proatherogenic as well as prothrombotic effects. Gene polymorphisms affecting the expression of these cytokines are thus plausible candidates as risk factors for BRVO. The purpose of the present study was to investigate hypothesized associations between cytokine gene polymorphisms and the presence of BRVO. Methods The present case-control study comprised 398 patients with BRVO and 355 control subjects. Using 5`exonuclease assays (TaqMan), genotypes of the following single nucleotide polymorphisms were determined: interleukin 1 beta (IL1B) -511C>T, interleukin 1 receptor antagonist (IL1RN) 1018T>C, interleukin 4 (IL4) -584C>T, interleukin 6 (IL6) -174G>C, interleukin 10 (IL10) -592C>A, interleukin 18 (IL18) 183A>G, tumor necrosis factor (TNF) -308G>A, monocyte chemoattractant protein 1 (CCL2) -2518A>G, interleukin 8 (IL8) -251A>T and RANTES (CCL5) -403G>A. Results Neither genotype distributions nor allele frequencies of any of the investigated polymorphisms differed significantly between BRVO patients and control subjects (IL1B -511TT: 7.8% vs. 9.6%, p=0.68; IL1RN 1018CC: 12.1% vs. 13.5%, p=0.15, IL4 -584TT: 1.3% vs. 2.3%, p=0.58; IL6 -174CC: 17.8% vs.18.6%, p=0.97; IL10 -592AA: 5.3% vs. 9.0, p=0.14; IL18 183GG: 3.0 vs. 6.2%, p=0.11; TNF -308AA: 1.5% vs. 1.4%, p=0.95; CCL2 -2518GG: 6.5% vs. 4.5%, p=0.48; IL8 -251TT: 26.9% vs. 28.7%, p=0.23; CCL5 -403AA: 3.3% vs. 4.5%, p=0.63). Conclusion Our data suggest that none of the investigated cytokine gene polymorphisms is likely a major risk factor for BRVO. [source] | |||||||||||||