651 research outputs found
Genetic linkage analysis supports the presence of two susceptibility loci for alcoholism and heavy drinking on chromosome 1p22.1-11.2 and 1q21.3-24.2
No full textBackground: In order to confirm a previous finding of linkage to alcoholism on chromosome 1 we have carried out a genetic linkage study.Methods: DNA from eighteen families, densely affected by alcoholism, was used to genotype a set of polymorphic microsatellite markers at loci approximately 10 centimorgans apart spanning the short arm and part of the long arm of chromosome 1. Linkage analyses were performed using the classical lod score and a model- free method. Three different definitions of affection status were defined, these were 1. Heavy Drinking ( HD) where affected subjects drank more than the Royal College of Psychiatrists recommended weekly amount. 2. The Research Diagnostic Criteria for alcoholism ( RDCA) 3. Alcohol Dependence Syndrome ( ADS) as defined by Edwards and Gross ( 1976) and now incorporated into ICD10 and DSMIV.Results: Linkage analyses with the markers D1S1588, D1S2134, D1S1675 covering the cytogenetic region 1p22.1- 11.2 all gave positive two point and multipoint lods with a maximum lod of 1.8 at D1S1588 ( 1p22.1) for the RDCA definition of alcoholism. Another lod of 1.8 was found with D1S1653 in the region 1q21.3- 24.2 using the HD affection model.Conclusion: These results both support the presence of linkage in the 1p22.1- 11.2 region which was previously implicated by the USA Collaborative Study of the Genetics of Alcoholism ( COGA) study and also suggest the presence of another susceptibility locus at 1q21.3- 24.2
Genetic Factors in External Apical Root Resorption Associated with Orthodontic Treatment
No full textIndiana University-Purdue University Indianapolis (IUPUI)External apical root resorption (EARR) is a common sequela of orthodontic treatment, although it may also occur without orthodontic treatment. Despite rigorous investigation, no single factor or group of factors that directly causes root resorption has been identified. Experiment 1. A sample of 83 pairs of full siblings who had undergone orthodontic treatment was studied. Measurements were made of the longest maxillary central incisor, mandibular central incisor and mesial and distal roots of the mandibular first molars. Heritability estimates were generated by generalized liner models. Our results showed that the heritability estimate of the EARR was 64% on average. It was concluded that there was sufficient heritability for EARR to pursue genetic analysis.
Experiment 2. Five polymorphic markers flanking or lying within the IL-IA , IL-JB, TNSALP, TNFA, and TNFRSFJ JA genes were used in a candidate gene approach to assess linkage and association with EARR in 38 pedigrees. Suggestive evidence for linkage between EARR and the polymorphic marker D18S64 was obtained with the analysis program MAPMAKER/SIBS (LOD score 2.51). The Q-TDT program showed highly significant (p = 0.0003) evidence of linkage disequilibrium of IL-1 B polymorphisms with EARR. Our analysis indicates that the JL -1 B polymorphism accounts for 15% of the total EARR variation. Experiment 3. Nine-week-old male mice were randomly selected as controls or for placement under anesthesia of an open coil spring ligated to the left maxillary first molar producing a force of approximately 25 g. The control (C) or treated (T) per strain were A/J (C=3,T=9), C57BL/6J (C=7,T=8), C3H/HeJ (C = 4,T=6), BALB/cJ (C=4,T=6), 129P3 /J (C=6,T=8), DBA/2J (C=8,T=9), SJL/J (C=8,T= 10), and AKR/J (C=9,T =8). Animals were sacrificed after nine days of treatment or control; maxillae were immediately removed, prepared, sectioned, mounted, stained with H&E, and observed microscopically at 1 OOX to determine root resorption. Mice were grouped into root resorption resistant (A/J, C57BL/6J and SJL/J); intermediate (C3H/HeJ and AKR/J); and susceptible (BALB/cJ, DBA/2J, and 129P3/J) strains. It was concluded that there were differential susceptibility or resistance to root resorption among inbred mouse strains, indicating that genotype is an influencing factor
Secret arsenal of a cereal killer- cryptic activation of secondary metabolism biosynthesis in Fusarium graminearum
No full textFusarium graminearum is a fungal pathogen and is a major causal agent of diseases in several agriculturally important crop species. In addition to the disease that diminishes grain yield, this pathogen produces secondary metabolites that are harmful to both plants and animals. Secondary metabolites are not essential for survival, instead, they enable the pathogen to successfully infect its host. In fungi, genes necessary to produce secondary metabolites are often arranged together in the genome, forming secondary metabolic clusters (SMCs). The F. graminearum genome contains 76 such clusters with a potential to produce a diverse array of secondary metabolites (SMs). However, given high functional specificity and energetic cost, most of these clusters remain silent, or "cryptic," unless the organism is subjected to an environment conductive to SM production. Alternatively, SMCs can be activated by genetically manipulating their activators or repressors. The goal of this dissertation is to establish the transcriptional factor TRI6 and the MAP kinase MGV1 as regulators of secondary metabolism by genetically altering their expression and thus activating cryptic SMCs in F. graminearum. TRI6 is a transcriptional factor that regulates the trichothecene group of mycotoxins and other non-trichothecene genes. MGV1 is a MAP kinase, implicated in regulation of diverse cellular responses, including secondary metabolite biosynthesis. We used transcriptomic and metabolomic analyses to identify SMCs regulated by TRI6 and MGV1. We discovered that at the transcriptional level, MGV1 and TRI6 co-regulate biosynthesis of four SMs; however, MGV1 also exerts its control of three SMCs at the post-transcriptional level. Finally, at the mechanistic level, we demonstrate that TRI6 regulates the trichothecene genes by directly binding to the promoters of the genes of the cluster. However, the regulation of other SMCs such as gramillin is achieved indirectly, through physical binding of TRI6 to the cluster-specific protein GRA2
Hydrogen-Bonding Interactions in T-2 Toxin Studied Using Solution and Solid-State NMR
No full textThe structure of T-2 toxin in the solid-state is limited to X-ray crystallographic studies, which lack sufficient resolution to provide direct evidence for hydrogen-bonding interactions. Furthermore, its solution-structure, despite extensive Nuclear Magnetic Resonance (NMR) studies, has provided little insight into its hydrogen-bonding behavior, thus far. Hydrogen-bonding interactions are often an important part of biological activity. In order to study these interactions, the structure of T-2 toxin was compared in both the solution- and solid-state using NMR Spectroscopy. It was determined that the solution- and solid-state structure differ dramatically, as indicated by differences in their carbon chemical shifts, these observations are further supported by solution proton spectral parameters and exchange behavior. The slow chemical exchange process and cross-relaxation dynamics with water observed between the hydroxyl hydrogen on C-3 and water supports the existence of a preferential hydrogen bonding interaction on the opposite side of the molecule from the epoxide ring, which is known to be essential for trichothecene toxicity. This result implies that these hydrogen-bonding interactions could play an important role in the biological function of T-2 toxin and posits towards a possible interaction for the trichothecene class of toxins and the ribosome. These findings clearly illustrate the importance of utilizing solid-state NMR for the study of biological compounds, and suggest that a more detailed study of this whole class of toxins, namely trichothecenes, should be pursued using this methodology
L1 coupling to ankyrin and the spectrin‐actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis
No full textEthanol causes fetal alcohol spectrum disorders (FASD) partly by inhibiting cell adhesion mediated by the L1 neural cell adhesion molecule. Ethanol interacts with an alcohol binding pocket in the L1 extracellular domain (ECD), and dephosphorylation of S1248 in the L1 cytoplasmic domain (CD) renders L1 adhesion insensitive to inhibition by ethanol (L1 insensitive). The mechanism underlying this inside-out signaling is unknown. Here we show that phosphorylation of the human L1-CD at S1152, Y1176, S1181, and S1248 renders L1 sensitive to ethanol by promoting L1 coupling with ankyrin-G and the spectrin-actin cytoskeleton. Knockdown of ankyrin-G or L1 mutations that uncouple L1 from ankyrin reduce L1 sensitivity to ethanol, but not methanol, consistent with a small conformational change in the extracellular alcohol binding pocket. Phosphorylation of Y1176 and ankyrin-G coupling with L1 are higher in NIH/3T3 clonal cell lines in which ethanol inhibits L1 adhesion than in ethanol-resistant NIH/3T3 clonal cell lines. Similarly, phosphorylation of Y1176 is higher in C57BL/6J mice that are sensitive to ethanol teratogenesis than in ethanol resistant C57BL/6N mice. Finally, polymorphisms in genes that encode ankyrin-G and p90rsk, a kinase that phosphorylates S1152, are linked to facial dysmorphology in children with heavy prenatal ethanol exposure. These findings indicate that genes that regulate L1 coupling to ankyrin may influence susceptibility to FASD.-Dou, X., Menkari, C., Mitsuyama, R., Foroud, T., Wetherill, L., Hammond, P., Suttie, M., Chen, X., Chen, S.-Y., Charness, M. E., Collaborative Initiative on Fetal Alcohol Spectrum Disorders. L1 coupling to ankyrin and the spectrin-actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis
• Dowlat va Foroudastan. Faraz va Foroud Tajaddod Ameraneh dar Torkiyeh va Iran,Gerdavarandeh va Talif
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Evaluation of the IL-6 Gene in External Apical Root Resorption Associated with Orthodontic Treatment
No full textIndiana University-Purdue University Indianapolis (IUPUI)The objective of this project is to investigate the possibility that a functional polymorphism of the interleukin-6 (IL-6) gene is associated with external apical root resorption (EARR) during orthodontic tooth movement. If genes that are involved in EARR could be identified and easily screened, the orthodontist could adjust the patient's treatment plan accordingly. Having information about a patient's susceptibility to EARR could help diagnose and treat a patient accordingly. This would allow orthodontists to monitor patients more closely or modify the treatment plan to minimize the amount EARR.
The study sample consists of 60 subjects from 36 different families. The siblings had received orthodontic treatment at Indiana University School of Dentistry or in the private practice of Dr. James V. Macri. EARR was not a prerequisite to be included in this sample. Informed consent was obtained for sample collection. This study received Indiana University School of Dentistry Student Research Subcommittee Review and Indiana University Purdue University at Indianapolis Institutional Review Board approval.
No significant difference between any of the IL-6 genotypes and EARR could be noted. The hypothesis that individuals with the IL-6 -174 C/C genotype would show a greater amount of EARR during orthodontic treatment could not be supported
Evaluation of the IL-6 Gene in External Apical Root Resorption Associated with Orthodontic Treatment
No full textIndiana University-Purdue University Indianapolis (IUPUI)The objective of this project is to investigate the possibility that a functional polymorphism of the interleukin-6 (IL-6) gene is associated with external apical root resorption (EARR) during orthodontic tooth movement. If genes that are involved in EARR could be identified and easily screened, the orthodontist could adjust the patient's treatment plan accordingly. Having information about a patient's susceptibility to EARR could help diagnose and treat a patient accordingly. This would allow orthodontists to monitor patients more closely or modify the treatment plan to minimize the amount EARR.
The study sample consists of 60 subjects from 36 different families. The siblings had received orthodontic treatment at Indiana University School of Dentistry or in the private practice of Dr. James V. Macri. EARR was not a prerequisite to be included in this sample. Informed consent was obtained for sample collection. This study received Indiana University School of Dentistry Student Research Subcommittee Review and Indiana University Purdue University at Indianapolis Institutional Review Board approval.
No significant difference between any of the IL-6 genotypes and EARR could be noted. The hypothesis that individuals with the IL-6 -174 C/C genotype would show a greater amount of EARR during orthodontic treatment could not be supported
Genetics of Root Resorption Associated with Orthodontic Force in Mice
No full textIndiana University-Purdue University Indianapolis (IUPUI)External apical root resorption (EARR) is a common complication of orthodontic treatment. Genetic factors account for approximately 50% of the variation in EARR. Data have indicated variation in histological root resorption associated with orthodontic force (RRAOF) among different inbred strains of mice. Differences in expression of RANKL and OPG were investigated in two strains of mice with different susceptibility to RRAOF using irnmunohistochemistry. Increased localization of RANKL was detected in the tissues surrounding the root of the susceptible strain compared to the resistant strain and the controls. In contrast, increased localization of OPG was found in the tissues surrounding the roots in the resistant A/J strain compared to the susceptible DBA/2J strain. We conclude that differences in the expression of these key bone resorption mediators play a role in determining RRAOF susceptibility. Changes in serum TRAP 5b level in response to orthodontic force were investigated among female A/J, DBA/2J and BALB/cJ mice. The three strains differed in their TRAP positive cell numbers as well as their serum TRAP 5b
level at baseline and when treated. A significant increase in the serum TRAP 5b level with treatment was only detected in the RRAOF susceptible DBA/2J strain, and not in RRAOF resistant strains. Our analysis indicates that differences in osteoclast/odontoclast activity play a role in susceptibility to RRAOF that is genetically determined. Serum TRAP 5b levels have a potential role in screening for individuals with greater susceptibility to root resorption. RRAOF was determined for male and female mice of the A/J, DBA/2J and BALB/cJ strains, as well as A/J x DBA/2J and A/J x BALB/cJ crosses. Sex differences were observed among the BALB/cJ strain only, with females more resistant to RRAOF when compared to males. Fis from the A/J x BALB/cJ cross were resistant suggesting that the A/J have dominant resistance alleles, while Fis from the A/J x DBA/2J cross had RRAOF intermediate between their parental A/J and DBA/2J mice, suggesting a polygenic trait. We concluded that the mode of inheritance of RRAOF in mice was polygenic in
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