Genetic Mapping of Modifiers in Prenatal Lethal Tgfb1 Knockout Mice

This thesis presents data obtained from genetic analysis of TGFB1 knockout neonates (Shull et al., 1992, Kulkarni et al., 1993) bred onto different genetic backgrounds. TGFB1(-/-) embryos were initially reported to develop to term normally and die by 3 weeks due to multisystemic inflammation (Shull et al., 1992; Kulkarni et al., 1993). Therefore, it was suggested that TGFB1 was not vital during embryogenesis. However, an independent group (Dickson et al., 1995) demonstrated the implication of TGFB1 in an early stage of embryogenesis. It was shown that 50% of the TGFB1(-/-) embryos died in uterus due to defects in yolk sac vasculogenesis and haematopoiesis, whereas the rest did not succumb to the yolk sac phenotype but developed to term normally and died by 3 weeks post-partum as described previously (Kulkarni et al 1993). It has also been shown that maternal TGFB1 can cross the placenta (Letterio et al., 1994). TGFB1 was detected in TGFB1(-/-) embryos born to TGFB1(+/-) females, whereas in those born to null females, TGFB1 was not detected. Thus, it has been suggested that Tgfb1 gene knockout was not equivalent to a protein knockout and the maternally acquired protein could rescue TGFB1(-/-) foetuses and embryos. The work accomplished in this project set out to determine the reason for the existence of at least two different phenotypes; yolk sac insufficiency and survival to birth, among TGFB1(-/-) conceptuses. During this study, the involvement of several possible genetic and/or non-genetic modifying factors in the different expressivity of the TGFB1(-/-) phenotype was examined. The phenotype of TGFB1(-/-) was studied by breeding the Tgfb1 null allele onto two inbred strains; NIH/Ola and C57BI/6J/Ola. Also TGFB1(-/+) heterozygous crosses between various combinations of NIH/Ola and C57BI/6J/Ola enabled study of the possible implications of maternal factors in the different expressivity of the TGFB1(-/-) phenotype. It was estimated that one locus with a codominant pattern of inheritance was responsible for the different expressivity. Due to the codominant behaviour of the modifying gene(s), the F2(NIH/Ola x C57BI/6J/Ola) intercross animals were considered to be the most informative animals for genetic linkage analysis. 50 polymorphic DNA markers were utilised to initiate a genome-wide search by screening 50 TGFB1(-/-) neonates from an F1 intercross. More than 90% of the genome was screened for modifying gene(s) during this study. Four regions of the genome showed suggestive linkage (P<0.05) in the first screen. To confirm the linkages, 30 extra null animals were screened with the interested markers. A small region of mouse chromosome 5 harbouring a genetic modifier met the criterion of definitive linkage (P?10-5). During this project, the feasibility of mapping genetic factors involved in determining early embryonic lethality without need to access the embryos was demonstrated. Fibroblast growth factor receptor type 3 {Fgfr3) and Fibroblast growth factor inducible gene 13 (Fin13), which mapped in the vicinity of the modifying gene, were considered as candidate genes. The expression of these genes were assessed in 9.5 d.pc. embryos and yolk sacs bred onto either NIH/Ola or C57BI/6J/Ola strains by application of RT-PCR. Also expression of Transforming growth factor beta I (Tgfb1) gene was examined in 9.5 d.pc both yolk sac and embryo bred onto either of the strains. By application of heteroduplex analysis (HA) and direct DNA sequencing, the possibility of genetic polymorphism within Fin13 between the two mouse strains was investigated over the coding region. The latter part of the thesis presents data about the genetical mapping of Transforming Growth Factor Beta type II receptor (Tgfbr2) and Plasminogen activator inhibitor type I (PlanHI) on the mouse genome. Following the mapping Tgfbr2 on the mouse genome, two uncloned mouse mutants which mapped in the vicinity of the Tgfbr2 location were examined, by Southern blotting, for the possibility of a large deletion in Tgfbr2 gene in either of these mutants

Association Analysis of LOC387715 Gene Polymorphism (A69S) rs10490924 with Age-Related Macular Degeneration in a Population of Tabriz

Background & objectives: Age-related macular degeneration (AMD) is a disease affecting the central vision and causing irreversible blindness in aging patients. AMD is a complex disease caused by the actions and interactions of multiple genes and environmental factors. Genomic region at chromosome 10q26 may have a bigger role in susceptibility to AMD. Age-related maculopathy susceptibility 2 (LOC387715/age-related maculopathy susceptibility 2(ARMS2)) gene at 10q26 is associated with the risk of AMD. Here we studied (A69S) rs10490924 polymorphism of LOC387715 gene in AMD patients from East Azerbaijan province of Iran. Methods: In this case-control study, the association of G>T in LOC387715/ARMS2 (A69S) rs10490924 polymorphism was investigated in 63 patients suffering from AMD and 150 healthy age, sex and ethnicity matched unrelated people as control group from northwest of Iran by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Results: Statistical analysis showed high frequency of TT genotype in AMD patients (34.92%) compared to those of control group (6.67%), (p value=0.000 OR=11.9). The frequency of heterozygotes (GT) was 32.67% in control group and 38.1% in the case group (p=0.422). The frequency of homozygotes (GG) was 60.66% in control group and 26.98% in the case group (p=0.000). Genotype analysis of LOC387715 like other studies in Chinese, Japan and a population in Iran revealed significant association in distribution between patients and controls. Conclusion: The data suggest that individuals from East Azerbaijan carrying TT genotype in LOC387715 have 11.9 times more risk of developing AMD compared to those carrying non-TT genotypes

Association of G103T Polymorphism of Coagulation Factor XIII with Recurrent Pregnancy Loss in Northwest of Iran

Background & objectives: Recurrent miscarriage (RM) occurs in 1&ndash;3% of couples attempting to bear children. Thrombophilia is one of the suspected causes of recurrent miscarriage. The factor XIII makes the clot stable at the end of coagulation cascade. The polymorphism G103T of factor XIII gene is the most common polymorphism that affects F XIII activity. We aimed to study the possible association of FXIII gene polymorphism (V34L) with recurrent miscarriage among patients in Northwest of Iran. Methods: The study groups consisted of 70 patients with two or more consecutive miscarriages. The control group included 50 women with at least two successful deliveries and no history of pregnancy loss.&nbsp; DNA from both groups analyzed for carrying mutation of FXIII by PCR-RFLP. The &nbsp;test used for statistical analyze. Results: Two patients (%2.85) in the case group were homozygote (TT) for 34 Leu mutation whereas no homozygote (TT) was found in control group (p>0.05). 19 patients (%27.1) in the case group and 13 women (%26) in the control group were found to be heterozygote for G103T polymorphism (p>0.05). No significant difference was observed between patients with RPL and healthy women for G103T mutation. Conclusion: No statistically difference was observed between case and control group

A protocol for digital signature based on the elliptic curve discrete logarithm problem

Digital signature and cryptography algorithms based on the Elliptic Curve Discrete Logarithm Problem (ECDLP) have recently received significant attention by researchers due to their high performances. In this research, a novel protocol for digital signature based on the ECDLP has been presented which in comparison with the other protocols is shown to be more efficient. An acceptable security level of the proposed protocol similar to other protocols is also verified. The performance and the time complexity of the proposed protocol in comparison to previous protocols is analyzed and some advantages outlined

Genetic pattern of cystic fibrosis patients in Azeri Turkish population

Objective ― This study was designed to analyze the genetic pattern of cystic fibrosis and effects on age, sex and mortality in the Azeri Turkish population in Iran. Material and Methods ― This study was a descriptive study that was conducted for cystic fibrosis patients in Azeri Turkish population in Iran from 2001 to 2014. Of 331 patients, the spectrum of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in 263 patients was reviewed. Demographic and genetic data of patients were summarized by descriptive analysis as frequency, percentage, mean and median. Results ― The frequency consanguineous marriages was 196 (59.2%) positive and 135 (40.8%) negative with a significant difference (P=0.001). We identified 32 known mutations and 74 kinds of genotypes. The most common mutation and genotype were ∆F508 138 (26.2%) and ∆F508/ ∆F508 41 (15.5%), respectively. The most mortality rate had observed in ∆F508 genotypes. Conclusion ― These findings indicate high frequency of consanguinity marriage in this area. A low frequency of the ∆F508 mutation and detection 32 mutations reflect a heterogeneous spectrum of the mutations in this ethnic group. Further examinations are necessary on CFTR gene and affect these items on on age, sex and mortality

Tumor necrosis factor gene polymorphisms in advanced non-exudative age-related macular degeneration

Purpose: To investigate tumor necrosis factor (TNF)-α gene polymorphisms in advanced dry-type age-related macular degeneration (AMD) in a population from Northeastern Iran. Methods: In this case-control study, 50 patients with geographic macular atrophy and 73 gender-matched controls were enrolled. Genomic deoxyribonucleic acid (DNA) was extracted from the peripheral blood. Polymerase chain reaction was performed to analyze 2 candidate single nucleotide polymorphisms in the TNF-α gene, namely −1031 thymine (T)/cytosine (C) and −308 guanine (G)/adenine (A). Results: The distribution of the - 1031 T/C genotype was TT, 62%; TC, 36%; CC, 2% in the patients and TT, 60%; TC, 36%; CC, 4% in the controls (P = 0.94). Genotype analysis of TNF-α −308 also revealed no significant difference in distribution between patients (G, 78%; GA, 22%; AA, 0%) and controls (GG, 74%; GA, 23%; AA, 3%) (P = 0.51). None of the haplotypes nor alleles of studied TNF-α polymorphisms were significantly associated with advanced dry-type AMD. Conclusion: The findings of this study show that polymorphisms in the TNF-α gene, do not play an important role in dry-type AMD in the studied population

A Multipurpose and Highly-Compact Plasmonic Filter based on Metal-Insulator-Metal Waveguides

A multipurpose and ultra-compact nanoplasmonic wavelength filter based on stub structure in a metal-insulator-metal (MIM) waveguide is suggested and numerically investigated. A novel approach of connecting two stepped-like apertures to both input and output ports is applied to form Fabry-Perot (FP) cavities, which enabled the structure to act as a dual band-pass filter at wavelengths 1310 nm and 1550 nm. It is shown that the variation in cavities’ length allows to realize a long-wavelength cutoff filter, and cutoff wavelength can be easily tuned by adjusting the length of the cavities. Furthermore, it is revealed that increasing the gap between the stepped-like apertures and the cavities provides a triple band-pass at telecom wavelengths, e.g. 1267.5nm, 1414.19 nm, and 1644.7 nm. The tunable broadband high-pass wavelength filter is then achieved while the lengths of stepped-like apertures and stub resonators are set to be identical. Finally, a tunable nearly perfect absorber can be obtained by varying the width of stub resonators. Therefore, because of functionality, size, as well as efficiency the proposed plasmonic filter may greatly contribute to miniaturization of next generation of photonic integrated circuits (PICs), and find applications in on-chip integration and wavelength-division multiplexing (WDM) in optical communication systems

Helicobacter pylori vacA i region polymorphism but not babA2 status associated to gastric cancer risk in northwestern Iran

Abstract Helicobacter pylori-specific genotypes have been strongly associated with an increased risk of gastric cancer (GC). The aim of the present work was to study the associations of H. pylori virulence factors, vacA i region polymorphisms and babA2 status with GC risk in Azerbaijan patients. The DNA extracted from gastric biopsy specimens was used to access the babA2 and vacA genotypes. Overall, babA2 was present in 85.39 % (76/89) of H. pylori strains: 19 out of 24 (79.16 %) strains from GC, 16 out of 17 (94.14 %) strains from peptic ulcer disease (PUD) and 41 out of 48 (85.14 %) strains from chronic gastritis. No significant association was found between babA2 genotype and clinical outcomes (P [ 0.05). i1 vacA polymorphism was detected in 46/89 (51.68 %) strains: in 21/24 (87.5 %), 6/17 (35.29 %) and 19/48 (39.58 %) patients with GC, PUD and chronic gastritis, respectively. i2 allele was detected in 43 (48.31 %) out of all 89 strains examined: 3 (14.28 %) of 24 strains from GC, 11 (64.71 %) of 17 from PUD, and 29 (60.42 %) of 48 strains from chronic gastritis. In this study, multiple linear regression analysis confirmed the strong association of i1 allele with GC (partial regression correlation 0.455 ± 0.101; P = 0). Results of multiple logistic regression analysis showed that vacA i1 genotype was significantly associated with GC compared with a control group (gastritis) (odds ratio 13.142, 95 % CI 3.116-55.430; P = 0). Findings from the measurement of H. pylori babA2 and vacA genotypes indicate a strong correlation between the vacA i1 allele and GC risk in the Azerbaijan area of Iran

Prevalence of the MEFV gene mutations and their clinical correlations in Azeri Turkish patients with childhood Henoch-Schonlein purpura: The role of M680I and E148Q mutations

Introduction: Patients with Henoch-Shonlein purpura (HSP) have higher rates of Mediterranean fever (MEFV) mutations comparing general population. To our knowledge, there is no report in this regard among Azeri Turkish children. In this study, we evaluated the prevalence of MEFV mutations and their clinical and laboratory correlations in Azeri Turkish children with HSP. Methods: In this case-control study, we included 40 unrelated patients from Azeri Turk origin diagnosed with HSP between January 2010 and March 2011. The control group consisted of 100 healthy unrelated subjects. Genomic deoxyribonucleic acid (DNA) was extracted from peripheral blood leukocytes using standard protocols. Each sample was initially analyzed for the five common mutations (M694V, M694I, M680I, V726A and E148Q). Results: From 40 patients with HSP, 10 patients (25.0%) had one MEFV mutation. Both patient groups (with and without mutation) were similar regarding clinical manifestations and age at the onset of disease. Frequency of female gender was higher in patients with the mutation. MEFV mutations were found in 26.0% of control group among them 19.2% had V726A and 80.8% had E148Q mutation. There was no significant difference in total mutations between patients and controls. Frequency of M680I mutation was significantly higher in HSP patients than controls (P = 0.020). E148Q mutation was much higher in the control group than HSP patients, but the difference was not statistically significant (P = 0.053). Conclusion: There was no difference in the clinical spectrum of patients with and without MEFV mutation. M680I mutation may have a probable predisposing role for HSP

MEFV mutations in Northwest of Iran: a cross sectional study

Objective(s):Familial Mediterranean Fever (FMF) is an autosomal recessive disorder characterized by recurrent episodes of fever accompanied by peritonitis, pleurisy, and arthritis. FMF affects mainly Mediterranean populations and is caused by mutations in the familial Mediterranean fever (MEFV) gene. The aim of this study was to identify the frequency and distribution of MEFV mutations in Iranian Azerbaijanis with FMF. Materials and Methods:Medical records of 1330 Iranian Azerbaijanis who were diagnosed with FMF according to Tel-Hashomer criteria from May 2006 to April 2013 were reviewed and 10 MEFV mutations were found in affected individuals. Results:243 patients (18.27%) were homozygous, 370 (27.82%) were compound heterozygous and 717 (53.91%) were identified as heterozygous for one of the studied mutations. Of the studied mutations, M694V, E148Q, V726A, M680I, and M694I accounted for 42%, 21%, 19%, 14% and 2% of mutations respectively. Conclusion:In our study, M694V was found to be the most prevalent mutation. M694I, the most common mutation among Arabs, is rare in this cohort. Allele frequencies of the common mutations in our studied population have some similarities to those of the Turkish population reported previously. However, M680I is less common in our cohort