LRRK2 and RIPK2 variants in the NOD 2-mediated signaling pathway are associated with susceptibility to Mycobacterium leprae in Indian populations

In recent years, genome wide association studies have discovered a large number of gene loci that play a functional role in innate and adaptive immune pathways associated with leprosy susceptibility. The immunological control of intracellular bacteria M. leprae is modulated by NOD2-mediated signaling of Th1 responses. In this study, we investigated 211 clinically classified leprosy patients and 230 ethnically matched controls in Indian population by genotyping four variants in NOD2 (rs9302752A/G), LRRK2 (rs1873613A/G), RIPK2 (rs40457A/G and rs42490G/A). The LRRK2 locus is associated with leprosy outcome. The LRRK2 rs1873613A minor allele and respective rs1873613AA genotypes were significantly associated with an increased risk whereas the LRRK2 rs1873613G major allele and rs1873613GG genotypes confer protection in paucibacillary and leprosy patients. The reconstructed GA haplotypes from RIPK2 rs40457A/G and rs42490G/A variants was observed to contribute towards increased risk whereas haplotypes AA was observed to confer protective role. Our results indicate that a possible shared mechanisms underlying the development of these two clinical forms of the disease as hypothesized. Our findings confirm and validates the role of gene variants involved in NOD2-mediated signalling pathways that play a role in immunological control of intracellular bacteria M. leprae

Haplogroup heterogeneity of LHON patients carrying the m.14484T>C mutation in India

Purpose: To investigate the clinical and mitochondrial DNA (mtDNA) haplogroup background of Indian Leber Hereditary Optic Neuropathy (LHON) patients carrying the m.14484T>C mutation. Methods: Detailed clinical investigation and complete mtDNA sequencing analysis was carried out for eight Indian LHON families with the m.14484T>C mutation. Haplogroup was constructed based on the evolutionarily important mtDNA variants. Results: In the present study, we characterized eight unrelated probands selected from 187 LHON cases. The overall penetrance of the disease was estimated to be 19.75% (16/81) in eight pedigrees with the m.14484T>C mutation and showed substantially higher sex bias (male:female = 13:3). The mtDNA haplogrouping revealed that they belong to diverse haplogroups; i.e. F1c1, M31a, U2a, M*, I1, M6, M3a1 and R30a. Interestingly, we did not find an association of the m.14484T>C mutation with any specific haplogroup within the Indian population. We also did not find any secondary mutation(s) in these pedigrees, which might affect the clinical expression of LHON. Conclusions: Contrary to earlier reports showing preferential association of the m.14484T>C mutation with western Eurasian haplogroup J and increased clinical penetrance when present in J1 subhaplogroup background, the present study shows that m.14484T>C arose independently in a different mtDNA haplogroup and ethnic background in India, which may influence the clinical expression of the disease

Explaining the Atypical Reaction Profiles of Heme Enzymes with a Novel Mechanistic Hypothesis and Kinetic Treatment

Many heme enzymes show remarkable versatility and atypical kinetics. The fungal extracellular enzyme chloroperoxidase (CPO) characterizes a variety of one and two electron redox reactions in the presence of hydroperoxides. A structural counterpart, found in mammalian microsomal cytochrome P450 (CYP), uses molecular oxygen plus NADPH for the oxidative metabolism (predominantly hydroxylation) of substrate in conjunction with a redox partner enzyme, cytochrome P450 reductase. In this study, we employ the two above-mentioned heme-thiolate proteins to probe the reaction kinetics and mechanism of heme enzymes. Hitherto, a substrate inhibition model based upon non-productive binding of substrate (two-site model) was used to account for the inhibition of reaction at higher substrate concentrations for the CYP reaction systems. Herein, the observation of substrate inhibition is shown for both peroxide and final substrate in CPO catalyzed peroxidations. Further, analogy is drawn in the “steady state kinetics” of CPO and CYP reaction systems. New experimental observations and analyses indicate that a scheme of competing reactions (involving primary product with enzyme or other reaction components/intermediates) is relevant in such complex reaction mixtures. The presence of non-selective reactive intermediate(s) affords alternate reaction routes at various substrate/product concentrations, thereby leading to a lowered detectable concentration of “the product of interest” in the reaction milieu. Occam's razor favors the new hypothesis. With the new hypothesis as foundation, a new biphasic treatment to analyze the kinetics is put forth. We also introduce a key concept of “substrate concentration at maximum observed rate”. The new treatment affords a more acceptable fit for observable experimental kinetic data of heme redox enzymes

COMPARATIVE AND CROSS-SECTIONAL STUDY OF SUCCESSES OF THE LEPROSY ELIMINATION STRATEGY BEFORE (2000 TO 2005) AND AFTER (2006 TO 2010) ERADICATION PERIOD IN REFERRAL HOSPITAL OF TAMIL NADU

To assess the successes of the leprosy elimination strategy before (2000 to 2005) and after (2006 to 2010) eradication period in referral hospital of Tamilnadu District. Retrospective  cross-sectional  study  of  all  registered  new cases  of  leprosy  carried out from records  over  a  ten  year  period from referral Sacred heart leprosy hospital, Kummbakkonam, Tamil Nadu. During the survey, total number of 5,794 new leprosy cases registered during 2000 to 2010 between before and after eradication period at referral leprosy hospital. Comparative analysis of 5 years of before and after eradication period survey shows that the total number of multibacillary and paucibacillary cases registered before eradication was 4177and after eradication it was reduced to1617, in that multibacillary cases reduced from 2724 to 1150 after eradication and paucibacillary cases reduced from 1453 to 467 cases. According to this analysed report concluding that the total number of leprosy cases reported in referral hospital per day before eradication was 2.28 and after eradication it was reduced to 0.88 cases per day. Leprosy was still an important public health problem and was getting out of control in some districts in Tamil Nadu, south India. However, leprosy elimination is well within sight, and after eradication period also risk of the leprosy cases in endemic districts. So leprosy awareness days and community-based surveillance could help to improve early detection, treatment, case holding and prevention of disabilities. Increase the awareness program for endemic districts is a very well method in decrease the leprosy. Keywords: Leprosy, Multibacillary, Paucibacillary, Multi Drug Therap

Analysis of isolated phase windings and permanent magnet assists high energy efficient hybrid‐reluctance motor for electric vehicle

Abstract This article describes the electromagnetic analysis of high efficient hybrid motor, which comprises the salient features of switched reluctance motor (SRM) and spoke‐type brushless DC motor. The main objective is to develop a motor with a high‐power density and winding faulty capability. Furthermore, this research article extends in the manner to increase the power density of the motor through the sensitivity analysis on rotor geometry by replacing the rotating part of SRM and adopting the rotor of spoke type brushless DC motor, originating the hybrid motor with the high‐power density and enhanced efficiency. To ensure the winding fault capability, a SRM‐based stator winding is adopted. Then, the modelling process for hybrid motor 48 V, 1500 RPM, 2 kW, and 12.7 Nm are detail in both analytical and finite element methods. The electromagnetic analysis is carried out to estimate the torque characteristics and flux pattern of the proposed motor. Furthermore, the proposed motor is analysed with the selection of laminating core material among M 27 24 Ga, 36F155, 46F165, 47F165, M 420 50D, and arnon 7. This infers 36F155 material assists proposed motor has high‐performance characteristics. The vibration frequencies are investigated in modal aspects to estimate the natural frequencies of vibrations. These analyses are validated among analytical and finite element results under no‐load conditions

Single nucleotide polymorphisms in homocysteine metabolism pathway genes: association of CHDH A119C and MTHFR C677T with hyperhomocysteinemia

Background—An elevated level of homocysteine (hyperhomocysteinemia) has been implicated as an independent risk factor for cardiovascular diseases. Deficiency of dietary factors like vitamin B12, folate and/or genetic variations can cause hyperhomocysteinemia. The prevalence of hyperhomocysteinemia in Indian population is likely to be high since a majority of Indians adhere to a vegetarian diet, deficient in vitamin B12. In the background of vitamin B12 deficiency, variations in genes involved in homocysteine metabolism might have a greater impact on homocysteine levels. Methods and Results—We genotyped 44 non-synonymous single nucleotide polymorphisms (nsSNPs) from 11 genes involved in homocysteine metabolism and found only 14 to be polymorphic. These 14 nsSNPs were genotyped in 546 individuals recruited from a tertiary care centre in New Delhi, India and it was found that choline dehydrogenase (CHDH A119C) and methylenetetrahydrofolate reductase (MTHFR C677T) were significantly associated with plasma total homocysteine levels (p=0.009 and p=0.001 respectively). These 2 SNPs were further genotyped in 330 individuals recruited from the same centre and the association remained significant even after increasing the sample size. Further, we found the possibility of a significant interaction between vegetarian diet and the two polymorphisms that could explain the variation of homocysteine levels. We also genotyped all the polymorphic nsSNPs in apparently healthy individuals recruited from 24 different sub-populations (based on their linguistic lineage) spread across the country to determine their basal frequencies. The frequencies of these SNPs varied significantly between linguistic groups. Conclusion—Vegetarian diet along with CHDH A119C and MTHFR C677T play an important role in modulating the homocysteine levels in Indian population

Genetic evidence of TAP1 gene variant as a susceptibility factor in Indian leprosy patients

The heterodimeric transporter associated with antigen processing (TAP) gene loci is known to play a vital role in immune surveillance. We investigated a possible association of gene polymorphisms both in TAP1 and TAP2 in a cohort of clinically classified leprosy patients (n = 222) and in ethnically matched controls (n = 223). The TAP1 and TAP2 genes were genotyped for four single nucleotide polymorphisms TAP1 (rs1057141 Iso333Val and rs1135216 Asp637Gly) and TAP2 (rs2228396 Ala565Thr and rs241447 Ala665Thr) by direct sequencing and ARMS-PCR. The minor allele of TAP1 637G contributes to an increased risk to leprosy compared to controls (OR: 1.68, 95% CI 1.2–2.36, P = 0.0057). An increased risk for the variant minor allele of the TAP1 637G to multibacillary (BL + LL) or paucibacillary (BT + TT) infections was also observed [multibacillary vs. controls (OR: 1.56, 95% CI 1.07–2.28, P = 0.054); paucibacillary vs. controls (OR: 1.92, 95% CI 1.21–3.01, P = 0.013)]. In the dominant model, the genotypes of the TAP1 rs1135216AG + GG additionally contributed to an increased risk. Overall our findings demonstrate that the TAP1 gene variant (rs1135216 Asp637Gly) influences the susceptibility to clinically classified leprosy patients in Indian population

Author Response: Penetrance of the LHON Mutation m.11778G>A May Depend on Factors Other Than Haplotype or Heteroplasmy Rate

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Distribution of investigated RIPK2 haplotypes in clinically classified leprosy patients and controls.

<p>Distribution of investigated RIPK2 haplotypes in clinically classified leprosy patients and controls.</p