Haplotype variation in the ACE gene in global populations, with special reference to India, and an alternative model of evolution of haplotypes

Angiotensin-I-converting enzyme (ACE) is known to be associated with human cardiovascular and psychiatric pathophysiology. We have undertaken a global survey of the haplotypes in ACE gene to study diversity and to draw inferences on the nature of selective forces that may be operating on this gene. We have investigated the haplotype profiles reconstructed using polymorphisms in the regulatory (rs4277405, rs4459609, rs1800764, rs4292, rs4291), exonic (rs4309, rs4331, rs4343), and intronic (rs4340; Alu [I/D]) regions covering 17.8 kb of the ACE gene. We genotyped these polymorphisms in a large number of individuals drawn from 15 Indian ethnic groups and estimated haplotype frequencies. We compared the Indian data with available data from other global populations. Globally, five major haplotypes were observed. High-frequency haplotypes comprising mismatching alleles at the loci considered were seen in all populations. The three most frequent haplotypes among Africans were distinct from the major haplotypes of other world populations. We have studied the evolution of the two major haplotypes (TATATTGIA and CCCTCCADG), one of which contains an Alu insertion (I) and the other a deletion (D), seen most frequently among Caucasians (68%), non-African HapMap populations (65–88%), and Indian populations (70–95%) in detail. The two major haplotypes among Caucasians are reported to represent two distinct clades A and B. Earlier studies have postulated that a third clade C (represented by the haplotypes TACATCADG and TACATCADA) arose from an ancestral recombination event between A and B. We find that a more parsimonious explanation is that clades A and B have arisen by recombination between haplotypes belonging to clade C and a high-frequency African haplotype CCCTTCGIA. The haplotypes, which according to our hypothesis are the putative non-recombinants (PuNR), are uncommon in all non-African populations (frequency range 0–12%). Conversely, the frequencies of the putative recombinant haplotypes (PuR) are very low in the Africans populations (2–8%), indicating that the recombination event is likely to be ancient and arose before, perhaps shortly prior to, the global dispersal of modern humans. The global frequency spectrum of the PuR and the PuNR is difficult to explain only by drift. It appears likely that the ACE gene has been undergoing a combination of different selective pressures. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11568-011-9153-6) contains supplementary material, which is available to authorized users

DNA sequence variation and haplotype structure of the ICAM1 and TNF genes in 12 ethnic groups of India reveal patterns of importance in designing association studies

We have examined the patterns of DNA sequence variation in and around the genes coding for ICAM1 and TNF, which play functional and correlated roles in inflammatory processes and immune cell responses, in 12 diverse ethnic groups of India. We aimed to (a) quantify the nature and extent of the variation, and (b) analyse the observed patterns of variation in relation to population history and ethnic background. At the ICAM1 and TNF loci, respectively, the total numbers of SNPs that were detected were 28 and 12. Many of these SNPs are not shared across ethnic groups and are unreported in the dbSNP or TSC databases, including two fairly common non-synonymous SNPs at positions 13487 and 13542 in the ICAM1 gene. Conversely, the TNF-376A SNP that is reported to be associated with susceptibility to malaria was not found in our study populations, even though some of the populations inhabit malaria endemic areas. Wide between-population variation in the frequencies of shared SNPs and coefficients of linkage disequilibrium have been observed. These findings have profound implications in case-control association studies

Expression of adenosine deaminase and 5’-nucleotidase in artificially induced deciduoma in rat and hamster

889-893<span style="font-size: 15.5pt;mso-bidi-font-size:8.5pt;font-family:" times="" new="" roman","serif";="" color:black"="">Enzymes adenosine deaminase (ADA) and 5-nucleotidase (5- 'NT) are known to play active role in tissue/cell proliferation and differentiation.  To validate this the two enzymes were studied in artificially induced  eciduoma of rat and hamster. The deciduoma was induced by traumatizing one of the uterine horns of progesterone primed animals .Non traumatized horn served as control. The animals were later maintained on progesterone, given alone (Gr.I) or conjointly with estrogen (Gr.II). <span style="font-size: 15.5pt;mso-bidi-font-size:8.5pt;font-family:" times="" new="" roman","serif";="" color:black"="">The weight of each uterine horn was recorded to determine the formation of deciduoma. There was no marked difference between the weights of traumatized and control horn on day 2 post- traumatization (PT), but a progressive rise was noticed after this day in both species. The ADA activity however differed, day and species wise. While in the rats of Gr.I it was low in the traumatized horn on all the days, in the hamsters it was remarkably high from day 2 to 6 PT. In the rats of Gr.II also the activity though was low in the traumatized horn, but on day 2 and 4 only; on day 6 and 7 PT it increased markedly. In hamster, on the contrary, again the enzyme activity was remarkably high on all the three days. The 5'-NT activity, however, did not show any marked difference between the two horns under Gr.I and II in both species. It was rather high in the control <span style="font-size:15.5pt;mso-bidi-font-size:8.5pt;line-height:115%; font-family:" times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";="" color:black;mso-ansi-language:en-us;mso-fareast-language:en-us;mso-bidi-language:="" ar-sa"="">horn of each group. The results suggest: <span style="font-size: 15.0pt;mso-bidi-font-size:8.0pt;line-height:115%;font-family:" times="" new="" roman","serif";="" mso-fareast-font-family:"times="" roman";color:black;mso-ansi-language:en-us;="" mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">(1) <span style="font-size:15.5pt;mso-bidi-font-size:8.5pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";color:black;="" mso-ansi-language:en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">the progesterone alone though produces a significant rise in the uterine weight of traumatized horn in both species, the ADA activity increases only in hamster, (2) under the conjoint treatment also the enzyme activity remains high in hamster; and (3) the activity of enzyme 5'-NT does not alter during the deciduoma formation in both the species.</span

Amphotericin B Nano-Assemblies Circumvent Intrinsic Toxicity and Ensure Superior Protection in Experimental Visceral Leishmaniasis with Feeble Toxic Manifestation

In spite of its high effectiveness in the treatment of both leishmaniasis as well as a range of fungal infections, the free form of the polyene antibiotic amphotericin B (AmB) does not entertain the status of the most preferred drug of choice in clinical settings. The high intrinsic toxicity of the principal drug could be considered the main impedance in the frequent medicinal use of this otherwise very effective antimicrobial agent. Taking into consideration this fact, the pharma industry has introduced many novel dosage forms of AmB to alleviate its toxicity issues. However, the limited production, high cost, requirement for a strict cold chain, and need for parenteral administration are some of the limitations that explicitly compel professionals to look for the development of an alternate dosage form of this important drug. Considering the fact that the nano-size dimensions of drug formulation play an important role in increasing the efficacy of the core drug, we employed a green method for the development of nano-assemblies of AmB (AmB-NA). The as-synthesized AmB-NA manifests desirable pharmacokinetics in the treated animals. The possible mechanistic insight suggested that as-synthesized AmB-NA induces necrosis-mediated cell death and severe mitochondrial dysfunction in L. donovani promastigotes by triggering depolarization of mitochondrial membrane potential. In vivo studies demonstrate a noticeable decline in parasite burden in the spleen, liver, and bone marrow of the experimental BALB/c mice host. In addition to successfully suppressing the Leishmania donovani, the as-formed AmB-NA formulation also modulates the host immune system with predominant Th1 polarization, a key immune defender that facilitates the killing of the intracellular parasite