Genetic variation of five blood group polymorphisms in ten populations of Assam,India

Six Mongoloid and four Caucasoid populations of Assam, India, were examined for A₁A₂BO, Rhesus, Duffy and Diego blood groups. The distribution of their phenotypes and allele frequencies are presented. In the perspective of the ethnographic background, the results have been discussed in terms of genetic variability among these populations and probable reasons for its existence. The major groups, namely Caucasoids and Mongoloids, appear to form two separate groups in terms of these blood groups, though evidence is there to suggest intermixture.     

A study of the A-1A-2BO blood group system and ABO(H) secretion in six endogamous groups of Punjab

2,596 Aroras and 2,629 Khatris comprising six endogamous groups of the Punjabis have been studied for A₁A₂BO blood groups and secretion of ABO(H) group specific substances. The values of chi-square and the genetical difference (G²) among these groups do not show statistically significant differences in these groups regarding the genetical characters studied. There is a closer affinity between Beri and Bunjahi on the one hand and Uttaradhi and Dhakhandian on the other and also between Uttaradhi and Khukhran; Dhakhandian and Sareen show a great difference among themselves as well as with other groups. The comparison of ABO blood group distribution and secretor factor among the different populations of India show that the distribution is similar among the North Indians.     

The SRY-1532 site of the human Y chromosome is subject to recurrent single nucleotide mutations

Haplotype determination based on three Y-linked polymorphic sites, 92R7 (C/T), SRY-1532 (A/G), and YAP (-/+), in 127 males belonging to three caste Hindu populations of South India (Vizag Brahmins, Peruru Brahmins, and Kammas) and 13 males belonging to a migrant group (the Siddis) showed the existence of all four haplotypes (CA-, CG-, TG-, and TA-) under the YAP- background. This finding suggests that the reverse mutation (G-->A) at the SRY-1532 site, described earlier in the literature, is present in South Indian populations as well. The YAP+ mutation was seen in only five Siddi individuals. Four of these were of the CG+ haplotype structure, but a novel haplotype (CA+) was found in one male. To explain the occurrence of the six haplotypes found within these three sites, a haplotype tree is constructed that introduces a new reverse mutation at the SRY-1532 site (G-->A), occurring under the CG+ background after the migrant Siddi population arrived in India.     

Blood groups of Roms (Gypsies) in Czechoslovakia

Blood groups in 2,935 Roms (Gypsies) of East Slovakia show the following frequencies of phenotypes and genes: A₁A₂BO phenotypes: A₁ — 32.91%, A₂ — 2.42%, B — 25.21%, O — 30.15%, A₁B — 8.45%, A₂B — 0.85%, A₁ — 0.2363, A₂ — 0.0217, B — 0.1929, O — 0.5491. MN phenotypes: M — 27.16%, MN — 51.60%, N — 21.23%; m — 0.5297, n — 0.4703. RH phenotypes: Rh positive — 89.54%, Rh negative — 10.46%; Rh – (D) — 0.6766, Rh (d) 0.3234. The frequencies are contrasted with those of other inhabitants, non-Roms of East Slovakia.     

ABO blood groups and ABH saliva secretion in Reddis and Kammas of Southern Andhra Pradesh

ABO blood groups and ABH saliva secretion were investigated in two caste populations, Reddis and Kammas of Southern Andhra Pradesh, and compared with the data of other populations. In ABO gene frequencies, the present series of Reddis and Kammas approach the values from other Andhra caste data. Moderate gene frequency of non-secretor gene in both Reddis and Kammas are noted.     

Distribution of HIV-1 resistance-conferring polymorphic allelesSDF-1-3′A, CCR2-64I andCCR5-Δ32 in diverse populations of Andhra Pradesh, South India

Polymorphic allelic variants of chemokine receptors CCR2 and CCR5, as well as of stromal-derived factor-1 SDF-1, the ligand for the chemokine receptor CXCR4, are known to have protective effects against HIV-1 infection and to be involved with delay in disease progression. We have studied the DNA polymorphisms at the loci that encode these proteins in 525 healthy individuals without any history of HIV-1 infection from 11 diverse populations of Andhra Pradesh, South India. The two protective allelesSDF-1-3′A andCCR2-64I at the SDF-1 and CCR2 loci, respectively, are present in all populations studied, although their frequencies differ considerably across populations (from 17% to 35% for theSDF-1-3′A allele, and from 3% to 17% forCCR2-64I). In contrast theCCR5-δ32 allele is observed only in three populations (Yamani, Pathan and Kamma), all in low frequencies (i.e. 1% to 3%). The mean number of mutant alleles (for the three loci together) carried by each individual varies from 0.475 (in Vizag Brahmins) to 0.959 (in Bohra Muslims). The estimated relative hazard values for the populations, computed from the three-locus genotype data, are comparable to those from Africa and Southeast Asia, where AIDS is known to be widespread.     

Microsatellite variation at 24 STR loci in three endogamous groups of Uttar Pradesh,India

We have studied variation at 24 microsatellite markers among 50 individuals from each of three endogamous groups, Bhargavas, Chaturvedis, and non-Bhargava, non-Chaturvedi Brahmins of Uttar Pradesh, India. The number of alleles at the loci tested varied from 4 to 11, with an average of 6 at each locus. Heterozygosity was found to be quite high at all loci in the three subpopulations. It varied between 0.44 to 0.84 among Bhargavas (average 0.6510), 0.44 to 0.80 among Chaturvedis (average 0.6633 +/-), and 0.42 to 0.85 among Brahmins (average 6.694 +/-). Hardy-Weinberg equilibrium analysis revealed that these populations are under genetic equilibrium at almost all the loci tested. Comparisons of allele frequency between Bhargavas and Chaturvedis showed that they differed significantly at 14 short tandem repeat (STR) markers (p < 0.001), while Chaturvedis and Brahmins differed at 6 (p < 0.05) and Brahmins and Bhargavas at 8 (p < 0.05). Average F(IS) and F(ST) for the 24 STR markers was -0.02 and 0.013, respectively. We used both un-weighted pair group with arithmetic mean and principal components analysis to evaluate genetic distances among the three groups. Our results revealed that although there were differences at particular allele frequencies between Bhargavas vs. Brahmins, Bhargavas vs. Chaturvedis, and Brahmins vs. Chaturvedis, these differences were not statistically significant when combined over all 24 STR markers between Chaturvedis vs. Brahmins and Bhargavas vs. Brahmins. The genetic distance analysis revealed that Bhargavas are slightly apart from the other two populations.     

Seasonal cycle in vitamin A1/A2-based visual pigment composition during the life history of coho salmon (Oncorhynchus kisutch)

Microspectrophotometry of rod photoreceptors was used to follow variations in visual pigment vitamin A₁/A₂ ratio at various life history stages in coho salmon. Coho parr shifted their A₁/A₂ ratio seasonally with A₂ increasing during winter and decreasing in summer. The cyclical pattern was statistically examined by a least-squares cosine model, fit to the 12-month data sets collected from different populations. A₁/A₂ ratio varied with temperature and day length. In 1+ (>12 month old) parr the A₂ to A₁ shift in spring coincided with smoltification, a metamorphic transition preceding seaward migration in salmonids. The coincidence of the shift from A₂ to A₁ with both the spring increase in temperature and day length, and with the timing of seaward migration presented a challenge for interpretation. Our data show a shift in A₁/A₂ ratio correlated with season, in both 0+ (<12 months old) coho parr that remained in fresh water for another year and in oceanic juvenile coho. These findings support the hypothesis that the A₁/A₂ pigment pair system in coho is an adaptation to seasonal variations in environmental variables rather than to a change associated with migration or metamorphosis.     

Glycolipid- and glycoprotein-based blood group A antigen expression in human thrombocytes. A1/A2 difference

Total non-acid glycolipid fractions and total sodium dodecylsulphate (SDS) solubilized protein fractions were isolated from human thrombocytes obtained from single human donors having different blood group A₁/A₂ phenotypes. The blood group A glycolipid antigens were characterized by immunostaining of thin layer plates with different monoclonal anti-A antibodies. The glycoproteins carrying blood group A epitopes were identified by SDS-PAGE and Western blot analysis using a monoclonal anti-A antibody. Blood group A glycolipid antigens were found in both A₁ and A₂ thrombocytes but the A₂ individuals expressed at least ten times less A glycolipids compared to the A₁ individuals. Expression of A type 3/4 chain and small amounts of A type 1 chain glycolipids were seen in thrombocytes of both A₁ and A₂ individuals, while the type 2 chain A glycolipids appeared to be missing from the A₂ thrombocytes. Blood group A reactive glycoproteins were only found in thrombocytes of A₁ individuals and could not be detected in A₂ individuals or a blood group O individual. The major blood group A glycoprotein were found as a double band migrating in the 130 kDa region.Abbreviations SDS sodium dodecyl sulfate - PAGE polyacrylamide gel electrophoresis - HPTLC high performance thin layer chromatography - CBB Coomassie brilliant blue - GVH graft versus host Part of this work was presented at the Xth International Symposium on Glycoconjugates, Jerusalem, Israel. September, 1989.In the short hand designation for glycolipids, the letter indicate blood group determinant, the first numeral, the number of sugar residues, and the second numeral, the type of carbohydrate chain. Thus, A-6-1 means a hexaglycosylceramide with a blood group A determinant based on the type 1 carbohydrate chain.     

Selective adenosine A2A receptor inhibitor SCH58261 reduces oligodendrocyte loss upon brain injury in young rats

Cellular elements of maturing brain are vulnerable to insults, which lead to neurodevelopmental defects. There are no established treatments at present. Here we examined the efficacy of selective adenosine A_2A receptor inhibitor SCH58261 to combat brain injury, particularly oligodendrocyte (OL) lineage cells, in young rats. Wistar rats (n = 24, 6.5 days old) were randomly divided into equal groups of four. The sham (SHAM) group received no treatment, the vehicle (VEHICLE) group received 0.1% dimethylsufoxide, the injury (INJ) group was exposed to oxygen-glucose deprivation insult, and the injury+SCH58261 (INJ+SCH58261) group was exposed to the insult and received 1 μM SCH58261. Immunocytochemical experiments revealed that there was a significant reduction in the populations of mature OL (MBP⁺ OLs) and immature OL precursors (NG2⁺ OPCs) in the INJ group compared to SHAM group. Furthermore, there was also a significant increase in the percent of apoptotic MBP⁺ OL and NG2⁺ OPC populations as evidenced by TUNEL assay. In addition, there was a significant reduction in the proliferation rate among NG2⁺ OPCs, which was confirmed by BrdU immunostaining. On the other hand, treatment with SCH58261 significantly enhanced survival, evidenced by the reduction in apoptotic indices for both cell types, and it is preserved the NG2⁺ OPC proliferation. Activation of adenosine A_2A receptors may contribute to OL lineage cell loss in association with decreased mitotic behavior of OPCs in neonatal brains upon injury. Future investigations assessing ability of SCH58261 to regenerate myelin will provide insights into its wider clinical relevance.     

Identification of novel thiazolo[5,4-d]pyrimidine derivatives as human A1 and A2A adenosine receptor antagonists/inverse agonists

In this study a new set of thiazolo[5,4-d]pyrimidine derivatives was synthesized. These derivatives bear different substituents at positions 2 and 5 of the thiazolopyrimidine core while maintaining a free amino group at position-7. The new compounds were tested for their affinity and potency at human (h) A₁, A_2A, A_2B and A₃ adenosine receptors expressed in CHO cells. The results reveal that the higher affinity of these new set of thiazolopyrimidines is toward the hA₁ and hA_2A adenosine receptors subtypes and is tuned by the substitution pattern at both the 2 and 5 positions of the thiazolopyrimidine nucleus. Functional studies evidenced that the compounds behaved as dual A₁/A_2A antagonists/inverse agonists. Compound 3, bearing a 5-((2-methoxyphenyl) methylamino) group and a phenyl moiety at position 2, displayed the highest affinity (hA₁ K_i?=?10.2?nM; hA_2A K_i?=?4.72?nM) and behaved as a potent A₁/A_2A antagonist/inverse agonist (hA₁ IC₅₀?=?13.4?nM; hA_2A IC₅₀?=?5.34?nM).     

Beta structure of periodic copolypeptides of L-alanine and glycine. Their relevance to the structure of silks

The β structure of seven periodic copolypeptides of l-alanine and glycine² namely: A₂G, AG, A₂G₂, A₃G₃, A₂G₃, AG₂ and AG₃ has been studied by infrared, X-ray and electron diffraction techniques. The sheets are made of anti-parallel chains and intersheet spacing is observed to depend both on residue sequence and composition. Samples with glycine molar fractions varying from 0.33 to 0.6 are found to be good models for group II of silk fibroins. The structure of Bombyx mori silk fibroin is discussed in the light of these new data.     

Modulation of Ca2+-currents by sequential and simultaneous activation of adenosine A1 and A2A receptors in striatal projection neurons

D₁- and D₂-types of dopamine receptors are located separately in direct and indirect pathway striatal projection neurons (dSPNs and iSPNs). In comparison, adenosine A₁-type receptors are located in both neuron classes, and adenosine A_2A-type receptors show a preferential expression in iSPNs. Due to their importance for neuronal excitability, Ca²⁺-currents have been used as final effectors to see the function of signaling cascades associated with different G protein-coupled receptors. For example, among many other actions, D₁-type receptors increase, while D₂-type receptors decrease neuronal excitability by either enhancing or reducing, respectively, Ca_V1 Ca²⁺-currents. These actions occur separately in dSPNs and iSPNs. In the case of purinergic signaling, the actions of A₁- and A_2A-receptors have not been compared observing their actions on Ca²⁺-channels of SPNs as final effectors. Our hypotheses are that modulation of Ca²⁺-currents by A₁-receptors occurs in both dSPNs and iSPNs. In contrast, iSPNs would exhibit modulation by both A₁- and A_2A-receptors. We demonstrate that A₁-type receptors reduced Ca²⁺-currents in all SPNs tested. However, A_2A-type receptors enhanced Ca²⁺-currents only in half tested neurons. Intriguingly, to observe the actions of A_2A-type receptors, occupation of A₁-type receptors had to occur first. However, A₁-receptors decreased Ca_V2 Ca²⁺-currents, while A_2A-type receptors enhanced current through Ca_V1 channels. Because these channels have opposing actions on cell discharge, these differences explain in part why iSPNs may be more excitable than dSPNs. It is demonstrated that intrinsic voltage-gated currents expressed in SPNs are effectors of purinergic signaling that therefore play a role in excitability.     

Discovery of benzothiazole-based adenosine A2B receptor antagonists with improved A2A selectivity

The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A_2B antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A_2A and A₁ receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A_2A and A₁ receptors.     

Female-to-Male Breeding Ratio in Modern Humans—an Analysis Based on Historical Recombinations

Was the past genetic contribution of women and men to the current human population equal? Was polygyny (excess of breeding women) present among hominid lineages? We addressed these questions by measuring the ratio of population recombination rates between the X chromosome and the autosomes, ρ_X/ρ_A. The X chromosome recombines only in female meiosis, whereas autosomes undergo crossovers in both sexes; thus, ρ_X/ρ_A reflects the female-to-male breeding ratio, β. We estimated β from ρ_X/ρ_A inferred from genomic diversity data and calibrated with recombination rates derived from pedigree data. For the HapMap populations, we obtained β of 1.4 in the Yoruba from West Africa, 1.3 in Europeans, and 1.1 in East Asian samples. These values are consistent with a high prevalence of monogamy and limited polygyny in human populations. More mutations occur during male meiosis as compared to female meiosis at the rate ratio referred to as α. We show that at α ≠ 1, the divergence rates and genetic diversities of the X chromosome relative to the autosomes are complex functions of both α and β, making their independent estimation difficult. Because our estimator of β does not require any knowledge of the mutation rates, our approach should allow us to dissociate the effects of α and β on the genetic diversity and divergence rate ratios of the sex chromosomes to the autosomes.     

Novel fluorescent triazinobenzimidazole derivatives as probes for labelling human A1 and A2B adenosine receptor subtypes

The expression levels and the subcellular localization of adenosine receptors (ARs) are affected in several pathological conditions as a consequence of changes in adenosine release and metabolism. In this respect, labelled probes able to monitor the AR expression could be a useful tool to investigate different pathological conditions. Herein, novel ligands for ARs, bearing the fluorescent 7-nitrobenzofurazan (NBD) group linked to the N¹ (1,2) or N¹⁰ (3,4) nitrogen of a triazinobenzimidazole scaffold, were synthesized. The compounds were biologically evaluated as fluorescent probes for labelling A₁ and A_2B AR subtypes in bone marrow-derived mesenchymal stem cells (BM-MSCs) that express both receptor subtypes. The binding affinity of the synthetized compounds towards the different AR subtypes was determined. The probe 3 revealed a higher affinity to A₁ and A_2B ARs, showing interesting spectroscopic properties, and it was selected as the most suitable candidate to label both AR subtypes in undifferentiated MSCs.Fluorescence confocal microscopy showed that compound 3 significantly labelled ARs on cell membranes and the fluorescence signal was decreased by the cell pre-incubation with the A₁ AR and A_2B AR selective agonists, R-PIA and BAY 60-6583, respectively, thus confirming the specificity of the obtained signal. In conclusion, compound 3 could represent a useful tool to investigate the expression pattern of both A₁ and A_2B ARs in different pathological and physiological processes. Furthermore, these results provide an important basis for the design of new and more selective derivatives able to monitor the expression and localization of each different ARs in several tissues and living cells.     

Chromosomal inversion polymorphism of Drosophila subobscura populations from Jastrebac Mountain shows temporal and habitat-related changes

Inversion polymorphism in populations of D. subobscura from a beech forest on Jastrebac mountain was studied in June 1990, 1993, and 1994, respectively. The same analysis was performed in 1990 for D. subobscura populations in a beech forest and an oak forest in the same region. Statistically significant differences in the frequencies of the gene arrangements of A₁, J and U chromosome were observed during the period of investigation. A tendency towards a decrease in the frequency of the standard gene arrangements was found for all chromosomes, but was particularly evident with chromosomes A and J. The frequency of the gene arrangements A₁ A₂, J₁ and U_1–2+6 increased at the same time. Differences in the frequency of the gene arrangements of A, J and U chromosomes were also observed when the populations from two ecologically different habitats (beech and oak forest) were compared in 1990.     

4-Substituted-7-N-alkyl-N-acetyl 2-aminobenzothiazole amides: Drug-like and non-xanthine based A2B adenosine receptor antagonists

7-N-Acetamide-4-methoxy-2-aminobenzothiazole 4-fluorobenzamide (compound 1) was chosen as a drug-like and non-xanthine based starting point for the discovery of A_2B receptor antagonists because of its slight selectivity against A₁ and A_2A receptors and modest A_2B potency. SAR exploration of compound 1 described herein included modifications to the 7-N-acetamide group, substitution of the 4-methoxy group by halogens as well as replacement of the p-flouro-benzamide side chain. This work culminated in the identification of compound 37 with excellent A_2B potency, modest selectivity versus A_2A and A₁ receptors, and good rodent PK properties.     

Gibberellin Structure-Dependent Interaction between Gibberellins and Deoxygibberellin C in the Growth of Dwarf Maize Seedlings

The effects of 3-deoxygibberellin C (DGC) on the growth-promoting actions of gibberellins A₁, A₂, A₃, A₄, A₅, A₇, A₈, A₉, A₁₃, A₁₈, A₁₉, A₂₀, and A₂₃ (GAn) as well as 13-deoxygibberellin A₅ (deoxy-GA₅) were tested with seedlings of gibberellin-deficient dwarf mutants (d₂ and d₅) of maize (Zea mays L.). It was found that DGC promoted the actions of gibberellins having both C-1 double bond and C-3 axial hydroxyl group, and it inhibited the action of gibberellins having the saturated ring A and lacking the C-3 axial hydroxyl group, whereas it did not affect that of the ones having the hydroxyl group. The presence of C-2 double bond, as in GA₅ and deoxy-GA₅, diminished the inhibitory action of DGC. The DGC inhibition was alleviated by raising the doses of the relevant GAs, suggesting that it is a competitive inhibition. These results and the finding that the growth of normal maize and rice seedlings are inhibited by DGC indicate that GA₉, GA₁₉, GA₂₀ or other gibberellins having ring A of the same structure are involved in the growth of these plants as active form(s) or as intermediate(s) leading to the active form(s).     

Imidazo[1,2-α]pyridines possess adenosine A1 receptor affinity for the potential treatment of cognition in neurological disorders

Previous research has shown that bicyclic 6:5-fused heteroaromatic compounds with two N-atoms have variable degrees of adenosine A₁ receptor antagonistic activity. Prompted by this imidazo[1,2-α]pyridine analogues were synthesized and evaluated for their adenosine A₁ and A_2A receptor affinity via radioligand binding studies and subjected to a GTP shift assay to determine its adenosine A₁ receptor agonistic or antagonistic functionality. Imidazo[1,2-α]pyridine, the parent scaffold, was found devoid of affinity for the adenosine A₁ and A_2A receptors. The influence of substitution on position C2 showed no improvement for either adenosine A₁ or A_2A receptor affinity. The addition of an amino or a cyclohexylamino group to position C3 also showed no improvement of adenosine A₁ or A_2A receptor affinity. Surprisingly para-substitution on the phenyl ring at position C2 in combination with a cyclohexylamino group at position C3 led to adenosine A₁ receptor affinity in the low micromolar range with compound 4d showing: (1) the highest affinity for the adenosine A₁ receptor with a K_i value of 2.06 µM and (2) adenosine A₁ receptor antagonistic properties. This pilot study concludes that para-substituted 3-cyclohexylamino-2-phenyl-imidazo[1,2-α]pyridine analogues represent an interesting scaffold to investigate further structure-activity relationships in the design of novel imidazo[1,2-α]pyridine-based adenosine A₁ receptor antagonists for the treatment of neurodegenerative disorders.