Synthesis and biological evaluation of trans 6-methoxy-1,1-dimethyl-2-phenyl-3-aryl-2,3-dihydro-1H-inden-4-yloxyalkylamine derivatives against drug susceptible,non-replicating M. tuberculosis H37Rv and clinical multidrug resistant strains

Synthesis of a library of novel trans 6-methoxy-1,1-dimethyl-2-phenyl-3-aryl-2,3-dihydro-1H-inden-4-yloxy alkyl amines and their antimycobacterial activity against drug sensitive and multidrug resistant strains of Mycobacterium tuberculosis have been reported. All the new compounds in the series exhibited MIC between 1.56 and 6.25 μg/ml. Two compounds 1i and 1j with low MIC and low cytotoxicity showed significant reduction in CFU in infected mouse macrophages at 1× MIC concentration. The compound 1i inhibited the growth of M. tuberculosis in mice at 100 mg/kg dose with 1.35 log₁₀ reduction of CFU in lungs tissue and was active against non-replicating Mycobacterium tuberculosis under anaerobic condition.     

Initial Commitment to Pre-Exposure Prophylaxis and Circumcision for HIV Prevention amongst Indian Truck Drivers

Studies of HIV prevention interventions such as pre-exposure prophylaxis (PREP) and circumcision in India are limited. The present study sought to investigate Indian truck-drivers initial commitment to PREP and circumcision utilizing the AIDS Risk Reduction Model. Ninety truck-drivers completed an in-depth qualitative interview and provided a blood sample for HIV and HSV-2 testing. Truck-drivers exhibited low levels of initial commitment towards PREP and even lower for circumcision. However, potential leverage points for increasing commitment were realized in fear of infecting family rather than self, self-perceptions of risk, and for PREP focusing on cultural beliefs towards medication and physicians. Cost was a major barrier to both HIV prevention interventions. Despite these barriers, our findings suggest that the ARRM may be useful in identifying several leverage points that may be used by peers, health care providers and public health field workers to enhance initial commitment to novel HIV prevention interventions in India.     

Lipid peroxidation in plumbagin administered rats

Plumbagin was administered to rats at a concentration of 1,2,4,8 and 16 mg per kg body weight. After 24 h lipid peroxide levels were found to decrease in subcellular fractions of liver. Plumbagin inhibited ascorbate and nicotinafde adenine dinucleotide phosphate (reduced) dependent lipid peroxidation but was without any effect on cumene hydroperoxide dependent lipid peroxidation. Injection of 16 mg of plumbagin per kg body weight was found to decrease liver total reduced glutathione and also fcrosomal glucose-6-phosphatase. The results are discussed with reference to the anti- and prooxidant properties of plumbagin.     

Effect of lithium on regulation of two molecular forms of Na+,K(+)-ATPase in rat brain

Effects of lithium in vivo and in vitro on the two molecular forms of Na+,K(+)-ATPase in rat brain were investigated. Inhibition by strophanthidin, affinity to monovalent cations and cellular localization of the enzyme were used to differentiate the two molecular forms. K+ dependent p-nitrophenylphosphatase activity and strophanthidin inhibition studies revealed selective increase in the activity of low affinity form but not high affinity form of the enzyme following lithium treatment. Na+ sensitivity of neither forms of Na+,K(+)-ATPase was changed but K+ sensitivity of low affinity form was increased due to lithium. Lithium showed biphasic effects on low affinity form of the enzyme; activation at low concentration and inhibition at high concentration. The results suggest that lithium in vivo regulates the concentration of extra cellular potassium by selectively acting at K+ site of low affinity form of the enzyme (astroglial) but not on high affinity form (neuronal enzyme) and leading to changes in neuronal depolarization.     

DNA sequence organization in the genomes of three related millet plant species

Summary A major portion of the genomes of three millet species, namely, barn yard millet, fox tail millet and little millet has been shown to consist of interspersed repeat and single copy DNA sequences. The interspersed repetitive DNA sequences are both short (0.15–1.0 kilo base pairs, 62–64% and long (>1.5 kilo base pairs, 36–38%) in barn yard millet and little millet while in fox tail millet, only long interspersed repeats (>1.5 kilo base pairs) are present. The length of the interspersed single copy DNA sequences varies in the range of 1.6–2.6 kilo base pairs in all the three species. The repetitive duplexes isolated after renaturation of 1.5 kilo base pairs and 20 kilo base pairs long DNA fragments exhibit a high thermal stability with Tms either equal to or greater than the corresponding native DNAs. The S1 nuclease resistant repetitive DNA duplexes also are thermally stable and reveal the presence of only 1–2% sequence divergence.The present data on the modes of sequence arrangement in millets substantiates the proposed trend in plants, namely, plants with 1C nuclear DNA content of less than 5 picograms have diverse patterns of sequence organization while those with 1C nuclear DNA content greater than 5 picograms have predominantly a short period interspersion pattern.Abbreviations kbp kilobase pairs NCL Communication No. 3606.     

Identification and sequence characterization of a 1.3 Kb EcoRI repeat fragment that harbors a DNA repair site of rat pachytene spermatocytes

Introduction of well-programmed nicks and gaps and the associated DNA repair activity in the genome at the pachytene interval is a characteristic feature of the meiotic prophase in organisms as varied as lilium and mouse. In the present study we have shown that the DNA synthetic activity in rat pachytene spermatocytes is insensitive to aphidicolin, a specific inhibitor of DNA polymerase , and , suggesting DNA -polymerase-mediated repair synthesis in these cells. We have developed a novel approach for the isolation of the DNA repair sites by combining two independent techniques. Following incorporation of BrdUrd into pachytene spermatocytes in the presence of aphidicolin, the repair sites were released as ssDNA fragments by treatment of nuclei with 30 mM NaOH. Subsequently, the BrdUrd containing ssDNA fragments were specifically isolated using polyclonal anti-BrdUrd antibodies. The DNA fragments released were of two size classes, namely 4–7S (major) and 9–12S (minor) and constituted approximately 1.75% of the pachytene genomic DNA. These DNA repair fragments were distinct from Okazaki fragments and other replicative intermediates isolated from rat bone marrow cells as evidenced by (a) their different size distribution and (b) little cross-hybridization. Southern hybridization of restriction enzyme digests of rat genomic DNA with probes made against BrdUrd-ssDNA fragments revealed that although the repair sites were distributed throughout the genome, strong hybridization signals were observed in EcoRI, (1.3 kb and 2.4 kb), BamH1 (9 kb) and HindIII (5 kb) repetetive DNA fragments. The EcoRI 1.3 kb family were cloned into M13 mp19, and a repair positive (1.3 A) and a repair negative (1.3 B) were identified and sequenced. The repair positive clone contained (a) (CA)₂₂ repeat, (b) a (CAGA)₆ repeat and (c) 4 sequences sharing high homology with various hypervariable minisatellite (HVMS) sequences. One of the HVMS sequence contained a GGCAGG motif known to be responsible for germline instability. The repair negative clone had (a) (CA)₆ repeat and (b) a HVMS like sequence without GGCAGG. The significance of these motifs and their relevance to the events of DNA metabolism at pachytene interval have been discussed.     

Prostaglandin H Synthetase-Mediated Metabolism of Dopamine: Implication for Parkinson's Disease

Abstract: Differences in prostaglandin H synthetase (PHS) activity in the substantia nigra of age- and post-mortem interval-matched parkinsonian, Alzheimer's, and normal control brain tissue were assessed. Prostaglandin E₂ (PGE₂, an index of PHS activity) was higher in substantia nigra of parkinsonian brain tissue than Alzheimer's or control tissue. Incubation of substantia nigra slices with arachidonic acid (AA) increased PGE₂ synthesis. Dopamine stimulated PHS synthesis of PGE₂. [³H]Dopamine was activated by PHS to electrophilic intermediate(s) that covalently bound to DNA, microtubulin protein, bovine serum albumin, and sulfhydryl reagents. When AA was replaced by hydrogen peroxide, PHS/H₂O₂-supported binding proceeded at rates similar to those observed with PHS/AA. Indomethacin and aspirin inhibited AA-mediated cooxidation of dopamine but not H₂O₂-mediated metabolism. PHS-mediated metabolism of dopamine was not affected by monoamine oxidase inhibitors. Substrate requirements and effects of specific inhibitors suggest cooxidation of dopamine is mediated by the hydroperoxidase activity of PHS. ³²P-postlabeling was used to detect dopamine-DNA adducts. PHS/AA activation of dopamine in the presence of DNA resulted in the formation of five dopamine-DNA adducts, i.e., 23, 43, 114, 70, and 270 amol/µg DNA. DNA adduct formation was PHS, AA, and dopamine dependent. PHS catalyzed cooxidation of dopamine in dopaminergic neuronal degeneration is discussed.     

Molecular organization of great millet (Sorghum vulgare) DNA

Approximately 52% of the nuclear genome of great millet(Sorghum vulgare) consists of repetitive DNA which can be grouped into very fast, fast and slow components. The reiteration frequencies of the fast and slow reassociating components are {dy7000} and 92 respectively. Approximately 90% of the genome consists of repeated sequences interspersed amongst themselves and with single copy sequences. The interspersed repeat sequences are of three sizesviz. > 1·5 kilobase pairs, 0·5–1·0 kilobase pairs and 0·15–0·30 kilobase pairs while the size of the single copy sequences is 3·0 kilobase pairs. Hence the genome organization of great millet is essentially of a mixed type NCL communication No. 3527.