Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia

Translocations involving the mixed lineage leukemia (MLL) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia (MEN1) gene. Here we present what are to our knowledge the first small-molecule inhibitors of the menin-MLL fusion protein interaction that specifically bind menin with nanomolar affinities. These compounds effectively reverse MLL fusion protein-mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compounds provides a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL fusion proteins. Our findings also highlight a new therapeutic strategy for aggressive leukemias with MLL rearrangements.     

Isolation and characterization of potential aerobic bacteria capable for pyridine degradation in presence of picoline,phenol and formaldehyde as co-pollutants

Pyridine, heterocyclic aromatic compound is known to be toxic, carcinogenic and teratogenic to several living organisms. In this study, two aerobic bacteria ITRCEM1 and ITRCEM2 capable for pyridine degradation were isolated and characterized as Bacillus cereus (DQ435020) and Alcaligenes faecalis (DQ435021), respectively. For pyridine degradation, mixed bacterial culture was found more effective compared to axenic culture ITRCEM1 and ITRCEM2 degrading 94.23, 67.84, and 83.35% pyridine, respectively, at 144 h incubation period at pH 7.0 ± 0.1, temp 37 ± 2°C and shaking rate 125 rpm in MSM containing 1% glucose and 0.2% peptone as carbon and nitrogen source, respectively. The presence of phenol and formaldehyde in MSM has shown inhibitory effect on pyridine degradation whereas picoline has favored the bacterial growths and pyridine degradation. Further, the HPLC analysis has shown the reduction in peaks compared to controls, indicating that reduction in peak area might be largely attributed to the bacterial degradation of pyridine by bacterial catabolic enzymes.     

The Kell blood group locus is close to the cystic fibrosis locus on chromosome 7

Summary Linkage analysis confirmed the assignment of the Kell blood group locus to chromosome 7.     

Relationship between mutation of serine residue at 315th position in M. tuberculosis catalase-peroxidase enzyme and Isoniazid susceptibility: An in silico analysis

Remarkable advances have been made in the drug therapy of tuberculosis. However much remains to be learned about the molecular and structural basis of drug resistance in Mycobacterium tuberculosis. It is known that, activation of Isoniazid (INH) is mediated by Mycobacterium tuberculosis catalase-peroxidase (MtBKatG) and mutation at position 315 (serine to threonine) leads to resistance. We have conducted studies on the drug resistance through docking and binding analysis supported by time-scale (∼1000 ps) and unrestrained all-atom molecular dynamics simulations of wild and mutant MtBKatG. The study showed conformational changes of binding residues. Mutant (S315T) showed high docking score and INH binding affinity as compared to wild enzyme. In molecular dynamics simulation, mutant enzyme exhibited less structure fluctuation at INH binding residues and more degree of fluctuation at C-terminal domain compared to wild enzyme. Our computational studies and data endorse that MtBKatG mutation (S315T) decrease the flexibility of binding residues and made them rigid by altering the conformational changes, in turn it hampers the INH activity. We ascertain from this work that, this study on structural mechanism of resistance development in Mycobacterium tuberculosis would lead to new therapeutics based on the result obtained in this study.     

Genetic variability in the complete mitochondrial control region of the Eurasian otter (Lutra lutra) in the Iberian Peninsula

Sequencing of the complete mitochondrial DNA control region from 31 samples of the Eurasian otter, Lutra lutra , enabled us to establish the length and structure of this fragment, as well as to describe, for the first time, the RS3 repetitive region located at the 3' end. In addition, genetic variability of the 5' end was examined in 63 individuals, 57 of which were wild otters from the Iberian Peninsula and six captive reared otters. This analysis resulted in extremely low variability. All the samples from the Iberian Peninsula share a single haplotype, Lut 1, the most common haplotype in Europe. Captive otters showed two haplotypes: Lut 3, which has been described in wild otters from eastern Germany, and Lut 6, an haplotype not described to date. Higher variability was observed in the repetitive RS3 region. The tandem repeat was composed of an array of ten repeat units of 22 bp with differences in the repetitive motifs that differed in the arrays of different specimens. In total, 20 different haplotypes from 31 individuals were found. However, the geographical distribution of these haplotypes did not generate a phylogeographical signal. © 2005 The Linnean Society of London, Biological Journal of the Linnean Society , 2005, 86 , 397–403.     

Influence of Diet Composition on Cattle Rumen Methanogenesis: A Comparative Metagenomic Analysis in Indian and Exotic Cattle

Comparative metagenomics approach has been used in this study to discriminate colonization of methanogenic population in different breeds of cattle. We compared two Indian cattle breeds (Gir and Kankrej) and two exotic cattle (Holstein and Jersey) breeds. Using a defined dietary plan for selected Indian varieties, the diet dependent shifts in microbial community and abundance of the enzymes associated with methanogenesis were studied. This data has been compared with the available rumen metagenome data from Holstein and Jersey dairy cattle. The abundance of genes for methanogenesis in Holstein and Jersey cattle came from Methanobacteriales order whereas, majority of the enzymes for methanogenesis in Gir and Kankrej cattle came from Methanomicrobiales order. The study suggested that by using slow/less digestible feed, the propionate levels could be controlled in rumen; and in turn, this would also help in further reducing the hydrogenotrophic production of methane. The study proposes that with the designed diet plan the overall methanogenic microbial pool or the individual methanogens could be targeted for development of methane mitigation strategies.     

Investigations on the interactions of scorpion neurotoxins with the predicted structure of D1 dopamine receptor by protein-protein docking method. A bioinformatics approach

Dopamine receptors play a critical role in the cell signalling process responsible for information transfer in neurons functioning in the nervous system. Development of improved therapeutics for disorders like Parkinson's disease and schizophrenia would be significantly enhanced with the availability of the 3D structure for the dopamine receptors. Scorpion neurotoxins are unique source of structural templates from which new therapeutic agents might be developed. We report here the 3D structure of the human D1 dopamine receptor, predicted from primary sequence using computational techniques. The predicted structure of the human D1 dopamine receptor is used to understand the mechanism of interactions between scorpion neurotoxins through the protein-protein docking method. CHARMM force field was used for the energy minimization step before applying the docking method.     

<Emphasis Type="Italic">In vitro</Emphasis> propagation of brown oak (<Emphasis Type="Italic">Quercus semecarpifolia</Emphasis> Sm.) from seedling explants

An efficient and reproducible method for the regeneration of multiple shoots of brown oak (Quercus semecarpifolia Sm.) has been developed in which a part of the petiolar tube containing a primary shoot is used as the explant. Explants derived from in vitro grown seedlings were cultured either on Murashige and Skoog or Woody Plant medium (WPM) containing different concentrations of benzyladenine (BAP) throughout the range of 1–20 μM. WPM supplemented with 20 μM BAP was found to be best for adventitious shoot induction and for the multiplication of individual shoots. In-vitro-produced shoots were rooted using a two-step method. Firstly, shoots were cultured on WPM containing indolebutyric acid (IBA) at either 50 or 100 μM for 24 or 48 h. Secondly, the shoots were transferred to plant-growth-regulator-free half-strength WPM. The second step not only considerably improved the rooting percentage but also minimized the formation of basal callus. The most effective first-step treatment was found to be 100 μM IBA for 24 h, which initiated rooting at a frequency of 100%. Well-rooted plants were transferred to plastic cups containing nonsterile, sieved soil and farmyard manure, hardened under greenhouse conditions, and then successfully established in pots. This procedure is suitable for use in large-scale production of plants and may have potential application in additional oak species.