The development of potent non-peptidic PTP-1B inhibitors

The SAR from our peptide libraries was exploited to design a series of potent deoxybenzoin PTP-1B inhibitors. The introduction of an ortho bromo substituent next to the difluoromethylphosphonate warhead gave up to 20-fold increase in potency compared to the desbromo analogues. In addition, these compounds were orally bioavailable and active in the animal models of non-insulin dependent diabetes mellitus (NIDDM).     

Discovery of novel aspartyl ketone dipeptides as potent and selective caspase-3 inhibitors

The discovery of a series of potent, selective and reversible dipeptidyl caspase-3 inhibitors are reported. The iterative discovery process of using combinatorial chemistry, parallel synthesis, moleculare modelling and structural biology will be discussed.     

Exploring QSAR of melatonin receptor ligand benzofuran derivatives using E-state index

Considering the recent challenge to the medicinal chemists for the development of selective melatonin receptor ligands, an attempt has been made to explore physicochemical requirements of benzofuran derivatives for binding with human MT1 and MT2 receptor subtypes and also to explore selectivity requirements. In this study, E-states of different common atoms of the molecules (calculated according to Kier and Hall) and physicochemical parameters (partition coefficient and molar refractivity) were used as independent variables along with suitable dummy parameters. The best equation describing MT1 binding affinity [n = 34, Q2 = 0.670, Ra2 = 0.790, R2 = 0.822, R = 0.907, s = 0.609, F = 25.8 (df 5, 28)] suggests that the binding affinity decreases as the value of n (number of CH2 spacer beside R2) increases while it increases with rise in electrotopological state values of different atoms of the benzofuran ring. Again, presence of methoxy group at R1 and hydrogen, unsubstituted phenyl or fluoro-substituted phenyl group at R2 is conducive to the MT1 binding affinity. The binding affinity decreases if furyl substitution at R3 position is present. The best equation describing MT2 binding affinity [n = 34, Q2 = 0.602, Ra2 = 0.755, R2 = 0.792, R = 0.890, s = 0.584, F = 213 (df 5, 28)] shows that the MT2 binding affinity depends on the similar factors as described for MT1 binding affinity; however, the contributions of the factors for the two affinities are different to some extent as evidenced from the regression coefficients. Among the selectivity relations, the best equation [n = 33, Q2 = 0.496 Ra2 = 0.681, R2 = 0.721, R = 0.849, s = 0.458, F = 18.1(df 4, 28)] suggests that MT2 binding increases with increase in value of n, presence of methoxy group at R1, and E-state values of different atoms of the benzofuran ring, while it decreases in presence of furyl group at R3 position.     

The effects of concurrent experimental infections of sheep with Trichostrongylus colubriformis and T. vitrinus on nematode distributions, numbers and on pathological changes

Simultaneous infections of Trichostrongylus colubriformis and T. vitrinus in the small intestine of the sheep were examined by comparing the numbers of worms which established and their distribution within the intestine in both monospecific infections and mixed infections. The results differed depending upon the species and number of parasites. The establishment of T. colubriformis was reduced and the distribution of the nematode population was displaced posteriorly within the intestine when 30,000 larvae of both species were administered, compared with pure infections of T. colubriformis. The reduced establishment was less marked with infections of 15,000 larvae of both species and there was only a slight posterior displacement of T. colubriformis. Neither effect was evident with infections of 7,500 larvae of both species. The rate of establishment and distribution of T. vitrinus were unaffected by the presence of T. colubriformis at all three rates of infection. Atrophy of villi and hypertrophy of crypts occurred at the main site of infection in the anterior duodenum. The severity of villus atrophy was related to the number of infective larvae administered and/or the worm burden. In the ileum, beyond the main site of infection, hypertrophy of villi was only found in sheep receiving the greatest number of infective larvae.     

The yeast Apq12 protein affects nucleocytoplasmic mRNA transport

An important step in mRNA biogenesis is the export of mRNA from the nucleus to the cytoplasm. In this work, we provide evidence that the previously uncharacterized gene APQ12 functions in nucleocytoplasmic mRNA transport in Saccharomyces cerevisiae. First, apq12delta strains manifest 3' hyperadenylated mRNA similar to other previously characterized RNA export mutants. Second, bulk poly(A)+ RNA is retained in the nucleus in apq12delta cells. Third, an Apq12p-GFP chimeric protein is localized to the nuclear periphery. Fourth, mRNA in apq12delta cells is stabilized, consistent with a defect in the rate of nuclear export. Interestingly, apq12delta mutants are severely compromised for growth and display atypical cell morphology. Because this aberrant cell morphology is not seen with other viable export mutants, Apq12p must have either an additional cellular function, or preferentially impinge on the export of mRNAs regulating cell growth. Together, these findings support a role for APQ12 in nucleocytoplasmic transport of mRNA.     

Modeling the relationship between LVAD support time and gene expression changes in the human heart by penalized partial least squares

MOTIVATION: Heart failure affects more than 20 million people in the world. Heart transplantation is the most effective therapy, but the number of eligible patients far outweighs the number of available donor hearts. The left mechanical ventricular assist device (LVAD) has been developed as a successful substitution therapy that aids the failing ventricle while a patient is waiting for the donor heart. We obtained genomics data from paired human heart samples harvested at the time of LVAD implant and explant. The heart failure patients in our study were supported by the LVAD for various periods of time. The goal of this study is to model the relationship between the time of LVAD support and gene expression changes. RESULTS: To serve the purpose, we propose a novel penalized partial least squares (PPLS) method to build a regression model. Compared with partial least squares and Breiman's random forest method, PPLS gives the best prediction results for the LVAD data.     

The rapidly evolving field of plant centromeres

Meiotic and mitotic chromosome segregation are highly conserved in eukaryotic organisms, yet centromeres--the chromosomal sites that mediate segregation--evolve extremely rapidly. Plant centromeres have DNA elements that are shared across species, yet they diverge rapidly through large- and small-scale changes. Over evolutionary time-scales, centromeres migrate to non-centromeric regions and, in plants, heterochromatic knobs can acquire centromere activity. Discerning the functional significance of these changes will require comparative analyses of closely related species. Combined with functional assays, continued efforts in plant genomics will uncover key DNA elements that allow centromeres to retain their role in chromosome segregation while allowing rapid evolution.