Point mutations in the HIV-1 matrix protein turn off the myristyl switch

During the late phase of human immunodeficiency virus type-1 (HIV-1) replication, newly synthesized retroviral Gag proteins are targeted to lipid raft regions of specific cellular membranes, where they assemble and bud to form new virus particles. Gag binds preferentially to the plasma membrane (PM) of most hematopoietic cell types, a process mediated by interactions between the cellular PM marker phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P(2)) and Gag's N-terminally myristoylated matrix (MA) domain. We recently demonstrated that PI(4,5)P(2) binds to a conserved cleft on MA and promotes myristate exposure, suggesting a role as both a direct membrane anchor and myristyl switch trigger. Here we show that PI(4,5)P(2) is also capable of binding to MA proteins containing point mutations that inhibit membrane binding in vitro, and in vivo, including V7R, L8A and L8I. However, these mutants do not exhibit PI(4,5)P(2) or concentration-dependent myristate exposure. NMR studies of V7R and L8A MA reveal minor structural changes that appear to be responsible for stabilizing the myristate-sequestered (myr(s)) species and inhibiting exposure. Unexpectedly, the myristyl group of a revertant mutant with normal PM targeting properties (V7R,L21K) is also tightly sequestered and insensitive to PI(4,5)P(2) binding. This mutant binds PI(4,5)P(2) with twofold higher affinity compared with the native protein, suggesting a potential compensatory mechanism for membrane binding.     

Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification

A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders.     

Molecular investigation of mental retardation locus gene PRSS12 by linkage analysis

The present study was carried out to determine the prevalence of families having mental retardation in Pakistani population. We enrolled seven mentally retarded (MR) families with two or more affected individuals. Family history was taken to minimize the chances of other abnormalities. Pedigrees were drawn using the Cyrillic software (version 2.1). The structure of pedigrees shows that all the marriages are consanguineous and the families have recessive mode of inheritance. All the families were studied by linkage analysis to mental retardation locus (MRT1)/gene PRSS12. Three STR markers (D4S191, D4S2392, and D4S3024) in vicinity of mental retardation (MR) locus (MRT1)/gene PRSS12 were amplified on all the sample of each family by PCR. The PCR products were then genotyped on non denaturing polyacrylamide gel electrophoresis (PAGE). The Haplotype were constructed to determine the pattern of inheritance and also to determine that a family was linked or unlinked to gene PRSS12. One out of the seven families was potentially linked to gene PRSS12, while the other six families remain unlinked.     

Removal of chromium on Polyalthia longifolia leaves biomass

Adsorption is an environmental friendly process for removal and/or recovery of heavy metals from wastewater. In recent years, it has been substantiated as a popular technique to treat industrial waste effluents, with significant advantages. In this work, batchwise removal of chromium (III) ions from water by Polyalthia longifolia leaves was studied as a function of adsorbent dose, pH, contact time, and agitation speed. Surface characteristics of the leaves were evaluated by recording IR spectra. The Langmuir, Freundlich, and Temkin adsorption isotherms were employed to explain the sorption process. It was found that one gram of leaves can remove 1.87 mg of trivalent chromium when working at pH 3.0. It has been concluded that Polyalthia longifolia leaves can be used as cost-effective and benign adsorbents for removal of Cr(III) ions from wastewater.     

A new genus and species of deep-sea glass sponge (Porifera, Hexactinellida, Aulocalycidae) from the Indian Ocean

New hexactinellid sponges were collected from 2589 m depth on the Carlsberg Ridge in the Indian Ocean during deep-sea dredging. All fragments belong to a new genus and species, Indiellagen. n.ridgenensissp. n., a representative of the family Aulocalycidae described here. The peculiar features of this sponge, not described earlier for other Aulocalycidae, are: longitudinal strands present in several layers and epirhyses channelization.     

Megafaunal community structure of Andaman seamounts including the Back-arc Basin--a quantitative exploration from the Indian Ocean

Species rich benthic communities have been reported from some seamounts, predominantly from the Atlantic and Pacific Oceans, but the fauna and habitats on Indian Ocean seamounts are still poorly known. This study focuses on two seamounts, a submarine volcano (cratered seamount--CSM) and a non-volcano (SM2) in the Andaman Back-arc Basin (ABB), and the basin itself. The main purpose was to explore and generate regional biodiversity data from summit and flank (upper slope) of the Andaman seamounts for comparison with other seamounts worldwide. We also investigated how substratum types affect the megafaunal community structure along the ABB. Underwater video recordings from TeleVision guided Gripper (TVG) lowerings were used to describe the benthic community structure along the ABB and both seamounts. We found 13 varieties of substratum in the study area. The CSM has hard substratum, such as boulders and cobbles, whereas the SM2 was dominated by cobbles and fine sediment. The highest abundance of megabenthic communities was recorded on the flank of the CSM. Species richness and diversity were higher at the flank of the CSM than other are of ABB. Non-metric multi-dimensional scaling (nMDS) analysis of substratum types showed 50% similarity between the flanks of both seamounts, because both sites have a component of cobbles mixed with fine sediments in their substratum. Further, nMDS of faunal abundance revealed two groups, each restricted to one of the seamounts, suggesting faunal distinctness between them. The sessile fauna corals and poriferans showed a significant positive relation with cobbles and fine sediments substratum, while the mobile categories echinoderms and arthropods showed a significant positive relation with fine sediments only.     

Recombinant prion protein induces rapid polarization and development of synapses in embryonic rat hippocampal neurons in vitro

While a beta-sheet-rich form of the prion protein (PrPSc) causes neurodegeneration, the biological activity of its precursor, the cellular prion protein (PrPC), has been elusive. We have studied the effect of purified recombinant prion protein (recPrP) on rat fetal hippocampal neurons in culture. Overnight exposure to Syrian hamster or mouse recPrP, folded into an alpha-helical-rich conformation similar to that of PrPC, resulted in a 1.9-fold increase in neurons with a differentiated axon, a 13.5-fold increase in neurons with differentiated dendrites, a fivefold increase in axon length, and the formation of extensive neuronal circuitry. Formation of synaptic-like contacts was increased by a factor of 4.6 after exposure to recPrP for 7 days. Neither the N-terminal nor C-terminal domains of recPrP nor the PrP paralogue doppel (Dpl) enhanced the polarization of neurons. Inhibitors of protein kinase C (PKC) and of Src kinases, including p59Fyn, blocked the effect of recPrP on axon elongation, while inhibitors of phosphatidylinositol 3-kinase showed a partial inhibition, suggesting that signaling cascades involving these kinases are candidates for transduction of recPrP-mediated signals. The results predict that full-length PrPC functions as a growth factor involved in development of neuronal polarity.