Restricted lateral mobility of plasma membrane CD4 impairs HIV-1 envelope glycoprotein mediated fusion

We investigated the effect of receptor mobility on HIV-1 envelope glycoprotein (Env)-triggered fusion using B16 mouse melanoma cells that are engineered to express CD4 and CXCR4 or CCR5. These engineered cells are resistant to fusion mediated CD4-dependent HIV-1 envelope glycoprotein. Receptor mobility was measured by fluorescence recovery after photobleaching (FRAP) using either fluorescently-labeled antibodies or transient expression of GFP-tagged receptors in the cells. No significant differences between B16 and NIH3T3 (fusion-permissive) cells were seen in lateral mobility of CCR5 or lipid probes. By contrast CD4 mobility in B16 cells was about seven-fold reduced compared to its mobility in fusion-permissive NIH3T3 cells. However, a CD4 mutant (RA5) that localizes to non-raft membrane microdomains exhibited a three-fold increased mobility in B16 cells as compared with WT-CD4. Interestingly, the B16 cells expressing the RA5 mutant (but not the wild type CD4) and coreceptors supported HIV-1 Env-mediated fusion. Our data demonstrate that the lateral mobility of CD4 is an important determinant of HIV-1 fusion/entry.     

Genome-wide SNP typing reveals signatures of population history

Single-nucleotide polymorphism (SNP) arrays have become a popular technology for disease-association studies, but they also have potential for studying the genetic differentiation of human populations. Application of the Affymetrix GeneChip Human Mapping 500K Array Set to a population of 102 individuals representing the major ethnic groups in the United States (African, Asian, European, and Hispanic) revealed patterns of gene diversity and genetic distance that reflected population history. We analyzed allelic frequencies at 388,654 autosomal SNP sites that showed some variation in our study population and 10% or fewer missing values. Despite the small size (23-31 individuals) of each subpopulation, there were no fixed differences at any site between any two subpopulations. As expected from the African origin of modern humans, greater gene diversity was seen in Africans than in either Asians or Europeans, and the genetic distance between the Asian and the European populations was significantly lower than that between either of these two populations and Africans. Principal components analysis applied to a correlation matrix among individuals was able to separate completely the major continental groups of humans (Africans, Asians, and Europeans), while Hispanics overlapped all three of these groups. Genes containing two or more markers with extraordinarily high genetic distance between subpopulations were identified as candidate genes for health differences between subpopulations. The results show that, even with modest sample sizes, genome-wide SNP genotyping technologies have great promise for capturing signatures of gene frequency difference between human subpopulations, with applications in areas as diverse as forensics and the study of ethnic health disparities.     

Life cycle assessment of Australian automotive door skins

Background, aim, and scope  Policy initiatives, such as the EU End of Life Vehicle (ELV) Directive for only 5% landfilling by 2015, are increasing the pressure for higher material recyclability rates. This is stimulating research into material alternatives and end-of-life strategies for automotive components. This study presents a Life Cycle Assessment (LCA) on an Australian automotive component, namely an exterior door skin. The functional unit for this study is one door skin set (4 exterior skins). The material alternatives are steel, which is currently used by Australian manufacturers, aluminium and glass-fiber reinforced polypropylene composite. Only the inputs and outputs relative to the door skin production, use and end-of-life phases were considered within the system boundary. Landfill, energy recovery and mechanical recycling were the end-of-life phases considered. The aim of the study is to highlight the most environmentally attractive material and end-of-life option. Methods  The LCA was performed according to the ISO 14040 standard series. All information considered in this study (use of fossil and non fossil based energy resources, water, chemicals etc.) were taken up in in-depth data. The data for the production, use and end-of-life phases of the door skin set was based upon softwares such as SimaPro and GEMIS which helped in the development of the inventory for the different end-of-life scenarios. In other cases, the inventory was developed using derivations obtained from published journals. Some data was obtained from GM-Holden and the Co-operative research Centre for Advanced Automotive Technology (AutoCRC), in Australia. In cases where data from the Australian economy was unavailable, such as the data relating to energy recovery methods, a generic data set based on European recycling companies was employed. The characterization factors used for normalization of data were taken from (Saling et. al. Int J Life Cycle Assess 7(4):203–218 2002) which detailed the method of carrying out an LCA. Results  The production phase results in maximum raw material consumption for all materials, and it is higher for metals than for the composite. Energy consumption is greatest in the use phase, with maximum consumption for steel. Aluminium consumes most energy in the production phase. Global Warming Potential (GWP) also follows a trend similar to that of energy consumption. Photo Oxidants Creation Potential (POCP) is the highest for the landfill scenario for the composite, followed by steel and aluminium. Acidification Potential (AP) is the highest for all the end-of-life scenarios of the composite. Ozone Depletion Potential (ODP) is the highest for the metals. The net water emissions are also higher for composite in comparison to metals despite high pollution in the production phases of metallic door skins. Solid wastes are higher for the metallic door skins. Discussion  The composite door skin has the lowest energy consumption in the production phase, due to the low energy requirements during the manufacturing of E-glass and its fusion with polypropylene to form sheet molding compounds. In general, the air emissions during the use phase are strongly dependent on the mass of the skins, with higher emissions for the metals than for the composite. Material recovery through recycling is the highest in metals due to efficient separation techniques, while mechanical recycling is the most efficient for the composite. The heavy steel skins produce the maximum solid wastes primarily due to higher fuel consumption. Water pollution reduction benefit is highest in case of metals, again due to the high efficiency of magnetic separation technique in the case of steel and eddy current separation technique in the case of aluminium. Material recovery in these metals reduces the amount of water needed to produce a new door skin set (water employed mainly in the ingot casting stage). Moreover, the use of heavy metals, inorganic salts and other chemicals is minimized by efficient material recovery. Conclusions  The use of the studied type of steel for the door skins is a poor environmental option in every impact category. Aluminium and composite materials should be considered to develop a more sustainable and energy efficient automobile. In particular, this LCA study shows that glass-fiber composite skins with mechanical recycling or energy recovery method could be environmentally desirable, compared to aluminium and steel skins. However, the current limit on the efficiency of recycling is the prime barrier to increasing the sustainability of composite skins. Recommendations and perspectives  The study is successful in developing a detailed LCA for the three different types of door skin materials and their respective recycling or end-of-life scenarios. The results obtained could be used for future work on an eco-efficiency portfolio for the entire car. However, there is a need for a detailed assessment of toxicity and risk potentials arising from each of the four different types of door skin sets. This will require greater communication between academia and the automotive industry to improve the quality of the LCA data. Sensitivity analysis needs to be performed such as the assessment of the impact of varying substitution factors on the life cycle of a door skin. Incorporation of door skin sets made of new biomaterials need to be accounted for as another functional unit in future LCA studies. Discussion contributions to this article from the readership would the highly welcome. The authors     

Loss of Myosin VI No Insert Isoform (NoI) Induces a Defect in Clathrin-mediated Endocytosis and Leads to Caveolar Endocytosis of Transferrin Receptor

Myosin VI is a motor protein that moves toward the minus end of actin filaments. It is involved in clathrin-mediated endocytosis and associates with clathrin-coated pits/vesicles at the plasma membrane. In this article the effect of the loss of myosin VI no insert isoform (NoI) on endocytosis in nonpolarized cells was examined. The absence of myosin VI in fibroblasts derived from the Snell''s waltzer mouse (myosin VI knock-out) gives rise to defective clathrin-mediated endocytosis with shallow clathrin-coated pits and a strong reduction in the internalization of clathrin-coated vesicles. To compensate for this defect in clathrin-mediated endocytosis, plasma membrane receptors such as the transferrin receptor (TfR) are internalized by a caveola-dependent pathway. Moreover the clathrin adaptor protein, AP-2, necessary for TfR internalization, follows the receptor and relocalizes in caveolae in Snell''s waltzer fibroblasts.     

Search for new pharmacophores for antimalarial activity. Part II: Synthesis and antimalarial activity of new 6-ureido-4-anilinoquinazolines

Synthesis of new 6-ureido-4-anilinoquinazolines have been accomplished and their in vitro antimalarial activity against chloroquine-sensitive P. falciparum have been examined. Out of 64 compounds evaluated, the IC₅₀ of 16 compounds which have displayed MIC of 0.25 μg/mL were also recorded. One of the compounds (24g) had IC₅₀ value of 2.27 ng/mL which was equipotent to the standard drug chloroquine used in the bioassay. The in vivo evaluation of a few compounds among the series led to discovery of one analog (30g) displaying 40% curative activity (28 days) against mdr P. yoeilli nigeriensis at an oral dose of 100 mg/kg × 4days.     

Peripartum Cardiomyopathy Presenting With Ventricular Tachycardia: A Rare Presentation

A 25-year-old previously asymptomatic pregnant woman at 36 weeks'' gestation was noticed to have repetitive monomorphic ventricular tachycardia. A dilated left ventricle with moderately reduced systolic function was found on echocardiographic examination. This is a very rare presentation of peripartum cardiomyopathy (PPCMP) presenting with repetitive monomorphic ventricular tachycardia.     

Regenerative pharmacology in the treatment of genetic diseases: the paradigm of muscular dystrophy

Current evidence supports the therapeutic potential of pharmacological interventions that counter the progression of genetic disorders by promoting regeneration of the affected organs or tissues. The rationale behind this concept lies on the evidence that targeting key events downstream of the genetic defect can compensate, at least partially, the pathological consequence of the related disease. In this regard, the beneficial effect exerted on animal models of muscular dystrophy by pharmacological strategies that enhance muscle regeneration provides an interesting paradigm. In this review, we describe and discuss the potential targets of pharmacological strategies that promote regeneration of dystrophic muscles and alleviate the consequence of the primary genetic defect. Regenerative pharmacology provides an immediate and suitable therapeutic opportunity to slow down the decline of muscles in the present generation of dystrophic patients, with the perspective to hold them in conditions such that they could benefit of future, more definitive, therapies.