Targeted disruption of the CCR5 gene in human hematopoietic stem cells stimulated by peptide nucleic acids

Peptide nucleic acids (PNAs) bind duplex DNA in a sequence-specific manner, creating triplex structures that can provoke DNA repair and produce genome modification. CCR5 encodes a chemokine receptor required for HIV-1 entry into human cells, and individuals carrying mutations in this gene are resistant to HIV-1 infection. Transfection of human cells with PNAs targeted to the CCR5 gene, plus donor DNAs designed to introduce stop codons mimicking the naturally occurring CCR5-delta32 mutation, produced 2.46% targeted gene modification. CCR5 modification was confirmed at the DNA, RNA, and protein levels and was shown to confer resistance to infection with HIV-1. Targeting of CCR5 was achieved in human CD34(+) hematopoietic stem cells (HSCs) with subsequent engraftment into mice and persistence of the gene modification more than four months posttransplantation. This work suggests a therapeutic strategy for CCR5 knockout in HSCs from HIV-1-infected individuals, rendering cells resistant to HIV-1 and preserving immune system function.     

Protective role of estrogen against excessive erythrocytosis in Monge’s disease

Monge’s disease (chronic mountain sickness (CMS)) is a maladaptive condition caused by chronic (years) exposure to high-altitude hypoxia. One of the defining features of CMS is excessive erythrocytosis with extremely high hematocrit levels. In the Andean population, CMS prevalence is vastly different between males and females, being rare in females. Furthermore, there is a sharp increase in CMS incidence in females after menopause. In this study, we assessed the role of sex hormones (testosterone, progesterone, and estrogen) in CMS and non-CMS cells using a well-characterized in vitro erythroid platform. While we found that there was a mild (nonsignificant) increase in RBC production with testosterone, we observed that estrogen, in physiologic concentrations, reduced sharply CD235a⁺ cells (glycophorin A; a marker of RBC), from 56% in the untreated CMS cells to 10% in the treated CMS cells, in a stage-specific and dose-responsive manner. At the molecular level, we determined that estrogen has a direct effect on GATA1, remarkably decreasing the messenger RNA (mRNA) and protein levels of GATA1 (p < 0.01) and its target genes (Alas2, BclxL, and Epor, p < 0.001). These changes result in a significant increase in apoptosis of erythroid cells. We also demonstrate that estrogen regulates erythropoiesis in CMS patients through estrogen beta signaling and that its inhibition can diminish the effects of estrogen by significantly increasing HIF1, VEGF, and GATA1 mRNA levels. Taken altogether, our results indicate that estrogen has a major impact on the regulation of erythropoiesis, particularly under chronic hypoxic conditions, and has the potential to treat blood diseases, such as high altitude severe erythrocytosis.Subject terms: Haematopoietic stem cells, Myeloproliferative disease     

Conformational studies by dynamic NMR. 91. Conformational stereodynamics of tetraethylmethane and analogous C(CH2X)4 compounds

Variable-temperature NMR studies of tetraethylmethane (1a), tetrapropylmethane (1b), tetrachloromethylmethane (1c), tetrabromomethylmethane (1d), tetracyclopropylmethylmethane (1e), and tetrabenzylmethane (1f) show a range of dynamic behavior. Separate signals for two types of conformation are observed for 1a, 1c, and 1d at low temperatures, with more than 95% of the molecules in a time-averaged D2d conformation, and the S4 conformation as the minor populated alternative. Compound 1e populates only S4-type conformations but equilibrates slowly between degenerate versions of these at low temperatures. Compounds 1b and 1f show a temperature-dependent spectrum but the low-temperature limit spectrum could not be observed. Ab initio calculations agree well with experiment on the conformational equilibria and suggest in particular that compounds 1b and 1f behave similarly to compounds 1a and 1e, respectively. A crystal structure of compound 1f is reported.     

Elastico-viscous flow engendered due to an impulsively started porous plane wall

Approximate solution for the flow past an impulsively started infinite porous plane wall in an elastico-viscous fluid is obtained for the velocity and shearing stress. The roles of elasticity of the liquid and the suction on the velocity and the shearing stress have been studied.     

Efficient total synthesis of sapinofuranone B

[structure: see text] An efficient enantioselective synthesis of sapinofuranone B (1) using Sharpless asymmetric dihydroxylation, Sonogashira coupling, and Wittig olefination as the key steps is described.     

Saturation Effects on Immunopathogenic Mechanism of Psoriasis: A theoretical approach

Psoriasis vulgaris is a common chronic autoimmune inflammatory skin disease characterized by T-cell mediated hyper proliferation of keratinocytes.This type of skin disorder is characterized by macroscopic and also microscopic skin alterations.It was observed that,psoriatic lesions are sharply demarcated,red and slightly raised lesions along with silver whitish scales.The striking feature of T-cell mediated chronic psoriatic lesions are the epidermal infiltration of predominantly oligoclonal CD8~+T-cells ...     

Effects of awareness program for controlling mosaic disease in Jatropha curcas plantations

The shrinkage of fossil fuel resources motivates many countries to search alternative energy sources. Jatropha curcas is a small drought‐resistant shrub from whose seeds a high grade fuel biodiesel can be produced. It is cultivated in many tropical countries including India. However, the plant is affected by the mosaic virus (Begomovirus) through infected white‐flies (Bemisia tabaci) which causes mosaic disease. Disease control is an important factor to obtain healthy crop but in agricultural practice, farming awareness is equally important. Here, we propose a mathematical model for media campaigns for raising awareness among people to protect this plant in small plots and control disease. In order to archive high crop yield, we consider the awareness campaign to be arranged in impulsive way to make people aware from infected white‐flies to protect Jatropha plants from mosaic virus. The study reveals that the spread of mosaic disease can be contained or even eradicated by the awareness campaigns. To attain an effective eradication, awareness campaign should be implemented at sufficiently short time intervals. Copyright © 2016 John Wiley & Sons, Ltd.     

The effect of data scaling on dual prices and sensitivity analysis in linear programs

In many practical situations scaling the data is necessary to solve linear programs. This note explores the relationships in translating the sensitivity analysis between the original and the scaled problems.     

A simple algorithm for the source-induced fixed-charge transportation problem

The fixed-charge problem is a non-linear programming problem of practical interest in business and industry. The source-induced fixed-charge transportation problem (SIFCTP) is a variation of the regular fixed-charge transportation problem (FCTP) in which a fixed cost is incurred for every supply point that is used in the solution, along with a variable cost that is proportional to the amount shipped. This problem is significantly different from the widely studied FCTP, where a fixed cost is incurred upon activation of a route. The introduction of the fixed costs in addition to variable costs results in the objective function being a step function. Therefore, fixed-charge problems are usually solved using sophisticated analytical or computer software. This paper deviates from that approach. It presents a computationally simple algorithm for the solution of source-induced fixed-charge problems. The results of empirical tests of the effectiveness of the proposed algorithm are presented.