The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission

1Infection of red blood cells (RBC) subjects the malaria parasite to oxidative stress. Therefore, efficient antioxidant and redox systems are required to prevent damage by reactive oxygen species. Plasmodium spp. have thioredoxin and glutathione (GSH) systems that are thought to play a major role as antioxidants during blood stage infection. In this report, we analyzed a critical component of the GSH biosynthesis pathway using reverse genetics. Plasmodium berghei parasites lacking expression of gamma-glutamylcysteine synthetase (γ-GCS), the rate limiting enzyme in de novo synthesis of GSH, were generated through targeted gene disruption thus demonstrating, quite unexpectedly, that γ-GCS is not essential for blood stage development. Despite a significant reduction in GSH levels, blood stage forms of pbggcs− parasites showed only a defect in growth as compared to wild type. In contrast, a dramatic effect on development of the parasites in the mosquito was observed. Infection of mosquitoes with pbggcs− parasites resulted in reduced numbers of stunted oocysts that did not produce sporozoites. These results have important implications for the design of drugs aiming at interfering with the GSH redox-system in blood stages and demonstrate that de novo synthesis of GSH is pivotal for development of Plasmodium in the mosquito

Forecast for HEAT on Dome A, Antarctica: the High Elevation Antarctic Terahertz Telescope

We have proposed to develop a prototype 0.5-meter far-infrared telescope and heterodyne receiver/spectrometer system for fully-automated remote operation at the summit of Dome A, the highest point on the Antarctic plateau. The unparalleled stability, exceptional dryness, low wind and extreme cold make Dome A a ground-based site without equal for astronomy at infrared and submillimeter wavelengths. HEAT, the High Elevation Antarctic Terahertz Telescope, will operate in the atmospheric windows between 150 and 400 microns, in which the most crucial astrophysical spectral diagnostics of the formation of galaxies, stars, planets, and life are found. At these wavelengths, HEAT will have high aperture efficiency and excellent atmospheric transmission most of the year. The proposed superheterodyne receiver system will be comprised of 0.8, 1.4 and 1.9 THz channels which will observe the pivotal J=7-6 line of CO, the J=2-1 line of atomic carbon, and the far-infrared fine structure lines of N+ and C+, the brightest emission lines in the entire Milky Way Galaxy. When combined with the HEAT telescope, the receiver system represents a uniquely powerful instrument for reconstructing the history of star formation in our Galaxy, with application to the distant Universe. The receiver system itself serves as a valuable testbed for heterodyne Terahertz components, using leading-edge mixer, local oscillator, low-noise amplifier, cryogenic, and digital signal processing technologies that will play essential roles in future Terahertz observatories. The proposed study will pave the way for future astronomical investigations from Dome A

Pre-HEAT: submillimeter site testing and astronomical spectra from Dome A, Antarctica

Pre-HEAT is a 20 cm aperture submillimeter-wave telescope with a 660 GHz (450 micron) Schottky diode heterodyne receiver and digital FFT spectrometer for the Plateau Observatory (PLATO) developed by the University of New South Wales. In January 2008 it was deployed to Dome A, the summit of the Antarctic plateau, as part of a scientific traverse led by the Polar Research Institute of China and the Chinese Academy of Sciences. Dome A may be one of the best sites in the world for ground based Terahertz astronomy, based on the exceptionally cold, dry and stable conditions which prevail there. Pre-HEAT is measuring the 450 micron sky opacity at Dome A and mapping the Galactic Plane in the ^(13)CO J=6-5 line, constituting the first submillimeter measurements from Dome A. It is field-testing many of the key technologies for its namesake -- a successor mission called HEAT: the High Elevation Antarctic Terahertz telescope. Exciting prospects for submillimeter astronomy from Dome A and the status of Pre-HEAT will be presented

2,4-Diaminopyrimidines as Potent Inhibitors of Trypanosoma brucei and Identification of Molecular Targets by a Chemical Proteomics Approach

The protozoan parasite Trypanosoma brucei is the causative agent of human African trypanosomiasis (HAT) or sleeping sickness, a fatal disease affecting nearly half a million people in sub-Saharan Africa. Current treatments for HAT have very poor safety profiles and are difficult to administer. There is an urgent need for new, safe and effective treatments for sleeping sickness. This work describes the discovery of 2,4-diaminopyrimidines, exemplified by 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid phenylamide or SCYX-5070, as potent inhibitors of T. brucei growth in vitro and also in animal models for HAT. To determine the parasite proteins responsible for interaction with SCYX-5070 and related compounds, affinity pull-downs were performed followed by sequence analysis and parasite genome database searching. The work revealed that mitogen-activated protein kinases (MAPKs) and cdc2-related kinases (CRKs) are the major proteins specifically bound to the immobilized compound, suggesting their potential participation in the pharmacological effects of 2,4-diaminopyrimidines against trypanosomatid protozoan parasites. These data strongly support the use of 2,4-diminipyrimidines as leads for the development of new drug candidates for the treatment of HAT

The VEGF -634G>C promoter polymorphism is associated with risk of gastric cancer

<p>Abstract</p> <p>Background</p> <p>Both TGF-β1 and VEGF play a critic role in the multiple-step process of tumorgenesis of gastric cancer. Single nucleotide polymorphisms (SNPs) of the <it>TGFB1 </it>and <it>VEGF </it>genes have been associated with risk and progression of many cancers. In this study, we investigated the association between potentially functional SNPs of these two genes and risk of gastric cancer in a US population.</p> <p>Methods</p> <p>The risk associated with genotypes and haplotypes of four <it>TGFB1 </it>SNPs and four <it>VEGF </it>SNPs were determined by multivariate logistic regression analysis in 171 patients with gastric cancer and 353 cancer-free controls frequency-matched by age, sex and ethnicity.</p> <p>Results</p> <p>Compared with the <it>VEGF</it>-634GG genotype, the -634CG genotype and the combined -634CG+CC genotypes were associated with a significantly elevated risk of gastric cancer (adjusted OR = 1.88, 95% CI = 1.24-2.86 and adjusted OR = 1.56, 95% CI = 1.07-2.27, respectively). However, none of other <it>TGFB1 </it>and <it>VEGF </it>SNPs was associated with risk of gastric cancer.</p> <p>Conclusion</p> <p>Our data suggested that the <it>VEGF</it>-634G>C SNP may be a marker for susceptibility to gastric cancer, and this finding needs to be validated in larger studies.</p

A Model of Mindful Parenting: Implications for Parent–Child Relationships and Prevention Research

This paper introduces a model of “mindful parenting” as a framework whereby parents intentionally bring moment-to-moment awareness to the parent–child relationship. This is done by developing the qualities of listening with full attention when interacting with their children, cultivating emotional awareness and self-regulation in parenting, and bringing compassion and nonjudgmental acceptance to their parenting interactions. First, we briefly outline the theoretical and empirical literature on mindfulness and mindfulness-based interventions. Next, we present an operational definition of mindful parenting as an extension of mindfulness to the social context of parent–child relationships. We discuss the implications of mindful parenting for the quality of parent–child relationships, particularly across the transition to adolescence, and we review the literature on the application of mindfulness in parenting interventions. We close with a synopsis of our own efforts to integrate mindfulness-based intervention techniques and mindful parenting into a well-established, evidence-based family prevention program and our recommendations for future research on mindful parenting interventions