The synthesis, conformation and hydrolytic stability of an N,S-bridging thiophosphoramidate analogue of thymidylyl-3 ',5 '-thymidine

A 3 ’ - N ,5 ’ - S -bridging thiophosphoramidate analogue of thymidylyl-3 ’ ,5 ’ -thymidine was synthesised underaqueous conditions.1H NMR conformational measurements show that the 3 ’ - N -substituted deoxyribosering is biased towards the ‘ north ’ , RNA-like conformation. Rate constants for hydrolysis of the analoguewere measured at 90 °C in the pH range 1.3 – 10.9. The pH-log k obs pro fi le displays a pH-independentregion between approximately pH 7 and 10 ( t 1/2 ∼ 13 days). Under acidic conditions, k obs displays a fi rstorder dependence on [H 3 O+]</p

Influence of the Built Environment on Pedestrian Route Choices of Adolescent Girls

We examined the influence of the built environment on pedestrian route selection among adolescent girls. Portable global positioning system units, accelerometers, and travel diaries were used to identify the origin, destination, and walking routes of girls in San Diego, CA and Minneapolis, MN. We completed an inventory of the built environment on every street segment to measure the characteristics of routes taken and not taken. Route-level variables covering four key conceptual built environment domains (Aesthetics, Destinations, Functionality, and Safety) were used in the analysis of route choice. Shorter distance had the strongest positive association with route choice, while the presence of a greenway or trail, higher safety, presence of sidewalks, and availability of destinations along a route were also consistently positively associated with route choice at both sites. The results suggest that it may be possible to encourage pedestrians to walk farther by providing high quality and stimulating routes

A Dopaminergic Gene Cluster in the Prefrontal Cortex Predicts Performance Indicative of General Intelligence in Genetically Heterogeneous Mice

Background: Genetically heterogeneous mice express a trait that is qualitatively and psychometrically analogous to general intelligence in humans, and as in humans, this trait co-varies with the processing efficacy of working memory (including its dependence on selective attention). Dopamine signaling in the prefrontal cortex (PFC) has been established to play a critical role in animals ’ performance in both working memory and selective attention tasks. Owing to this role of the PFC in the regulation of working memory, here we compared PFC gene expression profiles of 60 genetically diverse CD-1 mice that exhibited a wide range of general learning abilities (i.e., aggregate performance across five diverse learning tasks). Methodology/Principal Findings: Animals ’ general cognitive abilities were first determined based on their aggregate performance across a battery of five diverse learning tasks. With a procedure designed to minimize false positive identifications, analysis of gene expression microarrays (comprised of &lt;25,000 genes) identified a small number (,20) of genes that were differentially expressed across animals that exhibited fast and slow aggregate learning abilities. Of these genes, one functional cluster was identified, and this cluster (Darpp-32, Drd1a, and Rgs9) is an established modulator of dopamine signaling. Subsequent quantitative PCR found that expression of these dopaminegic genes plus one vascular gene (Nudt6) were significantly correlated with individual animal’s general cognitive performance. Conclusions/Significance: These results indicate that D1-mediated dopamine signaling in the PFC, possibly through it

Communications Biophysics

Contains reports on nine research projects split into four sections.National Institutes of Health (Grant 5 P01 NS13126)National Institutes of Health (Grant 5 K04 NS00113)National Institutes of Health (Training Grant 5 T32 NS07047)National Institutes of Health (Grant 5 ROl NS11153-03)National Institutes of Health (Fellowship 1 T32 NS07099-01)National Science Foundation (Grant BNS77-16861)National Institutes of Health (Grant 5 ROl NS10916)National Institutes of Health (Grant 5 ROl NS12846)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 1 RO1 NS14092)Health Sciences FundNational Institutes of Health (Grant 2 R01 NS11680)National Institutes of Health (Grant 2 RO1 NS11080)National Institutes of Health (Training Grant 5 T32 GM07301

Capacitive energy storage from -50 to 100 °C using an ionic liquid electrolyte

Relying on redox reactions, most batteries are limited in their ability to operate at very low or very high temperatures. While performance of electrochemical capacitors is less dependent on the temperature, present-day devices still cannot cover the entire range needed for automotive and electronics applications under a variety of environmental conditions. We show that the right combination of the exohedral nanostructured carbon (nanotubes and onions) electrode and a eutectic mixture of ionic liquids can dramatically extend the temperature range of electrical energy storage, thus defying the conventional wisdom that ionic liquids can only be used as electrolytes above room temperature. We demonstrate electrical double layer capacitors able to operate from -50 to 100 °C over a wide voltage window (up to 3.7 V) and at very high charge/discharge rates of up to 20 V/s

Communications Biophysics

Contains reports on eight research projects split into four sections.National Institutes of Health (Grant 5 P01 NS13126)National Institutes of Health (Grant 5 K04 NS00113)National Institutes of Health (Training Grant 5 T32 NS07047)National Science Foundation (Grant BNS80-06369)National Institutes of Health (Grant 5 ROl NS11153)National Institutes of Health (Fellowship 1 F32 NS06544)National Science Foundation (Grant BNS77-16861)National Institutes of Health (Grant 5 R01 NS10916)National Institutes of Health (Grant 5 RO1 NS12846)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 1 R01 NS14092)National Institutes of Health (Grant 2 R01 NS11680)National Institutes of Health (Grant 5 ROl1 NS11080)National Institutes of Health (Training Grant 5 T32 GM07301

Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma

Glioblastoma (GBM) is a highly aggressive brain tumour, where patients respond poorly to radiotherapy and exhibit dismal survival outcomes. The mechanisms of radioresistance are not completely understood. However, cancer cells with an immature stem-like phenotype are hypothesised to play a role in radioresistance. Since the progenitor marker neuron-glial-2 (NG2) has been shown to regulate several aspects of GBM progression in experimental systems, we hypothesised that its expression would influence the survival of GBM patients. Quantification of NG2 expression in 74 GBM biopsies from newly diagnosed and untreated patients revealed that 50% express high NG2 levels on tumour cells and associated vessels, being associated with significantly shorter survival. This effect was independent of age at diagnosis, treatment received and hypermethylation of the O6-methylguanine methyltransferase (MGMT) DNA repair gene promoter. NG2 was frequently co-expressed with nestin and vimentin but rarely with CD133 and the NG2 positive tumour cells harboured genetic aberrations typical for GBM. 2D proteomics of 11 randomly selected biopsies revealed upregulation of an antioxidant, peroxiredoxin-1 (PRDX-1), in the shortest surviving patients. Expression of PRDX-1 was associated with significantly reduced products of oxidative stress. Furthermore, NG2 expressing GBM cells showed resistance to ionising radiation (IR), rapidly recognised DNA damage and effectuated cell cycle checkpoint signalling. PRDX-1 knockdown transiently slowed tumour growth rates and sensitised them to IR in vivo. Our data establish NG2 as an important prognostic factor for GBM patient survival, by mediating resistance to radiotherapy through induction of ROS scavenging enzymes and preferential DNA damage signalling

Altered Immune Responses in Rhesus Macaques Co-Infected with SIV and Plasmodium cynomolgi: An Animal Model for Coincident AIDS and Relapsing Malaria

BACKGROUND:Dual epidemics of the malaria parasite Plasmodium and HIV-1 in sub-Saharan Africa and Asia present a significant risk for co-infection in these overlapping endemic regions. Recent studies of HIV/Plasmodium falciparum co-infection have reported significant interactions of these pathogens, including more rapid CD4+ T cell loss, increased viral load, increased immunosuppression, and increased episodes of clinical malaria. Here, we describe a novel rhesus macaque model for co-infection that supports and expands upon findings in human co-infection studies and can be used to identify interactions between these two pathogens. METHODOLOGY/PRINCIPAL FINDINGS:Five rhesus macaques were infected with P. cynomolgi and, following three parasite relapses, with SIV. Compared to macaques infected with SIV alone, co-infected animals had, as a group, decreased survival time and more rapid declines in markers for SIV progression, including peripheral CD4+ T cells and CD4+/CD8+ T cell ratios. The naïve CD4+ T cell pool of the co-infected animals was depleted more rapidly than animals infected with SIV alone. The co-infected animals also failed to generate proliferative responses to parasitemia by CD4+ and CD8+ T cells as well as B cells while also having a less robust anti-parasite and altered anti-SIV antibody response. CONCLUSIONS/SIGNIFICANCE:These data suggest that infection with both SIV and Plasmodium enhances SIV-induced disease progression and impairs the anti-Plasmodium immune response. These data support findings in HIV/Plasmodium co-infection studies. This animal model can be used to further define impacts of lentivirus and Plasmodium co-infection and guide public health and therapeutic interventions