Phase behavior and molecular scale dynamics of confined fluids using new atomistic simulation techniques: CRADA No. 1140 close-out report

The Mobil-nCUBE-Sandia CRADA No. 1140 was aimed at developing the tools and capabilities to model fluid phase behavior and flow in pores--ultimately leading to a better understanding of these phenomena. In this CRADA close-out report the collaboration`s original goals are revisited, the course of the CRADA is traced, and the technical accomplishments of the CRADA are presented

Application of fluorescence techniques to the study of protein adsorption and packing on biomaterial surfaces

[Excerpt] The ways proteins compete for the surface of biomaterials and change conformation are believed to be important for the host response to implants. It is possible to elucidate information on packing and any induced conformational change by making use of different fluorescence techniques on fluorescently labelled proteins. Employing probe-probe resonance energy transfer (RET) allows inter and intra protein interactions to be distinguished. Homo resonance energy transfer (hRET) avoids many problems with having two different probes and means that labelling and subsequent purification can be done in one step. [...]Portuguese Foundation for Science and Technology, project PROTEOLIGHT (PTDC/FIS/68517/2006) and J.B. grant SFRH/BPD/17584/2004. European Union NoE EXPERTISSUES (NMP3-CT-2004-500283) and European Union FP6 STREP project HIPPOCRATES (NMP3-CT-2003-505758).info:eu-repo/semantics/publishedVersio

Fermiology via the electron momentum distribution

Investigations of the Fermi surface via the electron momentum distribution reconstructed from either angular correlation of annihilation radiation (or Compton scattering) experimental spectra are presented. The basis of these experiments and mathematical methods applied in reconstructing three-dimensional densities from line (or plane) projections measured in these experiments are described. The review of papers where such techniques have been applied to study the Fermi surface of metallic materials with showing their main results is also done.Comment: 22 pages, 9 Figures, 4 Table

Anticancer Gene Transfer for Cancer Gene Therapy

Gene therapy vectors are among the treatments currently used to treat malignant tumors. Gene therapy vectors use a specific therapeutic transgene that causes death in cancer cells. In early attempts at gene therapy, therapeutic transgenes were driven by non-specific vectors which induced toxicity to normal cells in addition to the cancer cells. Recently, novel cancer specific viral vectors have been developed that target cancer cells leaving normal cells unharmed. Here we review such cancer specific gene therapy systems currently used in the treatment of cancer and discuss the major challenges and future directions in this field

Socio-Economic Variation in Price Minimizing Behaviors: Findings from the International Tobacco Control (ITC) Four Country Survey

This paper examines how socio-economic status (SES) modifies how smokers adjust to changes in the price of tobacco products through utilization of multiple price minimizing techniques. Data come from the International Tobacco Control Policy Evaluation (ITC) Four Country Survey, nationally representative samples of adult smokers and includes respondents from Canada, the United States, the United Kingdom and Australia. Cross-sectional analyses were completed among 8,243 respondents (7,038 current smokers) from the survey wave conducted between October 2006 and February 2007. Analyses examined predictors of purchasing from low/untaxed sources, using discount cigarettes or roll-your-own (RYO) tobacco, purchasing cigarettes in cartons, and engaging in high levels of price and tax avoidance at last purchase. All analyses tested for interactions with SES and were weighted to account for changing and under-represented demographics. Relatively high levels of price and tax avoidance behaviors were present; 8% reported buying from low or untaxed source; 36% used discount or generic brands, 13.5% used RYO tobacco, 29% reported purchasing cartons, and 63% reported using at least one of these high price avoidance behaviors. Respondents categorized as having low SES were approximately 26% less likely to report using low or untaxed sources and 43% less likely to purchase tobacco by the carton. However, respondents with low SES were 85% more likely to report using discount brands/RYO compared to participants with higher SES. Overall, lower SES smokers were 25% more likely to engage in at least one or more tax avoidance behaviors compared to their higher SES counterparts. Price and tax avoidance behaviors are relatively common among smokers of all SES strata, but strategies differed with higher SES groups more likely to report traveling to a low-tax location to avoid paying higher prices, purchase duty free tobacco, and purchase by cartons instead of packs all of which were less commonly reported by low SES smokers. Because of the strategies lower SES respondents are more likely to use, reducing price differentials between discount and premium brands may have a greater impact on them, potentially increasing the likelihood of quitting

A comparison of rotation- and blob-based system models for 3D SPECT with depth-dependent detector response

We compare two different implementations of a 3D SPECT system model for iterative reconstruction, both of which compensate for non-uniform photon attenuation and depth-dependent system response. One implementation performs fast rotation of images represented using a basis of rectangular voxels, whereas the other represents images using a basis of rotationally symmetric volume elements. In our simulations the blob-based approach was found to slightly outperform the rotation-based one in terms of the bias-variance trade-off in the reconstructed images. Their difference can be significant, however, in terms of computational load. The rotation-based method is faster for many typical SPECT reconstruction problems, but the blob-based one can be better-suited to cases where the reconstruction algorithm needs to process one volume element at a time.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48977/2/pmb4_11_003.pd

HMGA1 is a novel downstream nuclear target of the insulin receptor signaling pathway

High-mobility group AT-hook 1 (HMGA1) protein is an important nuclear factor that activates gene transcription by binding to AT-rich sequences in the promoter region of DNA. We previously demonstrated that HMGA1 is a key regulator of the insulin receptor (INSR) gene and individuals with defects in HMGA1 have decreased INSR expression and increased susceptibility to type 2 diabetes mellitus. In addition, there is evidence that intracellular regulatory molecules that are employed by the INSR signaling system are involved in post-translational modifications of HMGA1, including protein phosphorylation. It is known that phosphorylation of HMGA1 reduces DNA-binding affinity and transcriptional activation. In the present study, we investigated whether activation of the INSR by insulin affected HMGA1 protein phosphorylation and its regulation of gene transcription. Collectively, our findings indicate that HMGA1 is a novel downstream target of the INSR signaling pathway, thus representing a new critical nuclear mediator of insulin action and function

Insulin-like growth factor-I receptor activity is essential for Kaposi's sarcoma growth and survival

Kaposi's sarcoma (KS) is a highly vascular tumour and is the most common neoplasm associated with human immunodeficiency virus (HIV-1) infection. Growth factors, in particular vascular endothelial growth factor (VEGF), have been shown to play an important role in its development. The role of insulin-like growth factors (IGFs) in the pathophysiology of different tumours led us to evaluate the role of IGF system in KS. The IGF-I receptors (IGF-IR) were identified by immunohistochemistry in biopsies taken from patients with different AIDS/HIV-related KS stages and on KSIMM cells (an established KS-derived cell line). Insulin-like growth factor-I is a growth factor for KSIMM cells with a maximum increase of 3H-thymidine incorporation of 130±27.6% (P<0.05) similar to that induced by VEGF and with which it is additive (281±13%) (P<0.05). Moreover, specific blockade of the receptor (either by α IR3 antibody or by picropodophyllin, a recently described selective IGF-IR tyrosine phosphorylation inhibitor) induced KSIMM apoptosis, suggesting that IGF-IR agonists (IGF-I and -II) mediate antiapoptotic signals for these cells. We were able to identify an autocrine loop essential for KSIMM cell survival in which IGF-II is the IGF-IR agonist secreted by the cells. In conclusion, IGF-I pathway inhibition is a promising therapeutical approach for KS tumours

MAO-B Elevation in Mouse Brain Astrocytes Results in Parkinson's Pathology

Age-related increases in monoamine oxidase B (MAO-B) may contribute to neurodegeneration associated with Parkinson's disease (PD). The MAO-B inhibitor deprenyl, a long-standing antiparkinsonian therapy, is currently used clinically in concert with the dopamine precursor L-DOPA. Clinical studies suggesting that deprenyl treatment alone is not protective against PD associated mortality were targeted to symptomatic patients. However, dopamine loss is at least 60% by the time PD is symptomatically detectable, therefore lack of effect of MAO-B inhibition in these patients does not negate a role for MAO-B in pre-symptomatic dopaminergic loss. In order to directly evaluate the role of age-related elevations in astroglial MAO-B in the early initiation or progression of PD, we created genetically engineered transgenic mice in which MAO-B levels could be specifically induced within astroglia in adult animals. Elevated astrocytic MAO-B mimicking age related increase resulted in specific, selective and progressive loss of dopaminergic neurons in the substantia nigra (SN), the same subset of neurons primarily impacted in the human condition. This was accompanied by other PD-related alterations including selective decreases in mitochondrial complex I activity and increased mitochondrial oxidative stress. Along with a global astrogliosis, we observed local microglial activation within the SN. These pathologies correlated with decreased locomotor activity. Importantly, these events occurred even in the absence of the PD-inducing neurotoxin MPTP. Our data demonstrates that elevation of murine astrocytic MAO-B by itself can induce several phenotypes of PD, signifying that MAO-B could be directly involved in multiple aspects of disease neuropathology. Mechanistically this may involve increases in membrane permeant H2O2 which can oxidize dopamine within dopaminergic neurons to dopaminochrome which, via interaction with mitochondrial complex I, can result in increased mitochondrial superoxide. Our inducible astrocytic MAO-B transgenic provides a novel model for exploring pathways involved in initiation and progression of several key features associated with PD pathology and for therapeutic drug testing

Caloric vestibular stimulation for the management of motor and non-motor symptoms in Parkinson's disease

Introduction: A recent case study showed that repeated sessions of caloric vestibular stimulation (CVS) relieved motor and non-motor symptoms associated with Parkinson's disease (PD). Here we sought to confirm these results in a prospective, double-blind, randomized, placebo treatment-controlled study. Methods: 33 PD subjects receiving stable anti-Parkinsonian therapy completed an active (n = 16) or placebo (n = 17) treatment period. Subjects self-administered CVS at home twice-daily via a portable, pre-programmed, solid-state ThermoNeuroModulation (TNMTM) device, which delivered continually-varying thermal waveforms through aluminum ear-probes mounted on a wearable headset. Subjects were followed over a 4-week baseline period, 8 weeks of treatment and then at 5- and 24-weeks post-treatment. At each study visit, standardized clinical assessments were conducted during ON-medication states to evaluate changes in motor and non-motor symptoms, activities of daily living, and quality of life ratings. Results: Change scores between baseline and the end of treatment showed that active-arm subjects demonstrated clinically-relevant reductions in motor and non-motor symptoms that were significantly greater than placebo- arm subjects. Active treatment was also associated with improved scores on activities of daily living assessments. Therapeutic gains were still evident 5 weeks after the end of active treatment but had started to recede at 24 weeks follow-up. No serious adverse events were associated with device use, and there was high participant satisfaction and tolerability of treatment. Conclusion: The results provide evidence that repeated CVS can provide safe and enduring adjuvant relief for motor and non-motor symptoms associated with PD