Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients: Cellular model of pathology

The neurodegenerative disease Friedreich's ataxia (FRDA) is the most common autosomal-recessively inherited ataxia and is caused by a GAA triplet repeat expansion in the first intron of the frataxin gene. In this disease, transcription of frataxin, a mitochondrial protein involved in iron homeostasis, is impaired, resulting in a significant reduction in mRNA and protein levels. Global gene expression analysis was performed in peripheral blood samples from FRDA patients as compared to controls, which suggested altered expression patterns pertaining to genotoxic stress. We then confirmed the presence of genotoxic DNA damage by using a gene-specific quantitative PCR assay and discovered an increase in both mitochondrial and nuclear DNA damage in the blood of these patients (p<0.0001, respectively). Additionally, frataxin mRNA levels correlated with age of onset of disease and displayed unique sets of gene alterations involved in immune response, oxidative phosphorylation, and protein synthesis. Many of the key pathways observed by transcription profiling were downregulated, and we believe these data suggest that patients with prolonged frataxin deficiency undergo a systemic survival response to chronic genotoxic stress and consequent DNA damage detectable in blood. In conclusion, our results yield insight into the nature and progression of FRDA, as well as possible therapeutic approaches. Furthermore, the identification of potential biomarkers, including the DNA damage found in peripheral blood, may have predictive value in future clinical trials

Low-Temperature Operation of AlFaN Single-Quantum-Well Light-Emitting Diodes with Deep Ultraviolet Emission at 285 nm

We present a study of the electrical and optical characteristics of 285 nm emission deep ultraviolet light-emitting diodes(LED) at temperatures from 10 to 300 K. At low bias, our data show the tunneling carrier transport to be the dominant conduction mechanism. The room-temperature performance is shown to be limited mostly by poor electron confinement in the active region and a pronounced deep level assisted recombination but not by the hole injection into the active region. At temperatures below 100 K, the electroluminescence peak intensity increases by more than one order of magnitude indicating that with a proper device design and improved material quality, milliwatt power 285 nm LED are viable

Milliwatt Power Deep Ultraviolet Light-Emitting Diodes Over Sapphire with Emission at 278 nm

We report on AlGaN multiple-quantum-well (MQW)-based deep ultraviolet light-emitting diodes over sapphire with peak emission at 278 nm. A new buffer layer growth process was used to reduce the number of defects and hence the nonradiative recombination. The improved material quality and carrier confinement resulted in pulsed powers as high as 3 mW at 278 nm and a significantly reduced deep-level-assisted long-wavelength emission

Industrial methodology for process verification in research (IMPROVER): toward systems biology verification

Motivation: Analyses and algorithmic predictions based on high-throughput data are essential for the success of systems biology in academic and industrial settings. Organizations, such as companies and academic consortia, conduct large multi-year scientific studies that entail the collection and analysis of thousands of individual experiments, often over many physical sites and with internal and outsourced components. To extract maximum value, the interested parties need to verify the accuracy and reproducibility of data and methods before the initiation of such large multi-year studies. However, systematic and well-established verification procedures do not exist for automated collection and analysis workflows in systems biology which could lead to inaccurate conclusions

Public perceptions of quarantine: community-based telephone survey following an infectious disease outbreak

<p>Abstract</p> <p>Background</p> <p>The use of restrictive measures such as quarantine draws into sharp relief the dynamic interplay between the individual rights of the citizen on the one hand and the collective rights of the community on the other. Concerns regarding infectious disease outbreaks (SARS, pandemic influenza) have intensified the need to understand public perceptions of quarantine and other social distancing measures.</p> <p>Methods</p> <p>We conducted a telephone survey of the general population in the Greater Toronto Area in Ontario, Canada. Computer-assisted telephone interviewing (CATI) technology was used. A final sample of 500 individuals was achieved through standard random-digit dialing.</p> <p>Results</p> <p>Our data indicate strong public support for the use of quarantine when required and for serious legal sanctions against those who fail to comply. This support is contingent both on the implementation of legal safeguards to protect against inappropriate use and on the provision of psychosocial supports for those affected.</p> <p>Conclusion</p> <p>To engender strong public support for quarantine and other restrictive measures, government officials and public health policy-makers would do well to implement a comprehensive system of supports and safeguards, to educate and inform frontline public health workers, and to engage the public at large in an open dialogue on the ethical use of restrictive measures during infectious disease outbreaks.</p

Time-Resolved Electroluminescence of AlGaN-Based Light-Emitting Diodes with Emission at 285 nm

We present a study on the time evolution of the electroluminescence(EL)spectra of AlGaN-based deep ultraviolet light-emitting diodes(LEDs) under pulsed current pumping. The ELspectra peaks at 285 nm and 330 nm are found to result from recombination involving band-to-band and free carriers to deep acceptor level transitions. The 330 nm long-wavelength transitions to deep acceptor levels in the p-AlGaN layer as well as the nonradiative processes significantly influence the LED internal quantum efficiency

Probing the Interaction of the Diarylquinoline TMC207 with Its Target Mycobacterial ATP Synthase

Infections with Mycobacterium tuberculosis are substantially increasing on a worldwide scale and new antibiotics are urgently needed to combat concomitantly emerging drug-resistant mycobacterial strains. The diarylquinoline TMC207 is a highly promising drug candidate for treatment of tuberculosis. This compound kills M. tuberculosis by binding to a new target, mycobacterial ATP synthase. In this study we used biochemical assays and binding studies to characterize the interaction between TMC207 and ATP synthase. We show that TMC207 acts independent of the proton motive force and does not compete with protons for a common binding site. The drug is active on mycobacterial ATP synthesis at neutral and acidic pH with no significant change in affinity between pH 5.25 and pH 7.5, indicating that the protonated form of TMC207 is the active drug entity. The interaction of TMC207 with ATP synthase can be explained by a one-site binding mechanism, the drug molecule thus binds to a defined binding site on ATP synthase. TMC207 affinity for its target decreases with increasing ionic strength, suggesting that electrostatic forces play a significant role in drug binding. Our results are consistent with previous docking studies and provide experimental support for a predicted function of TMC207 in mimicking key residues in the proton transfer chain and blocking rotary movement of subunit c during catalysis. Furthermore, the high affinity of TMC207 at low proton motive force and low pH values may in part explain the exceptional ability of this compound to efficiently kill mycobacteria in different microenvironments

Body Mass Index, percent body fat, and regional body fat distribution in relation to leptin concentrations in healthy, non-smoking postmenopausal women in a feeding study

BACKGROUND: The relationship between BMI and leptin has been studied extensively in the past, but previous reports in postmenopausal women have not been conducted under carefully controlled dietary conditions of weight maintenance using precise measures of body fat distribution. The aim of the present study was to examine the association between serum leptin concentration and adiposity as estimated by BMI and dual energy x-ray absorptiometry (DEXA) measures (percent body fat, central and peripheral fat, and lean mass) in postmenopausal women. METHODS: This study was conducted as a cross-sectional analysis within the control segment of a randomized, crossover trial in which postmenopausal women (n = 51) consumed 0 (control), 15 (one drink), and 30 (two drinks) g alcohol (ethanol)/d for 8 weeks as part of a controlled diet. BMIs were determined and DEXA scans were administered to the women during the 0 g alcohol treatment, and a blood sample was collected at baseline and week 8 of each study period for leptin analysis. RESULTS AND DISCUSSION: In multivariate analysis, women who were overweight (BMI > 25 to ≤ 30 kg/m(2)) had a 2-fold increase, and obese women (BMI > 30 kg/m(2)) had more than a 3-fold increase in serum leptin concentrations compared to normal weight (BMI ≤25 kg/m(2)) women. When the models for the different measures of adiposity were assessed by multiple R(2), models which included percent body fat explained the highest proportion (approximately 80%) of the serum leptin variance. CONCLUSION: Under carefully controlled dietary conditions, we confirm that higher levels of adiposity were associated with higher concentrations of serum leptin. It appears that percent body fat in postmenopausal women may be the best adiposity-related predictor of serum leptin

RecA maintains the integrity of chloroplast DNA molecules in Arabidopsis

Although our understanding of mechanisms of DNA repair in bacteria and eukaryotic nuclei continues to improve, almost nothing is known about the DNA repair process in plant organelles, especially chloroplasts. Since the RecA protein functions in DNA repair for bacteria, an analogous function may exist for chloroplasts. The effects on chloroplast DNA (cpDNA) structure of two nuclear-encoded, chloroplast-targeted homologues of RecA in Arabidopsis were examined. A homozygous T-DNA insertion mutation in one of these genes (cpRecA) resulted in altered structural forms of cpDNA molecules and a reduced amount of cpDNA, while a similar mutation in the other gene (DRT100) had no effect. Double mutants exhibited a similar phenotype to cprecA single mutants. The cprecA mutants also exhibited an increased amount of single-stranded cpDNA, consistent with impaired RecA function. After four generations, the cprecA mutant plants showed signs of reduced chloroplast function: variegation and necrosis. Double-stranded breaks in cpDNA of wild-type plants caused by ciprofloxacin (an inhibitor of Escherichia coli gyrase, a type II topoisomerase) led to an alteration of cpDNA structure that was similar to that seen in cprecA mutants. It is concluded that the process by which damaged DNA is repaired in bacteria has been retained in their endosymbiotic descendent, the chloroplast