Multilevel Deconstruction of the In Vivo Behavior of Looped DNA-Protein Complexes

Protein-DNA complexes with loops play a fundamental role in a wide variety of cellular processes, ranging from the regulation of DNA transcription to telomere maintenance. As ubiquitous as they are, their precise in vivo properties and their integration into the cellular function still remain largely unexplored. Here, we present a multilevel approach that efficiently connects in both directions molecular properties with cell physiology and use it to characterize the molecular properties of the looped DNA-lac repressor complex while functioning in vivo. The properties we uncover include the presence of two representative conformations of the complex, the stabilization of one conformation by DNA architectural proteins, and precise values of the underlying twisting elastic constants and bending free energies. Incorporation of all this molecular information into gene-regulation models reveals an unprecedented versatility of looped DNA-protein complexes at shaping the properties of gene expression.Comment: Open Access article available at http://www.plosone.org/article/fetchArticle.action?articleURI=info%3Adoi%2F10.1371%2Fjournal.pone.000035

Long-term effects of chronic light pollution on seasonal functions of European blackbirds (turdus merula)

Light pollution is known to affect important biological functions of wild animals, including daily and annual cycles. However, knowledge about long-term effects of chronic exposure to artificial light at night is still very limited. Here we present data on reproductive physiology, molt and locomotor activity during two-year cycles of European blackbirds (Turdus merula) exposed to either dark nights or 0.3 lux at night. As expected, control birds kept under dark nights exhibited two regular testicular and testosterone cycles during the two-year experiment. Control urban birds developed testes faster than their control rural conspecifics. Conversely, while in the first year blackbirds exposed to light at night showed a normal but earlier gonadal cycle compared to control birds, during the second year the reproductive system did not develop at all: both testicular size and testosterone concentration were at baseline levels in all birds. In addition, molt sequence in light-treated birds was more irregular than in control birds in both years. Analysis of locomotor activity showed that birds were still synchronized to the underlying light-dark cycle. We suggest that the lack of reproductive activity and irregular molt progression were possibly the results of i) birds being stuck in a photorefractory state and/or ii) chronic stress. Our data show that chronic low intensities of light at night can dramatically affect the reproductive system. Future studies are needed in order to investigate if and how urban animals avoid such negative impact and to elucidate the physiological mechanisms behind these profound long-term effects of artificial light at night. Finally we call for collaboration between scientists and policy makers to limit the impact of light pollution on animals and ecosystems

Anorexia nervosa and Wernicke-Korsakoff syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>Wernicke's encephalopathy is an acute, potentially fatal, neuropsychiatric syndrome resulting from thiamine deficiency. The disorder is still greatly under-diagnosed, and failure to promptly identify and adequately treat the condition can lead to death or to the chronic form of the encephalopathy - Korsakoff's syndrome. Wernicke's encephalopathy has traditionally been associated with alcoholism but, in recent years, there has been an increase in the number of clinical settings in which the disorder is observed.</p> <p>Case presentation</p> <p>We report the case of a 45-year-old Caucasian woman who arrived at the emergency room presenting signs of marked malnutrition and mental confusion, ataxic gait and ophthalmoplegia. Main laboratory test findings included low serum magnesium and megaloblastic anemia. Brain magnetic resonance imaging revealed increased T2 signal in the supratentorial paraventricular region, the medial regions of the thalamus and the central and periaqueductal midbrain. The diagnosis of Wernicke's encephalopathy was made at once and immediate reposition of thiamine and magnesium was started. The patient had a long history of recurrent thoughts of being overweight, severe self-imposed diet restrictions and self-induced vomiting. She had also been drinking gin on a daily basis for the last eight years. One day after admittance the acute global confusional state resolved, but she presented severe memory deficits and confabulation. After six months of outpatient follow-up, memory deficits remained unaltered.</p> <p>Conclusion</p> <p>In this case, self-imposed long-lasting nutritional deprivation is thought to be the main cause of thiamine deficiency and subsequent encephalopathy, but adjunct factors, such as magnesium depletion and chronic alcohol misuse, might have played an important role, especially in the development of Korsakoff's syndrome. The co-morbidity between eating disorders and substance abuse disorders has emerged as a significant health issue for women, and the subgroup of patients with anorexia nervosa who also misuse alcohol is probably at a particular risk of developing Wernicke-Korsakoff syndrome. The present case report highlights this relevant issue.</p

Review of cigarette smoking and tuberculosis in China: intervention is needed for smoking cessation among tuberculosis patients

<p>Abstract</p> <p>Background</p> <p>As a risk factor of tuberculosis (TB), tobacco smoking has increased substantially over the past three decades, especially in developing countries. However, the association between smoking and TB, which has been shown to exist in different studies with different ethnic background, has not yet received sufficient attention in terms of TB care standards and research in China.</p> <p>Methods</p> <p>An observational study was conducted in two rural areas of China. A total of 613 TB patients frequency matched with 1226 controls were interviewed by using a structured questionnaire. The associations between cigarette smoking and risk of TB were estimated by computing odds ratios (ORs) and 95% confidence intervals (95% CIs) from logistic regression model. Patients' smoking behavior and patterns of smoking cessation were followed after TB diagnosis. Multivariate Cox proportional hazards model was applied to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) in analyzing the risk factors for smoking relapse. The Kaplan-Meier estimate was computed to plot the ability of smoking-free after cessation among different groups, with the Log-rank test being used to compare the difference.</p> <p>Results</p> <p>The proportion of cigarette smoking was 54.6% in TB cases, which was significantly higher than that in controls (45.1%) with adjusted OR of 1.93(95% CI: 1.51–2.48). Though 54.9% smokers stopped smoking after being diagnosed with TB, more than 18% relapsed during the follow-up period. The proportion of relapse was higher within 6–9 months (6%) and 12–15 months (11%) after cessation. In the Cox regression estimates adjusted for age and gender, compared with those highly educated and previously treated patients, the hazard ratios of smoking relapse were 3.48(95% CI: 1.28–9.47) for less educated (< 6 years) and 4.30(95% CI: 1.01–18.30) for newly treated patients, respectively.</p> <p>Conclusion</p> <p>Cigarette smoking is associated with TB in the Chinese. Interventions of smoking cessation are recommended to be included in the current TB control practice.</p

The Evolution of Bat Vestibular Systems in the Face of Potential Antagonistic Selection Pressures for Flight and Echolocation

PMCID: PMC3634842This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Mitochondria-dependent signalling pathway are involved in the early process of radiation-induced bystander effects

Bystander effects induced by cytoplasmic irradiation have been reported recently. However, the mechanism(s) underlying, such as the functional role of mitochondria, is not clear. In the present study, we used either mtDNA-depleted (ρ0) AL or normal (ρ+) AL cells as irradiated donor cells and normal human skin fibroblasts as receptor cells in a series of medium transfer experiments to investigate the mitochondria-related signal process. Our results indicated that mtDNA-depleted cells or normal AL cells treated with mitochondrial respiratory chain function inhibitors had an attenuated γ-H2AX induction, which indicates that mitochondria play a functional role in bystander effects. Moreover, it was found that treatment of normal AL donor cells with specific inhibitors of NOS, or inhibitor of mitochondrial calcium uptake (ruthenium red) significantly decreased γ-H2AX induction and that radiation could stimulate cellular NO and O2•− production in irradiated ρ+ AL cells, but not in ρ0 AL cells. These observations, together with the findings that ruthenium red treatment significantly reduced the NO and O2•− levels in irradiated ρ+ AL cells, suggest that radiation-induced NO derived from mitochondria might be an intracellular bystander factor and calcium-dependent mitochondrial NOS might play an essential role in the process

Fluconazole for empiric antifungal therapy in cancer patients with fever and neutropenia

BACKGROUND: Several clinical trials have demonstrated the efficacy of fluconazole as empiric antifungal therapy in cancer patients with fever and neutropenia. Our objective was to assess the frequency and resource utilization associated with treatment failure in cancer patients given empiric fluconazole antifungal therapy in routine inpatient care. METHODS: We performed a retrospective cohort study of cancer patients treated with oral or intravenous fluconazole between 7/97 and 6/01 in a tertiary care hospital. The final study cohort included cancer patients with neutropenia (an absolute neutrophil count below 500 cells/mm(3)) and fever (a temperature above 38°C or 100.4°F), who were receiving at least 96 hours of parenteral antibacterial therapy prior to initiating fluconazole. Patients' responses to empiric therapy were assessed by reviewing patient charts. RESULTS: Among 103 cancer admissions with fever and neutropenia, treatment failure after initiating empiric fluconazole antifungal therapy occurred in 41% (95% confidence interval (CI) 31% – 50%) of admissions. Patients with a diagnosis of hematological malignancy had increased risk of treatment failure (OR = 4.6, 95% CI 1.5 – 14.8). When treatment failure occurred the mean adjusted increases in length of stay and total costs were 7.4 days (95% CI 3.3 – 11.5) and $18,925 (95% CI 3,289 – 34,563), respectively. CONCLUSION: Treatment failure occurred in more than one-third of neutropenic cancer patients on fluconazole as empiric antifungal treatment for fever in routine clinical treatment. The increase in costs when treatment failure occurs is substantial

Dynamic metabolic patterns tracking neurodegeneration and gliosis following 26S proteasome dysfunction in mouse forebrain neurons

Metabolite profling is an important tool that may better capture the multiple features of neurodegeneration. With the considerable parallels between mouse and human metabolism, the use of metabolomics in mouse models with neurodegenerative pathology provides mechanistic insight and ready translation into aspects of human disease. Using 400MHz nuclear magnetic resonance spectroscopy we have carried out a temporal region-specifc investigation of the metabolome of neuron-specifc 26S proteasome knockout mice characterised by progressive neurodegeneration and Lewy-like inclusion formation in the forebrain. An early signifcant decrease in N-acetyl aspartate revealed evidence of neuronal dysfunction before cell death that may be associated with changes in brain neuroenergetics, underpinning the use of this metabolite to track neuronal health. Importantly, we show early and extensive activation of astrocytes and microglia in response to targeted neuronal dysfunction in this context, but only late changes in myo-inositol; the best established glial cell marker in magnetic resonance spectroscopy studies, supporting recent evidence that additional early neuroinfammatory markers are needed. Our results extend the limited understanding of metabolite changes associated with gliosis and provide evidence that changes in glutamate homeostasis and lactate may correlate with astrocyte activation and have biomarker potential for tracking neuroinfammation

Value of information analysis for assessing risks and benefits of nanotechnology innovation

Background Decisions on adoption of technological innovation are difficult for manufacturers, especially for small and medium enterprises (SMEs) who have limited resources but often drive product development. Decision analytic methods have been applied to regulatory issues in the nanotechnology sector but such applications to market innovation are not found in the literature. Value of information (VoI) is a decision analytic method for quantifying the benefit of acquiring additional information to support such analyses that can be used to help in a wide range of manufacturing decisions. Results This paper develops a VoI methodology for comparative evaluation of technological alternatives and applies it to a real case study aimed at the selection between a coating system containing nano-TiO2 and alternative conventional paints. The aim of this approach is to aid SMEs and larger industries in deciding whether to further develop the nano-enabled product and in evaluating to which extent investing in more research about risks and/or benefits would be worthwhile. Conclusions Results demonstrated how prioritization in information gaining can improve risk–benefit analyses and impact on both risk management and innovation decision making. By applying the proposed methodology, SMEs and larger industries might easily identify optimal data gathering and/or research strategies to formulate solid development and risk management plans