TNFalpha induces chromosomal abnormalities independent of ROS through IKK, JNK, p38 and caspase pathways

A role for pro-inflammatory cytokines in inflammation-related cancers has been suggested, but mechanisms are not defined. Here, we demonstrate that treatment of HeLa cells with TNFalpha increases chromosomal aberration. In contrast, IL-1beta did not increase, but rather decreased chromosomal aberration. TNFalpha and IL-1beta increased the production of H2O2 to similar levels in cells, suggesting that increased production of reactive oxygen species might not be the premier factor involved. Reducing H2O2 through overexpression of catalase or treatment of cells with NAC or BHA did not have an effect on TNF-induced chromosomal aberration. TNFalpha-induced NO production has been implicated in DNA damage. Inhibiting NO did not reduce TNF-induced chromosomal aberration. Inhibiting IKK, JNK, and p38 kinase as well as caspases decreased TNF-induced chromosomal aberration, and a correlation between TNF-induced apoptosis and CA generation was not found. Single-strand DNA breaks give rise to double-strand breaks, which then results in chromosomal breaks, when replication forks reach the single-strand breaks during S-phase. In cells progressing through S-phase, TNFalpha activation of IKK, JNK, and p38 is significantly reduced. However, these kinases were activated by IL-1beta in S-phase. The possibility that these pathways, in a TNF-specific manner, may regulate either the generation of single- and double-strand breaks or their repair, thereby resulting in increased chromosomal aberration, is discussed.     

Dietary salt reduction and cardiovascular disease rates in India: a mathematical model

Background

Reducing salt intake has been proposed to prevent cardiovascular disease in India. We sought to determine whether salt reductions would be beneficial or feasible, given the worry that unrealistically large reductions would be required, worsening iodine deficiency and benefiting only urban subpopulations.

Methods and Results

Future myocardial infarctions (MI) and strokes in India were predicted with a Markov model simulating men and women aged 40 to 69 in both urban and rural locations, incorporating the risk reduction from lower salt intake. If salt intake does not change, we expect ∼8.3 million MIs (95% CI: 6.9–9.6 million), 830,000 strokes (690,000–960,000) and 2.0 million associated deaths (1.5–2.4 million) per year among Indian adults aged 40 to 69 over the next three decades. Reducing intake by 3 g/day over 30 years (−0.1 g/year, 25% reduction) would reduce annual MIs by 350,000 (a 4.6% reduction; 95% CI: 320,000–380,000), strokes by 48,000 (−6.5%; 13,000–83,000) and deaths by 81,000 (−4.9%; 59,000–100,000) among this group. The largest decline in MIs would be among younger urban men, but the greatest number of averted strokes would be among rural men, and nearly one-third of averted strokes and one-fifth of averted MIs would be among rural women. Only under a highly pessimistic scenario would iodine deficiency increase (by <0.0001%, ∼1600 persons), since inadequate iodized salt access—not low intake of iodized salt—is the major cause of deficiency and would be unaffected by dietary salt reduction.

Conclusions

Modest reductions in salt intake could substantially reduce cardiovascular disease throughout India.     

A network synthesis model for generating protein interaction network families

In this work, we introduce a novel network synthesis model that can generate families of evolutionarily related synthetic protein-protein interaction (PPI) networks. Given an ancestral network, the proposed model generates the network family according to a hypothetical phylogenetic tree, where the descendant networks are obtained through duplication and divergence of their ancestors, followed by network growth using network evolution models. We demonstrate that this network synthesis model can effectively create synthetic networks whose internal and cross-network properties closely resemble those of real PPI networks. The proposed model can serve as an effective framework for generating comprehensive benchmark datasets that can be used for reliable performance assessment of comparative network analysis algorithms. Using this model, we constructed a large-scale network alignment benchmark, called NAPAbench, and evaluated the performance of several representative network alignment algorithms. Our analysis clearly shows the relative performance of the leading network algorithms, with their respective advantages and disadvantages. The algorithm and source code of the network synthesis model and the network alignment benchmark NAPAbench are publicly available at http://www.ece.tamu.edu/bjyoon/NAPAbench/.     

Possible transmission of human immunodeficiency virus-1 infection from an elite controller to a patient who progressed to acquired immunodeficiency syndrome: a case report

ABSTRACT: INTRODUCTION: Most individuals infected with human immunodeficiency virus-1, in the absence of antiretroviral therapy, exhibit persistent virus replication and declining CD4+ cell numbers, and progress to acquired immunodeficiency syndrome within 10 years of infection. Elite controllers are rare individuals with human immunodeficiency virus-1 infection who can maintain undetectable plasma virus levels and remain asymptomatic without antiretroviral therapy. It has been proposed that elite controllers benefit from being infected with attenuated human immunodeficiency virus-1 variants. CASE PRESENTATION: A 31-year-old African woman presented with human immunodeficiency virus-1 infection during pregnancy and was diagnosed with acquired immunodeficiency syndrome. Subsequently, her husband, a 31-year-old African man, was tested and found to be seropositive for human immunodeficiency virus-1. His plasma human immunodeficiency virus-1 ribonucleic acid level was found to be below the limit of detection of the clinical assay. CONCLUSION: This report provides evidence for the first described case of human immunodeficiency virus-1 infection possibly transmitted from an elite controller to a patient who progressed to acquired immunodeficiency syndrome. This observation strengthens the case against avirulence as a mechanism that protects elite controllers.     

Prediction of membrane protein types by means of wavelet analysis and cascaded neural networks

In this study, membrane proteins were classified using the information hidden in their sequences. It was achieved by applying the wavelet analysis to the sequences and consequently extracting several features, each of them revealing a proportion of the information content present in the sequence. The resultant features were made normalized and subsequently fed into a cascaded model developed in order to reduce the effect of the existing bias in the dataset, rising from the difference in size of the membrane protein classes. The results indicate an improvement in prediction accuracy of the model in comparison with similar works. The application of the presented model can be extended to other fields of structural biology due to its efficiency, simplicity and flexibility.     

Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology?

Establishing causal relationships between environmental exposures and common diseases is beset with problems of unresolved confounding, reverse causation and selection bias that may result in spurious inferences. Mendelian randomization, in which a functional genetic variant acts as a proxy for an environmental exposure, provides a means of overcoming these problems as the inheritance of genetic variants is independent of—that is randomized with respect to—the inheritance of other traits, according to Mendel’s law of independent assortment. Examples drawn from exposures and outcomes as diverse as milk and osteoporosis, alcohol and coronary heart disease, sheep dip and farm workers’ compensation neurosis, folate and neural tube defects are used to illustrate the applications of Mendelian randomization approaches in assessing potential environmental causes of disease. As with all genetic epidemiology studies there are problems associated with the need for large sample sizes, the non-replication of findings, and the lack of relevant functional genetic variants. In addition to these problems, Mendelian randomization findings may be confounded by other genetic variants in linkage disequilibrium with the variant under study, or by population stratification. Furthermore, pleiotropy of effect of a genetic variant may result in null associations, as may canalisation of genetic effects. If correctly conducted and carefully interpreted, Mendelian randomization studies can provide useful evidence to support or reject causal hypotheses linking environmental exposures to common diseases.     

Birth weight of offspring and insulin resistance in late adulthood: cross sectional survey

ObjectiveTo investigate the association between birth weight of offspring and mothers'' insulin resistance in late adulthood.DesignCross sectional survey.SettingGeneral practitioner''s surgeries in 23 towns in Great Britain.Participants4286 women aged 60-79 years.ResultsBirth weight of offspring was inversely related to maternal insulin resistance in late adulthood. For each 1 kg higher birth weight of offspring, women had a 15% reduction in the odds of being in the fourth with highest insulin resistance, compared to other fourths (odds ratio 0.85; 95% confidence interval 0.71 to 1.00). This increased to 27% (0.73; 0.60 to 0.90) after adjusting data for potential confounders. A U shaped relation between birth weight of offspring and diabetes in older age was found; women with the lightest and heaviest offspring had the highest prevalence of diabetes.ConclusionsBirth weight of offspring is inversely related to the mother''s insulin resistance in late adulthood, despite the association of glucose intolerance during pregnancy with heavier offspring at birth. Common genetic factors contribute to the relation between birth weight and risk of cardiovascular disease and diabetes in adults.

What is already known on this topic

Small birth weight is related to increased risk of cardiovascular disease and diabetes in adulthood; the underlying mechanisms are unclearSmall birth weight of offspring is related to parental cardiovascular disease, suggesting that common genetic factors affect birth weight and the risk of disease in adulthoodGenetic factors associated with the metabolism of insulin are plausible in linking birth weight and cardiovascular disease (the fetal insulin hypothesis)

What this study adds

Birth weight of offspring is inversely related to maternal insulin resistance in older ageGenetic factors related to both insulin resistance and birth weight explain at least part of the association between birth weight and risk of cardiovascular disease and diabetes in adulthood