100 research outputs found
Localization of hRad9 in breast cancer
<p>Abstract</p> <p>Background</p> <p><it>hRad9 </it>is a cell cycle checkpoint gene that is up-regulated in breast cancer. We have previously shown that the mRNA up-regulation correlated with tumor size and local recurrence. Immunohistochemical studies were made to better define the role of <it>hRad9 </it>in breast carcinogenesis.</p> <p>Methods</p> <p>Localisation of hRad9 protein were performed on paired tumor and normal breast tissues. Immunoblotting with and without dephosphorylation was used to define the protein isolated from breast cancer cells.</p> <p>Results</p> <p>Increased hRad9 protein was observed in breast cancer cells nucleus compared to non-tumor epithelium. This nuclear protein existed in hyperphosphorylated forms which may be those of the hRad9-hRad1-hHus1 complex.</p> <p>Conclusion</p> <p>Finding of hyperphosphorylated forms of hRad9 in the nucleus of cancer cells is in keeping with its function in ameliorating DNA instability, whereby it inadvertently assists tumor growth.</p
From Classical Genetics to Quantitative Genetics to Systems Biology: Modeling Epistasis
Gene expression data has been used in lieu of phenotype in both classical and quantitative genetic settings. These two disciplines have separate approaches to measuring and interpreting epistasis, which is the interaction between alleles at different loci. We propose a framework for estimating and interpreting epistasis from a classical experiment that combines the strengths of each approach. A regression analysis step accommodates the quantitative nature of expression measurements by estimating the effect of gene deletions plus any interaction. Effects are selected by significance such that a reduced model describes each expression trait. We show how the resulting models correspond to specific hierarchical relationships between two regulator genes and a target gene. These relationships are the basic units of genetic pathways and genomic system diagrams. Our approach can be extended to analyze data from a variety of experiments, multiple loci, and multiple environments
Maximal Extraction of Biological Information from Genetic Interaction Data
Targeted genetic perturbation is a powerful tool for inferring gene function in model organisms. Functional relationships between genes can be inferred by observing the effects of multiple genetic perturbations in a single strain. The study of these relationships, generally referred to as genetic interactions, is a classic technique for ordering genes in pathways, thereby revealing genetic organization and gene-to-gene information flow. Genetic interaction screens are now being carried out in high-throughput experiments involving tens or hundreds of genes. These data sets have the potential to reveal genetic organization on a large scale, and require computational techniques that best reveal this organization. In this paper, we use a complexity metric based in information theory to determine the maximally informative network given a set of genetic interaction data. We find that networks with high complexity scores yield the most biological information in terms of (i) specific associations between genes and biological functions, and (ii) mapping modules of co-functional genes. This information-based approach is an automated, unsupervised classification of the biological rules underlying observed genetic interactions. It might have particular potential in genetic studies in which interactions are complex and prior gene annotation data are sparse
Predicting Quantitative Genetic Interactions by Means of Sequential Matrix Approximation
Despite the emerging experimental techniques for perturbing multiple genes and measuring their quantitative phenotypic effects, genetic interactions have remained extremely difficult to predict on a large scale. Using a recent high-resolution screen of genetic interactions in yeast as a case study, we investigated whether the extraction of pertinent information encoded in the quantitative phenotypic measurements could be improved by computational means. By taking advantage of the observation that most gene pairs in the genetic interaction screens have no significant interactions with each other, we developed a sequential approximation procedure which ranks the mutation pairs in order of evidence for a genetic interaction. The sequential approximations can efficiently remove background variation in the double-mutation screens and give increasingly accurate estimates of the single-mutant fitness measurements. Interestingly, these estimates not only provide predictions for genetic interactions which are consistent with those obtained using the measured fitness, but they can even significantly improve the accuracy with which one can distinguish functionally-related gene pairs from the non-interacting pairs. The computational approach, in general, enables an efficient exploration and classification of genetic interactions in other studies and systems as well
Reverse Engineering a Signaling Network Using Alternative Inputs
One of the goals of systems biology is to reverse engineer in a comprehensive fashion the arrow diagrams of signal transduction systems. An important tool for ordering pathway components is genetic epistasis analysis, and here we present a strategy termed Alternative Inputs (AIs) to perform systematic epistasis analysis. An alternative input is defined as any genetic manipulation that can activate the signaling pathway instead of the natural input. We introduced the concept of an βAIs-Deletions matrixβ that summarizes the outputs of all combinations of alternative inputs and deletions. We developed the theory and algorithms to construct a pairwise relationship graph from the AIs-Deletions matrix capturing both functional ordering (upstream, downstream) and logical relationships (AND, OR), and then interpreting these relationships into a standard arrow diagram. As a proof-of-principle, we applied this methodology to a subset of genes involved in yeast mating signaling. This experimental pilot study highlights the robustness of the approach and important technical challenges. In summary, this research formalizes and extends classical epistasis analysis from linear pathways to more complex networks, facilitating computational analysis and reconstruction of signaling arrow diagrams
Validity of physical activity monitors for assessing lower intensity activity in adults
Background: Accelerometers can provide accurate estimates of moderate-to-vigorous physical activity (MVPA). However, one of the limitations of these instruments is the inability to capture light activity within an acceptable range of error. The purpose of the present study was to determine the validity of different activity monitors for estimating energy expenditure (EE) of light intensity, semi-structured activities.
Methods: Forty healthy participants wore a SenseWear Pro3 Armband (SWA, v.6.1), the SenseWear Mini, the Actiheart, ActiGraph, and ActivPAL monitors, while being monitored with a portable indirect calorimetry (IC). Participants engaged in a variety of low intensity activities but no formalized scripts or protocols were used during these periods.
Results: The Mini and SWA overestimated total EE on average by 1.0% and 4.0%, respectively, while the AH, the GT3X, and the AP underestimated total EE on average by 7.8%, 25.5%, and 22.2%, respectively. The pattern-recognition monitors yielded non-significant differences in EE estimates during the semi-structured period (p = 0.66, p = 0.27, and p = 0.21 for the Mini, SWA, and AH, respectively).
Conclusions: The SenseWear Mini provided more accurate estimates of EE during light to moderate intensity semi-structured activities compared to other activity monitors. This monitor should be considered when there is interest in tracking low intensity activities in groups of individuals.This research was funded by a grant from Bodymedia Inc. awarded to Dr. Greg Welk
"Predictability of body mass index for diabetes: Affected by the presence of metabolic syndrome?"
<p>Abstract</p> <p>Background</p> <p>Metabolic syndrome (MetS) and body mass index (BMI, kg.m<sup>-2</sup>) are established independent risk factors in the development of diabetes; we prospectively examined their relative contributions and joint relationship with incident diabetes in a Middle Eastern cohort.</p> <p>Method</p> <p>participants of the ongoing Tehran lipid and glucose study are followed on a triennial basis. Among non-diabetic participants agedβ₯ 20 years at baseline (8,121) those with at least one follow-up examination (5,250) were included for the current study. Multivariate logistic regression models were used to estimate sex-specific adjusted odd ratios (ORs) and 95% confidence intervals (CIs) of baseline BMI-MetS categories (normal weight without MetS as reference group) for incident diabetes among 2186 men and 3064 women, aged β₯ 20 years, free of diabetes at baseline.</p> <p>Result</p> <p>During follow up (median 6.5 years); there were 369 incident diabetes (147 in men). In women without MetS, the multivariate adjusted ORs (95% CIs) for overweight (BMI 25-30 kg/m2) and obese (BMIβ₯30) participants were 2.3 (1.2-4.3) and 2.2 (1.0-4.7), respectively. The corresponding ORs for men without MetS were 1.6 (0.9-2.9) and 3.6 (1.5-8.4) respectively. As compared to the normal-weight/without MetS, normal-weight women and men with MetS, had a multivariate-adjusted ORs for incident diabetes of 8.8 (3.7-21.2) and 3.1 (1.3-7.0), respectively. The corresponding ORs for overweight and obese women with MetS reached to 7.7 (4.0-14.9) and 12.6 (6.9-23.2) and for men reached to 3.4(2.0-5.8) and 5.7(3.9-9.9), respectively.</p> <p>Conclusion</p> <p>This study highlights the importance of screening for MetS in normal weight individuals. Obesity increases diabetes risk in the absence of MetS, underscores the need for more stringent criteria to define healthy metabolic state among obese individuals. Weight reduction measures, thus, should be encouraged in conjunction with achieving metabolic targets not addressed by current definition of MetS, both in every day encounter and public health setting.</p
Pervasive and Persistent Redundancy among Duplicated Genes in Yeast
The loss of functional redundancy is the key process in the evolution of duplicated genes. Here we systematically assess the extent of functional redundancy among a large set of duplicated genes in Saccharomyces cerevisiae. We quantify growth rate in rich medium for a large number of S. cerevisiae strains that carry single and double deletions of duplicated and singleton genes. We demonstrate that duplicated genes can maintain substantial redundancy for extensive periods of time following duplication (βΌ100 million years). We find high levels of redundancy among genes duplicated both via the whole genome duplication and via smaller scale duplications. Further, we see no evidence that two duplicated genes together contribute to fitness in rich medium substantially beyond that of their ancestral progenitor gene. We argue that duplicate genes do not often evolve to behave like singleton genes even after very long periods of time
The critical influence of nocturnal breathing complaints on the quality of sleep after stroke: the Pittsburgh Sleep Quality Index and STOP-BANG
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