1,671 research outputs found

    Increased entropy of signal transduction in the cancer metastasis phenotype

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    Studies into the statistical properties of biological networks have led to important biological insights, such as the presence of hubs and hierarchical modularity. There is also a growing interest in studying the statistical properties of networks in the context of cancer genomics. However, relatively little is known as to what network features differ between the cancer and normal cell physiologies, or between different cancer cell phenotypes. Based on the observation that frequent genomic alterations underlie a more aggressive cancer phenotype, we asked if such an effect could be detectable as an increase in the randomness of local gene expression patterns. Using a breast cancer gene expression data set and a model network of protein interactions we derive constrained weighted networks defined by a stochastic information flux matrix reflecting expression correlations between interacting proteins. Based on this stochastic matrix we propose and compute an entropy measure that quantifies the degree of randomness in the local pattern of information flux around single genes. By comparing the local entropies in the non-metastatic versus metastatic breast cancer networks, we here show that breast cancers that metastasize are characterised by a small yet significant increase in the degree of randomness of local expression patterns. We validate this result in three additional breast cancer expression data sets and demonstrate that local entropy better characterises the metastatic phenotype than other non-entropy based measures. We show that increases in entropy can be used to identify genes and signalling pathways implicated in breast cancer metastasis. Further exploration of such integrated cancer expression and protein interaction networks will therefore be a fruitful endeavour.Comment: 5 figures, 2 Supplementary Figures and Table

    Long-term glycine propionyl-l-carnitine supplemention and paradoxical effects on repeated anaerobic sprint performance

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    <p>Abstract</p> <p>Background</p> <p>It has been demonstrated that acute GPLC supplementation produces enhanced anaerobic work capacity with reduced lactate production in resistance trained males. However, it is not known what effects chronic GPLC supplementation has on anaerobic performances or lactate clearance.</p> <p>Purpose</p> <p>The purpose of this study was to examine the long-term effects of different dosages of GPLC supplementation on repeated high intensity stationary cycle sprint performance.</p> <p>Methods</p> <p>Forty-five resistance trained men participated in a double-blind, controlled research study. All subjects completed two testing sessions, seven days apart, 90 minutes following oral ingestion of either 4.5 grams GPLC or 4.5 grams cellulose (PL), in randomized order. The exercise testing protocol consisted of five 10-second Wingate cycle sprints separated by 1-minute active recovery periods. Following completion of the second test session, the 45 subjects were randomly assigned to receive 1.5 g, 3.0 g, or 4.5 g GPLC per day for a 28 day period. Subjects completed a third test session following the four weeks of GPLC supplementation using the same testing protocol. Values of peak power (PP), mean power (MP) and percent decrement of power (DEC) were determined per bout and standardized relative to body mass. Heart rate (HR) and blood lactate (LAC) were measured prior to, during and following the five sprint bouts.</p> <p>Results</p> <p>There were no significant effects of condition or significant interaction effects detected for PP and MP. However, results indicated that sprint bouts three, four and five produced 2 - 5% lower values of PP and 3 - 7% lower values of MP with GPLC at 3.0 or 4.5 g per day as compared to baseline values. Conversely, 1.5 g GPLC produced 3 - 6% higher values of PP and 2 -5% higher values of MP compared with PL baseline values. Values of DEC were significantly greater (15-20%) greater across the five sprint bouts with 3.0 g or 4.5 g GPLC, but the 1.5 g GPLC supplementation produced DEC values -5%, -3%, +4%, +5%, and +2% different from the baseline PL values. The 1.5 g group displayed a statistically significant 24% reduction in net lactate accumulation per unit power output (p < 0.05).</p> <p>Conclusions</p> <p>The effects of GPLC supplementation on anaerobic work capacity and lactate accumulation appear to be dosage dependent. Four weeks of GPLC supplementation at 3.0 and 4.5 g/day resulted in reduced mean values of power output with greater rates of DEC compared with baseline while 1.5 g/day produced higher mean values of MP and PP with modest increases of DEC. Supplementation of 1.5 g/day also produced a significantly lower rate of lactate accumulation per unit power output compared with 3.0 and 4.5 g/day. In conclusion, GPLC appears to be a useful dietary supplement to enhance anaerobic work capacity and potentially sport performance, but apparently the dosage must be determined specific to the intensity and duration of exercise.</p

    Identification of disease-causing genes using microarray data mining and gene ontology

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    Background: One of the best and most accurate methods for identifying disease-causing genes is monitoring gene expression values in different samples using microarray technology. One of the shortcomings of microarray data is that they provide a small quantity of samples with respect to the number of genes. This problem reduces the classification accuracy of the methods, so gene selection is essential to improve the predictive accuracy and to identify potential marker genes for a disease. Among numerous existing methods for gene selection, support vector machine-based recursive feature elimination (SVMRFE) has become one of the leading methods, but its performance can be reduced because of the small sample size, noisy data and the fact that the method does not remove redundant genes. Methods: We propose a novel framework for gene selection which uses the advantageous features of conventional methods and addresses their weaknesses. In fact, we have combined the Fisher method and SVMRFE to utilize the advantages of a filtering method as well as an embedded method. Furthermore, we have added a redundancy reduction stage to address the weakness of the Fisher method and SVMRFE. In addition to gene expression values, the proposed method uses Gene Ontology which is a reliable source of information on genes. The use of Gene Ontology can compensate, in part, for the limitations of microarrays, such as having a small number of samples and erroneous measurement results. Results: The proposed method has been applied to colon, Diffuse Large B-Cell Lymphoma (DLBCL) and prostate cancer datasets. The empirical results show that our method has improved classification performance in terms of accuracy, sensitivity and specificity. In addition, the study of the molecular function of selected genes strengthened the hypothesis that these genes are involved in the process of cancer growth. Conclusions: The proposed method addresses the weakness of conventional methods by adding a redundancy reduction stage and utilizing Gene Ontology information. It predicts marker genes for colon, DLBCL and prostate cancer with a high accuracy. The predictions made in this study can serve as a list of candidates for subsequent wet-lab verification and might help in the search for a cure for cancers

    First-phase ejection fraction by CMR predicts outcomes in aortic stenosis

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    BACKGROUND: First-phase ejection fraction (EF1; the ejection fraction measured during active systole up to the time of maximal aortic flow) measured by transthoracic echocardiography (TTE) is a powerful predictor of outcomes in patients with aortic stenosis. We aimed to assess whether cardiovascular magnetic resonance (CMR) might provide more precise measurements of EF1 than TTE and to examine the correlation of CMR EF1 with measures of fibrosis. METHODS: In 141 patients with at least mild aortic stenosis, we measured CMR EF1 from a short-axis 3D stack and compared its variability with TTE EF1, and its associations with myocardial fibrosis and clinical outcome (aortic valve replacement (AVR) or death). RESULTS: Intra- and inter-observer variation of CMR EF1 (standard deviations of differences within and between observers of 2.3% and 2.5% units respectively) was approximately 50% that of TTE EF1. CMR EF1 was strongly predictive of AVR or death. On multivariable Cox proportional hazards analysis, the hazard ratio for CMR EF1 was 0.93 (95% confidence interval 0.89–0.97, p = 0.001) per % change in EF1 and, apart from aortic valve gradient, CMR EF1 was the only imaging or biochemical measure independently predictive of outcome. Indexed extracellular volume was associated with AVR or death, but not after adjusting for EF1. CONCLUSIONS: EF1 is a simple robust marker of early left ventricular impairment that can be precisely measured by CMR and predicts outcome in aortic stenosis. Its measurement by CMR is more reproducible than that by TTE and may facilitate left ventricular structure–function analysis

    Janus monolayers of transition metal dichalcogenides.

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    Structural symmetry-breaking plays a crucial role in determining the electronic band structures of two-dimensional materials. Tremendous efforts have been devoted to breaking the in-plane symmetry of graphene with electric fields on AB-stacked bilayers or stacked van der Waals heterostructures. In contrast, transition metal dichalcogenide monolayers are semiconductors with intrinsic in-plane asymmetry, leading to direct electronic bandgaps, distinctive optical properties and great potential in optoelectronics. Apart from their in-plane inversion asymmetry, an additional degree of freedom allowing spin manipulation can be induced by breaking the out-of-plane mirror symmetry with external electric fields or, as theoretically proposed, with an asymmetric out-of-plane structural configuration. Here, we report a synthetic strategy to grow Janus monolayers of transition metal dichalcogenides breaking the out-of-plane structural symmetry. In particular, based on a MoS2 monolayer, we fully replace the top-layer S with Se atoms. We confirm the Janus structure of MoSSe directly by means of scanning transmission electron microscopy and energy-dependent X-ray photoelectron spectroscopy, and prove the existence of vertical dipoles by second harmonic generation and piezoresponse force microscopy measurements

    Evaluation and Management of Anal Intraepithelial Neoplasia in HIV-Negative and HIV-Positive Men Who Have Sex with Men

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    The incidence of human papillomavirus (HPV)–associated anal cancer in men who have sex with men (MSM) is striking and has not been mitigated by the use of highly active antiretroviral therapy. Detection and treatment of high-grade anal intraepithelial neoplasia (HGAIN) may reduce the incidence of anal cancer. Anal cytology is a useful tool to detect HGAIN; annual screening of HIV-positive MSM and biennial screening of HIV-negative MSM appears to be cost-effective. MSM with abnormal cytology should be referred for high-resolution anoscopy and biopsy. Individuals with HGAIN should receive treatment; treatment modalities for HGAIN demonstrate moderate efficacy and are usually well tolerated, but greater study is required to determine which treatment is optimal. Large prospective studies are needed to document the efficacy of screening and treatment of HGAIN on anal cancer incidence. The HPV vaccine holds promise for primary prevention of anal cancer in MSM, but significant implementation challenges remain

    A Dynamic Stochastic Model of Frequency-Dependent Stress Fiber Alignment Induced by Cyclic Stretch

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    BACKGROUND: Actin stress fibers (SFs) are mechanosensitive structural elements that respond to forces to affect cell morphology, migration, signal transduction and cell function. Cells are internally stressed so that SFs are extended beyond their unloaded lengths, and SFs tend to self-adjust to an equilibrium level of extension. While there is much evidence that cells reorganize their SFs in response to matrix deformations, it is unclear how cells and their SFs determine their specific response to particular spatiotemporal changes in the matrix. METHODOLOGY/PRINCIPAL FINDINGS: Bovine aortic endothelial cells were subjected to cyclic uniaxial stretch over a range of frequencies to quantify the rate and extent of stress fiber alignment. At a frequency of 1 Hz, SFs predominantly oriented perpendicular to stretch, while at 0.1 Hz the extent of SF alignment was markedly reduced and at 0.01 Hz there was no alignment at all. The results were interpreted using a simple kinematic model of SF networks in which the dynamic response depended on the rates of matrix stretching, SF turnover, and SF self-adjustment of extension. For these cells, the model predicted a threshold frequency of 0.01 Hz below which SFs no longer respond to matrix stretch, and a saturation frequency of 1 Hz above which no additional SF alignment would occur. The model also accurately described the dependence of SF alignment on matrix stretch magnitude. CONCLUSIONS: The dynamic stochastic model was capable of describing SF reorganization in response to diverse temporal and spatial patterns of stretch. The model predicted that at high frequencies, SFs preferentially disassembled in the direction of stretch and achieved a new equilibrium by accumulating in the direction of lowest stretch. At low stretch frequencies, SFs self-adjusted to dissipate the effects of matrix stretch. Thus, SF turnover and self-adjustment are each important mechanisms that cells use to maintain mechanical homeostasis

    Algorithm for identifying and separating beats from arterial pulse records

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    BACKGROUND: This project was designed as an epidemiological aid-selecting tool for a small country health center with the general objective of screening out possible coronary patients. Peripheral artery function can be non-invasively evaluated by impedance plethysmography. Changes in these vessels appear as good predictors of future coronary behavior. Impedance plethysmography detects volume variations after simple occlusive maneuvers that may show indicative modifications in arterial/venous responses. Averaging of a series of pulses is needed and this, in turn, requires proper determination of the beginning and end of each beat. Thus, the objective here is to describe an algorithm to identify and separate out beats from a plethysmographic record. A secondary objective was to compare the output given by human operators against the algorithm. METHODS: The identification algorithm detected the beat's onset and end on the basis of the maximum rising phase, the choice of possible ventricular systolic starting points considering cardiac frequency, and the adjustment of some tolerance values to optimize the behavior. Out of 800 patients in the study, 40 occlusive records (supradiastolic- subsystolic) were randomly selected without any preliminary diagnosis. Radial impedance plethysmographic pulse and standard ECG were recorded digitizing and storing the data. Cardiac frequency was estimated with the Power Density Function and, thereafter, the signal was derived twice, followed by binarization of the first derivative and rectification of the second derivative. The product of the two latter results led to a weighing signal from which the cycles' onsets and ends were established. Weighed and frequency filters are needed along with the pre-establishment of their respective tolerances. Out of the 40 records, 30 seconds strands were randomly chosen to be analyzed by the algorithm and by two operators. Sensitivity and accuracy were calculated by means of the true/false and positive/negative criteria. Synchronization ability was measured through the coefficient of variation and the median value of correlation for each patient. These parameters were assessed by means of Friedman's ANOVA and Kendall Concordance test. RESULTS: Sensitivity was 97% and 91% for the two operators, respectively, while accuracy was cero for both of them. The synchronism variability analysis was significant (p < 0.01) for the two statistics, showing that the algorithm produced the best result. CONCLUSION: The proposed algorithm showed good performance as expressed by its high sensitivity. The correlation analysis demonstrated that, from the synchronism point of view, the algorithm performed the best detection. Patients with marked arrhythmic processes are not good candidates for this kind of analysis. At most, they would be singled out by the algorithm and, thereafter, to be checked by an operator
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