227 research outputs found

    Inflammatory cytokines induce MAdCAM-1 in murine hepatic endothelial cells and mediate alpha-4 beta-7 integrin dependent lymphocyte endothelial adhesion In Vitro

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    <p>Abstract</p> <p>Background</p> <p>MAdCAM-1 plays a central role in T-lymphocyte homing to the gut, but its role in chronic liver inflammation remains unknown. Therefore, this study measured MAdCAM-1 expression, regulation, and function in cultured murine hepatic endothelial cells.</p> <p>Methods</p> <p>Cultures of hepatic endothelial cells (HEC) were prepared from mice expressing a temperature-sensitive SV40 large T antigen (<it>H-2K</it><sup><it>b</it></sup>-<it>tsA58</it>) under the control of an IFN-Îł promoter. Time and dose dependent expression of MAdCAM-1 in response to TNF-α, IL-1ÎČ and IFN-Îł was studied by immunoblotting. Lymphocyte adhesion was studied using α<sub>4</sub>ÎČ<sub>7</sub>integrin expressing lymphocytes (TK-1) +/- anti-MAdCAM-1 mAb.</p> <p>Results</p> <p>TNF-α induced MAdCAM-1 dose-and time-dependently with maximum expression at 20 ng/ml and at 48 hours. IL-1ÎČ also induced MAdCAM-1 to a lesser extent compared to TNF-α; IFN-Îł did not induce MAdCAM-1. TNF-α significantly increased lymphocyte-endothelial adhesion (<it>P </it>< 0.01), which was reversed by anti-MAdCAM-1 antibody. MAdCAM-1 expression was also reduced by N-acetylcysteine and by two NO donors (SperNO, DETANO) suggesting that hepatic endothelial MAdCAM-1 is oxidant and NO regulated.</p> <p>Conclusion</p> <p>MAdCAM-1 is a major determinant of leukocyte recruitment in chronic inflammation and is expressed by HEC in response to IL-1ÎČ and TNF-α. This system may provide a useful model for studying inflammatory mechanisms in liver disease and help determine if controlled MAdCAM-1 expression might influence inflammation in liver disease.</p

    Reversal of experimental colitis disease activity in mice following administration of an adenoviral IL-10 vector

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    Genetic deficiency in the expression of interleukin-10 (IL-10) is associated with the onset and progression of experimental inflammatory bowel disease (IBD). The clinical significance of IL-10 expression is supported by studies showing that immune-augmentation of IL-10 prevents inflammation and mucosal damage in animal models of colitis and in human colitis. Interleukin-10 (IL-10), an endogenous anti-inflammatory and immunomodulating cytokine, has been shown to prevent some inflammation and injury in animal and clinical studies, but the efficacy of IL-10 treatment remains unsatisfactory. We found that intra-peritoneal administration of adenoviral IL-10 to mice significantly reversed colitis induced by administration of 3% DSS (dextran sulfate), a common model of colitis. Adenoviral IL-10 (Ad-IL10) transfected mice developed high levels of IL-10 (394 +/- 136 pg/ml) within the peritoneal cavity where the adenovirus was expressed. Importantly, when given on day 4 (after the induction of colitis w/DSS), Ad-IL10 significantly reduced disease activity and weight loss and completely prevented histopathologic injury to the colon at day 10. Mechanistically, compared to Ad-null and DSS treated mice, Ad-IL10 and DSS-treated mice were able to suppress the expression of MAdCAM-1, an endothelial adhesion molecule associated with IBD. Our results suggest that Ad-IL10 (adenoviral IL-10) gene therapy of the intestine or peritoneum may be useful in the clinical treatment of IBD, since we demonstrated that this vector can reverse the course of an existing gut inflammation and markers of inflammation

    A novel LC–ESI-MS method for the simultaneous determination of etravirine, darunavir and ritonavir in human blood plasma

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    The new potent combination of antiretrovirals etravirine, darunavir, and ritonavir requires a new bioanalytical method for clinical pharmacology investigations and potential therapeutic drug monitoring. The development and validation of a novel LC–MS method for the simultaneous quantification of the most recently FDA-approved protease inhibitor and non-nucleoside reverse transcriptase inhibitor is described. This novel method was developed and validated using a sub-2 ÎŒm particle column, and provides excellent chromatographic separation and peak shape for all three analytes and internal standard. The method was validated over the range of 0.002–2.0 ÎŒg/mL. Intra- and inter-day accuracy of all analytes ranged from 88 to 106%, and intra- and inter-day precision was <7%. Dilution of samples 2-, 5-, and 10-fold maintained accuracy and precision, using a sample volume as low as 10 ÎŒL. Finally, the applicability of the method was investigated with clinical samples and external quality assurance proficiency testing samples

    No-Boundary Thinking in Bioinformatics

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    The following sections are included:Bioinformatics is a Mature DisciplineThe Golden Era of Bioinformatics Has BegunNo-Boundary Thinking in BioinformaticsReference

    No-Boundary Thinking in Bioinformatics Research

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    Currently there are definitions from many agencies and research societies defining bioinformatics as deriving knowledge from computational analysis of large volumes of biological and biomedical data. Should this be the bioinformatics research focus? We will discuss this issue in this review article. We would like to promote the idea of supporting human-infrastructure (HI) with no-boundary thinking (NT) in bioinformatics (HINT)

    Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

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    BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24&nbsp;months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500&nbsp;steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30&nbsp;minutes spent performing activities ≄500&nbsp;counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24&nbsp;months), both the number of steps per day (per 500&nbsp;steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≄500&nbsp;counts per minute (per 30&nbsp;minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score &gt;10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

    Big Data -- A 21st Century Science Maginot Line? No-Boundary Thinking: Shifting from the Big Data Paradigm

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    Whether your interests lie in scientific arenas, the corporate world, or in government, you have certainly heard the praises of big data: Big data will give you new insights, allow you to become more efficient, and/or will solve your problems. While big data has had some outstanding successes, many are now beginning to see that it is not the Silver Bullet that it has been touted to be. Here our main concern is the overall impact of big data; the current manifestation of big data is constructing a Maginot Line in science in the 21st century. Big data is not lots of data as a phenomena anymore; the big data paradigm is putting the spirit of the Maginot Line into lots of data. Big data overall is disconnecting researchers and science challenges. We propose No-Boundary Thinking (NBT), applying no-boundary thinking in problem defining to address science challenges

    Single- and Multiple-Dose Pharmacokinetics of Darunavir Plus Ritonavir and Etravirine in Semen and Rectal Tissue of HIV-Negative Men

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    Antiretroviral therapy (ART) has become a central component of combination HIV prevention efforts. Defining the individual exposure of commercially available ART in genital secretions and vulnerable mucosal tissues is paramount to designing future prevention interventions

    Aptamer-based multiplexed proteomic technology for biomarker discovery

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    Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine
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