tbuckley/cabot-search huggingface dataset:
Interleukin 1? inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance
Authors: Eric Assenat, Sabine Gerbal-Chaloin, Dominique Larrey, Jean Saric, Jean-Michel Fabre, Patrick Maurel, Marie-Jos� Vilarem, Jean Marc Pascussi
Journal: Hepatology (2004)

During the inflammatory response, intrahepatic cholestasis and decreased drug metabolism are frequently observed. At the hepatic level, the orphan nuclear constitutive androstane receptor (CAR) (NR1I3) controls phase I (cytochrome P450 [CYP] 2B and CYP3A), phase II (UGT1A1), and transporter (SLC21A6, MRP2) genes involved in drug metabolism and bilirubin clearance in response to xenobiotics such as phenobarbital or endobiotics such as bilirubin. We investigated the negative regulation of CAR, a glucocorticoid-responsive gene, via proinflammatory cytokine interleukin 1beta (IL-1beta) and lipopolysaccharides (LPSs) in human hepatocytes. We show that IL-1beta decreases CAR expression and decreases phenobarbital- or bilirubin-mediated induction of CYP2B6, CYP2C9, CYP3A4, UGT1A1, GSTA1, GSTA2, and SLC21A6 messenger RNA. This occurs via nuclear factor kappaB (NF-kappaB) p65 activation, which interferes with the enhancer function of the distal glucocorticoid response element that we have identified recently in the CAR promoter. We demonstrate that: (1) LPSs, IL-1beta, or overexpression of p65RelA inhibit glucocorticoid receptor (GR)-mediated CAR transactivation; (2) these suppressive effects can be blocked both by pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB activation, or by overexpression of SRIkBalpha, a NF-kappaB repressor; and (3) the GR agonist dexamethasone induces histone H4 acetylation at the proximal CAR promoter region, whereas LPSs and IL-1beta inhibit this acetylation as assessed via chromatin immunoprecipitation assay. In conclusion, GR/NF-kappaB interaction affects CAR gene transcription through chromatin remodeling and provide a mechanistic explanation for the long-standing observation that inflammation and sepsis inhibit drug metabolism while inducing intrahepatic cholestasis or hyperbilirubinemia.
Studies of Hemoglobin Denaturation and Heinz Body Formation in the Unstable Hemoglobins
Authors: Christine C. Winterbourn, R. W. Carrell
Journal: Journal of Clinical Investigation (1974)

The sequential changes that occur during the precipitation on mild heating of the unstable hemoglobins, Hb Christchurch, Hb Sydney, Hb Köln, and Hb A, were examined with particular attention to the possibility of an accompanying oxidative process. Hb Christchurch, Hb Sydney, and Hb A precipitated with equal amounts of alpha- and beta-chains and full heme complement. Hb Köln, however, was one-half hemedepleted and showed a slight excess of precipitated beta-chains. In all cases the spectrum of the precipitated material was typical of a hemichrome. There was no evidence that sulfhydryl oxidation contributed to the precipitation process. Reduced glutathione was unable to protect the hemoglobin against precipitation, and mixed disulfide formation between the precipitating hemoglobin and glutathione was insignificant, even in the presence of excess glutathione. No blockade of beta93 cysteines could be demonstrated in the unstable hemoglobins. Precipitation of oxyhemoglobin and carboxyhemoglobin in all cases gave nonspecific oxidation of approximately two of the six hemoglobin sulfhydryl groups to give intra- and intermolecular disulfide bonds. Single alpha- and beta-chains, plus polymers of up to five or six chains linked by disulfide bridges, were demonstrated by polyacrylamide gel electrophoresis. This disulfide oxidation was not observed with deoxy- or methemoglobin and did not appear to influence the rate of precipitation. These findings fit the theoretical prediction that autoxidation of oxy- and carboxyhemoglobin is accompanied by formation of a free radical, with the reactions of this free radical being confined intramolecularly.Together, these results are in keeping with predictions based on the known structural abnormalities of the unstable hemoglobins, all of which result in greater molecular flexibility. Our findings support the conclusion that the usual precipitating event is altered bonding at the heme to give the formation of hemichromes. There is no evidence of an accompanying oxidative process that could pose a threat to the integrity of the red cell.
Impact of asthma on self-reported health status and quality of life: a population based study of Australians aged 18-64
Authors: R D Ampon
Journal: Thorax (2005)

<b>Background:</b> The impact of asthma has traditionally been measured in terms of the prevalence of the disease, mortality rates, and levels of healthcare utilisation, particularly hospital admissions. However, the impact of asthma extends beyond these outcomes to include effects on lifestyle, well being, and perceived health status. <b>Methods:</b> Information on self-reported current asthma status, arthritis and diabetes as well as measures of life satisfaction, self-assessed health status, psychological distress, and interference with usual activities was obtained for 14 641 respondents aged 18–64 years in the 2001 National Health Survey of the general population in all states and territories in Australia. Log linear models were fitted separately for each of the dichotomised quality of life measures as dependent variables. The estimates of the adjusted rate ratio obtained from each model were used to compute the population attributable fraction (PAF) of self-reported asthma, arthritis, and diabetes for each of the health status and quality of life measures. <b>Results:</b> The presence of asthma accounted for 3.18% (95% CI 2.13 to 4.23) of people reporting poor life satisfaction, 8.12% (95% CI 6.57 to 9.67) of people reporting poor health status, 5.90% (95% CI 4.19 to 7.61) of people reporting high psychological distress, and 3.58% (95% CI 2.16 to 5.01) of people reporting any reduced activity days. The proportions of people with these adverse health states attributable to asthma were higher than the proportions attributable to diabetes but lower than the proportions attributable to arthritis. <b>Conclusion:</b> Asthma is an important contributor to the burden of ill health and impaired quality of life in the community. A strategic approach is needed to develop and implement strategies to address the impact of asthma on quality of life.
Evidence for natural antisense transcript-mediated inhibition of microRNA function
Authors: Mohammad Ali Faghihi, Ming Zhang, Jia Huang, Farzaneh Modarresi, Marcel P Van der Brug, Michael A Nalls, Mark R Cookson, Georges St-Laurent, Claes Wahlestedt
Journal: Genome biology (2010)

Abstract Background MicroRNAs (miRNAs) have the potential to regulate diverse sets of mRNA targets. In addition, mammalian genomes contain numerous natural antisense transcripts, most of which appear to be non-protein-coding RNAs (ncRNAs). We have recently identified and characterized a highly conserved non-coding antisense transcript for beta-secretase-1 ( BACE1 ), a critical enzyme in Alzheimer's disease pathophysiology. The BACE1 -antisense transcript is markedly up-regulated in brain samples from Alzheimer's disease patients and promotes the stability of the (sense) BACE1 transcript. Results We report here that BACE1 -antisense prevents miRNA-induced repression of BACE1 mRNA by masking the binding site for miR-485-5p. Indeed, miR-485-5p and BACE1 -antisense compete for binding within the same region in the open reading frame of the BACE1 mRNA. We observed opposing effects of BACE1 -antisense and miR-485-5p on BACE1 protein in vitro and showed that Locked Nucleic Acid-antimiR mediated knockdown of miR-485-5p as well as BACE1 -antisense over-expression can prevent the miRNA-induced BACE1 suppression. We found that the expression of BACE1 -antisense as well as miR-485-5p are dysregulated in RNA samples from Alzheimer's disease subjects compared to control individuals. Conclusions Our data demonstrate an interface between two distinct groups of regulatory RNAs in the computation of BACE1 gene expression. Moreover, bioinformatics analyses revealed a theoretical basis for many other potential interactions between natural antisense transcripts and miRNAs at the binding sites of the latter.
Baseline and 1-year magnetic resonance imaging of the sacroiliac joint and lumbar spine in very early inflammatory back pain. Relationship between symptoms, HLA-B27 and disease extent and persistence
Authors: H Marzo-Ortega, D McGonagle, P O'Connor, E M A Hensor, A N Bennett, M J Green, P Emery
Journal: Annals of the Rheumatic Diseases (2008)

The precise anatomical location of pathology associated with inflammatory back pain (IBP) in early spondyloarthropathy (SpA) remains unclear.To use MRI to study the sacroiliac joint (SIJ) and lumbar spine (LS) and explore the relationship between sites and extent of inflammation and HLA-B27 status over 12 months.54 patients with IBP; median duration 24 weeks (54% HLA-B27 positive; median Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 5.65) and 22 control subjects (11 with mechanical back pain; 11 volunteers) were recruited and 63% (n = 34) were reassessed at 1 year. Fat saturation and T1-weighted MRI was performed with images being scored for active bone marrow oedema (BMO) lesions representative of inflammation.At baseline 46/54 (85%) patients had BMO (SIJs and LS) compared with 40% in the control group. The majority of affected patients had inflammation at the SIJ level (96% (n = 44); 23.5% (n = 12) LS) and 28.3% (n = 13) at both sites simultaneously. The SIJ activity score confirmed more severe inflammation (BMO grade 2 or 3: 52.2%) in the IBP group (controls = BMO grade 1: 100%; p<0.001). HLA-B27 was associated with both the severity (p = 0.009) and number of baseline SIJ lesions (p = 0.045) and with persistence (SIJ or LS) at 1 year (p = 0.02). 90% of reattenders fulfilled European Spondyloarthropathy Study Group criteria; 73.5% showed MRI inflammation despite clinical improvement (median BASDAI 5.65 to 3.05; p<0.009).LS and SIJ involvement may occur simultaneously in very early SpA and may be differentiated from non-inflammatory back pain by the severity of MRI lesions. HLA-B27 is associated with both the severity of osteitis and its persistence.
<i>IDH1</i>and<i>IDH2</i>Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives
Authors: Hui Yang, Dan Ye, Kun-Liang Guan, Yue Xiong
Journal: Clinical Cancer Research (2012)

Abstract Genes encoding for isocitrate dehydrogenases 1 and 2, IDH1 and IDH2, are frequently mutated in multiple types of human cancer. Mutations targeting IDH1 and IDH2 result in simultaneous loss of their normal catalytic activity, the production of α-ketoglutarate (α-KG), and gain of a new function, the production of 2-hydroxyglutarate (2-HG). 2-HG is structurally similar to α-KG, and acts as an α-KG antagonist to competitively inhibit multiple α-KG–dependent dioxygenases, including both lysine histone demethylases and the ten-eleven translocation family of DNA hydroxylases. Abnormal histone and DNA methylation are emerging as a common feature of tumors with IDH1 and IDH2 mutations and may cause altered stem cell differentiation and eventual tumorigenesis. Therapeutically, unique features of IDH1 and IDH2 mutations make them good biomarkers and potential drug targets. Clin Cancer Res; 18(20); 5562–71. ©2012 AACR.
Novel Population Genetics in Ciliates due to Life Cycle and Nuclear Dimorphism
Authors: David W Morgens, Timothy C Stutz, Andre R O Cavalcanti
Journal: Molecular Biology and Evolution (2014)

Our understanding of population genetics comes primarily from studies of organisms with canonical life cycles and nuclear organization, either haploid or diploid, sexual, or asexual. Although this template yields satisfactory results for the study of animals and plants, the wide variety of genomic organizations and life cycles of unicellular eukaryotes can make these organisms behave differently in response to mutation, selection, and drift than predicted by traditional population genetic models. In this study, we show how each of these unique features of ciliates affects their evolutionary parameters in mutation-selection, selection-drift, and mutation-selection-drift situations. In general, ciliates are less efficient in eliminating deleterious mutations-these mutations linger longer and at higher frequencies in ciliate populations than in sexual populations--and more efficient in selecting beneficial mutations. Approaching this problem via analytical techniques and simulation allows us to make specific predictions about the nature of ciliate evolution, and we discuss the implications of these results with respect to the high levels of polymorphism and high rate of protein evolution reported for ciliates.
Apoptotic Proteins in the Temporal Cortex in Schizophrenia: High Bax/Bcl-2 Ratio Without Caspase-3 Activation
Authors: L. Fredrik Jarskog, Elzbieta S. Selinger, Jeffrey A. Lieberman, John H. Gilmore
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Neuroimaging findings have identified lower cortical gray matter volume in schizophrenia. Apoptosis (programmed cell death) has been proposed as a contributing pathophysiological mechanism. Levels of antiapoptotic Bcl-2 protein are low in the temporal cortex of schizophrenia patients. Bcl-2 interacts with the proapoptotic Bax protein at an upstream checkpoint to regulate the activation of apoptosis by caspase-3 and other proteolytic caspase proteins. A high Bax/Bcl-2 ratio is associated with greater vulnerability to apoptotic activation, while a high caspase-3 level is often associated with apoptotic activity. It was hypothesized that the Bax/Bcl-2 ratio, but not caspase-3, would be high in the temporal cortex of patients with chronic schizophrenia. METHOD: Bax, Bcl-2, and caspase-3 proteins were measured by semiquantitative Western blot in Brodmann's area 21 (middle temporal gyrus) of postmortem tissue from patients with schizophrenia (N=15), bipolar disorder (N=15), or major depression (N=15) and nonpsychiatric comparison subjects (N=15). RESULTS: The Bax/Bcl-2 ratio was 50% higher in the schizophrenia patients than the nonpsychiatric comparison subjects. The level of caspase-3 (inactive zymogen and activated subunits) was not significantly different. CONCLUSIONS: The higher Bax/Bcl-2 ratio suggests that cortical cells are vulnerable to apoptosis in chronic schizophrenia. However, the normal caspase-3 level suggests that apoptosis is not active in this illness phase. Furthermore, the results appear to distinguish the pathophysiology of schizophrenia from most classic neurodegenerative disorders, in which postmortem caspase-3 levels are high. Further studies are needed to investigate the implications of abnormal apoptotic proteins in schizophrenia.
Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease. Development and Validation of the COPD Lung Cancer Screening Score
Authors: Juan P. de-Torres, David O. Wilson, Pablo Sanchez-Salcedo, Joel L. Weissfeld, Juan Berto, Arantzazu Campo, Ana B. Alcaide, Marta García-Granero, Bartolome R. Celli, Javier J. Zulueta
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Patients with chronic obstructive pulmonary disease (COPD) are at high risk for lung cancer (LC) and represent a potential target to improve the diagnostic yield of screening programs.To develop a predictive score for LC risk for patients with COPD.The Pamplona International Early Lung Cancer Detection Program (P-IELCAP) and the Pittsburgh Lung Screening Study (PLuSS) databases were analyzed. Only patients with COPD on spirometry were included. By logistic regression we determined which factors were independently associated with LC in PLuSS and developed a COPD LC screening score (COPD-LUCSS) to be validated in P-IELCAP.By regression analysis, age greater than 60, body mass index less than 25 kg/m(2), pack-years history greater than 60, and emphysema presence were independently associated with LC diagnosis and integrated into the COPD-LUCSS, which ranges from 0 to 10 points. Two COPD-LUCSS risk categories were proposed: low risk (scores 0-6) and high risk (scores 7-10). In comparison with low-risk patients, in both cohorts LC risk increased 3.5-fold in the high-risk category.The COPD-LUCSS is a good predictor of LC risk in patients with COPD participating in LC screening programs. Validation in two different populations adds strength to the findings.
Tissue Advanced Glycation End-products Are Associated With Diastolic Dysfunction and Aerobic Exercise Capacity in Diabetic Patients With Heart Failure
Authors: Suzan Willemsen, Jasper W. Hartog, Yoran M. Hummel, Marieke H. van Ruijven, Dirk J. Van Veldhuisen, Adriaan A. Voors
Journal: Circulation (2009)
NKG2A Complexed with CD94 Defines a Novel Inhibitory Natural Killer Cell Receptor
Authors: Andrew G. Brooks, Phillip E. Posch, Christopher J. Scorzelli, Francisco Borrego, John E. Coligan
Journal: The Journal of Experimental Medicine (1997)

CD94 is a C-type lectin expressed by natural killer (NK) cells and a subset of T cells. Blocking studies using anti-CD94 mAbs have suggested that it is a receptor for human leukocyte antigen class I molecules. CD94 has recently been shown to be a 26-kD protein covalently associated with an unidentified 43-kD protein(s). This report shows that NKG2A, a 43-kD protein, is covalently associated with CD94 on the surface of NK cells. Cell surface expression of NKG2A is dependent on the association with CD94 as glycosylation patterns characteristic of mature proteins are found only in NKG2A that is associated with CD94. Analysis of NK cell clones showed that NKG2A was expressed in all NK cell clones whose CD16-dependent killing was inhibited by cross-linking CD94. The induction of an inhibitory signal is consistent with the presence of two immunoreceptor tyrosine-based inhibitory motifs (V/LXYXXL) on the cytoplasmic domain of NKG2A. Similar motifs are found on Ly49 and killer cell inhibitory receptors, which also transmit negative signals to NK cells.
Associations of Physical Activity With Inflammatory Factors, Adipocytokines, and Metabolic Syndrome in Middle-Aged and Older Chinese People
Authors: Zhijie Yu, Xingwang Ye, Jing Wang, Qibin Qi, Oscar H. Franco, Kirsten L. Rennie, An Pan, Huaixing Li, Yong Liu, Frank B. Hu, Xu Lin
Journal: Circulation (2009)

Inflammatory factors, adipocytokines, and the metabolic syndrome are important determinants of cardiometabolic disease. It remains unclear how physical activity is related to these risk factors. Our objective was to investigate single and joint associations of physical activity with inflammatory factors, adipocytokines, and the metabolic syndrome among middle-aged and older Chinese people.A total of 3289 individuals (1458 men, 1831 women) 50 to 70 years of age participated in a population-based cross-sectional survey in Beijing and Shanghai, China. Levels of total physical activity were assessed with the International Physical Activity Questionnaire. High-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha receptor 2, adiponectin, and retinol-binding protein 4 were measured. The metabolic syndrome was defined using the updated National Cholesterol Education Program/Adult Treatment Panel III criteria for Asian Americans. Plasma concentrations of high-sensitivity C-reactive protein were 1.58, 1.74, and 1.27 mg/L (P=0.0138) and of adiponectin were 16.12, 16.20, and 17.21 mg/L (P=0.0078) among individuals with low, medium, and high levels of total physical activity, respectively, with adjustment for potential confounders. In the multivariable-adjusted logistic regression analyses, participants with higher levels of total physical activity had a lower risk of having the metabolic syndrome (odds ratio, 0.68; 95% confidence interval, 0.54 to 0.85; P for trend=0.001) compared with those with lower levels.Being physically active is associated with a better profile of inflammatory factors and adipocytokines and a reduced risk of having the metabolic syndrome among Chinese people.
Participatory medicine: a driving force for revolutionizing healthcare
Authors: Leroy Hood, Charles Auffray
Journal: Genome Medicine (2013)

Healthcare is undergoing a profound revolution as a consequence of three contemporary thrusts: systems medicine [1][2][3][4], big data and patient involvement in their own health through social networks.This convergence is leading to a medicine that is predictive, preventive, personalized and participatory (P4) [4][5][6][7].The first three Ps, predictive, preventive and personalized, were delineated in the early 2000s [1,2], whereas the fourth P, participatory, was added later.To achieve a participatory healthcare system, major technical and societal challenges will need to be overcome, and this will require close integration with systems medicine and big data.Before commenting further on participatory medicine, let us first delineate the essence of systems medicine and big data and their implications for P4 medicine.Systems medicine, the application of systems biology approaches to disease [3,4,6,8,9], is already changing how healthcare is practiced (Table 1).We predict that in 5 to 10 years each patient will be surrounded by a virtual cloud of billions of data points -molecular, clinical chemistries, cellular, organ, phenotypic, imaging, social networks, and so on.We also predict that we will have the analytical tools to reduce this big data cloud to simple models that will guide improvements in health and minimize disease.This requires addressing two grand challenges: the signal-to-noise issues intrinsic to big data and integration of multi-scale data into predictive models.In addition, for each individual patient we foresee that we will be able to integrate an individual's genetic, molecular, cellular, organ and social networks into an overall 'network of networks ' [10].Disease leads to the perturbation of the network of networks and this alters the information the network manages.The availability of a personal data cloud will allow one to characterize an individual's network of networks in its normal or disease-perturbed states.This altered, disease-perturbed information will provide deep insights into disease mechanisms, new approaches to diagnostics and therapeutics, and a platform for participatory medicine.
Prolonged shedding of rhinovirus and re-infection in adults with respiratory tract illness
Authors: Kalina T. Zlateva, Jutte J.C. de Vries, Frank E.J. Coenjaerts, Anton M. van Loon, Theo Verheij, Paul Little, Christopher C. Butler, Herman Goossens, Margareta Ieven, Eric C.J. Claas
Journal: European Respiratory Journal (2014)

Rhinovirus infections occur frequently throughout life and have been reported in about one-third of asymptomatic cases. The clinical significance of sequential rhinovirus infections remains unclear. To determine the incidence and clinical relevance of sequential rhinovirus detections, nasopharyngeal samples from 2485 adults with acute cough/lower respiratory illness were analysed. Patients were enrolled prospectively by general practitioners from 12 European Union countries during three consecutive years (2007–2010). Nasopharyngeal samples were collected at the initial general practitioner consultation and 28 days thereafter and symptom scores were recorded by patients over that period. Rhinovirus RNA was detected in 444 (18%) out of 2485 visit one samples and in 110 (4.4%) out of 2485 visit two respiratory samples. 21 (5%) of the 444 patients had both samples positive for rhinovirus. Genotyping of both virus detections was successful for 17 (81%) out of 21 of these patients. Prolonged rhinovirus shedding occurred in six (35%) out of 21 and re-infection with a different rhinovirus in 11 (65%) out of 21. Rhinovirus re-infections were significantly associated with chronic obstructive pulmonary disease (p=0.04) and asthma (p=0.02) and appeared to be more severe than prolonged infections. Our findings indicate that in immunocompetent adults rhinovirus re-infections are more common than prolonged infections, and chronic airway comorbidities might predispose to more frequent rhinovirus re-infections.