tbuckley/cabot-search huggingface dataset:
ADAMTS-7 Inhibits Re-endothelialization of Injured Arteries and Promotes Vascular Remodeling Through Cleavage of Thrombospondin-1
Authors: Thorsten Kessler, Lu Zhang, Ziyi Liu, Xiaoke Yin, Yaqian Huang, Yingbao Wang, Yi Fu, Manuel Mayr, Qing Ge, Qingbo Xu, Yi Zhu, Xian Wang, Kjestine Schmidt, Cor de Wit, Jeanette Erdmann, Heribert Schunkert, Zouhair Aherrahrou, Wei Kong
Journal: Circulation (2015)

Background— ADAMTS-7, a member of the disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, was recently identified to be significantly associated genomewide with coronary artery disease. However, the mechanisms that link ADAMTS-7 and coronary artery disease risk remain elusive. We have previously demonstrated that ADAMTS-7 promotes vascular smooth muscle cell migration and postinjury neointima formation via degradation of a matrix protein cartilage oligomeric matrix protein. Because delayed endothelium repair renders neointima and atherosclerosis plaque formation after vessel injury, we examined whether ADAMTS-7 also inhibits re-endothelialization. Methods and Results— Wire injury of the carotid artery and Evans blue staining were performed in Adamts7 –/– and wild-type mice. Adamts-7 deficiency greatly promoted re-endothelialization at 3, 5, and 7 days after injury. Consequently, Adamts-7 deficiency substantially ameliorated neointima formation in mice at days 14 and 28 after injury in comparison with the wild type. In vitro studies further indicated that ADAMTS-7 inhibited both endothelial cell proliferation and migration. Surprisingly, cartilage oligomeric matrix protein deficiency did not affect endothelial cell proliferation/migration and re-endothelialization in mice. In a further examination of other potential vascular substrates of ADAMTS-7, a label-free liquid chromatography-tandem mass spectrometry secretome analysis revealed thrombospondin-1 as a potential ADAMTS-7 target. The subsequent studies showed that ADAMTS-7 was directly associated with thrombospondin-1 by its C terminus and degraded thrombospondin-1 in vivo and in vitro. The inhibitory effect of ADAMTS-7 on postinjury endothelium recovery was circumvented in Tsp1 –/– mice. Conclusions— Our study revealed a novel mechanism by which ADAMTS-7 affects neointima formation. Thus, ADAMTS-7 is a promising treatment target for postinjury vascular intima hyperplasia.
Toward Improved Diagnosis of Early Asthma
Authors: John M. Brehm
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

remain with patients who spontaneously generate large tidal volumes, we agree with this recommendation that ICU clinicians should rarely set or target a tidal volume much above 6 ml/kg PBW.The issue of timing of treatment is familiar to critical care physicians in sepsis, trauma, acute myocardial infarction, and acute cerebrovascular accidents.It should not be surprising that timely recognition and treatment of ARDS should also be important.With this study, Needham and colleagues have brought the issue to forefront and started the clock.
KLF2 Is a Novel Transcriptional Regulator of Endothelial Proinflammatory Activation
Authors: Sucharita SenBanerjee, Zhiyong Lin, G. Brandon Atkins, Daniel M. Greif, Ravi M. Rao, Ajay Kumar, Mark W. Feinberg, Zhiping Chen, Daniel I. Simon, F. William Luscinskas, Thomas M. Michel, Michael A. Gimbrone, Guillermo García-Cardeña, Mukesh K. Jain
Journal: The Journal of Experimental Medicine (2004)

The vascular endothelium is a critical regulator of vascular function. Diverse stimuli such as proinflammatory cytokines and hemodynamic forces modulate endothelial phenotype and thereby impact on the development of vascular disease states. Therefore, identification of the regulatory factors that mediate the effects of these stimuli on endothelial function is of considerable interest. Transcriptional profiling studies identified the Kruppel-like factor (KLF)2 as being inhibited by the inflammatory cytokine interleukin-1β and induced by laminar shear stress in cultured human umbilical vein endothelial cells. Overexpression of KLF2 in umbilical vein endothelial cells robustly induced endothelial nitric oxide synthase expression and total enzymatic activity. In addition, KLF2 overexpression potently inhibited the induction of vascular cell adhesion molecule-1 and endothelial adhesion molecule E-selectin in response to various proinflammatory cytokines. Consistent with these observations, in vitro flow assays demonstrate that T cell attachment and rolling are markedly attenuated in endothelial monolayers transduced with KLF2. Finally, our studies implicate recruitment by KLF2 of the transcriptional coactivator cyclic AMP response element–binding protein (CBP/p300) as a unifying mechanism for these various effects. These data implicate KLF2 as a novel regulator of endothelial activation in response to proinflammatory stimuli.
ANKK1, TTC12, and NCAM1 Polymorphisms and Heroin Dependence
Authors: Elliot C Nelson, Michael T Lynskey, Andrew C Heath, Naomi Wray, Arpana Agrawal, Fiona L Shand, Anjali K Henders, Leanne Wallace, Alexandre A Todorov, Andrew J Schrage, Nancy L Saccone, Pamela A F Madden, Louisa Degenhardt, Nicholas G Martin, Grant W Montgomery
Journal: JAMA Psychiatry (2013)

The genetic contribution to liability for opioid dependence is well established; identification of the responsible genes has proved challenging.To examine association of 1430 candidate gene single-nucleotide polymorphisms (SNPs) with heroin dependence, reporting here only the 71 SNPs in the chromosome 11 gene cluster (NCAM1, TTC12, ANKK1, DRD2) that include the strongest observed associations.Case-control genetic association study that included 2 control groups (lacking an established optimal control group).Semistructured psychiatric interviews.A total of 1459 Australian cases ascertained from opioid replacement therapy clinics, 531 neighborhood controls ascertained from economically disadvantaged areas near opioid replacement therapy clinics, and 1495 unrelated Australian Twin Registry controls not dependent on alcohol or illicit drugs selected from a twin and family sample.Lifetime heroin dependence.Comparison of cases with Australian Twin Registry controls found minimal evidence of association for all chromosome 11 cluster SNPs (P ≥ .01); a similar comparison with neighborhood controls revealed greater differences (P ≥ 1.8 × 10(-4)). Comparing cases (n = 1459) with the subgroup of neighborhood controls not dependent on illicit drugs (n = 340), 3 SNPs were significantly associated (correcting for multiple testing): ANKK1 SNP rs877138 (most strongly associated; odds ratio = 1.59; 95% CI, 1.32-1.92; P = 9.7 × 10(-7)), ANKK1 SNP rs4938013, and TTC12 SNP rs7130431. A similar pattern of association was observed when comparing illicit drug-dependent (n = 191) and nondependent (n = 340) neighborhood controls, suggesting that liability likely extends to nonopioid illicit drug dependence. Aggregate heroin dependence risk associated with 2 SNPs, rs877138 and rs4492854 (located in NCAM1), varied more than 4-fold (P = 2.7 × 10(-9) for the risk-associated linear trend).Our results provide further evidence of association for chromosome 11 gene cluster SNPs with substance dependence, including extension of liability to illicit drug dependence. Our findings highlight the necessity of considering drug exposure history when selecting control groups for genetic investigations of illicit drug dependence.
Effect of increasing the fat content but not the energy load of a meal on gastro-oesophageal reflux and lower oesophageal sphincter motor function
Authors: R Penagini, M Mangano, P A Bianchi
Journal: Gut (1998)

Background —Although fatty foods are commonly considered detrimental in patients with reflux disease, no objective data exist that substantiate this belief. Aims —To investigate the effect of fat on gastro-oesophageal reflux and lower oesophageal sphincter (LOS) motor activity. Subjects —Thirteen healthy subjects and 14 patients with reflux disease. Methods —Oesophageal pH, LOS, and oesophageal pressures were recorded for 180 minutes after a high fat (52% fat) and a balanced (24% fat) meal (both 3.18 MJ) on two different occasions. Eight controls and seven patients were studied in the recumbent position and the others in the sitting position. Results —The percentage of time at pH less than 4 and the rate of reflux episodes were higher (p&lt;0.01) in the patients than in the healthy subjects (mean 14.1% versus 1.7% and 4.4/h versus 0.8/h respectively), as was the percentage of transient LOS relaxations associated with reflux (62% versus 32%, p&lt;0.01). The high fat meal did not increase the rate of reflux episodes nor exposure to oesophageal acid in either group regardless of body posture.The rate of transient LOS relaxations, their association with reflux, and basal LOS pressure were also unaffected. Conclusions —Increasing fat intake does not affect gastro-oesophageal reflux or oesophagogastric competence for at least three hours after a meal.
A 26 week randomised, double blind, placebo controlled exploratory study of sulfasalazine in juvenile onset spondyloarthropathies
Authors: R Burgos-Vargas
Journal: Annals of the Rheumatic Diseases (2002)

Juvenile onset spondyloarthropathies (SpA) comprise a group of conditions, characterised by recurrent episodes of arthritis and enthesitis that may lead to structural changes and functional impairment.1 Except for mild to moderate cases, the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) appears limited and glucocorticoids may induce severe adverse events. According to open trials,2–6 sulfasalazine (SSZ) appears to be a good alternative for treating juvenile onset SpA. Consequently, we conducted a phase III, exploratory, 26 week prospective, randomised, double blind, placebo controlled trial of SSZ in active juvenile SpA.

Patients with the seronegative enthesopathy and arthropathy syndrome (SEA)7 or ankylosing spondylitis (AS)8 (onset age 16 years; current age 20 years) fulfilling the three following criteria despite stable NSAID treatment in the previous four weeks were enrolled in the trial: ( a ) ≥4 active joints; ( b ) ≥3 tender entheses; and ( c ) erythrocyte sedimentation rate …
α-enolase specific T cells in rheumatoid arthritis – a MHC class II tetramer approach
Authors: Jennifer Pieper, Mary Rieck, Eddie James, Charlotta Sandin, Lars Klareskog, Jane H. Buckner, Vivianne Malmström
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> Antibodies against citrullinated proteins are highly specific for rheumatoid arthritis (RA) and found in approximately 60% of patients and their presence is strongly associated with the human leucocyte antigen (HLA)-DRB1*0401 allele. α-enolase is one of these citrullinated antigens and antibodies against certain epitopes of this autoantigen are found in 40% of RA patients and are enriched in their synovial fluid. Here, the authors aimed to identify novel HLA-DRB1*0401 restricted T cell epitopes of α-enolase in order to construct and utilise major histocompatibility complex (MHC) class II tetramers to determine the frequency of cit-α-enolase-specific T cells in blood of DRB1*0401 RA patients. <h3>Material and methods</h3> Overlapping peptides, both native and citrullinated versions, of full length α-enolase were analysed for 0401 binding via the Proimmune Class II Reveal assay and 13 citrullinated peptides came out as candidates. Following our own validation of HLA-DRB1*0401 binding, the authors constructed class II MHC tetramers loaded with either the native or citrullinated form of one of the peptides. Peripheral blood mononuclear cells (PBMCs) from HLA-DRB1*0401 RA patients were then screened for α-enolase specific T cells. T cells recognising the α-enolase peptide were identified using direct ex vivo analysis and additional analysis of the T cell phenotypes was performed by multi-colour flow cytometry. PBMCs from these patients were also expanded in vitro for 14 days with haemagglutinin (HA) or either the native or the citrullinated version of the α-enolase peptide and analysed on a FACS calibur. <h3>Results</h3> In our binding assays the native and citrullinated form of our novel epitope bound to HLA-DRB1*0401 with a similar affinity. Tetramers were constructed and allowed for the detection of α-enolase specific T cells in the blood of DRB1*0401 RA patients. The frequency varied and was markedly lower than that of HA-specific T cells in the same individuals. When comparing the phenotype, our preliminary results suggest that T cells specific for the native α-enolase peptide are predominantly of a naïve phenotype, whereas the T cells specific for the citrullinated version are of a memory phenotype. <h3>Conclusions</h3> The authors have identified a novel α-enolase T cell epitope that binds HLA-DRB1*0401 in both its native and citrullinated form. Interestingly it appears that the cit-specific T cells are antigen-experienced and have previously been activated in the patients, while the native-specific T cells appeared naïve. In the future the authors plan to further enumerate and characterise cit-α-enolase specific T cells in RA and controls and to extend these studies to synovial fluid.
Phosphorylation Meets Ubiquitination: The Control of NF-κB Activity
Authors: Michael Karin, Yinon Ben-Neriah
Journal: Annual Review of Immunology (2000)

NF-kappaB (nuclear factor-kappaB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-kappaB is found in essentially all cell types and is involved in activation of an exceptionally large number of genes in response to infections, inflammation, and other stressful situations requiring rapid reprogramming of gene expression. NF-kappaB is normally sequestered in the cytoplasm of nonstimulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-kappaB is controlled by a family of inhibitory proteins, IkappaBs, which bind NF-kappaB and mask its nuclear localization signal, thereby preventing nuclear uptake. Exposure of cells to a variety of extracellular stimuli leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of IkappaB, which frees NF-kappaB to translocate to the nucleus where it regulates gene transcription. NF-kappaB activation represents a paradigm for controlling the function of a regulatory protein via ubiquitination-dependent proteolysis, as an integral part of a phosphorylationbased signaling cascade. Recently, considerable progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1. The multisubunit IkappaB kinase (IKK) responsible for inducible IkappaB phosphorylation is the point of convergence for most NF-kappaB-activating stimuli. IKK contains two catalytic subunits, IKKalpha and IKKbeta, both of which are able to correctly phosphorylate IkappaB. Gene knockout studies have shed light on the very different physiological functions of IKKalpha and IKKbeta. After phosphorylation, the IKK phosphoacceptor sites on IkappaB serve as an essential part of a specific recognition site for E3RS(IkappaB/beta-TrCP), an SCF-type E3 ubiquitin ligase, thereby explaining how IKK controls IkappaB ubiquitination and degradation. A variety of other signaling events, including phosphorylation of NF-kappaB, hyperphosphorylation of IKK, induction of IkappaB synthesis, and the processing of NF-kappaB precursors, provide additional mechanisms that modulate the level and duration of NF-kappaB activity.
An In Vivo Functional Analysis System for Renal Gene Discovery in Drosophila Pericardial Nephrocytes
Authors: Fujian Zhang, Ying Zhao, Zhe Han
Journal: Journal of the American Society of Nephrology (2013)

The difficulty in accessing mammalian nephrons in vivo hinders the study of podocyte biology. The Drosophila nephrocyte shares remarkable similarities to the glomerular podocyte, but the lack of a functional readout for nephrocytes makes it challenging to study this model of the podocyte, which could potentially harness the power of Drosophila genetics. Here, we present a functional analysis of nephrocytes and establish an in vivo system to screen for renal genes. We found that nephrocytes efficiently take up secreted fluorescent protein, and therefore, we generated a transgenic line carrying secreted fluorescent protein and combined it with a nephrocyte-specific driver for targeted gene knockdown, allowing the identification of genes required for nephrocyte function. To validate this system, we examined the effects of knocking down sns and duf, the Drosophila homologs of nephrin and Neph1, respectively, in pericardial nephrocytes. Knockdown of sns or duf completely abolished the accumulation of the fluorescent protein in pericardial nephrocytes. Examining the ultrastructure revealed that the formation of the nephrocyte diaphragm and lacunar structure, which is essential for protein uptake, requires sns. Our preliminary genetic screen also identified Mec2, which encodes the homolog of mammalian Podocin. Taken together, these data suggest that the Drosophila pericardial nephrocyte is a useful in vivo model to help identify genes involved in podocyte biology and facilitate the discovery of renal disease genes.
Role of superoxide anion radicals in ethanol metabolism by blood monocyte-derived human macrophages.
Authors: S N Wickramasinghe
Journal: The Journal of Experimental Medicine (1989)

The effects of a number of additives on the rate of conversion of ethanol (1 mg/ml; 21.7 mM) to acetate by monolayers of blood monocyte-derived human macrophages were investigated. The additives studied were superoxide dismutase (SOD; 1,500 U/ml), catalase (1,500 U/ml), tetrahydrofurane (20 mM), and PMA (20 nM), either singly or in various combinations. SOD, catalase, SOD plus catalase, tetrahydrofurane, and tetrahydrofurane plus SOD inhibited ethanol oxidation by 49.2, 12.1, 52.9, 60.4, and 66.8%, respectively. PMA caused a 4.0-8.3-fold increase in the rate of ethanol metabolism and this increase was completely suppressed in the presence of SOD. The data indicate that a substantial proportion of the ethanol metabolism by both unstimulated and PMA-stimulated blood monocyte-derived macrophages was dependent on the generation of superoxide anion radicals.
Severe B Cell Deficiency in Mice Lacking the Tec Kinase Family Members Tec and Btk
Authors: Wilfried Ellmeier, Steffen Jung, Mary Jean Sunshine, Farah Hatam, Yang Xu, David Baltimore, Hiroyuki Mano, Dan R. Littman
Journal: The Journal of Experimental Medicine (2000)

The cytoplasmic protein tyrosine kinase Tec has been proposed to have important functions in hematopoiesis and lymphocyte signal transduction. Here we show that Tec-deficient mice developed normally and had no major phenotypic alterations of the immune system. To reveal potential compensatory roles of other Tec kinases such as Bruton's tyrosine kinase (Btk), Tec/Btk double-deficient mice were generated. These mice exhibited a block at the B220+CD43+ stage of B cell development and displayed a severe reduction of peripheral B cell numbers, particularly immunoglobulin (Ig)MloIgDhi B cells. Although Tec/Btknull mice were able to form germinal centers, the response to T cell–dependent antigens was impaired. Thus, Tec and Btk together have an important role both during B cell development and in the generation and/or function of the peripheral B cell pool. The ability of Tec to compensate for Btk may also explain phenotypic differences in X-linked immunodeficiency (xid) mice compared with human X-linked agammaglobulinemia (XLA) patients.
Global economic consequences of selected surgical diseases: a modelling study
Authors: Blake C Alkire, Mark G Shrime, Anna J Dare, Jeffrey R Vincent, John G Meara
Journal: The Lancet Global Health (2015)

BackgroundThe surgical burden of disease is substantial, but little is known about the associated economic consequences. We estimate the global macroeconomic impact of the surgical burden of disease due to injury, neoplasm, digestive diseases, and maternal and neonatal disorders from two distinct economic perspectives.MethodsWe obtained mortality rate estimates for each disease for the years 2000 and 2010 from the Institute of Health Metrics and Evaluation Global Burden of Disease 2010 study, and estimates of the proportion of the burden of the selected diseases that is surgical from a paper by Shrime and colleagues. We first used the value of lost output (VLO) approach, based on the WHO's Projecting the Economic Cost of Ill-Health (EPIC) model, to project annual market economy losses due to these surgical diseases during 2015–30. EPIC attempts to model how disease affects a country's projected labour force and capital stock, which in turn are related to losses in economic output, or gross domestic product (GDP). We then used the value of lost welfare (VLW) approach, which is conceptually based on the value of a statistical life and is inclusive of non-market losses, to estimate the present value of long-run welfare losses resulting from mortality and short-run welfare losses resulting from morbidity incurred during 2010. Sensitivity analyses were performed for both approaches.FindingsDuring 2015–30, the VLO approach projected that surgical conditions would result in losses of 1·25% of potential GDP, or $20·7 trillion (2010 US$, purchasing power parity) in the 128 countries with data available. When expressed as a proportion of potential GDP, annual GDP losses were greatest in low-income and middle-income countries, with up to a 2·5% loss in output by 2030. When total welfare losses are assessed (VLW), the present value of economic losses is estimated to be equivalent to 17% of 2010 GDP, or $14·5 trillion in the 175 countries assessed with this approach. Neoplasm and injury account for greater than 95% of total economic losses with each approach, but maternal, digestive, and neonatal disorders, which represent only 4% of losses in high-income countries with the VLW approach, contribute to 26% of losses in low-income countries.InterpretationThe macroeconomic impact of surgical disease is substantial and inequitably distributed. When paired with the growing number of favourable cost-effectiveness analyses of surgical interventions in low-income and middle-income countries, our results suggest that building surgical capacity should be a global health priority.FundingUS National Institutes of Health/National Cancer Institute.