bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis
Authors: Tucker Erik I. , Verbout Norah G. , Leung Philberta Y. , Hurst Sawan , McCarty Owen J. T. , Gailani David , Gruber András 
Published: March 2012

AbstractSevere bacterial sepsis often leads to a systemic procoagulant and proinflammatory condition that can manifest as disseminated intravascular coagulation, septic shock, and multiple organ failure. Because activation of the contact proteases factor XII (FXII), prekallikrein, and factor XI (FXI) can trigger coagulation and inflammatory responses, the contact factors have been considered potential targets for the treatment of sepsis. However, the pathogenic role of contact activation in severe infections has not been well defined. We therefore investigated whether an anticoagulant antibody (14E11) that selectively inhibits prothrombotic FXI activation by activated FXII (FXIIa) modifies the course of bowel perforation-induced peritoneal sepsis in mice. Early anticoagulation with 14E11 suppressed systemic thrombin- antithrombin complex formation, IL-6, and TNF-α levels, and reduced platelet consumption in the circulation and deposition in the blood vessels. Treatment with 14E11 within 12 hours after bowel perforation significantly improved survival compared with vehicle treatment, and the saturating dose did not increase tail bleeding. These data suggest that severe polymicrobial abdominal infection induces prothrombotic FXI activation, to the detriment of the host. Systemic anticoagulation by inhibiting FXI activation or FXIIa procoagulant activity during sepsis may therefore limit the development of disseminated intravascular coagulation without increasing bleeding risks.
Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection
Authors: Elahi Shokrollah , Niki Toshiro , Hirashima Mitsuomi , Horton Helen 
Published: March 2012

Abstract
Galectin-9 (Gal-9) is a tandem repeat-type member of the galectin family and is a ligand for T-cell immunoglobulin mucin domain 3 (Tim-3), a type-I glycoprotein that is persistently expressed on dysfunctional T cells during chronic infection. Studies in autoimmune diseases and chronic viral infections show that Tim-3 is a regulatory molecule that inhibits Th1 type immune responses. Here we show that soluble Gal-9 interacts with Tim-3 expressed on the surface of activated CD4+ T cells and renders them less susceptible to HIV-1 infection and replication. The Gal-9/Tim-3 interaction on activated CD4+ T cells, leads to down-regulation of HIV-1 coreceptors and up-regulation of the cyclin-dependent kinase inhibitor p21 (also known as cip-1 and waf-1). We suggest that higher expression of Tim-3 during chronic infection has evolved to limit persistent immune activation and associated tissue damage. These data demonstrate a novel mechanism for Gal-9/Tim-3 interactions to induce resistance of activated CD4+ T cells to HIV-1 infection and suggest that Gal-9 may play a role in HIV-1 pathogenesis and could be used as a novel microbicide to prevent HIV-1 infection.
MHC I–associated peptides preferentially derive from transcripts bearing miRNA response elements
Authors: Granados Diana Paola , Yahyaoui Wafaa , Laumont Céline M. , Daouda Tariq , Muratore-Schroeder Tara L. , Côté Caroline , Laverdure Jean-Philippe , Lemieux Sébastien , Thibault Pierre , Perreault Claude 
Published: March 2012

Abstract
MHC I–associated peptides (MIPs) play an essential role in normal homeostasis and diverse pathologic conditions. MIPs derive mainly from defective ribosomal products (DRiPs), a subset of nascent proteins that fail to achieve a proper conformation and the physical nature of which remains elusive. In the present study, we used high-throughput proteomic and transcriptomic methods to unravel the structure and biogenesis of MIPs presented by HLA-A and HLA-B molecules on human EBV-infected B lymphocytes from 4 patients. We found that although HLA-different subjects present distinctive MIPs derived from different proteins, these MIPs originate from proteins that are functionally interconnected and implicated in similar biologic pathways. Secondly, the MIP repertoire of human B cells showed no bias toward conserved versus polymorphic genomic sequences, were derived preferentially from abundant transcripts, and conveyed to the cell surface a cell-type–specific signature. Finally, we discovered that MIPs derive preferentially from transcripts bearing miRNA response elements. Furthermore, whereas MIPs of HLA-disparate subjects are coded by different sets of transcripts, these transcripts are regulated by mostly similar miRNAs. Our data support an emerging model in which the generation of MIPs by a transcript depends on its abundance and DRiP rate, which is regulated to a large extent by miRNAs.
A role for 12R-lipoxygenase in MUC5AC expression by respiratory epithelial cells
Authors: Garcia-Verdugo Ignacio , BenMohamed Fatima , Tattermusch Sonja , Leduc Dominique , Charpigny Gilles , Chignard Michel , Ollero Mario , Touqui Lhousseine 
Published: March 2012

Eicosanoids are metabolites of arachidonic acid produced by cyclooxygenases (COXs) or lipoxygenases (LOXs). They mediate inflammation and mucus secretion in chronic pulmonary inflammatory diseases. The gel-forming mucin MUC5AC is over-expressed in the airways of patients with these diseases. MUC5AC expression is mediated by an extracellular signal-regulated kinase (ERK)/Sp1 dependent mechanism.Our aim was to study the role of eicosanoids and their signalling pathways in MUC5AC expression.Inhibitors of 12-LOX, but not those of COX, 5-LOX or 15-LOX, reduce MUC5AC expression induced by phorbol myristate acetate (PMA) in the bronchial epithelial cell line NCI-H292. These inhibitors also abrogate the production of whole mucus by cell monolayers. Two forms of 12-LOX (R and S) exist in mammals. Using siRNAs we show that 12R-LOX but not 12S-LOX is involved in MUC5AC expression induced by PMA, lipopolysaccharide or transforming growth factor-α. 12R-LOX also participates in MUC2 and MUC5B expression, although to a lesser extent than for MUC5AC. Contrarily, 12R-LOX silencing does not modify interleukin-8 production. 12-LOX inhibitors reduce ERK activation and Sp1 translocation induced by PMA. Moreover, the 12R-LOX product 12(R)-hydroxyeicosatetraenoic acid, induces MUC5AC expression, ERK activation and Sp1 translocation.12R-LOX is involved in MUC5AC expression. This occursviaERK- and Sp1-signalling pathways.
Reduced nuclear factor-κB repressing factor: a link toward systemic inflammation in COPD
Authors: Lee Kang-Yun , Ho Shu-Chuan , Chan Yao-Fei , Wang Chun-Hua , Huang Chien-Da , Liu Wen-Te , Lin Shu-Min , Lo Yu-Lun , Chang Ya-Ling , Kuo Lu-Wei , Kuo Han-Pin 
Published: March 2012

Chronic systemic inflammation is implicated in the systemic manifestations and, probably, the excess mortality risk of chronic obstructive pulmonary disease (COPD). The role of nuclear factor (NF)-κB repressing factor (NRF), a DNA-binding, protein-inhibiting NF-κB response gene, in human diseases has not been explored. We hypothesised that the NRF-negative regulatory mechanism is impaired in COPD peripheral blood mononuclear cells (PBMCs) leading to excessive interleukin (IL)-8/CXCL8 production.NRF expression, NF-κB activation, IL-8/CXCL8 release and intracellular oxidative stress were assessed in PBMCs of normal subjects and stable COPD patients. Primary PBMCs with NRF overexpression, NRF knockdown and exposure to H2O2were used to elucidate the mechanisms.Stable COPD patients, especially those with severe COPD, showed decreased NRF expression, enhanced NF-κB activation and increased IL-8/CXCL8 release in PBMCs compared with normal subjects. This was associated with reduced NRF and increased RNA polymerase II occupancy at theIL-8/CXCL8promoter. NRF knockdown enhanced IL-8/CXCL8 production in normal PBMCs, whilst NRF overexpression attenuated IL-8/CXCL8 production. Intracellular oxidative stress was increased in COPD PBMCs. H2O2-decreased NRF expression and -enhanced IL-8/CXCL8 production was augmented in COPD PBMCs.NRF expression is reduced in PBMCs of stable COPD patients, probably through oxidative stress, leading to increased production of IL-8/CXCL8 and potentially chronic systemic inflammation.
CHRNA3genotype, nicotine dependence, lung function and disease in the general population
Authors: Kaur-Knudsen Diljit , Nordestgaard Børge G. , Bojesen Stig E. 
Published: March 2012

TheCHRNA3rs1051730 polymorphism has been associated to chronic obstructive pulmonary disease (COPD), lung cancer and nicotine dependence in case–control studies with high smoking exposure; however, its influence on lung function and COPD severity in the general population is largely unknown.We genotyped 57,657 adult individuals from the Copenhagen General Population Study, of whom 34,592 were ever-smokers. Information on spirometry, hospital admissions, smoking behaviour and use of nicotinic replacement therapy was recorded.In homozygous (11%), heterozygous (44%) and noncarrier (45%) ever-smokers, forced expiratory volume in 1 s (FEV1) was 94.1% predicted, 95.3% pred and 96.5% pred, forced vital capacity (FVC) was 97.1% pred, 97.5% pred and 98.3% pred, and FEV1/FVC was 0.770, 0.773 and 0.777, respectively (all p<0.001 for trend). Smoking interacted with genotype on FEV1% pred and FEV1/FVC (both p<0.001). When adjusted for cumulative tobacco consumption, these associations remained significant. In ever-smokers, odds ratios for COPD in homozygotesversusnoncarriers were 1.3 (95% CI 1.2–1.4) for Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I–IV, 1.4 (95% CI 1.2–1.6) for GOLD II–IV and 1.7 (95% CI 1.3–2.1) for GOLD III–IV. The corresponding value for lung cancer was 1.8 (95% CI 1.2–2.6). Genotype was also associated with daily and cumulative tobacco consumption and with use of nicotinic replacement therapy in former smokers.In ever-smokers, theCHRNA3rs1051730 genotype associated with reduced lung function and increased COPD severity.
Streptococcus pneumoniae-induced regulation of cyclooxygenase-2 in human lung tissue
Authors: Szymanski Kolja V. , Toennies Mario , Becher Anne , Fatykhova Diana , N'Guessan Philippe D. , Gutbier Birgitt , Klauschen Frederick , Neuschaefer-Rube Frank , Schneider Paul , Rueckert Jens , Neudecker Jens , Bauer Torsten T. , Dalhoff Klaus , Drömann Daniel , Gruber Achim D. , Kershaw Olivia , Temmesfeld-Wollbrueck Bettina , Suttorp Norbert , Hippenstiel Stefan , Hocke Andreas C. 
Published: March 2012

The majority of cases of community-acquired pneumonia are caused byStreptococcus pneumoniaeand most studies on pneumococcal host interaction are based on cell culture or animal experiments. Thus, little is known about infections in human lung tissue.Cyclooxygenase-2 and its metabolites play an important regulatory role in lung inflammation. Therefore, we established a pneumococcal infection model on human lung tissue demonstrating mitogen-activated protein kinase (MAPK)-dependent induction of cyclooxygenase-2 and its related metabolites.In addition to alveolar macrophages and the vascular endothelium, cyclooxygenase-2 was upregulated in alveolar type II but not type I epithelial cells, which was confirmed in lungs of patients suffering from acute pneumonia. Moreover, we demonstrated the expression profile of all four E prostanoid receptors at the mRNA level and showed functionality of the E prostanoid4receptor by cyclic adenosine monophosphate production. Additionally, in comparison to previous studies, cyclooxygenase-2/prostaglandin E2related pro- and anti-inflammatory mediator regulation was partly confirmed in human lung tissue after pneumococcal infection.Overall, cell type-specific and MAPK-dependent cyclooxygenase-2 expression and prostaglandin E2formation in human lung tissue may play an important role in the early phase of pneumococcal infections.
What shall we do with the damaged proteins in lung disease? Ask the proteasome!
Authors: Meiners Silke , Eickelberg Oliver 
Published: March 2012

The proteasome constitutes the main protein waste disposal and recycling system of the cell. Together with endoplasmic reticulum stress and the autophagosome pathway, it takes centre stage in cellular protein quality control.In lung research, the proteasome is, first of all, a promising therapeutic target to intervene in the malignant growth of lung cancer cells. Therapeutic targeting of the proteasome has also been extended to pulmonary fibrosis and asthma using animal models. Moreover, the proteasome is involved in lung pathogenesis. In cystic fibrosis, rapid proteasomal degradation of mutant cystic fibrosis transmembrane conductance regulator contributes to loss of function of lung epithelial cells. In chronic obstructive pulmonary disease (COPD), pulmonary proteasome expression and activity are downregulated and inversely correlate with lung function. In addition, as the proteasome degrades signalling mediators that have been oxidatively modified in COPD, it contributes to further compromise cellular function.The consequences of proteasomal dysfunction are loss of protein quality control, accumulation of misfolded proteins and exacerbation of cellular stress, which are also hallmarks of protein quality diseases and premature ageing. This suggests that proteasome dysfunction can be regarded as a new pathomechanism for chronic lung diseases, awaiting further therapeutic exploration in the future.
Serial computed tomography and lung function testing in pulmonary Langerhans’ cell histiocytosis
Authors: Tazi Abdellatif , Marc Karima , Dominique Stéphane , de Bazelaire Cédric , Crestani Bruno , Chinet Thierry , Israel-Biet Dominique , Cadranel Jacques , Frija Jacques , Lorillon Gwenael , Valeyre Dominique , Chevret Sylvie 
Published: March 2012

Little is known about longitudinal lung function variation in patients with pulmonary Langerhans’ cell histiocytosis (LCH). The contribution of serial lung computed tomography (CT) to managing these patients has not been evaluated.This long-term retrospective study included 49 patients who were serially evaluated by lung CT and pulmonary function tests. The lung function variation was categorised as improvement or deterioration. The extent of the CT lesions was correlated with lung function.Lung function deteriorated in ∼60% of the patients. Forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DL,CO) were the parameters that most frequently deteriorated. A subgroup of patients experienced a dramatic decline in FEV1within 2 yrs of diagnosis. Airway obstruction was the major functional pattern observed. In a multivariate analysis, % predicted FEV1at diagnosis was the only factor associated with the incidence of airway obstruction. The increase in cystic lesions on the lung CTs was associated with impaired lung function but did not anticipate the decline in FEV1orDL,CO.Serial lung function tests are essential for following patients with pulmonary LCH, who frequently develop airway obstruction. A lung CT at diagnosis is informative, but routine sequential CTs seem less useful. A prospective study is needed to characterise those patients with early progressive disease.
Increased frequencies of pulmonary regulatory T-cells in latentMycobacterium tuberculosisinfection
Authors: Herzmann Christian , Ernst Martin , Ehlers Stefan , Stenger Steffen , Maertzdorf Jeroen , Sotgiu Giovanni , Lange Christoph 
Published: March 2012

Regulation of specific immune responses following exposure toMycobacterium tuberculosisin humans and the role of regulatory T (Treg) cells in the immune control of latent infection withM. tuberculosisare incompletely understood.Latent infection was assayed by an interferon-γ release assay (IGRA) in healthcare workers regularly exposed to tuberculosis (TB) patients and in household TB contacts in Germany. Immunophenotypes of bronchoalveolar lavage (BAL) mononuclear cells and peripheral blood mononuclear cells (PBMCs) were analysed by fluorescence-activated cell sorting.All TB contacts with latent infection (n=15) had increased (p<0.0001) frequencies of CD4+ CD25+ CD127- Treg cells (median 2.12%, interquartile range (IQR) 1.63–3.01%) among BAL mononuclear cells compared with contacts (n=25) with negative IGRA results (median 0.68%, IQR 0.32–0.96%) No differences were seen when PBMC immunophenotypes of IGRA+ and IGRA- TB contacts were compared (IGRA+ median 9.6%, IQR 5.9–10.1%; IGRA- median 7.7%, IQR 4.6–11.3%; p=0.47). Five out of 25 contacts with negative blood IGRAs showed a positive IGRA from BAL cells, possibly indicating a limited local immune response.In Germany, latent infection withM. tuberculosis, as defined by a positiveM. tuberculosis-specific IGRA response on cells from the peripheral blood, is characterised by an increased frequency of Treg cells in the BAL.
Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study
Authors: Jones Paul W. , Singh Dave , Bateman Eric D. , Agusti Alvar , Lamarca Rosa , de Miquel Gonzalo , Segarra Rosa , Caracta Cynthia , Garcia Gil Esther 
Published: March 2012

The efficacy and safety of two doses of aclidinium bromide were evaluated in patients with moderate to severe chronic obstructive pulmonary disease (COPD).In this 24-week, double-blind trial, patients were randomised to twice-daily aclidinium (200 μg or 400 μg) or placebo. The primary efficacy end-point was change in trough forced expiratory volume in 1 s (FEV1) at week 24. Other end-points included peak FEV1, health status (St George's Respiratory Questionnaire; SGRQ) and dyspnoea (Transitional Dyspnoea Index; TDI).Overall, 828 patients were randomised. At week 24, significant improvements from baseline were observed with aclidinium 200 μg and 400 μgversusplacebo for trough FEV1(99 and 128 mL; both p<0.0001) and peak FEV1(185 and 209 mL; both p<0.0001). Peak FEV1improvements on day 1 were comparable with week 24. Aclidinium 200 μg and 400 μg produced significant improvements over placebo in baseline-adjusted mean SGRQ total score (-3.8 and -4.6 units; p<0.001 and p<0.0001) and TDI focal score (0.6 and 1.0 units; p<0.05 and p<0.001) at week 24. With both aclidinium doses, the incidence of anticholinergic adverse events was low, and similar to placebo.Twice-daily aclidinium significantly improved bronchodilation, health status and dyspnoea, and was well tolerated in patients with COPD.
Prediction of a deletion copy number variant by a dense SNP panel
Authors: Kadri Naveen K , Koks Patrick D , Meuwissen Theo H E 
Published: March 2012

Abstract

Background
A newly recognized type of genetic variation, Copy Number Variation (CNV), is detected in mammalian genomes, e.g. the cattle genome. This form of variation can potentially cause phenotypic variation. Our objective was to determine whether dense SNP (single nucleotide polymorphisms) panels can capture the genetic variation due to a simple bi-allelic CNV, with the prospect of including the effect of such structural variations into genomic predictions.

Methods
A deletion type CNV on bovine chromosome 6 was predicted from its neighboring SNP with a multiple regression model. Our dataset consisted of CNV genotypes of 1,682 cows, along with 100 surrounding SNP genotypes. A prediction model was fitted considering 10 to 100 surrounding SNP and the accuracy obtained directly from the model was confirmed by cross-validation.

Results and conclusions
The accuracy of prediction increased with an increasing number of SNP in the model and the predicted accuracies were similar to those obtained by cross-validation. A substantial increase in accuracy was observed when the number of SNP increased from 10 to 50 but thereafter the increase was smaller, reaching the highest accuracy (0.94) with 100 surrounding SNP. Thus, we conclude that the genotype of a deletion type CNV and its putative QTL effect can be predicted with a maximum accuracy of 0.94 from surrounding SNP. This high prediction accuracy suggests that genetic variation due to simple deletion CNV is well captured by dense SNP panels. Since genomic selection relies on the availability of a dense marker panel with markers in close linkage disequilibrium to the QTL in order to predict their genetic values, we also discuss opportunities for genomic selection to predict the effects of CNV by dense SNP panels, when CNV cause variation in quantitative traits.
Strategies of exploitation of mammalian reservoirs by Bartonella species
Authors: Deng Hongkuan , Le Rhun Danielle , Buffet Jean-Philippe R , Cotté Violaine , Read Amanda , Birtles Richard J , Vayssier-Taussat Muriel 
Published: March 2012

AbstractNumerous mammal species, including domestic and wild animals such as ruminants, dogs, cats and rodents, as well as humans, serve as reservoir hosts for variousBartonellaspecies. Some of those species that exploit non-human mammals as reservoir hosts have zoonotic potential. Our understanding of interactions between bartonellae and reservoir hosts has been greatly improved by the development of animal models for infection and the use of molecular tools allowing large scale mutagenesis ofBartonellaspecies. By reviewing and combining the results of these and other approaches we can obtain a comprehensive insight into the molecular interactions that underlie the exploitation of reservoir hosts byBartonellaspecies, particularly the well-studied interactions with vascular endothelial cells and erythrocytes.
Correlation set analysis: detecting active regulators in disease populations using prior causal knowledge
Authors: Huang Chia-Ling , Lamb John , Chindelevitch Leonid , Kostrowicki Jarek , Guinney Justin , DeLisi Charles , Ziemek Daniel 
Published: March 2012

Abstract

Background
Identification of active causal regulators is a crucial problem in understanding mechanism of diseases or finding drug targets. Methods that infer causal regulators directly from primary data have been proposed and successfully validated in some cases. These methods necessarily require very large sample sizes or a mix of different data types. Recent studies have shown that prior biological knowledge can successfully boost a method's ability to find regulators.

Results
We present a simple data-driven method, Correlation Set Analysis (CSA), for comprehensively detecting active regulators in disease populations by integrating co-expression analysis and a specific type of literature-derived causal relationships. Instead of investigating the co-expression level between regulators and their regulatees, we focus on coherence of regulatees of a regulator. Using simulated datasets we show that our method performs very well at recovering even weak regulatory relationships with a low false discovery rate. Using three separate real biological datasets we were able to recover well known and as yet undescribed, active regulators for each disease population. The results are represented as a rank-ordered list of regulators, and reveals both single and higher-order regulatory relationships.

Conclusions
CSA is an intuitive data-driven way of selecting directed perturbation experiments that are relevant to a disease population of interest and represent a starting point for further investigation. Our findings demonstrate that combining co-expression analysis on regulatee sets with a literature-derived network can successfully identify causal regulators and help develop possible hypothesis to explain disease progression.