bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasmodium falciparum-Specific Cellular Immune Responses after Immunization with the RTS,S/AS02D Candidate Malaria Vaccine in Infants Living in an Area of High Endemicity in Mozambique
Authors: Barbosa Arnoldo , Naniche Denise , Aponte John J. , Manaca M. Nelia , Mandomando Inacio , Aide Pedro , Sacarlal Jahit , Renom Montse , Lafuente Sarah , Ballou W. Ripley , Alonso Pedro L. 
Published: August 2009

ABSTRACTResults from clinical trials in areas where malaria is endemic have shown that immunization with RTS,S/AS02A malaria vaccine candidate induces partial protection in adults and children and cellular effector and memory responses in adults. For the first time in a malaria vaccine trial, we sought to assess the cell-mediated immune responses to RTS,S antigen components in infants under 1 year of age participating in a clinical phase I/IIb trial of RTS,S/AS02D in Mozambique. Circumsporozoite protein (CSP)-specific responses were detected in approximately half of RTS,S-immunized infants and included gamma interferon (IFN-γ), interleukin-2 (IL-2), and combined IL-2/IL-4 responses. The median stimulation indices of cytokine-producing CD4+and CD8+cells were very low but significantly higher in RTS,S-immunized infants than in infants that received the comparator vaccine. Protection against subsequent malarial infection tended to be associated with a higher percentage of individuals with CSP-specific IL-2 in the supernatant (P= 0.053) and with higher CSP-specific IFN-γ-producing CD8+T-cell responses (P= 0.07). These results report for the first time the detection of malaria-specific cellular immune responses after vaccination of infants less than 1 year of age and pave the way for future field studies of cellular immunity to malaria vaccine candidates.
Nitrite Reductase NirS Is Required for Type III Secretion System Expression and Virulence in the Human Monocyte Cell Line THP-1 by
Pseudomonas aeruginosa
Authors: Van Alst Nadine E. , Wellington Melanie , Clark Virginia L. , Haidaris Constantine G. , Iglewski Barbara H. 
Published: August 2009

ABSTRACT

The nitrate dissimilation pathway is important for anaerobic growth in
Pseudomonas aeruginosa
. In addition, this pathway contributes to
P. aeruginosa
virulence by using the nematode
Caenorhabditis elegans
as a model host, as well as biofilm formation and motility. We used a set of nitrate dissimilation pathway mutants to evaluate the virulence of
P. aeruginosa
PA14 in a model of
P. aeruginosa
-phagocyte interaction by using the human monocytic cell line THP-1. Both membrane nitrate reductase and nitrite reductase enzyme complexes were important for cytotoxicity during the interaction of
P. aeruginosa
PA14 with THP-1 cells. Furthermore, deletion mutations in genes encoding membrane nitrate reductase (Δ
narGH
) and nitrite reductase (Δ
nirS
) produced defects in the expression of type III secretion system (T3SS) components, extracellular protease, and elastase. Interestingly, exotoxin A expression was unaffected in these mutants. Addition of exogenous nitric oxide (NO)-generating compounds to Δ
nirS
mutant cultures restored the production of T3SS phospholipase ExoU, whereas nitrite addition had no effect. These data suggest that NO generated via nitrite reductase NirS contributes to the regulation of expression of selected virulence factors in
P. aeruginosa
PA14.
Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN
Authors: Driessen Nicole N. , Ummels Roy , Maaskant Janneke J. , Gurcha Sudagar S. , Besra Gurdyal S. , Ainge Gary D. , Larsen David S. , Painter Gavin F. , Vandenbroucke-Grauls Christina M. J. E. , Geurtsen Jeroen , Appelmelk Ben J. 
Published: August 2009

ABSTRACTThe C-type lectin dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is the major receptor on DCs for mycobacteria of theMycobacterium tuberculosiscomplex. Recently, we have shown that although the mannose caps of the mycobacterial surface glycolipid lipoarabinomannan (ManLAM) are essential for the binding to DC-SIGN, genetic removal of these caps did not diminish the interaction of whole mycobacteria with DC-SIGN and DCs. Here we investigated the role of the structurally related glycolipids phosphatidylinositol mannosides (PIMs) as possible ligands for DC-SIGN. In a binding assay with both synthetic and natural PIMs, DC-SIGN exhibited a high affinity for hexamannosylated PIM6, which contains terminal α(1→2)-linked mannosyl residues identical to the mannose cap on ManLAM, but not for di- and tetramannosylated PIM2and PIM4, respectively. To determine the role of PIM6in the binding of whole mycobacteria to DC-SIGN, a mutant strain ofM. bovisbacillus Calmette-Guérin deficient in the production of PIM6(ΔpimE) was created, as well as a double knockout deficient in the production of both PIM6and the mannose caps on LAM (ΔpimEΔcapA). Compared to the wild-type strain, both mutant strains bound similarly well to DC-SIGN and DCs. Furthermore, the wild-type and mutant strains induced comparable levels of interleukin-10 and interleukin-12p40 when used to stimulate DCs. Hence, we conclude that, like ManLAM, PIM6represents a bona fide DC-SIGN ligand but that other, as-yet-unknown, ligands dominate in the interaction between mycobacteria and DCs.
The Transcriptional Regulator Rv0485 Modulates the Expression of a
pe
and
ppe
Gene Pair and Is Required for
Mycobacterium tuberculosis
Virulence
Authors: Goldstone Rachael M. , Goonesekera Sunali D. , Bloom Barry R. , Sampson Samantha L. 
Published: August 2009

ABSTRACT

The
pe
and
ppe
genes are unique to mycobacteria and are widely speculated to play a role in tuberculosis pathogenesis. However, little is known about how expression of these genes is controlled. Elucidating the regulatory control of genes found exclusively in mycobacteria, such as the
pe
and
ppe
gene families, may be key to understanding the success of this pathogen. In this study, we used a transposon mutagenesis approach to elucidate
pe
and
ppe
regulation. This resulted in the identification of Rv0485, a previously uncharacterized transcriptional regulator. Microarray and quantitative real-time PCR analysis confirmed that disruption of Rv0485 reduced the expression of the
pe13
and
ppe18
gene pair (Rv1195 and Rv1196), defined the Rv0485 regulon, and emphasized the lack of global regulation of
pe
and
ppe
genes. The in vivo phenotype of the Rv0485 transposon mutant strain (Rv0485::Tn) was investigated in the mouse model, where it was demonstrated that the mutation has minimal effect on bacterial organ burden. Despite this, disruption of Rv0485 allowed mice to survive for significantly longer, with substantially reduced lung pathology in comparison with mice infected with wild-type
Mycobacterium tuberculosis
. Infection of immune-deficient SCID mice with the Rv0485::Tn strain also resulted in extended survival times, suggesting that Rv0485 plays a role in modulation of innate immune responses. This is further supported by the finding that disruption of Rv0485 resulted in reduced secretion of proinflammatory cytokines by infected murine macrophages. In summary, we have demonstrated that disruption of a previously uncharacterized transcriptional regulator, Rv0485, results in reduced expression of
pe13
and
ppe18
and attenuation of
M. tuberculosis
virulence.
Levels of von Willebrand factor antigen and von Willebrand factor cleaving protease (ADAMTS13) activity predict clinical events in chronic heart failure
Authors: Gombos Tímea , Makó Veronika , Cervenak László , Papassotiriou Jana , Kunde Jan , Hársfalvi Jolán , Förhécz Zsolt , Pozsonyi Zoltán , Borgulya Gábor , Jánoskuti Lívia , Prohászka Zoltán 
Published: August 2009

SummaryDecreased activity of ADAMTS13, the von Willebrand factor (VWF) cleaving protease, was recently reported in cardiovascular diseases and in hepatic failure. Chronic heart failure (CHF) is characterised by abnormalities of left ventricular function accompanied by the failure of the liver and dysregulation of endothelial activation. Therefore, the aim of our study was to measure ADAMTS13 activity in CHF, and determine the prognostic value of VWF and ADAMTS13 on major clinical events in CHF.ADAMTS13 activity (measured by FRETS-VWF73 substrate) was decreased in CHF (n = 152, left ventricular ejection fraction <45%), and it correlated negatively with B-type natriuretic peptide (BNP) NYHA (New York Heart Association) classes, markers of synthetic capacity of the liver and endothelial dysfunction (all p<0.005). Both, high VWF:Ag levels (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.189–1.943), and low ADAMTS13/VWF:Ag ratios (HR 0.70, 95% CI 0.58–0.84) independently and significantly predicted short-term (1 year followup) clinical adverse events in heart failure (HF).Decreased activity of ADAMTS13 with concomitant high VWF:Ag levels is a significant independent predictor of clinical events in CHF. The levels of the two molecules may integrate the impaired synthetic capacity of the liver and the disturbed endothelial regulation and can therefore be a useful tool to predict clinical events in CHF.
Pneumococcal association to platelets is mediated by soluble fibrin and supported by thrombospondin-1
Authors: Heilmann Christine , Rennemeier Claudia , Peters Georg , Hammerschmidt Sven , Niemann Silke , Kehrel Beate E. 
Published: August 2009

SummaryPlatelets and coagulation are involved in bacterial colonisation of the host. Streptocococcus pneumoniae (pneumococcus) are important etiologic agents of respiratory tract infections in humans. The formation of pneumococci-platelet associations may facilitate haematogenous dissemination of pneumococci by providing an adhesive surface on damaged endothelium. However, the formation of platelet-pneumococci associations and the factors involved in this process have not been described so far. The formation of platelet-pneumococci associates was analysed and quantified using flow cytometry. Binding of pneumococci to platelets was significantly increased after activation of platelets with thrombin, while platelet activation by ADP or collagen did not promote formation of platelet-pneumococci associates. In addition to be a platelet agonist, thrombin cleaves fibrinogen, which results in the generation of fibrin. The simultaneous formation of fibrin and activation of platelets was shown to be a prerequisite for a high number of platelet-pneumococci associates. Moreover, exogenously added human thrombospondin-1 (TSP-1) significantly enhanced the association of pneumococci with activated platelets. Soluble fibrin and TSP-1 are key co-factors of platelet-pneumococci-association. Similar results were recently demonstrated for S. aureus-platelet adhesion. Consequently, we hypothesise that the described mechanism of platelet-bacteriaassociation might represent a general and important strategy of Gram-positive bacteria during development of invasive diseases.
A G-quartet oligonucleotide blocks glycoprotein Ib-mediated platelet adhesion and aggregation under flow conditions
Authors: Zhou Zhou , Bernardo Aubrey , Zhu Qiqing , Guan Yongli , Sun Wensheng , Lopez Jose A. , Jing Naijie , Dong Jing-fei 
Published: August 2009

SummaryPlatelets arrest bleeding by adhering to and aggregating on the subendothelium exposed at the site of vessel injury.This process is initiated by the interaction between the subendothelium von Willebrand factor (VWF) and the glycoprotein (GP) Ib-IX-V complex on platelets.However,the same interaction also results in thrombosis at the site of a ruptured atherosclerotic plaque. Reagents regulating the GP Ib-VWF interaction will therefore have direct impact on haemostasis and thrombosis. We have characterised an oligonucleotide G-quartet (T30923) that specifically blocks VWF binding to GP Ibα, theVWF-binding subunit of the GP Ib-IX-V complex.We evaluated the potential interactions of T30923 with GP Ibα and VWF A1 domain by computer simulated molecular dockings, which identified four T30923 docking sites in the β-sheets of the N-terminal region of GP Ibα (E14-D18, S39, D63-S64, and D83-S85). Experimentally,T30923 bound GP Ibα and dose-dependently blocked platelet aggregation induced by ristocetin and thrombin, but not by botrocetin, collagen, TRAP, and ADP. It also blocked shear-induced platelet aggregation and thrombus formation on immobilized VWF under arterial shear stress. These results demonstrate that T30923 may have therapeutic potentials to regulate the GP IbαVWF interaction.
Molecular diversity of anticoagulants from haematophagous animals
Authors: Koh Cho , Kini R. Manjunatha 
Published: August 2009

SummaryTo obtain blood meals, haematophagous animals are armed with potent pharmacological molecules to overcome several of their hosts’ response systems. Among them, a large number of exogenous anticoagulants which target the haemostatic system have been identified and characterised. Studies on these anticoagulants have expanded our knowledge on the blood coagulation system, and provided a valuable source of antithrombotic therapeutic agents. Advances in genomic, transcriptomic, structural and proteomic tools greatly accelerated the discovery and analysis of the exogenous anticoagulants in recent years. The molecular diversity observed in these molecules is huge and is constantly expanding. In this review, we will provide an overview on the structure, function and mechanism of the exogenous anticoagulants from haematophagous animals and rationalise their molecular diversity.
Tissue factor activity of blood mononuclear cells is increased after total knee arthroplasty
Authors: Leis Linda A. , Bach Ronald R. , Johnson Gerhard J. 
Published: August 2009

SummaryTissue factor (TF) is present in small quantities in normal blood and is reported to be elevated in arterial and venous thrombosis. Patients undergoing total knee arthoplasty (TKA) are at high risk of post-operative venous thromboembolism (VTE). To evaluate the possible contribution of elevated blood TF to VTE risk, we performed serial studies of peripheral blood mononuclear cell (PBMC) functional TF procoagulant activity (PCA) in 19 patients after TKA. PBMC and platelet TF PCA were measured by a functional, clot-based assay following decryption with a calcium ionophore. Plasma TF antigen levels were measured by ELISA. All subjects received chemoprophylaxis and none had VTE. After TKA total TF PCA of PBMC was elevated in 19 of 19 subjects. The peak increase above preoperative levels was 1. 1–13.6 fold (>two-fold in 58% and >three-fold in 42%). Median TF PCA of PBMC was not elevated following tourniquet removal, but it was significantly elevated on postoperative days 1 and 2. Thereafter, it decreased to near preoperative values at day 6. Neither platelet TF PCA nor plasma TF antigen levels increased significantly. Since the PBMC count did not rise, the increase in TF PCA was attributable to cell synthesis. The increase in blood TF PCA preceded the median time of diagnosis of venous thromboembolism after TKA established previously. These observations indicate a) TKA stimulates synthesis of encrypted PBMC TF PCA which is likely to contribute to the pathophysiology of VTE; b) TF antigen is not a reliable indicator of TF PCA.
The influence of clinical characteristics, laboratory and inflammatory markers on ‘high on-treatment platelet reactivity’ as measured with different platelet function tests
Authors: Elsenberg Ellen H. A. M. , van de Wal Ruud M. A. , Zomer Carla A. , Bouman Heleen J. , Verheugt Freek W. A. , ten Berg Jurriën M. , Hackeng Christian M. , van Werkum Jochem W. 
Published: August 2009

SummaryHigh on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) are independently associated with an increased risk of atherothrombotic events. However, despite this positive correlation, the definitions of both HCPR and HAPR vary largely throughout studies and between different platelet function assays.The aim of the present study was to explore clinical and laboratory parameters that are associated with HCPR and HAPR as measured with different platelet function tests. 530 clopidogrel and aspirin pre-treated patients undergoing elective PCI (percutaneous coronary intervention) were enrolled. Platelet function measurements were performed with: optical aggregometry, the VerifyNow device and PFA-100 cartridges (including the novel INNOVANCE® P2Y assay). HCPR as measured with Adenosin-Di-Phospate-induced (ADP) aggregation based tests was associated with clinical factors such as older age, female gender and Diabetes mellitus (DM).TheVerifyNow P2Y12 assay was significantly influenced by haemoglobin and haematocrit levels. HAPR as measured with aggregation based tests was significantly influenced by the presence of malignancy, BMI (Body-Mass Index), older age and increased levels of hsCRP (high sensitivity c-reactive proteine).The PFA-100 COL/ EPI (collagen-epinephrine) and COL/ADP (collagen-ADP) cartridges were significantly influenced by monocyte count,hs-CRP, MPV (mean platelet volume), vWF-antigen (von Willebrand factor) and vWF-activity. HCPR as measured with the novel INNOVANCE® P2Y cartridge was associated with clinical determinants such as BMI,female gender,impaired LVEF (left ventricular ejection fraction), renal failure and dosing of clopidogrel. Laboratory markers that were associated with HCPR as measured with INNOVANCE® P2Y were platelet count, white blood cells (WBC), hsCRP and fibrinogen.Both HCPR and HAPR are highly dependent on the type of platelet function assay. Each platelet function assay, in turn, is significantly influenced by distinct clinical and laboratory variables.
Bivalirudin as compared to unfractionated heparin among patients undergoing coronary angioplasty
Authors: Cassetti Ettore , Verdoia Monica , Marino Paolo , De Luca Giuseppe 
Published: August 2009

SummaryIt has been shown that bleeding complications are associated with higher mortality rates among patients undergoing coronary angioplasty. Due to its properties, bivalirudin may provide benefits in terms of bleeding and thrombotic complications as compared to unfractionated heparin (UFH).The aim of the current study was to perform a meta-analysis of randomised trials to evaluate whether bivalirudin might offer benefits in terms of mortality as compared to UFH.We obtained results from all randomised trials evaluating the benefits of adjunctive bivalirudin as compared to UFH with or without Gp IIb-IIIa inhibitors among patients undergoing coronary angioplasty. The literature was scanned by formal searches of electronic databases (MEDLINE and CENTRAL) from January 1990 to October 2008.The following keywords were used: randomised trial, coronary angioplasty, stent, reperfusion, primary angioplasty, bivalirudin, direct thrombin inhibitors, hirulog. Primary endpoint was mortality. Secondary endpoint was infarction. Safety endpoint was the risk of major bleeding complications. No language restriction was applied.A total of nine randomised trials were included in the metaanalysis, with 15655 patients randomised to bivalirudin and 13104 patients randomised to UFH. We did not observe any difference in mortality between bivalirudin and UFH (1.73% vs 1.67%, p = 0.15) without any relationship between the baseline risk of mortality (r = 0.17, p = 0.71) or the reduction in major bleeding complications (r = –0.29, p = 0.53) and the benefits in mortality with bivalirudin. A trend in higher risk of myocardial infarction was observed with bivalirudin (6.9% vs 5.9%, p = 0.07, p het = 0.65). Bivalirudin was associated with a significant reduction in major bleeding complications (1.7% vs 3.4%, p < 0.0001), as compared to UFH.This meta-analysis shows that among patients undergoing coronary angioplasty, bivalirudin is associated with significant reduction in major bleeding complications. However, these benefits did not translate into benefits in mortality, with even a trend in higher risk of myocardial infarction.
The Effect of Local Circulation Variability on the Detection and Attribution of New Zealand Temperature Trends
Authors: Dean S. M. , Stott P. A. 
Published: August 2009

Abstract
A representative temperature record for New Zealand based on station data from 1853 onward is used in conjunction with four coupled climate models to investigate the causes of recent warming over this small midlatitude country. The observed variability over interannual and decadal time scales is simulated well by the models. The variability of simulated 50-yr trends is consistent with the very short observational record. For a simple detection analysis it is not possible to separate the observed 30- and 50-yr temperature trends from the distribution created by internal variability in the model control simulations. A pressure index that is representative of meridional flow (M1) is used to show that the models fail to simulate an observed trend to more southerly flows in the region. The strong relationship between interannual temperature variability and the M1 index in both the observations and the models is used to remove the influence of this circulation variability from the temperature records. Recent 50-yr trends in the residual temperature record cannot be explained by natural climate variations, but they are consistent with the combined climate response to anthropogenic greenhouse gas emissions, ozone depletion, and sulfate aerosols, demonstrating a significant human influence on New Zealand warming. This result highlights the effect of circulation variability on regional detection and attribution analyses. Such variability can either mask or accelerate human-induced warming in observed trends, underscoring the importance of determining the underlying forced trend, and the need to adequately capture regional circulation effects in climate models.
Empirical Orthogonal Functions: The Medium is the Message
Authors: Monahan Adam H. , Fyfe John C. , Ambaum Maarten H. P. , Stephenson David B. , North Gerald R. 
Published: August 2009

Abstract
Empirical orthogonal function (EOF) analysis is a powerful tool for data compression and dimensionality reduction used broadly in meteorology and oceanography. Often in the literature, EOF modes are interpreted individually, independent of other modes. In fact, it can be shown that no such attribution can generally be made. This review demonstrates that in general individual EOF modes (i) will not correspond to individual dynamical modes, (ii) will not correspond to individual kinematic degrees of freedom, (iii) will not be statistically independent of other EOF modes, and (iv) will be strongly influenced by the nonlocal requirement that modes maximize variance over the entire domain. The goal of this review is not to argue against the use of EOF analysis in meteorology and oceanography; rather, it is to demonstrate the care that must be taken in the interpretation of individual modes in order to distinguish the medium from the message.