Lactate Dehydrogenase as a Biomarker for Prediction of Refractory Mycoplasma pneumoniae Pneumonia

Lactate Dehydrogenase as a Biomarker for Prediction of Refractory Mycoplasma pneumoniae Pneumonia tài liệu, giáo án, bài...

MINIREVIEW Alternative splicing: regulation of HIV-1 multiplication as a target for therapeutic action Jamal Tazi 1 , Nadia Bakkour 1 , Virginie Marchand 2 , Lilia Ayadi 2 , Amina Aboufirassi 1 and Christiane Branlant 2 1 Universite ´ Montpellier 2 Universite ´ Montpellier 1 CNRS, Institut de Ge ´ ne ´ tique Mole ´ culaire de Montpellier (IGMM), UMR5535, IFR122, Montpellier, France 2 Universite ´ Henri Poincare-Nancy I, CNRS UMR 7214, Vandoeuvre-les-Nancy, France Introduction The HIV ⁄ AIDS epidemic is one of the primary health concerns worldwide [1]. Despite significant advances in anti-HIV chemotherapy, the treatment and ⁄ or preven- tion of the disease remains a largely unsolved problem. Current routine drug regimens, typically consisting of various combinations of compounds targeting the viral proteins reverse transcriptase, protease and gp120, have revolutionized the treatment of HIV ⁄ AIDS [2–4]. However, a number of problems with current therapies limit their usefulness. First, the cost of the drugs constitutes a significant burden to individuals and governments worldwide, and virtually eliminates their availability in developing countries. Additional prob- lems include the inconvenient and complicated medica- tion schedules, the lack of patient compliance, side- effects associated with the drugs, and, ominously, the development of drug-resistant HIV. For these reasons, alternative or adjuvant treatment strategies for HIV infection are being investigated. Understanding the mechanism of HIV replication in host cells will help to develop unexplored strategies for HIV therapy. This review will focus on alternative splicing, a key event for HIV replication. HIV-1 alternative splicing mechanism The HIV-1 DNA genome expresses a primary tran- script of 9 kb that not only serves as genomic RNA Keywords alternative splicing; HIV-1; hnRNP proteins; retroviral therapy; SR proteins Correspondence J. Tazi, Institut de Ge ´ ne ´ tique Mole ´ culaire de Montpellier (IGMM), 1919 route de Mende, F-34293 Montpellier, Cedex 5, France Fax: +33 4 67 04 02 31 Tel: +33 4 67 61 36 32 E-mail: jamal.tazi@igmm.cnrs.fr (Received 28 August 2009, revised 31 October 2009, accepted 26 November 2009) doi:10.1111/j.1742-4658.2009.07522.x The retroviral life cycle requires that significant amounts of RNA remain unspliced and perform several functions in the cytoplasm. Thus, the full- length RNA serves both the viral genetic material that will be encapsulated in viral particles and the mRNA encoding structural and enzymatic pro- teins required for viral replication. Simple retroviruses produce one single- spliced env RNA from the full-length precursor RNA, whereas complex retroviruses, such as HIV, are characterized by the production of multiple- spliced RNA species. In this review we will summarize the current acknowledge about the HIV-1 alternative splicing mechanism and will describe how this malleable process can help further understanding of infection, spread and dissemination through splicing regulation. Such stud- ies coupled with the testing of splicing inhibitors should help the develop- ment of new therapeutic antiviral agents. Abbreviations 3¢ss, 3¢ splice site; 5¢ss, 5¢ splice site; ESE, exonic splicing enhancer; ESS, exonic splicing silencer; ESSV, exonic splicing silencer of Vpr; hnRNP, heterogeneous nuclear ribonucleoprotein; ISS, intronic splicing silencer; PPT, polypyrimidine tract; RRE, Rev response element; snRNP, small nuclear ribonucleoprotein; SR protein, serine and arginine rich protein. FEBS Journal 277 (2010) 867–876 Journal compilation ª 2010 FEBS. No claim to original French government works 867 for progeny virus, but also as the mRNA that encodes the Lactate Dehydrogenase as a Biomarker for Prediction of Refractory Mycoplasma pneumoniae Pneumonia in Children BS NGUYỄN THỊ NGỌC DIỄM KHOA NỘI Introduction - Mycoplasma pneumoniae (MP): one of the most prevalent pathogens causing CAP in children (40% CAP,18% require hospitalization) hospitalization - Mycoplasma pneumoniae pneumonia (MPP) : +usually self-limited +sometimes various pulmonary and extra-pulmonary extra complications +the host’s immune response >> direct microbial damage - Refractory Mycoplasma pneumoniae pneumonia (RMPP): +clinical and radiological deterioration /macrolide / antibiotic therapy >=7 days +steroid administration is reported to be effective in this situation  to recognize RMPP early ? Does LDH predict RMPP? Clinical implications of interleukin-18 interleukin levels in pediatric patients with MPP Tomohiro Oishi et al 2011 Management of RMPP: Utility of measuring serum lactate dehydrogenase level Norikazu Inamura et al 2014 Lactate Dehydrogenase as a Biomarker for Prediction of RMPP in Children Aizhen Lu MD PhD et al 2015 The Clinical Characteristics and Predictors of RMPP Yuanyuan Zhang et al 2016 METHODS - admitted to the Niigata Prefectural Shibata Hospital - from 8/ 2006 to 2/ 2008, n = 23 RESULTS -IL-18 levels :abnormally elevated, Relationship between IL-18 values and severity -the correlation between IL-18 and LDH: LDH statistically significant (r2= 0.64) /other clinical parameters: WBC, NEU, CRP, -AST, -ALT: not significant  the usefulness LDH levels : measures of the severity of pediatric MPP METHODS -4 /2010 to 11/ 2012 -admitted admitted Kawasaki Medical School Hospital and Yamaguchi University Hospital Hospita 20 pediatric patients MP (+) 5 RMPP / 15 GMPP (control group) group RESULTS -At admission: no significant -At the initiation of steroid use: use serum LDH, ALT, AST and IL-18 18 levels significantly higher in RMPP The correlation between IL-18 and LDH: statistically significant  LDH instead of IL-18 as a predictor of RMPP - the serum LDH cut-off level / the initiation of steroid therapy: 412 IU/L (ss 80%, sp 100% ) - serum LDH levels : useful marker for the evaluation of therapeutic efficacy in RMPP Lactate Dehydrogenase as a Biomarker for Prediction of Refractory Mycoplasma pneumoniae Pneumonia in Children Aizhen Lu MD PhD, Chuankai Wang, Xiaobo Zhang MD PhD, Libo Wang MD, and Liling Qian MD PhD METHODS -a prospective cohort study -children with MPP admitted to the Children’s Hospital of Fudan University -September 2012 to August 2013 n= 653, groups:RMPP group(( 300) and GMPP group (353) Results - serum LDH (odds ratio of 1.01, 95% CI 1.00–1.01, 1.00 P< 0.001) significant risk factors for RMPP / on admission -The optimal cutoff of LDH for predicting RMPP: 379 IU/L ss: 48%, sp 85.8%, ppv74.2%, 74.2%, npv 65.9% METHODS -Retrospective analysis -admitted admitted to Children’s hospital, Zhejiang University School of Medicine - January 1, 2011 and December 31, 2014 n= 634, divided into two groups: groups GMPP (489 patients) and RMPP (145 patients ) RESULTS - the cut-off values for LDH in differentiating RMPP from GMPP :417IU/L - the sensitivity and specificity : 79.7% and 65.0% SUMMARY • Many study indicates that serum LDH was elevated in RMPP: serum LDH can be used as a biomarker for predicting refractory RMPP and determining candidates who may benefit from corticosteroid therapy during the early stages of hospitalization • However, the present study is limited by the small sample sizes of the component studies Thank you for your attention! Molecular characterization of recombinant mouse adenosine kinase and evaluation as a target for protein phosphorylation Bogachan Sahin 1 , Janice W. Kansy 1 , Angus C. Nairn 2,3 , Jozef Spychala 4 , Steven E. Ealick 5 , Allen A. Fienberg 3,6 , Robert W. Greene 1,7 and James A. Bibb 1 1 The University of Texas Southwestern Medical Center, Dallas, TX; 2 Yale University School of Medicine, New Haven, CT; 3 The Rockefeller University, New York, NY; 4 University of North Carolina, Chapel Hill, NC; 5 Cornell University, Ithaca, NY; 6 Intra-Cellular Therapies Inc., New York, NY; 7 Veterans Administration Medical Center, Dallas, TX, USA The regulation of adenosine kinase (AK) activity has the potential to control intracellular and interstitial adenosine (Ado) concentrations. In an effort to study the role of AK in Ado homeostasis in the central nervous system, two iso- forms of the en zyme wer e cloned f rom a mouse b rain cDNA library. F ollowing overexpression in bacterial cells, the cor- responding proteins were purified to homogeneity. Both isoforms were enzymatically active and found to possess K m and V max values in agreement with kinetic parameters des- cribed for other forms of AK. The distribution of AK in discrete brain regions and various peripheral tissues was defined. To investigate the possibility that AK activity is regulated by protein phosphorylation, a panel of protein kinases was screened for ability to phosphorylate recom- binant mouse AK. Data from these in vitro phosphorylation studies suggest t hat AK is most likely not an efficient s ub- strate for PKA, PKG, CaMKII, CK1, CK2, MAPK, C d k1, or Cdk5. PKC was found to phosphorylate recombinant AK efficiently in vitro. Further analysis revealed, however, that this PKC-dependent phosphorylation occurred at one or more serine residues associated with the N -terminal affinity tag used for protein purification. Keywords: adenosine kinase; adenosine r egulation; protein serine/threonine kinases; CNS. Adenosine (Ado) is a potent biological mediator and a key participant in cellular energy metabolism. In the central nervous system (CNS), extracellular Ado behaves primarily as a tonic inhibitory neuromodulator that controls neuronal excitability through its interaction with four distinct subtypes of G p rotein-coupled receptors, A 1 ,A 2A ,A 2B , and A 3 [1]. A 1 receptor signaling in the cholinergic arousal centers of the basal forebrain and brainstem reduces cholinergic CNS tone, facilitating the transition from waking to sleep [2]. A 2A receptors in the striatum are involved in the modulation of locomotor a ctivity, p ain sensitivity, vigilance, and aggression [3]. Caffeine, t he most widely used psychomotor stimulant substance in the world, is a well-known Ado antagonist of both A 1 and A 2A receptor subtypes [4]. Facilitated diffusion of Ado across the cell membrane via equilibrative nucleoside t ransporters closely c ouples baseline Ado concentrations in the intracellular and extracellular compartments [5]. Adeno sine kinase ( AK), which catalyzes the transfer of the c-phosphate from ATP to the 5¢-hydroxyl of Ado, generating AMP and ADP, is one of several enzymes responsible for maintaining steady-state Ado levels [6]. The structure of AK has been determined at 1.5 A ˚ resolution and c onsists of one large and one small a/b domain and two Ado binding sites [7]. AK has a low K m value [8] that falls within the range of extracellular Ado levels (25–250 n M ) [9], suggesting that the reaction it catalyzes may be the primary route The S100A8/A9 protein as a partner for the cytosolic factors of NADPH oxidase activation in neutrophils Jacques Doussiere, Farid Bouzidi and Pierre V. Vignais Laboratoire de Biochimie et Biophysique des Syste ` mes Inte ´ gre ´ s (UMR 5092 CEA-CNRS-UJF), De ´ partement Re ´ ponse et Dynamique Cellulaires, CEA-Grenoble, France In a previous study, the S100A8/A9 protein, a Ca 2+ -and arachidonic acid-binding protein, abundant in neutrophil cytosol, was found to potentiate the activation of the redox component of the O 2 – generating oxidase in neutrophils, namely the membrane-bound flavocytochrome b,bythe cytosolic phox proteins p67phox, p47phox and Rac (Doussie ` re J., Bouzidi F. and Vignais P.V. (2001) Biochem. Biophys. Res. Commun. 285, 1317–1320). This led us to check by immunoprecipitation and protein fractionation whether the cytosolic phox proteins could bind to S100A8/A9. Fol- lowing incubation of a cytosolic extract from nonactivated bovine neutrophil with protein A–Sepharose bound to anti- p67phox antibodies, the recovered immunoprecipitate con- tained the S100 protein, p47phox and p67phox. Cytosolic protein fractionation comprised two successive chromato- graphic steps on hydroxyapatite and DEAE cellulose, fol- lowed by isoelectric focusing. The S100A8/A9 heterodimeric protein comigrated with the cytosolic phox proteins, and more particularly with p67phox and Rac2, whereas the isolated S100A8 protein displayed a tendancy to bind to p47phox. Using a semirecombinant cell-free system of oxidase activation consisting of recombinant p67phox, p47phox and Rac2, neutrophil membranes and arachidonic acid, we found that the S100A8/A9-dependent increase in the elicited oxidase activity corresponded to an increase in the turnover of the membrane-bound flavocytochrome b, but not to a change of affinity for NADPH or O 2 .Inthe absence of S100A8/A9, oxidase activation departed from michaelian kinetics above a critical threshold concentration of cytosolic phox proteins. Addition of S100A8/A9 to the cell-free system rendered the kinetics fully michaelian. The propensity of S100A8/A9 to bind the cytosolic phox pro- teins, and the effects of S100A8/A9 on the kinetics of oxidase activation, suggest that S100A8/A9 might be a scaffold protein for the cytosolic phox proteins or might help to deliver arachidonic acid to the oxidase, thus favoring the productive interaction of the cytosolic phox proteins with the membrane-bound flavocytochrome b. Keywords: NADPH oxidase activation; superoxide O 2 – ; neutrophils; phox proteins; S100A8/ A9 protein. The heterodimeric Ca 2+ -binding protein S100A8/A9, also referred to in the literature as MRP8/MRP14, is expressed constitutively in large amounts in neutrophils and mono- cytes [1–3], where it plays a role in the activation process (reviewed in [4]) and adhesion [5]. The S100A8/A9 protein might also serve as a reservoir and a carrier of arachidonic acid [6–8]. This latter finding is all the more noteworthy as arachidonic acid is currently used in cell-free system to activate the O 2 – generating NADPH oxidase, an enzymatic complex responsible for the microbicidal function of neutrophils and macrophages [9]. In its activated form, the NADPH oxidase complex is composed A PROLOG IMPLEMENTATION OF LEXICAL FUNCTIONAL GRAMMAR AS A BASE FOR A NATURAL LANGUAGE PROCESSING SYSTEM Werner Frey and Uwe Reyle Department of Llngulstlcs University of Stuttgart W-Germany O. ABSIRACr ~ne aim of this paper is to present parts of our system [2], which is to construct a database out of a narrative natural la~ text. We think the parts are of interest in their o~. The paper consists of three sections: (I) We give a detailed description of the PROLOG - implementation of the parser which is based on the theory of lexical functional grammar (I/V.). The parser covers the fragment described in [1,94]. I.e., it is able to analyse constructions involving functional control and long distance dependencies. We will to show that - PROLOG provides an efficient tool for LFG-implementation: a phrase structure rule annotated with ftmctional schemata like~ M~ w~is ~^ be interpreted as, first, identifying the special grmr, m/tical relation of subject position of any sentence analyzed by this clause to he the h~ appearing in it, and second, as identifying all g~,~mtical relations of the sentence with those of the VP. This ~iversal interpretation of the ~tavariables ~ and & corresponds to the universal quantification of variables appearing in PROl/~uses. The procedural ssm~ntios of PROLOG is such that the instantietion of the ~ariables in a clause is inherited from the instantiation given by its subgoals, if they succeed. Thus there is no need for a separate component which solves the set of equations obtained by applying the I/G algorithm. -there is a canonical way of translati~ LFG into a PROLOG progz~,~. (II) For the se~ntic representation of texts we use the Discourse Representation q]neory developped by Psns [,a~p. At present the implerentation includes the fragment described in [4]. In addition it analyses different types of negation and certain equi- and raising-verbs. We postulate some requirenents a semantic representation has to fulfill in order to he able to analyse whole texts. We show how K~p's theory meets these requirements by analyzing sample disconrses involving amaphoric ~'s. (III) Finally we sketch how the parser formalism ca~ be augmented to yield as output discourse representation structures. To do this we introduce the new notion of 'logical head' in addition to the LFG notion of 'grmmmtical head'. reason is the wellknown fact that the logical structure of a sentence is induced by the determiners and not by the verb which on the other hand determines the thenatic structure of the sentence. However the verb is able to restrict quantifier scope anbiguities or to induce a preference ordering on the set of possible quantifier scope relations. ~-erefore there must he an interaction between the grammatical head and the logical head of a phrase. I. A PROLOG ~W[/94~NTATION OF LFG A main topic in AI research is the interaction between different components of a systen. But insights in this field are primarily reached by experience in constructing a complem system. Right frcm the beginning, however, one should choose formalisms which are suitable for a s~nple and transparent transportion of information. We think LFG meets this requirenent. The formalism exhibiting the analysis of a sentence c~ he expanded in a simple way to contain entries which are used during the parse of a whole text, for ... efficacy in RMPP Lactate Dehydrogenase as a Biomarker for Prediction of Refractory Mycoplasma pneumoniae Pneumonia in Children Aizhen Lu MD PhD, Chuankai Wang, Xiaobo Zhang MD PhD, Libo Wang MD, and... pediatric patients with MPP Tomohiro Oishi et al 2011 Management of RMPP: Utility of measuring serum lactate dehydrogenase level Norikazu Inamura et al 2014 Lactate Dehydrogenase as a Biomarker for. .. - Mycoplasma pneumoniae (MP): one of the most prevalent pathogens causing CAP in children (40% CAP,18% require hospitalization) hospitalization - Mycoplasma pneumoniae pneumonia (MPP) : +usually