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Structures and biological functions of IL-31 and IL-31 receptors

Structures and biological functions of IL-31 and IL-31 receptors
Structures and biological functions of IL-31 and IL-31 receptors

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Structures and biological functions of IL-31and IL-31receptors

Qing Zhang a ,Prabhakar Putheti b ,Qiang Zhou b ,Quansheng Liu a ,*,Wenda Gao b ,*

a

Division of Medical Cell Biology,College of Life Sciences,Sichuan University,29Wangjiang Road,Chengdu 610041,PR China

b

Department of Medicine,Division of Transplant Immunology and Transplant Research Center,

Beth Israel Deaconess Medical Center,Harvard Medical School,77Avenue Louis Pasteur,Boston,MA 02115,USA

Available online 15October 2008

Abstract

Interleukin-31,produced mainly by activated CD4+T cells,is a newly discovered member of the gp130/IL-6cytokine family.Unlike all the other family members,IL-31does not engage gp130.Its receptor heterodimer consists of a unique gp130-like receptor chain IL-31RA,and the receptor subunit OSMR b that is shared with another family member oncostatin M (OSM).Binding of IL-31to its receptor activates Jak/STAT,PI3K/AKT and MAPK pathways.IL-31acts on a broad range of immune-and non-immune cells and therefore possesses potential pleiotropic physiological functions,including regulating hematopoiesis and immune response,causing in?ammatory bowel disease,airway hypersensitivity and dermatitis.This review summarizes the recent ?ndings on the biological characterization and physiological roles of IL-31and its receptors.

#2008Elsevier Ltd.All rights reserved.

Keywords:IL-31;Receptors;Biological function;Immunological regulation

Contents 1.Introduction ..............................................................................3482.Discovery of IL-31and IL-31receptors ...........................................................3483.Characterization of IL-31receptors ..............................................................3484.

Signal transduction pathways of IL-31............................................................3504.1.MAPK and PI3K/AKT pathways ...........................................................3504.2.Jak/STAT pathway .....................................................................3515.

Biological activities of IL-31...................................................................3525.1.Regulation of cell proliferation and hematopoiesis ...............................................2525.2.Induction of cytokines and chemokines.......................................................3525.3.Regulation of in?ammation and immune response ...............................................3526.

Role of IL-31in diseases .....................................................................3526.1.IL-31in dermatitis .....................................................................3526.2.IL-31in in?ammatory bowel disease ........................................................3536.3.IL-31in airway hypersensitivity............................................................3547.

Perspectives ..............................................................................354Acknowledgements .........................................................................354References ................................

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*Corresponding authors.

E-mail addresses:qliu77@https://www.doczj.com/doc/7717579675.html, (Q.Liu),wgao@https://www.doczj.com/doc/7717579675.html, (W.Gao).1359-6101/$–see front matter #2008Elsevier Ltd.All rights reserved.doi:10.1016/j.cytogfr.2008.08.003

1.Introduction

IL-31is a recently discovered helical cytokine[1], belonging to the gp130/IL-6cytokine family that includes IL-6,viral IL-6,IL-11,IL-27[2],leukemia inhibitory factor (LIF),oncostatin M(OSM),ciliary neurotrophic factor (CNTF),cardiotrophin-1(CT-1),cardiotrophin-like cyto-kine(CLC)[3,4](also reported as neurotrophin-1(NNT-1)/ B cell-stimulating factor-3(BSF-3)[5]),and neuropoietin (NP)[6].All the members of this family share the common chain of glycoprotein130(gp130)in their multi-unit receptor complexes(except for IL-31that uses gp130-like receptor[7]),and are involved in a variety of fundamental physiological processes,such as neuronal growth,bone metabolism,cardiac development,and immune regulation [8].Members of this family share very low sequence homology,and consequently the identi?cation of novel family members has proved challenging.The receptors for IL-6family are type I receptors,and they share a number of common structural motifs,such as the cytokine-binding domain with two pairs of conserved cysteine residues and a WSXWS sequence motif in the extracellular domain.Novel receptors are therefore more readily identi?ed and they have been utilized as a means to uncover new members of the gp130/IL-6cytokine family.IL-31was identi?ed following the discovery of its receptor,IL-31RA[1](also named as GLM-R[9]or GPL[7]).IL-31is expressed preferentially by activated Th2CD4+T cells,signaling through a hetero-dimeric receptor complex composed of IL-31RA and OSMR b[1].Its pleiotropic effects on the immune system are just beginning to be examined.

2.Discovery of IL-31and IL-31receptors

The gene encoding human IL-31is located on chromo-some12q24.31and the mouse ortholog is situated in a syntenic region of chromosome5.The IL-31cDNA is composed of an open reading frame encoding a164amino acid(aa)precursor and a predicted141aa mature polypeptide containing the four a-helix structure[1].Based on overall length and secondary structure,IL-31is suggested to belong to the short-chain cytokine group,although it has no apparent sequence homology to other known four helical-bundle cytokines[1,10].At amino acid level,mature mouse IL-31protein shares31%identity with its human counter-part[1].However,there is no cross-species activity,i.e., mouse IL-31fails to interact with human IL-31receptor and vice versa[11].Dillon et al.cloned IL-31gene using a functional cloning approach,based on the proliferation of cells bearing the novel IL-31RA and other known receptors of the gp130family[1].IL-31mRNA is preferentially but not exclusively expressed by Th2CD4+T cells after activation[1],and by skin-homing CD45RO+(memory) cutaneous lymphocyte-associated antigen(CLA)-positive T cells in patients with atopic dermatitis[12].IL-31mRNA was also found in testis,bone marrow,skeletal muscle, kidney,colon,thymus,small intestine,trachea[1]and dorsal root ganglia[13].

IL-31RA is a novel type I cytokine receptor that mediates IL-31signaling when coupled with OSMR[1].The IL-31R was discovered independently by three research groups using bioinformatic tools to search gene databases for novel cytokine receptors that share the conserved structural motifs of a type I cytokine receptor.Ghilardi et al.scanned the public database for putative cytokine receptors and a cDNA encoding full-length human gp130-like monocyte receptor (GLM-R)was subsequently cloned from a pooled tissue cDNA library.Murine GLM-R was obtained by a combina-tion of cross-species library screening and PCR cloning from a murine spleen cDNA library[9].

Diveu et https://www.doczj.com/doc/7717579675.html,ed gp130cDNA sequence to screen the human genomic database at NCBI.cDNAs encoding a novel cytokine receptor were isolated from the U937myelomo-nocytic and the GO-G-UVM glioblastoma cell lines. According to its homology to gp130,this novel cytokine receptor was named gp130-like receptor(GPL)[7].

When searching the translated human genomic sequence database with known cytokine receptor sequence,Dillon et al.identi?ed an exon encoding part of a leukemia inhibitory factor receptor-like(LIFR-like)cytokine recep-tor.Subsequent cDNA cloning from activated peripheral blood mononuclear cells(PBMC)produced four splice variants of a type1cytokine receptor,which were later named as IL-31RAv1–v4.They also isolated two splice variants of mouse IL-31RA from a mouse testis cDNA library[1].Next,Dillon et al.constructed a series of BaF3 cell lines expressing human IL-31RA alone or in combina-tion with gp130,IL-12R b1,IL-12R b2,IL-27RA(WSX-1), IL-23R or OSMR.They assayed each cell line for proliferation in response to conditioned media from activated human peripheral T cells or from an activated T cell line CCRFCEM,and found that only the cells expressing GPL together with OSMR were able to proliferate in response to a soluble factor in the conditioned media,which was identi?ed to be IL-31.Furthermore,the addition of an anti-OSMR antibody to the cultures abrogated the proliferation of BaF3cells in response to IL-31[1]. Hence,the functional receptor complex for IL-31is composed of IL-31RA and OSMR.

3.Characterization of IL-31receptors

IL-31RA belongs to the gp130-subfamily of type I cytokine receptors.It displays28%amino acid identity with the common receptor component glycoprotein130(gp130) shared by the IL-6family of cytokines,but lacks the Ig-like domain present at the N-terminus of gp130[1,7,9].Human IL-31RA gene is located on5q11.2,only24kb downstream of gp130,with opposite transcriptional orientations to each other[7,9].To date,IL-31receptor exists in several different

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isoforms as follows:GPL560,GPL610,GPL626,GPL745, CRL3,GLM-R and IL-31RAv1–v4[1,7,9](Fig.1). GPL560,GPL610,GPL626and GPL745consist of560 aa,610aa,626aa and745aa,respectively[7].CRL3is the soluble form of GPL that only encodes its truncated509aa extracellular domain[7,14].IL-31RAv1,v2,v3,and v4 contain649aa,324aa,764aa and662aa,respectively[1]. GLM-R was initially reported to have732aa[9],but now has been revised to include the additional32aa upstream, making it100%identical with IL-31RAv3.IL-31RAv1and IL-31RAv2all have a potential hydrophobic signal peptide of19aa[1].GPL560,GPL610,GPL626and GPL745all include a signal peptide of33aa[7].The signal peptides of GLM-P/IL-31RAv3and IL-31RAv4consist of51aa and32 aa,respectively[1].After the signal peptides,GLM-R/IL-31RAv3,GPL610,GPL626,GPL745,IL-31RAv1and IL-31RAv4all have the characteristic features of type I cytokine receptors:a cytokine receptor homology domain with two pairs of conserved cysteine residues and a WSDWS signature motif,followed by three?bronectin type III-like domains and a single transmembrane region connected to an intracellular tail.Within the cytoplasmic tail,there is a box-1 motif typically involved in the association with cytoplasmic tyrosine kinases of the Jak family.GLM-R/IL-31RAv3and GPL745are different from each other only in signal peptides.They contain three additional tyrosine residues in the cytoplasmic tail,which serve as docking sites for downstream signaling molecules with SH2domains[1,7,9]. GPL560only has extracellular and transmembrane domains, whereas CRL3and IL-31RAv2are two soluble receptors without transmembrane region[1,7].Additional studies determined that only GLM-R/IL-31RAv3,GPL745and IL-31RAv4can transduce an intracellular signal[1,7,9].In mouse,IL-31RA is separated by only19kb from gp130in a syntenic region on mouse chromosome13[7].It has two splice variants.One is homologous to human IL-31RAv4, and the other is a soluble form consisting of the cytokine-binding domain(CBD)and?bronectin type III domains. Full-length mouse IL-31RA shares61%identity with the human IL-31RA in amino acid sequence[1].

Northern blot experiments showed that constitutive expression of human and mouse IL-31RA mRNA can be detected in skin,brain,lung,trachea,skeletal muscle,testis, ovary,prostate,placenta,spleen,thymus,bone marrow and blood leukocytes[1,7].In addition,some human cell lines also express IL-31RA,for instance glia-derived cell lines GO-G-UVM and U87MG,melanoma cell line A375, myelomonocytic cell lines U937and THP1[7].Human IL-31RA mRNA,although undetectable in fresh peripheral blood monocytes,is upregulated substantially in monocytes cultured with Interferon-g(IFN-g)[1].OSMR mRNA is more ubiquitously expressed,with the highest levels in trachea,thymus and skin.OSMR mRNA expression can be induced in monocytes treated with lipopolysaccharide (LPS).Thus,IFN-g and LPS together induce the expression of both receptor chains of IL-31R in human monocytes[1] (Fig.2).The expression pro?le of functional IL-31R on mouse immune cells is less clear.One study showed that, compared to wild type counterparts,CD4+T cells from IL-31RAà/àmice proliferate stronger and secrete more Th2 cytokines when stimulated under neutral or Th2conditions, suggesting the presence of IL-31R on mouse CD4+T cells [15].Nevertheless,the kinetic expression of functional IL-31R on different T cell subsets and antigen-presenting cells, under resting and activation conditions,warrants further detailed study.

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Fig.1.Isoforms of human and mouse IL-31RA.S,signal peptide;CBD,cytokine-binding domain;FnIII,?bronectin type III;TMD,transmembrane domain; Box1/2,cytoplasmic box1and box2signaling motifs;Y,location of tyrosine in the cytoplasmic domain.GLM-R and IL-31RAv3are exactly the same.GPL745 differs from GLM-R only at the signal peptide region with GPL745shorter for19aa.IL-31RAv4starts at the same aa with CRL3and GPL745.GenBank accession numbers:IL-31RAv1,AY499339;IL-31RAv2,AY499340;IL-31RAv3,AY499341;IL-31RAv4,AY499342;GLM-R,NM_139017;CRL3, AF106913;mIL-31RAv1,AY509150;mIL-31RAv2,AY509151.

The receptor chains of the IL-6family have a modular organization containing in their extracellular part at least one Ig-like domain,at least one CBD with conserved cysteine positions and a WSXWS motif,and FnIII domains [16–18](Fig.1).Structural analyses of this receptor family revealed that high af?nity binding of the cytokine to its receptor complex involves on one side the CBD of a ?rst receptor subunit and on the other side the Ig-like domain of the second receptor component [17–21].The IL-31RA is devoid of Ig-like module and binds IL-31through its CBD.Although OSMR may also recognize IL-31through its Ig-like domain,immunoprecipitation experiments suggest that IL-31binds predominantly to IL-31RA but not OSMR in the IL-31R complex [22].OSMR nevertheless increases IL-31binding when coupled with IL-31RA [22].In this regard,IL-31is very similar to OSM.In human,OSM (as well as LIF)binds to the common LIF/OSM type I receptor complex composed of the gp130and LIF receptor b (LIFR b )subunits.In addition,human OSM also speci?cally recognizes a type II receptor in which the gp130receptor chain is associated with the OSMR b -chain [23–25].In mouse,OSM and LIF do not share functional receptors,and OSM is only recognized by the type II receptor gp130–OSMR b complex [26–28].Regardless of the species difference and unlike the other family members,OSM and IL-31are similar in that both show predominant binding to gp130or its high homology relative GPL (IL-31RA)over individual LIFR or OSMR,which are only converted into high-af?nity receptors after forming hetero-dimer complexes [22–25].Although IL-31and OSM do not

appear to cross-activate the receptor of each other,as indica-ted by receptor transfection and immunoprecipitation assays [22],it will be of interest to further study to what extent IL-31and OSM share similar intracellular signaling pathways.

4.Signal transduction pathways of IL-31

Initial Northern blot and PCR experiments showed that IL-31RA is abundantly expressed in tissues involved in reproduction,in spleen,thymus,lung,skin and trachea,and in cells of myelomonocytic lineage [1,7,9].These tissues are also normally positive for OSMR,and thus potentially responsive to IL-31.However,Diveu et al.reported that in human only the longest form (GPL745)contains full signaling capacity whilst the truncated form (GPL560)that lacks Jak binding box 1motif serves as a dominant negative [22].Given the fact that a mere two-fold expression in favor of GPL560over GPL745strongly neutralizes the signals of the latter,it would be prudent to re-evaluate the tissue expression pro?les of signaling vs.antagonizing IL-31RA isoforms in determining IL-31responsiveness.4.1.MAPK and PI3K/AKT pathways

The extracellular signal regulated kinase (ERK)1/ERK2MAP kinases play important roles in mediating the mitogenic effects of the IL-6family members [29].The study in glioblastoma cell line expressing both IL-31RA and

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350Fig.2.Interleukin-31is produced mainly by activated CD4+T cells,and targets a broad range of cells expressing IL-31RA and OSMR.Monocytes express IL-31RA and OSMR when activated by IFN-g and LPS.Constitutive expression of both receptor units is found in many tissues.

OSMR showed that stimulation of the cells with IL-31quickly increased MAPK phosphorylation [22].Never-theless,IL-31RA or OSMR alone is insuf?cient to activate ERK1/2.In this signaling pathway,it seems that IL-31RA contributes only indirectly by cytokine binding and recruitment of OSMR,whereas the important MAPK-activating activity exclusively relies on the signal-transdu-cing partner of receptor OSMR [14].

This theme is reiterated in the activation of PI3K/AKT pathway.When the IL-31RA/OSMR complex is activated by IL-31,a slight but signi?cant tyrosine phosphorylation of PI3K (phosphoinositide-3-kinase)and a marked increase of AKT phosphorylation could be observed [22].Yet,tyrosine-phosphorylated IL-31RA itself is incompetent in recruiting tyrosine phosphatase SHP-2and the adaptor protein Shc,both of which are recruited by OSMR [14].4.2.Jak/STAT pathway

IL-31can activate Janus kinase (Jak)1and Jak2signaling molecules after binding to its receptor complex.Once activated,Jaks are known to stimulate the phosphorylation of downstream signaling molecules signal transducer and activator of transcription (STAT)-3,STAT-5and to a lesser degree STAT-1[1,7,14](Fig.3).Dillon et al.showed that STAT-1,STAT-3and STAT-5were activated in transfectants expressing IL-31RA and OSMR,but cell lines and primary cells expressing native receptors signaled mainly through STAT-3[1].

Except for the expression of dominant negative isoforms of IL-31RA,intracellular molecules responsible for ?ne-tuning IL-31signaling are not well-studied.It is known that STAT signaling can be negatively regulated through the following three main mechanisms:(1)dephosphorylation of Jaks or STATs by various protein tyrosine phosphatases;(2)inactivation of Jaks by the suppressor of cytokine signaling (SOCS)proteins;and (3)inhibition of the transcriptional

activity of STATs by protein inhibitor of activated STAT (PIAS)proteins (for review,see ref.[30]).PIAS1and PIAS3function to block the DNA-binding activity of STAT-1and STAT-3,respectively [31,32],whereas PIAS4suppresses STAT-1transcriptional activity without interfering its DNA-binding capacity [33].Regulation by PIAS proteins may ?ne-tune the signals from diverse cytokines that converge at STAT activation.For example,we found that IL-31and LIF

each regulated distinctive sets of PIAS proteins in na?

¨ve mouse CD4+

T cells differentiated into Th1and Th17cells (Fig.4).Compared to medium control,LIF inhibited PIAS1,PIAS3,and PIAS4induction under Th1condition,whereas

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351

Fig.3.Interleukin-31acts through three signaling pathways:Jak/STAT pathway,PI3K/AKT pathway and MAPK

pathway.

Fig.4.IL-31and LIF regulate distinctive sets of PIAS proteins in mouse CD4+T cells differentiated into Th1and Th17cells.Puri?ed mouse CD4+T cells were stimulated with plate-bound anti-CD3(10m g/mL)and soluble anti-CD28(1m g/mL)in the presence of various cytokines and neutralizing antibodies.Th0:anti-CD3/28only;Th1:+IL-12+anti-IL-4;Th2:+IL-4+anti-IFN-g ;Th17:+TGF-b +IL-6+anti-IL-4+anti-IFN-g ;induced regulatory T cells (iTreg):+TGF-b .TGF-b was added at 1ng/mL.All the other cytokines were added at 50ng/mL.Neutralizing antibodies were added at 10m g/mL.PIAS messages are compared by real-time PCR after 3days.

IL-31inhibited PIAS1,PIAS3,and PIAS4induction under Th17condition.IL-31even induced more than two-fold PIAS4in Th1cells.By real-time PCR,we also found that LIF inhibited the transcription of IFN-g in Th1cells,but not IL-17A/F in Th17cells;whereas IL-31increased IFN-g message in Th1cells,and dramatically inhibited IL-17A/F mRNA synthesis in Th17cells(manuscript in preparation). These polar opposite effects by IL-31and its related family member LIF offer a platform to further study in greater detail the signals from STAT,PIAS to downstream molecules that shape the differentiation of T helper subsets.

5.Biological activities of IL-31

5.1.Regulation of cell proliferation and hematopoiesis

In vitro,the effect of IL-31on cell proliferation is cell type-,cell density-and cytokine concentration-dependent. Although IL-31was originally identi?ed to stimulate the proliferation of BaF3cells(a mouse pro-B cell line),a recent study demonstrated that IL-31is highly effective in suppressing the proliferation of lung epithelial cells by up-regulating p27Kip1and down-regulating cyclin B1, cdc2,cdk6,mcm4and Rb[34].In the colorectal cancer cell line HCT116,IL-31at high doses signi?cantly suppresses cell proliferation when the cell density is low.However,it loses antiproliferative activity and even stimulates cell proliferation when the cell density is high[35].It is likely that additional signals from different cell types modulate IL-31activity in cell proliferation.

Helical cytokines and their receptors play important roles in regulating hematopoiesis in vivo.Oncostatin M,a cytokine sharing a receptor subunit with IL-31,is implicated in the homeostasis of myeloid progenitor cells(MPC)[36]. Compared to wild type animals,OSMRà/àmice have reduced frequencies of erythroid and megakaryocyte pro-genitors in bone marrow[37].IL-31signals through STAT-3 and STAT-5,the activation of which by a number of cytokines has already been shown to be required for hematopoiesis. Direct evidence on IL-31regulation of hematopoiesis came from the studies comparing IL-31Rà/àmice and their littermate wild type controls,which showed that IL-31R de?ciency signi?cantly decreased absolute numbers and cycling status of immature subsets of hematopoietic progenitor cells(HPC)in bone marrow and spleen[11]. Thus,IL-31and its receptors are positively involved in the regulation of hematopoietic progenitor cell homeostasis. 5.2.Induction of cytokines and chemokines

Study in normal human epidermal keratinocytes (NHEKs)showed that several chemokine genes were induced(3–9.5-fold)in the cells stimulated with human IL-31,including those encoding GRO1-a(CXCL1),TARC (CCL17),MIP-3b(CCL19),MDC(CCL22),MIP-3(CCL23),MIP-1b(CCL4)and I-309[1].Another studies in human colonic subepithelial myo?broblasts(SEMFs)and bronchial epithelial cells also showed that IL-31stimulated secretion of proin?ammatory cytokines,chemokines and matrix metalloproteinases(MMPs)[38,39].These data indicate that IL-31may function as a proin?ammatory cytokine involved in recruitment of polymorphonuclear cells,monocytes and T cells to an in?ammatory site in vivo.

5.3.Regulation of in?ammation and immune response

Both subunits of IL-31receptor are expressed in human monocytes activated with IFN-g and LPS[1].LPS activates cells through Toll-like receptor4and is required for adaptive Th1responses[40],but can also induce a Th2response in a mouse model of allergic sensitization[41,42].Our own in vitro observation indicates that IL-31can positively and negatively affect Th1and Th17differentiation in an APC-free system(Fig.4).These data suggest a potential function for IL-31in regulating immune responses through modulating antigen-presenting cells or more directly T cell themselves.

In a recent study,investigators found that after intravenous injection of Schistosoma mansoni eggs,IL-31RAà/àmice developed more severe pulmonary in?am-mation,characterized by enlarged area of granulomatous in?ammation,increased number of cells positive for resistin-like molecule a,and enhanced collagen deposition, than wild type animals[15].Under neutral or Th2-polarizing conditions,IL-31RAà/àT cells produced signi?cantly more IL-4,IL-5and IL-13than their wild type counterparts. When co-stimulating T cells under Th2-polarizing condi-tion,IL-31RAà/àmacrophages exhibited enhanced acces-sory function compared to wild type cells.In contrast,the generation of CD4+T cell-mediated Th1responses was normal in IL-31RAà/àmice.These data implicate IL-31/ IL-31R signaling as a negative regulatory pathway that speci?cally limits type2in?ammation[15].However,one potential caveat of the study is that the effects on Th subset differentiation were not examined under the in?uence of exogenously added IL-31cytokine.As IL-31is mainly produced by activated Th2cells,lack of in vitro effect by IL-31RA de?ciency in non-Th2subsets does not necessarily exclude the possibility that these cells can be affected by Th2-derived IL-31in vivo.In addition,these?ndings were based on an acute model of type2in?ammation in the lung, whether this pathway in?uences pathologic consequences of chronic type2in?ammation such as?brosis and tissue remodeling will require further investigation.

6.Role of IL-31in diseases

6.1.IL-31in dermatitis

It is well established that T cell-mediated in?ammation plays a major role in the development of most skin

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diseases,including atopic dermatitis(AD),allergic contact dermatitis(ACD),and psoriasis.Atopic dermatitis is a chronic relapsing in?ammatory skin disease characterized by skin lesions with‘licheni?cation’,pruritic excoriations and a susceptibility to cutaneous infections[43].Atopic dermatitis is mediated by T cells,characteristic with a predominant Th2type response[44],and is often associated with other Th2-mediated allergic diseases such as asthma[43].Transgenic mice over-expressing IL-31or wild type mice administrated with recombinant IL-31 protein all developed a notable skin phenotype that closely mimicked that of patients with atopic dermatitis[1]. Higher levels of IL-31expression were found in biopsy specimens taken from patients with atopic dermatitis than those from healthy individuals[12,45].These data imply an important role for IL-31in the pathogenesis of atopic dermatitis.

An examination of IL-31mRNA expression in NC/Nga mice as an animal modal of atopic dermatitis showed that the expression of IL-31mRNA in the skin of NC/Nga mice with scratching behavior was signi?cantly higher than that in NC/ Nga mice without scratching behavior[46,47].Comparison of IL-31mRNA expression in healthy individuals and in patients with pruritic or nonpruritic in?ammatory skin diseases showed that human IL-31was over-expressed in the pruritic atopic dermatitis but not in the nonpruritic psoriatic lesions[13].Notably,lesional skin of patients with prurigo nodularis,one of the most pruritic forms among in?amma-tory skin diseases,showed the highest levels of IL-31mRNA expression[13].These results suggest that IL-31mainly plays a role in inducing pruritus but not in directly causing lesions per se.The development of lesions may arise over time from the excessive scratching behavior of the patients [13].

In unstimulated PBMCs from patients with atopic dermatitis,IL-31levels did not differ from those in PBMCs from healthy,nonatopic controls.However,after staphylococcal enterotoxin B(SEB)or anti-CD3stimula-tion,PBMCs from patients with atopic dermatitis expressed higher levels of IL-31mRNA compared with nonatopic subjects[13].Recently,an IL-31gene haplotype has been identi?ed to be linked to the genetic susceptibility to nonatopic eczema.Upon activation, PBMCs from individuals homozygous for this haplotype produced3.8-fold more IL-31than those from hetero-zygous carriers[48].These observations suggest that PBMCs from susceptible individuals have an increased tendency to produce higher levels of IL-31in response to superantigen stimulation or polyclonal activation,which may contribute to the development of pruritus in these patients.

In human keratinocytes,IL-31induces several chemo-kine genes that have been associated with atopic skin in?ammation such as CCL1,CCL17,and CCL22[1]. Hence,elevated levels of IL-31in atopic dermatitis lesions may enhance skin in?ammation through the induction of chemokines,which subsequently lead to the recruitment of T cells.In turn,activated skin-in?ltrating T cells may become new sources of IL-31,thereby amplifying atopic skin in?ammation and pruritus.

Analysis of the tissue distribution of IL-31receptor heterodimer revealed that IL-31RA transcripts are most abundantly expressed in dorsal root ganglia of63different human tissues,where the cell bodies of primary sensory neurons reside[13].This?nding is particularly interesting because the sensation of itch,similar to pain,is directly mediated by unmyelinated C?bers of primary sensory neurons whose cell bodies reside within dorsal root ganglia[49,50].Similar to IL-31RA,several cytokine and chemokine receptors have been detected in dorsal root ganglia,and signaling through these receptors is thought to contribute to hyperalgesia during in?ammation[51–53].Moreover,functional OSMR,the other essential receptor subunit for IL-31signaling,has been detected on a speci?c subset of nociceptive neurons in dorsal root ganglia[54,55],which project to the dermis of the skin [55].These data suggest that IL-31might induce pruritus by directly modulating the function of sensory neurons. Alternatively,IL-31may exert its pruritic effects via indirect activation of IL-31R-expressing keratinocytes, which may induce a yet unknown keratinocyte-derived mediator that subsequently activates unmyelinated C ?bers in the skin[56].Regardless the mechanism,IL-31 and the IL-31R are promising targets for the treatment of in?ammatory and itchy dermatoses such as atopic dermatitis.

6.2.IL-31in in?ammatory bowel disease

Colorectal cancer derived intestinal epithelial cell(IEC) lines express both subunits of the IL-31receptor,while their expression in unstimulated primary murine IEC is low.LPS and the proin?ammatory cytokines TNF-a,IL-1b and IFN-g can increase IL-31,IL-31RA and OSMR mRNA expression. IL-31can mediate ERK1/2,AKT,STAT-1and STAT-3 activation and enhance IL-8expression in IEC[35].There are reports showing that activation of AKT and STAT proteins mediates IEC proliferation and migration[57–60]. Likewise,IL-31shows chemotactic properties and increases IEC migration.In addition,IL-31can effectively induce chemokines[IL-8,GRO-a(growth-related oncogene-a), MCP-3(monocyte chemoattractant protein-3),CXCL3, CCL13and CCL15],proin?ammatory cytokines(IL-6,IL-16and IL-32)and matrix metalloproteinases(MMP-1, MMP-3,MMP-25and MMP-7)in human colonic sub-epithelial myo?broblasts.The effects of IL-31are compar-able to IL-17A,and these two cytokines show additive effects in stimulating the secretion of cytokines and chemokines[38].These data suggest a role for this cytokine in the pathogenesis of IBD by promoting proin?ammatory gene expression and modulating IEC barrier function [35].

Q.Zhang et al./Cytokine&Growth Factor Reviews19(2008)347–356353

6.3.IL-31in airway hypersensitivity

Bronchial and alveolar epithelial cells,pulmonary ?broblasts and macrophages are the primary targets of IL-31in the lung [61].IL-31can signi?cantly elevate the gene and protein expressions of epidermal growth factor (EGF),vascular endothelial growth factor (VEGF)and monocyte chemoattractant protein-1(MCP-1/CCL2)in human bronchial epithelial cells in a time-and dose-dependent manner [39].The activation of MAPKs is crucial for IL-31induced bronchial in?ammation.Serum concen-trations of IL-31in allergic asthmatic patients,but not control patients,were signi?cantly higher than those in normal control subjects (50.15pg/ml vs.10.01pg/ml,P <0.001)[62].These observations suggest IL-31may play a pathogenic role in airway hypersensitivity.

7.Perspectives

The production of IL-31mainly by CD4+

T helper cells,and the broad spectrum of its receptor expression on immune-and non-immune cells suggest that this novel cytokine may have potential multiple,pleiotropic phy-siological functions (Fig.5).Several studies now support a role for IL-31in dermatitis and epithelial pathologies [1,13,15,45–47].However,how IL-31acts in concert with known mediators of pruritus/dermatitis,such as IL-4,IL-7,histamines and neuropeptides,remains to be determined.A precise understanding of the involvement of this novel cytokine in the development of these diseases is critical for more effective strategies for disease intervention.

The gene cluster for the cytokine receptors of IL-6family is very conserved during evolution.IL-31RA displays homology with Dome,a cytokine receptor in Drosophila.The CBDs and FnIII domains of IL-31RA and Dome are 29.7%similar,suggesting that they may evolve from a common ancestor [7].It is noteworthy that Dome and its ligand,UPD,play important functions in Drosophila embryonic segmentation and maintenance of the niche for germ-line stem cells in the follicles and testis [63,64].Interestingly,IL-31RA transcripts are also present in ovary,prostate,and placenta.Furthermore,very high level of

human IL-31RA mRNA expression is detected in testis [1,7].The tissue distribution and protein homology between human IL-31RA and Drosophila receptor Dome suggest that the IL-31/IL-31R pathway might have important functions in mammalian reproduction as well.Given the lack of a gross phenotype in naive IL-31RA à/àmice [1,15],it is likely that some other immune mediators may have redundant functions with IL-31and could compensate the loss of IL-31RA signaling.

Elucidation of the biological activities of IL-31has only just begun.Further investigation of its signal transduction pathways and in vivo functions will undoubtedly result in a better understanding of the intricate regulation of the immune system,and the role of this cytokine in health and disease.

Competing interest statement

The authors declare that they have no competing ?nancial interests.

Acknowledgements

This work was supported by grants from National Science Foundation of China (grant no.30371307,Q.L.)and Juvenile Diabetes Research Foundation (1-2007-551and 5-2007-690,W.G.)

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1998;12:3252–63.

Qing Zhang is a graduate student in Dr.Liu’s lab

at Sichuan University in China,studying the role

of IL-31in animal

models.

Prabhakar Putheti,M.Sc.Ph.D.,got his M.Sc.

in biochemistry in India(1998–2000)and subse-

quently moved to the Karolinska Institute,Stock-

holm,Sweden for Ph.D.study(2001–2004).His

thesis was on the role of human CD4+CD25+

regulatory T cells in multiple sclerosis(MS).He

is currently working as a postdoctoral fellow in Dr.

Terry B.Strom’s lab,where he is developing a

molecular signature of transplant

rejection.

Qiang Zhou studied immunology earning his

Ph.D.in2003at the Peking University,China.

He did postdoctoral research with Dr.Bryon

Johnson at the Medical college of Wisconsin,

WI from2004to2006,and then joined the group

of Dr.Wenda Gao in Transplant Research Center

at Beth Israel Deaconess Medical Center,Har-

vard Medical School in2007.Mechanisms and

modulation of Treg differentiation are his major

research

interest.

Quansheng Liu,Ph.D.,is currently an Associate

Professor in Sichuan University in China.He

received postdoc training in Stanford University

on the role of24p3(NGAL)in in?ammation.

Through the years,Dr.Liu and Dr.Gao have

collaborated in multiple areas in translational

medicine,particularly in the cytokine effects

on in?ammation and

diseases.

Wenda Gao,Ph.D.,is currently an Assistant

Professor in Medicine at Beth Israel Deaconess

Medical Center,Harvard Medical School.He got

his Ph.D.from Tufts University School of Med-

icine,and received postdoc training in Dr.Terry

B.Strom’s lab at Harvard Medical School on

negative co-stimulation and transplantation tol-

erance.He is now studying the role of graft-

protecting regulatory T cells(Treg)and graft-

destroying Th1/Th17cells in transplantation.In recent years,he and collaborators have published a series of papers in Nature,Nature Medicine,Journal of Experimental Medicine,Journal of Clinical Investigation,and American Journal of Transplantation,describing the effects of pro-in?ammatory cytokines on the development of Treg and Th17cells.Particularly,he is interested in the role of IL-6family cytokines in CD4+T helper subset differentiation.

Q.Zhang et al./Cytokine&Growth Factor Reviews19(2008)347–356 356

检测机构通用要求培训试卷

RB/T 214:2017检验检测机构资质认定能力评价检验检测机构通用要求培训考核试卷部门:姓名:成绩: 一、判断题(每题4分,共40分) 1、检验检测机构中所有可能影响检验检测活动的人员,无论是内部还是外部人员,均应行为公正,受到监 督,胜任工作,并按照管理体系要求履行职责。() 2、设备出现故障或者异常时,检验检测机构应采取相应措施,如停止使用、隔离或加贴停用标签、标记, 直至设备技术工程师维修完好,表明能正常工作为止。() 3、检验检测机构不得使用同时在两个及以上检验检测机构从业的人员。() 4、检验检测标准或者技术规范对环境条件有要求时或环境条件影响检验检测结果时,应监测、控制和记录 环境条件。当环境条件不利于检验检测的开展时,应停止检验检测活动。() 5、检验检测机构应对检验检测结果、抽样结果的准确性或有效性有影响或计量溯源性有要求的设备有计划 地实施检定或校准,不包括用于测量环境条件等辅助测量设备。() 6、检验检测机构应建立和保持记录管理程序,确保每一项检验检测活动技术记录的信息充分,确保记录的 标识、贮存、保护、检索、保留和处置符合要求。() 7、内部审核通常每年一次,由质量负责人策划内审并制定审核方案。若资源允许,内审员应独立于被审核 的活动。() 8、检验检测机构应建立和保持管理评审的程序。管理评审通常12个月一次,由最高管理者负责。() 9、检验检测方法包括标准方法、非标准方法(含自制方法)。应优先使用标准方法,并确保使用标准的有 效版本。在使用标准方法前,应进行验证。() 10、检验检测机构应建立和保持样品管理程序,以保护样品的完整性并为客户保密。检验检测机构应有样品 的标识系统,为确保平行样的一一对应,平行样品标识应与原样品标识相同。()

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Chapter 1: Overview Introduction The Advanced Research WRF (ARW) modeling system has been in development for the past few years. The current release is Version 3, available since April 2008. The ARW is designed to be a flexible, state-of-the-art atmospheric simulation system that is portable and efficient on available parallel computing platforms. The ARW is suitable for use in a broad range of applications across scales ranging from meters to thousands of kilometers, including: ?Idealized simulations (e.g. LES, convection, baroclinic waves) ?Parameterization research ?Data assimilation research ?Forecast research ?Real-time NWP ?Coupled-model applications ?Teaching 简介 Advanced Research WRF (ARW)模式系统在过去的数年中得到了发展。最近公布了第三版,从2008年4月开始可供使用。ARW是灵活的,最先进的大气模拟系统,它易移植,并且有效的应用于各种操作系统。ARW适用于从米到成千上万公里尺度的各种天气系统的模拟,它的功能包括: ?理想化模拟(如,LES,对流,斜压波) ?参数化研究 ?数据同化研究 ?预报研究 ?实时数值天气预报 ?耦合模式应用 ?教学 The Mesoscale and Microscale Meteorology Division of NCAR is currently maintaining and supporting a subset of the overall WRF code (Version 3) that includes: ?WRF Software Framework (WSF) ?Advanced Research WRF (ARW) dynamic solver, including one-way, two-way nesting and moving nest. ?The WRF Preprocessing System (WPS) ?WRF Variational Data Assimilation (WRF-Var) system which currently supports 3DVAR capability ?Numerous physics packages contributed by WRF partners and the research community ?Several graphics programs and conversion programs for other graphics tools And these are the subjects of this document. The WRF modeling system software is in the public domain and is freely available for community use.

检验检测机构资质认定能力评价检验检测机构通用要求(RBT214-2017)

检验检测机构资质认定能力评价 检验检测机构通用要求 1 范围 本标准规定了对检验检测机构进行资质认定能力评价时,在机构、人员、场所环境、设备设施、管理体系方面的通用要求。 本标准适用于向社会出具具有证明作用的数据、结果的检验检测机构的资质认定能力评价,也适用于检验检测机构的自我评价 2 规范性引用文件 下列文件对于本文件的应用是必不可少的。凡是注日期的引用文件,仅注日期的版本适用于本文件。凡是不注日期的引用文件,其最新版本(包括所有的修改单)适用于本文件。 GB/T 19000 质量管理体系基础和术语 GB/T 27000 合格评定词汇和通用原则 GB/T 27020 合格评定各类检验机构运作要求 GB/T 27025 检测和校准实验室能力的通用要求 JJF1001 通用计量术语及定义 3 术语和定义 GB/T19000、GB/T27000、GB/T27020、GB/T27025、JJF1001界定的以及下列术语和定义适用于本文件。 3.1 检验检测机构 inspection body and laboratory 依法成立,依据相关标准或者技术规范,利用仪器设备、环境设施等技术条件和专业技能,对产品或者法律法规规定的特定对象进行检验检测的专业技

术组织。 3.2 资质认定 mandatory approval 国家认证认可监督管理委员会和省级质量技术监督部门依据有关法律法规和标准、技术规范的规定,对检验检测机构的基本条件和技术能力是否符合法定要求实施的评价许可。 3.3 资质认定评审 assessment of mandatory approval 国家认证认可监督管理委员会和省级质量技术监督部门依据《中华人民共和国行政许可法》的有关规定,自行或者委托专业技术评价机构,组织评审人员,对检验检测机构的基本条件和技术能力是否符合《检验检测机构资质认定评审准则》和评审补充要求所进行的审查和考核。 3.4 公正性 impartiality 检验检测活动不存在利益冲突。 3.5 投诉 complaint 任何人员或组织向检验检测机构就其活动或结果表达不满意,并期望得到回复的行为。 3.6 能力验证 proficiency testing 依据预先制定的准则,采用检验检测机构间比对的方式,评价参加者的能力。 3.7

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R B T检测机构通用要求 培训试卷 Company number【1089WT-1898YT-1W8CB-9UUT-92108】

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允许,内审员应独立于被审核的活动。() 8、检验检测机构应建立和保持管理评审的程序。管理评审通常12个月一次, 由最高管理者负责。() 9、检验检测方法包括标准方法、非标准方法(含自制方法)。应优先使用标 准方法,并确保使用标准的有效版本。在使用标准方法前,应进行验证。 () 10、检验检测机构应建立和保持样品管理程序,以保护样品的完整性并为客户 保密。检验检测机构应有样品的标识系统,为确保平行样的一一对应,平行样品标识应与原样品标识相同。() 二、不定项选择题(每题5分,共60分) 1、检验检测机构管理体系至少应包括:() A 质量手册和程序文件、作业指导书、各项实验室记录、资质证书及附 表、营业执照 B 管理体系文件、管理体系文件的控制、记录控制、应对风险和机遇的措 施、改进、纠正措施 C 内部审核和管理评审 D 以上都是 2、管理评审输出应包括以下内容:() A 管理体系及其过程的有效性 B 符合本标准要求的改进 C 提供所需的资源 D 变更的需求

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RB/T 214: 2017检验检测机构资质认定能力评价检验检测机构通用要求培训考核试卷部门:姓名:成绩: 、判断题(每题4分,共40分) 1、检验检测机构中所有可能影响检验检测活动的人员,无论是内部还是外部人员,均应行为公正,受到监 督,胜任工作,并按照管理体系要求履行职责。() 2、设备出现故障或者异常时,检验检测机构应采取相应措施,如停止使用、隔离或加贴停用标签、标记, 直至设备技术工程师维修完好,表明能正常工作为止。() 3、检验检测机构不得使用同时在两个及以上检验检测机构从业的人员。() 4、检验检测标准或者技术规范对环境条件有要求时或环境条件影响检验检测结果时,应监测、控制和记录 环境条件。当环境条件不利于检验检测的开展时,应停止检验检测活动。() 5、检验检测机构应对检验检测结果、抽样结果的准确性或有效性有影响或计量溯源性有要求的设备有计划 地实施检定或校准,不包括用于测量环境条件等辅助测量设备。() 6、检验检测机构应建立和保持记录管理程序,确保每一项检验检测活动技术记录的信息充分,确保记录的 标识、贮存、保护、检索、保留和处置符合要求° () 7、内部审核通常每年一次,由质量负责人策划内审并制定审核方案。若资源允许,内审员应独立于被审核 的活动。() 8、检验检测机构应建立和保持管理评审的程序。管理评审通常12个月一次,由最高管理者负责。() 9、检验检测方法包括标准方法、非标准方法(含自制方法)o应优先使用标准方法,并确保使用标准的有 效版本。在使用标准方法前,应进行验证C () 10、检验检[则机构应建立和保持样品管理程序,以保护样品的完整性并为客户保密C检验检测机构应有样 品的标识系统,为确保平行样的一一对应,平行样品标识应与原样品标识相同。() 、不定项选择题(每题5分,共60分) 1、检验检测机构管理体系至少应包括:() A质量手册和程序文件、作业指导书、各项实验室记录、资质证书及附表、营业执照 B管理体系文件、管理体系文件的控制、记录控制、应对风险和机遇的措施、改进、纠正措施 C内部审核和管理评审 D以上都是 2、管理评审输出应包括以下内容:() A管理体系及其过程的有效性 B符合本标准要求的改进 C提供所需的资源 D变更的需求 3、质量手册中提出的公司质量方针是:() A科学严谨、程序规范、求真务实、潜心钻研 B科学规范、及时准确、客观公正、优质服务 C数据准确、质量保证、履行承诺、优质高效 D态度和蔼、业务精通、纪律严明、接受监督 4、检验检测机构应建立和保持监控结果有效性的程序。检验检测机构可采用以下方式() A运用工作标准与控制图

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WRFChem安装及使用说明手册

WRF-Chem安装及使用说明手册 V1.0 编写者:王彬 2015年6月

目录 1. 引言 (3) 1.1 编写目的 (3) 1.2 背景 (3) 1.3 参考资料 (4) 2. 安装过程 (4) 2.1 设定环境变量 (4) 2.2 WRFV3安装 (5) 2.3 WPS与WRFDA的安装 (6) 3. 使用过程 (6) 3.1 WPS数据准备说明 (7) 3.2 气象初始场的准备说明 (8) 3.3 化学数据前处理程序的使用说明 (8) 3.4 化学数据转化程序的使用说明 (9) 附录1 (prep_chem_sources.inp) (14) 附录2(ncl程序) (18) 附录3(convert.f90) (19)

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RB/T 214 :2017 检验检测机构资质认定能力评价检验检测机构通用要求培训考核试卷姓名:成绩:1、国际标准化组织( ISO)和国际电工委员会( ) 于2017 年 11 月30 日正式发布了《检测和校准实验室能力的》 ( ISO/IEC 17025: )。 2、中国合格评定国家认可委员会( ) 于2018年3月1日正式发布了CNAS-CL01: 《检测和校准实验室能力认可准则》,于2018 年月1 日实施。 3、国家认监委于2017年10 月16日发布了《检验检测机构资质认定能力评价检验检测机构通用要求》 (RB/T -2017 ),该标准吸 纳了新版标准的内容。 4、《检验检测机构资质认定能力评价检验检测机构》 (RB/T214-2017)并于年月1 日正式实施。 5、国家认监委2018年5月11日颁布国认实〔2018〕28 号国家认监委《关于检验检测机构资质认定工作采用相关认证认可行业标准的通知》,要求从2018 年月1 日起启用《检验检测机构资质认定能力评价检验检测机构通用要求》( RB/T214-2017),替代2016 年5月31日国家认监委印发的《国家认监委关于印发 < > 及释义》。 6、国家认监委要求RB/T214-2017与2018年月1 日起为过渡期,年月1 日全面实施 7、俭验检测机构应明确其组织结构及管理、技术运作和支持服务之间

的关系。检验检测机构应配备检验检测活功所需的、、、及服务。 8、检验检测机构应建立识别出现公正性风险的机制。如识别出公正性风险,检验检测机构应能或该 风险。若检验检测机构所在的组织还从事检验检测以外的活动,应识别并避免潜在的利益冲突。 9、检验检测机构不得使用同时在个及以上检验检测机构从业 的人员。 10、检验检测机构应建立和保持保护客户秘密和所有权的程序,该程序应包括存储和传输结果的的要求。检验检测机构及其人员应对其在检验检测活功中听知悉的国家秘密、和技术秘密负有保密义务。并制定和实施相应的 11、检验检测机构中所有可能影响检验检测活动的人员。无论是还是人员,均应行为,受到,胜任,并按照管理体系要求履行12、检验检测机构应确定的管理层,管理层应履行其对管理体系的作用和: 13、检验检测机构的授权签字人应具有及以上专业技术职称或,并经过资质认定部门,非授权签字人签发检验检测报告或证书。 14、检验检测机构应保留人员的相关资格、确认、授权、教育、和的记录,记录包含的确定、人员选择、人员培训、人员监督、人员授权和监控

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7、俭验检测机构应明确其组织结构及管理、技术运作和支持服务之间的关系。检验检测机构应配备检验检测活功所需的、、、及服务。 8、检验检测机构应建立识别出现公正性风险的机制。如识别出公正性风险,检验检测机构应能或该风险。若检验检测机构所在的组织还从事检验检测以外的活动,应识别并 避免潜在的利益冲突。 9、检验检测机构不得使用同时在个及以上检验检测机构从业的人员。 10、检验检测机构应建立和保持保护客户秘密和所有权的程序,该程序应包括存储和传输结果的的要求。检验检测机构及其人员应对其在检验检测活功中听知悉的国家秘密、和技术秘密负有保密义务。并制定和实施相应的 11、检验检测机构中所有可能影响检验检测活动的人员。无论是还是 人员,均应行为,受到,胜任,并按照管理体系要求履行 12、检验检测机构应确定的管理层,管理层应履行其对管理体系的作用和 : 13、检验检测机构的授权签字人应具有及以上专业技术职称 或,并经过资质认定部门,非授权签字人签发检验检测报告或证书。

检验检测机构资质认定能力评价检验检测机构通用要求(RBT214_2017)

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术组织。 3.2 资质认定 mandatory approval 国家认证认可监督管理委员会和省级质量技术监督部门依据有关法律法规和标准、技术规范的规定,对检验检测机构的基本条件和技术能力是否符合法定要求实施的评价许可。 3.3 资质认定评审 assessment of mandatory approval 国家认证认可监督管理委员会和省级质量技术监督部门依据《中华人民共和国行政许可法》的有关规定,自行或者委托专业技术评价机构,组织评审人员,对检验检测机构的基本条件和技术能力是否符合《检验检测机构资质认定评审准则》和评审补充要求所进行的审查和考核。 3.4 公正性 impartiality 检验检测活动不存在利益冲突。 3.5 投诉 complaint 任何人员或组织向检验检测机构就其活动或结果表达不满意,并期望得到回复的行为。 3.6 能力验证 proficiency testing 依据预先制定的准则,采用检验检测机构间比对的方式,评价参加者的能力。 3.7

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word完美格式 管理体系内审检查表(××××年第××次) ××××××××××公司

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