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Interferon-stimulated genes roles in viral pathogenesis

Interferon-stimulated genes roles in viral pathogenesis
Interferon-stimulated genes roles in viral pathogenesis

Interferon-stimulated genes:roles in viral pathogenesis John W Schoggins

Interferon-stimulated genes(ISGs)are critical for controlling virus infections.As new antiviral ISGs continue to be identi?ed and characterized,their roles in viral pathogenesis are also being explored in more detail.Our current understanding of how ISGs impact viral pathogenesis comes largely from studies in knockout mice,with isolated examples from human clinical data.This review outlines recent developments on the contributions of various ISGs to viral disease outcomes in vivo.

Addresses

Department of Microbiology,University of Texas Southwestern Medical Center,Dallas,TX75390,United States

Corresponding author:Schoggins,John W

(john.schoggins@https://www.sodocs.net/doc/683452276.html,)

Current Opinion in Virology2014,6:40–46

This review comes from a themed issue on Viral pathogenesis Edited by Mark Heise

For a complete overview see the Issue and the Editorial

Available online5th April2014

1879-6257/$–see front matter,#2014Elsevier B.V.All rights reserved. https://www.sodocs.net/doc/683452276.html,/10.1016/j.coviro.2014.03.006

Introduction

Interferons(IFN)are secreted cytokines that impact numerous host processes and are well known for their antiviral and antiproliferative properties.Among the three main IFN families,Type I(IFN a/b)and III(IFN l)IFNs are considered the primary antiviral IFNs,although type II (IFN g)has well-characterized antiviral effects[1].IFNs are transcriptionally activated by a highly orchestrated sequence of signaling events composed of viral sensors, adaptor proteins,kinases,and transcription factors (Figure1)[2,3].Newly synthesized IFNs are secreted from the infected cell,bind their cognate receptors,and initiate signaling through the JAK/STAT pathway.The result is the transcriptional induction of interferon-stimu-lated genes(ISGs),which encode direct antiviral effectors or molecules with the potential to positively and negatively regulate IFN signaling and other host responses. Genome-wide transcriptional pro?ling has identi?ed hun-dreds of ISGs[4].Recent functional screening efforts, both ectopic overexpression and gene silencing,have begun to catalog antiviral ISGs and identify targets for mechanistic characterization[5,6,7 ,8 ,9 ,10 ,11–16].For the ISGs that have been characterized,their mechanisms generally target conserved aspects of viral infection. Examples include ISGs that modulate nucleic acid integrity(OAS/RNAse L,ADAR1,and APOBEC family members),virus entry(IFITM3),protein translation (PKR,IFIT family members),and virus egress(BST2/ tetherin)[17].The functions of the majority of antiviral ISGs,however,remain unknown.Indeed,determining the mechanisms of antiviral ISGs is a major goal of future research in innate immunity.Moreover,while these recent screening studies provide targets for mechanistic characterization,an additional question that remains is: do in vitro ISG studies predict physiologically relevant functions of antiviral molecules in vivo?

IFN responses and ISGs in viral pathogenesis The role of IFNs in viral pathogenesis is well established in mice and humans.Both type I IFN receptor knockout (Ifnarà/à)and STAT1knockout(Stat1à/à)mice are highly susceptible to numerous viruses[18–21].Mice with defects in IFN or ISG production,due to genetic ablation of Rig-I,Mda5,cGas,Tlr3,Mavs,Irf1,Irf3,or Irf7 also exhibit enhanced viral pathogenesis[7 ,22–26].Sim-ilarly,humans with inborn de?ciencies in STAT1,TYK2, NEMO,TBK1,TLR3,UNC93B1,TRIF,or TRAF3have defective IFN responses and are often highly susceptible to one or more viral diseases[27].

The disease outcomes in mice and humans with these various genetic de?ciencies strongly implicate IFNs,and by extension,ISGs as primary genes controlling the repli-cation and spread of viruses in vivo.However,of the hundreds of known ISGs,relatively few have been charac-terized in vivo for their contributions to antiviral immune responses.This is likely due to several reasons.First,the breadth of the ISG response was not uncovered until use of genome-wide transcriptional pro?ling over a decade ago [4].Second,until the publication of recent ISG screening efforts,relatively few of the hundreds of ISGs had been characterized for antiviral phenotypes in vitro.Since the decision to carry out genetic studies in mice typically requires strong rationale from validated in vitro studies, in vivo targeting has been limited to a few genes.Third, genes that control IFN production(e.g.,Rig-i/Ddx58)or signaling(e.g.,Stat1)are more attractive targets for genetic ablation in mice since their absence would a priori be predicted to confer strong viral phenotypes.By contrast, deleting a single ISG from a large pool of IFN-induced genes carries an inherent risk of not detecting a viral phenotype due to redundancy in the ISG effector system. Nonetheless,a subset of these downstream ISGs has been targeted for genetic disruption in mice,with promising results(Table1).The data from these studies are providing new insight into ISG speci?city against distinct classes of virus and in unique cell or tissue types.

Available online at https://www.sodocs.net/doc/683452276.html, ScienceDirect

PKR,MX1,OAS-RNase L

Three of the so-called ‘classical ISGs’include:interferon-induced,double-stranded RNA-activated protein kinase (PKR,encoded by Eif2ak2),the myxovirus (in?uenza

virus)resistance 1,interferon-inducible protein p78(MX1or MXA,encoded by Mx1)and the 20,50-oligoade-nylate synthetase/RNase L system (OAS1,OAS2,OAS3,encoded by Oas1,Oas2,Oas3).The mechanisms of these

ISGs in viral pathogenesis Schoggins 41

Figure 1

Current Opinion in Virology

sensor IFN

IFNAR1 & IFNAR2

IL10RB & IL28RA

receptor JAK1, TYK2

STAT1/2IRF9

STAT1/2IRF9

signal transducer transcription factor

transcription factor

adaptor TBK1

IRF3, IRF7

IRF3, IRF7cytoplasm nucleus

IFN ISGs

(PKR, MX1, OAS1, PML ISG15, IFIT1/2/3/5, IFITM1/2/3,RSAD2, CH25H, APOBEC3,SAMHD1, BST2)

MAVS, MYD88

TRIF, STING signal transducer transcription factor transcription factor RIG-I, MDA5, TLR3

cGAS, IFI16, others Overview of the general innate immune response to viral infection.Incoming or replicating viral genomes are detected by viral sensors.Adaptor proteins initiate a signaling cascade that results in activation of transcription factors.Type I/III IFNs and are produced and secreted from the infected cell.They act on neighboring cells through the JAK/STAT pathway,leading to widespread ISG induction.The majority of downstream ISGs that have been targeted for deletion in mice are listed in this figure.

Table 1

Viral pathogenic outcomes in ISG-deficient mice

ISG

Virus

Pathogenic outcome (lethality,titers,or disease)

Eif2ak2/Pkr ,Oas1b ,Rnasel EMCV,VSV,HSV-1,HSV-2,CVB4,MHV,VV,?avivirus Increased

(single or double mutants)SINV,Friend retrovius No difference,subclinical Trim19/Pml LCMV,EMCV,SFV

Increased Isg15

CHIKV,MHV68,HSV-1,FLUAV,FLUBV,SINV,VV Increased LCMV,VSV No difference Zbtb16/Plzf EMCV,SFV

Increased I?t1WNV,HCoV (lacking 20-O-methyltransferase activity)Increased I?t2

VSV,WNV,MHV-A59Increased I?tm3/I?tm locus FLUAV,RSV Increased Rsad2/viperin

WNV,CHIKV Increased FLUAV No difference

Ch25h MHV68

Not determined,increased virus replication Apobec3MMLV,Friend retrovius Increased

Samhd1

HIV-1-based vectors Not determined,increased transduction Bst2/tetherin

MMLV,MCMV,VSV

Mixed,subclinical

Abbreviations :CHIKV,chikungunya virus,CVB,coxsackie virus,EMCV encephalomyocarditis virus,FLUAV,in?uenza A virus,FLUBV,in?uenza B virus,HCoV,human coronavirus,HIV,human immunode?ciency virus,HSV,herpese simplex virus,LCMV,lymphocytic choriomeningitis virus,MCMV,murine cytomegalovirus,MMLV,Moloney murine leukemia virus,RSV,respiratory syncytial virus,SFV,Semliki Forest virus,SINV,Sindbis virus,VSV,vesicular stomatitis virus,VV,vaccinia virus,WNV,West Nile virus.

effectors have been studied for years and are the subjects of recent reviews[28–30].Brie?y,PKR is a known inhibi-tor of cellular and viral mRNA translation,and is involved in a variety of cellular processes including in?ammation and apoptosis.Several members of the OAS enzyme family are activated by double-stranded RNA to catalyze the formation of20,50-oligoadenylates,which activate cellular RNase L to degrade viral genomes.MX1is a dynamin-like GTPase that appears to target viral nucleo-capsids,resulting in viral inhibition prior to the establish-ment of replication.Most inbred strains of laboratory mice are de?cient in functional MX1protein expression and are more susceptible to in?uenza A virus infection than non-laboratory,wild type strains[28].Thus,any ISG knockout made on a standard mouse background must minimally be considered a functional‘double knockou-t’of Mx1and the ISG of interest.

Studies have shown that mice de?cient in RNase L,PKR, or both have a range of pathogenic phenotypes in response to numerous viruses.The viruses tested in these mice include encephalomyocarditis virus[31,32]vesicu-lar stomatitis virus[33–35],herpes simplex virus types1 and2[36–38],coxsackievirus B4[39],West Nile virus [40],murine coronavirus[41],and vaccinia virus[42]. Depending on the study,pathogenic outcomes for many of these viruses typically include increased mortality, higher viremia and/or viral burden in various tissues, and accelerated onset of clinical disease.However,the effects are not universal since Rnaselà/àmice are not more susceptible than wild type mice to retroviral infection [43],and Rnaselà/àx Pkrà/àknockouts exhibit only subclinical phenotypes when infected with Sindbis virus [44].Mice with a natural mutation in Oas1b,the so-called Flv or?avivirus resistance gene[45],are also well charac-terized for their susceptibility to a range of?aviviruses [46,47].Taken together,these in vivo studies establish roles for PKR and the antiviral OAS system in controlling pathogenic viruses,and highlight the virus-speci?c inhibitory nature of these ISGs.

PML and PLZF

The promyelocytic leukemia(PML)protein was origin-ally discovered as part of an oncogenic fusion protein with the retinoic acid receptor alpha in patients with acute promyelocytic leukemia[48].Encoded by Trim19,PML is an IFN-induced protein that organizes the formation of structurally distinct nuclear bodies composed of perma-nent proteins Daxx and SP100,as well as a number of transient proteins such as P53and ATM.PML bodies regulate a wide range of cellular processes,including responses to DNA damage,stress,apoptotic stimuli, and viral infection.Regarding the latter,the antiviral mechanisms of PML in cell culture appear to be varied, depending on the virus.Examples of PML-mediated antiviral function include inhibition of viral transcription, sequestration of viral proteins,and reduction of IFN antiviral ef?cacy.When Trim19à/à(formerly Pmlà/à) mice were challenged with lymphocytic choriomeningitis virus(LCMV),increased viral titers were observed in spleen when compared to wild type mice[49].Trim19à/àmice also exhibited more severe footpad swelling reac-tions after subcutaneous intrafootpad inoculation.When the knockout mice were infected with a hepatotropic strain of LCMV,a pronounced terminal immunpatholo-gical hepatitis that correlated with elevated liver trans-aminase levels was observed.When Trim19à/àmice were infected with a low dose of LCMV by intracerebral inoculation,they exhibited a more severe cytotoxic T cell-mediated choriomeningitis compared to wild type mice.A more recent study has implicated a PML binding protein,the transcription factor PLZF(encoded by Zbtb16),as critical for regulating the expression of a subset of ISGs during the IFN response[50].Zbtb16à/àmice are more susceptible to EMCV infection than wild type mice, and are not protected by IFN treatment prior to Semliki Forest virus(SFV)infection.Accordingly,SFV titers were 3logs higher in numerous organs of Zbtb16à/àmice when compared to wild type.These in vivo studies provide direct evidence that PML and related pathways contrib-ute to controlling viral spread and immunopathological outcomes of certain viral infections.

ISG15

Interferon stimulated gene15,(encoded by Isg15)is a small,ubiquitin-like molecule that has well characterized antiviral properties.A recent,comprehensive review dis-cusses ISG15function,activity,and contributions to innate immune responses in vitro and in vivo[51].In brief,ISG15has numerous antiviral functions including inhibition of virus release,ISGylation of both viral and host proteins,and immunomodulatory cytokine-like properties in its unconjugated form.Isg15à/àmice have been challenged with at least ten viruses,and many of these infected mice showed increased mortality when compared to wild type mice[51,52].Studies in Ube1là/àmice,which lack the ISG15conjugating enzyme,indicate that while ISG15conjugation is required for antiviral activity again some viruses(e.g.,in?uenza virus),it is dispensable for viruses such as CHIKV[51].The com-plexity of ISG15function is highlighted further by the recent identi?cation of humans with inherited ISG15 de?ciency.These patients were found to have increased susceptibility to mycobacterial,but not viral disease,and the phenotypes were correlated with impaired IFN g immunity mediated by secreted ISG15[53 ].ISG15 may be unique in that its role in the immune response is species-speci?c.

IFIT and IFITM families

The interferon-induced protein with tetratricopeptide repeats(IFIT)family and the IFN-induced transmem-brane protein family(IFITM)family have been aggres-sively studied in recent years.These proteins are the

42Viral pathogenesis

subjects of several recent reviews[54–57];thus only highlights of the latest developments with respect to the roles of these effectors in viral pathogenesis will be addressed here.The human and mouse IFIT family consists of IFIT1,IFIT2,and IFIT3,and humans have an additional member not found in mouse,IFIT5.The IFIT family members have a variety of antiviral mech-anisms,including translational inhibition,recognition of viral RNAs that lack20-O methylation,and recognition of viral RNAs that contain50-triphosphates.I?t1à/àmice have been well characterized with respect to enhanced susceptibility to mutant viruses(WNV,poxvirus,and coronavirus)lacking20-O-methyltransferase activity [54].I?t2à/àmice were recently generated and were shown to be highly susceptible to VSV-mediated neuro-pathogenesis and lethality[58 ].When challenged with a neurotropic coronavirus or WNV,I?t2à/àmice showed greater signs of clinical disease,accompanied by increased infection in the central nervous system [59 ,60 ].These studies support a role for I?t2in con-trolling replication and pathogenic outcomes of neuro-tropic viruses and highlight differential in vivo functions for related IFIT family members.

The IFITM family consists of four(human)or six (mouse)proteins,all of which are highly homologous and presumably structurally related.However,they do exhibit preferential antiviral speci?cities that appear to be linked to their mechanisms of action.In general,IFITMs have been shown to inhibit an early viral entry step,with numerous studies implicating virion fusion[54,61–64]. Their speci?city is thought to be dictated in part by the cellular location of virion fusion,for example,late endo-somes or lysosomes.IFITM proteins were originally shown to potently inhibit in?uenza A virus and several ?aviviruses[64],and the list of targeted viruses continues to grow[54].I?tm3à/àmice were recently generated and showed fulminant viral pneumonia and a striking mortality phenotype when challenged with an in?uenza A virus that exhibits otherwise low pathogenicity in wild type mice[65 ].Similar results were obtained with mice that lack the entire I?tm locus[66 ].I?tm3à/àmice have also been shown to be more susceptible to respiratory syncytial virus[67].It should be noted,again,that these laboratory Iftimà/àstrains are also functional Mx1-null mice.The striking pathogenic phenotypes with in?uenza A virus must therefore be considered in the context of this double I?tm/Mx1-null genotype.Of the hundreds of human ISGs that have been tested in vitro for antiviral against in?uenza A virus,IFITM3and MX1appear to be two of the most potent[7 ].Thus,the I?tm/Mx1-null mouse is likely an extreme example of innate ISG-mediated immunode?ciency,at least in the context of in?uenza A virus infection.Notably,IFITM3is one of the few ISG effectors that have been linked to pathogenic outcomes of viral infection in humans.A genetic survey of patients hospitalized with seasonal in?uenza showed enrichment for a minor IFITM3allele(SNP rs12252-C) that generates a splice variant of IFITM3with reduced antiviral ef?cacy[65 ].This human clinical data strongly support the mouse studies and helps solidify IFITM3as an antiviral effector that is critical for controlling patho-genic outcomes of certain viral infections.

RSAD2/viperin

Viperin(encoded by Rsad2)is a radical SAM domain-containing molecule with diverse antiviral activities,most of which appear to tie into lipid biosynthetic or fatty acid metabolic pathways[68,69].In vitro,viperin has been implicated in controlling a number of viruses,including human cytomegalovirus,in?uenza A virus,Sindbis virus (an alphavirus),and?aviviruses such as WNV and dengue virus.In vivo,Rsad2à/àmice have been challenged with in?uenza A virus,WNV,and chikungunya virus(an alphavirus).Lethal challenge with in?uenza A virus showed that viperin knockout and wild type mice were similar with respect to mortality rates,viral titers in lungs, and lung pathology[70].By contrast,Rsad2à/àmice were more susceptible to WNV and CHIKV infection when compared to wild type mice.In a footpad model of CHIKV infection,Rsad2à/àmice did not exhibit enhanced mortality.However,these mice showed higher virus replication in footpad,increased viremia in blood, and more pronounced joint swelling and subcutaneous edema[71].After subcutaneous or intracranial challenge with WNV,Rsad2à/àmice had higher rates of mortality and increased viral replication in brain and spinal cord [72].Thus,with respect to positive-stranded RNA viruses (?avivirus and alphavirus),these in vivo studies largely corroborate some in vitro?ndings.The lack of a distinct phenotype in Rsad2à/àmice after in?uenza A virus in-fection stands in contrast to in vitro studies.This may be due to numerous reasons,including experimental parameters of the in vivo studies,compensatory action of additional ISGs in vivo,or cell type speci?city of viperin action in mice.

25-Hydroxycholesterol and CH25H

The strerol biosynthetic pathway has recently been impli-cated in antiviral immunity.25-Hydroxycholesterol (25HC)is a naturally occurring oxysterol synthesized from cholesterol by the enzyme cholesterol25-hydroxylase (Ch25h in mice;CH25H in humans).Metabolomic and genetic screens independently uncovered25HC as a potent antiviral lipid mediator[73,74 ].25HC modulates lipid composition and likely inhibits virus infection early in the life cycle,at either fusion or at a post-entry step.Indeed, several enveloped viruses are susceptible to25HC-mediated inhibition,but a non-enveloped adenovirus is not.When challenged with murine gammaherpesvirus MHV68,Ch25hà/àmice were more susceptible to infection [74 ].25HC also had direct antiviral effects against HIV-1 replication in a humanized mouse model of infection. These studies establish a role for25HC in suppressing

ISGs in viral pathogenesis Schoggins43

virus replication in vivo.However,additional studies in these mice are needed to evaluate the contribution of CH25H and25HC in controlling viral pathogenesis. Retroviral restriction factors:APOBEC3,SAMHD1,

BST2/tetherin

Of the known IFN-inducible retrovirus restriction factors, several have been targeted for gene deletion in mice, including Apobec3,Samhd1,and Bst2/tetherin.Humans have seven APOBEC3genes,with APOBEC3G being the best characterized with respect to antiviral function. APOBEC3G encodes a cytosine deaminase that restricts HIV-1by deleterious modi?cation of reverse transcribed viral DNA[75].Since mice only have one Apobec3gene,it is presumed that this single gene would confer anti-retroviral activity in mice similar to the human homologs. Indeed,when Apobec3à/àmice were infected with Molo-ney murine leukemia virus(MMLV),they showed higher levels of infection in bone marrow and spleen[76].More-over loss of one or both copies of Apobec3resulted in a more rapid development of T cell leukemia.In a separate study,Apobec3à/àmice were infected with Friend retro-virus,followed by systemic IFN a treatment[77].In wild type mice,IFN treatment signi?cantly reduced viral loads in plasma and proviral loads in spleen and bone marrow,but this effect was compromised in Apobec3à/àmice.Together,these studies suggest that Apobec3con-tributes signi?cantly to IFN-induced antiviral effects against retroviruses in mice.

SAMHD1is a dTNP hydrolase that reduces the concen-tration of intracellular dNTP pools,and this activity is implicated in the ability of SAMHD1to restrict retro-viruses in non-cycling cells[78].Two variants of Samhd1 knockout mice have been generated to assess the role of this effector in controlling retroviral infection in vivo [79,80].Notably,Samhd1à/àmice do not exhibit the severe autoimmune disease that is characteristic of human Aicardi–Goutieres syndrome patients with https://www.sodocs.net/doc/683452276.html,ing different experimental sys-tems and HIV-1-based vectors,both studies show some level of Samhd1-mediated control of HIV-1vector trans-duction.However,pathogenesis in this relatively new mouse model has not been addressed.

Tetherin(encoded by human BST2)is a membrane bound protein that inhibits viral particle release from the cell surface[75].Originally identi?ed to block HIV-1release, tetherin has now been shown to have similar activities against other enveloped viruses[81].Bst2à/àmice were recently generated,and challenged with several viruses [82].Systemic infection of tetherin knockout mice with MMLV resulted in a slightly higher,but not statistically signi?cant,viral burden in spleen compared to wild type mice.Both strains also had similar tissue viral burdens after systemic infection with murine cytomegalovirus or VSV. Surprisingly,local intranasal infection of VSV or in?uenza B virus resulted in lower viral titers in lungs of knockout mice compared to wild type,but only at early time points post-infection.Another unexpected result indicated that Bst2à/àmice secreted less IFN than wild type mice in response to viral challenge,suggesting that tetherin may play a role in IFN induction.While additional pathogenesis studies need to be performed in Bst2à/àmice,this single study highlights a potentially complex phenotype for the antiviral function of tetherin in mice.

Perspectives

In recent years,the pace of discovery of ISG-mediated antiviral mechanisms has rapidly increased.As new anti-viral ISGs are identi?ed and characterized,their contri-butions to immune responses in vivo will need be addressed.While the major genes that modulate IFN production or signaling have been targeted for deletion in mice,relatively few downstream ISG effector knockouts exist.Of those ISGs that have been targeted,most have shown observable phenotypes with respect to viral patho-genesis,although the phenotypes are typically more mod-est when compared to mice lacking major IFN signaling components such as IFNAR1or STAT1.This is not unexpected given the presumed redundancy in the ISG effector system.Additional insight into ISG mechanisms in vivo may be obtained by crossing ISG knockout mice to a Stat1à/àbackground,thereby precluding interference from endogenous IFN signaling.Alternatively,ISG trans-genics,or‘knock-ins’,onto a Stat1à/àbackground may help determine which ISGs are suf?cient to inhibit viruses in vivo.Such an approach would complement current knockout strategies,which mostly assess the necessity of an ISG in host antiviral responses.Moreover,most in vitro and in vivo ISG studies to date have focused on single genes in isolation,either by ectopic expression or gene silencing/ deletion.Moving forward,new approaches to understand the combinatorial nature of ISG interaction networks will be needed.This may be accomplished by proteomic studies in cell culture,or by multiple gene deletions in mice,perhaps via recent CRISPR technologies[83].None-theless,the fact that single ISG deletions have observable pathogenic phenotypes in vivo suggests that these genes do provide critical functions in protecting the host from viral disease.They may,therefore,be valid targets for the development of novel antiviral therapeutics. Acknowledgements

This work was funded in part by NIH Grant DK095031.I thank Neal Alto for a critical reading of the manuscript.

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46Viral pathogenesis

The Belbin Team Roles

What follows are a number of views about Belbin

Belbin according to (Handy 1985) Belbin's original book ("Management Teams - why they succeed or fail") is still in print and is a good place to go to understand his concept. Following the wide acceptance of the Team Roles concept, he later published "Team Roles at Work", exploring the practical application of his ideas in more detail. You can also buy team games that bring out each person's roles, as well as electronic or paper-based questionnaires.

Belbin’s Team Roles as seen by (Cartwright 2002) Belbin saw that an individual had a dual role ?Your own skills ?How you used them in the team Individuals could have a 'secondary' team role they could display if no other team member had the role as their primary one. Allowable weaknesses One of the key concepts in Belbin's work is that of allowable weaknesses. Every team type has its strengths but each also has an 'opposite side of the coin' - weaknesses. Where these weaknesses are such that if they were removed it might also impact on the effectiveness of the strengths then they are allowable and need to be managed rather than removed. An example is the lack of attention to detail in the team type known as a Plant (see later). A Plant - naturally creative as he or she is - can be forced to concentrate on details but the danger is that the creativity will be lost. A more effective solution is to ensure that there is a team member whose strength is attention to detail (A Completer-Finisher) working alongside the Plant as this allows both to play to their strengths. Belbin's eight team roles The eight team types which Dr Belbin and his colleagues originally identified were: ?Co-ordinator ?Plant ?Shaper ?Monitor-Evaluator ?Implementer ?Resource Investigator ?Team Worker ?Completer-Finisher ?Specialist (added later). Co-ordinator (Traits stable, dominant and extrovert). Co-ordinators was originally entitled 'Chairman', a term that was both misleading and would today be considered politically incorrect. It was misleading, as a strong coordinator may well not be the leader of their team. However, it is team leadership that such individuals are best fitted for. The name was later changed to title that better expresses the nature of the team contribution. The Co-ordinator is the one who presides over the team and coordinates its efforts to meet external goals and targets. Co-ordinators are distinguished by their preoccupation with objectives and an ability to include all team members in discussions. Co-ordinators are intelligent but not in any sense brilliant - and not outstanding creative thinkers: it is rare for any of the creative ideas to originate with them. They often display charisma, a concept to be considered in later chapters under leadership. Co-ordinators also possess natural 'people skills.' Co-ordinators are dominant, but in a relaxed and unassertive way - they are not domineering. They may, however tend to be manipulative, but in a covert manner Co-ordinators tend to trust people unless there is very strong evidence that they are untrustworthy and they are singularly free from jealousy.

Men and Women’s Roles in a family

Men and Women’s Roles in a family Family is a very important concept in every culture. People throughout history depended on families. Men and women cooperate with each other and play different roles in a family. In tradition family, definite gender roles existed between men and women. The man worked at an outside job for the family's income, fixed the family car and did the manly "handyman" jobs. The woman stayed at home, cared for children and cooked and cleaned. “Men’s work centers around outside, women’s work centers around the home” described the traditional Chinese family roles exactly. They had a clear division of work and worked together. However, in this relationship women had a lower position than men. This was an obvious manifestation of the inequality between men and women. In recent decades, with the globalization and the cultural exchange, the family roles of men and women in China have changed dramatically. In modern Chinese family, the husband and the wife almost have the equal position. Women also have their own jobs and will not be driven to stay at home. And househusband becomes more and more popular in modern China. This is the positive aspect. However, in many cases, women who work full time are still perceived as having the primary responsibility of caring for the children and home. If one of the children is sick, the mother leaves the office to pick up the child. Women still do more housework than their husbands, although men now do more chores than their fathers did. It’s hard for women to balance work and family. It is clear that in a family the roles of men and women are not sharply separated. However, roles should be clearly identifiable. Individual family members must know and acknowledge their roles and responsibilities. Establishing clear, flexible roles is a key to successful family. Only in this way can we enable the family function steadily and keep the society run effectively.

Man and women's roles in a family

Man and women's roles in a family As we say the man and women's roles in a family, Many people would naturally assume that the traditional role of a man within a family is that of primary breadwinner, while a woman's job is to care for the children. But now, in the wake of development with the society,In earlier generations, men and women both took active roles in commerce and child-rearing. Let's talk about the tradition the roles man and women’s in a family. about ten hundred years ago, Men go out to work, ploughing to earn money to make family to live a better life, The woman weaving at home, Aio Noriko, obey the three obediences and the four virtues, this is a man-dominated society. What is the effect now that the man and women's roles in a family? It is difficult to answer this question separating the role of man and women because they actually should work together in harmony as a unit. Man have the primary role of supporting and sustaining the family and women the role of raising the children, but this simplistic description doesn't really address what is most important. That is that the man and women communicate and plan through inspiration, mutual respect, love, and charity for the development of a rich family life that prepares children to be independent and successful in their own lives.After the children are grown, the process continues mutually working together to serve each other and others gaining greater understanding and preparing for Eternal life.Though man and womens have different skills and characteristics, each of them contributes to the success of a happy home. Both provide an environment that is conducive to learning, living, and loving. The ideal is full, the reality is skinny.Chinese traditional men are superior to women lead to man's increase. At the same time reduce the woman. so, the man called women for “daye”. Not only did man need to make earn life, but also do all housework. It was more than that! AS a man, you need to learn Say sweet words and Remember all kinds of holiday to send women gifts. Only in this way, the family maybe include a women!As a real man, I don’t want to say more ,it is full of tears!

Unit5 Gender Roles课文翻译

变更的性别角色 1.下午六点在巴内特的家庭。亚历克斯和苏珊已经下班回家约 15 分钟。这次轮到亚历克斯做晚饭。现在,苏珊本来可以休息一下,但她在厨房里开始生气。 2.亚历克斯刚刚挂了订购比萨饼的电话----本月第三次。当轮到她做晚饭时,苏珊总是试图准备美味又低脂肪的东西。她希望自己5岁的女儿,伊丽莎,在年轻的时候学会健康饮食。然而,亚历克斯,很少关注她的担忧:“晚饭吃披萨会对伊丽莎有坏处?” 3.争论几分钟后,苏珊意识到有比眼前看到的更多的。“这不是披萨的问题——它只是当你不得不在这里帮忙时总会偷懒的做法” 4.亚历克斯反驳道:"为什么你总是挑剔我怎么做事情?几乎所有我从你那听到的都是我从来没有做的足够在和我做的事情是永远不足够好。在这里我做的很多,我从来没有得到任何表扬!” 5.更多可能,对于我们每一个人这场争论听起来很熟悉。我们生活在一个性别角色正在发生变化时代,我们试着处理我们的生活工作中的关系找出正确的方式解决两性问题,可是没有前路可寻。是什么让两性关系复杂,今天我们的世界40 年前几乎无法想象。 6.今天两性关系呈现一个令人费解的画面。一方面,我们被告知,妇女和男子都迅速成为平等的伙伴在家里和工作场所。随着妇女和男子进入彼此的传统领域,这似乎合乎情理的,我们将终于能够理解彼此的经验。现在,妇女不得不日复一日辛苦工作支撑他们的家庭。他们经常和男人一样瞄准相同的目标,今天是这样,例如,在很多的专业学校女性多于男性。现在妇女肯定能理解她们的丈夫一直觉得的社会压力。 7.随着越来越多的妻子进入工作场所,丈夫不得不承担更多的妇女传统的育儿和家务责任。他们现在似乎可以理解这些责任、无休止的护理和危机。 8.另一方面,我们被告知,我们的社会经历被光年隔开,我们不知道彼此说什么。与此同时,报纸和电视上每天都有关于丈夫和妻子吵架、打架和离婚的报道。 9.在过去40年里,没有明显改变的是男女希望找出适合自己和异性的东西——找到共同生活的方法。改变的是,我们现在不太清楚什么是做一个男人或女人的正确的方式。 10.所以你们,我们,亚历克斯和苏珊每天都在处理性别问题。去年年底,苏珊在工作上被提升为银行副行长。她现在赚的钱比在一家生产农产品的大公司做化验员的亚历克斯多。在保持银行投资有利可图的巨大压力下,苏珊经常加班。她努力工作为了不负众望,亚历克斯不得不做一些家务。当他在职业生涯的头几年受到很大压力的时候,苏珊在家里承担着沉重的负担,所以现在他更加理解她。但正如我们所看到的,有时同情是不足以填平现实和期望之间的鸿沟!

teacher‘s roles

班级:外09.3 姓名:马丽学号:20090541164 Title:Teacher’s Roles and Their Impact upon Middle Student’s Learning Process Thesis Statement: With the development of teaching process, teachers’roles have a great impact on Middle students’ learning English, so teachers should guide students to learn rather than telling everything for them; organize the activities to arouse the interest of students, and facilitate students to learn rather than simply transmitting knowledge. Outline: 1.Introduction 2.There are some problems in traditional English teaching. 3.It is necessary for teachers to change roles in new teaching cource. 4.The roles of teachers in English class and their impact upon the learners. 4.1 Guide students to learn rather than telling everything for them. 4.2 Organize some interesting activities rather than reading textbook directly. 4.3 Facilitate students to learn rather than simply transmitting knowledge. 5. Conclusion Body: Teacher’s Roles and Their Impact upon Middle Student’s Learning Process 1.Introduction Education is a sacred cause vital to the survival, development and civilization of mankind, for its mission is to make men. Being one devoted to this sacred cause, a teacher should be a person with a real sense of commitment and responsibility. He should contribute his talents, ability and efforts to the job of a teacher. He should always prepare the lecture and plan the classroom activities carefully, try to understand the students’ knowledge level, difficulties, and unceasingly improve his teaching to suit and benefit the students so as to achieve optimum teaching result. A teacher should not just read the textbook for students, while students should not listen to what a teacher said to them at the same time, then repeat what they have learned, and do some exercise from time to time. A teacher, therefore, should be one who enlightens the students to learn more than he does. In the teaching process, What

Male and Female Roles

Male and Female Roles In all societies, male and female roles are regarded differently. The mother role is universally carried out by women, which is biologically based. Roles defined by sex also characterize the economic sphere so that the tasks men perform are different from those women perform. This difference is not any outgrowth of the biological differences between men and women. A specific task may be associated with men in one society and with women in another. Milking herd animals, for example, may be women's task in some societies and a man's task in others. Males and females are each associated with different kinds of behavior. These concepts of male and female behavior extended to how people walk, sit, talk and dress. In our society, as in all others, men walk and talk in certain ways and until recently dressed very differently from women. In some societies, different spatial areas are associated with males and females. Women in many Middle Eastern societies are restricted to certain parts of the house and may only come into contact with the males who are members of their family. In such societies, the coffee house and the market are defined as male domains. In contrast, in some West African societies, women most often appear in the marketplace. Sometimes, men choose to carry out female rather than male roles. In some cases, some men dress like women and perform female tasks. On the other hand, females who carry out male roles usually dress and act like men. Because of women's association with mothering and the home, women are associated with the domestic affairs and men are associated with the public affairs. In a number of New Guinea societies, men are associated with the men's house in which they eat and sleep while women are associated with their own dwelling houses. In our own and other Western societies this division was true until the beginning of the 20th century. Politics, the courts, businesses, banks, and so forth were male areas, and so too were the social clubs where real business was carried out. At the beginning of the 20th century, women began to question the assignment of the male and female role. They formed social groups and began to demand the right to vote. They began to move into the business and professional worlds as well. Men regarded the women pioneers in this movement as very manlike. Even today women in business, law or banking wear very tailored, conservative suits to work. As these changes occur in female roles in contemporary American society, men are increasingly taking on child care and domestic tasks.

TWELVE SYSTEMS ENGINEERING ROLES

TWELVE SYSTEMS ENGINEERING ROLES Sarah A. Sheard Software Productivity Consortium 2214 Rock Hill Rd, Herndon VA 22070 sheard@https://www.sodocs.net/doc/683452276.html,, (703) 742-7106 Abstract. Twelve roles are described which are occasionally or frequently assumed to constitute the practice of systems engineering. Some roles fit naturally as life-cycle roles, others fit the Program Management set of roles, while still others are not normally thought of in either group. Interactions between the roles are discussed, and the systems engineering roles assumed by the papers in the inaugural issue of Systems Engineering, the Journal of INCOSE, are compared to these categories. INTRODUCTION Since its inception, INCOSE has been attempting to resolve the question of what, exactly, is systems engineering. Several dualities have been explored, in-cluding whether systems engineers are specialists or generalists, and whether systems engineering is a set o f life-cycle roles, such as the generation of specifications and verification programs, or an overall program man-agement discipline. There has even been a discussion on whether systems engineering is a discipline or an attitude [Mar 92]. Worthy and wise arguments have been put forth on both sides of each issue, leaving some to despair of ever being able to pin down definitions that all can agree on. A local chapter presentation on the value o f systems engineering1 provided the impetus for this paper. The presenters seemed to be talking about entirely different definitions of systems engineering and the roles that systems engineers play. A compilation o f the roles seemed essential to deciding many important questions in the field of systems engineering. A companion paper in this volume, òThe Value o f Twelve Systems Engineering Rolesó [Sheard 96], addresses the value of systems engineering from the point of view of the roles described in this paper. To derive these twelve systems engineering roles, papers in the inaugural issue of Systems Engineering, the Journal of INCOSE, were reviewed for assumptions about roles that systems engineers play. More than sixty descriptions of roles were collected and grouped into the twelve groupings presented below. Then four 1òWhat is the Value of Systems Engineering,ó at the Washington Metropolitan Area chapter, October 10, 1995. Panelists included Dorothy McKinney, Andrew Sage, Dale Langston, and John Snoderly.years of INCOSE symposium proceedings were scanned to ensure that most of the possible systems engineering roles were captured. The intent was to include roles applicable both to the typical DOD and aerospace envi-ronment and to less standard systems engineering environments such as smaller programs and commercial companies. Finally, the Washington Post newspaper?s òHigh Techó classified advertisement section was examined to determine what the world of employers considered systems engineering to be. This paper is organized in four sections. First, the meaning of òsystems engineering rolesó is discussed. Next, twelve systems engineering roles are defined. These roles are then considered in relation to òlife-cycleó and òprogram managementó roles, the two major paradigms of systems engineering responsibility. Finally, the roles assumed in the first issue of Systems Engineering are characterized with respect to the twelve defined roles. SYSTEMS ENGINEERING ROLES VERSUS SYSTEMS ENGINEERS? ROLES There has been much discussion about whether INCOSE is about systems engineers or about systems engineering. The difference here is whether all engineers should be included as systems engineers or just those with a òsystems engineeringó title or job. If all engi-neers can do systems engineering, it is by considering the item they are engineering to be a system within a larger system, and by investigating operational issues, interfaces, and architecture of both systems. The confusion comes about in part because many of the companies who have provided the basis for the field of systems engineering have done so by creating òsystems engineeringó departments or other groups, and charging them with systems engineering the product that is delivered to the customer. Within the company, those engineers who work on the subsystems or elements that are integrated to form the larger system are often not called or considered òsystems engineers,óbut rather òtransmitter engineers,ó òelectrical engineers,ó or òsoftware engineers.ó Conversely, those with the title of òsystems engineersó work in these companies only on the larger system, not the subsystems or elements. In this paper, the distinction is not really relevant. Although the author?s experience is primarily in such

gender roles

Section 1 Aside:Former two pictures tell us that assuming our own gender roles is very important.Most important of all ,we must know what it is. Gender roles are the roles that society assigns to men and women based on their gender. For example,men are known to be rational and strong.While women are known to be weak, moody, emotional.This method lead to different ways men and women live, especially their jobs.Let's share a video at first. That day ,the dogs and cats rain in the sky. A woman run into a coffee resturant , water on her pretty face, we can?t distinguish whether it is rain or tear. When she want to take her order , a man sit opposite her. A: Hi,B. What a surprise to meet you here! B:So luck to meet you here. But my mood is blue. A: Wha t …s wrong with you? B: I think my interview is great but they didn?t hire me finally as the result of I?m only a woman, that?s so crazy.Why man is different from woman? Why man could take high salary position? I don?t reckon all human being is equal. Tonight I wanna cry. A:B. Be calm. This company might only hire people who could stay up, you know, staying up is bad to people, especially pretty girl. B: (smiling) You are kidding me. A: There is no denying that woman take more and more important part in our society. Those days when Males are superior, while females are inferior have gone. For example, I am respecting you now. Come on, it?s over. Let?s face it. B: After listening your words. I feel the clouds in my heart has gone away. Let?s take something to drink. Waiter. Aside:Gender discrimination which is a extreme expression way of gender roles is no excepted when you search a job. This thought can date back 5000 years ago. In acient China , old people often said “Men mind the external affa irs and women the internal affairs”, “Males are superior; females are inferior”. For example, If the woman chose to have instinct", and her partner was often considered inadequate, as it was assumed he was not a "good provider" women were supposed to get married and stay home to raise a family. The man was expected to go out to work to support his family. a career, she was considered "barren" or "lacking in maternal along with the rapid development of modern economic and social labor the changes to the way, further open society, more adult women to participate in social activities, engaged in the past men traditional profession, While men Shared by some of the women scored all the housework. Not only that, in fashion, clothing and habits, etc also played a significant change. Let?s share a video again. Section 2 Aside:Believing is just the beginning......

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