The happy-productive worker thesis (HPWT) assumes that happy employees perform better. Given the relevance of teams and work-units in organizations, our aim is to analyze the state of the art on happy-productive work-units (HPWU) through a systematic review and integrate existing research on different collective well-being constructs and collective performance. Research on HPWU  has developed through different constructs of well-being  and diverse operationalizations of performance , thus creating a disintegrated body of knowledge about HPWU. The theoretical frameworks to explain the HPWU relationship are attitude–behavior models, broaden-and-build theory, and the job-demands-resources model. Research models include a variety of antecedents, mediators, and moderating third variables. Most studies are cross-sectional, all propose a causal happy–productive relationship (not the reverse), and generally find positive significant relationships. Scarce but interesting time-lagged evidence supports a causal chain in which collective well-being leads to team performance , which then leads to objective work-unit performance. To conclude, we identify common issues and challenges across the studies on HPWU, and set out an agenda for future research. The happy-productive worker thesis (HPWT) has a long tradition in work and organizational psychology since the human relations movement (Hawthorne studies in the 1930s). This movement showed the importance of groups in affecting the behavior of individuals at work and strongly contributed to the generalized belief that a happy worker is more productive. Years later, an influential review expanded the widespread belief that the relationship between satisfaction and job performance was just an ‘illusory correlation’ r = 0.17)  and more  and morMost research on HPWT has taken place at the individual level. However, the changes and transformation in the world of work and organizations has led to a growing relevance of work teams and work-units in current organizations. More than half of all employees in the 28 member states of the European Union work in a team that has common tasks and can plan its work . DespiteTo achieve our main objective, we undertake a systematic review of peer-reviewed research on HPWU from 2001 to 2018. Considering the limitations of HPWT research at the individual level ,13,14, wIn this review, we first describe the conceptualization of the two key constructs in the HPWT (happiness and productivity). Second, we explain the methodological approach adopted for the systematic review. In the results section, we present a brief description of the studies identified, and then proceed to report the main findings structured around the research questions. Finally, we discuss the state of the art of research on HPWU, limitations, and challenges for future research. Scholars have treated happiness as well-being and have studied it through different constructs that overlap with the broad concept of happiness . There are two main perspectives about happiness or well-being: hedonic and eudaimonic . The “heSo far, research on the HPWT has focused mainly on hedonic constructs . However, the last decades have seen a growth on research on individual-level eudaimonic constructs such as engagement or flow , thrivinRecognizing the social dimension of work, well-being may be studied at the collective level as research on affective and emotional climates has shown . CollectMeasuring collective well-being presents important methodological issues. Most measures of collective well-being arise from evaluations provided by individuals , which are statistically aggregated to the collective level. A majority of researchers interested in group or team processes have adopted either a direct consensus or a referent-shift consensus model to aggregate individual responses ,28. In tThe approach taken to define and measure performance differs depending on the level at which performance is assessed . At the team level, it is important to make a conceptual distinction between team performance and team effectiveness. Following Salas et al. : “Team performance accounts for the outcomes of the team’s actions regardless of how the team may have accomplished the task. Conversely, team effectiveness takes a more holistic perspective in considering not only whether the team performed  but also how the team interacted  to achieve the team outcome. This is an important differentiation because many factors external to the team may contribute to the success (or failure) of the team, and therefore in some cases team performance measures may be deficient in understanding the team” (p. 557).Although team effectiveness is the appropriate term, to keep in line with the expressions used in the HPWT literature we will also use the expressions ‘collective performance’ and ‘productive teams’ to refer to measures of both the team’s achievements and actions for the remainder of the article. Building on previous research, we contend that a comprehensive evaluation of a team’s effectiveness needs to include measures of different aspects of the team’s interaction (processes) and performance (outcomes) , as wellTeam performance may refer to different aspects of the work content  ; may refCustomers’ evaluations constitute another relevant source to assess team’s effectiveness. It is externally rated, and it usually reflects a combined evaluation of both processes and outcomes . Customers’ evaluations typically include facets such as service quality and customer satisfaction. Another performance category includes work-unit objective/financial indicators. In this case, team productivity refers to a combination of efficiency and effectiveness and encompasses a number of results-oriented outcomes such as profit, return-on-investment, and sales . These oThe association between well-being and performance may vary with the type of performance considered . The divTo address our research questions, we conducted a systematic literature review searching the PsycINFO and PsycARTICLES databases for empirical studies in peer-reviewed journal articles that addressed the HPWT in groups/teams/work-units between 2001 and 2018 published in English or Spanish. This search took place in June 2019. For a comprehensive inclusion of all potential terms referring to happy teams and productive teams, we used the following keywords (and combinations thereof): happy ; productive ; and team . We included all studies about groups, teams, work-units, and branches because all represent the same meso-level of analysis as opposed to individual and organizational levels. We broadly define team or work-unit as a group of three or more employees who meet on a regular basis, are jointly responsible for one or more tasks, and are nested in a larger social system  . In thisIn each case, two independent evaluators analyzed all abstracts to check if they met two inclusion criteria: (1) the study reported collective level measurements of well-being and performance; (2) it presented empirical research undertaken with work samples (e.g. we excluded students and athletes). Agreement between evaluators reached 96%. After solving discrepancies, evaluators selected 87 abstracts.In the next stage, we proceeded with full-text analysis. We searched and found 87 manuscripts. We discarded the studies that while studying team phenomena, analyzed the data at the individual or organizational level, or did not report correlations between well-being and performance. We also discarded nine studies on collective satisfaction and one on group affect, which did not propose a happy-productive or the reversed productive-happy research model. These 10 studies presented models akin to input-processes-outcomes models of team effectiveness and considered both collective well-being and collective performance as dependent variables. The final sample of empirical studies with this systematic literature review yielded 30 studies relating happy work-units and performance strictly at the collective level of analysis. A PRISMA  flowchart  summarizFirst, we read the 30 manuscripts and extracted relevant information which we report in the We identified seven empirical studies relating collective satisfaction and collective performance in work-units or teams. Samples were drawn from different sectors , and countries  with representations from four continents. Samples sizes ranged from 28 to 171 work-units. Most studies used a cross-sectional design, with three using time-lagged performance indicators ,36,37.We identified 14 empirical studies relating group affect and collective performance in work-units or teams. Samples were drawn from sectors such as electronic industry, service organizations, sales, banks, orchestras, etc., and different countries  with representations from three continents. Samples sizes ranged from 22 to 417 work-units. Most studies used a cross-sectional design, with two using time-lagged performance indicators ,39.We identified nine empirical studies relating team engagement and collective performance. Empirical research exploring the collective engagement-performance relationship varies considerably in terms of sample size (54 to 242 teams), types of company/sector . All studies have taken place in European countries  and one in Vietnam. All studies used a cross-sectional design.In this section, we review the main features of the conceptualization and operationalization of collective well-being. We review the definitions, instruments, informants and referents used within the literature identified in the systematic review.Definition of Collective Satisfaction. An important theoretical contribution in defining satisfaction at the unit-level as a different phenomenon to individual job satisfaction is the work by Whitman et al. [sharedness as a critical precondition to forming collective job satisfaction. The antecedents to this sharedness are both situational  and dispositional . These antecedents lead to a common interpretation, understanding, and attitudinal evaluation of the job experience [n et al.  (p. 46).perience .Within the reviewed literature, four studies omit a definition of collective satisfaction and three studies adopt the ”group task satisfaction” definition, which refers to “the group’s shared attitude toward its tasks and work environment”  (p. 1). Operationalization of Collective Satisfaction. Operationalizations of collective satisfaction appear in diverse formats across studies: global vs. facets satisfaction, individual vs. team referents, and different instruments.Global vs. Facets Satisfaction. Six studies reported global measures of job satisfaction, in which a few items capture an overall feeling about satisfaction with the team or work-unit . Global satisfaction refers to a general attitude towards the team, and is distinct from satisfaction with facets or various features of the job. One study reported measures of satisfaction with facets such as tasks, rewards, supervision [ervision . Both glervision ,41. Informants and Referents. Team or work-unit members were the informants of job satisfaction in all studies and their responses were aggregated at the unit level. Six studies reported the use of individual referents , and Mason & Griffin [ Griffin  used bot Griffin  advocate Griffin  in theirCollective Satisfaction Measures. We found two validated instruments of satisfaction used at the collective level to grasp the extent to which members are satisfied with their teamwork. The “group task satisfaction scale” [n scale”  consistsn scale”  ”. However, many studies have used individual referents and relied on a measure of “aggregated individual job satisfactions”. As an attitude, definitions incorporate both cognitive and affective evaluations of shared job experiences, but the evaluations of work-unit satisfaction are predominantly cognitive and stable [d stable  and “thed stable  (p. 362)Overall, the lack of homogeneity in the use of instruments, number and content of items, and scale origin is remarkable. The widespread heterogeneity in operationalizations of team satisfaction is likely to affect the comparability of studies and results. We believe using validated team satisfaction scales , and combining global and team-facets satisfaction measures would strongly contribute to a more appropriate operationalization and understanding of team satisfaction and of its connection with team performance.Definition of Group Affect. Group affect refers to the homogeneous affective states within the group [he group  (p. 781)he group . Researche group . Most auhe group . All thehe group .Group affect, as a collectively shared pattern of affective states among group members, is a meaningful construct at the team level of analysis and an important factor that shapes group processes and outcomes . FollowiOperationalization of Group Affect. Seven studies used validated measures of positive group affect, namely six studies used PANAS  [e Scale) , and onee Scale) . The rese Scale) . The periods and statements accompanying the items are also diverse. One study measured group mood felt “at the very particular moment”, four studies have referred to “the past week”, one “in the last weeks”, one “in the past two weeks”, one “in the past six months”, two “in the past year”, two “in general”, and two do not specify time frames. There is a debate about the advantages and disadvantages of different time frames to measure group affect. Although “current mood states may be more accurately and reliably reported than recalled moods”  (p. 345)Additionally, operationalizations refer to how the team members have felt at work/job/at the store (five studies), at team meetings (three studies), or do not refer a particular situation (six studies). Regarding informants, team-members reported their positive affect in 13 studies, and only Rego et al.  had the Summary Group Affect. Group positive affect refers to how the team members have felt for a certain period of time . Similar to collective satisfaction, group affect focuses on the affective component of working in a team or work-unit. As opposed to team satisfaction (with affective-cognitive components), there only appears an affective component, and there is no reference to specific aspects of the job/work, just affect  while working or at work or at team meetings. Definition of Team Work Engagement. The concept of personal engagement was introduced by Kahn [ by Kahn  as “the  by Kahn  built on by Kahn  defined  by Kahn ,54 but tA second conceptualization with a business engagement perspective refers to engagement as “the individual’s involvement and satisfaction with as well as enthusiasm for work” . This definition has been criticized for evaluating satisfaction together with, or instead of, engagement ; and theTeam engagement refers to “a positive, fulfilling, work-related and shared psychological state characterized by team work vigor, dedication and absorption which emerges from the interaction and shared experiences of the members of a work team”  (p. 107)Sonnentag  attemptsOperationalization of Team Work Engagement. We identified two measures of team work engagement: UWES and Team Work Engagement construct. In all cases, team members were the informants about the team’s work engagement and their responses were aggregated at the team level. Seven studies measured team engagement through different versions of the UWES scale: one used the 18-item version, one used the 17-item version, four used the 9-item version, and two used the 3-item version. Five studies used a team referent , three used an individual referent , and one study used both individual and team referents [eferents . A seconeferents , has beeSummary Team Work Engagement. Although different conceptualizations of engagement exist, when it comes to research of collective work engagement at the team level within our literature review, all authors have defined it following the Utrecht perspective: “a positive, fulfilling, work-related and shared psychological state characterized by team work vigor, dedication and absorption which emerges from the interaction and shared experiences of the members of a work team” [rk team” . Some aurk team” . Team work team” , than a rk team” . Thus, eUnfortunately, operationalizations of collective engagement following the North American perspective based on the work by Kahn, and Macey and Schneider  have beeIn this section, we describe the main theoretical frameworks underpinning the relationship between collective well-being and collective performance see . We struThe Collective Satisfaction Literature: Theoretical Frameworks. The seven studies identified in the systematic review considered collective satisfaction as an antecedent of collective performance. The main theoretical framework supporting the research models is the HPWT applied to the team level. In the early 1990s, Ostroff [ Ostroff  applied  Ostroff . A centrAt the unit-level, Koys  proposedOne study within the reviewed literature  found emA related and complementary argument why happy work-units would be productive work-units refers to social exchange theory . Thus, tRegarding empirical support, 15 out 22 correlations reported in cross-sectional studies proposing a happy–productive relationship are statistically significant and positive (range 0.17 to 0.63); seven with team task performance (range 0.27 to 0.63), three with team contextual performance (range 0.36 to 0.61), two with customer satisfaction (range 0.49 to 0.57) and four with objective financial criteria (range 0.19 to 0.43). Non-significant results are obtained between collective satisfaction and one measure of supervisor-rated performance , one witCollective Satisfaction: Third Variables Included in HP Research Models. Antecedents affecting work-unit satisfaction (and collective performance) are related to transformational leadership and leader empowering behaviors, team task characteristics, high-performance work systems, and work-unit climate. In one study, leaders’ positive moods led to both transformational leadership and positive group affective tone, which then led to team processes such as team satisfaction, and in turn enhanced team sales performance [formance . A seconformance . Team taformance . In anotformance . Finallyformance  found thFurthermore, Whitman et al.  analyzedIn summary, the theoretical arguments within the collective satisfaction literature refer to the HPWT, the general attitude-behavior link, social exchange theory, and linkage research model or service-profit chain. Both theory and empirical evidence suggests that contextual performance  is a mediator between collective satisfaction and objective performance, i.e., attitudes lead to collaborative behaviors. The HPWU relationship seems stronger for higher degrees of sharedness of collective satisfaction . Work-unGroup Affect Literature: Theoretical Frameworks. All fourteen studies on group affect consider group affect as the antecedent of performance. The dominant theoretical framework in the group affect–performance literature is the “broaden-and-build” theory [” theory , which h” theory , recentl” theory  (p. 74).Rhee  exploredThe literature reviewed on group affect has proposed and tested cognitive, motivational, attitudinal, and behavioral team processes as mediators between group affective tone and team performance. For example, transformational leadership and positive affective tone enhanced team performance (perceived and objective) through team goal commitment , team satisfaction , and team helping behavior  in a sample of 85 sales teams in Taiwan . In anotSeong & Choi  reportedAs mentioned earlier, a second relevant theoretical framework to explain the relationship between group affect and collective performance refers to the mood-as-input theory . This moRegarding empirical support, 16 out 24 correlations reported in group affect cross-sectional studies proposing a happy–productive relationship are statistically significant and positive (range 0.13 to 0.58); two with member-rated task performance , four with leader-rated task performance (range 0.13 to 0.58), one with member-rated contextual performance (0.40), two with leader-rated contextual performance , one with member-rated creativity (0.34), four with leader-rated creativity (range 0.40 to 0.47), and two with objective financial criteria (range 0.19 to 0.43). Group Affect: Third Variables Included in HP Research Models. Antecedents of group affect found in the literature are related to organizational support climate and leadership. For instance, team climate of support from the organization  was shown to be positively related to positive team mood, which in turn was relating to team performance in a sample of bank branches [branches . Regardibranches  and posibranches ,78. Finabranches .Moderators. A meta-analysis showed that positive group affect has consistent positive effects on task performance regardless of contextual factors such as group affect source (exogenous or endogenous to the group) and group life span . HoweverIn summary, the theoretical frameworks underpinning the HPWU literature on group affect are the broaden-and-build theory and the mood-as-input theory. Following these theories, positive group affect broadens and activates the teams’  processes and interactions over a specific period of time leading to improved team performance. Moreover, this literature is starting to take into account the potential interaction of positive and negative group affect and the influence of contextual conditions  on the HPWU relationship.Team Work Engagement Literature: Theoretical Frameworks. Team work engagement is considered a predictor of collective performance in the nine studies we found in the systematic review. The job demands-resources model of work engagement (JDR-WE model) is the main theoretical framework used to explain why higher levels of engagement lead to increased performance [formance . The JDRformance . Its maiThe mechanisms operating between team engagement and performance replicate the arguments given at the individual level on how vigor, dedication, and absorption may lead to increased performance. For example, Mäkikangas  stated tFurthermore, it is worth mentioning some multilevel efforts in the team work engagement–collective performance literature, which contribute to clarify the relationship between team-level constructs and individual level constructs. For instance, individual and team work engagement were associated with high levels of perceived team performance in 102 Finnish teams from the educational sector . AnotherRegarding mediators, only one study proposed and found support for service climate and employee performance to mediate an indirect relationship between team engagement and customer loyalty in 114 service units in the hospitality industry .The nine cross-sectional studies proposing a happy–productive relationship based on team work engagement reported 8 out of 11 correlations to be statistically significant and positive (range 0.24 to 0.54); four with member-rated task performance (range 0.30 to 0.54), three with leader-rated task performance (range 0.24 to 0.30), one with member-rated contextual performance (0.38). Although two correlations between team work engagement and customer satisfaction were not significant, results with path analysis found an indirect relationship with customer satisfaction  and resuTeam Work Engagement: Third Variables included in HP Research ModelsRegarding antecedents, a meta-analysis by Christian et al.  found thAnother antecedent of team work engagement is team job crafting or collaborative crafting . Team job crafting predicted team work engagement which then predicted leader-rated performance , and teaModerators. Some moderators have been shown to strengthen the influence of team work engagement on performance such as task conflict , and cliIn summary, the main theoretical framework at the base of the HPWU literature on team work engagement is the job–demands–resources model of work engagement. Thus, team resources increase engagement, particularly when challenging demands are high, creating a positive affective-motivational shared state, which leads to improved team performance. This literature emphasizes a varied array of team resources, which increase team work engagement, and in turn enhance team performance. Moreover, it benefits from some examples of multilevel research, which takes into account the effects of team-level well-being and behavioral processes together with individual well-being and performance.Despite the frequently reported positive significant correlations, the causal relationship between well-being and performance is far from clear. Does well-being increase performance? Or does good performance increase well-being? In the most recent meta-analysis about satisfaction, citizenship behaviors, and performance in work units, Whitman et al.  reportedTwo important meta-analyses published at the individual and organizational level provide interesting findings on causal relationships between well-being and performance. At the individual level, Riketta (2008) conducted a meta-analysis of 16 panel studies finding support for job attitudes to increase performance  after controlling for baseline performance, whereas effects of performance on subsequent job attitudes were nonsignificant. Effects of job attitudes on performance were stronger for shorter time lags (less than 6 months compared to longer time lags) suggesting that time lag was a moderator of the cross-lagged relationship. Riketta  suggestsAt the organizational level, a meta-analysis by Schneider et al.  using da2 = 0.14, and 0.17), with only OCB having a significant beta weight. The same independent variables predicted customer satisfaction at year 2 (R2 = 0.31), with only unit-level employee satisfaction having a significant beta weight. Thus, OCB had an impact on profitability, and employee satisfaction had an impact on customer satisfaction. This research supports the idea that unit-level employee satisfaction leads to OCB, which in turn leads to profitability; and additionally, employee satisfaction leads to customer satisfaction.Five studies investigated time-lagged or longitudinal HP relationships at the work-unit level, three on collective satisfaction ,36,37, aMessersmith et al.  studied A third study explored the longitudinal relationships between work-unit climate and labor productivity in a sample of 171 bank branches in the Netherlands . Based oTwo time-lagged studies explored the relationship between group affect and collective performance. In a study with Spanish bank branches, a team climate of support from the organization was positively related to positive team mood, which in turn was positively related to team members’ ratings of team performance but not to leader-rated team performance . AnotherTwo of these studies additionally explored a reverse causality direction ,37 from In summary, four out of five studies exploring causal relationships between collective well-being and collective performance at the unit level provide empirical support to a happy–productive direction. Three of them obtain support for a causal chain between unit-level well-being (work-unit satisfaction or group positive affect), unit-level behaviors (OCB or team creativity), and objective unit-level performance  ,36,38. TThe aim of this systematic review was to offer an integrated overview on the literature on happy-productive work-units (HPWU). More specifically, we reviewed quantitative peer-reviewed studies published between 2001 and 2018 on the relationship between collective happiness and collective performance for teams and work-units. With our systematic review, we found 30 empirical studies on HPWU, which adopted three main collective well-being constructs and four categories of collective performance. Research has focused on hedonic well-being , and more recently on eudaimonic well-being . We could not identify research on other eudaimonic constructs applied to teams , which could, we believe, further explain extra-ordinary team efforts and success . On the other hand, collective performance relies mainly on team performance , and less so on customer satisfaction or financial/objective ratings. The literature on HPWU is scarce, diverse, and disintegrated. There is diversity both in the operationalization of collective well-being and performance and in the theoretical frameworks used.Our main contribution is the analysis of the strengths, commonalities, and differences across these three well-being literatures to get a comprehensive picture of what is known on happy–productive teams. To do so, we reviewed and summarized how collective well-being and performance is measured, the theories that attempt to explain how happy teams become productive teams or productive teams become happy, and whether both collective phenomena reciprocate. In this section, we summarize and discuss the results following the research questions set out for the review, reflect on the limitations of our study, and suggest avenues for future research. The HPWU literature builds on diverse conceptualizations and operationalizations of well-being and performance. A question that remains open is about the relationship among the three constructs of collective well-being and their relative contribution to collective performance. Far from addressing this issue, the reviewed literature about collective well-being mostly ignores it. An exception is the work by Mason & Griffin , who difRegarding collective performance, the overreliance on subjective effectiveness measures is an additional weakness of existing research. Although team-member and leader-rated team performance are valid and useful measures of performance, studying more distal  or objective team performance criteria would add extra value to future research. Task and contextual team performance are the main focus of collective performance by the three well-being literatures. A particular strength of the collective satisfaction literature is evaluating performance not only through team performance (task performance and OCB) but also through distal team effectiveness outcomes . Besides, only group affect researchers study team performance by means of team creativity. Using a combination of multiple valid operationalizations of collective well-being and collective performance would contribute to a more comprehensive picture of the HPWU relationship and allow for sound comparisons among HP constructs. Regarding operationalizations of collective well-being, despite some valuable contributions in defining and measuring work-unit satisfaction ,35, theyIn general, recommendations for appropriate measurement of team-level well-being includes use of valid instruments, use of team referents , and use of multiple informants . Furthermore, collective well-being ratings generally rely on the aggregated unit’s average score. This method emphasizes sharedness of well-being, a core quality of collective well-being, however there are calls to investigate the effects of the strength of well-being among team-members and over time. Additionally, an issue of substantial interest is to examine the amount of variability and dispersion of work-unit well-being within a team and its influence on collective performance ,96.Overall, the variety in definitions and operationalizations of collective constructs make it difficult to reach consistent conclusions about HP relationships but it provides a more comprehensive and holistic view on these relationships.The theoretical frameworks on the HPWU relationship and mechanisms linking collective well-being and collective performance are specific for each body of literature. Regardless of the consideration of well-being as hedonic or eudaimonic, it is implicitly or explicitly assumed that well-being shared among team-members is a relevant antecedent of collective performance. In this section, we reflect on the strengths of different theoretical efforts to explain how collective well-being influences collective performance and the mechanisms through which shared well-being translates into better team performance. The literature on team satisfaction builds on the general research on attitudes and behavior. The predominant theoretical framework expands the happy–productive thesis to the team level, complemented with additional theoretical models like social exchange theory, linkage research, or the service–profit chain. The rationale behind the HPWU thesis is that when collective satisfaction emerges as a shared phenomenon, it activates collaboration and OCBs among team members , which subsequently leads to improved (objective) performance. Thus, team satisfaction facilitates collaborative effort towards, and acceptance of, organizational objectives. The literature in satisfaction proposes and finds empirical support for “OCB” as a key mediator between collective well-being and objective/financial performance, following a causal chain “collective satisfaction–team performance (OCB)–financial performance” ,33,97. The literature on group affect showed a strong focus on uncovering the mediating mechanisms between well-being and performance. Building on the broaden-and-build theory , the ratResearch on team work engagement benefits from a sound theoretical framework , a precise concept, and well-established instruments. Research linking team work engagement and collective performance argues that a balance between team resources and challenging demands promotes energized team members, who consider their task meaningful and show active, productive, and helpful behaviors. Research interest in the engagement literature emphasizes the identification of team resources as antecedents of well-being .The reviewed studies offer empirical evidence of the relevance of multiple antecedents of well-being, and moderators of the HP collective relationship. Regarding antecedents, the role of leadership seems especially relevant, in particular transformational and charismatic leadership behaviors have shown a significant effect on a work unit’s collective well-being and behavior ,45,57. OThe predominant view in previous research and across the 30 HPWU studies identified in our review is that collective well-being is an antecedent of collective performance. The happy–productive relationship obtains generalized empirical support as a positive and significant relationship both in previous meta-analyses and in our findings. Previous meta-analyses have provided moderate corrected correlations between work-unit satisfaction and performance (r = 0.34) , group aTwo meta-analyses on longitudinal relationships between well-being and performance are available at the individual  and orgaFurthermore, stronger correlations in the direction of well-being to performance than the reverse were found at the individual level , and mixThe findings from this systematic review suggest several implications for practice on how to increase collective well-being, and how to enhance transformation of collective well-being into collective performance. Based on the empirical evidence reviewed, strategies to improve collective well-being should focus on relevant antecedents such as implementing HPWS, encouraging transformational and charismatic leadership, allowing for collaborative job crafting, improving team work design, promoting organizational support climate, and providing team resources. Building on the mediating mechanisms identified, it is also recommended to train team leaders and members on team work processes  and on how to maintain positive interactions . Finally, attending to (instead of ignoring) important moderators such as negative affect or task conflict help teams to focus efforts on relevant team problems and avoid defective team decision-making.The relationship between well-being and performance is more complex than the HPWT proposes and needs to be re-defined . Beyond Relationship between hedonic and eudaimonic well-being. A relevant question for future research is the relationship between hedonic well-being and eudaimonic well-being. In other words, can team members be hedonically satisfied and not feel engaged? Can team members feel engaged while experimenting negative affect or dissatisfaction? The likely answer is “yes” they can, but additional questions arise. How long can a team stay in a situation in which eudaimonic well-being is present but hedonic well-being is absent? How do they move or which dispositional or situational factors help the team stay in one state or change from one well-being form to another? This issue is related to team dynamics and transitions over time.There is too limited longitudinal evidence to draw conclusions about the causal ordering of team happiness and productivity. Most likely collective well-being and collective performance maintain a reciprocal and dynamic relationship as teams and team-members move through affective states and performance episodes. Previous research has found empirical support for gain spirals between resources and work engagement , and betThere may be other factors, beyond the work environment, that could affect work performance and well-being. For example, employee impaired health can be critical for organizations, because workers with worse health often lose more work hours, ask for more sick leave, and are resultantly less productive than healthy workers . Recent The use of a multilevel methodology would be highly recommended to explore cross-level relationships among organizational, unit-level, and individual constructs. For instance, Tims et al.  found suSome recommendations on methodological issues can be drawn from previous research ,95. RecoThere are important limitations to consider within the literature identified through the systematic review. First, there is a dearth of research on eudaimonic constructs beyond team engagement, and theoretically relevant perspectives such as Kahn’s conceptualization are not developed at the team/work-unit level. Second, collective performance relies on single measurements, one-faceted, and mainly on subjective evaluations of team performance rather than objective measurements. Third, most studies rely on cross-sectional designs to test proposed causal models. At review level, there are some limiting factors worth mentioning. The focus of our review was on happy–productive teams and work-units. Therefore, we adopted a positive perspective and excluded concepts that indicate ill-being or lack of well-being such as dissatisfaction, burnout or negative affect just to name a few. Obviously, teams and work-units go through bad times and the management of dissatisfaction, conflict, and frustration may be more important than the management of well-being. Previous research has studied how dissatisfaction or negative affect influences group performance, and found promising results on how negative well-being can lead to improved performance under certain conditions . HoweverDespite all its limitations, literature on collective well-being has contributed to understanding the relevant role of affective processes happening in teams and work groups, which have largely been ignored compared to cognitive processes. Theoretical frameworks underpinning the collective well-being–performance relationship are mainly the happy-productive worker thesis and general attitude-behavior link for collective satisfaction; the broaden-and-build theory and input-as-mood theory for group affect; and the job-demands-resources model and broaden-and-build theory for team engagement. The positive effects of collective well-being (or affective climates) on team performance, team creativity, customer satisfaction, and financial performance have been empirically tested and found throughout the studies included in this systematic review. Across a diversity of samples, organizational sectors, countries, conceptualizations, and operationalizations of well-being and performance, collective well-being is positively correlated to collective performance at the meso-level of analysis . In particular, the satisfaction and group affect literatures have shed light on mediating team processes that explain the link between collective well-being and performance. Additionally, literature found on the three collective well-being constructs offers very interesting inputs on antecedents , and moderators of the HPWT  at the unit-level.


Ischemic diseases in an aging population pose a heavy social encumbrance. Moreover, current therapeutic approaches, which aimed to prevent or minimize ischemia-induced damage, are associated with relevant costs for healthcare systems. Early reperfusion by primary percutaneous coronary intervention (PPCI) has undoubtedly improved patient’s outcomes; however, the prevention of long-term complications is still an unmet need. To face these hurdles and improve patient’s outcomes, novel pharmacological and interventional approaches, alone or in combination, reducing myocardium oxygen consumption or supplying blood flow via collateral vessels have been proposed. A number of clinical trials are ongoing to validate their efficacy on patient’s outcomes. Alternative options, including stem cell-based therapies, have been evaluated to improve cardiac regeneration and prevent scar formation. However, due to the lack of long-term engraftment, more recently, great attention has been devoted to their paracrine mediators, including exosomes (Exo) and microvesicles (MV). Indeed, Exo and MV are both currently considered to be one of the most promising therapeutic strategies in regenerative medicine. As a matter of fact, MV and Exo that are released from stem cells of different origin have been evaluated for their healing properties in ischemia reperfusion (I/R) settings. Therefore, this review will first summarize mechanisms of cardiac damage and protection after I/R damage to track the paths through which more appropriate interventional and/or molecular-based targeted therapies should be addressed. Moreover, it will provide insights on novel non-invasive/invasive interventional strategies and on Exo-based therapies as a challenge for improving patient’s long-term complications. Finally, approaches for improving Exo healing properties, and topics still unsolved to move towards Exo clinical application will be discussed. The ischemic cascade was first described over 30 years ago . The imbwww.exocarta.org) [http://www.evpedia.org/) [EV are small vesicles with a lipid bilayer membrane that is secreted by almost all cell types. EV are considered a novel paracrine and endocrine mechanism of cell-to-cell communication. The transfer of their composite cargo, consisting of lipids, proteins, RNA, including mRNA , microRNrta.org)  or EVpedia.org/)  provide EV were first described as plasma membrane fragments released by platelets as part of the coagulation process by Peter Wolf in 1967 . From thThe first part of this review will introduce the most relevant mechanisms of damage and cardioprotection, as the therapeutic strategies are mainly based on specific targeting approaches. Moreover, it will provide an overview on multitarget pharmacological/non-pharmacological approaches and on the promising mechanical reperfusion techniques that were developed to protect myocardium from I/R damage. In addition, recent advances in using EV for cardioprotection/cardiac regeneration will be reported. Finally, approaches for improving EV healing properties and the hurdles still unsolved for moving from bench to bedside will be discussed.MI results from both coronary artery occlusion and reperfusion damage. The reperfusion time, the presence of collateral vessels and the patient’s hemodynamic status dictate the fate of the myocardial area at risk. However, despite advances in PPCI, the management of microvascular damage in the reperfused myocardium remains a challenge. As originally demonstrated by Maroko et al.  and furtThe questioned concept of lethal reperfusion injury has been currently accepted, owing to the results that were obtained by Zhao et al. . The autMicrovascular damage, also known as no-reflow phenomenon, was first described by Kloner et al. , as a crc subunits of the adenosine triphosphate (ATP) synthase [Independent of the mechanisms accounting for the reperfusion damage, mPTP opening is considered to be the key driver of injury . Brieflysynthase . During synthase . When resynthase ,44. Thissynthase .c or the activation of caspase-9 and 3 receptively [mPTP opening drives cell towards necrosis (if stably opened) or apoptosis (if transiently opened), depending on the release of cytochrome eptively . The bioeptively . Indeed,eptively . Howevereptively  and TRO4eptively  -AKT and Mitogen-Activated protein kinase (MEK)/Extracellular Signal-Regulated Kinase (ERK) cascade, was first described by Yellon et al. . HoweverThe SAFE pathway is an alternative survival kinase cascade that converges on the Signal Transducer and Activator of Transcription-3 (STAT3). In mice, the inhibition of the mPTP opening  and the Cyclic guanosine-monophosphate (cGMP) and cGMP-dependent protein kinase type I (PKG aka cGKI) are known to prevent both I/R damage and cardiac remodeling . The nitAutophagy is a self-phagocytic phenomenon in which lysosomes degrade intracellular molecules and organelles . AutophaThe failure to develop new therapeutic options that are able to effectively prevent reperfusion injury fully reflects the complexity of this process. In the last decades, a number of different strategies have been investigated . Herein,Historically, coronary artery disease (CAD) and myocardial ischemic damage were clearly defined by the concept that “time is muscle”. Back-to-back studies demonstrated that early reperfusion effectively protects myocardium from I/R damage. The demonstration that coronary thrombosis is the most relevant mechanism of damage  has spurPlatelets, besides playing a crucial role in the first phase of thrombus formation, undergo activation during fibrinolysis. The efficacy of antiplatelet/thrombolytic combo treatment was first demonstrated by the ISIS-2 trial , provingThe effects of several beta-blockers have been investigated in order to reduce oxygen consumption and decrease ischemic damage. However, only the intravenous administration of metoprolol before PPCI was able to significantly reduce the infarct size in patients with STEMI . The inhGiven the pivotal role of inflammation in accelerating atherosclerosis and CAD, a number of preclinical and clinical studies have been performed. In particular, due to the crucial role of Interleukin-1 (IL-1) in mediating ischemia-induced inflammatory response, several IL-1 inhibitors have been investigated in preclinical and clinical studies. In rats, the anti-IL-1b antibody, gevokizumab, prevented HF progression . SimilarIn pilot studies, adenosine administration was reported to reduce the infarct size ,122. TheThe role of ischemic pre-conditioning was first described by Murry et al. . They haIn human studies, post-conditioning has been obtained by performing cycles of 1-min. inflation and 1-min. deflation of the angioplasty balloon, just after reperfusion by direct stenting. This approach was proved to reduce Creatine Kinase (CK), a surrogate marker of the infarct size, in a prospective, randomized, controlled, multicenter study . MoreoveInterventional approaches are spreading in cardiology, and new invasive therapeutic options have been investigated to avoid I/R injury. The reduction of myocardial oxygen consumption or an improvement of heart collateral blood supply were expected. An improvement of myocardial salvage was reported using Intra-Aortic Balloon Pump (IABP) before reperfusion in the first preclinical studies ,126. Unf® heart pump, are under investigation. In preclinical studies, trans-valvular left ventricle unloading with Impella® was found to limit MI and promote the expression of genes that are associated with mitochondrial respiration [® followed by immediate reperfusion and patients that were subjected to 30 min. LV unloading before reperfusion [Alternative approaches, such as the Impellapiration . Evidencerfusion . Similarerfusion .® consists of a balloon-tipped catheter that is placed into the coronary sinus (CS). It has been shown that a balloon, alternately inflated and deflated, can intermittently increase the CS pressure and induce venous blood redistribution via collaterals. The high expression of vascular endothelial growth factor (VEGF) and hemoxigenase was found in experimental approaches applying PICSO® [®-mediated beneficial effects [® in patients with ACS and positive physiological index of microvascular dysfunction was reported [PICSOg PICSO® . Moreove effects . Recentlreported . FurtherThe lack of effective cardioprotective treatments has spurred both biologists and clinicians to move towards the progressive development of concepts for future therapeutic options. Cell-based therapies have drawn the path towards a new class of therapeutic strategies ,133. In According to the Minimal Information for Studies of EV (MISEV) classification, three different EV subclasses have been identified. These subclasses include Exosomes (Exo), Microvesicles (MV), and Apoptotic Bodies .Exo, the smallest EV, ranging from 30 to 100 nm, were first described by Pan and Johnstone ,143. ExoMid-size EV range from 100 to 1000 nm and include microvesicles (MV), microparticles, or ectosomes. In this review, this EV subclass will be referred as MV. The most accepted mechanism of formation and release is the shedding after membrane budding . TherefoThe largest EV, also known as apoptotic bodies, range from 800 to 5000 nm  and willIn the last decades, EV have emerged as crucial mediators of biological signals among different cells to regulate discrete biological processes. As their action mainly recapitulates that of their cell of origin, a number of studies have been performed to investigate the healing properties of EV derived from different cell sources on scar formation and HF progression upon I/R damage . When coCirculating MV have been implicated in several physiological functions, such as the coagulation, reticulocyte maturation, angiogenesis, tissue repair, and inflammation ,151,152.The role of MV in I/R damage is however controversial, since their effects could depend not only on the cell of origin, but also on the microenvironment of releasing cells. Herein, the protective or damaging effects exerted by MV derived from different cell types will be described .PMV were the first identified MV . PMV areHowever, PMV can also play a beneficial role in I/R setting. Indeed, it has been reported that PMV locally injected induce angiogenesis and stimulate post-ischaemic revascularization in a rat model of MI. This protective effect relies on VEGF-mediated activation of the RISK Pathway .In addition, PMV have been also involved in rIPC-mediated cardioprotection . rIPC isEMV, expressing CD144 or CD31, play an important role as markers of endothelial activation in several pathological conditions , and, asMV can be released by different cells after I/R and can exert discrete actions. CM-derived MV after AMI (marked by the expression of Caveolin 3 and Troponin T) are internalized by infiltrating monocytes and regulate the local inflammatory response . MV, relExo that are derived from different stem cell sources are known to act by releasing their composite cargo, including lipids, proteins, and genetic information into recipient cells . For carAlthough Exo can be released from different stem cells, it has been reported that Exo released by MSCs and CPCs are much more effective in term of cardioprotection and cardiac regeneration. Moreover, it has been demonstrated that stem cell-Exo exert their healing effects by a fine-tune control of processes involved in autophagy and inflammation. Therefore, cardioprotection, autophagy, and inflammation will be considered as showcases of Exo actions, and the MSC- and CPC-Exo properties will be much more deeply discussed. Finally, relevant data on the role of cardiac telocytes (CT) in cardioprotection will be briefly reported .MSCs are nonhematopoietic multipotent stromal cells that are isolated from bone marrow able to differentiate towards mesodermal lineages . Lim et 144/451) induced by GATA-4 [miR-144 belongs to a cluster of miRs , a protease that regulates the release of active insulin growth factor-1 (IGF-1), has been suggested to exert cardioprotective action upon CPC-Exo treatment . MoreoveExo can trigger both activation or the inhibition of autophagy . It has As demonstrated by knocking-down CD4, the activation of CD4+ T-Helper has a beneficial effect in reducing LV dilation after MI . Exo derParticular attention has been recently focused on the role of CT-Exo in cardioprotection . TelocytAfter damage tissue regeneration depends on the expansion of resident stem-progenitor cells, however, as compared to the fetal heart, a low self-renewal capability has been reported in the adult human heart . TherefoIt has been reported that the intramyocardial injection of CPC-Exo increases vessel density, reduces scar size, and improves LVEF recovery in preclinical MI models. These effects have been associated with miR-132 Exo content, which promotes neovessel formation by regulating the expression of the RasGAP-p120 protein ,187. A dThe pro-angiogenic effect of MSC-Exo has been linked to the enrichment in PDGF (platelet-derived growth factor), EGF , FGF (fibroblast growth factor), NF-kB , and in Adipose cells have been exploited as a source of MSCs and their role in promoting angiogenesis has been asserted in several studies . ADSC-ExIt has been reported that Exo derived from plasma of MI patients boost ECs proliferation, migration, and tube formation via miR-939-iNOS-NO-mediated pathway, both in vitro and in vivo. Such Exo have different cell of origin. It has been postulated that they can be released by CMs that were subjected to ischemic stress or from resident cardiac ECs . Indeed,As extensively reported, scar formation should be prevented and tissue damage restored to improve long-term patient’s outcomes. This implies that efforts should be directed to the identification of cells or much better their derivatives able to induce cardiac regeneration by expanding resident CSCs. A number of studies have been published. Herein, only data that unquestionably demonstrated the contribution of stem cell-Exo in promoting regeneration by expanding resident CSCs have been reported.It has been shown that ESC-Exo promote cardiac repair after MI by supporting angiogenesis and increasing the survival and proliferation of c-kit+ CSC both in vitro and in vivo. miR-294, enriched in ESC-Exo, mediates CSC expansion .MSC-Exo also improve proliferation of c-kit+ CSC in vitro and enhance their engraftment after transplantation. The improved engraftment depends on MSC-Exo expressing miR-760 and miR-326, which induce the angiogenic switch and myocyte differentiation .Exo possess several therapeutic advantages when compared to stem cells. They are biocompatible, non-immunogenic, non-tumorigenic, and more stable in the circulation. Moreover, they cross the blood–brain barrier (BBB) . The lipThe isolation method is still tricky. While various techniques have been evaluated, currently the most widely accepted is the differential ultracentrifugation. Differential ultracentrifugation provides high Exo purity, and is thereby optimal for research purposes. However, it requires special equipment and the low-yield still remains the main drawback for the transition to clinical application . Additio10/mL), and plasma-derived Exo have been reported to induce cardioprotection [13/mL) has been reported for CPCs [The selection of robust sources of Exo is still a matter of debate for their production and scalability. As plasma is enriched in Exo -tagged Exo have provided promising results on cardiac homing to the infarct area, induction of CM proliferation, angiogenesis, and scar size . A 15% iNovel approaches for increasing Exo targeting have been proposed in cancer. Drug-loaded Exo targeting cancer cells has been tested. The most intriguing approach so far provided is magnetic-field Exo targeting, as obtained by iron-oxide nanoparticle preloading ,255. FurExo contain many active components, including proteins and RNAs. Insight into the components that play a role in their regenerative capacity is still under investigation. Even if Exo could be considered a feasible therapeutic option by themselves, their functional capability could be optimised by modifying their cargo. Owing to their effect on epigenome, miRs are the most studied component of the Exo cargo, and the manipulation of their expression is the most promising approach in regenerative medicine. Indeed, many preclinical studies have been performed by upregulating the expression of specific miRs in Exo to induce cardiac regeneration. Ischemic preconditioning, either in vitro or in vivo, is an effective method for upregulating the expression of specific miRs in Exo ,212,213.More selective methods involve direct cell manipulation by genetic approaches. Knocking-down β2-microglobulin in MSC using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) strategy , or upreCell overexpression of selected miRs to obtain Exo enrichment has been extensively exploited and investigated in preclinical models recapitulating different clinical settings ,217. MorAlternatively, extracellular loading strategies have been proposed, as the EV electroporation . miR-132® provided promising results in a preclinical study [® in a subset of ACS patients has been reported [Current therapeutic approaches to prevent or reduce long-term complications in MI patients pose a heavy social and healthcare burden. Pharmacological and non-pharmacological approaches, alone or in combination, have provided advantages in preventing ischemia-induced damage and improving patient’s outcomes. Interventional approaches as new invasive therapeutic options have been investigated. In particular, trans-valvular left ventricle unloading with Impellaal study  and evidal study . Likewisreported . Moreovereported . Howeverreported ,133,217.reported ,211,261.reported . TherefoA number of miRs that were carried by Exo derived from different cell sources has been reported to drive cardioprotection ,207,257.Moreover, Exo-based drug development would require optimization, including the identification of feasible cell sources for a large production of functional Exo, as well as standardisation in production. Indeed, the standardization of protocols for Exo production to achieve reproducibility, large scalability, quality control, and legislation are still an unmet need. Moreover, a GMP-compliant production of therapeutic Exo has to deal with several hurdles, even though some studies provide interesting perspectives ,245,246.


On average, PCTs met twice (range 2–4 times) between workshop sessions. Learners valued the PCTs, and 1 commented on the value of working with peers in PCTs, having no one in a similar position within his immediate work environment. Participants’ written comments strongly endorsed the value of the workshops for their work, with the coaching skills session seen as the most valuable. Some participants worry that skills will decrease over time without continued reinforcement. All but 1 participant reported that they planned to continue with the PCT. DISCUSSION/SIGNIFICANCE OF IMPACT: The number of applicants to our program suggests a need and motivation for staff to participate in the STEP-MDP. Participants’ reported improved skills and sense of community. To maintain the COP and address worry about degradation of skills we are planning to remind PCTs to meet once a month and will follow-up with them 3 and 6 months post intervention to evaluate their continued development. This spring a second cohort will receive the training. We believe developing these core teamwork skills will lead to more collaborative, efficient, and innovative research. We have implemented a successful program targeting critical members of research teams with potential to facilitate expansion of institutional capacity for translational research. It will be important to understand the long-term impact of the program on individuals, on team science, on research, and ultimately on the health of the public.OBJECTIVES/SPECIFIC AIMS: Skillful research staff members are critical to productive translational research teams and yet their ongoing professional development is rarely formally addressed. Through the Strategic Teamwork for Effective Practice-Mentor Development Program (STEP-MDP), we aimed to both create a community of practice (COP) for research staff and build the skills needed to enhance research team performance. METHODS/STUDY POPULATION: We selected 16 participants of 32 staff-level applicants from among the NYU Schools of Medicine, Social Work and Nursing for the first STEP-MDP cohort. Participants included research assistants, coordinators, managers, and directors. We delivered 3, two-hour workshops, scheduled 3 weeks apart, focused on team communication, identifying team areas for improvement, and mentorship/coaching skills. Peer-Coaching Teams (PCTs) were created by pairing participants at the same position level, and PCTs worked together at each session to explore and practice learned skills. Sessions featured brief didactics, group-based learning and exercises based on participants’ real issues. A variety of active learning techniques such as brainstorming, role-playing, problem solving, and peer coaching were used. Practical core readings, worksheets, and summary cards were provided. PCTs met between sessions to practice coaching skills, and troubleshoot problems. RESULTS/ANTICIPATED RESULTS: Participants (n=16) completed a 37-item retrospective pre/post self-assessment of team behaviors and skills, and a STEP-MDP evaluation survey at the end. We saw pre-post improvements in each of 5 self-assessment domains: Communication (4 items, pre-mean 2.66, post mean 3.36,


Hyperspectral data processing technique has gained increasing interests in the field of chemical and biomedical analysis. However, appropriate approaches to fusing features of hyperspectral data-cube are still lacking. In this paper, a new data fusion approach was proposed and applied to discriminate Rhizoma Atractylodis Macrocephalae (RAM) slices from different geographical origins using hyperspectral imaging. Spectral and image features were extracted from hyperspectral data in visible and near-infrared  and short-wave infrared  ranges, respectively. Effective wavelengths were extracted from pre-processed spectral data by successive projection algorithm (SPA). Meanwhile, gray-level co-occurrence matrix (GLCM) and gray-level run-length matrix (GLRLM) were employed to extract textural variables. The fusion of spectrum-image in VNIR and SWIR ranges (VNIR-SWIR-FuSI) was implemented to integrate those features on three fusion dimensions, i.e., VNIR and SWIR fusion, spectrum and image fusion, and all data fusion. Based on data fusion, partial least squares-discriminant analysis (PLS-DA) and support vector machine (SVM) were utilized to establish calibration models. The results demonstrated that VNIR-SWIR-FuSI could achieve the best accuracies on both full bands (97.3%) and SPA bands (93.2%). In particular, VNIR-SWIR-FuSI on SPA bands achieved a classification accuracy of 93.2% with only 23 bands, which was significantly better than those based on spectra (80.9%) or images (79.7%). Thus it is more rapid and possible for industry applications. The current study demonstrated that hyperspectral imaging technique with data fusion holds the potential for rapid and nondestructive sorting of traditional Chinese medicines (TCMs). Jatropha curcas L. seeds [Hyperspectral imaging (HSI) is an analytical tool merging conventional imaging and spectroscopy to simultaneously provide physical features and internal chemical composition of the detected object . ConventL. seeds . HoweverL. seeds ,9,10.Rhizoma Atractylodis Macrocephalae (RAM) is one of the most commonly used herbal medicines in China. It has shown various pharmacological activities including immunomodulatory , anti-oxTraditionally, the origins of TCMs are identified based on physical characteristics in macroscopical and microcosmic morphology, as well as color, odor, taste, weight, and density. These methods are direct, but subjective and inaccurate. Modern analytical methods including high-performance liquid chromatography (HPLC) , gas chrHSI system in this study employs both VNIR and SWIR ranges. Hyperspectral data-cube in each range contains both spectral and image information. Therefore, it is feasible to integrate data from spectral and image in different ranges, thus improving the classification performance while reducing the environmental sensitivity  of spectroscopy to some extent.The main purpose of this paper was to develop an effective and reliable HSI method to classify geographical origins of RAM slices. Firstly, hyperspectral data of the samples were acquired in both VNIR (435–1042 nm) and SWIR (898–1751 nm) ranges. The regions of interest (ROIs) in both ranges were identified respectively. Then, the spectral features corresponding to ROIs were pre-processed by five pre-processing algorithms. Next, successive projections algorithm (SPA) was applied to gain effective wavelengths. In the same ROIs, texture features were extracted by gray-level co-occurrence matrix (GLCM) and gray-level run-length matrix (GLRLM). After all features were acquired, the fusion of spectrum-image in VNIR and SWIR ranges (VNIR-SWIR-FuSI) was performed, in three different ways: (1) VNIR and SWIR fusion, (2) spectrum and image fusion, and (3) all data fusion. Finally, Partial least squares-discriminant analysis (PLS-DA) and support vector machine (SVM) were used as classification models. The enhancement of VNIR-SWIR-FuSI was discussed in two parts: full bands, SPA bands. In addition, classification maps were used to visualize different RAM slice origins based on data fusion.An HSI system combining VNIR (435–1042 nm) and SWIR (898–1751 nm) spectral ranges in reflection mode was used in the study . The sysThe operation parameters in the VNIR range were set as follows: speed of the mobile platform 13 mm/s, distance between the lens and the sample 25 cm, exposure time 17 ms. Hyperspectral data-cubes were obtained with 512 pixels wide, 1200 pixels long, and 237 wavelengths ranging from 435 to 1042 nm at intervals of 2.60 nm. The pixel size was 0.16 mm × 0.16 mm. The parameters in the SWIR range were set as follows: speed of the mobile platform 4.5 mm/s, distance between the lens and the sample 25 cm, exposure time 42 ms. Hyperspectral data-cubes were obtained with 640 pixels wide, 1500 pixels long, and 512 wavelengths ranging from 898 nm to 1751 nm at intervals of 1.67 nm. The pixel size was 0.23 mm × 0.23 mm. In fact, for either of two ranges, the length of the distance that mobile platform moved varied among samples even if the start and end point were fixed. Therefore, the lengths of data-cubes were padding to 1200 and 1500 for VNIR and SWIR ranges, respectively, for consistency. Atractylodes macrocephala Koidz, also known as white atractylodes) from Anhui, of China were provided by Jiuzhou Fangyuan . All the RAMs were fully washed, cut into slices and sun-dried. The samples were placed in plastic bags and stored at room temperature before use. There were 16 batches, six batches and six batches from Anhui, Zhejiang, and Hebei respectively. A total of 224 RAM slices (8 RAM slices for every batch) were randomly picked. Samples from each geographical origin were randomly divided into a training set and testing set by a ratio of 2:1. Finally, 149 RAM slices and 75 RAM slices were used for calibration and prediction, respectively. Rhizoma Atractylodis macrocephalaes  cameras, as well as the differences in the physical configuration of the hyperspectral imaging system. Therefore, the images were calibrated with the white and dark reference images as follows: After the calibration of images, the ROI of each RAM slice was identified automatically in Spyder (Python 3.6). In this study, the processes of ROI identification included background segmentation, transferring to binary-level images, and sequential ROI extraction of each RAM slice. In order to maximize the contrast of relative reflectance intensity between background and samples, new gray-level images were generated by subtracting the images with lowest intensity from those with highest intensity. Then binary threshold segmentation was applied to new gray-level images to remove background and gain binary-level images. Corresponding ROIs of RAM slices in binary-level images were extracted by the built-in function “findContours” of Spyder (Python 3.6).In this study, two steps were used for the extraction of spectral features. Firstly, spectra were pre-processed by five pre-processing methods. Then effective wavelengths were selected by SPA.Spectra in 898–1042 nm of the VNIR range and in 1601–1751 nm of the SWIR range were not included due to low signal-to-noise ratios. Besides, a few pixel values of gray-level images at 898 nm of the SWIR range were nonnumeric. Thus, the reserved spectral ranges were 435–898 nm with 182 wavelength bands, 900–1601 nm with 421 wavelength bands for VNIR and SWIR, respectively. Due to the noises from electromagnetic radiation of cameras and uneven surface of samples, spectra in VNIR and SWIR ranges were significantly influenced by scatter effects which led to baseline shift and non-linearity . SuitablIn order to reduce computation load and eliminate redundant information of hyperspectral data, effective wavelengths were chosen. SPA has been regarded as a powerful waveband selection method, which can minimize the multi-collinearity among variables . TherefoTextural features extracted by GLCM and GLRLM were employed for geographical origin identification. GLCM is a classic method for extracting textural properties, which can describe intensity change in the local spatial domain . GLCM teIn most cases, GLCM and GLRLM are used for extracting textural features from mono-spectral images. However, hyperspectral images have hundreds of bands. If GLCM and GLRLM textures are calculated for all gray-level images corresponding to their bands, there will be a mass of redundant information, which will increase the computing complexity. Therefore, only texture information in the gray-level image in each effective wavelength was extracted in this study. Data fusion has gained rising interest due to the boost it gives to multiple analysis tasks. The fusion of data from various sources can provide complementary information and increase the robustness and accuracy of the built models . In thisIn this work, supervised pattern recognition models were adopted for the origin identification of RAM slices. There have been a variety of models available for classification, including partial least square-discriminant analysis (PLS-DA) ,35, linePLS-DA is an adaptation of PLS regression to the problem of supervised classification. PLS-DA is performed in order to sharpen boundaries among classes of observations by projecting the input features to the most discriminative directions . SVM is Classification accuracy is widely used to evaluate model performance, while it has some limitations in practical applications, especially for class distribution imbalance problem and unequal classification error costs . TherefoIt is obvious that the geographical origins of RAM slices are difficult to be identified by the naked eye. Classification map  can be uThe representative RGB images of RAMs from three different geographical origins are shown in Pre-processing of spectral data is a crucial step prior to chemometrics modeling. As shown in In order to minimize redundant information of hyperspectral data, effective wavelengths were selected by SPA. This approach has been used as an effective variable selection algorithm to solve the collinearity problem of hyperspectral data. The selection of effective wavebands is shown in 2O, polysaccharides, and resins. The wavelengths at 1477, 1484, 1546 and 1564 nm corresponded to N-H stretching (first overtone) of amino acids and O-H stretching (first overtone) of polysaccharides. The wavelengths at 1576, 1597 nm corresponded to O-H stretching (first overtone) of resins.The interpretation of selected wavelengths referred to the work of Workman et al. . Figure In this section, VNIR-SWIR-FuSI was used for classification purpose in full bands. The classification performance using VNIR and SWIR fusion, spectrum and image fusion, and all data fusion was compared to that based solely on spectral or textural features, respectively. The effect of VNIR and SWIR fusion was evaluated in two parts: spectra (A), and images (B). The texture features were acquired from hyperspectral images using GLCM and GLRLM. The fusion effects of spectra in tandem with GLCM or GLRLM textures were evaluated separately in two parts: VNIR (I), and SWIR (II). For the GLCMs in The all data fusion method integrated spectral and textural variables in both VNIR and SWIR ranges. Fusion effects could be discussed in two parts due to two different series of textural features. The results were presented where Besides classification accuracies, ROC curves were used to evaluate the fusion methods. ROC curves were plotted based on PLS-DA classifier due to its better performance, simple calculation and highly interpretability. As GLRLMs were turned out to be superior to GLCMs above, the image features referred in particular to GLRLMs only. VNIR-SWIR-FuSI was also used to discriminate origins in SPA bands. As shown in This section was divided into two parts: spectra (A), images (B). As shown in An overview of As shown in The classifier and image features chosen by ROC curves were the same as The geographical origins of RAM slices were classified by the HSI system using VNIR-SWIR-FuSI approach. The results show that data fusion on three dimensions of VNIR-SWIR-FuSI generally had a positive effect on classification performance. The highest classification accuracy of 97.30% was achieved by the PLS-DA model using all data fusion, which was better than those using spectra (93.2%) or textures (79.7%) in one spectral range solely. Although the classification performance of spectra selected by SPA was not so satisfactory (highest 80.9%), the result in SPA bands employing VNIR-SWIR-FuSI could still be fairly good, with highest accuracy of 93.2%. ROC curves also illustrated the reliability of VNIR-SWIR-FuSI in which all data fusion had the greatest AUC values. The optimal result of SPA was almost the same as the result of SWIR spectra. However, as SPA selected only 23 bands which were much less than 422 bands of SWIR spectra, it is possible to develop an online and real-time multi-spectral system for TCMs sorting in further studies.


Rheumatoid arthritis (RA) is a chronic, autoimmune, systemic, inflammatory disorder that affects synovial joints, both small and large joints, in a symmetric pattern. This disorder usually does not directly cause death but significantly reduces the quality of life and life expectancy of patients if left untreated. There is no cure for RA but, patients are usually on long-term disease modifying anti-rheumatic drugs (DMARDs) to suppress the joint inflammation, to minimize joint damage, to preserve joint function, and to keep the disease in remission. RA is strongly associated with various immune cells and each of the cell type contributes differently to the disease pathogenesis. Several types of immunomodulatory molecules mainly cytokines secreted from immune cells mediate pathogenesis of RA, hence complicating the disease treatment and management. There are various treatments for RA depending on the severity of the disease and more importantly, the patient’s response towards the given drugs. Early diagnosis of RA and treatment with (DMARDs) are known to significantly improve the treatment outcome of patients. Sensitive biomarkers are crucial in early detection of disease as well as to monitor the disease activity and progress. This review aims to discuss the pathogenic role of various immune cells and immunological molecules in RA. This review also highlights the importance of understanding the immune cells in treating RA and in exploring novel biomarkers. Rheumatoid arthritis (RA) is a chronic, autoimmune, systemic disorder that manifests as inflammation of synovial joints, leading to joint destruction and deformity. Although RA is not a fatal disease in general, but the complication associated with RA such as heart diseases and respiratory problems can lead to increased mortality. Common conditions in RA patients are Carpal tunnel syndrome, tendon rupture, cervical myelopathy and joint damage. Other inflammatory complications are Sjögren’s syndrome, pericarditis, pleuritis, scleritis, vasculitis and sexual dysfunction. Due to the long-term disease complication, RA is also associated with a reduced life expectancy. The clinical presentation of rheumatoid arthritis appears between the age of 20 and 40 years old, more commonly in women than in men with a 2–3:1 ratio [Since RA is a chronic disease, the treatment mainly focuses on alleviating pain, prevent or limit joint damage, improve or preserve function of the joints and optimize the quality of life . DMARDs Depending on the patients’ condition, more specific treatments are being used to treat RA. TNF inhibitors are one of the approved target-specific treatments for RA . In thisToday, medical practitioners stress the importance of early diagnosis and personalized treatment in preventing or minimizing joint destruction in treating RA . Having As an autoimmune disorder, immune cells mainly B-cells, T-cells and macrophages play critical roles in RA pathogenesis. These cells can either reside in synovium or circulate in peripheral blood. B-cells secrete physiologically important proteins such as rheumatoid factors (RFs), anti-citrullinated protein antibodies (ACPA) and pro-inflammatory cytokines in supporting RA. B-cells also mediate T-cell activation through expression of costimulatory molecules. In RA, the main function of T-cells is to activate macrophages and fibroblasts and transform them into tissue-destructive cells. Similar to T- and B-cells, activated macrophages produce a variety of cytokines and chemokines to support the inflammation in the joints. This section provides detailed information on how various immune cells contribute to RA pathogenesis.B-cells are well known to be an important component in the human adaptive immunity but in the case of RA it also functions as one of the underlying factors of RA onset . AutoreaPTPN22 gene that disrupts the BCR signaling pathway in central B-cell tolerance checkpoint [In RA patients, both checkpoints are usually defective, leading to the large production of autoreactive mature naïve B-cells. As shown in a previous study, untreated RA patients shows a 3.4-fold increase in autoreactive B-cells in the peripheral blood compared to non-RA patients . Such deeckpoint . The impeckpoint . The impeckpoint . The pereckpoint ,18. BAFFeckpoint . The maieckpoint . The undeckpoint . The twoeckpoint . This B-eckpoint . The boneckpoint . The sameckpoint .null correlated with systemic morbidities associated with RA such as vasculitis and acute coronary syndrome [In the past decade, extensive studies have been carried out trying to understand the role of T-cells in RA especially the T-cell activation . T-cellssyndrome . In addition to cell-to-cell interaction, current evidences also suggest that CD4+ T-helper (Th) cells mainly contribute to the pathogenesis of RA through the secretion of cytokines and chemokines  . However−PD-1hi Tph cells once activated, secrete CXCL13 to recruit B cells for IL-21 production and help in B-cell survival, proliferation and maturation [Note worthily, T-cells also play pivotal role in stimulating B-cells responses and antibody production, which consequently contributes to the pathogenesis of RA . T follituration .Taken together, multiple T-cells and the respective effector pathways contribute to RA by primarily mediating the chronic inflammatory process. Th-1 cells that specifically secrete pro-inflammatory cytokines were thought to be the main cells causing RA. Following the discovery of other T-cell subtypes and their role in RA such as Th-2, Th-17 and Treg cells as mentioned above, it is clear that RA pathogenesis is much more complicated. This enhanced our understanding in RA and has significant impact on the disease management and treatment.Macrophages (Mɸ) are consistently found in synovial tissue. Most Mɸ reside within the tissues in a resting state under normal conditions . HoweverDue to the important roles in RA, targeting macrophages have been reported to turn the disease into remission mainly by inhibiting inflammation and bone erosion . The swiin vivo in RA [In addition to B-cells, T-cells and macrophages, other immune cells such as mast cell, DCs and natural killer (NK) cells have also been reported to mediate RA pathophysiology. Their roles in RA and potential therapeutic values are tabulated in vo in RA . The safvo in RA . HoweverPro-inflammatory cytokines play pivotal roles in the pathogenesis of RA . CytokinGenerally, the production of cytokines is initiated by the activated CD4+ T-cells . Other cAutoantibodies play significant roles in the pathogenesis of various autoimmune diseases including RA . When imIn the past few years, more studies have been conducted on an antibody against carbamylated antigens (known as anti-CarP antibodies). Anti-CarP antibodies was found to correlate with the patients’ joint erosion score but not ACPA . The samOther antibodies that are also known to associate with RA are anti-K8, anti-p68 and anti-Sa antibodies . KeratinIn addition to the cytokines and antibodies that play important immune-regulatory roles in RA, other soluble mediators such as synovium markers , cartilaCartilage-specific markers such as cartilage oligomeric matrix protein (COMP) have also been found to contribute to RA . COMP isDue to the indispensable roles of immunological components in RA pathogenesis, they have been targeted for clinical therapies development. These RA-specific targets comprise of immune or non-immune cells, cellular receptors and soluble factors. The cell-based therapies include B-cells and T-cell depletion . The RA Disease-modifying anti-rheumatic drugs (DMARDs) are standard medication for RA patients, methotrexate is one of the commonly used drug to suppress autoimmune response but its side effects is notorious . Over thVarious treatments targeting immune cells and related components are currently being evaluated in clinical trials . As statCurrently, the diagnostic markers for RA stated in the ACR/EULAR 2010 criteria are RF and anti-CCP antibodies ,109. AntAs RA treatment advances, the need of a specific and effective treatment is required. The introduction of biological treatment allows doctors to better manage RA and the increase in understanding of RA allow more specific treatment to be developed. However, studies have reported that some of the patients are non-respondent when treated with biological drugs . In ordeDespite the advancement of technologies and understanding about the disease, there is still no cure and no ‘preventive’ measures for RA. Efforts are ongoing to develop a prophylactic or therapeutic vaccine for RA which prevents the disease and the later, improve the therapeutic outcome of disease, respectively. So far, the most prominent RA prophylactic vaccine comprised of autologous DCs that had been modified by NF-κβ inhibitor and exposed to ACPA (designated as Rheumavax) before injecting back into patients. In 2015, the phase I trial using Rheumavax was completed and produced promising results with a few adverse events . HoweverPro-inflammatory cytokines play substantial role in RA pathogenesis. Hence, cytokines have been targeted for therapeutic vaccine development. These cytokines include macrophage inhibitory protein (MIF) , IL-2 reSalmonella vector with colonization factor antigen-I [Escherichia coli enterotoxin B heat labile [There have been numerous vaccination strategies that are targeting collagens or the related peptides . Substanntigen-I  and Escht labile  could poWith the enhanced understanding of disease and advancement of therapy, the medical management of RA has significantly been improved in the past decades. The therapeutic objective of RA has been shifted from relieving the disease symptoms to arresting the disease processes. In addition to type of RA treatment, early detection of disease, method of disease measurement, disease classification and the criteria for remission play decisive roles in improving the patient’s treatment outcomes. Immune cells particularly B- and T-lymphocytes are key components involved in each of the aspect as abovementioned. Current evidences suggest that these immune cells can be targeted as one of the therapeutic approaches for RA such as T-cell and B-cell depletion and tolDCs treatments. Further investigations are warranted for in-depth understanding of the functions of immune cells in RA. This shall ultimately lead to a more effective therapeutic modality and improve the life quality of the RA patients.


Microfluidic devices are widely used for cell analysis, including applications for single-cell analysis, healthcare, environmental monitoring, and organs-on-a-chip that mimic organs in microfluidics. Moreover, to enable high-throughput cell analysis, real-time monitoring, and non-invasive cell assays, electric and electrochemical systems have been incorporated into microfluidic devices. In this mini-review, we summarize recent advances in these systems, with applications from single cells to three-dimensional cultured cells and organs-on-a-chip. First, we summarize microfluidic devices combined with dielectrophoresis, electrophoresis, and electrowetting-on-a-dielectric for cell manipulation. Next, we review electric and electrochemical assays of cells to determine chemical section activity, and oxygen and glucose consumption activity, among other applications. In addition, we discuss recent devices designed for the electric and electrochemical collection of cell components from cells. Finally, we highlight the future directions of research in this field and their application prospects. Cell analysis is essential for healthcare and environmental monitoring, and has recently benefited from the organs-on-a-chip technique that can effectively mimic organs and their microfluidics -based assays. Electric and electrochemical approaches are widely used for all of these applications, including electrophoresis, dielectrophoresis (DEP), and electrowetting-on-dielectric (EWOD).Driven by the negative charges of cell membranes, cells can be moved from a microfluidic channel to an electrode applied at a positive potential. For example, yeast cells were trapped using electrophoresis, and a reporter protein was electrochemically evaluated using the electrode  devices are widely used for cell manipulation , and PCR. However, these traditional techniques are time-consuming, require manual sample collection from the microfluidic system, and necessitate large working volumes. Therefore, there is strong demand for the integration of online sensor capabilities.Recently, electric and electrochemical systems have been used for evaluating cells in microfluidic devices, and some of these key applications are highlighted below.2 is reduced to H2O to obtain oxygen reduction currents at the electrodes. Some electrochemical sensors have been developed with gas-permeable membranes, known as Clark-type sensors. Moya et al. reported a liver chip integrated with multiple sensors and a porous, delicate membrane  electrodes are used for measuring the amount of dissolved oxygen near the cells, because O2O2 or redox mediators, are measured. Misun et al. reported a droplet array device with enzyme-modified electrodes for body-on-a-chip applications  using electrochemical methods -MB as a biomarker secreted from a damaged cardiac spheroid. Electrochemical impedance spectroscopy (EIS) was adopted to the sensor system comprising a microelectrode functionalized with CK-MB-specific aptamers.Shin et al. reported a microfluidic aptamer-based electrochemical sensor for monitoring damage to cardiac organoids  vesicles secreted from various cells, and are recognized as important mediators of intracellular communication or transporters of pathogenic proteins. Moreover, exosomes have recently attracted attention as candidate biomarkers of various diseases such as cancers and metabolic disorders. Exosomes have been monitored using aptamer-based electrochemical sensors  is another approach used to analyze exosomes and extracellular vesicles. Akagi et al. developed a microCE chip and applied it to an on-chip immunoelectrophoresis assay for extracellular vesicles (EVs) of human breast cancer cells  is a widely used parameter for evaluating Similar to TEER measurements, an electrochemical permeability assay was reported for evaluating cell monolayer permeability  technology will be used for incorporating many addressable electrodes into microfluidic devices. Indeed, LSI devices have already been used for electrochemical imaging (Inoue et al., Since electrodes are inevitably fouled during the measurement, long-term assays remain a challenge of this technology. For example, measurement of oxygen consumption using non-modified electrodes can only be continuously performed for 2 days. For long-term monitoring, the electrodes should be modified with certain materials, or the electrodes will need to be changed every 2 days. For this purpose, the attachment and connectors should be improved. In addition, enzymes might be unsuitable for long-term measurement because their activity gradually decreases. To solve these problems, non-enzyme electrochemical sensors using metal nanoparticles and porous surfaces have been reported (Niu et al., For multiplex assays, individual sensors should be modified with different materials such as glucose oxidase and HRP. For this purpose, electrodeposition is a useful technique for addressable and individual electrode arrays. Since electrodeposition is also applied for hydrogel formation (Ozawa et al., in vitro cell monitoring (Curto et al., In general device fabrication, photolithography, and metal-sputtering techniques are typically used. In contrast, it is expected that printing techniques will become more widely used in future applications, including inkjet printing (Bachmann et al., Nanodevices are also increasingly used for cell analysis in microfluidic chips. For example, nanopores were used for measuring oligonucleotides and microvesicles via detection of ion currents when passing through the pores (Anderson et al., In this review, we described the electric and electrochemical devices for heart-on-a-chip, liver-on-a-chip, carcinoma microtissue models, and so on. Since lung-on-chip (Huh et al., In this review, we discuss the cell manipulation for cell analysis in microfluidic devices. In future, these techniques will also be used for fabrication of functional tissue models. Some studies have reported the fabrication of tissue models for manipulating cells and scaffold materials using DEP (Ramón-Azcón et al., We believe, the presented electric and electrochemical techniques have high expectations to broaden the possibilities of microfluidic devices and cell analysis.All authors wrote the manuscript. KoI and HS supervised preparation of the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes (MLS) are the two main cellular components of the synovium. It has been widely reported that FLS and MLS play essential roles in the joint pathology of rheumatoid arthritis (RA). Although various studies have analyzed both human and animal tissues and have shown that both cell types are involved in different stages of RA, ontology, and specific functions of both cell populations and their interactions are not well understood. In this review, we will summarize recent research on FLS and MLS in RA and focus on the development and function of two predominant synovial cell types. In addition, we will discuss the communication between FLS or MLS and highlight potential treatments for RA that involve synoviocytes. The lining of the synovium inside the fibrous outer layer (subintima) consists of two to three layers of cells. This intimal synovial lining (intima) is composed predominantly of two cell types: MLS (or type A synoviocytes) and FLS (or type B synoviocytes) .+ mesenchymal stromal/stem cells in the synovial tissue. These experiments showed a potential contribution of these stem cells to synovial homeostasis  and Ly6C but are also F4/80intermediate. The ontogeny of macrophages is summarized in Figure A major problem for the identification of individual monocyte/macrophage populations is the redundancy of marker molecules. Generally, murine tissue-resident macrophages which are derived from embryonic precursor cells are F4/80A transcriptome profiling of FLS and MLS isolated from rheumatoid arthritis (RA) patients confirmed that MLS are macrophages and have strong inflammatory tendencies. Interestingly, it also showed that FLS were able to substantially contribute to the inflammatory response . HoweverThe role of FLS in RA has been well established . FLS areIn rheumatoid inflammation, FLS secrete various pro-inflammatory factors. The main cytokine secreted by FLS is interleukin (IL)-6 , which iin vitro, even in the absence of exogenous stimuli  or factors with a combination of pro-inflammatory and anti-inflammatory effects under inflammatory conditions. For example, transforming growth factor β secreted by FLS has a dual effect on MLS in RA, depending on concentration and exposure time , 33. Oth stimuli  indicate stimuli .Fibroblast-like synoviocytes hyperplasia in the inflamed synovium is a hallmark of RA. This increased presence of FLS is due to strong proliferation and reduced apoptosis , 37. TheAfter activation by other cellular components in the pathological RA synovium (including MLS), FLS produce several enzymes that are important for their invasive features and contribute to tissue destruction. Matrix metalloproteinases are known to cause degradation of the extracellular matrix. Other factors secreted by FLS include collagenases, aggrecanases, cathepsins, and RANKL, which play an important role in the invasive activities of FLS and subsequent bone and cartilage destruction , 15. Conin vivo and their slow or non-existent proliferation in vitro. It has been shown that MLS contribute to RA progression by secretion of various factors, including reactive oxygen species, nitric oxide intermediates, and matrix-degrading enzymes  suppresses the secretion of pro-inflammatory cytokines and ameliorates the inflammatory response . In addiytokines . Furthere damage . This reic cells .in vivo in mouse models, indicating the pharmacological potential of MKK3 and MKK6 inhibitors for MLS/FLS-targeted therapy of RA  pathway  Figure . It is wpy of RA , 51.via regulation of macrophage-secreted pro-inflammatory cytokines, in particular, IL-6 and TNF-α. These pro-inflammatory cytokines have been extensively studied in clinical trials, and drugs that specifically target these two cytokines have been identified and are used in therapy (Disease-modifying anti-rheumatic drugs (DMARDs) are the most commonly used drugs for RA . Althoug therapy . TNF mon therapy . The cur therapy . Therefo therapy , Sirukum therapy , Clazaki therapy , Olokizu therapy , Sarilum therapy , and toc therapy , are in  therapy .via repressing MAPK and NF-κB pathways.Based on previous findings, targeting of FLS definitely should be considered an option for RA therapy. FLS are directly involved in RA pathogenesis and produce pro-inflammatory cytokines. Therefore, either alternative or complementary anti-inflammatory or anti-immune therapy can be used to target FLS. CDH11 is the first specific factor proven to be an essential, functional surface protein of FLS in RA. As indicated in Table Besides the specific expression of CDH11 in FLS, other common markers of both FLS and MLS can also be considered as potential RA targets. For example, suppression of an essential gene, such as the c-Jun N-terminal kinase (JNK) in the MAPK pathway also attenuates the effect of RA in rodent models . The JNKin vitro , either in experimental or therapeutic applications , 71. As + MLS were observed in synovia from RA patients, and experimental therapy with an anti-GM-CSF-R antibody  is a downstream target of GM-CSF/GM-CSF-R signaling in monocytes . An incrRA model . IRF5 caed joint . In addi−/− mice , confirm−/− mice . Therefo lesions . HoweverEven in a “homogeneous” cell population (such as MLS and FLS), the isolation of specific cellular groups is dependent on positive or negative sorting according to several markers. Therefore, a considerable variation between individual cells will still be detected. Detection of variations at the single-cell level can reveal the heterogeneity of FLS and MLS involvement in the RA synovium from individual patients, enabling identification of cell origin and more specific cell populations for the use in RA therapy. For example, single-cell RNA sequencing provides unbiased identification of FLS and MLS subtypes in RA synovium . Variablin vivo in RA has not yet been analyzed at the single-cell level. Finally, to understand the cross talk between microenvironment and MLS/FLS in synovium, it will be essential to deciper the contribution of this cell types to RA pathology. We suggest that the abovementioned options should be considered and deserve further investigation in future work.Although the main two types of synovicytes in synovium (MLS and FLS) have been identified for a long time, researcher began to notice the essential roles of these two types of cells in the RA development only recently. MLS and FLS have been proven to contribute to RA pathology collaboratively. A range of novel methods have been developed for the evaluation of new potential RA therapies that target MLS and FLS in the inflamed synovium Figure . Some cuJT drafted the manuscript. WH, PZ, XW, HK, and WW revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.