Mesenchymal stem cells and a vitamin D receptor agonist additively suppress T helper 17 cells and the related inflammatory response in the kidney.

Mesenchymal stem cells (MSCs) suppress T helper (Th)17 cell differentiation and are being clinically pursued for conditions associated with aberrant Th17 responses. Whether such immunomodulatory effects are enhanced by coadministration of MSCs with other agents is not well known. In the present study, individual and combined effects of MSCs and the vitamin D receptor (VDR) agonist paricalcitol on Th17 induction were investigated in vitro and in a mouse model of sterile kidney inflammation (unilateral ureteral obstruction). In vitro, MSCs and paricalcitol additively suppressed Th17 differentiation, although only MSCs suppressed expression of Th17-associated transcriptions factors. Combined administration of MSCs and paricalcitol resulted in an early (day 3) reduction of intrarenal CD4(+) and CD8(+) T cells, CD11b(+)/lymphocyte antigen 6G(+) neutrophils, and inflammatory (lymphocyte antigen 6C(hi)) monocytes as well as reduced transcript for IL-17 compared with untreated animals. Later (day 8), obstructed kidneys of MSC/paricalcitol double-treated mice, but not mice treated with either intervention alone, had reduced tubular injury and interstitial fibrosis as well as lower numbers of neutrophils and inflammatory monocytes and an increase in the ratio between M2 (CD206(+)) and M1 (CD206(-)) macrophages compared with control mice. Adjunctive therapy with VDR agonists may enhance the immunosuppressive properties of MSCs in the setting of pathogenic Th17-type immune responses and related inflammatory responses.

The influence of hypoxia on the differentiation capacities and immunosuppressive properties of clonal mouse mesenchymal stromal cell lines.

Multipotent mesenchymal stromal cells are multipotent cells capable of differentiating into different mesodermal cell types. Enigmatically, mesenchymal stromal cells present in the bone marrow support early lymphopoiesis yet can inhibit mature lymphocyte growth. Critical features of the bone marrow microenvironment, such as the level of oxygen, play an important role in mesenchymal stromal cell biology. Herein, we show that a panel of continuously growing mouse mesenchymal stromal cell lines, namely OP9, MS5, PA6, ST2 and B16-14, exhibit mesenchymal stromal cell characteristic phenotypes and respond physiologically to oxygen deprivation. Culturing freshly isolated bone marrow-derived mesenchymal stromal cells or cell lines at 5% O2 resulted in a dramatic increase in expression of hypoxia-inducible factor family members and of key genes involved in their differentiation. Phenotypically, their osteogenic and adipogenic differentiation capacity was generally improved in hypoxia, whereas their inhibitory effects on in vitro T-cell proliferation were preserved. Taken together, we conclude that these continuously growing mouse cell lines behave as canonical mesenchymal stromal cells and respond physiologically to hypoxia, thereby providing a potent tool for the study of different aspects of mesenchymal stromal cell biology.

IL-10 mediates the immunoregulatory response in conjugated linoleic acid-induced regression of atherosclerosis.

Conjugated linoleic acid (CLA) induces regression of preestablished atherosclerosis in the ApoE(-/-) mouse. Understanding the mechanisms involved may help in identifying novel pathways associated with the regression of human disease. Animals were administered a 1% cholesterol diet for 12 wk, with 1% CLA supplementation from wk 8 to 12. ApoE(-/-) mice fed only the 1% cholesterol diet for 12 wk were employed as controls. Transcriptomic analysis of mouse aorta showed that many of the components of the IL-10 signaling pathway were modified during CLA-induced regression. Real-time PCR and Western blot analysis showed increased IL-10 receptor expression, phosphorylation of STAT3, and downstream target gene expression in the aorta, alongside an increase in serum IL-10 (79.8 ± 22.4 vs. 41.9 ± 5.5 pg/ml, n = 10; P < 0.01). CLA -supplementation also increased IL-10 production in bone marrow-derived macrophages (143.6 ± 28.6 vs. 94 ± 5.6 pg/ml, n = 5; P < 0.05). To explore the mechanisms for altered IL-10 production, we examined the profile of monocyte/macrophage phenotype in the vessel wall, bone marrow, and spleen. CLA increased macrophage polarization toward an anti-inflammatory M2 phenotype in vivo, increasing the population of Ly6C(lo) monocytes (29 vs. 77 ± 14, n=5, P < 0.05) in the aorta. CLA had similar effects on monocytes/macrophages differentiated from marrow-derived progenitor cells and on splenocytes. The induction of IL-10 on CLA supplementation in this model may reflect a systemic alteration toward an anti-inflammatory phenotype, which, in turn promotes increased vascular infiltration by Ly6C(lo) monocytes. These cells may contribute to CLA-induced disease regression.

Limitations associated with transcranial direct current stimulation for enhancement: considerations of performance tradeoffs in active-duty Soldiers.

Introduction: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation method, popular due to its low cost, ease-of-application, and portability. As such, it has gained traction in examining its potential for cognitive enhancement in a diverse range of populations, including active-duty military. However, current literature presents mixed results regarding its efficacy and limited evaluations of possible undesirable side-effects (such as degradation to cognitive processes). Methods: To further examine its potential for enhancing cognition, a double-blind, randomized, sham-controlled, within-subjects design, was used to evaluate both online active-anodal and -cathodal on several cognitive tasks administered. Potential undesirable side effects related to mood, sleepiness, and cognitive performance, were also assessed. Active tDCS was applied for 30 min, using 2 mA, to the left dorsolateral prefrontal cortex with an extracephalic reference placed on the contralateral arm of 27 (14 males) active-duty Soldiers. Results: We report mixed results. Specifically, we found improvements in sustained attention (active-anodal) for males in reaction time (p = 0.024, ηp 2 = 0.16) and for sensitivity index in females (p = 0.013, ηp 2 = 0.18). In addition, we found faster reaction time (p = 0.034, ηp 2 = 0.15) and increased accuracy (p = 0.029, ηp 2 = 0.16) associated with executive function (active-anodal and -cathodal), and worsened working memory performance (active-cathodal; p = 0.008, ηp 2 = 0.18). Additionally, we found increased risk-taking with active-anodal (p = 0.001, ηp 2 = 0.33). Discussion: tDCS may hold promise as a method for cognitive enhancement, as evidenced by our findings related to sustained attention and executive function. However, we caution that further study is required to better understand additional parameters and limitations that may explain results, as our study only focused on anode vs. cathode stimulation. Risk-taking was examined secondary to our main interests which warrants further experimental investigation isolating potential tradeoffs that may be associated with tDCS simulation.

Eco-anxiety among regional Australian youth with mental health problems: A qualitative study.

AIM: In Australia, climate-related disasters disproportionately affect rural, regional and remote young people with effects ranging from severe flooding and catastrophic fires to unbearable heat and yet most studies on eco-anxiety are based on reports by urban youth who do not have direct experiences of such impacts. Furthermore, there is a dearth of research on how eco-anxiety impacts those who already experience mental health problems. The present study aims to address this gap by focussing on the lived experiences of regional Australian youth with recent experience of climate-related disasters alongside clinical insights from those involved in their care. METHODS: Two groups, a clinician and client group, were recruited through headspace Port Macquarie-a primary youth mental health service in a regional city of New South Wales, Australia. In all, 25 participants took part in focus group discussions, including 13 clinicians and 12 clients of the service. Clients and clinicians responded to a version of the same questions: (1) whether the effects of climate change impact on regional youth with mental health problems, (2) how young people cope with eco-anxiety and (3) how regional communities can help young people cope with eco-anxiety better. Group discussions were audio-recorded and transcribed. Transcripts were analysed according to the principles of Interpretative Phenomenological Analysis using a team approach. RESULTS: Three dimensions of eco-anxiety were identified by clinicians and clients-helplessness in the present, hopelessness about the future and acute stress and anxiety related to experiences of severe flooding and fires. Clinicians and clients also thought that a misalignment between young people and older generations, including government, was a source of eco-anxiety and having a collective voice was seen as important for regional youth as was community support through social media sites. Clinicians thought that eco-anxiety was 'in the background' for their clients, whereas the clients who participated were clearly experiencing eco-anxiety. Whereas clinicians could identify potential coping strategies, clients could not. CONCLUSIONS: Eco-anxiety can be experienced by regional youth with mental health problems as both an acute response to natural hazards and a more sustained sense of hopelessness about the future. Impacts of acute anxiety and chronic hopelessness, with its associated depression risk, among young people with pre-existing mental health problems warrants further investigation as this study suggests that it may exacerbate their existing conditions. Clinicians and clients in this region would benefit from specific training and resources related to the identification and treatment of eco-anxiety. Future research on climate-related mental health should be inclusive of the perspectives of those who have direct experience of climate-related adverse events.

When narcissists exemplify ethics: Contingent consequences of ethical leadership.

Organizations increasingly encourage, recognize, and reward ethical leadership to preempt the economic and reputational risks associated with ethical failures. At the same time, organizational leadership positions are disproportionately occupied by individuals higher in narcissism. We highlight how the combination of these two phenomena carries important organizational implications by examining how ethical leadership behaviors differentially impact leaders based on their level of narcissism. Building upon self-concordance theory, we introduce a model of contingent consequences of ethical leadership. Our model identifies motivational (i.e., self-efficacy of the leader) and social (i.e., admiration of the leader) mechanisms that explain why ethical leadership positively predicts leadership effectiveness for some leaders, but not for others. We test our model using a field study and two experiments. Findings from these three studies point to a problematic leadership paradox: When leaders higher in narcissism behave more ethically, they incur higher motivational costs and reap fewer social benefits compared to their peers who are lower in narcissism. Results reveal risks to leadership effectiveness for narcissistic leaders who attempt to lead more ethically. We discuss implications for ethical leadership research and practice. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Interleukin-1 accounts for intrarenal Th17 cell activation during ureteral obstruction.

Interleukin 17A-secreting T-helper 17 (Th17) cells are pathogenic in inflammatory kidney diseases, but their intrarenal regulation is poorly understood. In order to better define Th17 cell dynamics during interstitial inflammation, we utilized the mouse unilateral ureteral obstruction model to analyze inflammatory cell subtypes by multicolor flow cytometry and cell sorting and by effects on in vitro-generated Th17 cells. Interleukin 17A expression localized to CCR6(+)CCR4(+/-)CD4(+) T-cells and progressively increased in obstructed kidneys. The number of CCR6(+)CD4(+) T-cells increased over 10-fold by 72 h, were enriched for interleukin 17A production, and were highly proliferative based on in vivo bromodeoxyuridine incorporation. Secreted products of leukocytes isolated from obstructed kidneys enhanced the interleukin 17A production of in vitro-generated Th17 cells. This Th17-enhancing activity was identified as interleukin-1 produced by renal dendritic cells and monocytes. The in vivo validity of these findings was confirmed in mice lacking the interleulin-1 receptor and in mice treated with a recombinant interleukin-1 receptor antagonist, each of which exhibited reduced intrarenal Th17 activity compared with control mice. Thus, the inflamed kidney accumulates CCR6(+) Th17 cells that undergo activation and proliferation. Production of interleukin 1 family cytokines by resident dendritic cells and infiltrating monocytes enhances intrarenal Th17 activation in acute kidney injury.

Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor.

Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naïve T cells remain unclear. MSC influence on the differentiation of naïve and memory CD4(+) T cells toward the Th17 phenotype was examined. CD4(+) T cells exposed to Th17-skewing conditions exhibited reduced CD25 and IL-17A expression following MSC co-culture. Inhibition of IL-17A production persisted upon re-stimulation in the absence of MSCs. These effects were attenuated when cell-cell contact was prevented. Th17 cultures from highly purified naïve- and memory-phenotype responders were similarly inhibited. Th17 inhibition by MSCs was reversed by indomethacin and a selective COX-2 inhibitor. Media from MSC/Th17 co-cultures contained increased prostaglandin E2 (PGE2) levels and potently suppressed Th17 differentiation in fresh cultures. MSC-mediated Th17 inhibition was reversed by a selective EP4 antagonist and was mimicked by synthetic PGE2 and a selective EP4 agonist. Activation-induced IL-17A secretion by naturally occurring, effector-memory Th17 cells from a urinary obstruction model was also inhibited by MSC co-culture in a COX-dependent manner. Overall, MSCs potently inhibit Th17 differentiation from naïve and memory T-cell precursors and inhibit naturally-occurring Th17 cells derived from a site of inflammation. Suppression entails cell-contact-dependent COX-2 induction resulting in direct Th17 inhibition by PGE2 via EP4.

Gender, bottom-line mentality, and workplace mistreatment: The roles of gender norm violation and team gender composition.

Although gender has been identified as an important antecedent in workplace mistreatment research, empirical research has shown mixed results. Drawing on role congruity theory, we propose an interactive effect of gender and bottom-line mentality on being the target of mistreatment. Across two field studies, our results showed that whereas women experienced more mistreatment when they had higher levels of bottom-line mentality, men experienced more mistreatment when they had lower levels of bottom-line mentality. In another field study, using round-robin survey data, we found that team gender composition influenced the degree to which the adoption of a bottom-line mentality by female team members was perceived to be a gender norm violation, which subsequently predicted their likelihood of being mistreated. Specifically, women who had higher (vs. lower) levels of bottom-line mentality were more likely to be perceived to violate gender norms in teams with a lower proportion of women, and in turn, perceived gender norm violation was positively associated with being mistreated. We discuss theoretical and practical implications of our findings and directions for future research. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Being present and thankful: A multi-study investigation of mindfulness, gratitude, and employee helping behavior.

Gratitude plays an integral role in promoting helping behavior at work. Thus, cultivating employees' experiences of gratitude represents an important imperative in modern organizations that rely on teamwork and collaboration to achieve organizational goals. Yet, today's workplace presents a complex array of demands that make it difficult for employees to fully attend to and appreciate the various benefits they receive at work. As such, gratitude is difficult for employers to promote and for employees to experience. Despite these observations, the role of attention and awareness in facilitating employees' feelings of gratitude is largely overlooked in the extant literature. In this study, we examined whether one notable form of present moment attention, mindfulness, may promote helping behavior by stimulating the positive, other-oriented emotion of gratitude. Across two experimental studies, a semiweekly, multisource diary study, and a 10-day experience sampling investigation, we found converging evidence for a serial mediation model in which state mindfulness, via positive affect and perspective taking, prompts greater levels of gratitude, prosocial motivation, and, in turn, helping behavior at work. We discuss the theoretical and practical implications of our investigation, as well as avenues for the future research. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Evaluation of myCOPD Digital Self-management Technology in a Remote and Rural Population: Real-world Feasibility Study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common, costly, and incurable respiratory disease affecting 1.2 million people in the United Kingdom alone. Acute COPD exacerbations requiring hospitalization place significant demands on health services, and the incidence of COPD in poor, remote, and rural populations is up to twice that of cities. OBJECTIVE: myCOPD is a commercial, digital health, self-management technology designed to improve COPD outcomes and mitigate demands on health services. In this pragmatic real-world feasibility study, we aimed to evaluate myCOPD use and its clinical effectiveness at reducing hospitalizations, inpatient bed days, and other National Health Service (NHS) resource use. METHODS: myCOPD engagement and NHS resource use was monitored for up to 1 year after myCOPD activation and was compared against health service use in the year prior to activation. A total of 113 participants from predominantly remote and rural communities were recruited via community-based care settings, including scheduled home visits, outpatient appointments, pulmonary rehabilitation, and phone or group appointments. There were no predetermined age, disease severity, geographical, or socioeconomic inclusion or exclusion criteria. RESULTS: Out of 113 participants, 89 activated myCOPD (78.8%), with 56% (50/89) of those participants doing so on the day of enrollment and 90% (80/89) doing so within 1 month. There was no correlation between participant enrollment, activation, or myCOPD engagement and either age, socioeconomics, rurality, or COPD severity. Most active participants used at least one myCOPD module and entered their symptom scores at least once (79/89, 89%). A subgroup (15/89, 17%) recorded their symptom scores very frequently (>1 time every 5 days), 14 of whom (93%) also used four or five myCOPD modules. Overall, there were no differences in hospital admissions, inpatient bed days, or other health service use before or after myCOPD activation, apart from a modest increase in home visits. Subgroup analysis did, however, identify a trend toward reduced inpatient bed days and hospital admissions for those participants with very high myCOPD usage. CONCLUSIONS: Our results suggest that neither age, wealth, nor geographical location represent significant barriers to using myCOPD. This finding may help mitigate perceived risks of increased health inequalities associated with the use of digital health technologies as part of routine care provision. Despite high levels of activation, myCOPD did not reduce overall demands on health services, such as hospital admissions or inpatient bed days. Subgroup analysis did, however, suggest that very high myCOPD usage was associated with a moderate reduction in NHS resource use. Thus, although our study does not support implementation of myCOPD to reduce health service demands on a population-wide basis, our results do indicate that highly engaged patients may derive benefits.

The whiplash effect: The (moderating) role of attributed motives in emotional and behavioral reactions to abusive supervision.

Although extant research shows a clear link between abusive supervision and detrimental consequences for organizations and their members, the popular press and media are replete with suggestions that abusive supervision can be positive and motivating. Drawing from the social functional view of emotions and emerging research on attributed motives of abusive supervision, we examine this phenomenon, which we refer to as the whiplash effect-the notion that subordinates may display different emotional and behavioral reactions to supervisory abuse depending on their attributions for abuse. We conduct 3 studies to examine this effect at both the between- and within person level. Results from a multisource, time-lagged field study (between-person) and a laboratory-based experiment (between-person) indicate that when subordinates believe that the abusive supervisor is motivated by desires to cause harm (i.e., injury initiation attribution is higher), abusive supervision is more likely to engender anger, which, in turn, elicits more deviant behaviors and fewer organizational citizenship behaviors; however, when subordinates believe the abusive supervisor is motivated by desires to improve performance (i.e., performance promotion attribution is higher), abusive supervision is more likely to evoke guilt, which, in turn, elicits fewer deviant behaviors and more organizational citizenship behaviors. These results were then expanded in an experience sampling study (within-person), which allowed us to further examine how general interpretations of supervisors' motives behind abusive supervision shape employees' momentary emotional and behavioral responses toward daily abusive supervisor behavior. Theoretical and practical implications are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

An under-met and over-met expectations model of employee reactions to merit raises.

The authors developed a model of how raise expectations influence the relationship between merit pay raises and employee reactions and tested it using a sample of hospital employees. Pay-for-performance (PFP) perceptions were consistently related to personal reactions (e.g., pay raise happiness, pay-level satisfaction, and turnover intentions). Merit pay raises were strongly related to reactions only among employees with high raise expectations and high PFP perceptions. The interactive effects of under-met/over-met expectations and PFP perceptions were mediated by the extent to which participants saw the raise as generous and they were happy with the raises they received. The authors discuss the implications of these findings for expectation-fulfillment theories, merit pay research, and the administration of incentives.

Abusive supervision and subordinates' organization deviance.

The authors developed an integrated model of the relationships among abusive supervision, affective organizational commitment, norms toward organization deviance, and organization deviance and tested the framework in 2 studies: a 2-wave investigation of 243 supervised employees and a cross-sectional study of 247 employees organized into 68 work groups. Path analytic tests of mediated moderation provide support for the prediction that the mediated effect of abusive supervision on organization deviance (through affective commitment) is stronger when employees perceive that their coworkers are more approving of organization deviance (Study 1) and when coworkers perform more acts of organization deviance (Study 2).

The moderating roles of self-esteem and neuroticism in the relationship between group and individual undermining behavior.

The authors developed and tested a multilevel interactive model of the relationship between group undermining and individual undermining behavior in 2 multiwave studies of group members. Integrating the literature on group influences on individual behavior with the individual difference literature, the authors predicted a 3-way Group Undermining x Self-Esteem x Neuroticism interaction, such that the relationship between group and individual undermining would be strongest among those simultaneously high in self-esteem and neuroticism. The 3-way interaction was supported in Study 1 (457 participants in 103 groups) and replicated in Study 2 (415 participants in 93 groups) with additional controls and alternative measures of key constructs. The authors discuss the implications of the research and identify future research directions.

Why victims of undermining at work become perpetrators of undermining: An integrative model.

We develop and test an integrative model explaining why victims of workplace social undermining become perpetrators of undermining. Conceptualizing social undermining as a norm-violating and a resource-depleting experience, we theorize that undermining victimization lowers interpersonal justice perceptions and depletes self-regulatory resources, and these 2 mechanisms in tandem trigger a moral disengagement process that influences subsequent undermining behaviors. We further theorize that moral identity functions as a boundary condition: high moral identity attenuates whether interpersonal injustice and resource depletion shape moral disengagement and whether moral disengagement translates to subsequent undermining. A field study of bank employees provides empirical support for the mediating mechanisms, and shows that employees who have high moral identity are less likely to respond to interpersonal injustice by morally disengaging and to translate moral disengagement to undermining. (PsycINFO Database Record

Abusive supervision and subordinates' organizational citizenship behavior.

The relationship between subordinates' perceptions of abusive supervision and supervisors' evaluations of subordinates' organizational citizenship behavior (OCB) was explored among a sample of 373 Air National Guard members and their military supervisors. As predicted, the relationship between abusive supervision and subordinates' OCB was stronger among subordinates who defined OCB as extra-role behavior (compared with those defining OCB as in-role behavior), and this effect was fully mediated by the interactive effect of procedural justice and OCB role definitions. The study's implications for theory and research are discussed, its limitations are identified, and directions for future research are suggested.

Moderators of the relationships between coworkers' organizational citizenship behavior and fellow employees' attitudes.

The authors developed and tested the prediction that the relationship hetween coworkers' organizational citizenship behaviors (OCBs) and fellow employees' attitudes depends on the supervisors' abusiveness. Results of a longitudinal study using data collected from 173 supervised employees at 2 points in time (separated by 7 months) suggested that coworkers' OCB was positively related to fellow employees' job satisfaction and affective commitment when abusive supervision was low. However, when abusive supervision was high, coworkers' OCB was negatively related to job satisfaction and was unrelated to organizational commitment. The results of a 2nd study were consistent with the idea that the attributions employees make for their coworkers' OCB explains the moderating effect of abusive supervision on the relationship between coworkers' OCB and job satisfaction.

Reactions to merit pay increases: a longitudinal test of a signal sensitivity perspective.

The relationships among merit pay raises, trait positive affectivity (PA), and reactions to merit pay increases (pay attitudes and behavioral intentions) were explored in a longitudinal study of hospital employees. Drawing on signal sensitivity theory, the authors expected that PA would moderate the relationship between merit pay raise size and reactions to the increase such that pay raise size would be more strongly related to pay attitudes and behavioral intentions among those low in PA. Results strongly supported the predictions in the case of reactions to the raise amount (happiness and effort intentions) but not for pay level satisfaction. Implications of the results and directions for future research are identified.

Back from the brink: a mesenchymal stem cell infusion rescues kidney function in acute experimental rhabdomyolysis.

Systemic administration of mesenchymal stem (stromal) cells (MSCs) has shown benefit in a range of experimental models of acute kidney injury, although the reported mechanisms of action and requirement for MSC localization to the kidney have varied. Geng and colleagues now demonstrate that a single intravenous infusion of MSCs given 6 hours after induction of acute muscle necrosis (rhabdomyolysis) robustly ameliorates the resulting acute kidney injury and promotes early intra-renal accumulation of CD206+ (M2) macrophages. The benefit occurred in the absence of MSC localization to the kidney and could be reproduced by adoptive transfer of ex vivo-programmed M2 macrophages.