Interplay between CCN1 and Wnt5a in endothelial cells and pericytes determines the angiogenic outcome in a model of ischemic retinopathy

CYR61-CTGF-NOV (CCN)1 is a dynamically expressed extracellular matrix (ECM) protein with critical functions in cardiovascular development and tissue repair. Angiogenic endothelial cells (ECs) are a major cellular source of CCN1 which, once secreted, associates with the ECM and the cell surface and tightly controls the bidirectional flow of information between cells and the surrounding matrix. Endothelium-specific CCN1 deletion in mice using a cre/lox strategy induces EC hyperplasia and causes blood vessels to coalesce into large flat hyperplastic sinuses with no distinctive hierarchical organization. This is consistent with the role of CCN1 as a negative feedback regulator of vascular endothelial growth factor (VEGF) receptor activation. In the mouse model of oxygen-induced retinopathy (OIR), pericytes become the predominant CCN1 producing cells. Pericyte-specific deletion of CCN1 significantly decreases pathological retinal neovascularization following OIR. CCN1 induces the expression of the non-canonical Wnt5a in pericyte but not in EC cultures. In turn, exogenous Wnt5a inhibits CCN1 gene expression, induces EC proliferation and increases hypersprouting. Concordantly, treatment of mice with TNP470, a non-canonical Wnt5a inhibitor, reestablishes endothelial expression of CCN1 and significantly decreases pathological neovascular growth in OIR. Our data highlight the significance of CCN1-EC and CCN1-pericyte communication signals in driving physiological and pathological angiogenesis

Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells

CCN1/CYR61 promotes angiogenesis, tumor growth and chemoresistance by binding to its integrin receptor αvβ3 in endothelial and breast cancer (BC) cells. CCN1 controls also tissue regeneration by engaging its integrin receptorα6β1 to induce fibroblast senescence. Here, we explored if the ability of CCN1 to drive an endocrine resistancephenotype in estrogen receptor-positive BC cells relies on interactions with either αvβ3 or α6β1. First, we tookadvantage of site-specific mutagenesis abolishing the CCN1 receptor-binding sites to αvβ3 and α6β1 to determine theintegrin partner responsible for CCN1-driven endocrine resistance. Second, we explored a putative nuclear role ofCCN1 in regulating ERα-driven transcriptional responses. Retroviral forced expression of a CCN1 derivative with asingle amino acid change (D125A) that abrogates binding to αvβ3 partially phenocopied the endocrine resistancephenotype induced upon overexpression of wild-type (WT) CCN1. Forced expression of the CCN1 mutant TM,which abrogates all the T1, H1, and H2 binding sites to α6β1, failed to bypass the estrogen requirement foranchorage-independent growth or to promote resistance to tamoxifen. Wild-type CCN1 promoted estradiol-independent transcriptional activity of ERα and enhanced ERα agonist response to tamoxifen. The α6β1-binding-defective TM-CCN1 mutant lost the ERα co-activator-like behavior of WT-CCN1. Co-immunoprecipitation assaysrevealed a direct interaction between endogenous CCN1 and ERα, and in vitro approaches confirmed the ability ofrecombinant CCN1 to bind ERα. CCN1 signaling via α6β1, but not via αvβ3, drives an endocrine resistance phenotypethat involves a direct binding of CCN1 to ERα to regulate itstranscriptional activity in ER+ BC cells.Fil: Espinoza, Ingrid. University of Mississippi; Estados Unidos. Mayo Clinic ; Estados UnidosFil: Yang, Lin. Mayo Clinic ; Estados UnidosFil: Steen, Travis Vander. Mayo Clinic ; Estados UnidosFil: Vellón, Luciano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Cuyàs, Elisabet. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi); EspañaFil: Verdura, Sara. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi); EspañaFil: Lau, Lester. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi); España. University of Illinois; Estados UnidosFil: Menendez, Javier A.. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi); EspañaFil: Lupu, Ruth. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi); Españ

Regulatory Problems in Very Preterm and Full-Term Infants Over the First 18 Months

Objective: This study is an investigation of differences in regulatory problems (RPs; crying, sleeping, feeding) expressed by infants born very preterm (VP; <32 wk gestation) or with very low birth weight (VLBW; <1500 g) and infants born at full term (FT) during the first 18 months of life. It investigates the prevalence of single and multiple RPs, their persistence and how early in infancy RPs still found at 18 months of age can be predicted. Method: This prospective longitudinal study of 73 VP/VLBW and 105 FT infants utilized a standard interview of mothers to assess regulatory problems among the infants at term, 3, 6, and 18 months of age. Results: Few differences were found between VP/VLBW and FT infants in the first 6 months. At 18 months, VP/VLBW infants had more single sleeping (RR = 2.2, CI = 1.3–3.7), feeding (RR = 1.4, CI = 1.03–1.8), and multiple RPs (RR = 1.7, CI = 1.02–2.8) than FT infants. In VP/VLBW infants, RPs as early as 3 months and in FT infants RPs as early as 6 months predicted RPs at 18 months. Those infants who had persistent RPs in the first 6 months of life were more likely to still have RPs at 18 months. Conclusion: VP/VLBW children are at slightly increased risk for RPs at term and in the second year of life. Clinicians should be aware that RPs that persist across the first 6 months point to increased risk of continuing RPs into toddlerhood in both VP/VLBW and FT infants

Impact of ocean warming on tropical cyclone track over the western north pacific: A numerical investigation based on two case studies

The impact of ocean warming on tropical cyclone (TC) track over the western North Pacific is an open issue. Relatively little is known about possible changes in TC tracks under ocean warming conditions due to both inhomogeneous observation networks and large natural variability over a relatively short observational period. A suite of semiidealized numerical experiments on two TC cases is conducted to investigate the response of TC tracks to increases in sea surface temperature (SST). It is found that the simulated TC track is highly sensitive to underlying SST. Specifically, through its influence on the radial distribution of sea surface enthalpy, ocean warming can lead to changes in the tangential wind profile and thus increase the TC size in terms of the radius of gale force wind, which is attributed to the increase in maximum wind speed, the expansion of the radius of maximum wind, and the additional increase in outer winds. The increased TC size, as suggested by previous studies, further leads to the eastward withdrawal of the western Pacific subtropical high (WPSH) and thus a northward turning of the TC. Results of climate simulations in the present study provide further evidence for the aforementioned impact of ocean warming on TC size and thus the WPSH and TC track. Results of the present study also imply that the threat of storms to countries in East Asia may be reduced due to possible changes in TC tracks if ocean warming continues in the future

Interpretation of ambiguity: differences between children and adolescents with and without an anxiety disorder

Background: Theory and treatment of anxiety disorders in young people are commonly based on the premise that interpretation biases found in anxious adults are also found in children and adolescents. Although there is some evidence that this may be the case, studies have not typically taken age into account, which is surprising given the normative changes in cognition that occur throughout childhood. The aim of the current study was to identify whether associations between anxiety disorder status and interpretation biases differed in children and adolescents. Methods: The responses of children (7-10 years) and adolescents (13-16 years) with and without anxiety disorders (n = 120) were compared on an ambiguous scenarios task. Results: Children and adolescents with an anxiety disorder showed significantly higher levels of threat interpretation and avoidant strategies than non-anxious children and adolescents. However, age significantly moderated the effect of anxiety disorder status on interpretation of ambiguity, in that adolescents with anxiety disorders showed significantly higher levels of threat interpretation and associated negative emotion than non-anxious adolescents, but a similar relationship was not observed among children. Conclusions: The findings suggest that theoretical accounts of interpretation biases in anxiety disorders in children and adolescents should distinguish between different developmental periods. For both ages, treatment that targets behavioral avoidance appears warranted. However, while adolescents are likely to benefit from treatment that addresses interpretation biases, there may be limited benefit for children under the age of ten

Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines

Recent studies have revealed an unexpected synergism between two seemingly unrelated protein families: CCN matricellular proteins and the tumor necrosis factor (TNF) family of cytokines. CCN proteins are dynamically expressed at sites of injury repair and inflammation, where TNF cytokines are also expressed. Although TNFα is an apoptotic inducer in some cancer cells, it activates NFκB to promote survival and proliferation in normal cells, and its cytotoxicity requires inhibition of de novo protein synthesis or NFκB signaling. The presence of CCN1, CCN2, or CCN3 overrides this requirement and unmasks the apoptotic potential of TNFα, thus converting TNFα from a proliferation-promoting protein into an apoptotic inducer. These CCN proteins also enhance the cytotoxicity of other TNF cytokines, including LTα, FasL, and TRAIL. Mechanistically, CCNs function through integrin α6β1 and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism. Mutant CCN1 proteins defective for binding α6β1-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines. Further, knockin mice that express an α6β1-HSPG-binding defective CCN1 are blunted in TNFα- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes. These findings implicate CCN proteins as contextual regulators of the inflammatory response by dictating or enhancing the cytotoxicity of TNFα and related cytokines

Perceived mastery climate, felt trust, and knowledge sharing

Interpersonal trust is associated with a range of adaptive outcomes, including knowledge sharing. However, to date, our knowledge of antecedents and consequences of employees feeling trusted by supervisors in organizations remains limited. On the basis of a multisource, multiwave field study among 956 employees from 5 Norwegian organizations, we examined the predictive roles of perceived mastery climate and employee felt trust for employees' knowledge sharing. Drawing on the achievement goal theory, we develop and test a model to demonstrate that when employees perceive a mastery climate, they are more likely to feel trusted by their supervisors at both the individual and group levels. Moreover, the relationship between employees' perceptions of a mastery climate and supervisor-rated knowledge sharing is mediated by perceptions of being trusted by the supervisor. Theoretical contributions and practical implications of our findings are discussed

The effectiveness, acceptability and cost-effectiveness of psychosocial interventions for maltreated children and adolescents: an evidence synthesis.

BACKGROUND: Child maltreatment is a substantial social problem that affects large numbers of children and young people in the UK, resulting in a range of significant short- and long-term psychosocial problems. OBJECTIVES: To synthesise evidence of the effectiveness, cost-effectiveness and acceptability of interventions addressing the adverse consequences of child maltreatment. STUDY DESIGN: For effectiveness, we included any controlled study. Other study designs were considered for economic decision modelling. For acceptability, we included any study that asked participants for their views. PARTICIPANTS: Children and young people up to 24 years 11 months, who had experienced maltreatment before the age of 17 years 11 months. INTERVENTIONS: Any psychosocial intervention provided in any setting aiming to address the consequences of maltreatment. MAIN OUTCOME MEASURES: Psychological distress [particularly post-traumatic stress disorder (PTSD), depression and anxiety, and self-harm], behaviour, social functioning, quality of life and acceptability. METHODS: Young Persons and Professional Advisory Groups guided the project, which was conducted in accordance with Cochrane Collaboration and NHS Centre for Reviews and Dissemination guidance. Departures from the published protocol were recorded and explained. Meta-analyses and cost-effectiveness analyses of available data were undertaken where possible. RESULTS: We identified 198 effectiveness studies (including 62 randomised trials); six economic evaluations (five using trial data and one decision-analytic model); and 73 studies investigating treatment acceptability. Pooled data on cognitive-behavioural therapy (CBT) for sexual abuse suggested post-treatment reductions in PTSD [standardised mean difference (SMD) -0.44 (95% CI -4.43 to -1.53)], depression [mean difference -2.83 (95% CI -4.53 to -1.13)] and anxiety [SMD -0.23 (95% CI -0.03 to -0.42)]. No differences were observed for post-treatment sexualised behaviour, externalising behaviour, behaviour management skills of parents, or parental support to the child. Findings from attachment-focused interventions suggested improvements in secure attachment [odds ratio 0.14 (95% CI 0.03 to 0.70)] and reductions in disorganised behaviour [SMD 0.23 (95% CI 0.13 to 0.42)], but no differences in avoidant attachment or externalising behaviour. Few studies addressed the role of caregivers, or the impact of the therapist-child relationship. Economic evaluations suffered methodological limitations and provided conflicting results. As a result, decision-analytic modelling was not possible, but cost-effectiveness analysis using effectiveness data from meta-analyses was undertaken for the most promising intervention: CBT for sexual abuse. Analyses of the cost-effectiveness of CBT were limited by the lack of cost data beyond the cost of CBT itself. CONCLUSIONS: It is not possible to draw firm conclusions about which interventions are effective for children with different maltreatment profiles, which are of no benefit or are harmful, and which factors encourage people to seek therapy, accept the offer of therapy and actively engage with therapy. Little is known about the cost-effectiveness of alternative interventions. LIMITATIONS: Studies were largely conducted outside the UK. The heterogeneity of outcomes and measures seriously impacted on the ability to conduct meta-analyses. FUTURE WORK: Studies are needed that assess the effectiveness of interventions within a UK context, which address the wider effects of maltreatment, as well as specific clinical outcomes. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013003889. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Mutual trust between leader and subordinate and employee outcomes

Stable and enduring cooperative relationships among people are primarily based on mutual trust. However, little evidence exists about the effects of mutual trust between supervisor and subordinate on work outcomes. To understand better the dynamics of trust in supervisor–subordinate relationships, we examined how mutual trust between supervisor and subordinate is associated with work outcomes. Based on a sample of 247 subordinate–supervisor pairs, multilevel analyses revealed a positive effect of perceived mutual trust on task performance and interpersonal facilitation after controlling for trust in leader and felt trust. In addition, task performance and interpersonal facilitation increased as trust in leader and felt trust or trust in subordinate both increased