The Dermatan Sulfate Proteoglycan Decorin Modulates α2β1 Integrin and the Vimentin Intermediate Filament System during Collagen Synthesis.

Decorin, a small leucine-rich proteoglycan harboring a dermatan sulfate chain at its N-terminus, is involved in regulating matrix organization and cell signaling. Loss of the dermatan sulfate of decorin leads to an Ehlers-Danlos syndrome characterized by delayed wound healing. Decorin-null (Dcn(-/-)) mice display a phenotype similar to that of EDS patients. The fibrillar collagen phenotype of Dcn(-/-) mice could be rescued in vitro by decorin but not with decorin lacking the glycosaminoglycan chain. We utilized a 3D cell culture model to investigate the impact of the altered extracellular matrix on Dcn(-/-) fibroblasts. Using 2D gel electrophoresis followed by mass spectrometry, we identified vimentin as one of the proteins that was differentially upregulated by the presence of decorin. We discovered that a decorin-deficient matrix leads to abnormal nuclear morphology in the Dcn(-/-) fibroblasts. This phenotype could be rescued by the decorin proteoglycan but less efficiently by the decorin protein core. Decorin treatment led to a significant reduction of the α2β1 integrin at day 6 in Dcn(-/-) fibroblasts, whereas the protein core had no effect on β1. Interestingly, only the decorin core induced mRNA synthesis, phosphorylation and de novo synthesis of vimentin indicating that the proteoglycan decorin in the extracellular matrix stabilizes the vimentin intermediate filament system. We could support these results in vivo, because the dermis of wild-type mice have more vimentin and less β1 integrin compared to Dcn(-/-). Furthermore, the α2β1 null fibroblasts also showed a reduced amount of vimentin compared to wild-type. These data show for the first time that decorin has an impact on the biology of α2β1 integrin and the vimentin intermediate filament system. Moreover, our findings provide a mechanistic explanation for the reported defects in wound healing associated with the Dcn(-/-) phenotype

Beyond Prejudice as Simple Antipathy: Hostile and Benevolent Sexism Across Cultures

The authors argue that complementary hostile and benevolent componen:s of sexism exist ac ro.ss cultures. Male dominance creates hostile sexism (HS). but men's dependence on women fosters benevolent sexism (BS)-subjectively positive attitudes that put women on a pedestal but reinforce their subordination. Research with 15,000 men and women in 19 nations showed that (a) HS and BS are coherenl constructs th at correlate positively across nations, but (b) HS predicts the ascription of negative and BS the ascription of positive traits to women, (c) relative to men, women are more likely to reject HS than BS. especially when overall levels of sexism in a culture are high, and (d) national averages on BS and HS predict gender inequal ity across nations. These results challenge prevailing notions of prejudice as an antipathy in that BS (an affectionate, patronizing ideology) reflects inequality and is a cross-culturally pervasive complement to HS

Investigating possible ethnicity and sex bias in clinical examiners: an analysis of data from the MRCP(UK) PACES and nPACES examinations

Bias of clinical examiners against some types of candidate, based on characteristics such as sex or ethnicity, would represent a threat to the validity of an examination, since sex or ethnicity are 'construct-irrelevant' characteristics. In this paper we report a novel method for assessing sex and ethnic bias in over 2000 examiners who had taken part in the PACES and nPACES (new PACES) examinations of the MRCP(UK)

Conceptualising computerized adaptive testing for measurement of latent variables associated with physical objects

The notion of that more or less of a physical feature affects in different degrees the users' impression with regard to an underlying attribute of a product has frequently been applied in affective engineering. However, those attributes exist only as a premise that cannot directly be measured and, therefore, inferences based on their assessment are error-prone. To establish and improve measurement of latent attributes it is presented in this paper the concept of a stochastic framework using the Rasch model for a wide range of independent variables referred to as an item bank. Based on an item bank, computerized adaptive testing (CAT) can be developed. A CAT system can converge into a sequence of items bracketing to convey information at a user's particular endorsement level. It is through item banking and CAT that the financial benefits of using the Rasch model in affective engineering can be realised

Improving together: better science writing through peer learning

Science, in our case the climate and geosciences, is increasingly interdisciplinary. Scientists must therefore communicate across disciplinary boundaries. For this communication to be successful, scientists must write clearly and concisely, yet the historically poor standard of scientific writing does not seem to be improving. Scientific writing must improve, and the key to long-term improvement lies with the early-career scientist (ECS). Many interventions exist for an ECS to improve their writing, like style guides and courses. However, momentum is often difficult to maintain after these interventions are completed. Continuity is key to improving writing. This paper introduces the ClimateSnack project, which aims to motivate ECSs to develop and continue to improve their writing and communication skills. The project adopts a peer-learning framework where ECSs voluntarily form writing groups at different institutes around the world. The group members learn, discuss, and improve their writing skills together. Several ClimateSnack writing groups have formed. This paper examines why some of the groups have flourished and others have dissolved. We identify the challenges involved in making a writing group successful and effective, notably the leadership of self-organized groups, and both individual and institutional time management. Within some of the groups, peer learning clearly offers a powerful tool to improve writing as well as bringing other benefits, including improved general communication skills and increased confidence

Role of cellular senescence and NOX4-mediated oxidative stress in systemic sclerosis pathogenesis.

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by progressive fibrosis of skin and numerous internal organs and a severe fibroproliferative vasculopathy resulting frequently in severe disability and high mortality. Although the etiology of SSc is unknown and the detailed mechanisms responsible for the fibrotic process have not been fully elucidated, one important observation from a large US population study was the demonstration of a late onset of SSc with a peak incidence between 45 and 54 years of age in African-American females and between 65 and 74 years of age in white females. Although it is not appropriate to consider SSc as a disease of aging, the possibility that senescence changes in the cellular elements involved in its pathogenesis may play a role has not been thoroughly examined. The process of cellular senescence is extremely complex, and the mechanisms, molecular events, and signaling pathways involved have not been fully elucidated; however, there is strong evidence to support the concept that oxidative stress caused by the excessive generation of reactive oxygen species may be one important mechanism involved. On the other hand, numerous studies have implicated oxidative stress in SSc pathogenesis, thus, suggesting a plausible mechanism in which excessive oxidative stress induces cellular senescence and that the molecular events associated with this complex process play an important role in the fibrotic and fibroproliferative vasculopathy characteristic of SSc. Here, recent studies examining the role of cellular senescence and of oxidative stress in SSc pathogenesis will be reviewed

Ablation of integrin-mediated cell-collagen communication alleviates fibrosis

Objectives Activation of fibroblasts is a hallmark of fibrotic processes. Besides cytokines and growth factors, fibroblasts are regulated by the extracellular matrix environment through receptors such as integrins, which transduce biochemical and mechanical signals enabling cells to mount appropriate responses according to biological demands. The aim of this work was to investigate the in vivo role of collagen–fibroblast interactions for regulating fibroblast functions and fibrosis. Methods Triple knockout (tKO) mice with a combined ablation of integrins α1β1, α2β1 and α11β1 were created to address the significance of integrin-mediated cell–collagen communication. Properties of primary dermal fibroblasts lacking collagen-binding integrins were delineated in vitro. Response of the tKO mice skin to bleomycin induced fibrotic challenge was assessed. Results Triple integrin-deficient mice develop normally, are transiently smaller and reveal mild alterations in mechanoresilience of the skin. Fibroblasts from these mice in culture show defects in cytoskeletal architecture, traction stress generation, matrix production and organisation. Ablation of the three integrins leads to increased levels of discoidin domain receptor 2, an alternative receptor recognising collagens in vivo and in vitro. However, this overexpression fails to compensate adhesion and spreading defects on collagen substrates in vitro. Mice lacking collagen-binding integrins show a severely attenuated fibrotic response with impaired mechanotransduction, reduced collagen production and matrix organisation. Conclusions The data provide evidence for a crucial role of collagen-binding integrins in fibroblast force generation and differentiation in vitro and for matrix deposition and tissue remodelling in vivo. Targeting fibroblast–collagen interactions might represent a promising therapeutic approach to regulate connective tissue deposition in fibrotic diseases