Regulation of cardiovascular connexins by mechanical forces and junctions

Connexins form a family of transmembrane proteins that consists of 20 members in humans and 21 members in mice. Six connexins assemble into a connexon that can function as a hemichannel or connexon that can dock to a connexon expressed by a neighbouring cell, thereby forming a gap junction channel. Such intercellular channels synchronize responses in multicellular organisms through direct exchange of ions, small metabolites, and other second messenger molecules between the cytoplasms of adjacent cells. Multiple connexins are expressed in the cardiovascular system. These connexins not only experience the different biomechanical forces within this system, but may also act as effector proteins in co-ordinating responses within groups of cells towards these forces. This review discusses recent insights regarding regulation of cardiovascular connexins by mechanical forces and junctions. It specifically addresses effects of (i) shear stress on endothelial connexins, (ii) hypertension on vascular connexins, and (iii) changes in afterload and the composition of myocardial mechanical junctions on cardiac connexin

Endothelial Connexin37 and Connexin40 participate in basal but not agonist-induced NO release.

BACKGROUND: Connexin37 (Cx37) and Cx40 are crucial for endothelial cell-cell communication and homeostasis. Both connexins interact with endothelial nitric oxide synthase (eNOS). The exact contribution of these interactions to the regulation of vascular tone is unknown. RESULTS: Cx37 and Cx40 were expressed in close proximity to eNOS at cell-cell interfaces of mouse aortic endothelial cells. Absence of Cx37 did not affect expression of Cx40 and a 50 % reduction of Cx40 in Cx40(+/-) aortas did not affect the expression of Cx37. However, absence of Cx40 was associated with reduced expression of Cx37. Basal NO release and the sensitivity for ACh were decreased in Cx37(-/-) and Cx40(-/-) aortas but not in Cx40(+/-) aortas. Moreover, ACh-induced release of constricting cyclooxygenase products was present in WT, Cx40(-/-) and Cx40(+/-) aortas but not in Cx37(-/-) aortas. Finally, agonist-induced NO-dependent relaxations and the sensitivity for exogenous NO were not affected by genotype. CONCLUSIONS: Cx37 is more markedly involved in basal NO release, release of cyclooxygenase products and the regulation of the sensitivity for ACh as compared to Cx40

Student teachers' motives for participating in the teacher training program: A qualitative comparison between continuing students and switch students

Item does not contain fulltextOver the last few decades, the Netherlands has been experiencing that numerous student teachers (i.e., pre-service teachers) leave teacher training after a short period of time. To address this attrition problem the current study aimed to gain insight into student teachers' motives for enrolling, continuing or withdrawing from a primary teacher education program, and compare these motives between continuing students and switch students before and after their enrolment. Twenty-two Dutch student teachers (continuing students: N = 10; 70.0% females, Mage = 20.00, switch students: N = 12; 66.7% females, Mage = 20.83) participated in this interview study. Several motives regarding the teacher education program were identified. Both groups primarily cited intrinsic motives for enrolling in the program. Disappointment in the profession, as well as content of the program and difficulty level of the program, were the main motives to leave. Enthusiasm about the profession and the social environment were the primary motives to continue in the program.25 p

Civic Cohesion in Turbulent Times: Galbert of Bruges, the Urban Community and the Murder of the Count of Flanders in 1127

This contribution will examine the nature of the urban community in early twelfth-century Flanders on the basis of Galbert of Bruges’ De multro, traditione et occisione Karoli comitis Flandriarum, an account of the murder of Charles the Good, the count of Flanders, in 1127. A clerk at the chancery of the Flemish counts in Bruges, Galbert wrote an insider’s perspective on an urban community in turmoil. His work was an attempt to come to terms with a disruptive episode in the city’s recent past and reaffirm its civic identity, towards the citizens themselves and in relation to its worldly overlords and neighbouring towns. This article thus explores a number of crucial aspects of citizenship in the high medieval Low Countries, e.g. who belonged to the urban community and who did not; which public actions were legitimate and which ones were to be avoided; what goals an urban community should pursue, who was to pursue them and through what means

De wetenschapstaal van de Eeuwige Stad

Contains fulltext : 177325.pdf (Publisher’s version ) (Open Access)15 p

Contesting Philosophical Authority in the Belly of El Monstruo: A Case Study in Nonideal Political Theory and Epistemic Democracy

What is philosophical inquiry about, how does one do it, and what is it good for? This paper draws upon original empirical work and is, in part, an instance of what students of the social sciences, especially those engaged in qualitative approaches to research such as ethnography, will recognize as what Fred Erickson termed a “natural history of inquiry.” During the summers of 2009 and 2010, I spent about two months conducting research in collaboration with a small, independent community located in Itztapalapa, an impoverished neighborhood of Mexico City. I set out to test one possible conceptualization of a political philosophical problem (related to self--‐determination, though specifics of this stage of the research aren’t the focus of my paper) against the actual discursive practice of a community in conflict with powerful and often corrupt government institutions. I initially hoped that this empirical work would enable me to test a hypothesis concerning the usefulness of a particular conceptual schema in practice. When my initial research questions ran up against the constraints and exigencies of democratic inquiry, beyond the ordinary parameters of the (white, Anglophone) academic community, new questions emerged that concern philosophical methodology at its foundations. The unexpected turn my research has taken speaks to a contemporary struggle in the self--‐understanding of (again, mostly white, Anglophone) philosophers (including philosophers of education). This paper reviews recent developments in nonideal theorizing as well as attempts to naturalize and democratize moral epistemology. Using my own experience in Mexico as illustrative, I assess the promise of attempts at naturalization and democratization for revitalizing philosophy as a professional discourse. I argue that efforts to naturalize and democratize philosophical methodology are necessary if we are to clarify what philosophical inquiry can and ought to be good for, in relation to educational issues and other academic disciplines. Ultimately, philosophical inquiry so understood provides an invaluable tool for addressing the pressing problems that motivate all of our best and most justifiable inquiries into the meaning and nature of things

Ostéo-myxo-fibrome de la corne chez un bœuf

Lombard Charles, Meens L. Ostéo-myxo-fibrome de la corne chez un bœuf. In: Bulletin de l'Académie Vétérinaire de France tome 111 n°1, 1958. pp. 41-43

Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats

Arteries from young healthy animals respond to chronic changes in blood flow and blood pressure by structural remodeling. We tested whether the ability to respond to decreased (-90%) or increased (+100%) blood flow is impaired during the development of deoxycorticosterone acetate (DOCA)-salt hypertension in rats, a model for an upregulated endothelin-1 system. Mesenteric small arteries (MrA) were exposed to low blood flow (LF) or high blood flow (HF) for 4 or 7 weeks. The bioavailability of vasoactive peptides was modified by chronic treatment of the rats with the dual neutral endopeptidase (NEP)/endothelin-converting enzyme (ECE) inhibitor SOL1. After 3 or 6 weeks of hypertension, the MrA showed hypertrophic arterial remodeling (3 weeks: media cross-sectional area (mCSA): 10 +/- 1 x 10(3) to 17 +/- 2 x 10(3) mu m(2); 6 weeks: 13 +/- 2 x 10(3) to 24 +/- 3 x 10(3) mu m(2)). After 3, but not 6, weeks of hypertension, the arterial diameter was increased (empty set: 385 +/- 13 to 463 +/- 14 mu m). SOL1 reduced hypertrophy after 3 weeks of hypertension (mCSA: 6 x 10(3) +/- 1 x 10(3) mu m(2)). The diameter of the HF arteries of normotensive rats increased (empty set: 463 +/- 22 mu m) but no expansion occurred in the HF arteries of hypertensive rats (empty set: 471 +/- 16 mu m). MrA from SOL1-treated hypertensive rats did show a significant diameter increase (empty set: 419 +/- 13 to 475 +/- 16 mu m). Arteries exposed to LF showed inward remodeling in normotensive and hypertensive rats (mean empty set between 235 and 290 mu m), and infiltration of monocyte/ macrophages. SOL1 treatment did not affect the arterial diameter of LF arteries but reduced the infiltration of monocyte/ macrophages. We show for the first time that flow-induced remodeling is impaired during the development of DOCA-salt hypertension and that this can be prevented by chronic NEP/ECE inhibition. Hypertension Research (2012) 35, 1093-1101; doi:10.1038/hr.2012.94; published online 12 July 201

The membrane cytoskeletal crosslinker ezrin is required for metastasis of breast carcinoma cells

INTRODUCTION: The membrane cytoskeletal crosslinker ezrin participates in several functions including cell adhesion, motility and cell survival, and there is increasing evidence that it regulates tumour progression. However, the role played by ezrin in breast cancer metastasis has not been clearly delineated. METHODS: We examined the role of ezrin in metastasis using a highly metastatic murine mammary carcinoma cell line, namely AC2M2. Stable cell clones that overexpress wild-type ezrin or a dominant-negative amino-terminal domain of ezrin were selected. They were then tested for cell motility and invasion in vitro, and metastasis in a mouse in vivo tumour transplantation model. RESULTS: Parental AC2M2 cells and cells overexpressing wild-type ezrin were transplanted into the mammary fat pad of syngeneic recipient mice; these animals subsequently developed lung metastases. In contrast, expression of the dominant-negative amino-terminal ezrin domain markedly inhibited lung metastasis. Consistent with this effect, we observed that the expression of amino-terminal ezrin caused strong membrane localization of cadherin, with increased cell–cell contact and a decrease in cell motility and invasion, whereas cells expressing wild-type ezrin exhibited strong cytoplasmic expression of cadherins and pseudopodia extensions. In addition, inhibitors of phosphatidylinositol 3-kinase and c-Src significantly blocked cell motility and invasion of AC2M2 cells expressing wild-type ezrin. We further found that overexpression of amino-terminal ezrin reduced levels of Akt pS473 and cytoskeletal-associated c-Src pY418 in AC2M2 cells, which contrasts with the high levels of phosphorylation of these proteins in cells expressing wild-type ezrin. Phosphorylated Erk1/2 was also reduced in amino-terminal ezrin expressing cells, although a mitogen-activated protein kinase kinase (MEK) inhibitor had no detectable effect on cell motility or invasion in this system. CONCLUSION: Our findings indicate that ezrin is required for breast cancer metastasis, and that c-Src and phosphatidylinositol 3-kinase/Akt are effectors of ezrin in the cell motility and invasion stages of the metastatic process. Together, these results suggest that blocking ezrin function may represent a novel and effective strategy for preventing breast cancer metastasis

With one foot in the font. The failed baptism of the Frisian king Radbod and the eighth century discussion about the fate of unbaptized forefathers

This contribution tries to outline a context for the well-known story of the Frisian King Radbod withdrawing from the baptismal font when hearing that his ancestors would not receive the same privilege. This story is transmitted in the Vita Wulframni, a text that has been regarded as a forgery. Following a summary of Stephane Lebecq’s analysis of the Vita, the story about Radbod’s failed baptism can be shown to belong to a part of this text that was composed by the Frisian monk Ovo in the AD 740s. As such, it is a central document in the debate about the fate of pagan ancestors vibrant at precisely this time, with Boniface and the Irish bishop Clemens being the best-known protagonists. The anecdote was not written to deny Willibrord his pride of place in the Christianization of Frisia, but rather to corroborate Boniface’s point of view with Willibrord’s authority. There is some indication suggesting that Willibrord himself had a different opinion in this question, a crucial element in the process of Christianization