Hedging for Better Bets: Power Shifts, Credible Signals, and Preventive Conflict

10.1177/0022002718772349Journal of Conflict Resolutio

Lack of Primary Cilia Primes Shear-Induced Endothelial-to-Mesenchymal Transition

Rationale: Primary cilia are cellular protrusions that serve as mechanosensors for fluid flow. In endothelial cells (ECs), they function by transducing local blood flow information into functional responses, such as nitric oxide production and initiation of gene expression. Cilia are present on ECs in areas of low or disturbed flow and absent in areas of high flow. In the embryonic heart, high-flow regime applies to the endocardial cushion area, and the absence of cilia here coincides with the process of endothelial-to-mesenchymal transition (EndoMT). Objective: In this study, we investigated the role of the primary cilium in defining the responses of ECs to fluid shear stress and in EndoMT. Methods and Results: Nonciliated mouse embryonic ECs with a mutation in Tg737/Ift88 were used to compare the response to fluid shear stress to that of ciliated ECs. In vitro, nonciliated ECs undergo shear-induced EndoMT, which is accompanied by downregulation of Klf4. This Tgf beta/Alk5-dependent transformation is prevented by blocking Tgf beta signaling, overexpression of Klf4, or rescue of the primary cilium. In the hearts of Tg737(orpk/orpk) embryos, Tgf beta/Alk5 signaling was activated in areas in which ECs would normally be ciliated but now lack cilia because of the mutation. In these areas, ECs show increased Smad2 phosphorylation and expression of alpha-smooth muscle actin. Conclusions: This study demonstrates the central role of primary cilia in rendering ECs prone to shear-induced activation of Tgf beta/Alk5 signaling and EndoMT and thereby provides a functional link between primary cilia and flow-related endothelial performance. (Circ Res. 2011;108:1093-1101.)Signal transduction in aging related disease

KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome

Contains fulltext : 152408.pdf (publisher's version ) (Open Access)BACKGROUND: Joubert syndrome (JBTS) and related disorders are defined by cerebellar malformation (molar tooth sign), together with neurological symptoms of variable expressivity. The ciliary basis of Joubert syndrome related disorders frequently extends the phenotype to tissues such as the eye, kidney, skeleton and craniofacial structures. RESULTS: Using autozygome and exome analyses, we identified a null mutation in KIAA0556 in a multiplex consanguineous family with hallmark features of mild Joubert syndrome. Patient-derived fibroblasts displayed reduced ciliogenesis potential and abnormally elongated cilia. Investigation of disease pathophysiology revealed that Kiaa0556 (-/-) null mice possess a Joubert syndrome-associated brain-restricted phenotype. Functional studies in Caenorhabditis elegans nematodes and cultured human cells support a conserved ciliary role for KIAA0556 linked to microtubule regulation. First, nematode KIAA0556 is expressed almost exclusively in ciliated cells, and the worm and human KIAA0556 proteins are enriched at the ciliary base. Second, C. elegans KIAA0056 regulates ciliary A-tubule number and genetically interacts with an ARL13B (JBTS8) orthologue to control cilium integrity. Third, human KIAA0556 binds to microtubules in vitro and appears to stabilise microtubule networks when overexpressed. Finally, human KIAA0556 biochemically interacts with ciliary proteins and p60/p80 katanins. The latter form a microtubule-severing enzyme complex that regulates microtubule dynamics as well as ciliary functions. CONCLUSIONS: We have identified KIAA0556 as a novel microtubule-associated ciliary base protein mutated in Joubert syndrome. Consistent with the mild patient phenotype, our nematode, mice and human cell data support the notion that KIAA0556 has a relatively subtle and variable cilia-related function, which we propose is related to microtubule regulation

Acanthamoeba Keratitis: Current Status and Urgent Research Priorities

Background: First discovered in the early 1970s, Acanthamoeba keratitis has remained a major eye infection and presents a significant threat to the public health, especially in developing countries. The aim is to present a timely review of our current understanding of the advances made in this field in a comprehensible manner and includes novel concepts and provides clear directions for immediate research priorities.Methods: We undertook a search of bibliographic databases for peer-reviewed research literature and also summarized our published results in this field.Results: The present review focuses on novel diagnostic and therapeutic strategies in details which can provide access to management and treatment of Acanthamoeba keratitis. This coupled with the recently available genome sequence information together with high throughput genomics technology and innovative approaches should stimulate interest in the rational design of preventative and therapeutic measures. Current treatment of Acanthamoeba keratitis is problematic and often leads to infection recurrence. Better understanding of diagnosis, pathogenesis, pathophysiology and therapeutic regimens, would lead to novel strategies in treatment and prophylaxis