Interleukin-1β sequesters hypoxia inducible factor 2α to the primary cilium.

BACKGROUND: The primary cilium coordinates signalling in development, health and disease. Previously we have shown that the cilium is essential for the anabolic response to loading and the inflammatory response to interleukin-1β (IL-1β). We have also shown the primary cilium elongates in response to IL-1β exposure. Both anabolic phenotype and inflammatory pathology are proposed to be dependent on hypoxia-inducible factor 2 alpha (HIF-2α). The present study tests the hypothesis that an association exists between the primary cilium and HIFs in inflammatory signalling. RESULTS: Here we show, in articular chondrocytes, that IL-1β-induces primary cilia elongation with alterations to cilia trafficking of arl13b. This elongation is associated with a transient increase in HIF-2α expression and accumulation in the primary cilium. Prolyl hydroxylase inhibition results in primary cilia elongation also associated with accumulation of HIF-2α in the ciliary base and axoneme. This recruitment and the associated cilia elongation is not inhibited by blockade of HIFα transcription activity or rescue of basal HIF-2α expression. Hypomorphic mutation to intraflagellar transport protein IFT88 results in limited ciliogenesis. This is associated with increased HIF-2α expression and inhibited response to prolyl hydroxylase inhibition. CONCLUSIONS: These findings suggest that ciliary sequestration of HIF-2α provides negative regulation of HIF-2α expression and potentially activity. This study indicates, for the first time, that the primary cilium regulates HIF signalling during inflammation

Primary cilia elongation in response to interleukin-1 mediates the inflammatory response

Primary cilia are singular, cytoskeletal organelles present in the majority of mammalian cell types where they function as coordinating centres for mechanotransduction, Wnt and hedgehog signalling. The length of the primary cilium is proposed to modulate cilia function, governed in part by the activity of intraflagellar transport (IFT). In articular cartilage, primary cilia length is increased and hedgehog signaling activated in osteoarthritis (OA). Here, we examine primary cilia length with exposure to the quintessential inflammatory cytokine interleukin-1 (IL-1), which is up-regulated in OA. We then test the hypothesis that the cilium is involved in mediating the downstream inflammatory response. Primary chondrocytes treated with IL-1 exhibited a 50 % increase in cilia length after 3 h exposure. IL-1-induced cilia elongation was also observed in human fibroblasts. In chondrocytes, this elongation occurred via a protein kinase A (PKA)-dependent mechanism. G-protein coupled adenylate cyclase also regulated the length of chondrocyte primary cilia but not downstream of IL-1. Chondrocytes treated with IL-1 exhibit a characteristic increase in the release of the inflammatory chemokines, nitric oxide and prostaglandin E2. However, in cells with a mutation in IFT88 whereby the cilia structure is lost, this response to IL-1 was significantly attenuated and, in the case of nitric oxide, completely abolished. Inhibition of IL-1-induced cilia elongation by PKA inhibition also attenuated the chemokine response. These results suggest that cilia assembly regulates the response to inflammatory cytokines. Therefore, the cilia proteome may provide a novel therapeutic target for the treatment of inflammatory pathologies, including OA

Concert recording 2014-04-08

[Track 01]. Madama Butterfly. Un bel di vedremo / Glacomo Puccini -- [Track 02]. Hello again. Tom / Michael John LaCiusa -- [Track 03]. Mein schoner stern! (my lovely star) / Robert Schumann -- [Track 04]. Into the night / Robert Schumann -- [Track 05]. Per la Gloria / Giovanni B. Bonocirii -- [Track 06]. Bonjour, Suzon! / Leo Delibes -- [Track 07]. Die Winterreise. Erstarrung (numbness) / Franz Schubert -- [Track 08]. West Side Story. Something\u27s coming / Leonard Bernstein -- [Track 09]. Un ballo in maschera. Saper vorreste / Giuseppe Verdi -- [Track 10]. O del mio amato ben / Stefeno Donaudy -- [Track 11]. O del mio dolce ardor / Christoph W. von Gluck -- [Track 12]. My fair lady. I could have danced all night / Loewe & Lerner -- [Track 13]. Vergebliches standchen (The vain suit) / Johannes Brahms

Mechanical loading induces primary cilia disassembly in tendon cells via TGF beta and HDAC6

D. Rowson was funded through an EPSRC PhD studentship awarded via the Institute of Bioengineering at Queen Mary University of London

User-centered virtual environment design for virtual rehabilitation

<p>Abstract</p> <p>Background</p> <p>As physical and cognitive rehabilitation protocols utilizing virtual environments transition from single applications to comprehensive rehabilitation programs there is a need for a new design cycle methodology. Current human-computer interaction designs focus on usability without benchmarking technology within a user-in-the-loop design cycle. The field of virtual rehabilitation is unique in that determining the efficacy of this genre of computer-aided therapies requires prior knowledge of technology issues that may confound patient outcome measures. Benchmarking the technology (e.g., displays or data gloves) using healthy controls may provide a means of characterizing the "normal" performance range of the virtual rehabilitation system. This standard not only allows therapists to select appropriate technology for use with their patient populations, it also allows them to account for technology limitations when assessing treatment efficacy.</p> <p>Methods</p> <p>An overview of the proposed user-centered design cycle is given. Comparisons of two optical see-through head-worn displays provide an example of benchmarking techniques. Benchmarks were obtained using a novel vision test capable of measuring a user's stereoacuity while wearing different types of head-worn displays. Results from healthy participants who performed both virtual and real-world versions of the stereoacuity test are discussed with respect to virtual rehabilitation design.</p> <p>Results</p> <p>The user-centered design cycle argues for benchmarking to precede virtual environment construction, especially for therapeutic applications. Results from real-world testing illustrate the general limitations in stereoacuity attained when viewing content using a head-worn display. Further, the stereoacuity vision benchmark test highlights differences in user performance when utilizing a similar style of head-worn display. These results support the need for including benchmarks as a means of better understanding user outcomes, especially for patient populations.</p> <p>Conclusions</p> <p>The stereoacuity testing confirms that without benchmarking in the design cycle poor user performance could be misconstrued as resulting from the participant's injury state. Thus, a user-centered design cycle that includes benchmarking for the different sensory modalities is recommended for accurate interpretation of the efficacy of the virtual environment based rehabilitation programs.</p

How many motoric body representations can we grasp?

At present there is a debate on the number of body representations in the brain. The most commonly used dichotomy is based on the body image, thought to underlie perception and proven to be susceptible to bodily illusions, versus the body schema, hypothesized to guide actions and so far proven to be robust against bodily illusions. In this rubber hand illusion study we investigated the susceptibility of the body schema by manipulating the amount of stimulation on the rubber hand and the participant’s hand, adjusting the postural configuration of the hand, and investigating a grasping rather than a pointing response. Observed results showed for the first time altered grasping responses as a consequence of the grip aperture of the rubber hand. This illusion-sensitive motor response challenges one of the foundations on which the dichotomy is based, and addresses the importance of illusion induction versus type of response when investigating body representations

Characterization of the Modular Design of the Autolysin/Adhesin Aaa from Staphylococcus Aureus

BACKGROUND: Staphylococcus aureus is a frequent cause of serious and life-threatening infections, such as endocarditis, osteomyelitis, pneumonia, and sepsis. Its adherence to various host structures is crucial for the establishment of diseases. Adherence may be mediated by a variety of adhesins, among them the autolysin/adhesins Atl and Aaa. Aaa is composed of three N-terminal repeated sequences homologous to a lysin motif (LysM) that can confer cell wall attachment and a C-terminally located cysteine, histidine-dependent amidohydrolase/peptidase (CHAP) domain having bacteriolytic activity in many proteins. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show by surface plasmon resonance that the LysM domain binds to fibrinogen, fibronectin, and vitronectin respresenting a novel adhesive function for this domain. Moreover, we demonstrated that the CHAP domain not only mediates the bacteriolytic activity, but also adherence to fibrinogen, fibronectin, and vitronectin, thus demonstrating for the first time an adhesive function for this domain. Adherence of an S. aureus aaa mutant and the complemented aaa mutant is slightly decreased and increased, respectively, to vitronectin, but not to fibrinogen and fibronectin, which might at least in part result from an increased expression of atl in the aaa mutant. Furthermore, an S. aureus atl mutant that showed enhanced adherence to fibrinogen, fibronectin, and endothelial cells also demonstrated increased aaa expression and production of Aaa. Thus, the redundant functions of Aaa and Atl might at least in part be interchangeable. Lastly, RT-PCR and zymographic analysis revealed that aaa is negatively regulated by the global virulence gene regulators agr and SarA. CONCLUSIONS/SIGNIFICANCE: We identified novel functions for two widely distributed protein domains, LysM and CHAP, i.e. the adherence to the extracellular matrix proteins fibrinogen, fibronectin, and vitronectin. The adhesive properties of Aaa might promote S. aureus colonization of host extracellular matrix and tissue, suggesting a role for Aaa in the pathogenesis of S. aureus infections

Acquisition of Complement Inhibitor Serine Protease Factor I and Its Cofactors C4b-Binding Protein and Factor H by Prevotella intermedia

Infection with the Gram-negative pathogen Prevotella intermedia gives rise to periodontitis and a growing number of studies implies an association of P. intermedia with rheumatoid arthritis. The serine protease Factor I (FI) is the central inhibitor of complement degrading complement components C3b and C4b in the presence of cofactors such as C4b-binding protein (C4BP) and Factor H (FH). Yet, the significance of complement inhibitor acquisition in P. intermedia infection and FI binding by Gram-negative pathogens has not been addressed. Here we show that P. intermedia isolates bound purified FI as well as FI directly from heat-inactivated human serum. FI bound to bacteria retained its serine protease activity as shown in degradation experiments with 125I-labeled C4b. Since FI requires cofactors for its activity we also investigated the binding of purified cofactors C4BP and FH and found acquisition of both proteins, which retained their activity in FI mediated degradation of C3b and C4b. We propose that FI binding by P. intermedia represents a new mechanism contributing to complement evasion by a Gram-negative bacterial pathogen associated with chronic diseases

Two eyes in action

Do relative binocular disparities guide our movements in depth? In order to find out we asked subjects to move a 'cursor' to a target within a simulated horizontal plane at eye height. They did so by moving a computer mouse. We determined how quickly subjects responded to the target jumping in depth. We found that it took subjects about 200 ms to respond to changes in binocular disparity. Subjects responded just as quickly if the cursor was temporarily only visible to one eye near the time that the target jumped in depth, and less vigorously, though just as quickly, if the cursor jumped rather than the target, so the fastest binocular responses cannot be based directly on the relative retinal disparity between the target and the cursor. Subjects reacted faster to changes in the target's height in the visual field than to changes in binocular disparity, but did not react faster to changes in image size. These results suggest that binocular vision mainly improves people's everyday movements by giving them a better sense of the distances of relevant objects, rather than by relative retinal disparities being used to directly guide the movement. We propose that relative disparities only guide parts of very slow movements that require extreme precision. © Springer-Verlag 2005

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac