Syndecan-3 is selectively pro-inflammatory in the joint and contributes to antigen-induced arthritis in mice

INTRODUCTION: Syndecans are heparan sulphate proteoglycans expressed by endothelial cells. Syndecan-3 is expressed by synovial endothelial cells of rheumatoid arthritis (RA) patients where it binds chemokines, suggesting a role in leukocyte trafficking. The objective of the current study was to examine the function of syndecan-3 in joint inflammation by genetic deletion in mice and compare with other tissues. METHODS: Chemokine C-X-C ligand 1 (CXCL1) was injected in the joints of syndecan-3-/-and wild-type mice and antigen-induced arthritis performed. For comparison chemokine was administered in the skin and cremaster muscle. Intravital microscopy was performed in the cremaster muscle. RESULTS: Administration of CXCL1 in knee joints of syndecan-3-/-mice resulted in reduced neutrophil accumulation compared to wild type. This was associated with diminished presence of CXCL1 at the luminal surface of synovial endothelial cells where this chemokine clustered and bound to heparan sulphate. Furthermore, in the arthritis model syndecan-3 deletion led to reduced joint swelling, leukocyte accumulation, cartilage degradation and overall disease severity. Conversely, CXCL1 administration in the skin of syndecan-3 null mice provoked increased neutrophil recruitment and was associated with elevated luminal expression of E-selectin by dermal endothelial cells. Similarly in the cremaster, intravital microscopy showed increased numbers of leukocytes adhering and rolling in venules in syndecan-3-/-mice in response to CXCL1 or tumour necrosis factor alpha. CONCLUSIONS: This study shows a novel role for syndecan-3 in inflammation. In the joint it is selectively pro-inflammatory, functioning in endothelial chemokine presentation and leukocyte recruitment and cartilage damage in an RA model. Conversely, in skin and cremaster it is anti-inflammatory

A novel role for syndecan-3 in angiogenesis.

Syndecan-3 is one of the four members of the syndecan family of heparan sulphate proteoglycans and has been shown to interact with numerous growth factors via its heparan sulphate chains. The extracellular core proteins of syndecan-1,-2 and -4 all possess adhesion regulatory motifs and we hypothesized that syndecan-3 may also possess such characteristics. Here we show that a bacterially expressed GST fusion protein consisting of the entire mature syndecan-3 ectodomain has anti-angiogenic properties and acts via modulating endothelial cell migration. This work identifies syndecan-3 as a possible therapeutic target for anti-angiogenic therapy.This work was funded by Arthritis Research-UK (Grant No. 19207) and funds from the William Harvey Research Foundation both to JRW

Mouse nuclear myosin I knock-out shows interchangeability and redundancy of myosin isoforms in the cell nucleus.

Nuclear myosin I (NM1) is a nuclear isoform of the well-known "cytoplasmic" Myosin 1c protein (Myo1c). Located on the 11(th) chromosome in mice, NM1 results from an alternative start of transcription of the Myo1c gene adding an extra 16 amino acids at the N-terminus. Previous studies revealed its roles in RNA Polymerase I and RNA Polymerase II transcription, chromatin remodeling, and chromosomal movements. Its nuclear localization signal is localized in the middle of the molecule and therefore directs both Myosin 1c isoforms to the nucleus. In order to trace specific functions of the NM1 isoform, we generated mice lacking the NM1 start codon without affecting the cytoplasmic Myo1c protein. Mutant mice were analyzed in a comprehensive phenotypic screen in cooperation with the German Mouse Clinic. Strikingly, no obvious phenotype related to previously described functions has been observed. However, we found minor changes in bone mineral density and the number and size of red blood cells in knock-out mice, which are most probably not related to previously described functions of NM1 in the nucleus. In Myo1c/NM1 depleted U2OS cells, the level of Pol I transcription was restored by overexpression of shRNA-resistant mouse Myo1c. Moreover, we found Myo1c interacting with Pol II. The ratio between Myo1c and NM1 proteins were similar in the nucleus and deletion of NM1 did not cause any compensatory overexpression of Myo1c protein. We observed that Myo1c can replace NM1 in its nuclear functions. Amount of both proteins is nearly equal and NM1 knock-out does not cause any compensatory overexpression of Myo1c. We therefore suggest that both isoforms can substitute each other in nuclear processes

Geometrid Notes

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Three-dimensional modelling of fluid flow and heat transfer in micro-channels with synthetic jet

A three-dimensional computational model was developed to investigate the effect of synthetic jet interaction with cross flow in micro-channel on the cooling of microchip. A range of parametric studies by varying heat fluxes at the surface of the top of the silicon wafer and membrane oscillating amplitudes was conducted. The resulting complex, conjugate heat transfer through the silicon substrate was analysed. When the actuator was switched on, noticeable temperature drop was observed at all points in the substrate. Quasi steady states have been reached for the presented results which indicated the available cooling potential of single synthetic jet actuator. [An erratum exists for this article. It can be found in: International journal of heat and mass transfer 2012 Volume 55(9-10) p. 2746 at DOI: 10.1016/j.ijheatmasstransfer.2012.01.022]16 page(s

Heat transfer enhancement in micro-channel with multiple synthetic jets

A three-dimensional computational model has been developed to investigate the effect of multiple synthetic jets interaction with cross-flow in micro-channel on the cooling of microchip. Studies were performed with the use of two micro jets being in-phase and 180°out-of-phase at two different operating frequencies and a fixed diaphragm amplitude. The addition of one synthetic jet was shown to achieve greater mixing of flow in the micro-channel than those with single synthetic jet. Greater heat transfer enhancement was achieved with double synthetic jets. Results showed that greater cooling enhancement could be achieved with the out-of-phase flow configuration at oscillating frequency of 560 Hz compared with the in-phase flow configuration. However, the effect of the actuation phase at a frequency of 1120 Hz was found to be insignificant. With double synthetic jet actuators operating out-of-phase, a mere 0.1 K reduction was achieved in maximum silicon temperature compared with in-phase flow jets. The greater the mixing of flow in the micro-channel in either in-phase or out-of-phase flow configuration due to higher jets Reynolds number resulted in the constraint in further cooling enhancement despite having different phases of the flow configuration.14 page(s

Flow structure generated by two synthetic jets in a channel : effect of phase and frequency

A three-dimensional computational model was developed to investigate the interaction of two synthetic jets with cross flow in micro-channel. An experimental validation of the formation of synthetic jet was presented at the same scale as those used in this numerical work. Good agreement was obtained between the experimental results and the numerical data. The numerical approach was then used to perform studies with the two jets being in-phase and 180°out-of-phase at various operating frequencies and diaphragm amplitudes with fixed jet Reynolds number. The addition of one synthetic jet was shown to achieve greater mixing of flow in the micro-channel than those with single synthetic jet. Velocity field obtained from 180°out-of-phase configurations show a distinct pattern of vortex formation which results in continuous mixing of the flow in the channel throughout the cycle. When the synthetic jet actuators were driven at different membrane frequencies and amplitudes, the main difference was the variation of the size and number of the vortices downstream and upstream of the office. The structure of the flow in the micro-channel is strongly dependent on the period of the oscillation of the membrane of the synthetic jet actuators.14 page(s