BCP crystals increase prostacyclin production and upregulate the prostacyclin receptor in OA synovial fibroblasts: potential effects on mPGES1 and MMP-13

SummaryObjectiveTo investigate the potential involvement of prostacyclin in basic calcium phosphate (BCP) crystal-induced responses in osteoarthritic synovial fibroblasts (OASF).MethodsOASF grown in culture were stimulated with BCP crystals. Prostacyclin production was measured by enzyme immunoassay. Expression of messenger RNA (mRNA) transcripts was assessed by real-time polymerase chain reaction (PCR). Expression of prostacyclin synthase (PGIS) and the prostacyclin (IP) receptor was measured. The effects of iloprost, a prostacyclin analogue, on expression of genes implicated in osteoarthritis such as microsomal prostaglandin E2 synthase 1 (mPGES1) and matrix metalloproteinases (MMPs) were also studied. FPT inhibitor II, a farnesyl transferase inhibitor, was used to antagonize iloprost-induced responses.ResultsBCP crystal stimulation led to a five-fold increase in prostacyclin production in OASF compared to untreated cells. This induction was attenuated by cyclooxygenase (COX)-2 and COX-1 inhibition at 4 and 32h, respectively. PGIS and IP receptor transcripts were constitutively expressed in OASF. BCP crystals upregulated IP receptor expression two-fold. While iloprost diminished BCP crystal-stimulated IP receptor upregulation, the inhibitory effect of iloprost was blocked by the farnesyl transferase inhibitor. In addition, iloprost upregulated mPGES1 and downregulated MMP-13 expression in BCP crystal-stimulated OASF, effects that were not influenced by the farnesyl transferase inhibitor.ConclusionsThese data showed for the first time that BCP crystals can increase prostacyclin production and upregulate expression of the IP receptor in OASF. The potential of prostacyclin to influence BCP crystal-stimulated responses was supported by the effects of iloprost on the expression of the IP receptor, mPGES1 and MMP-13. These data demonstrate the potential involvement of prostacyclin in BCP crystal-associated osteoarthritis (OA) and suggest that inhibition of PG synthesis with non-steroidal anti-inflammatory drugs may have both deleterious and beneficial effects in BCP crystal-associated OA

A Process and Outcome Evaluation of a Shelter for Homeless Young Women

To evaluate the processes and outcomes of a short-term shelter, both quantitative and qualitative data were gathered via participant observation, focus group interviews with shelter staff and residents, and individual interviews with a sample of 40 young women who had been homeless prior to using the shelter. The process evaluation showed that the shelter staff strived to utilize an empowerment philosophy in their relationships with residents, but that there were many challenges to implementing this philosophy. The outcome evaluation showed that, at a 3-month follow-up, the participants reported significant improvements in housing, income, independence, and life satisfaction, but most continued to experience poverty and a number of other difficulties. The results were discussed in terms of the implications for future research and the value and limitations of shelters for dealing with homeless youth. The need for more sustained and comprehensive program interventions and supportive social policies was underscored

Incoherent dynamics of vibrating single-molecule transistors

We study the tunneling conductance of nano-scale quantum ``shuttles'' in connection with a recent experiment (H. Park et al., Nature, 407, 57 (2000)) in which a vibrating C^60 molecule was apparently functioning as the island of a single electron transistor (SET). While our calculation starts from the same model of previous work (D. Boese and H. Schoeller, Europhys. Lett. 54, 66(2001)) we obtain quantitatively different dynamics. Calculated I-V curves exhibit most features present in experimental data with a physically reasonable parameter set, and point to a strong dependence of the oscillator's potential on the electrostatics of the island region. We propose that in a regime where the electric field due to the bias voltage itself affects island position, a "catastrophic" negative differential conductance (NDC) may be realized. This effect is directly attributable to the magnitude of overlap of final and initial quantum oscillator states, and as such represents experimental control over quantum transitions of the oscillator via the macroscopically controllable bias voltage.Comment: 6 pages, LaTex, 6 figure

Molecular mechanism of basic calcium phosphate crystal-induced activation of human fibroblasts: Role of nuclear factor κB, activator protein 1, and protein kinase C

Synovial fluid basic calcium phosphate (BCP) crystals are markers of severe joint degeneration in osteoarthritis. BCP crystals cause mitogenesis of articular cells and stimulate matrix metalloprotease production, thus promoting degradation of articular tissues. Previous work suggested that BCP crystal-induced cell activation required intracellular crystal dissolution, induction of proto-oncogene expression, and activation of signal transduction pathways involving protein kinase C and mitogen-activated protein kinases. Here we further elucidate the mechanisms of BCP crystal-induced cell activation as BCP crystals activate transcription factors nuclear factor κB and activator protein I in human fibroblasts. We confirm the role of protein kinase C in BCP crystal-induced mitogenesis in human fibroblasts. In contrast, we demonstrate that BCP crystals do not activate signal transduction pathways involving protein tyrosine kinases or phosphatidylinositol 3-kinase. These data further define the mechanism of cell activation by BCP crystals and confirm its selectivity, an observation that may have therapeutic implications

PLOS Genetics Data Sharing Policy: In Pursuit of Functional Utility

About a year ago, PLOS implemented a new process intended to further the overarching principle that data used in the work we publish should be accessible and reusable. The motivation goes hand-in-hand with both our open access ethos and the scientific method itself: the validity of a conclusion depends on the ability to reproduce the underlying results

Prediction of pH Change in Processed Acidified Turnips

The acetic acid uptake by turnips was studied during an acidification process in containers. The process was successfully described by a Fickian diffusion, using a correlation for the buffer effect. Diffusion coefficients (0.629 to 3.99 × 10-9 m2/sec) and partition coefficients (0.8 to 1.1) were obtained by optimization of the fit between experimental and theoretical values, using the simplex method. The partition coefficient did not show an evident dependence on temperature, while diffusivity followed an Arrhenius type behavior. The relationship between acid concentration and pH was described using a cubic model with parameters independent of temperature. Results showed that the combination of these models describing the acid diffusion into the food and the buffering effects of the food allowed accurate prediction of pH evolution in the acidification process

Physics, Topology, Logic and Computation: A Rosetta Stone

In physics, Feynman diagrams are used to reason about quantum processes. In the 1980s, it became clear that underlying these diagrams is a powerful analogy between quantum physics and topology: namely, a linear operator behaves very much like a "cobordism". Similar diagrams can be used to reason about logic, where they represent proofs, and computation, where they represent programs. With the rise of interest in quantum cryptography and quantum computation, it became clear that there is extensive network of analogies between physics, topology, logic and computation. In this expository paper, we make some of these analogies precise using the concept of "closed symmetric monoidal category". We assume no prior knowledge of category theory, proof theory or computer science.Comment: 73 pages, 8 encapsulated postscript figure

Phenomenology of the Lense-Thirring effect in the Solar System

Recent years have seen increasing efforts to directly measure some aspects of the general relativistic gravitomagnetic interaction in several astronomical scenarios in the solar system. After briefly overviewing the concept of gravitomagnetism from a theoretical point of view, we review the performed or proposed attempts to detect the Lense-Thirring effect affecting the orbital motions of natural and artificial bodies in the gravitational fields of the Sun, Earth, Mars and Jupiter. In particular, we will focus on the evaluation of the impact of several sources of systematic uncertainties of dynamical origin to realistically elucidate the present and future perspectives in directly measuring such an elusive relativistic effect.Comment: LaTex, 51 pages, 14 figures, 22 tables. Invited review, to appear in Astrophysics and Space Science (ApSS). Some uncited references in the text now correctly quoted. One reference added. A footnote adde

Origin of depleted basalts during subduction initiation and early development of the Izu-Bonin-Mariana island arc: Evidence from IODP expedition 351 site U1438, Amami-Sankaku basin

The Izu-Bonin-Mariana (IBM) island arc formed following initiation of subduction of the Pacific plate beneath the Philippine Sea plate at about 52 Ma. Site U1438 of IODP Expedition 351 was drilled to sample the oceanic basement on which the IBM arc was constructed, to better understand magmatism prior to and during the subduction initiation event. Site U1438 igneous basement Unit 1 (150 m) was drilled beneath 1460 m of primarily volcaniclastic sediments and sedimentary rock. Basement basalts are microcrystalline to fine-grained flows and form several distinct subunits (1a-1f), all relatively mafic (MgO = 6.5–13.8%; Mg# = 52–83), with Cr = 71–506 ppm and Ni = 62–342 ppm. All subunits are depleted in non-fluid mobile incompatible trace elements. Ratios such as Sm/Nd (0.35–0.44), Lu/Hf (0.19–0.37), and Zr/Nb (55–106) reach the highest values found in MORB, while La/Yb (0.31–0.92), La/Sm (0.43–0.91) and Nb/La (0.39–0.59) reach the lowest values. Abundances of fluid-mobile incompatible elements, K, Rb, Cs and U, vary with rock physical properties, indicating control by post-eruptive seawater alteration, but lowest abundances are typical of fresh, highly depleted MORBs. Mantle sources for the different subunits define a trend of progressive incompatible element depletion. Inferred pressures of magma segregation are 0.6–2.1 GPa with temperatures of 1280–1470 °C. New 40Ar/39Ar dates for Site U1438 basalts averaging 48.7 Ma (Ishizuka et al., 2018) are younger that the inferred age of IBM subduction initiation based on the oldest ages (52 Ma) of IBM forearc basalts (FAB) from the eastern margin of the Philippine Sea plate. FAB are hypothesized to be the first magma type erupted as the Pacific plate subsided, followed by boninites, and ultimately typical arc magmas over a period of about 10 Ma. Site U1438 basalts and IBM FABs are similar, but Site U1438 basalts have lower V contents, higher Ti/V and little geochemical evidence for involvement of slab-derived fluids. We hypothesize that the asthenospheric upwelling and extension expected during subduction initiation occurred over a broad expanse of the upper plate, even as hydrous fluids were introduced near the plate edge to produce FABs and boninites. Site U1438 basalts formed by decompression melting during the first 3 Ma of subduction initiation, and were stranded behind the early IBM arc as mantle conditions shifted to flux melting beneath a well-defined volcanic front

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results