Osteoblasts from osteoarthritis patients show enhanced susceptibility to Ross River virus infection associated with delayed type I interferon responses

BACKGROUND Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) have caused widespread outbreaks of chronic polyarthritis. The inflammatory responses in alphavirus-induced arthritis and osteoarthritis (OA) share many similar features, which suggests the possibility of exacerbated alphavirus-induced bone pathology in individuals with pre-existing OA. Here, we investigated the susceptibility of osteoblasts (OBs) from OA patients to RRV infection and dissected the immune mechanisms elicited from infection. METHODS Primary hOBs obtained from trabecular bone of healthy donors and OA patients were infected with RRV. Infectivity and viral replication were determined using flow cytometry and plaque assay, respectively. Real-time PCR was performed to determine expression kinetics of type I interferon (IFN)-related immune mediators and osteotropic factors. RESULTS OA hOBs showed enhanced RRV infectivity and replication during infection, which was associated with delayed induction of IFN-β and RIG-I expression. Enhanced susceptibility of OA hOBs to RRV was associated with a more pronounced increase in RANKL/OPG ratio and expression of osteotropic factors (IL-6, IL-1β, TNF-α and CCL2) in comparison to RRV-infected healthy hOBs. CONCLUSIONS Delayed activation of type I IFN-signalling pathway may have contributed to enhanced susceptibility to RRV infection in hOBs from OA patients. RRV-induced increases in RANKL/OPG ratio and expression of osteotropic factors that favour bone resorption, which may be exacerbated during osteoarthritis. This study provides the novel insight that osteoarthritis may be a risk factor for exacerbated arthritogenic alphaviral infection.SM is the recipient of an Australian National Health and Medical Research Council (NHMRC) Senior Research Fellowship (APP1059167). This project was supported by funding from the Australian NHMRC grant to SM (grant APP1047252)

Randomized trial of enteric-coated mycophenolate sodium versus mycophenolate mofetil in multi-system autoimmune disease.

BACKGROUND: The use of mycophenolate mofetil (MMF) in autoimmune disease is often limited by adverse effects. In this single-centre, open label, parallel design study, we investigated whether enteric-coated mycophenolate sodium (MS) is better tolerated and therefore more efficacious than MMF in primary systemic vasculitis (PSV) and systemic lupus erythematosus (SLE). METHODS: Forty patients with vasculitis or systemic lupus erythematosus (SLE) due to commence MMF for active disease or remission maintenance were randomized to receive either 1440 mg/day MS or 2000 mg/day MMF (18 PSV, 2 SLE per group) in addition to corticosteroids. Random allocation was performed by minimization for age, diagnosis and renal function using a computer algorithm. Twenty-five were treated for active disease (5 first-line therapy, 20 salvage therapy) and 15 for remission maintenance. The composite primary end point was treatment failure and/or drug intolerance over 12 months. Treatment failure was defined as failure to achieve remission by 6 months or disease relapse and treatment intolerance was defined as inability to tolerate and maintain the target dose of MS or MMF within 12 months. RESULTS: Forty patients were included in the analyses. MS was associated with a lower primary end point rate [hazard ratio (HR) 0.37; 95% CI 0.17-0.80; P = 0.012] (11/20, 55% patients) compared with MMF (17/20, 85% patients). Treatment failure alone was less common in the MS group (HR 0.28; 95% CI 0.095-0.82; P = 0.020), although drug intolerance did not differ between groups (HR 0.53; 95% CI 0.20-1.42; P = 0.21). Despite randomization, patients in the MMF group may have had a higher baseline risk for treatment failure; more MMF patients had refractory disease and granulomatosis with polyangiitis (Wegener's). A glomerular filtration rate (GFR) ≤40 mL/min was associated with intolerance. Serious adverse events were common (55% MMF and 45% MS patients). CONCLUSIONS: No differences in treatment tolerance were observed between the MS and MMF groups. Despite similar treatment intolerance, MS was associated with improved efficacy in PSV and SLE compared with MMF. However, baseline group imbalances in factors potentially affecting remission and relapse may have influenced the results. Treatment intolerance was common and strongly associated with low GFR. Further treatment trials are warranted to investigate the effect of GFR on mycophenolic acid pharmacokinetics and clinical outcomes (ISRCTN83027184; EUDRACT 2005-002207-16; Funding Novartis UK)

The Weak Clustering of Gas-Rich Galaxies

We examine the clustering properties of HI-selected galaxies through an analysis of the HI Parkes All-Sky Survey Catalogue (HICAT) two-point correlation function. Various sub-samples are extracted from this catalogue to study the overall clustering of HI-rich galaxies and its dependence on luminosity, HI gas mass and rotational velocity. These samples cover the entire southern sky Dec < 0 deg, containing up to 4,174 galaxies over the radial velocity range 300-12,700 km/s. A scale length of r_0 = 3.45 +/- 0.25 Mpc/h and slope of gamma = 1.47 +/- 0.08 is obtained for the HI-rich galaxy real-space correlation function, making gas-rich galaxies among the most weakly clustered objects known. HI-selected galaxies also exhibit weaker clustering than optically selected galaxies of comparable luminosities. Good agreement is found between our results and those of synthetic HI-rich galaxy catalogues generated from the Millennium Run CDM simulation. Bisecting HICAT using different parameter cuts, clustering is found to depend most strongly on rotational velocity and luminosity, while the dependency on HI mass is marginal. Splitting the sample around v_rot = 108 km/s, a scale length of r_0 = 2.86 +/- 0.46 Mpc/h is found for galaxies with low rotational velocities compared to r_0 = 3.96 +/- 0.33 Mpc/h for the high rotational velocity sample.Comment: Accepted for publication in the Astrophysical Journa

An algorithm for the direct reconstruction of the dark matter correlation function from weak lensing and galaxy clustering

The clustering of matter on cosmological scales is an essential probe for studying the physical origin and composition of our Universe. To date, most of the direct studies have focused on shear-shear weak lensing correlations, but it is also possible to extract the dark matter clustering by combining galaxy-clustering and galaxy-galaxy-lensing measurements. In this study we develop a method that can constrain the dark matter correlation function from galaxy clustering and galaxy-galaxy-lensing measurements, by focusing on the correlation coefficient between the galaxy and matter overdensity fields. To generate a mock galaxy catalogue for testing purposes, we use the Halo Occupation Distribution approach applied to a large ensemble of N-body simulations to model pre-existing SDSS Luminous Red Galaxy sample observations. Using this mock catalogue, we show that a direct comparison between the excess surface mass density measured by lensing and its corresponding galaxy clustering quantity is not optimal. We develop a new statistic that suppresses the small-scale contributions to these observations and show that this new statistic leads to a cross-correlation coefficient that is within a few percent of unity down to 5 Mpc/h. Furthermore, the residual incoherence between the galaxy and matter fields can be explained using a theoretical model for scale-dependent bias, giving us a final estimator that is unbiased to within 1%. We also perform a comprehensive study of other physical effects that can affect the analysis, such as redshift space distortions and differences in radial windows between galaxy clustering and weak lensing observations. We apply the method to a range of cosmological models and show the viability of our new statistic to distinguish between cosmological models.Comment: 23 pages, 14 figures, accepted by PRD; minor changes to V1, 1 new figure, more detailed discussion of the covariance of the new ADSD statisti

The COBE DIRBE Point Source Catalog

We present the COBE DIRBE Point Source Catalog, an all-sky catalog containing infrared photometry in 10 bands from 1.25 microns to 240 microns for 11,788 of the brightest near and mid-infrared point sources in the sky. Since DIRBE had excellent temporal coverage (100 - 1900 independent measurements per object during the 10 month cryogenic mission), the Catalog also contains information about variability at each wavelength, including amplitudes of variation observed during the mission. Since the DIRBE spatial resolution is relatively poor (0.7 degrees), we have carefully investigated the question of confusion, and have flagged sources with infrared-bright companions within the DIRBE beam. In addition, we filtered the DIRBE light curves for data points affected by companions outside of the main DIRBE beam but within the `sky' portion of the scan. At high Galactic latitudes (|b| > 5 degrees), the Catalog contains essentially all of the unconfused sources with flux densities greater than 90, 60, 60, 50, 90, and 165 Jy at 1.25, 2.2, 3.5, 4.9, 12, and 25 microns, respectively, corresponding to magnitude limits of approximately 3.1, 2.6, 1.7, 1.3, -1.3, and -3.5. At longer wavelengths and in the Galactic Plane, the completeness is less certain because of the large DIRBE beam and possible contributions from extended emission. The Catalog also contains the names of the sources in other catalogs, their spectral types, variability types, and whether or not the sources are known OH/IR stars. We discuss a few remarkable objects in the Catalog. [abridged]Comment: Accepted for publication in the Astrophysical Journal Supplement. The full tables are available at http://www.etsu.edu/physics/bsmith/dirbe

Resources, key traits and the size of fungal epidemics in Daphnia populations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111939/1/jane12363.pd

Doctoral Students’ Perceived Barriers that Slow the Progress toward Completing a Doctoral Dissertation: A Mixed Analysis

The non-completion of doctoral degrees has been a concern due to its economic, social, and personal consequences. In the current study, the researchers investigated perceived barriers of select doctoral students in completing their doctoral degrees by utilizing a fully mixed sequential mixed research design. The quantitative and qualitative data were concurrently collected using identical samples (n = 205) via a Reading Interest Survey questionnaire. A sequential mixed analysis revealed 6 emergent themes: external obligations (36%), challenges to doctoral-level researchers (34%), practical/logistical constraints (23%), emotional concerns (15%), program structure (9%), and support for completion (8%). Also, 3 meta-themes were identified (i.e., dissociation, external/internal barriers, and institutional/personal barriers), which aided in explaining the relationships among the 6 primary themes. Implications of the findings are discussed

The effect of rituximab therapy on immunoglobulin levels in patients with multisystem autoimmune disease.

BACKGROUND: Rituximab is a B cell depleting anti-CD20 monoclonal antibody. CD20 is not expressed on mature plasma cells and accordingly rituximab does not have immediate effects on immunoglobulin levels. However, after rituximab some patients develop hypogammaglobulinaemia. METHODS: We performed a single centre retrospective review of 177 patients with multisystem autoimmune disease receiving rituximab between 2002 and 2010. The incidence, severity and complications of hypogammaglobulinaemia were investigated. RESULTS: Median rituximab dose was 6 g (1-20.2) and total follow-up was 8012 patient-months. At first rituximab, the proportion of patients with IgG <6 g/L was 13% and remained stable at 17% at 24 months and 14% at 60 months. Following rituximab, 61/177 patients (34%) had IgG <6 g/L for at least three consecutive months, of whom 7/177 (4%) had IgG <3 g/L. Low immunoglobulin levels were associated with higher glucocorticoid doses during follow up and there was a trend for median IgG levels to fall after ≥ 6 g rituximab. 45/115 (39%) with IgG ≥ 6 g/L versus 26/62 (42%) with IgG <6 g/L experienced severe infections (p=0.750). 6/177 patients (3%) received intravenous immunoglobulin replacement therapy, all with IgG <5 g/L and recurrent infection. CONCLUSIONS: In multi-system autoimmune disease, prior cyclophosphamide exposure and glucocorticoid therapy but not cumulative rituximab dose was associated with an increased incidence of hypogammaglobulinaemia. Severe infections were common but were not associated with immunoglobulin levels. Repeat dose rituximab therapy appears safe with judicious monitoring

A general method for manipulating DNA sequences from any organism with optical tweezers

Mechanical manipulation of single DNA molecules can provide novel information about DNA properties and protein–DNA interactions. Here we describe and characterize a useful method for manipulating desired DNA sequences from any organism with optical tweezers. Molecules are produced from either genomic or cloned DNA by PCR using labeled primers and are tethered between two optically trapped microspheres. We demonstrate that human, insect, plant, bacterial and viral sequences ranging from ∼10 to 40 kilobasepairs can be manipulated. Force-extension measurements show that these constructs exhibit uniform elastic properties in accord with the expected contour lengths for the targeted sequences. Detailed protocols for preparing and manipulating these molecules are presented, and tethering efficiency is characterized as a function of DNA concentration, ionic strength and pH. Attachment strength is characterized by measuring the unbinding time as a function of applied force. An alternative stronger attachment method using an amino–carboxyl linkage, which allows for reliable DNA overstretching, is also described