ADAMTS proteinases: a multi-domain, multi-functional family with roles in extracellular matrix turnover and arthritis

Members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family are known to influence development, angiogenesis, coagulation and progression of arthritis. As proteinases their substrates include the von Willebrand factor precursor and extracellular matrix components such as procollagen, hyalectans (hyaluronan-binding proteoglycans including aggrecan), decorin, fibromodulin and cartilage oligomeric matrix protein. ADAMTS levels and activities are regulated at multiple levels through the control of gene expression, mRNA splicing, protein processing and inhibition by TIMP (tissue inhibitor of metalloproteinases). A recent screen of human cartilage has shown that multiple members of the ADAMTS family may be important in connective tissue homeostasis and pathology

The role of proteases in pathologies of the synovial joint

Synovial (diarthrodial) joints are employed within the body to provide skeletal mobility and have a characteristic structure adapted to provide a smooth almost frictionless surface for articulation. Pathologies of the synovial joint are an important cause of patient morbidity and can affect each of the constituent tissues. A common feature of these pathologies is degenerative changes in the structure of the tissue which is mediated, at least in part, by proteolytic activity. Most tissues of the synovial joint are composed primarily of extracellular matrix and key pathological roles in the degeneration of this matrix are performed by metalloproteinases such as matrix metallproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS). However, other proteases such as cathepsin K are likely to play an important role, especially in bone turnover. In addition to the cleavage of structural proteins, proteolytic activities are employed to regulate the activity of other proteases, growth factors, cytokines and other inflammatory mediators. Proteases combine to form complex regulatory networks, the correct functioning of which is required for tissue homeostasis and the imbalance of which may be a feature of pathology. A precise understanding of the proteases involved in these networks is required for a true understanding of the associated pathology

An emerging learning design for student-generated 'iVideos'

This paper describes an emerging learning design for a popular genre of learner-generated video projects: Ideas Videos or iVideos. These advocacy-style videos are short, two-minute, digital videos designed âto evoke powerful experiences about educative ideasâ (Wong, Mishra, Koehler & Siebenthal, 2007, p1). We draw on a recent study in teacher education to present a structured description of a pedagogical approach to iVideo filmmaking. A visual learning design representation (Agostinho, Harper, Oliver, Hedberg & Wills, 2008) and a LAMS-based generic learning design template (Cameron, 2008) form part of this description

Gas and star formation from HD and dust emission in a strongly lensed galaxy

The molecular gas content of high-redshift galaxies is a highly sought-after property. However, H$_2$ is not directly observable in most environments, so its mass is probed through other emission lines (e.g., CO, [CI], [CII]), or through a gas-to-dust ratio. Each of these methods depends on several assumptions, and are best used in parallel. In this work, we extend an additional molecular gas tracer to high-redshift studies by observing hydrogen deuteride (HD) emission in the strongly lensed $z=5.656$ galaxy SPT0346-52 with ALMA. While no HD(1-0) emission is detected, we are able to place an upper limit on the gas mass of $\rm M_{H_2}<6.4\times10^{11} M_{\odot}$. This is used to find a limit on the $\rm L'_{CO}$ conversion factor of $\rm\alpha_{CO}<5.8$ M$_{\odot}$(K km s$^{-1}$ pc$^2$)$^{-1}$. In addition, we construct the most complete spectral energy distribution (SED) of this source to date, and fit it with a single-temperature modified blackbody using the nested sampling code MultiNest, yielding a best-fit dust mass $\rm M_{dust}=10^{8.92\pm0.02}$ M$_{\odot}$, dust temperature $78.6\pm0.5$ K, dust emissivity spectral index $\beta=1.81\pm0.03$, and star formation rate $\rm SFR=3800\pm100$ M$_{\odot}$ year$^{-1}$. Using the continuum flux densities to estimate the total gas mass of the source, we find $\rm M_{H_2}<2.4\times10^{11}$ M$_{\odot}$, assuming sub-solar metallicity. This implies a CO conversion factor of $\rm \alpha_{CO}<2.2$, which is between the standard values for MW-like galaxies and starbursts. These properties confirm that SPT0346-52 is a heavily starbursting, gas rich galaxy.STFC ER

What drives galaxy quenching? A deep connection between galaxy kinematics and quenching in the local Universe

We develop a 2D inclined rotating disc model, which we apply to the stellar velocity maps of 1862 galaxies taken from the MaNGA survey (SDSS public Data Release 15). We use a random forest classifier to identify the kinematic parameters that are most connected to galaxy quenching. We find that kinematic parameters that relate predominantly to the disc (such as the mean rotational velocity) and parameters that characterise whether a galaxy is rotation- or dispersion-dominated (such as the ratio of rotational velocity to velocity dispersion) are not fundamentally linked to the quenching of star formation. Instead, we find overwhelmingly that it is the absolute level of velocity dispersion (a property that relates primarily to a galaxy's bulge/spheroidal component) that is most important for separating star forming and quenched galaxies. Furthermore, a partial correlation analysis shows that many commonly discussed correlations between galaxy properties and quenching are spurious, and that the fundamental correlation is between quenching and velocity dispersion. In particular, we find that at fixed velocity dispersion, there is only a very weak dependence of quenching on the disc properties, whereby more discy galaxies are slightly more likely to be forming stars. By invoking the tight relationship between black hole mass and velocity dispersion, and noting that black hole mass traces the total energy released by AGN, we argue that these data support a scenario in which quenching occurs by preventive feedback from AGN. The kinematic measurements from this work are publicly available

Genotypic variation in phosphorus efficiency between wheat cultivars grown under greenhouse and field conditions

Phosphorus (P) efficiency (relative growth), which is described as the ratio of shoot dry matter or grain yield at deficient P supply to that obtained under adequate P supply, was compared in 25 winter wheat cultivars grown under greenhouse and field conditions with low and adequate P levels in a P-deficient calcareous soil. Adequate P supply resulted in significant increases in shoot dry weight and grain yield under both experimental conditions. In the greenhouse experiment, the increases in shoot dry weight under adequate P supply (80 mg kg(-1)) were from 0% (cv: C-1252) to 34% (cv: Dagdas). Under field conditions, the cultivars showed much greater variation in their response to adequate P supply (60 kg ha(-1)): the increases in shoot dry weight and grain yield with adequate P supply were between -2% (cv: Sivas-111/33) and 25% (cv: Kirac-66) for shoot dry matter production at the heading stage and between 0% (cv: Kirkpinar-79) and 76% (cv: Kate A-1) for grain yield at maturity. Almost all cultivars behaved totally different in their response to P deficiency under greenhouse and field conditions. Phosphorus efficiency ratios (relative growth) under greenhouse conditions did not correlate with the P efficiency ratios under field conditions. In general, durum wheat cultivars were found to be more P efficient compared with bread wheat cultivars. The results of this study indicated that there is wide variation in tolerance to P deficiency among wheat cultivars that can be exploited in breeding new wheat cultivars for high P deficiency tolerance. The results also demonstrated that P efficiency was expressed differently among the wheat cultivars when grown under greenhouse and field conditions and, therefore, special attention should be paid to growth conditions in screening wheat for P efficiency

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)

Detection of a high-redshift molecular outflow in a primeval hyperstarburst galaxy

We report the discovery of a high-redshift, massive molecular outflow in the starburst galaxy SPT0346-52 (z = 5:656) via the detected absorption of high-excitation water transitions (H2O 42;3 41;4 and H2O 33;0 32;1) with the Atacama Large Millimeter/ submillimeter Array (ALMA). The host galaxy is one of the most powerful starburst galaxies at high redshift (star formation rate; SFR ~ 3,600M $_{\odot}$ year{^{-}}1), with an extremely compact (~ 320 pc) star formation region and a star formation rate surface density ($\Sigma$SFR ~ 5; 500M$_{\odot}$ year{^{-}}1 kpc{^{-}}2) five times higher than ‘maximum’ (i.e. Eddington-limited) starbursts, implying a highly transient phase. The estimated outflow rate is ~ 500M$_{\odot}$ year{^{-}}1, which is much lower than the SFR, implying that in this extreme starburst the outflow capabilities saturate and the outflow is no longer capable of regulating star formation, resulting in a runaway process in which star formation will use up all available gas in less than 30 Myr. Finally, while previous kinematic investigations of this source revealed possible evidence for an ongoing major merger, the coincidence of the hyper-compact starburst and high-excitation water absorption indicates that this is a single starburst galaxy surrounded by a disc.Includes STFC and ERC

Successful field trial of attractive toxic sugar bait (ATSB) plant-spraying methods against malaria vectors in the Anopheles gambiae complex in Mali, West Africa

<p>Abstract</p> <p>Background</p> <p>Based on highly successful demonstrations in Israel that attractive toxic sugar bait (ATSB) methods can decimate local populations of mosquitoes, this study determined the effectiveness of ATSB methods for malaria vector control in the semi-arid Bandiagara District of Mali, West Africa.</p> <p>Methods</p> <p>Control and treatment sites, selected along a road that connects villages, contained man-made ponds that were the primary larval habitats of <it>Anopheles gambiae </it>and <it>Anopheles arabiensis</it>. Guava and honey melons, two local fruits shown to be attractive to <it>An. gambiae </it>s.l., were used to prepare solutions of Attractive Sugar Bait (ASB) and ATSB that additionally contained boric acid as an oral insecticide. Both included a color dye marker to facilitate determination of mosquitoes feeding on the solutions. The trial was conducted over a 38-day period, using CDC light traps to monitor mosquito populations. On day 8, ASB solution in the control site and ATSB solution in the treatment site were sprayed using a hand-pump on patches of vegetation. Samples of female mosquitoes were age-graded to determine the impact of ATSB treatment on vector longevity.</p> <p>Results</p> <p>Immediately after spraying ATSB in the treatment site, the relative abundance of female and male <it>An. gambiae </it>s.l. declined about 90% from pre-treatment levels and remained low. In the treatment site, most females remaining after ATSB treatment had not completed a single gonotrophic cycle, and only 6% had completed three or more gonotrophic cycles compared with 37% pre-treatment. In the control site sprayed with ASB (without toxin), the proportion of females completing three or more gonotrophic cycles increased from 28.5% pre-treatment to 47.5% post-treatment. In the control site, detection of dye marker in over half of the females and males provided direct evidence that the mosquitoes were feeding on the sprayed solutions.</p> <p>Conclusion</p> <p>This study in Mali shows that even a single application of ATSB can substantially decrease malaria vector population densities and longevity. It is likely that ATSB methods can be used as a new powerful tool for the control of malaria vectors, particularly since this approach is highly effective for mosquito control, technologically simple, inexpensive, and environmentally safe.</p