Development and validation of a high-throughput cell-based screen to identify activators of a bacterial two-component signal transduction system

CpxRA is a two-component signal transduction system (2CSTS) found in many drug-resistant Gram-negative bacteria. In response to periplasmic stress, CpxA autophosphorylates and donates a phosphoryl group to its cognate response regulator, CpxR. Phosphorylated CpxR (CpxR-P) upregulates genes involved in membrane repair and downregulates multiple genes that encode virulence factors, which are trafficked across the cell membrane. Mutants that constitutively activate CpxRA in Salmonella enterica serovar Typhimurium and Haemophilus ducreyi are avirulent in mice and humans, respectively. Thus, the activation of CpxRA has high potential as a novel antimicrobial/antivirulence strategy. Using a series of Escherichia coli strains containing a CpxR-P-responsive lacZ reporter and deletions in genes encoding CpxRA system components, we developed and validated a novel cell-based high-throughput screen (HTS) for CpxRA activators. A screen of 36,000 compounds yielded one hit compound that increased reporter activity in wild-type cells. This is the first report of a compound that activates, rather than inhibits, a 2CSTS. The activity profile of the compound against CpxRA pathway mutants in the presence of glucose suggested that the compound inhibits CpxA phosphatase activity. We confirmed that the compound induced the accumulation of CpxR-P in treated cells. Although the hit compound contained a nitro group, a derivative lacking this group retained activity in serum and had lower cytotoxicity than that of the initial hit. This HTS is amenable for the screening of larger libraries to find compounds that activate CpxRA by other mechanisms, and it could be adapted to find activators of other two-component systems

Science for Society Workshop Summary Report

Science for Society, a workshop held at the Oak Ridge National Laboratory (ORNL) on September 27, 20111, explored ways to move Laboratory science toward use. It sought actionable recommendations. Thus the workshop focused on: (1) current practices that promote and inhibit the translation of science into use, (2) principles that could lead to improving ORNL's translational knowledge and technology transfer efforts, and (3) specific recommendations for making these principles operational. This highly interactive workshop struck a positive chord with participants, a group of 26 ORNL staff members from diverse arenas of science and technology (S and T), technology transfer, and external laboratory relations, who represented all levels of science, technology, and management. Recognizing that the transformation of fundamental principles into operational practices often follows a jagged path, the workshop sought to identify key choices that could lead to a smoother journey along this path, as well as choices that created roadblocks and bottlenecks. The workshop emphasized a portion of this pathway, largely excluding the marketplace. Participants noted that research translation includes linkages between fundamental and applied research and development (R and D), and is not restricted to uptake by manufacturers, consumers, or end users. Three crosscutting ideas encapsulate workshop participants observations: (1) ORNL should take more action to usher the translation of its S and T products toward use, so as to make a positive national and global impact and to enhance its own competitiveness in the future; (2) ORNL (and external entities such as DOE and Congress) conveys inconsistent messages with regard to the importance of research translation and application, which (a) creates confusion, (b) poses disincentives to pursue research translation, (c) imposes barriers that inhibit cross-fertilization and collaboration, and (d) diminishes the effectiveness of both the science mission and the translation of that science for use; and (3) ORNL should design its commitments and actions for helping move science from the Laboratory toward use to align with one another and should integrate them into its institutional culture in such a way as to elevate research translation and application to coequal status with scientific excellence. Participants made several actionable recommendations for enhancing research translation at ORNL, some of which were particular to specific S and T domains. Among the recommendations that participants agreed apply Lab-wide are to: align metrics and incentives with research translation goals; manage risks and conflicts of interest instead of avoiding them; and create programs (e.g., entrepreneurial leave) that promote interactions between key ORNL staff and industry in ways that complement careers at ORNL

The Second-Generation Guide Star Catalog: Description and Properties

The GSC-II is an all-sky database of objects derived from the uncompressed DSS that the STScI has created from the Palomar and UK Schmidt survey plates and made available to the community. Like its predecessor (GSC-I), the GSC-II was primarily created to provide guide star information and observation planning support for HST. This version, however, is already employed at some of the ground-based new-technology telescopes such as GEMINI, VLT, and TNG, and will also be used to provide support for the JWST and Gaia space missions as well as LAMOST, one of the major ongoing scientific projects in China. Two catalogs have already been extracted from the GSC-II database and released to the astronomical community. A magnitude-limited (R=18.0) version, GSC2.2, was distributed soon after its production in 2001, while the GSC2.3 release has been available for general access since 2007. The GSC2.3 catalog described in this paper contains astrometry, photometry, and classification for 945,592,683 objects down to the magnitude limit of the plates. Positions are tied to the ICRS; for stellar sources, the all-sky average absolute error per coordinate ranges from 0.2" to 0.28" depending on magnitude. When dealing with extended objects, astrometric errors are 20% worse in the case of galaxies and approximately a factor of 2 worse for blended images. Stellar photometry is determined to 0.13-0.22 mag as a function of magnitude and photographic passbands (B,R,I). Outside of the galactic plane, stellar classification is reliable to at least 90% confidence for magnitudes brighter than R=19.5, and the catalog is complete to R=20.Comment: 52 pages, 33 figures, to be published in AJ August 200

Joint Arthroplasties other than the Hip in Solid Organ Transplant Recipients

Transplantation Surgery has undergone a great development during the last thirty years and the survival of solid organ recipients has increased dramatically. Osteo-articular diseases such as osteoporosis, fractures, avascular bone necrosis and osteoarthritis are relatively common in these patients and joint arthroplasty may be required. The outcome of hip arthroplasty in patients with osteonecrosis of the femoral head after renal transplantation has been studied and documented by many researchers. However, the results of joint arthroplasties other than the hip in solid organs recipients were only infrequently reported in the literature. A systematic review of the English literature was conducted in order to investigate the outcome of joint arthroplasties other than the hip in kidney, liver or heart transplant recipients. Nine pertinent articles including 51 knee arthroplasties, 8 shoulder arthroplasties and 1 ankle arthroplasty were found. These articles reported well to excellent results with a complication rate and spectrum comparable with those reported in nontransplant patients

Review debate: we need human rights not nationalism 'lite': globalization and British solidarity

The article explores the relationship of multiculturalism to social solidarity. The multicultural nature of Britain is accepted as a welcome reality but certain problems in relation to the development of multiculturalism in Britain are acknowledged. Various approaches to buttress or replace multiculturalism are reviewed. These are: a strengthened and/or reconstituted nationalism (`Britishness'); human rights; and social equality. The issue of citizenship recurs throughout. It is argued that a combined emphasis on human rights and greater social equality offer a better basis than nationalism for strengthening solidarity in Britain, especially in the longer term. Sociological theory offers a fruitful if strangely neglected starting point for understanding social solidarity. I draw critically on Durkheim and Marx to obtain some objective perspective on this controversial matter. Copyright 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution

Citizenship Education and Liberalism: A State of the Debate Analysis 1990–2010

What kind of citizenship education, if any, should schools in liberal societies promote? And what ends is such education supposed to serve? Over the last decades a respectable body of literature has emerged to address these and related issues. In this state of the debate analysis we examine a sample of journal articles dealing with these very issues spanning a twenty-year period with the aim to analyse debate patterns and developments in the research field. We first carry out a qualitative analysis where we design a two-dimensional theoretical framework in order to systematise the various liberal debate positions, and make us able to study their justifications, internal tensions and engagements with other positions. In the ensuing quantitative leg of the study we carry out a quantitative bibliometric analysis where we weigh the importance of specific scholars. We finally discuss possible merits and flaws in the research field, as evidenced in and by the analysis

A multinational randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis [ISRCTN25142273]

BACKGROUND: Etoricoxib is a highly selective COX-2 inhibitor which was evaluated for the treatment of rheumatoid arthritis (RA). METHODS: Double-blind, randomized, placebo and active comparator-controlled, 12-week study conducted at 67 sites in 28 countries. Eligible patients were chronic NSAID users who demonstrated a clinical worsening of arthritis upon withdrawal of prestudy NSAIDs. Patients received either placebo, etoricoxib 90 mg once daily, or naproxen 500 mg twice daily (2:2:1 allocation ratio). Primary efficacy measures included direct assessment of arthritis by counts of tender and swollen joints, and patient and investigator global assessments of disease activity. Key secondary measures included the Stanford Health Assessment Questionnaire, patient global assessment of pain, and the percentage of patients who achieved ACR20 responder criteria response (a composite of pain, inflammation, function, and global assessments). Tolerability was assessed by adverse events and routine laboratory evaluations. RESULTS: 1171 patients were screened, 891 patients were randomized (N = 357 for placebo, N = 353 for etoricoxib, and N = 181 for naproxen), and 687 completed 12 weeks of treatment (N = 242 for placebo, N = 294 for etoricoxib, and N = 151 for naproxen). Compared with patients receiving placebo, patients receiving etoricoxib and naproxen showed significant improvements in all efficacy endpoints (p<0.05). Treatment responses were similar between the etoricoxib and naproxen groups for all endpoints. The percentage of patients who achieved ACR20 responder criteria response was 41% in the placebo group, 59% in the etoricoxib group, and 58% in the naproxen group. Etoricoxib and naproxen were both generally well tolerated. CONCLUSIONS: In this study, etoricoxib 90 mg once daily was more effective than placebo and similar in efficacy to naproxen 500 mg twice daily for treating patients with RA over 12 weeks. Etoricoxib 90 mg was generally well tolerated in RA patients

Report of depressive symptoms on waiting list and mortality after liver and kidney transplantation: a prospective cohort study

International audienceABSTRACT: BACKGROUND: Little research has explored pre-transplantation psychological factors as predictors of outcome after liver or kidney transplantation. Our objective is to determine whether report of depressive symptoms on waiting list predicts outcome of liver and kidney transplantation. METHODS: Patients on waiting list for liver or kidney transplantation were classified for report or non-report of depressive symptoms on waiting list. 339 were transplanted 6 months later on average, and followed prospectively. The main outcome measures were graft failure and mortality 18 months post-transplantation. RESULTS: Among the 339 patients, 51.6% reported depressive symptoms on waiting list, 16.5% had a graft failure and 7.4% died post-transplantation. Report of depressive symptoms on waiting list predicted a 3 to 4-fold decreased risk of graft failure and mortality 18-months post-transplantation, independently from age, gender, current cigarette smoking, anxiety symptoms, main primary diagnosis, UNOS score, number of comorbid diagnoses and history of transplantation. Data were consistent for liver and kidney transplantations. Other baseline predictive factors were: for graft failure, the main primary diagnosis and a shorter length since this diagnosis, and for mortality, older age, male gender and the main primary diagnosis. CONCLUSION: Further studies are needed to understand the underlying mechanisms of the association between report of depressive symptoms on waiting list and decreased risk of graft failure and mortality after transplantation

Latino Communities in the United States: Place-Making in the Pre-World War II, Postwar, and Contemporary City

Scholarship on Latino communities in the United States has yet to catch up with the rapid growth of this ethnic population in the country. Understanding the Latino urban experience and developing plans to better respond to both the needs of Latino communities and their integration within society is not only relevant, but also urgently necessary. Using the city of Los Angeles as a main lens, in addition to a general look at the urban Southwest, we contribute to the scholarship on the subject with a review of literature on Latino communities. We structure the review as an assessment of the various challenges and opportunities for urban Latinos in the pre-war, postwar, and contemporary city. Focusing on space, culture, economy, and governance, we chart the various roles both the private and public sectors play in meeting these challenges. Our reading of the literature shows that particular government actions in the economic and governance domains in the past had positive impacts on Latino integration, and we call for a similar effort today in addressing contemporary challenges. We conclude by suggesting that future planning scholarship on Latino communities engage the wider urban studies literature, focus on emerging forms of urbanization, and call on planners to sustain increased academic and practical interest in the topic