Targeting danger molecules in tendinopathy: the HMGB1/TLR4 axis

Objectives: To seek evidence of the danger molecule, high-mobility group protein B1 (HMGB1) expression in human tendinopathy and thereafter, to explore mechanisms where HMGB1 may regulate inflammatory mediators and matrix regulation in human tendinopathy. Methods: Torn supraspinatus tendon (established pathology) and matched intact subscapularis tendon (representing ‘early pathology’) biopsies were collected from patients undergoing arthroscopic shoulder surgery. Control samples of subscapularis tendon were collected from patients undergoing arthroscopic stabilisation surgery. Markers of inflammation and HMGB1 were quantified by reverse transcriptase PCR (RT-PCR) and immunohistochemistry. Human tendon-derived primary cells were derived from hamstring tendon tissue obtained during hamstring tendon anterior cruciate ligament reconstruction and used through passage 3. In vitro effects of recombinant HMGB1 on tenocyte matrix and inflammatory potential were measured using quantitative RT-PCR, ELISA and immunohistochemistry staining. Results: Tendinopathic tissues demonstrated significantly increased levels of the danger molecule HMGB1 compared with control tissues with early tendinopathy tissue showing the greatest expression. The addition of recombinant human HMGB1 to tenocytes led to significant increase in expression of a number of inflammatory mediators, including interleukin 1 beta (IL-1β), IL-6, IL-33, CCL2 and CXCL12, in vitro. Further analysis demonstrated rhHMGB1 treatment resulted in increased expression of genes involved in matrix remodelling. Significant increases were observed in Col3, Tenascin-C and Decorin. Moreover, blocking HMGB1 signalling via toll-like receptor 4 (TLR4) silencing reversed these key inflammatory and matrix changes. Conclusion: HMGB1 is present in human tendinopathy and can regulate inflammatory cytokines and matrix changes. We propose HMGB1 as a mediator driving the inflammatory/matrix crosstalk and manipulation of the HMGB1/TLR4 axis may offer novel therapeutic approaches targeting inflammatory mechanisms in the management of human tendon disorders

Changes in Older and Younger Woods in West-Central Ohio

Author Institution: Dept. of Biological Sciences, Wright State University, OHThis study examines changes in two forest stands in the Quercus-Acer saccharum forest region of west central Ohio: an old-growth stand changing from Quercus-dominated to Acer saccharum-dominated and a stand established following agricultural abandonment about 1950. Both stands are in the Wright State University woods. Permanent plots were sampled in 1980 (younger stand only), 1982 (older stand only), 1993, and 2000. The older stand had more small, fewer intermediate, and more large stems than the younger stand. The plot in the new stand showed a bell-shaped distribution with most stems established shortly after land abandonment. Mortality decreased and growth increased with stem size for both stands. Acer saccharum in all sizes and large Quercus dominated the older stand. The younger stand was dominated by Robinia pseudo-acacia with Acer saccharum also important. In the older plots small stems generally were clustered, intermediate-sized stems randomly distributed, and the largest stems regularly distributed. In the younger plot small stems were aggregated while larger ones were randomly distributed. Quercus regenerated well until the late 1800s, singly or in small groups, but few stems have become established since 1900. Quercus may need fires or grazing to regenerate successfully. Both stands are changing to increased dominance by Acer saccharum and other shade-tolerant species as they lose species (Robinia pseudo-acacia in the younger stand, Quercus in the older stand) more successful under past than present conditions

Intellectual Property and Public Health – A White Paper

On October 26, 2012, the University of Akron School of Law’s Center for Intellectual Property and Technology hosted its Sixth Annual IP Scholars Forum. In attendance were thirteen legal scholars with expertise and an interest in IP and public health who met to discuss problems and potential solutions at the intersection of these fields. This report summarizes this discussion by describing the problems raised, areas of agreement and disagreement between the participants, suggestions and solutions made by participants and the subsequent evaluations of these suggestions and solutions. Led by the moderator, participants at the Forum focused generally on three broad questions. First, are there alternatives to either the patent system or specific patent doctrines that can provide or help provide sufficient incentives for health-related innovation? Second, is health information being used proprietarily and if so, is this type of protection appropriate? Third, does IP conflict with other non-IP values that are important in health and how does or can IP law help resolve these conflicts? This report addresses each of these questions in turn

The MIT Emissions Prediction and Policy Analysis (EPPA) Model: Version 4

Abstract in HTML and technical report in PDF available on the Massachusetts Institute of Technology Joint Program on the Science and Policy of Global Change website (http://mit.edu/globalchange/www/).The Emissions Prediction and Policy Analysis (EPPA) model is the part of the MIT Integrated Global Systems Model (IGSM) that represents the human systems. EPPA is a recursive-dynamic multi-regional general equilibrium model of the world economy, which is built on the GTAP dataset and additional data for the greenhouse gas and urban gas emissions. It is designed to develop projections of economic growth and anthropogenic emissions of greenhouse related gases and aerosols. The main purpose of this report is to provide documentation of a new version of EPPA, EPPA version 4. In comparison with EPPA3, it includes greater regional and sectoral detail, a wider range of advanced energy supply technologies, improved capability to represent a variety of different and more realistic climate policies, and enhanced treatment of physical stocks and flows of energy, emissions, and land use to facilitate linkage with the earth system components of the IGSM. Reconsideration of important parameters and assumptions led to some revisions in reference projections of GDP and greenhouse gas emissions. In EPPA4 the global economy grows by 12.5 times from 2000 to 2100 (2.5% per year) compared with an increase of 10.7 times (2.4% per year) in EPPA3. This is one of the important revisions that led to an increase in CO2 emissions to 25.7 GtC in 2100, up from 23 GtC in 2100 projected by EPPA3. There is considerable uncertainty in such projections because of uncertainty in various driving forces. To illustrate this uncertainty we consider scenarios where the global GDP grows 0.5% faster (slower) than the reference rate, and these scenarios result in CO2 emissions in 2100 of 34 (17) GtC. A sample greenhouse gas policy scenario that puts the world economy on a path toward stabilization of atmospheric CO2 at 550 ppmv is also simulated to illustrate the response of EPPA4 to a policy constraint.This research was supported by the U.S Department of Energy, U.S. Environmental Protection Agency, U.S. National Science Foundation, U.S. National Aeronautics and Space Administration, U.S. National Oceanographic and Atmospheric Administration; and the Industry and Foundation Sponsors of the MIT Joint Program on the Science and Policy of Global Change: Alstom Power (France), American Electric Power (USA), BP p.l.c. (UK/USA), Chevron Corporation (USA), CONCAWE (Belgium), DaimlerChrysler AG (Germany), Duke Energy (USA), J-Power (Japan), Electric Power Research Institute (USA), Electricité de France, ExxonMobil Corporation (USA), Ford Motor Company (USA), General Motors (USA), Murphy Oil Corporation (USA), Oglethorpe Power Corporation (USA), RWE Power (Germany), Shell Petroleum (Netherlands/UK), Southern Company (USA), Statoil ASA (Norway), Tennessee Valley Authority (USA), Tokyo Electric Power Company (Japan), Total (France), G. Unger Vetlesen Foundation (USA)

CERKL regulates autophagy via the NAD-dependent deacetylase SIRT1

<p>Macroautophagy/autophagy is an important intracellular mechanism for the maintenance of cellular homeostasis. Here we show that the <i>CERKL</i> (ceramide kinase like) gene, a retinal degeneration (RD) pathogenic gene, plays a critical role in regulating autophagy by stabilizing SIRT1. <i>In vitro</i> and <i>in vivo</i>, suppressing CERKL results in impaired autophagy. SIRT1 is one of the main regulators of acetylation/deacetylation in autophagy. In CERKL-depleted retinas and cells, SIRT1 is downregulated. ATG5 and ATG7, 2 essential components of autophagy, show a higher degree of acetylation in CERKL-depleted cells. Overexpression of SIRT1 rescues autophagy in CERKL-depleted cells, whereas CERKL loses its function of regulating autophagy in SIRT1-depleted cells, and overexpression of CERKL upregulates SIRT1. Finally, we show that CERKL directly interacts with SIRT1, and may regulate its phosphorylation at Ser27 to stabilize SIRT1. These results show that CERKL is an important regulator of autophagy and it plays this role by stabilizing the deacetylase SIRT1.</p

Adequacy of milk intake during exclusive breastfeeding : a longitudinal study

Mean intakes of human milk provide sufficient energy and protein to meet mean requirements during the first 6 months of infancy. Since infant growth potential drives milk production, the distribution of intakes likely matches the distribution of energy and protein requirements. This longitudinal study describes the adequacy of milk intake during exclusive breastfeeding

Removing Orbital Debris with Lasers

Orbital debris in low Earth orbit (LEO) are now sufficiently dense that the use of LEO space is threatened by runaway collisional cascading. A problem predicted more than thirty years ago, the threat from debris larger than about 1 cm demands serious attention. A promising proposed solution uses a high power pulsed laser system on the Earth to make plasma jets on the objects, slowing them slightly, and causing them to re-enter and burn up in the atmosphere. In this paper, we reassess this approach in light of recent advances in low-cost, light-weight modular design for large mirrors, calculations of laser-induced orbit changes and in design of repetitive, multi-kilojoule lasers, that build on inertial fusion research. These advances now suggest that laser orbital debris removal (LODR) is the most cost-effective way to mitigate the debris problem. No other solutions have been proposed that address the whole problem of large and small debris. A LODR system will have multiple uses beyond debris removal. International cooperation will be essential for building and operating such a system.Comment: 37 pages, 15 figures, in preparation for submission to Advances in Space Researc