Controversies in software engineering

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In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi.

BackgroundCruzain, the major cysteine protease of Trypanosoma cruzi, is an essential enzyme for the parasite life cycle and has been validated as a viable target to treat Chagas' disease. As a proof-of-concept, K11777, a potent inhibitor of cruzain, was found to effectively eliminate T. cruzi infection and is currently a clinical candidate for treatment of Chagas' disease.Methodology/principal findingsWRR-483, an analog of K11777, was synthesized and evaluated as an inhibitor of cruzain and against T. cruzi proliferation in cell culture. This compound demonstrates good potency against cruzain with sensitivity to pH conditions and high efficacy in the cell culture assay. Furthermore, WRR-483 also eradicates parasite infection in a mouse model of acute Chagas' disease. To determine the atomic-level details of the inhibitor interacting with cruzain, a 1.5 A crystal structure of the protease in complex with WRR-483 was solved. The structure illustrates that WRR-483 binds covalently to the active site cysteine of the protease in a similar manner as other vinyl sulfone-based inhibitors. Details of the critical interactions within the specificity binding pocket are also reported.ConclusionsWe demonstrate that WRR-483 is an effective cysteine protease inhibitor with trypanocidal activity in cell culture and animal model with comparable efficacy to K11777. Crystallographic evidence confirms that the mode of action is by targeting the active site of cruzain. Taken together, these results suggest that WRR-483 has potential to be developed as a treatment for Chagas' disease

IL-21 receptor expression in human tendinopathy

The pathogenetic mechanisms underlying tendinopathy remain unclear, with much debate as to whether inflammation or degradation has the prominent role. Increasing evidence points toward and early inflammatory infiltrate and associated inflammatory cytokine production in human and animal models of tendon disease. The IL-21/IL-21R axis is a proinflammatory cytokine complex that has been associated with chronic inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. This project aimed to investigate the role and expression of the cytokine/receptor pair IL-21/IL-21R in human tendinopathy. We found significantly elevated expression of IL-21 receptor message and protein in human tendon samples but found no convincing evidence of the presence of IL-21 at message or protein level. The level of expression of IL-21R message/protein in human tenocytes was significantly up regulated by proinflammatory cytokines (TNFα/IL-1β) in vitro. These findings demonstrate that IL-21R is present in early human tendinopathy mainly expressed by tenocytes and macrophages. Despite a lack of IL-21 expression these data again suggest that early tendinopathy has an inflammatory/cytokine phenotype, which may provide novel translational targets in the treatment of tendinopathy

MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease

MicroRNA (miRNA) has the potential for cross-regulation and functional integration of discrete biological processes during complex physiological events. Utilizing the common human condition tendinopathy as a model system to explore the cross-regulation of immediate inflammation and matrix synthesis by miRNA we observed that elevated IL-33 expression is a characteristic of early tendinopathy. Using in vitro tenocyte cultures and in vivo models of tendon damage, we demonstrate that such IL-33 expression plays a pivotal role in the transition from type 1 to type 3 collagen (Col3) synthesis and thus early tendon remodelling. Both IL-33 effector function, via its decoy receptor sST2, and Col3 synthesis are regulated by miRNA29a. Downregulation of miRNA29a in human tenocytes is sufficient to induce an increase in Col3 expression. These data provide a molecular mechanism of miRNA-mediated integration of the early pathophysiologic events that facilitate tissue remodelling in human tendon after injury

As-Flown Shuttle Micro-Meteoroid Orbital Debris (MMOD) Assessment History

The final flight of the Space Shuttle program was completed on July 21st of 2011. The reusable nature of the Orbiter vehicles has provided NASA with a unique opportunity to inspect and sample spacecraft surfaces exposed to the MMOD environment in low Earth orbit. This paper will provide details of MMOD damages found on Orbiter surfaces after recent flights, as well as putting these damages in context by providing historical comparisons of recent damage to previous flights. The Bumper threat assessment computer code is used by NASA to determine spacecraft MMOD penetration risk. The tool was used before each mission to estimate pre-flight MMOD risk for the Shuttle Program Office using planned vehicles attitudes and exposure times. This paper summarizes the efforts of the authors to assess the expected number MMOD impacts of selected particles sizes of 52 shuttle missions ranging from STS-50 (1992) through STS-133 (2011) using as-flown attitude data. The missions encompass the Shuttle/Mir precursors to the International Space Station (ISS) as well as the ISS assembly flights. The paper includes a comparison of observed MMOD impact damage to the predicted number of impacts from Bumper code assessments. This data can be used to validate engineering models of the orbital debris and micrometeoroid environment, such NASA s ORDEM debris model and MEM meteoroid model

Micrometeoroid and Orbital Debris Threat Mitigation Techniques for the Space Shuttle Orbiter

An overview of significant Micrometeoroid and Orbital Debris (MMOD) impacts on the Payload Bay Door radiators, wing leading edge reinforced carbon-carbon panels and crew module windows will be presented, along with a discussion of the techniques NASA has implemented to reduce the risk from MMOD impacts. The concept of "Late Inspection" of the Nose Cap and Wing leading Edge (WLE) Reinforced Carbon Carbon (RCC) regions will be introduced. An alternative mated attitude with the International Space Station (ISS) on shuttle MMOD risk will also be presented. The significant threat mitigation effect of these two techniques will be demonstrated. The wing leading edge impact detection system, on-orbit repair techniques and disabled vehicle contingency plans will also be discussed

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

Coupled Replicator Equations for the Dynamics of Learning in Multiagent Systems

Starting with a group of reinforcement-learning agents we derive coupled replicator equations that describe the dynamics of collective learning in multiagent systems. We show that, although agents model their environment in a self-interested way without sharing knowledge, a game dynamics emerges naturally through environment-mediated interactions. An application to rock-scissors-paper game interactions shows that the collective learning dynamics exhibits a diversity of competitive and cooperative behaviors. These include quasiperiodicity, stable limit cycles, intermittency, and deterministic chaos--behaviors that should be expected in heterogeneous multiagent systems described by the general replicator equations we derive.Comment: 4 pages, 3 figures, http://www.santafe.edu/projects/CompMech/papers/credlmas.html; updated references, corrected typos, changed conten

Relativistic Aharonov-Casher Phase in Spin One

The Aharonov-Casher (AC) phase is calculated in relativistic wave equations of spin one. The AC phase has previously been calculated from the Dirac-Pauli equation using a gauge-like technique \cite{MK1,MK2}. In the spin-one case, we use Kemmer theory (a Dirac-like particle theory) to calculate the phase in a similar manner. However the vector formalism, the Proca theory, is more widely known and used. In the presence of an electromagnetic field, the two theories are `equivalent' and may be transformed into one another. We adapt these transformations to show that the Kemmer theory results apply to the Proca theory. Then we calculate the Aharonov-Casher phase for spin-one particles directly in the Proca formalism.Comment: 12 page