Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease

Oxidative stress is proposed as an important factor in osteoarthritis (OA). To investigate the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA. SOD expression was determined by real-time PCR and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin–Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulphite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression. All three SOD were abundantly expressed in human cartilage but were markedly downregulated in end-stage OA cartilage, especially SOD2. In the Dunkin–Hartley guinea pig spontaneous OA model, SOD2 expression was decreased in the medial tibial condyle cartilage before, and after, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes increased ROS but decreased collagenase expression. This is the first comprehensive expression profile of all SOD genes in cartilage and, importantly, using an animal model, it has been shown that a reduction in SOD2 is associated with the earliest stages of OA. A decrease in SOD2 was found to be associated with an increase in ROS but a reduction of collagenase gene expression, demonstrating the complexities of ROS function

The crystal structure of Pneumolysin at 2.0 Å resolution reveals the molecular packing of the pre-pore complex

Pneumolysin is a cholesterol-dependent cytolysin (CDC) and virulence factor of Streptococcus pneumoniae. It kills cells by forming pores assembled from oligomeric rings in cholesterol-containing membranes. Cryo-EM has revealed the structures of the membrane-surface bound pre-pore and inserted-pore oligomers, however the molecular contacts that mediate these oligomers are unknown because high-resolution information is not available. Here we have determined the crystal structure of full-length pneumolysin at 1.98 Å resolution. In the structure, crystal contacts demonstrate the likely interactions that enable polymerisation on the cell membrane and the molecular packing of the pre-pore complex. The hemolytic activity is abrogated in mutants that disrupt these intermolecular contacts, highlighting their importance during pore formation. An additional crystal structure of the membrane-binding domain alone suggests that changes in the conformation of a tryptophan rich-loop at the base of the toxin promote monomer-monomer interactions upon membrane binding by creating new contacts. Notably, residues at the interface are conserved in other members of the CDC family, suggesting a common mechanism for pore and pre-pore assembly

What's the point of knowing how?

Why is it useful to talk and think about knowledge-how? Using Edward Craig’s discussion of the function of the concepts of knowledge and knowledge-how as a jumping off point, this paper argues that considering this question can offer us new angles on the debate about knowledge-how. We consider two candidate functions for the concept of knowledge-how: pooling capacities, and mutual reliance. Craig makes the case for pooling capacities, which connects knowledge-how to our need to pool practical capacities. I argue that the evidence is much more equivocal. My suggested diagnosis is that the concept of knowledge-how plays both functions, meaning that the concept of knowledge-how is inconsistent, and that the debate about knowledge-how is at least partly a metalinguistic negotiation. In closing, I suggest a way to revise the philosophical concept of knowledge how

Control of threshold voltage in E-mode and D-mode GaN-on-Si metal-insulator-semiconductor heterostructure field effect transistors by in-situ fluorine doping of atomic layer deposition Al2O3 gate dielectrics

We report the modification and control of threshold voltage in enhancement and depletion mode AlGaN/GaN metal-insulator-semiconductor heterostructure field effect transistors through the use of in-situ fluorine doping of atomic layer deposition Al2O3. Uniform distribution of F ions throughout the oxide thickness are achievable, with a doping level of up to 5.5 × 1019 cm−3 as quantified by secondary ion mass spectrometry. This fluorine doping level reduces capacitive hysteretic effects when exploited in GaN metal-oxide-semiconductor capacitors. The fluorine doping and forming gas anneal also induces an average positive threshold voltage shift of between 0.75 and 1.36 V in both enhancement mode and depletion mode GaN-based transistors compared with the undoped gate oxide via a reduction of positive fixed charge in the gate oxide from +4.67 × 1012 cm−2 to −6.60 × 1012 cm−2. The application of this process in GaN based power transistors advances the realisation of normally off, high power, high speed devices

Community-based perceptions of emergency care in Kenya

Access to quality emergency services is an essential component of the human right to health, but barriers to emergency care are found throughout Africa and the wider world. Data to support the development of emergency care are essential to improve access to care and further infrastructure development. We undertook this study to understand the community\u27s emergency care needs and the barriers they face when trying to access care and to engage community members with developing high impact solutions to expand access to essential emergency services. To accomplish this, we used a qualitative research methodology to conduct 59 focus groups with 528 total Kenyan community member participants. Data were coded, aggregated, and analysed using the content analysis approach. Participants were uniformly selected from all eight of the historical Kenyan provinces (Central. Coast, Eastern, Nairobi, North Eastern, Nyanza, Rift Valley, and Western), with equal rural and urban community representation. We found that socioeconomic and cultural factors play a major role both in seeking and reaching emergency care. Community members in Kenya experience a wide range of medical emergencies and seem to understand their time-critical nature. They rely on one another for assistance in the face of substantial barriers to care: a lack of a structured system, resources, transportation, trained healthcare providers, and initial care on scene. The results of this study indicate the need for specific interventions to reduce barriers to access essential emergency services in Kenya. Access to emergency care can be improved by encouraging recognition and initial treatment of emergent illness in the community, strengthening the pre­-hospital care system, improving emergency care delivery at health facilities, and creating new policies at both county and national levels

Patterns of care and survival for patients aged under 40 years with bone sarcoma in Britain, 1980–1994

The purpose of the study was to calculate population-based survival rates for osteosarcoma (OS) and Ewing's sarcoma (ES) in Great Britain during 1980–1994, determine proportions of patients treated at specialist centres or entered in national and international clinical trials, and investigate effects of these factors on survival. Data on a population-based series of 1349 patients with OS and 849 with ES were compiled from regional and national cancer registries, UK Children's Cancer Study Group, regional bone tumour registries and clinical trials. Follow-up was through population registers. Survival was analysed by actuarial analysis with log-rank tests and by Cox's proportional hazards analysis. Five-year survival rates during 1980–1984, 1985–1989 and 1990–1994 were 42% (95% CI: 37, 46), 54% (95% CI: 50, 59) and 53% (95% CI: 48, 57), respectively, for OS and 31% (95% CI: 26, 37), 46% (95% CI: 40, 51) and 51% (95% CI: 45, 57) for ES. Proportions of patients treated at a supraregional bone tumour centre or a paediatric oncology centre in the three quinquennia were 36, 56 and 67% for OS and 41, 60 and 69% for ES. In 1983–1992, 48% of OS patients were entered in a national trial; for ES, 27% were entered in 1980–1986 and 54% in 1987–1994. Survival was similar for trial and nontrial patients with OS. For ES, trial patients had consistently higher 5-year survival than nontrial patients: 1980–1986, 42 vs 30%; 1987–1992, 59 vs 42%; 1993–1994, 54 vs 43%. During 1985–1994, patients with OS or ES whose main treatment centre was a nonteaching hospital had lower survival rates. In multivariate analyses of patients diagnosed during 1985–1994 that also included age, sex, primary site, surgical treatment centre, the results relating to main treatment centre for both OS and ES retained significance but the survival advantage of trial entry for ES became nonsignificant. For both OS and ES diagnosed since 1985, patients whose main treatment centre was a nonspecialist hospital had a lower survival rate

Spatial coherence and density correlations of trapped Bose gases

We study first and second order coherence of trapped dilute Bose gases using appropriate correlation functions. Special attention is given to the discussion of second order or density correlations. Except for a small region around the surface of a Bose-Einstein condensate the correlations can be accurately described as those of a locally homogeneous gas with a spatially varying chemical potential. The degrees of first and second order coherence are therefore functions of temperature, chemical potential, and position. The second order correlation function is governed both by the tendency of bosonic atoms to cluster and by a strong repulsion at small distances due to atomic interactions. In present experiments both effects are of comparable magnitude. Below the critical temperature the range of the bosonic correlation is affected by the presence of collective quasi-particle excitations. The results of some recent experiments on second and third order coherence are discussed. It is shown that the relation between the measured quantities and the correlation functions is much weaker than previously assumed.Comment: RevTeX, 25 pages with 7 Postscript figure

Hydrologic Terrain Processing Using Parallel Computing

Abstract: Topography in the form of Digital Elevation Models (DEMs), is widely used to derive information for the modeling of hydrologic processes. Hydrologic terrain analysis augments the information content of digital elevation data by removing spurious pits, deriving a structured flow field, and calculating surfaces of hydrologic information derived from the flow field. The increasing availability of large terrain datasets with very small ground sample distance (GSD) poses a challenge for existing algorithms that process terrain data to extract this hydrologic information. This paper will describe a parallel algorithm that has been developed to enhance hydrologic terrain pre-processing so that larger datasets can be more efficiently computed. This paper describes a Message Passing Interface (MPI) parallel implementation for Pit Removal. This key functionality is used within the Terrain Analysis Using Digital Elevation Models (TauDEM) package to remove spurious elevation depressions that are an artifact of the raster representation of the terrain. The parallel algorithm works by decomposing the domain into stripes or tiles where each tile is processed by a separate processor. This method also reduces the memory requirements of each processor so that larger size grids can be processed. The parallel pit removal algorithm is adapted from the method of Planchon and Darboux that starts from a large elevation then iteratively scans the grid, lowering each grid cell to the maximum of the original elevation or the lowest neighbor. The MPI implementation reconcile

Dendritic Spine Shape Analysis: A Clustering Perspective

Functional properties of neurons are strongly coupled with their morphology. Changes in neuronal activity alter morphological characteristics of dendritic spines. First step towards understanding the structure-function relationship is to group spines into main spine classes reported in the literature. Shape analysis of dendritic spines can help neuroscientists understand the underlying relationships. Due to unavailability of reliable automated tools, this analysis is currently performed manually which is a time-intensive and subjective task. Several studies on spine shape classification have been reported in the literature, however, there is an on-going debate on whether distinct spine shape classes exist or whether spines should be modeled through a continuum of shape variations. Another challenge is the subjectivity and bias that is introduced due to the supervised nature of classification approaches. In this paper, we aim to address these issues by presenting a clustering perspective. In this context, clustering may serve both confirmation of known patterns and discovery of new ones. We perform cluster analysis on two-photon microscopic images of spines using morphological, shape, and appearance based features and gain insights into the spine shape analysis problem. We use histogram of oriented gradients (HOG), disjunctive normal shape models (DNSM), morphological features, and intensity profile based features for cluster analysis. We use x-means to perform cluster analysis that selects the number of clusters automatically using the Bayesian information criterion (BIC). For all features, this analysis produces 4 clusters and we observe the formation of at least one cluster consisting of spines which are difficult to be assigned to a known class. This observation supports the argument of intermediate shape types.Comment: Accepted for BioImageComputing workshop at ECCV 201

Data for 'Something in the way she moves': the functional significance of flexibility in the multiple roles of protein disulfide isomerase (PDI)

Protein disulfide isomerase (PDI) has diverse functions in the endoplasmic reticulum as catalyst of redox transfer, disulfide isomerization and oxidative protein folding, as molecular chaperone and in multi-subunit complexes. It interacts with an extraordinarily wide range of substrate and partner proteins, but there is only limited structural information on these interactions. Extensive evidence on the flexibility of PDI in solution is not matched by any detailed picture of the scope of its motion. A new rapid method for simulating the motion of large proteins provides detailed molecular trajectories for PDI demonstrating extensive changes in the relative orientation of its four domains, great variation in the distances between key sites and internal motion within the core ligand-binding domain. The review shows that these simulations are consistent with experimental evidence and provide insight into the functional capabilities conferred by the extensive flexible motion of PDI