Tenascin-C fragments are endogenous inducers of cartilage matrix degradation

Cartilage destruction is a hallmark of osteoarthritis (OA) and is characterized by increased protease activity resulting in the degradation of critical extracellular matrix (ECM) proteins essential for maintaining cartilage integrity. Tenascin-C (TN-C) is an ECM glycoprotein, and its expression is upregulated in OA cartilage. We aimed to investigate the presence of TN-C fragments in arthritic cartilage and establish whether they promote cartilage degradation. Expression of TN-C and its fragments was evaluated in cartilage from subjects undergoing joint replacement surgery for OA and RA compared with normal subjects by western blotting. The localization of TN-C in arthritic cartilage was also established by immunohistochemistry. Recombinant TN-C fragments were then tested to evaluate which regions of TN-C are responsible for cartilage-degrading activity in an ex vivo cartilage explant assay measuring glycosaminoglycan (GAG) release, aggrecanase and matrix metalloproteinase (MMP) activity. We found that specific TN-C fragments are highly upregulated in arthritic cartilage. Recombinant TN-C fragments containing the same regions as those identified from OA cartilage mediate cartilage degradation by the induction of aggrecanase activity. TN-C fragments mapping to the EGF-L and FN type III domains 3-8 of TN-C had the highest levels of aggrecan-degrading ability that was not observed either with full-length TN-C or with other domains of TN-C. TN-C fragments represent a novel mechanism for cartilage degradation in arthritis and may present new therapeutic targets for the inhibition of cartilage degradation

Who decides about change and restructuring in organizations?

The authors of this paper model the determinants of who makes decisions, the principal or an agent, when there are multiple decisions. Decision making takes effort and time; and, once implemented, the expected loss from a particular decision (or project) increases with the length of time since the last decision was made. The model shows delegation is more likely as: (i) controllable uncertainty increases; (ii) uncontrollable uncertainty decreases; (iii) the number of plants in the firm decreases; (iv) the complexity of the decision increases; and (v) the importance of the decision increases. The theoretical predictions are consistent with the authors\u27 novel empirical results on the delegation of major organizational change decisions using workplace data. Their unique data allows them to identify who made a decision to implement a significant change, as well as key internal and external factors highlighted as potentially important in their theory. Empirically, delegation is more likely in organizations that: face a competitive product market; export; have predictable product demand; have a larger workplace; and that have fewer other workplaces in the same organization producing a similar output. The authors find business strategy is not related to the allocation of decision making authority; delegation, however, is associated with the use of human resource techniques such as the provision of bonuses to employees

A Computational Channel Model for Magnetic Induction-Based Subsurface Applications

There are many underground applications based on magnetic fields generated by an oscillating magnetic source. For them, a magnetic dipole in a three-layered region with upper semi-infinite air layer can be a convenient idealization used for their planning, development, and operation. Solutions are in the form of the well-known Sommerfeld integral expressions that can be evaluated by numerical methods. A set of field expressions to be numerically evaluated by an efficient algorithm are not collected comprehensively yet, or at least in a directly usable form. In this paper, the explicit magnetic field solutions for the vertical magnetic dipole and the horizontal magnetic dipole for a general source-observer location are derived from the Hertz vector. They can be properly combined to model the problem of a tilted magnetic dipole source for horizontally or inclined stratified media. As a result, a complete set of integral equations of the Sommerfeld type valid from the near zone to the far zone are formulated. A method for numerical evaluation of the field expressions for high accurate computations is described. The numerical results are validated using the finite element method for all the possible source-receiver configurations and three well-spanned frequencies of typical subsurface applications. Both numerical solutions agree according to the normalized root-mean-square error-based fit metric. Numerical results for two cases of study are presented to see its usefulness for subsurface applications. A MATLAB implementation of the mathematical description outlined in this paper and the proposed evaluation method is freely available for download

Changes in male rat urinary protein profile during puberty: a pilot study

BACKGROUND: Androgen-dependent proteins (lipocalins) circulate in blood of male rats and mice and, being small (~ 18 kDa), pass freely into glomerular filtrate. Some are salvaged in proximal nephrons but some escape in urine. Several organic molecules can bind to these proteins causing, where salvage occurs, nephropathy including malignancy in renal cortex. In urine, both free lipocalins and ligands contribute to an increasingly-recognised vital biological role in social communication between adults, especially in the dark where reliance is on smell and taste. Crystal structure of the first-characterised lipocalin of male rats, α2u-globulin, has been determined and peptide sequences for others are available, but no study of occurrence during early puberty has been made. We have followed temporal occurrence in urine of juveniles (n = 3) for non-invasive pilot study by high resolution gradient mini-gel electrophoresis, tryptic digest of excised protein bands, and LC-MS/MS of digest to identify peptide fragments and assign to specific lipocalins. Study objective refers directly to external availability for social communication but also indirectly to indicate kinetics of circulating lipocalins to which some xenobiotics may bind and constitute determinants of renal disease. RESULTS: Mini-gels revealed greater lipocalin complexity than hitherto recognised, possibly reflecting post-translational modifications. Earliest patterns comprised rat urinary protein 1, already evident in Sprague-Dawley and Wistar strains at 36 and 52 days, respectively. By 44 and 57 days major rat protein (α2u-globulin) occurred as the progressively more dominant protein, though as two forms with different electrophoretic mobility, characterised by seven peptide sequences. No significant change in urinary testosterone had occurred in Wistars when major rat protein became evident, but testosterone surged by 107 days concomitant with the marked abundance of excreted lipocalins. CONCLUSIONS: Qualitative temporal changes in the composition of excreted lipocalins early in puberty, and apparent increase in major urinary protein as two resolvable forms, should catalyse systematic non-invasive study of urinary lipocalin and testosterone dynamics from early age, to illuminate this aspect of laboratory rodent social physiology. It could also define the potential temporal onset of nephrotoxic ligand risk, applicable to young animals used as toxicological models

IDENTIFICATION OF NONLINEARITIES IN AN 8-DOF SYSTEM THROUGH SPECTRAL FEEDBACK

The accurate detection and characterization of nonlinearities associated with damage in structural systems is an area of vibration analysis that is being widely researched. In this paper, nonlinear behavior is considered a potential indicator of damage. Most conventional damage detection methods, such as those based on resonant frequencies and mode shapes, do not accurately identify the location and extent of nonlinearities present in a given structural system. As an extension of previous work at LANL, an effort is made to validate a damage detection method proposed by Adams. This method states that the frequency response function (FRF) matrix obtained from a low-level vibration test approximates the underlying linear FRF matrix of the system. The nonlinear systems' responses to high level excitation are combined with the linear FRF in a classic feedback loop to obtain the contributions of nonlinear internal forces. The temporal and spatial characteristics of the nonlinearities present in a structural system are identified. An 8-DOF system is used as a test case to validate the aforementioned method. Results of the tests and important issues concerning the method are presented

Kick Stability Analysis of the LHC Inflectors

Two sets of four LHC inflector magnet systems must produce a kick of 1.36 Tm each with a duration of 6.5 µs, a rise time of 750 ns, and an overall stability of ± 0.5%. The electrical circuit of the complete system, including all known stray quantities, has been simulated with PSpice. Many stray elements were determined from Opera2D simulations which included eddy-currents. 3D analyses have also been carried out for the kicker magnet using the electromagnetic analysis code Opera3D. Equivalent circuits which simulate the frequency dependence of inductance and resistance of the Pulse Forming Network (PFN) have been derived. The dimensions of the PFN coil have been selected to give the correct pulse response. The end cells of the PFN have also been optimised. The discharge stability of various PFN capacitors has been measured. This paper presents the results of both the analyses and measurements

Design of the injection kicker magnet system for CERN's 14 TeV proton collider LHC

Two counter-rotating proton beams will be injected into the LHC at an energy of 450 GeV by two kicker magnet systems, producing magnetic field pulses of approximately 750 ns rise time and 6.6 µs flat top duration. To avoid dilution of the beam emittance during injection, a stringent design requirement of the system is a flat top ripple of the magnetic field of less than ± 0.5%. Both injection systems are composed of 4 travelling wave kicker magnets of 2.17 m length each, powered by pulse forming networks (PFN's) and matched to their characteristic impedance. To achieve the high required kick strength of 1.2 Tm, for a compact and cost efficient design, a comparably low characteristic impedance of 5 has been chosen. The electrical circuit of the system is being designed with the help of PSpice computer modelling. Most known parasitic elements are included in the model to obtain a realistic pulse response prediction. The present paper reports on design and modeling results of the LHC injection kicker magnet system that has several novel and demanding design requirements

High voltage measurements on a prototype PFN for the LHC injection kickers

Two LHC injection kicker magnet systems must produce a kick of 1.3 T.m each with a flattop duration of 4.25 mu s or 6.5 mu s, a rise time of 900 ns, and a fall time of 3 mu s. The ripple in the field must be less than +or-0.5The electrical circuit of the complete system has been simulated with PSpice. The model includes a 66 kV resonant charging power supply (RCPS), a 5 Omega pulse forming network (PFN), a terminated 5 Omega kicker magnet, and all known parasitic quantities. Component selection for the PEN was made on the basis of models in which a theoretical field ripple of less than +or-0.1as attained. A prototype 66 kV RCPS was built at TRIUMF and shipped to CERN. A prototype 5 Omega system including a PFN, thyratron switches, and terminating resistors, was built at CERN. The system (without a kicker magnet) was assembled as designed without trimming of any PFN component values. The PFN was charged to 60 kV via the RCPS operating at 0.1 Hz. The thyratron timing was adjusted to provide a 30 kV, 5.5 mu s duration pulse on a 5 Omega terminating resistor. Measurement data is presented for the prototype PFN, connected to resistive terminators. A procedure has been developed for compensating the probe and oscilloscope amplifier calibration errors. The top of the 30 kV pulse is flat to +or-0.3after an initial oscillation of 600 ns total duration. The post-pulse period is flat to within +or-0.1after approximately 600 ns from the bottom of the falling edge of the pulse. A calculation was performed in which a measured 27.5 kV pulse with a 5.5 mu s flattop was fed into a PSpice model of a kicker magnet with a 690 ns delay length. The resultant predicted kick rise time, from 0.2to 99.8, is 834 ns and the fall time 2.94 mu s, for a field pulse with a flattop of 4.69 mu s and a ripple of less than +or-0.2(12 refs)