Ageing and the pathogenesis of osteoarthritis

Ageing-associated changes that affect articular tissues promote the development of osteoarthritis (OA). Although ageing and OA are closely linked, they are independent processes. Several potential mechanisms by which ageing contributes to OA have been elucidated. This Review focuses on the contributions of the following factors: age-related inflammation (also referred to as 'inflammaging'); cellular senescence (including the senescence-associated secretory phenotype (SASP)); mitochondrial dysfunction and oxidative stress; dysfunction in energy metabolism due to reduced activity of 5'-AMP-activated protein kinase (AMPK), which is associated with reduced autophagy; and alterations in cell signalling due to age-related changes in the extracellular matrix. These various processes contribute to the development of OA by promoting a proinflammatory, catabolic state accompanied by increased susceptibility to cell death that together lead to increased joint tissue destruction and defective repair of damaged matrix. The majority of studies to date have focused on articular cartilage, and it will be important to determine whether similar mechanisms occur in other joint tissues. Improved understanding of ageing-related mechanisms that promote OA could lead to the discovery of new targets for therapies that aim to slow or stop the progression of this chronic and disabling condition

Equalization in redundant channels

A miscomparison between a channel's configuration data base and a voted system configuration data base in a redundant channel system having identically operating, frame synchronous channels triggers autoequalization of the channel's historical signal data bases in a hierarchical, chronological manner with that of a correctly operating channel. After equalization, symmetrization of the channel's configuration data base with that of the system permits upgrading of the previously degraded channel to full redundancy. An externally provided equalization command, e.g., manually actuated, can also trigger equalization

On the Short-Term Variability of Turbulence and Temperature in the Winter Mesosphere

Four mesosphere–lower thermosphere temperature and turbulence profiles were obtained in situ within ∼30 min and over an area of about 100 by 100 km during a sounding rocket experiment conducted on 26 January 2015 at Poker Flat Research Range in Alaska. In this paper we examine the spatial and temporal variability of mesospheric turbulence in relationship to the static stability of the background atmosphere. Using active payload attitude control, neutral density fluctuations, a tracer for turbulence, were observed with very little interference from the payload spin motion, and with high precision (%) at sub-meter resolution. The large-scale vertical temperature structure was very consistent between the four soundings. The mesosphere was almost isothermal, which means more stratified, between 60 and 80 km, and again between 88 and 95 km. The stratified regions adjoined quasi-adiabatic regions assumed to be well mixed. Additional evidence of vertical transport and convective activity comes from sodium densities and trimethyl aluminum trail development, respectively, which were both observed simultaneously with the in situ measurements. We found considerable kilometer-scale temperature variability with amplitudes of 20 K in the stratified region below 80 km. Several thin turbulent layers were embedded in this region, differing in width and altitude for each profile. Energy dissipation rates varied between 0.1 and 10 mW kg−1, which is typical for the winter mesosphere. Very little turbulence was observed above 82 km, consistent with very weak small-scale gravity wave activity in the upper mesosphere during the launch night. On the other hand, above the cold and prominent mesopause at 102 km, large temperature excursions of +40 to +70 K were observed. Simultaneous wind measurements revealed extreme wind shears near 108 km, and combined with the observed temperature gradient, isolated regions of unstable Richardson numbers (0Kp∼5)

Self-care Barriers Reported by Emergency Department Patients With Acute Heart Failure: A Sociotechnical Systems-based Approach

Study objective We pilot tested a sociotechnical systems-based instrument that assesses the prevalence and nature of self-care barriers among patients presenting to the emergency department (ED) with acute heart failure. Methods A semistructured instrument for measuring self-reported self-care barriers was developed and administered by ED clinicians and nonclinician researchers to 31 ED patients receiving a diagnosis of acute heart failure. Responses were analyzed with descriptive statistics and qualitative content analysis. Feasibility was assessed by examining participant cooperation rates, instrument completion times, item nonresponse, and data yield. Results Of 47 distinct self-care barriers assessed, a median of 15 per patient were indicated as “sometimes” or “often” present. Thirty-four specific barriers were reported by more than 25% of patients and 9 were reported by more than 50%. The sources of barriers included the person, self-care tasks, tools and technologies, and organizational, social, and physical contexts. Seven of the top 10 most prevalent barriers were related to patient characteristics; the next 3, to the organizational context (eg, life disruptions). A preliminary feasibility assessment found few item nonresponses or comprehension difficulties, good cooperation, and high data yield from both closed- and open-ended items, but also found opportunities to reduce median administration time and variability. Conclusion An instrument assessing self-care barriers from multiple system sources can be feasibly implemented in the ED. Further research is required to modify the instrument for widespread use and evaluate its implementation across institutions and cultural contexts. Self-care barriers measurement can be one component of broader inquiry into the distributed health-related “work” activity of patients, caregivers, and clinicians

DNA condensation in live E. coli provides evidence for transertion

Condensation studies of chromosomal DNA in E. coli with a tetra nuclear ruthenium complex are carried out and images obtained with wide-field fluorescence microscopy. Remarkably different condensate morphologies resulted, depending upon the treatment protocol. The occurrence of condensed nucleoid spirals in live bacteria provides evidence for the transertion hypothesis

An X-ray Selected Galaxy Cluster at z=1.26

We report the discovery of an X-ray luminous galaxy cluster at z=1.26. RXJ0848.9+4452 was selected as an X-ray cluster candidate in the ROSAT Deep Cluster Survey, on the basis of its spatial extent. Deep optical and near-IR imaging have revealed a galaxy overdensity around the peak of the X-ray emission, with a significant excess of red objects with J-K colors typical of elliptical galaxies at z>1. Spectroscopic observations at the Keck II telescope have secured 6 galaxy redshifts in the range 1.257=1.261), within a 35 arcsec radius around the peak X-ray emission. This system lies only 4.2 arcmin away (5.0 h^{-1}_{50} comoving Mpc, q_0=0.5) from the galaxy cluster ClG J0848+4453, which was identified by Stanford et al. (1997) at z=1.273 in a near-IR field galaxy survey, and is also known to be X-ray luminous. Assuming that the X-ray emission is entirely due to hot intra-cluster gas, both these systems have similar rest frame luminosities L_x ~=1x10^{44} ergs/s (0.5-2.0 keV band). In combination with our spectrophotometric data for the entire 30 arcmin^2 field, this suggests the presence of a superstructure, consisting of two collapsed, possibly virialized clusters, the first detected to date at z>1.Comment: To appear in The Astronomical Journal, 24 pages, 8 figures, 1 color jpg plate (fig.7), see http://www.eso.org/~prosati/lynx/plate_fig7.jp

Structural analysis of X-Linked Retinoschisis mutations reveals distinct classes which differentially effect retinoschisin function

Retinoschisin, an octameric retinal-specific protein, is essential for retinal architecture with mutations causing X-linked retinoschisis (XLRS), a monogenic form of macular degeneration. Most XLRS-associated mutations cause intracellular retention, however a subset are secreted as octamers and the cause of their pathology is ill-defined. Therefore, here we investigated the solution structure of the retinoschisin monomer and the impact of two XLRS-causing mutants using a combinatorial approach of biophysics and cryo-EM. The retinoschisin monomer has an elongated structure which persists in the octameric assembly. Retinoschisin forms a dimer of octamers with each octameric ring adopting a planar propeller structure. Comparison of the octamer with the hexadecamer structure indicated little conformational change in the retinoschisin octamer upon dimerization, suggesting that the octamer provides a stable interface for construction of the hexadecamer. The H207Q XLRS-associated mutation was found in the interface between octamers and destabilized both monomeric and octameric retinoschisin. Octamer dimerization is consistent with the adhesive function of retinoschisin supporting interactions between retinal cell layers, so disassembly would prevent structural coupling between opposing membranes. In contrast, cryo-EM structural analysis of the R141H mutation at ~4.2Å resolution was found to only cause a subtle conformational change in the propeller tips, potentially perturbing an interaction site. Together, these findings support distinct mechanisms of pathology for two classes of XLRS-associated mutations in the retinoschisin assembly

Orbital Solutions and Absolute Elements of the Short-Period Eclipsing Binary ES Librae

We have obtained new differential UBV photoelectric photometry and radial velocities of both components of the short-period eclipsing binary ES Lib. The system has a circular orbit with a period of 0.883040928 days and is seen at an inclination of 70.1°. With the Wilson-Devinney analysis program, we obtained a simultaneous solution of our photometric and spectroscopic observations that resulted in masses of M1 = 2.30 ± 0.03 M⊙ and M2 = 0.97 ± 0.01 M⊙ and the equal-volume radii of R1 = 2.69 ± 0.02 R⊙ and R2 = 1.83 ± 0.01 R⊙ for the primary and secondary, respectively. The secondary is oversized and overluminous for its mass. The effective temperatures of the primary and secondary are 8500 K (fixed) and 5774 ± 57 K, respectively. Despite the very large temperature difference, our photometric and spectroscopic data indicate that ES Lib is not semidetached but rather require it to be in an overcontact state, where both components exceed their critical Roche lobes. Given its nonthermal equilibrium state, if the overcontact solution correctly characterizes the system, the change from being semidetached to overcontact may have occurred recently. While the asymmetry of the light curves can be modeled well with a large, hot starspot or a large, cool one on the secondary component, we prefer the latter interpretation because cool spots are a typical feature on many contact binaries

Eukaryotic Cell Toxicity and HSA Binding of [Ru(Me4phen)(bb7)]2+ and the Effect of Encapsulation in Cucurbit[10]uril

The toxicity (IC50) of a series of mononuclear ruthenium complexes containing bis[4(4′-methyl-2,2′-bipyridyl)]-1,n-alkane (bbn) as a tetradentate ligand against three eukaryotic cell lines—BHK (baby hamster kidney), Caco-2 (heterogeneous human epithelial colorectal adenocarcinoma) and Hep-G2 (liver carcinoma)—have been determined. The results demonstrate that cis-α-[Ru(Me4phen)(bb7)]2+ (designated as α-Me4phen-bb7, where Me4phen = 3,4,7,8-tetramethyl-1,10-phenanthroline) showed little toxicity toward the three cell lines, and was considerably less toxic than cis-α-[Ru(phen)(bb12)]2+ (α-phen-bb12) and the dinuclear complex [{Ru(phen)2}2{μ-bb12}]4+. Fluorescence spectroscopy was used to study the binding of the ruthenium complexes with human serum albumin (HSA). The binding of α-Me4phen-bb7 to the macrocyclic host molecule cucurbit[10]uril (Q[10]) was examined by NMR spectroscopy. Large upfield 1H NMR chemical shift changes observed for the methylene protons in the bb7 ligand upon addition of Q[10], coupled with the observation of several intermolecular ROEs in ROESY spectra, indicated that α-Me4phen-bb7 bound Q[10] with the bb7 methylene carbons within the cavity and the metal center positioned outside one of the portals. Simple molecular modeling confirmed the feasibility of the binding model. An α-Me4phen-bb7-Q[10] binding constant of 9.9 ± 0.2 × 106 M−1 was determined by luminescence spectroscopy. Q[10]-encapsulation decreased the toxicity of α-Me4phen-bb7 against the three eukaryotic cell lines and increased the binding affinity of the ruthenium complex for HSA. Confocal microscopy experiments indicated that the level of accumulation of α-Me4phen-7 in BHK cells is not significantly affected by Q[10]-encapsulation. Taken together, the combined results suggest that α-Me4phen-7 could be a good candidate as a new antimicrobial agent, and Q[10]-encapsulation could be a method to improve the pharmacokinetics of the ruthenium complex