Pro-Secretory Activity and Pharmacology in Rabbits of an Aminophenyl-1,3,5-Triazine CFTR Activator for Dry Eye Disorders.

PurposePharmacological activation of ocular surface cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels is a potential pro-secretory approach to treat dry eye disorders. We previously reported the discovery of aminophenyl-1,3,5-triazines, one of which, N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine (herein called CFTRact-K267), fully activated human wildtype CFTR with EC50 ∼ 30 nM and increased tear volume for 8 hours in mice. Here, functional and pharmacological studies of CFTRact-K267 were done in adult New Zealand white rabbits.MethodsCFTR chloride conductance was measured in vivo by ocular surface potential differences and in ex vivo conjunctiva by short-circuit current. Tear volume was measured by the Schirmer tear test II and CFTRact-K267 pharmacokinetics and tissue distribution by liquid chromatography/mass spectrometry. Toxicity profile was studied for 28 days with twice-daily topical administration.ResultsElectrophysiological measurements in vivo and in ex vivo conjunctiva demonstrated CFTR activation by CFTRact-K267. A single topical dose of 3 nmol CFTRact-K267 increased tear production by >5 mm for 9 hours by the Schirmer tear test, with predicted therapeutic concentrations maintained in tear fluid. No tachyphylaxis was seen following 28-day twice-daily administration, and changes were not observed in corneal surface integrity or thickness, intraocular pressure, or ocular histology. At day 28, CFTRact-K267 was concentrated in the cornea and conjunctiva and was not detectable in blood or peripheral organs.ConclusionsThese studies support the development of CFTRact-K267 as a pro-secretory therapy for dry eye disorders

Simultaneous X-ray and Ultraviolet Observations of the SW Sextantis Star DW Ursae Majoris

We present the first pointed X-ray observation of DW Ursae Majoris, a novalike cataclysmic variable (CV) and one of the archetype members of the SW Sextantis class, obtained with the XMM-Newton satellite. These data provide the first detailed look at an SW Sex star in the X-ray regime (with previous X-ray knowledge of the SW Sex stars limited primarily to weak or non-detections in the ROSAT All Sky Survey). It is also one of only a few XMM-Newton observations (to date) of any high mass transfer rate novalike CV, and the only one in the evolutionarily important 3-4 hr orbital period range. The observed X-ray spectrum of DW UMa is very soft, with ~95% of the detected X-ray photons at energies <2 keV. The spectrum can be fit equally well by a one-component cooling flow model, with a temperature range of 0.2-3.5 keV, or a two-component, two-temperature thermal plasma model, containing hard (~5-6 keV) and soft (~0.8 keV) components. The X-ray light curve of DW UMa shows a likely partial eclipse, implying X-ray reprocessing in a vertically extended region, and an orbital modulation, implying a structural asymmetry in the X-ray reprocessing site (e.g., it cannot be a uniform corona). We also obtained a simultaneous near-ultraviolet light curve of DW UMa using the Optical Monitor on XMM-Newton. This light curve is similar in appearance to published optical-UV light curves of DW UMa and shows a prominent deep eclipse. Regardless of the exact nature of the X-ray reprocessing site in DW UMa, the lack of a prominent hard X-ray total eclipse and very low fraction of high energy X-rays point to the presence of an optically and geometrically thick accretion disk that obscures the boundary layer and modifies the X-ray spectrum emitted near the white dwarf

Plasma proteome correlates of lipid and lipoprotein: biomarkers of metabolic diversity and inflammation in children of rural Nepal.

Proteins involved in lipoprotein metabolism can modulate cardiovascular health. While often measured to assess adult metabolic diseases, little is known about the proteomes of lipoproteins and their relation to metabolic dysregulation and underlying inflammation in undernourished child populations. The objective of this population study was to globally characterize plasma proteins systemically associated with HDL, LDL, and triglycerides in 500 Nepalese children. Abnormal lipid profiles characterized by elevated plasma triglycerides and low HDL-cholesterol (HDL-C) concentrations were common, especially in children with subclinical inflammation. Among 982 proteins analyzed, the relative abundance of 11, 12, and 52 plasma proteins was correlated with LDL-cholesterol (r = -0.43∼0.70), triglycerides (r = -0.39∼0.53), and HDL-C (r = -0.49∼0.79) concentrations, respectively. These proteins included apolipoproteins and numerous unexpected intracellular and extracellular matrix binding proteins, likely originating in hepatic and peripheral tissues. Relative abundance of two-thirds of the HDL proteome varied with inflammation, with acute phase reactants higher by 4∼40%, and proteins involved in HDL biosynthesis, cholesterol efflux, vitamin transport, angiogenesis, and tissue repair lower by 3∼20%. Untargeted plasma proteomics detects comprehensive sets of both known and novel lipoprotein-associated proteins likely reflecting systemic regulation of lipoprotein metabolism and vascular homeostasis. Inflammation-altered distributions of the HDL proteome may be predisposing undernourished populations to early chronic disease

Culture and Mobility Determine the Importance of Similarity in Friendship

We test whether the ability to start friendships—and end them—determines what we look for in friends. We hypothesized that individual differences in beliefs about relationship choice would translate into differences in similarity of relationship partners. To test the constructs across their spectrum, we sampled both American and Korean relationships (N=1,603). Study 1 field-sampled naturally-occurring relationship pairs in the USA and Korea; independent self-construal was positively correlated with relational mobility and similarity within relationship pairs. Using the entire data set, relational mobility was positively correlated with similarity, but the two were negatively correlated within nations. Study 2 identified two components of relational mobility, Entry and Exit. Easy entry to relationships correlated with high importance of similarity; easy exit from relationships correlated with low importance of similarity. An experiment (Study 3) manipulating both ease of entry to and exit from friendship found the belief that people are relatively free to end an unsatisfying friendship reduced the importance of similarity for friendship selection

Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study

Objectives The interleukin-6 receptor (IL-6R) blocker tocilizumab (TCZ) reduces inflammatory disease activity in rheumatoid arthritis (RA) but elevates lipid concentrations in some patients. We aimed to characterise the impact of IL-6R inhibition on established and novel risk factors in active RA. Methods Randomised, multicentre, two-part, phase III trial (24-week double-blind, 80-week open-label), MEASURE, evaluated lipid and lipoprotein levels, high-density lipoprotein (HDL) particle composition, markers of coagulation, thrombosis and vascular function by pulse wave velocity (PWV) in 132 patients with RA who received TCZ or placebo. Results Median total-cholesterol, low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels increased in TCZ versus placebo recipients by week 12 (12.6% vs 1.7%, 28.1% vs 2.2%, 10.6% vs −1.9%, respectively; all p&#60;0.01). There were no significant differences in mean small LDL, mean oxidised LDL or total HDL-C concentrations. However, HDL-associated serum amyloid A content decreased in TCZ recipients. TCZ also induced reductions (&#60;30%) in secretory phospholipase A2-IIA, lipoprotein(a), fibrinogen and D-dimers and elevation of paraoxonase (all p&#60;0.0001 vs placebo). The ApoB/ApoA1 ratio remained stable over time in both groups. PWV decreases were greater with placebo than TCZ at 12 weeks (adjusted mean difference 0.79 m/s (95% CI 0.22 to 1.35; p=0.0067)). Conclusions These data provide the first detailed evidence for the modulation of lipoprotein particles and other surrogates of vascular risk with IL-6R inhibition. When compared with placebo, TCZ induced elevations in LDL-C but altered HDL particles towards an anti-inflammatory composition and favourably modified most, but not all, measured vascular risk surrogates. The net effect of such changes for cardiovascular risk requires determination.</p

Alternative Solution of the Path Integral for the Radial Coulomb Problem

In this Letter I present an alternative solution of the path integral for the radial Coulomb problem which is based on a two-dimensional singular version of the Levi-Civita transformation.Comment: 7 pages, Late

Some discussions of D. Fearnhead and D. Prangle's Read Paper "Constructing summary statistics for approximate Bayesian computation: semi-automatic approximate Bayesian computation"

This report is a collection of comments on the Read Paper of Fearnhead and Prangle (2011), to appear in the Journal of the Royal Statistical Society Series B, along with a reply from the authors.Comment: 10 page

Signal peptide peptidases and gamma-secretase: Cousins of the same protease family?

Signal peptide peptidase (SPIP) is an unusual aspartyl protease, which mediates clearance of signal peptides by proteolysis within the endoplasmic reticulum (ER). Like presenilins, which provide the proteolytically active subunit of the,gamma-secretase complex, SPP contains a conserved GxGD motif in its C-terminal domain which is critical for its activity. While SPIP is known to be an aspartyl protease of the GxGD type, several presenilin homologues/SPP-like proteins (PSHs/ SPPL) of unknown function have been identified by database searches. In contrast to SPP and SPPL3, which are both restricted to the endoplasmic reticulum, SPPL2b is targeted through the secretory pathway to endosomes/lysosomes. As suggested by the differential subcellular localization of SPPL2b and SPPL3 distinct phenotypes were found upon antisense gripNA-mediated knockdown in zebrafish. spp and sppl3 knockdowns in zebrafish result in cell death within the central nervous system, whereas reduction of sppl2b expression causes erythrocyte accumulation in an enlarged caudal vein. Moreover, expression of D/A mutants of the putative C-terminal active sites of spp, sppl2, and spp13 produced phenocopies of the respective knockdown phenotypes. These data suggest that all investigated PSHs/SPPLs are members of the novel family of GxGD aspartyl proteases. More recently, it was shown that SPPL2b utilizes multiple intramembrane cleavages to liberate the TNF(x intracellular domain into the cytosol and to release the C-terminal counterpart into the lumen. These findings suggest common principles of intramembrane proteolysis by GxGD type aspartyl proteases. In this article,we will review the similarities of SPPs and gamma-secretase based on recent findings by us and others

Dynamic Front Transitions and Spiral-Vortex Nucleation

This is a study of front dynamics in reaction diffusion systems near Nonequilibrium Ising-Bloch bifurcations. We find that the relation between front velocity and perturbative factors, such as external fields and curvature, is typically multivalued. This unusual form allows small perturbations to induce dynamic transitions between counter-propagating fronts and nucleate spiral vortices. We use these findings to propose explanations for a few numerical and experimental observations including spiral breakup driven by advective fields, and spot splitting