Visfatin reduces gap junction mediated cell-to-cell communication in proximal tubule-derived epithelial cells

Background/Aims: In the current study we examined if the adipocytokine, visfatin, alters connexin-mediated intercellular communication in proximal tubule-derived epithelial cells. Methods: The effects of visfatin (10-200ng/mL) on cell viability and cytotoxicity in HK2-cells were assessed by MTT, crystal violet and lactate dehydrogenase assays. Western blot analysis was used to confirm expression of Cx26, Cx40 and Cx43. The effect of visfatin (10-200ng/mL) on TGF-β1 secretion was confirmed by ELISA, and the effects of both TGF-β1 (2-10ng/mL) and visfatin (10-200ng/mL) on connexin expression were assessed by western blot. Functional intercellular communication was determined using transfer of Lucifer Yellow and paired-whole cell patch clamp electrophysiology. Results: In low glucose (5mM), visfatin (10-200ng/mL) did not affect membrane integrity, cytotoxicity or cell viability at 48hrs, but did evoke a concentration-dependent reduction in Cx26 and Cx43 expression. The expression of Cx40 was unaffected. At 48hrs, visfatin (10-200ng/mL) increased the secretion of TGF-β1 and the visfatin-evoked changes in connexin expression were mimicked by exogenous application of the pro-fibrotic cytokine (2-10ng/ml). Visfatin reduced dye transfer between coupled cells and decreased functional conductance, with levels falling by 63% as compared to control. Although input resistance was increased following visfatin treatment by 166%, the change was not significant as compared to control. The effects of visfatin on Cx-expression and cell-coupling were blocked in the presence of a TGF-β1 specific neutralizing antibody. Conclusions: The adipocytokine visfatin selectively evoked a non-toxic reduction in connexin expression in HK2-cells. The loss in gap-junction associated proteins was mirrored by a loss in functional conductance between coupled cells. Visfatin increased TGF-β secretion and the pattern of change for connexins expression was mimicked by exogenous application of TGF-β1. The effect of visfatin on Cx-expression and dye transfer were negated in the presence of a TGF-β1 neutralising antibody. These data suggest that visfatin reduces connexin-mediated intercellular communication in proximal tubule-derived epithelial cells via a TGF-β dependent pathway. © 2013 S. Karger AG, Base

Bile acid receptor in GtoPdb v.2023.1

The bile acid receptor (GPBA) responds to bile acids produced during the liver metabolism of cholesterol. Selective agonists are promising drugs for the treatment of metabolic disorders, such as type II diabetes, obesity and atherosclerosis

Bile acid receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The bile acid receptor (GPBA) responds to bile acids produced during the liver metabolism of cholesterol. Selective agonists are promising drugs for the treatment of metabolic disorders, such as type II diabetes, obesity and atherosclerosis

Self-monitoring of oral anticoagulation: does it work outside trial conditions?

Background: Patient self-monitoring (PSM) of oral anticoagulation therapy (OAT) can improve anticoagulant control, but poor uptake and high dropout rates have prompted suggestions that PSM is suitable for only a minority of patients in the UK.Aims: To determine whether PSM could be a viable alternative to regular hospital anticoagulant clinic attendance, if offered from the start of treatment.Methods: 318 consecutive patients referred, for the first time, to an anticoagulation clinic were assessed for eligibility using established criteria. Patients electing for PSM attended training and, following successful assessment, performed a capillary blood INR every two weeks or more frequently if directed to do so by the anticoagulation clinic. Primary outcome measures were uptake of PSM and the percentage time in target therapeutic INR range (TIR) compared to patients electing for routine clinic care.Results: Of 318 patients referred for OAT, 188 were eligible for PSM. 84 (26%) elected to self-monitor, of whom 72 (23%) remained self-monitoring or had completed their course of treatment at the end of the audit. Self-monitoring patients had significantly better anticoagulant control than those receiving routine hospital anticoagulation clinic care (TIR 71% vs 60%, p = 0.003) and significantly less time outside critical limits, ie, INR5.0 (0.45% vs 2.04%, p = 0.008).Conclusions: Patients offered PSM from the start of treatment show increased uptake compared to previous UK studies and a level of oral anticoagulation control comparable to that reported in previous clinical trials

Global three-dimensional flow of a neutron superfluid in a spherical shell in a neutron star

We integrate for the first time the hydrodynamic Hall-Vinen-Bekarevich-Khalatnikov equations of motion of a $^{1}S_{0}$-paired neutron superfluid in a rotating spherical shell, using a pseudospectral collocation algorithm coupled with a time-split fractional scheme. Numerical instabilities are smoothed by spectral filtering. Three numerical experiments are conducted, with the following results. (i) When the inner and outer spheres are put into steady differential rotation, the viscous torque exerted on the spheres oscillates quasiperiodically and persistently (after an initial transient). The fractional oscillation amplitude ($\sim 10^{-2}$) increases with the angular shear and decreases with the gap width. (ii) When the outer sphere is accelerated impulsively after an interval of steady differential rotation, the torque increases suddenly, relaxes exponentially, then oscillates persistently as in (i). The relaxation time-scale is determined principally by the angular velocity jump, whereas the oscillation amplitude is determined principally by the gap width. (iii) When the mutual friction force changes suddenly from Hall-Vinen to Gorter-Mellink form, as happens when a rectilinear array of quantized Feynman-Onsager vortices is destabilized by a counterflow to form a reconnecting vortex tangle, the relaxation time-scale is reduced by a factor of $\sim 3$ compared to (ii), and the system reaches a stationary state where the torque oscillates with fractional amplitude $\sim 10^{-3}$ about a constant mean value. Preliminary scalings are computed for observable quantities like angular velocity and acceleration as functions of Reynolds number, angular shear, and gap width. The results are applied to the timing irregularities (e.g., glitches and timing noise) observed in radio pulsars.Comment: 6 figures, 23 pages. Accepted for publication in Astrophysical Journa

Investigation of factors influencing the immunogenicity of hCG as a potential cancer vaccine

Human hCG and its β‐subunit (hCGβ) are tumour autocrine growth factors whose presence in the serum of cancer patients has been linked to poorer prognosis. Previous studies have shown that vaccines, which target these molecules and/or the 37 amino acid C‐terminal hCGβ peptide (hCGβCTP), induce antibody responses in a majority of human recipients. Here we explored whether the immunogenicity of vaccines containing an hCGβ mutant (hCGβR68E, designed to eliminate cross‐reactivity with luteinizing hormone) or hCGβCTP could be enhanced by coupling the immunogen to different carriers (KLH or Hsp70) using different cross‐linkers (EDC or GAD) and formulated with different adjuvants (RIBI or Montanide ISA720). While there was little to choose between KLH and Hsp70 as carriers, their influence on the effectiveness of a vaccine containing the BAChCGβR68E mutant was less marked, presumably because being a foreign species, this mutant protein itself might provide T‐helper epitopes. The mutant provided a significantly better vaccine than the hCGβCTP peptide irrespective of the carrier used, how it was cross‐linked to the carrier or which adjuvant was used when hCG was the target. Nonetheless, for use in humans where hCG is a tolerated self‐protein, the need for a carrier is of fundamental importance. Highest antibody titres were obtained by linking the BAChCGβR68E to Hsp70 as a carrier by GAD and using RIBI as the adjuvant, which also resulted in antibodies with significantly higher affinity than those elicited by hCGβCTP peptide vaccine. This makes this mutant vaccine a promising candidate for therapeutic studies in hCGβ‐positive cancer patients

Dissipative dynamics of superfluid vortices at non-zero temperatures

We consider the evolution and dissipation of vortex rings in a condensate at non-zero temperature, in the context of the classical field approximation, based on the defocusing nonlinear Schr\"odinger equation. The temperature in such a system is fully determined by the total number density and the number density of the condensate. A vortex ring is introduced into a condensate in a state of thermal equilibrium, and interacts with non-condensed particles. These interactions lead to a gradual decrease in the vortex line density, until the vortex ring completely disappears. We show that the square of the vortex line length changes linearly with time, and obtain the corresponding universal decay law. We relate this to mutual friction coefficients in the fundamental equation of vortex motion in superfluids.Comment: 4 pages, 3 figure

A new model of a tidally disrupted star

A new semi-analytical model of a star evolving in a tidal field is proposed. The model is a generalization of the so-called 'affine' stellar model. In our model the star is composed of elliptical shells with different parameters and different orientations, depending on time and on the radial Lagrangian coordinate of the shell. The evolution equations of this model are derived from the virial relations under certain assumptions, and the integrals of motion are identified. It is shown that the evolution equations can be deduced from a variational principle. The evolution equations are solved numerically and compared quantitatively with the results of 3D numerical computations of the tidal interaction of a star with a supermassive black hole. The comparison shows very good agreement between the main ``integral'' characteristics describing the tidal interaction event in our model and in the 3D computations. Our model is effectively a one-dimensional Lagrangian model from the point of view of numerical computations, and therefore it can be evolved numerically $10^{2}-10^{3}$ times faster than the 3D approach allows. This makes our model well suited for intensive calculations covering the whole parameter space of the problem.Comment: This version is accepted for publication in ApJ. Stylistic and grammatical changes, new Appendix adde

A Derivation of Three-Dimensional Inertial Transformations

The derivation of the transformations between inertial frames made by Mansouri and Sexl is generalised to three dimensions for an arbitrary direction of the velocity. Assuming lenght contraction and time dilation to have their relativistic values, a set of transformations kinematically equivalent to special relativity is obtained. The ``clock hypothesis'' allows the derivation to be extended to accelerated systems. A theory of inertial transformations maintaining an absolute simultaneity is shown to be the only one logically consistent with accelerated movements. Algebraic properties of these transformations are discussed. Keywords: special relativity, synchronization, one-way velocity of light, ether, clock hypothesis.Comment: 16 pages (A5), Latex, one figure, to be published in Found. Phys. Lett. (1997

Inflation and Transition to a Slowly Accelerating Phase from S.S.B. of Scale Invariance

We consider the effects of adding a scale invariant $R^{2}$ term to the action of the scale invariant model (SIM) studied previously by one of us (E.I.G., Mod. Phys. Lett. A14, 1043 (1999)). The SIM belongs to the general class of theories, where an integration measure independent of the metric is introduced. To implement scale invariance (S.I.), a dilaton field is introduced. The integration of the equations of motion associated with the new measure gives rise to the spontaneous symmetry breaking (S.S.B) of S.I.. After S.S.B. of S.I. in the model with the $R^{2}$ term, it is found that a non trivial potential for the dilaton is generated. This potential contains two flat regions: one associated with the Planck scale and with an inflationary phase, while the other flat region is associated to a very small vacuum energy (V.E.) and is associated to the present slowly accelerated phase of the universe (S.A.PH). The smallness of the V.E. in the S.A.PH. is understood through the see saw mechanism introduced in S.I.M.Comment: 22 pages, latex, three figures now in separate file