Colchicine depolymerizes microtubules, increases junctophilin-2, and improves right ventricular function in experimental pulmonary arterial hypertension

Background Pulmonary arterial hypertension (PAH) is a lethal disease characterized by obstructive pulmonary vascular remodeling and right ventricular (RV) dysfunction. Although RV function predicts outcomes in PAH, mechanisms of RV dysfunction are poorly understood, and RV‐targeted therapies are lacking. We hypothesized that in PAH, abnormal microtubular structure in RV cardiomyocytes impairs RV function by reducing junctophilin‐2 (JPH2) expression, resulting in t‐tubule derangements. Conversely, we assessed whether colchicine, a microtubule‐depolymerizing agent, could increase JPH2 expression and enhance RV function in monocrotaline‐induced PAH. Methods and Results Immunoblots, confocal microscopy, echocardiography, cardiac catheterization, and treadmill testing were used to examine colchicine's (0.5 mg/kg 3 times/week) effects on pulmonary hemodynamics, RV function, and functional capacity. Rats were treated with saline (n=28) or colchicine (n=24) for 3 weeks, beginning 1 week after monocrotaline (60 mg/kg, subcutaneous). In the monocrotaline RV, but not the left ventricle, microtubule density is increased, and JPH2 expression is reduced, with loss of t‐tubule localization and t‐tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves t‐tubule morphology in RV cardiomyocytes. Colchicine therapy diminishes RV hypertrophy, improves RV function, and enhances RV–pulmonary artery coupling. Colchicine reduces small pulmonary arteriolar thickness and improves pulmonary hemodynamics. Finally, colchicine increases exercise capacity. Conclusions Monocrotaline‐induced PAH causes RV‐specific derangement of microtubules marked by reduction in JPH2 and t‐tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves both t‐tubule architecture and RV function. Colchicine also reduces adverse pulmonary vascular remodeling. These results provide biological plausibility for a clinical trial to repurpose colchicine as a RV‐directed therapy for PAH

Generalized conductance sum rule in atomic break junctions

When an atomic-size break junction is mechanically stretched, the total conductance of the contact remains approximately constant over a wide range of elongations, although at the same time the transmissions of the individual channels (valence orbitals of the junction atom) undergo strong variations. We propose a microscopic explanation of this phenomenon, based on Coulomb correlation effects between electrons in valence orbitals of the junction atom. The resulting approximate conductance quantization is closely related to the Friedel sum rule.Comment: 4 pages, 1 figure, appears in Proceedings of the NATO Advanced Research Workshop ``Size dependent magnetic scattering'', Pecs, Hungary, May 28 - June 1, 200

Chaotic flow and efficient mixing in a micro-channel with a polymer solution

Microscopic flows are almost universally linear, laminar and stationary because Reynolds number, $Re$, is usually very small. That impedes mixing in micro-fluidic devices, which sometimes limits their performance. Here we show that truly chaotic flow can be generated in a smooth micro-channel of a uniform width at arbitrarily low $Re$, if a small amount of flexible polymers is added to the working liquid. The chaotic flow regime is characterized by randomly fluctuating three-dimensional velocity field and significant growth of the flow resistance. Although the size of the polymer molecules extended in the flow may become comparable with the micro-channel width, the flow behavior is fully compatible with that in a table-top channel in the regime of elastic turbulence. The chaotic flow leads to quite efficient mixing, which is almost diffusion independent. For macromolecules, mixing time in this microscopic flow can be three to four orders of magnitude shorter than due to molecular diffusion.Comment: 8 pages,7 figure

The Dwarf Novae of Shortest Period

We present observations of the dwarf novae GW Lib, V844 Her, and DI UMa. Radial velocities of H-alph yield orbital periods of 0.05332 +- 0.00002 d (= 76.78 m) for GW Lib and and 0.054643 +- 0.000007 d (= 78.69 m) for V844 Her. Recently, the orbital period of DI UMa was found to be only 0.054564 +- 0.000002 d (= 78.57 m) by Fried et al. (1999), so these are the three shortest orbital periods among dwarf novae with normal-abundance secondaries. GW Lib has attracted attention as a cataclysmic binary showing apparent ZZ Ceti-type pulsations of the white dwarf primary. Its spectrum shows sharp Balmer emission flanked by strong, broad Balmer absorption, indicating a dominant contribution by white-dwarf light. Analysis of the Balmer absorption profiles is complicated by the unknown residual accretion luminosity and lack of coverage of the high Balmer lines. Our best-fit model atmospheres are marginally hotter than the ZZ Ceti instability strip, in rough agreement with recent ultraviolet results from HST. The spectrum and outburst behavior of GW Lib make it a near twin of WZ Sge, and we estimate it to have a quiescent V absolute magnitude 12. Comparison with archival data reveals proper motion of 65 +- 12 mas/yr. The mean spectrum of V844 Her is typical of SU UMa dwarf novae. We detected superhumps in the 1997 May superoutburst with superhump period = 0.05597 +- 0.00005 d. The spectrum of DI UMa appears normal for a dwarf nova near minimum light. These three dwarf novae have nearly identical short periods but completely dissimilar outburst characteristics. We discuss possible implications.Comment: Accepted for publication in Publications of the Astronomical Society of the Pacific; 16 pages, 6 figure

Kepler Presearch Data Conditioning I - Architecture and Algorithms for Error Correction in Kepler Light Curves

Kepler provides light curves of 156,000 stars with unprecedented precision. However, the raw data as they come from the spacecraft contain significant systematic and stochastic errors. These errors, which include discontinuities, systematic trends, and outliers, obscure the astrophysical signals in the light curves. To correct these errors is the task of the Presearch Data Conditioning (PDC) module of the Kepler data analysis pipeline. The original version of PDC in Kepler did not meet the extremely high performance requirements for the detection of miniscule planet transits or highly accurate analysis of stellar activity and rotation. One particular deficiency was that astrophysical features were often removed as a side-effect to removal of errors. In this paper we introduce the completely new and significantly improved version of PDC which was implemented in Kepler SOC 8.0. This new PDC version, which utilizes a Bayesian approach for removal of systematics, reliably corrects errors in the light curves while at the same time preserving planet transits and other astrophysically interesting signals. We describe the architecture and the algorithms of this new PDC module, show typical errors encountered in Kepler data, and illustrate the corrections using real light curve examples.Comment: Submitted to PASP. Also see companion paper "Kepler Presearch Data Conditioning II - A Bayesian Approach to Systematic Error Correction" by Jeff C. Smith et a

Four Dimensional Black Holes in String Theory

Exact solutions of heterotic string theory corresponding to four-dimensional charge Q magnetic black holes are constructed as tensor products of an SU(2)/Z(2Q+2) WZW orbifold with a (0,1) supersymmetric SU(1,1)/U(1) WZW coset model. The spectrum is analyzed in some detail. ``Bad'' marginal operators are found which are argued to deform these theories to asymptotically flat black holes. Surprising behaviour is found for small values of Q, where low-energy field theory is inapplicable. At the minimal value Q=1, the theory degenerates. Renormalization group arguments are given that suggest the potential gravitational singularity of the low-energy field theory is resolved by a massive two-dimensional field theory. At Q=0, a stable, neutral ``remnant,'' of potential relevance to the black hole information paradox, is found.Comment: 37 pages + 1 figure (tar compressed and uuencoded

Quantum fluctuations can promote or inhibit glass formation

The very nature of glass is somewhat mysterious: while relaxation times in glasses are of sufficient magnitude that large-scale motion on the atomic level is essentially as slow as it is in the crystalline state, the structure of glass appears barely different than that of the liquid that produced it. Quantum mechanical systems ranging from electron liquids to superfluid helium appear to form glasses, but as yet no unifying framework exists connecting classical and quantum regimes of vitrification. Here we develop new insights from theory and simulation into the quantum glass transition that surprisingly reveal distinct regions where quantum fluctuations can either promote or inhibit glass formation.Comment: Accepted for publication in Nature Physics. 22 pages, 3 figures, 1 Tabl

New liquid crystal materials enabling revolutionary display devices

The Display and Beam Steering Thrust of the AFOSR Liquid Crystal MURI addressed key materials and device technology issues affecting performance of liquid crystal (LC) electro-optic (EO) devices, particularly device structures useful in information Displays and for Laser Beam Steering and Switching. Two basic themes were development of bulk LCs having high performance characteristics (nematic LCs, and chiral smectic LC devices having analog response), and development of novel LC electro-optic structures. Research on novel device structures led to advances in LC alignment and on photonic band-gap materials