Molecular mechanism of action of trimethylangelicin derivatives as CFTR modulators

The psoralen-related compound, 4,6,40-trimethylangelicin (TMA) potentiates the cAMP/PKA-dependent activation of WT-CFTR and rescues F508del-CFTR-dependent chloride secretion in both primary and secondary airway cells homozygous for the F508del mutation. We recently demonstrated that TMA, like lumacaftor (VX-809), stabilizes the first membrane-spanning domain (MSD1) and enhances the interface between NBD1 and ICL4 (MSD2). TMA also demonstrated anti-inflammatory properties, via reduction of IL-8 expression, thus making TMA a promising agent for treatment of cystic fibrosis. Unfortunately, TMA was also found to display potential phototoxicity and mutagenicity, despite the fact that photo-reactivity is absent when the compound is not directly irradiated with UVA light. Due to concerns about these toxic effects, new TMA analogs, characterized by identical or better activity profiles and minimized or reduced side effects, were synthesized by modifying specific structural features on the TMA scaffold, thus generating compounds with no mutagenicity and phototoxicity. Among these compounds, we found TMA analogs which maintained the potentiation activity of CFTR in FRT-YFP-G551D cells. Nanomolar concentrations of these analogs significantly rescued F508del CFTR-dependent chloride efflux in FRT-YFP-F508del, HEK-293 and CF bronchial epithelial cells. We then investigated the ability of TMA analogs to enhance the stable expression of varying CFTR truncation mutants in HEK-293 cells, with the aim of studying the mechanism of their corrector activity. Not surprisingly, MSD1 was the smallest domain stabilized by TMA analogs, as previously observed for TMA. Moreover, we found that TMA analogs were not effective on F508del-CFTR protein which was already stabilized by a second-site mutation at the NBD1-ICL4 interface. Altogether, our findings demonstrate that these TMA analogs mediate correction by modifying MSD1 and indirectly stabilizing the interface between NBD1 and CL4

New Clock Comparison Searches for Lorentz and CPT Violation

We present two new measurements constraining Lorentz and CPT violation using the Xe-129 / He-3 Zeeman maser and atomic hydrogen masers. Experimental investigations of Lorentz and CPT symmetry provide important tests of the framework of the standard model of particle physics and theories of gravity. The two-species Xe-129 / He-3 Zeeman maser bounds violations of CPT and Lorentz symmetry of the neutron at the 10^-31 GeV level. Measurements with atomic hydrogen masers provide a clean limit of CPT and Lorentz symmetry violation of the proton at the 10^-27 GeV level.Comment: 11 pages, 5 figures. To appear in the Proceedings of the 3rd International Symposium on Symmetries in Subatomic Physic

Golgi polarity does not correlate with speed or persistence of freely migrating fibroblasts

The polarization of the Golgi has long been thought to be important for cell migration. Here we show that Rat2 cells at the edge of an artificial wound repolarize the Golgi relative to the nucleus to face the direction of migration into the wound. However, in the absence of cues from neighboring cells, individual cells do not display Golgi polarity relative to the direction in which they are moving. Instead, the positioning of the Golgi relative to the nucleus remains relatively constant over time and does not reflect changes in the direction of migration. Consistent with this observation, we observe only a slight bias in Golgi positioning to the front of the nucleus and this bias is not higher during periods of time when the cell is moving in a persistent manner. Taken together, these data suggest that Golgi polarity is not a requirement for cell migration

Limit on Lorentz and CPT Violation of the Neutron Using a Two-Species Noble-Gas Maser

A search for sidereal variations in the frequency difference between co-located 129-Xe and 3-He Zeeman masers sets the most stringent limit to date on leading-order Lorentz and CPT violation involving the neutron, consistent with no effect at the level of 10^{-31} GeV

Convergence of a positive nonlinear control volume finite element scheme for an anisotropic seawater intrusion model with sharp interfaces

International audienceWe consider a degenerate parabolic system modelling the flow of fresh and saltwater in an anisotropic porous medium in the context of seawater intrusion. We propose and analyze a nonlinear Control Volume Finite Element scheme. This scheme ensures the nonnegativity of the discrete solution without any restriction on the mesh and on the anisotropy tensor. Moreover It also provides a control on the entropy. Based on these nonlinear stability results, we show that the scheme converges towards a weak solution to the problem. Numerical results are provided to illustrate the behavior of the model and of the scheme

Observations of Giant Pulses from Pulsar PSR B0950+08 using LWA1

We report the detection of giant pulse emission from PSR B0950+08 in 24 hours of observations made at 39.4 MHz, with a bandwidth of 16 MHz, using the first station of the Long Wavelength Array, LWA1. We detected 119 giant pulses from PSR B0950+08 (at its dispersion measure), which we define as having SNRs at least 10 times larger than for the mean pulse in our data set. These 119 pulses are 0.035% of the total number of pulse periods in the 24 hours of observations. The rate of giant pulses is about 5.0 per hour. The cumulative distribution of pulse strength $S$ is a steep power law, $N(>S)\propto S^{-4.7}$, but much less steep than would be expected if we were observing the tail of a Gaussian distribution of normal pulses. We detected no other transient pulses in a dispersion measure range from 1 to 90 pc cm$^{-3}$, in the beam tracking PSR B0950+08. The giant pulses have a narrower temporal width than the mean pulse (17.8 ms, on average, vs. 30.5 ms). The pulse widths are consistent with a previously observed weak dependence on observing frequency, which may be indicative of a deviation from a Kolmogorov spectrum of electron density irregularities along the line of sight. The rate and strength of these giant pulses is less than has been observed at $\sim$100 MHz. Additionally, the mean (normal) pulse flux density we observed is less than at $\sim$100 MHz. These results suggest this pulsar is weaker and produces less frequent giant pulses at 39 MHz than at 100 MHz.Comment: 27 pages, 12 figures, typos correcte

Imbibition in mesoporous silica: rheological concepts and experiments on water and a liquid crystal

We present, along with some fundamental concepts regarding imbibition of liquids in porous hosts, an experimental, gravimetric study on the capillarity-driven invasion dynamics of water and of the rod-like liquid crystal octyloxycyanobiphenyl (8OCB) in networks of pores a few nanometers across in monolithic silica glass (Vycor). We observe, in agreement with theoretical predictions, square root of time invasion dynamics and a sticky velocity boundary condition for both liquids investigated. Temperature-dependent spontaneous imbibition experiments on 8OCB reveal the existence of a paranematic phase due to the molecular alignment induced by the pore walls even at temperatures well beyond the clearing point. The ever present velocity gradient in the pores is likely to further enhance this ordering phenomenon and prevent any layering in molecular stacks, eventually resulting in a suppression of the smectic phase in favor of the nematic phase.Comment: 18 pages, 8 figure

Multi-messenger astronomy of gravitational-wave sources with flexible wide-area radio transient surveys

We explore opportunities for multi-messenger astronomy using gravitational waves (GWs) and prompt, transient low-frequency radio emission to study highly energetic astrophysical events. We review the literature on possible sources of correlated emission of gravitational waves and radio transients, highlighting proposed mechanisms that lead to a short-duration, high-flux radio pulse originating from the merger of two neutron stars or from a superconducting cosmic string cusp. We discuss the detection prospects for each of these mechanisms by low-frequency dipole array instruments such as LWA1, LOFAR and MWA. We find that a broad range of models may be tested by searching for radio pulses that, when de-dispersed, are temporally and spatially coincident with a LIGO/Virgo GW trigger within a \usim 30 second time window and \usim 200 \mendash 500 \punits{deg}^{2} sky region. We consider various possible observing strategies and discuss their advantages and disadvantages. Uniquely, for low-frequency radio arrays, dispersion can delay the radio pulse until after low-latency GW data analysis has identified and reported an event candidate, enabling a \emph{prompt} radio signal to be captured by a deliberately targeted beam. If neutron star mergers do have detectable prompt radio emissions, a coincident search with the GW detector network and low-frequency radio arrays could increase the LIGO/Virgo effective search volume by up to a factor of \usim 2. For some models, we also map the parameter space that may be constrained by non-detections.Comment: 31 pages, 4 figure