Tumor cell invasion of collagen matrices requires coordinate lipid agonist-induced G-protein and membrane-type matrix metalloproteinase-1-dependent signaling

BACKGROUND: Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are bioactive lipid signaling molecules implicated in tumor dissemination. Membrane-type matrix metalloproteinase 1 (MT1-MMP) is a membrane-tethered collagenase thought to be involved in tumor invasion via extracellular matrix degradation. In this study, we investigated the molecular requirements for LPA- and S1P-regulated tumor cell migration in two dimensions (2D) and invasion of three-dimensional (3D) collagen matrices and, in particular, evaluated the role of MT1-MMP in this process. RESULTS: LPA stimulated while S1P inhibited migration of most tumor lines in Boyden chamber assays. Conversely, HT1080 fibrosarcoma cells migrated in response to both lipids. HT1080 cells also markedly invaded 3D collagen matrices (~700 μm over 48 hours) in response to either lipid. siRNA targeting of LPA(1 )and Rac1, or S1P(1), Rac1, and Cdc42 specifically inhibited LPA- or S1P-induced HT1080 invasion, respectively. Analysis of LPA-induced HT1080 motility on 2D substrates vs. 3D matrices revealed that synthetic MMP inhibitors markedly reduced the distance (~125 μm vs. ~45 μm) and velocity of invasion (~0.09 μm/min vs. ~0.03 μm/min) only when cells navigated 3D matrices signifying a role for MMPs exclusively in invasion. Additionally, tissue inhibitors of metalloproteinases (TIMPs)-2, -3, and -4, but not TIMP-1, blocked lipid agonist-induced invasion indicating a role for membrane-type (MT)-MMPs. Furthermore, MT1-MMP expression in several tumor lines directly correlated with LPA-induced invasion. HEK293s, which neither express MT1-MMP nor invade in the presence of LPA, were transfected with MT1-MMP cDNA, and subsequently invaded in response to LPA. When HT1080 cells were seeded on top of or within collagen matrices, siRNA targeting of MT1-MMP, but not other MMPs, inhibited lipid agonist-induced invasion establishing a requisite role for MT1-MMP in this process. CONCLUSION: LPA is a fundamental regulator of MT1-MMP-dependent tumor cell invasion of 3D collagen matrices. In contrast, S1P appears to act as an inhibitory stimulus in most cases, while stimulating only select tumor lines. MT1-MMP is required only when tumor cells navigate 3D barriers and not when cells migrate on 2D substrata. We demonstrate that tumor cells require coordinate regulation of LPA/S1P receptors and Rho GTPases to migrate, and additionally, require MT1-MMP in order to invade collagen matrices during neoplastic progression

Supervised Machine Learning for Intercomparison of Model Grids of Brown Dwarfs: Application to GJ 570D and the Epsilon Indi B Binary System

Self-consistent model grids of brown dwarfs involve complex physics and chemistry, and are often computed using proprietary computer codes, making it challenging to identify the reasons for discrepancies between model and data as well as between the models produced by different research groups. In the current study, we demonstrate a novel method for analyzing brown dwarf spectra, which combines the use of the Sonora, AMES-Cond and HELIOS model grids with the supervised machine learning method of the random forest. Besides performing atmospheric retrieval, the random forest enables information content analysis of the three model grids as a natural outcome of the method, both individually on each grid and by comparing the grids against one another, via computing large suites of mock retrievals. Our analysis reveals that the different choices made in modelling the alkali line shapes hinder the use of the alkali lines as gravity indicators. Nevertheless, the spectrum longward of 1.2 micron encodes enough information on the surface gravity to allow its inference from retrieval. Temperature may be accurately and precisely inferred independent of the choice of model grid, but not the surface gravity. We apply random forest retrieval to three objects: the benchmark T7.5 brown dwarf GJ 570D; and Epsilon Indi Ba (T1.5 brown dwarf) and Bb (T6 brown dwarf), which are part of a binary system and have measured dynamical masses. For GJ 570D, the inferred effective temperature and surface gravity are consistent with previous studies. For Epsilon Indi Ba and Bb, the inferred surface gravities are broadly consistent with the values informed by the dynamical masses.Comment: Accepted for publication in The Astronomical Journa

Diurnal, seasonal, and annual trends in atmospheric CO₂ at southwest London during 2000-2012:Wind sector analysis and comparison with Mace Head, Ireland

In-situ measurements of atmospheric CO have been made at Royal Holloway University of London (RHUL) in Egham (EGH), Surrey, UK from 2000 to 2012. The data were linked to the global scale using NOAA-calibrated gases. Measured CO varies on time scales that range from minutes to inter-annual and annual cycles. Seasonality and pollution episodes occur each year. Diurnal cycles vary with daylight and temperature, which influence the biological cycle of CO and the degree of vertical mixing. Anthropogenic emissions of CO dominate the variability during weekdays when transport cycles are greater than at weekends. Seasonal cycles are driven by temporal variations in biological activity and changes in combustion emissions. Maximum mole fractions (μmol/mol) (henceforth referred to by parts per million, ppm) occur in winter, with minima in late summer. The smallest seasonal amplitude observed, peak to trough, was 17.0ppm CO in 2003, whereas the largest amplitude observed was 27.1ppm CO in 2008.Meteorology can strongly modify the CO mole fractions at different time scales. Analysis of eight 45° wind sectors shows that the highest CO mole fractions were recorded from the E and SE sectors. Lowest mole fractions were observed for air masses from the S and SW. Back-trajectory and meteorological analyses of the data confirm that the dominant sources of CO are anthropogenic emissions from London and SE England. The largest annual rate of increase in the annual average of CO, 3.26ppmyr (

A Laminin G-EGF-Laminin G Module in Neurexin IV Is Essential for the Apico-Lateral Localization of Contactin and Organization of Septate Junctions

Septate junctions (SJs) display a unique ultrastructural morphology with ladder-like electron densities that are conserved through evolution. Genetic and molecular analyses have identified a highly conserved core complex of SJ proteins consisting of three cell adhesion molecules Neurexin IV, Contactin, and Neuroglian, which interact with the cytoskeletal FERM domain protein Coracle. How these individual proteins interact to form the septal arrays that create the paracellular barrier is poorly understood. Here, we show that point mutations that map to specific domains of neurexin IV lead to formation of fewer septae and disorganization of SJs. Consistent with these observations, our in vivo domain deletion analyses identified the first Laminin G-EGF-Laminin G module in the extracellular region of Neurexin IV as necessary for the localization of and association with Contactin. Neurexin IV protein that is devoid of its cytoplasmic region is able to create septae, but fails to form a full complement of SJs. These data provide the first in vivo evidence that specific domains in Neurexin IV are required for protein-protein interactions and organization of SJs. Given the molecular conservation of SJ proteins across species, our studies may provide insights into how vertebrate axo-glial SJs are organized in myelinated axons

Nonequilibrium Critical Dynamics of a Three Species Monomer-Monomer Model

We study a three species monomer-monomer catalytic surface reaction model with a reactive steady state bordered by three equivalent unreactive phases where the surface is saturated with one species. The transition from the reactive to a saturated phase shows directed percolation critical behavior. Each pair of these reactive-saturated phase boundaries join at a bicritical point where the universal behavior is in the even branching annihilating random walk class. We find the crossover exponent from bicritical to critical behavior and a new exponent associated with the bicritical interface dynamics.Comment: 4 pages RevTex. 4 eps figures included with psfig.sty. Uses multicol.sty. Accepted for publication in PR

Cytoplasmic dynein nomenclature

A variety of names has been used in the literature for the subunits of cytoplasmic dynein complexes. Thus, there is a strong need for a more definitive consensus statement on nomenclature. This is especially important for mammalian cytoplasmic dyneins, many subunits of which are encoded by multiple genes. We propose names for the mammalian cytoplasmic dynein subunit genes and proteins that reflect the phylogenetic relationships of the genes and the published studies clarifying the functions of the polypeptides. This nomenclature recognizes the two distinct cytoplasmic dynein complexes and has the flexibility to accommodate the discovery of new subunits and isoforms

Dynamical simulation of transport in one-dimensional quantum wires

Transport of single-channel spinless interacting fermions (Luttinger liquid) through a barrier has been studied by numerically exact quantum Monte Carlo methods. A novel stochastic integration over the real-time paths allows for direct computation of nonequilibrium conductance and noise properties. We have examined the low-temperature scaling of the conductance in the crossover region between a very weak and an almost insulating barrier.Comment: REVTex, 4 pages, 2 uuencoded figures (submitted to Phys. Rev. Lett.

The GALFA-HI Survey: Data Release 1

We present the Galactic Arecibo L-Band Feed Array HI (GALFA-HI) survey, and its first full data release (DR1). GALFA-HI is a high resolution (~ 4'), large area (13000 deg^2), high spectral resolution (0.18 km/s), wide band (-700 < v_LSR < +700 km/s) survey of the Galactic interstellar medium in the 21-cm line hyperfine transition of neutral hydrogen conducted at Arecibo Observatory. Typical noise levels are 80 mK RMS in an integrated 1 km/s channel. GALFA-HI is a dramatic step forward in high-resolution, large-area Galactic HI surveys, and we compare GALFA-HI to past, present, and future Galactic HI surveys. We describe in detail new techniques we have developed to reduce these data in the presence of fixed pattern noise, gain variation, and inconsistent beam shapes, and we show how we have largely mitigated these effects. We present our first full data release, covering 7520 square degrees of sky and representing 3046 hours of integration time, and discuss the details of these data.Comment: Accepted to the ApJ

Diurnal, seasonal, and annual trends in tropospheric CO in Southwest London during 2000–2015: Wind sector analysis and comparisons with urban and remote sites

Ambient carbon monoxide (CO) and meteorological parameters measured at the Egham (EGH) semi-rural site in SW London during 2000–2015 have permitted wind sector analysis of diurnal and seasonal cycles, and interpretation of long-term trends. CO daily amplitudes are used as a proxy for anthropogenic emissions. At EGH, morning and evening peaks in CO arise from the dominant contribution of road transport sources. Smaller amplitudes are observed during weekends than weekdays due to lower combustion emissions, and for mornings compared to evenings due to the timing of the development and break-up of the nocturnal inversion layer or planetary boundary layer (PBL). A wavelet transform revealed that the dominant mode of CO variability is the annual cycle, with apparent winter maxima likely due to increased CO emissions from domestic heating with summer minima ascribed to enhanced dispersion and dilution during the annual maximum of PBL mixing heights. Over the last two decades, both mitigation measures to reduce CO emissions and also a major switch to diesel cars, have accompanied a change at EGH from the dominance of local diurnal sources to a site measuring close to Atlantic background levels in summer months. CO observed in the S and SW wind sectors has declined by 4.7 and 5.9 ppb yr−1 respectively. The EGH CO record shows the highest levels in the early 2000s, with levels in E and calm winds comparable to those recorded at background stations in Greater London. However, since 2012, levels in S-SW sector have become more comparable with Mace Head background except during rush-hour periods. Marked declines in CO are observed during 2000–2008 for the NE, E, SE (London) and calm wind sectors, with the smallest declines observed for the S, SW and W (background) sectors. For the majority of wind sectors, the decline in CO is less noticeable since 2008, with an apparent stabilisation for NE, E and SE after 2009. The EGH CO data record exhibits a similar but slower exponential decay, but from a much lower starting concentration, than do CO data recorded at selected monitoring sites in urban areas in SE England. CO/CO2 residuals determined using a 1 h window data in the diurnal cycle demonstrate a clear decline in CO from 2000 to 2015 during daily periods of increased vehicle traffic, which is consistent with a sustained reduction in CO emissions from the road transport sector