492 research outputs found

    Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension

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    BACKGROUND AND AIMS: Hepatic stellate cells (HSCs) are vital to hepatocellular function and the liver response to injury. They share a phenotypic homology with astrocytes that are central in the pathogenesis of hepatic encephalopathy, a condition in which hyperammonemia plays a pathogenic role. This study tested the hypothesis that ammonia modulates human HSC activation in vitro and in vivo, and evaluated whether ammonia lowering, by using l-ornithine phenylacetate (OP), modifies HSC activation in vivo and reduces portal pressure in a bile duct ligation (BDL) model. METHODS: Primary human HSCs were isolated and cultured. Proliferation (BrdU), metabolic activity (MTS), morphology (transmission electron, light and immunofluorescence microscopy), HSC activation markers, ability to contract, changes in oxidative status (ROS) and endoplasmic reticulum (ER) were evaluated to identify effects of ammonia challenge (50 μM, 100 μM, 300 μM) over 24–72 h. Changes in plasma ammonia levels, markers of HSC activation, portal pressure and hepatic eNOS activity were quantified in hyperammonemic BDL animals, and after OP treatment. RESULTS: Pathophysiological ammonia concentrations caused significant and reversible changes in cell proliferation, metabolic activity and activation markers of hHSC in vitro. Ammonia also induced significant alterations in cellular morphology, characterised by cytoplasmic vacuolisation, ER enlargement, ROS production, hHSC contraction and changes in pro-inflammatory gene expression together with HSC-related activation markers such as α-SMA, myosin IIa, IIb, and PDGF-Rβ. Treatment with OP significantly reduced plasma ammonia (BDL 199.1 μmol/L ± 43.65 vs. BDL + OP 149.27 μmol/L ± 51.1, p <0.05) and portal pressure (BDL 14 ± 0.6 vs. BDL + OP 11 ± 0.3 mmHg, p <0.01), which was associated with increased eNOS activity and abrogation of HSC activation markers. CONCLUSIONS: The results show for the first time that ammonia produces deleterious morphological and functional effects on HSCs in vitro. Targeting ammonia with the ammonia lowering drug OP reduces portal pressure and deactivates hHSC in vivo, highlighting the opportunity for evaluating ammonia lowering as a potential therapy in cirrhotic patients with portal hypertension

    EpCAM aptamer mediated cancer cell specific delivery of EpCAM siRNA using polymeric nanocomplex

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    BACKGROUND: Epithelial cell adhesion molecule (EpCAM) is overexpressed in solid tumors and regarded as a putative cancer stem cell marker. Here, we report that employing EpCAM aptamer (EpApt) and EpCAM siRNA (SiEp) dual approach, for the targeted delivery of siRNA to EpCAM positive cancer cells, efficiently inhibits cancer cell proliferation. RESULTS: Targeted delivery of siRNA using polyethyleneimine is one of the efficient methods for gene delivery, and thus, we developed a novel aptamer-PEI-siRNA nanocomplex for EpCAM targeting. PEI nanocomplex synthesized with EpCAM aptamer (EpApt) and EpCAM siRNA (SiEp) showed 198&nbsp;nm diameter sized particles by dynamic light scattering, spherical shaped particles, of 151&thinsp;&plusmn;&thinsp;11&nbsp;nm size by TEM. The surface charge of the nanoparticles was -30.0&nbsp;mV using zeta potential measurements. Gel retardation assay confirmed the PEI-EpApt-SiEp nanoparticles formation. The difference in size observed by DLS and TEM could be due to coating of aptamer and siRNA on PEI nanocore. Flow cytometry analysis revealed that PEI-EpApt-SiEp has superior binding to cancer cells compared to EpApt or scramble aptamer (ScrApt) or PEI-ScrApt-SiEp. PEI-EpApt-SiEp downregulated EpCAM and inhibited selectively the cell proliferation of MCF-7 and WERI-Rb1 cells. CONCLUSIONS: The PEI nanocomplex fabricated with EpApt and siEp was able to target EpCAM tumor cells, deliver the siRNA and silence the target gene. This nanocomplex exhibited decreased cell proliferation than the scrambled aptamer loaded nanocomplex in the EpCAM expressing cancer cells and may have potential for EpCAM targeting in vivo

    High throughput screening for discovery of materials that control stem cell fate

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    Insights into the complex stem cell niche have identified the cell–material interface to be a potent regulator of stem cell fate via material properties such as chemistry, topography and stiffness. In light of this, materials scientists have the opportunity to develop bioactive materials for stem cell culture that elicit specific cellular responses. To accelerate materials discovery, high throughput screening platforms have been designed which can rapidly evaluate combinatorial material libraries in two and three-dimensional environments. In this review, we present screening platforms for the discovery of material properties that influence stem cell behavior

    Population of Merging Compact Binaries Inferred Using Gravitational Waves through GWTC-3

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    We report on the population properties of compact binary mergers inferred from gravitational-wave observations of these systems during the first three LIGO-Virgo observing runs. The Gravitational-Wave Transient Catalog 3 (GWTC-3) contains signals consistent with three classes of binary mergers: binary black hole, binary neutron star, and neutron star-black hole mergers. We infer the binary neutron star merger rate to be between 10 and 1700 Gpc-3 yr-1 and the neutron star-black hole merger rate to be between 7.8 and 140 Gpc-3 yr-1, assuming a constant rate density in the comoving frame and taking the union of 90% credible intervals for methods used in this work. We infer the binary black hole merger rate, allowing for evolution with redshift, to be between 17.9 and 44 Gpc-3 yr-1 at a fiducial redshift (z=0.2). The rate of binary black hole mergers is observed to increase with redshift at a rate proportional to (1+z)κ with κ=2.9-1.8+1.7 for z≲1. Using both binary neutron star and neutron star-black hole binaries, we obtain a broad, relatively flat neutron star mass distribution extending from 1.2-0.2+0.1 to 2.0-0.3+0.3M⊙. We confidently determine that the merger rate as a function of mass sharply declines after the expected maximum neutron star mass, but cannot yet confirm or rule out the existence of a lower mass gap between neutron stars and black holes. We also find the binary black hole mass distribution has localized over- and underdensities relative to a power-law distribution, with peaks emerging at chirp masses of 8.3-0.5+0.3 and 27.9-1.8+1.9M⊙. While we continue to find that the mass distribution of a binary's more massive component strongly decreases as a function of primary mass, we observe no evidence of a strongly suppressed merger rate above approximately 60M⊙, which would indicate the presence of a upper mass gap. Observed black hole spins are small, with half of spin magnitudes below χi≈0.25. While the majority of spins are preferentially aligned with the orbital angular momentum, we infer evidence of antialigned spins among the binary population. We observe an increase in spin magnitude for systems with more unequal-mass ratio. We also observe evidence of misalignment of spins relative to the orbital angular momentum

    All-sky search for long-duration gravitational-wave bursts in the third Advanced LIGO and Advanced Virgo run

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    After the detection of gravitational waves from compact binary coalescences, the search for transient gravitational-wave signals with less well-defined waveforms for which matched filtering is not well suited is one of the frontiers for gravitational-wave astronomy. Broadly classified into “short” ≲1  s and “long” ≳1  s duration signals, these signals are expected from a variety of astrophysical processes, including non-axisymmetric deformations in magnetars or eccentric binary black hole coalescences. In this work, we present a search for long-duration gravitational-wave transients from Advanced LIGO and Advanced Virgo’s third observing run from April 2019 to March 2020. For this search, we use minimal assumptions for the sky location, event time, waveform morphology, and duration of the source. The search covers the range of 2–500 s in duration and a frequency band of 24–2048 Hz. We find no significant triggers within this parameter space; we report sensitivity limits on the signal strength of gravitational waves characterized by the root-sum-square amplitude hrss as a function of waveform morphology. These hrss limits improve upon the results from the second observing run by an average factor of 1.8

    Constraints on dark photon dark matter using data from LIGO's and Virgo's third observing run

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    We present a search for dark photon dark matter that could couple to gravitational-wave interferometers using data from Advanced LIGO and Virgo's third observing run. To perform this analysis, we use two methods, one based on cross-correlation of the strain channels in the two nearly aligned LIGO detectors, and one that looks for excess power in the strain channels of the LIGO and Virgo detectors. The excess power method optimizes the Fourier Transform coherence time as a function of frequency, to account for the expected signal width due to Doppler modulations. We do not find any evidence of dark photon dark matter with a mass between mA10141011m_{\rm A} \sim 10^{-14}-10^{-11} eV/c2c^2, which corresponds to frequencies between 10-2000 Hz, and therefore provide upper limits on the square of the minimum coupling of dark photons to baryons, i.e. U(1)BU(1)_{\rm B} dark matter. For the cross-correlation method, the best median constraint on the squared coupling is 1.31×1047\sim1.31\times10^{-47} at mA4.2×1013m_{\rm A}\sim4.2\times10^{-13} eV/c2c^2; for the other analysis, the best constraint is 2.4×1047\sim 2.4\times 10^{-47} at mA5.7×1013m_{\rm A}\sim 5.7\times 10^{-13} eV/c2c^2. These limits improve upon those obtained in direct dark matter detection experiments by a factor of 100\sim100 for mA[24]×1013m_{\rm A}\sim [2-4]\times 10^{-13} eV/c2c^2, and are, in absolute terms, the most stringent constraint so far in a large mass range mAm_A\sim 2×10138×10122\times 10^{-13}-8\times 10^{-12} eV/c2c^2.Comment: 20 pages, 7 figure

    The population of merging compact binaries inferred using gravitational waves through GWTC-3

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    We report on the population properties of 76 compact binary mergers detected with gravitational waves below a false alarm rate of 1 per year through GWTC-3. The catalog contains three classes of binary mergers: BBH, BNS, and NSBH mergers. We infer the BNS merger rate to be between 10 Gpc3yr1\rm{Gpc^{-3} yr^{-1}} and 1700 Gpc3yr1\rm{Gpc^{-3} yr^{-1}} and the NSBH merger rate to be between 7.8 Gpc3yr1\rm{Gpc^{-3}\, yr^{-1}} and 140 Gpc3yr1\rm{Gpc^{-3} yr^{-1}} , assuming a constant rate density versus comoving volume and taking the union of 90% credible intervals for methods used in this work. Accounting for the BBH merger rate to evolve with redshift, we find the BBH merger rate to be between 17.9 Gpc3yr1\rm{Gpc^{-3}\, yr^{-1}} and 44 Gpc3yr1\rm{Gpc^{-3}\, yr^{-1}} at a fiducial redshift (z=0.2). We obtain a broad neutron star mass distribution extending from 1.20.2+0.1M1.2^{+0.1}_{-0.2} M_\odot to 2.00.3+0.3M2.0^{+0.3}_{-0.3} M_\odot. We can confidently identify a rapid decrease in merger rate versus component mass between neutron star-like masses and black-hole-like masses, but there is no evidence that the merger rate increases again before 10 MM_\odot. We also find the BBH mass distribution has localized over- and under-densities relative to a power law distribution. While we continue to find the mass distribution of a binary's more massive component strongly decreases as a function of primary mass, we observe no evidence of a strongly suppressed merger rate above 60M\sim 60 M_\odot. The rate of BBH mergers is observed to increase with redshift at a rate proportional to (1+z)κ(1+z)^{\kappa} with κ=2.91.8+1.7\kappa = 2.9^{+1.7}_{-1.8} for z1z\lesssim 1. Observed black hole spins are small, with half of spin magnitudes below χi0.25\chi_i \simeq 0.25. We observe evidence of negative aligned spins in the population, and an increase in spin magnitude for systems with more unequal mass ratio

    Search for anisotropic gravitational-wave backgrounds using data from Advanced LIGO and Advanced Virgo's first three observing runs

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    We report results from searches for anisotropic stochastic gravitational-wave backgrounds using data from the first three observing runs of the Advanced LIGO and Advanced Virgo detectors. For the first time, we include Virgo data in our analysis and run our search with a new efficient pipeline called {\tt PyStoch} on data folded over one sidereal day. We use gravitational-wave radiometry (broadband and narrow band) to produce sky maps of stochastic gravitational-wave backgrounds and to search for gravitational waves from point sources. A spherical harmonic decomposition method is employed to look for gravitational-wave emission from spatially-extended sources. Neither technique found evidence of gravitational-wave signals. Hence we derive 95\% confidence-level upper limit sky maps on the gravitational-wave energy flux from broadband point sources, ranging from Fα,Θ<(0.0137.6)×108ergcm2s1Hz1,F_{\alpha, \Theta} < {\rm (0.013 - 7.6)} \times 10^{-8} {\rm erg \, cm^{-2} \, s^{-1} \, Hz^{-1}}, and on the (normalized) gravitational-wave energy density spectrum from extended sources, ranging from Ωα,Θ<(0.579.3)×109sr1\Omega_{\alpha, \Theta} < {\rm (0.57 - 9.3)} \times 10^{-9} \, {\rm sr^{-1}}, depending on direction (Θ\Theta) and spectral index (α\alpha). These limits improve upon previous limits by factors of 2.93.52.9 - 3.5. We also set 95\% confidence level upper limits on the frequency-dependent strain amplitudes of quasimonochromatic gravitational waves coming from three interesting targets, Scorpius X-1, SN 1987A and the Galactic Center, with best upper limits range from h0<(1.72.1)×1025,h_0 < {\rm (1.7-2.1)} \times 10^{-25}, a factor of 2.0\geq 2.0 improvement compared to previous stochastic radiometer searches.Comment: 23 Pages, 9 Figure

    Erratum: “Searches for Gravitational Waves from Known Pulsars at Two Harmonics in 2015–2017 LIGO Data” (2019, ApJ, 879, 10)

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    Due to an error at the publisher, in the published article the number of pulsars presented in the paper is incorrect in multiple places throughout the text. Specifically, "222" pulsars should be "221." Additionally, the number of pulsars for which we have EM observations that fully overlap with O1 and O2 changes from "168" to "167." Elsewhere, in the machine-readable table of Table 1 and in Table 2, the row corresponding to pulsar J0952-0607 should be excised as well. Finally, in the caption for Table 2 the number of pulsars changes from "188" to "187.
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