Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology

Cholangiocytes are epithelial cells lining the biliary epithelium. Cholangiocytes play several key roles in the modification of ductal bile and are also the target cells in chronic cholestatic liver diseases (i.e., cholangiopathies) such as PSC, PBC, polycystic liver disease (PCLD) and cholangiocarcinoma (CCA). During these pathologies, cholangiocytes (which in normal condition are in a quiescent state) begin to proliferate acquiring phenotypes of neuroendocrine cells, and start secreting different cytokines, growth factors, neuropeptides, and hormones to modulate cholangiocytes proliferation and interaction with the surrounding environment, trying to reestablish the balance between proliferation/loss of cholangiocytes for the maintenance of biliary homeostasis. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. To clarify the mechanisms of action of these factors we will provide new potential strategies for the management of chronic liver diseases

Black hole masses of tidal disruption event host galaxies

The mass of the central black hole in a galaxy that hosted a tidal disruption event (TDE) is an important parameter in understanding its energetics and dynamics. We present the first homogeneously measured black hole masses of a complete sample of 12 optically/UV selected TDE host galaxies (down to $g_{host}$$\leq$22 mag and $z$=0.37) in the Northern sky. The mass estimates are based on velocity dispersion measurements, performed on late time optical spectroscopic observations. We find black hole masses in the range 3$\times$10$^5$ M$_{\odot}$$\leq$M$_{\rm BH}$$\leq$2$\times$10$^7$ M$_{\odot}$. The TDE host galaxy sample is dominated by low mass black holes ($\sim$10$^6$ M$_{\odot}$), as expected from theoretical predictions. The blackbody peak luminosity of TDEs with M$_{\rm BH}$$\leq$10$^{7.1}$ M$_{\odot}$ is consistent with the Eddington limit of the SMBH, whereas the two TDEs with M$_{\rm BH}$$\geq$10$^{7.1}$ M$_{\odot}$ have peak luminosities below their SMBH Eddington luminosity, in line with the theoretical expectation that the fallback rate for M$_{\rm BH}$$\geq$10$^{7.1}$ M$_{\odot}$ is sub-Eddington. In addition, our observations suggest that TDEs around lower mass black holes evolve faster. These findings corroborate the standard TDE picture in 10$^6$ M$_{\odot}$ black holes. Our results imply an increased tension between observational and theoretical TDE rates. By comparing the blackbody emission radius with theoretical predictions, we conclude that the optical/UV emission is produced in a region consistent with the stream self-intersection radius of shallow encounters, ruling out a compact accretion disk as the direct origin of the blackbody radiation at peak brightness.Comment: 16 pages, 9 figures. Submitted to MNRAS; including minor revisions suggested by the refere

Insight into the HEV/PHEV optimal control solution based on a new tuning method

The paper presents a formulation of the energy management problem for Hybrid Electrical Vehicles and Plug-in Hybrid Electrical Vehicles alike, which permits to consider different cost indexes like fuel consumption, total and primary energy consumption, economic cost or CO2 footprint. In-depth analysis of the problem optimal solution is done by means of the application of the λ-plot method, which also permits the optimal tuning of other implementable control strategies. Such an approach is used to understand the effect of the selected cost index, the regional energetic share, the driving conditions, and for deriving rules for battery sizing.C. Guardiola and B. Pla research has been partially supported by Ministerio de Ciencia e Innovacion through Project TRA2010-16205 uDiesel, and the Universitat Politecnica de Valencia through Grants PAID-00-11 2105 and PAID-00-11 2106.Guardiola García, C.; Plá Moreno, B.; Onori, S.; Rizzoni, G. (2014). Insight into the HEV/PHEV optimal control solution based on a new tuning method. Control Engineering Practice. 29:247-256. https://doi.org/10.1016/j.conengprac.2014.01.022S2472562

Picosecond Internal Dynamics of Lysozyme as Affected by Thermal Unfolding in Nonaqueous Environment

AbstractA neutron-scattering investigation of the internal picosecond dynamics of lysozyme solvated in glycerol as a function of temperature in the range 200–410K has been undertaken. The inelastic contribution to the measured intensity is characterized by the presence of a bump generally known as “boson peak”, clearly distinguishable at low temperature. When the temperature is increased the quasielastic component of the spectrum becomes more and more intrusive and progressively overwhelms the vibrational bump. This happens especially for T>345K when the protein goes through an unfolding process, which leads to the complete denaturation. The quasielastic term is the superposition of two components whose intensities and linewidths have been studied as a function of temperature. The slower component describes motions with characteristic times of ∼4ps corresponding to reorientations of polypeptide side chains. Both the intensity and linewidth of this kind of relaxations show two distinct regimes with a crossover in the temperature range where the melting process occurs, thus suggesting the presence of a dynamical transition correlated to the protein unfolding. Conversely the faster component might be ascribed to the local dynamics of hydrogen atoms caged by the nearest neighbors with characteristic time of ∼0.3ps

H3 histamine receptor-mediated activation of protein kinase calpha inhibits the growth of cholangiocarcinoma in vitro and in vivo

Histamine regulates functions via four receptors (HRH1, HRH2, HRH3, and HRH4). The D-myo-inositol 1,4,5-trisphosphate (IP(3))/Ca(2+)/protein kinase C (PKC)/mitogen-activated protein kinase pathway regulates cholangiocarcinoma growth. We evaluated the role of HRH3 in the regulation of cholangiocarcinoma growth. Expression of HRH3 in intrahepatic and extrahepatic cell lines, normal cholangiocytes, and human tissue arrays was measured. In Mz-ChA-1 cells stimulated with (R)-(alpha)-(-)-methylhistamine dihydrobromide (RAMH), we measured (a) cell growth, (b) IP(3) and cyclic AMP levels, and (c) phosphorylation of PKC and mitogen-activated protein kinase isoforms. Localization of PKC alpha was visualized by immunofluorescence in cell smears and immunoblotting for PKC alpha in cytosol and membrane fractions. Following knockdown of PKC alpha, Mz-ChA-1 cells were stimulated with RAMH before evaluating cell growth and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation. In vivo experiments were done in BALB/c nude mice. Mice were treated with saline or RAMH for 44 days and tumor volume was measured. Tumors were excised and evaluated for proliferation, apoptosis, and expression of PKC alpha, vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF receptor 2, and VEGF receptor 3. HRH3 expression was found in all cells. RAMH inhibited the growth of cholangiocarcinoma cells. RAMH increased IP(3) levels and PKC alpha phosphorylation and decreased ERK1/2 phosphorylation. RAMH induced a shift in the localization of PKC alpha expression from the cytosolic domain into the membrane region of Mz-ChA-1 cells. Silencing of PKC alpha prevented RAMH inhibition of Mz-ChA-1 cell growth and ablated RAMH effects on ERK1/2 phosphorylation. In vivo, RAMH decreased tumor growth and expression of VEGF and its receptors; PKC alpha expression was increased. RAMH inhibits cholangiocarcinoma growth by PKC alpha-dependent ERK1/2 dephosphorylation. Modulation of PKC alpha by histamine receptors may be important in regulating cholangiocarcinoma growth. (Mol Cancer Res 2009;7(10):1704-13

The Hepatic Microcirculation in Experimental Cirrhosis a Scanning Electron Microscopy Study of Microcorrosion Casts

The experimental model of liver cirrhosis induced by intragastric administration of CCl4 reproduces not only the histological picture of the postnecrotic cirrhosis but also its pathophysiological features. Corrosion casts of livers affected by CCl4-induced cirrhosis show the loss of the lobular pattern. Once the cirrhosis has completely developed, the whole microvascular bed appears to be composed of groups of sinusoid nodules of diameters varying between 0.3 and 1.5 mm.. Pre- and post-sinusoidal vessels and anastomoses between the former and the latter are mainly located at the perinodular spaces. This microvascular situation modifies the normal perfusion gradient within the parenchyma. Nevertheless, it can allow a still viable function

Quasi-simultaneous INTEGRAL, SWIFT, and NuSTAR Observations of the New X-Ray Clocked Burster 1RXS J180408.9-342058

We report the quasi-simultaneous INTEGRAL, SWIFT, and NuSTAR observations showing spectral state transitions in the neutron star low-mass X-ray binary 1RXS J180408.9−342058 during its 2015 outburst. We present results of the analysis of high-quality broad energy band (0.8–200 keV) data in three different spectral states: high/soft, low/very-hard, and transitional state. The broadband spectra can be described in general as the sum of thermal Comptonization and reflection due to illumination of an optically thick accretion disk. During the high/soft state, blackbody emission is generated from the accretion disk and the surface of the neutron star. This emission, measured at a temperature of kT_(bb) ~ 1.2 keV, is then Comptonized by a thick corona with an electron temperature of ~2.5 keV. For the transitional and low/very-hard state, the spectra are successfully explained with emission from a double Comptonizing corona. The first component is described by thermal Comptonization of seed disk/neutron star photons (kT_(bb) ~ 1.2 keV) by a cold corona cloud with kT_e ~ 8–10 keV, while the second one originates from lower temperature blackbody photons (kT_(bb) ≤ 0.1 keV) Comptonized by a hot corona (kT_e ~ 35 keV). Finally, from NuSTAR observations, there is evidence that the source is a new clocked burster. The average time between two successive X-ray bursts corresponds to ~7.9 and ~4.0 ks when the persistent emission decreases by a factor of ~2, moving from a very hard to transitional state. The accretion rate (~4 x 10⁻⁹ M⊙ yr ⁻¹) and the decay time of the X-ray bursts longer than ~30 s suggest that the thermonuclear emission is due to mixed H/He burning triggered by thermally unstable He ignition

SMN protein promotes membrane compartmentalization of ribosomal protein S6 transcript in human fibroblasts

Alterations of RNA homeostasis can lead to severe pathological conditions. The Survival of Motor Neuron (SMN) protein, which is reduced in Spinal Muscular Atrophy, impacts critical aspects of the RNA life cycle, such as splicing, trafficking, and translation. Increasing evidence points to a potential role of SMN in ribosome biogenesis. Our previous study revealed that SMN promotes membrane-bound ribosomal proteins (RPs), sustaining activity-dependent local translation. Here, we suggest that plasma membrane domains could be a docking site not only for RPs but also for their encoding transcripts. We have shown that SMN knockdown perturbs subcellular localization as well as translation efficiency of RPS6 mRNA. We have also shown that plasma membrane-enriched fractions from human fibroblasts retain RPS6 transcripts in an SMN-dependent manner. Furthermore, we revealed that SMN traffics with RPS6 mRNA promoting its association with caveolin-1, a key component of membrane dynamics. Overall, these findings further support the SMN-mediated crosstalk between plasma membrane dynamics and translation machinery. Importantly, our study points to a potential role of SMN in the ribosome assembly pathway by selective RPs synthesis/localization in both space and time

Chronic MPTP in Mice Damage-specific Neuronal Phenotypes within Dorsal Laminae of the Spinal Cord

The neurotoxin 1-methyl, 4-phenyl, 1, 2, 3, 6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism. Such a disease is characterized by neuronal damage in multiple regions beyond the nigrostriatal pathway including the spinal cord. The neurotoxin MPTP damages spinal motor neurons. So far, in Parkinson’s disease (PD) patients alpha-synuclein aggregates are described in the dorsal horn of the spinal cord. Nonetheless, no experimental investigation was carried out to document whether MPTP affects the sensory compartment of the spinal cord. Thus, in the present study, we investigated whether chronic exposure to small doses of MPTP (5 mg/kg/X2, daily, for 21 days) produces any pathological effect within dorsal spinal cord. This mild neurotoxic protocol produces a damage only to nigrostriatal dopamine (DA) axon terminals with no decrease in DA nigral neurons assessed by quantitative stereology. In these experimental conditions we documented a decrease in enkephalin-, calretinin-, calbindin D28K-, and parvalbumin-positive neurons within lamina I and II and the outer lamina III. Met-Enkephalin and substance P positive fibers are reduced in laminae I and II of chronically MPTP-treated mice. In contrast, as reported in PD patients, alpha-synuclein is markedly increased within spared neurons and fibers of lamina I and II after MPTP exposure. This is the first evidence that experimental parkinsonism produces the loss of specific neurons of the dorsal spinal cord, which are likely to be involved in sensory transmission and in pain modulation providing an experimental correlate for sensory and pain alterations in PD