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

Equalization of a 10 Gbps IMDD signal by a small silicon photonics time delayed neural network

A small 4-channels time-delayed complex perceptron is used as a silicon photonics neural network (NN) device to compensate for chromatic dispersion in optical fiber links. The NN device is experimentally tested with non-return-to-zero optical signals at 10 Gbps after propagation through up to 125 km optical fiber link. During the learning phase, a separation-loss function is optimized in order to maximally separate the transmitted levels of 0s from the 1s, which implies an optimization of the bit-error-rate. Testing of the NN device shows that the excess losses introduced by the NN device are compensated by the gain in transmitted signal equalization for a link longer than 100 km. The measured data are reproduced by a model which accounts for the optical link and the neural network device. This allows simulating the network performances for higher data rates, where the device shows improvement with respect to the benchmark both in terms of performance as well as ease of use.Comment: 14 pages, 6 figure

Geology of the Raditladi quadrangle, Mercury (H04)

In this work, we present a 1:3,000,000-scale geologic map of the Raditladi quadrangle (H04) of Mercury. The area covers nearly 7% of the entire planet and encompasses several features of interest such as the Caloris basin, the Raditladi basin, hollow clusters and volcanic features. The mapping took advantage of the data produced during MESSENGER's orbital phase. The mapped deposits include impact-related units observed at several scales from the Caloris basin to the secondary crater chains. The Smooth Plains unit covers the majority of the area, mantling the older Intercrater Plains and Bright Intercrater Plains units. Results show that the emplacement of all the main units and the Caloris impact event, representing the main geologic events in the quadrangle, were concentrated between 3.96 and 3.72 Ga. After this intense phase, the geologic framework was modified only by local events such as impact craters and hollow formation. This map is among the first products for the detailed geologic characterization of Mercury at such a scale. It will contribute as a constraint and a support for both further local investigation and mapping, and targeting of the forthcoming BepiColombo ESA/JAXA joint exploration mission to Mercury

Physics of electrical treeing in Silicon Gel

Silicone gel is commonly employed in electrical insulation, especially in power module encapsulation. In the recent years, the increase of the operation voltage of this application led to a higher electrical stress on the silicone gel, thus, electrical treeing has become a serious issue to the reliability of power modules. In this research, the degradation produced by the electrical treeing has been evaluated dividing it into two main parts: the tree inception and the tree growth, which have been assessed for different waveforms of the applied voltage. The tree inception, the preliminary stage of this phenomenon, has been tested and an innovative model has been proposed explaining this stage. The tree growth has been evaluated in function of the waveform voltage obtaining useful comparisons between the possible electrical stresses. This thesis highlights the peculiar behavior of silicone gel under high electric field and furnishes useful guidelines for designing and testing the electrical insulation made by silicone gel

Reconfigurable optical routers based on Coupled Resonator Induced Transparency resonances.

The interferometric coupling of pairs of resonators in a resonator sequence generates coupled ring induced transparency (CRIT) resonances. These have quality factors an order of magnitude greater than those of single resonators. We show that it is possible to engineer CRIT resonances in tapered SCISSOR (Side Coupled Integrated Space Sequence of Resonator) to realize fast and efficient reconfigurable optical switches and routers handling several channels while keeping single channel addressing capabilities. Tapered SCISSORs are fabricated in silicon-on-insulator technology. Furthermore, tapered SCISSORs show multiple-channel switching behavior that can be exploited in DWDM applications

PRECISE Photonic hybRid EleCtromagnetic SolvEr

The Photonic hybRid EleCtromagnetic SolvEr (PRECISE) is a Matlab based library to model large and complex photonics integrated circuits. Each circuit is modularly described in terms of waveguide segments connected through multiport nodes. Linear, nonlinear, and dynamical phenomena are simulated by solving the system of differential equations describing the effect to be considered. By exploiting the steady state approximation of the electromagnetic field within each node device, the library can handle large and complex circuits even on desktop PC. We show that the steady state assumption is fulfilled in a broad number of applications and we compare its accuracy with analytical model (coupled mode theory) and experimental results. PRECISE is highly modular and easily extensible to handle equations different from those already implemented and is, thus, a flexible tool to model the increasingly complex photonic circuits.Comment: 21 pages, 13 figure

Vasopressin regulates the growth of the biliary epithelium in polycystic liver disease

The neurohypophysial hormone arginine vasopressin (AVP) acts by three distinct receptor subtypes: V1a, V1b, and V2. In the liver, AVP is involved in ureogenesis, glycogenolysis, neoglucogenesis and regeneration. No data exist about the presence of AVP in the biliary epithelium. Cholangiocytes are the target cells in a number of animal models of cholestasis, including bile duct ligation (BDL), and in several human pathologies, such as polycystic liver disease characterized by the presence of cysts that bud from the biliary epithelium. In vivo, liver fragments from normal and BDL mice and rats as well as liver samples from normal and ADPKD patients were collected to evaluate: (i) intrahepatic bile duct mass by immunohistochemistry for cytokeratin-19; and (ii) expression of V1a, V1b and V2 by immunohistochemistry, immunofluorescence and real-time PCR. In vitro, small and large mouse cholangiocytes, H69 (non-malignant human cholangiocytes) and LCDE (human cholangiocytes from the cystic epithelium) were stimulated with vasopressin in the absence/presence of AVP antagonists such as OPC-31260 and Tolvaptan, before assessing cellular growth by MTT assay and cAMP levels. Cholangiocytes express V2 receptor that was upregulated following BDL and in ADPKD liver samples. Administration of AVP increased proliferation and cAMP levels of small cholangiocytes and LCDE cells. We found no effect in the proliferation of large mouse cholangiocytes and H69 cells. Increases were blocked by preincubation with the AVP antagonists. These results showed that AVP and its receptors may be important in the modulation of the proliferation rate of the biliary epithelium

Coupled-resonator-induced-transparency concept for wavelength routing applications

The presence of coupled resonators induced transparency (CRIT) effects in side-coupled integrated spaced sequence of resonators (SCISSOR) of different radii has been studied. By controlling the rings radii and their center to center distance, it is possible to form transmission channels within the SCISSOR stop-band. Two different methods to exploit the CRIT effect in add/drop filters are proposed. Their performances, e. g. linewidth, crosstalk and losses, are examined also for random variations in the structural parameters. Finally, few examples of high performances mux/demux structures and 2 × 2 routers based on these modified SCISSOR are presented. CRIT based SCISSOR optical devices are particularly promising for ultra-dense wavelength division multiplexing applications

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