Finite time stability design via feedback linearization

A new nonlinear design technique for Finite-Time Stability for a class of nonlinear systems is developed using feedback linearization. Moreover, a new concept, namely the Finite-Time Contractive Stability with fixed settling time is introduced, giving sufficient conditions for analysis and design. An example illustrates the theoretical results

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

Viral hepatitis and iron dysregulation: molecular pathways and the role of lactoferrin

The liver is a frontline immune site specifically designed to check and detect potential pathogens from the bloodstream to maintain a general state of immune hyporesponsiveness. One of the main functions of the liver is the regulation of iron homeostasis. The liver detects changes in systemic iron requirements and can regulate its concentration. Pathological states lead to the dysregulation of iron homeostasis which, in turn, can promote infectious and inflammatory processes. In this context, hepatic viruses deviate hepatocytes' iron metabolism in order to better replicate. Indeed, some viruses are able to alter the expression of iron-related proteins or exploit host receptors to enter inside host cells. Lactoferrin (Lf), a multifunctional iron-binding glycoprotein belonging to the innate immunity, is endowed with potent antiviral activity, mainly related to its ability to block viral entry into host cells by interacting with viral and/or cell surface receptors. Moreover, Lf can act as an iron scavenger by both direct iron-chelation or the modulation of the main iron-related proteins. In this review, the complex interplay between viral hepatitis, iron homeostasis, and inflammation as well as the role of Lf are outlined

Different iron-handling in inflamed small and large cholangiocytes and in small and large-duct type intrahepatic cholangiocarcinoma

Cholangiocarcinoma (CCA) represents the second most common primary hepatic malignancy and originates from the neoplastic transformation of the biliary cells. The intrahepatic subtype includes two morpho-molecular forms: large-duct type intrahepatic CCA (iCCA) and small-duct type iCCA. Iron is fundamental for the cellular processes, contributing in tumor development and progression. The aim of this study was to evaluate iron uptake, storage, and efflux proteins in both lipopolysaccharide-inflamed small and large cholangiocytes as well as in different iCCA subtypes. Our results show that, despite an increase in interleukin-6 production by both small and large cholangiocytes, ferroportin (Fpn) was decreased only in small cholangiocytes, whereas transferrin receptor-1 (TfR1) and ferritin (Ftn) did not show any change. Differently from in vitro models, Fpn expression was increased in malignant cholangiocytes of small-duct type iCCA in comparison to large-duct type iCCA and peritumoral tissues. TfR1, Ftn and hepcidin were enhanced, even if at different extent, in both malignant cholangiocytes in comparison to the surrounding samples. Lactoferrin was higher in large-duct type iCCA in respect to small-duct type iCCA and peritumoral tissues. These findings show a different iron handling by inflamed small and large cholangiocytes, and small and large-duct type iCCA. The difference in iron homeostasis by the iCCA subtypes may have implications for the tumor management

GRB host galaxies with VLT/X-Shooter: properties at 0.8 < z < 1.3

Long gamma-ray bursts (LGRBs) are associated with the death of massive stars. Their host galaxies therefore represent a unique class of objects tracing star formation across the observable Universe. Indeed, recently accumulated evidence shows that GRB hosts do not differ substantially from general population of galaxies at high (z > 2) redshifts. However, it has been long recognised that the properties of z < 1.5 hosts, compared to general star-forming population, are unusual. To better understand the reasons for the supposed difference in LGRB hosts properties at z < 1.5, we obtained VLT/X- Shooter spectra of six hosts lying in the redshift range of 0.8 < z < 1.3. Some of these hosts have been observed before, yet we still lack well constrained information on their characteristics such as metallicity, dust extinction and star formation rate. We search for emission lines in the VLT/X-Shooter spectra of the hosts and measure their fluxes. We perform a detailed analysis, estimating host average extinction, star-formation rates, metallicities and electron densities where possible. Measured quantities of our hosts are compared to a larger sample of previously observed GRB hosts at z < 2. Star-formation rates and metallicities are measured for all the hosts analyzed in this paper and metallicities are well determined for 4 hosts. The mass-metallicity relation, the fundamental metallicity relation and SFRs derived from our hosts occupy similar parameter space as other host galaxies investigated so-far at the same redshift. We therefore conclude that GRB hosts in our sample support the found discrepancy between the properties of low-redshift GRB hosts and the general population of star- forming galaxies.Comment: 13 pages, 6 figures, accepted for publication in MNRA

Distinct EpCAM-Positive stem cell niches are engaged in chronic and neoplastic liver diseases

In normal human livers, EpCAMpos cells are mostly restricted in two distinct niches, which are (i) the bile ductules and (ii) the mucous glands present inside the wall of large intrahepatic bile ducts (the so-called peribiliary glands). These EpCAMpos cell niches have been proven to harbor stem/progenitor cells with great importance in liver and biliary tree regeneration and in the pathophysiology of human diseases. The EpCAMpos progenitor cells within bile ductules are engaged in driving regenerative processes in chronic diseases affecting hepatocytes or interlobular bile ducts. The EpCAMpos population within peribiliary glands is activated when regenerative needs are finalized to repair large intra- or extra-hepatic bile ducts affected by chronic pathologies, including primary sclerosing cholangitis and ischemia-induced cholangiopathies after orthotopic liver transplantation. Finally, the presence of distinct EpCAMpos cell populations may explain the histological and molecular heterogeneity characterizing cholangiocarcinoma, based on the concept of multiple candidate cells of origin. This review aimed to describe the precise anatomical distribution of EpCAMpos populations within the liver and the biliary tree and to discuss their contribution in the pathophysiology of human liver diseases, as well as their potential role in regenerative medicine of the liver

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&nbsp;mg/kg/X2, daily, for 21&nbsp;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

The emerging role of ferroptosis in liver cancers

: Liver cancer represents a global health challenge with worldwide growth. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Indeed, approximately 90% of HCC cases have a low survival rate. Moreover, cholangiocarcinoma (CC) is another malignant solid tumor originating from cholangiocytes, the epithelial cells of the biliary system. It is the second-most common primary liver tumor, with an increasing course in morbidity and mortality. Tumor cells always show high metabolic levels, antioxidant modifications, and an increased iron uptake to maintain unlimited growth. In recent years, alterations in iron metabolism have been shown to play an important role in the pathogenesis of HCC. Several findings show that a diet rich in iron can enhance HCC risk. Hence, elevated iron concentration inside the cell may promote the development of HCC. Growing evidence sustains that activating ferroptosis may potentially block the proliferation of HCC cells. Even in CC, it has been shown that ferroptosis plays a crucial role in the treatment of tumors. Several data confirmed the inhibitory effect in cell growth of photodynamic therapy (PDT) that can induce reactive oxygen species (ROS) in CC, leading to an increase in malondialdehyde (MDA) and a decrease in intracellular glutathione (GSH). MDA and GSH depletion/modulation are crucial in inducing ferroptosis, suggesting that PDT may have the potential to induce this kind of cell death through these ways. A selective induction of programmed cell death in cancer cells is one of the main treatments for malignant tumors; thus, ferroptosis may represent a novel therapeutic strategy against HCC and CC

Pulsating in unison at optical and X-ray energies: simultaneous high-time resolution observations of the transitional millisecond pulsar PSR J1023+0038

PSR J1023+0038 is the first millisecond pulsar discovered to pulsate in the visible band; such a detection took place when the pulsar was surrounded by an accretion disk and also showed X-ray pulsations. We report on the first high time resolution observational campaign of this transitional pulsar in the disk state, using simultaneous observations in the optical (TNG, NOT, TJO), X-ray (XMM-Newton, NuSTAR, NICER), infrared (GTC) and UV (Swift) bands. Optical and X-ray pulsations were detected simultaneously in the X-ray high intensity mode in which the source spends $\sim$ 70% of the time, and both disappeared in the low mode, indicating a common underlying physical mechanism. In addition, optical and X-ray pulses were emitted within a few km, had similar pulse shape and distribution of the pulsed flux density compatible with a power-law relation $F_{\nu} \propto \nu^{-0.7}$ connecting the optical and the 0.3-45 keV X-ray band. Optical pulses were detected also during flares with a pulsed flux reduced by one third with respect to the high mode; the lack of a simultaneous detection of X-ray pulses is compatible with the lower photon statistics. We show that magnetically channeled accretion of plasma onto the surface of the neutron star cannot account for the optical pulsed luminosity ($\sim 10^{31}$ erg/s). On the other hand, magnetospheric rotation-powered pulsar emission would require an extremely efficient conversion of spin-down power into pulsed optical and X-ray emission. We then propose that optical and X-ray pulses are instead produced by synchrotron emission from the intrabinary shock that forms where a striped pulsar wind meets the accretion disk, within a few light cylinder radii away, $\sim$ 100 km, from the pulsar.Comment: 26 pages, 14 figures, first submitted to ApJ on 2019, January 1

Activation of Fas/FasL pathway and the role of c-FLIP in primary culture of human cholangiocarcinoma cells

Intrahepatic cholangiocarcinoma (iCCA) represents a heterogeneous group of malignancies emerging from the biliary tree, often in the context of chronic bile ducts inflammation. The immunological features of iCCA cells and their capability to control the lymphocytes response have not yet been investigated. The aims of the present study were to evaluate the interaction between iCCA cells and human peripheral blood mononuclear cells (PBMCs) and the role of Fas/FasL in modulating T-cells and NK-cells response after direct co-culture. iCCA cells express high levels of Fas and FasL that increase after co-culture with PBMCs inducing apoptosis in CD4(+), CD8(+) T-cells and in CD56(+) NK-cells. In vitro, c-FLIP is expressed in iCCA cells and the co-culture with PBMCs induces an increase of c-FLIP in both iCCA cells and biliary tree stem cells. This c-FLIP increase does not trigger the caspase cascade, thus hindering apoptotis of iCCA cells which, instead, underwent proliferation. The increased expression of Fas, FasL and c-FLIP is confirmed in situ, in human CCA and in primary sclerosing cholangitis. In conclusion our data indicated that iCCA cells have immune-modulatory properties by which they induce apoptosis of T and NK cells, via Fas/FasL pathway, and escape inflammatory response by up-regulating c-FLIP system