Toll-like receptor 4-mediated inflammation triggered by extracellular IFI16 is enhanced by lipopolysaccharide binding

A cornucopia of biological activities has been attributed to the IFI16 protein, including cell cycle regulation, tumor suppression, DNA damage signaling, virus sensing, and virus restriction. In addition, aberrant IFI16 expression and release in the extracellular space has been reported in a series of inflammatory conditions. The current hypothesis is that overexpression of the IFI16 protein occurs in tissue compartments where it is not physiologically expressed during inflammation. The ensuing release of the IFI16 protein into the extracellular space may allow it to behave like a damage-associated molecular pattern (DAMP) that signals through the Toll-like receptor 4 (TLR4) triggering inflammation by itself or through interaction with exogenous molecules, e.g., lipopolysaccharide (LPS). Pull down assays and ELISA were used to characterize IFI16 binding activity to LPS. Human and murine cells were used as target cells to define IFI16-induced proinflammatory activity. Co-IP, SPR, and silencing experiments were used to define IFI16 signaling. We show that the IFI16 HINB domain binds to the lipid A moiety of different LPS variants. Treatment of target cells with IFI16 led to increased production of proinflammatory cytokines, which was further enhanced when IFI16 was pre-complexed with sub-toxic doses of high TLR4 agonist LPS but not low agonists. Silencing of TLR4/MD-2 or MyD88 abolished cytokine production. These findings alongside with other in vitro binding experiments indicate that PYRIN domain of IFI16 interacts and signals through TLR4. Collectively, our data provide compelling evidence that: i) IFI16 is a DAMP that triggers inflammation through the TLR4/MD2-MyD88 pathway; and ii) its activity is strongly enhanced upon binding to LPS variants regarded as full TLR4 activators. These data strengthen the notion that extracellular IFI16 functions as DAMP and point to new pathogenic mechanisms involving the crosstalk between IFI16 and subtoxic doses of LPS

Study of Methanol Concentration Effect in Direct Methanol Fuel Cells by Electrochemical Impedance Spectroscopy

This paper analyzes and discusses the performance of a DMFC as a function of methanol aqueous solution concentration fed at the anode, using the Electrochemical Impedance Spectroscopy (EIS). Impedance data obtained were analyzed through the development of an equivalent circuit model. Electrochemical impedance spectroscopy was used to estimate the membrane conductivity and to model the electrochemical behavior of electrodic reactions inside the fuel cell, revealing a worse overall performance by increasing methanol concentration at the anode

A rare case report of hypertrophic cardiomyopathy induced by catecholamine-producing tumor

RATIONALE: Catecholamine-producing tumors are rare, occurring in less than 0.2% of patients with hypertension, but can have relevant cardiovascular morbidity and mortality. PATIENT CONCERNS: A 37-year-old woman presented with a history of dyspnea, chest pain, palpitations, and paroxysmal hypertension. Electrocardiogram, echocardiogram, and cardiac magnetic resonance showed severe LVH with a prevalent involvement of the anterior portion of interventricular septum. Endomyocardial biopsy found severe hypertrophy with disarray of cardiomyocytes and ultrastructural evidence of contraction and necrosis of myocytes. Hormone investigations revealed high values of 24-hours urinary metanephrines. Abdominal computed tomography (CT) showed an enlarged left adrenal gland with a strong uptake of I-metaiodobenzylguanidine at scintigraphy scan. INTERVENTIONS:Thus, the adrenal tumor was surgically removed. OUTCOMES: At follow-up examination, the patient's metanephrines levels were normalized and the transthoracic echocardiogram showed a reduction of LVH. DIAGNOSIS AND LESSONS: We report a rare case of catecholamine-induced cardiomyopathy due to an adrenal adenoma mixed with nodules enriched in epinephrine-types secreting granules

Effect of TiO2 and Al2O3 Addition on the Performance of Chitosan/Phosphotungstic Composite Membranes for Direct Methanol Fuel Cells

: Composite chitosan/phosphotungstic acid (CS/PTA) with the addition of TiO2 and Al2O3 particles were synthesized to be used as proton exchange membranes in direct methanol fuel cells (DMFCs). The influence of fillers was assessed through X-ray diffraction, scanning electron microscopy, thermogravimetric analysis, liquid uptake, ion exchange capacity and methanol permeability measurements. The addition of TiO2 particles into proton exchange membranes led to an increase in crystallinity and a decrease in liquid uptake and methanol permeability with respect to pristine CS/PTA membranes, whilst the effect of the introduction of Al2O3 particles on the characteristics of membranes is almost the opposite. Membranes were successfully tested as proton conductors in a single module DMFC of 1 cm2 as active area, operating at 50 °C fed with 2 M methanol aqueous solution at the anode and oxygen at the cathode. Highest performance was reached by using a membrane with TiO2 (5 wt.%) particles, i.e., a power density of 40 mW cm-2, almost doubling the performance reached by using pristine CS/PTA membrane (i.e., 24 mW cm-2)

Characterization of the Santa Maria del Fiore Cupola construction tools using X-ray fluorescence

This paper presents the characterization of different tools employed in the construction of the Santa Maria del Fiore cathedral in Florence; they are part of the Opera di Santa Maria del Fiore collection and are currently exhibited in the Museo dell’Opera del Duomo. The analyzed objects are turnbuckles, pulleys, three-legged lewises, and pincers; indeed, despite their uniqueness and their importance from the historical point of view, this study is the first one that investigates their alloys composition. Actually, this information can be of great interest for curators to find the best conservation strategies and to have new insights on the production techniques typical of the Renaissance. The study was performed using X-Ray Fluorescence (XRF) in order to identify the materials constituting the objects. Then, XRF spectra were analyzed using chemometric techniques, namely Principal Components Analysis (PCA), in order to investigate possible similarities among different alloys and thus provide new indications to help collocating these tools in a specific historical period

Insulin-like Growth Factor II mRNA-Binding Protein 1 Regulates Pancreatic Cancer Cell Growth through the Surveillance of CDC25A mRNA

: A number of data indicate that the sources of different kinds of PDAC may be discovered at the transcription/transduction stage. RNA metabolism is manipulated at various steps by different RNA-binding proteins (RBPs), and the deregulation or irregular activity of RBPs is known to contribute to tumor promotion and progression. The insulin-like growth factor 2 mRNA-binding protein family (IMPs), and IMP1 in particular, has been linked with a poor prognosis in PDAC patients; however, little is known about its contribution in PDAC carcinogenesis. In this study, we investigated the function of IMP1 in PDAC. To evaluate IMP1 expression and correlation with PDAC prognosis, we utilized several public databases. Using a specific siRNA IMP1, we analyzed cell death and cell cycle progression in PDAC cell lines and 3D spheroids. the role of IMP1 was also evaluated in vivo in a panc-1-derived tumor xenograft murine model. Public data suggest that PDAC patients with higher expression of IMP1 showed poor overall and progression-free survival. IMP1 silencing leads to reduced cell growth in PDAC cells and three-dimensional spheroids. Abrogation of IMP1 in PDAC cells showed lower levels of CDC25A, increased phosphorylation of the cyclin-dependent kinase (CDK)2, and accumulation of PDAC cells in the G1 phase. immunoprecipitation experiments revealed that IMP1 binds CDC25A mRNA, thus controlling cell-cycle progression. Ultimately, we proved that suppression of IMP1 blocked in vivo growth of Panc-1 transferred into immunodeficient mice. Our results indicate that IMP1 drives the PDCA cell cycle and represents a novel strategy for overcoming PDCA cell proliferation

Synthetic Glycolipids as Molecular Vaccine Adjuvants: Mechanism of Action in Human Cells and In Vivo Activity

Modern adjuvants for vaccine formulations are immunostimulating agents whose action is based on the activation of pattern recognition receptors (PRRs) by well-defined ligands to boost innate and adaptive immune responses. Monophosphoryl lipid A (MPLA), a detoxified analogue of lipid A, is a clinically approved adjuvant that stimulates toll-like receptor 4 (TLR4). The synthesis of MPLA poses manufacturing and quality assessment challenges. Bridging this gap, we report here the development and preclinical testing of chemically simplified TLR4 agonists that could sustainably be produced in high purity and on a large scale. Underpinned by computational and biological experiments, we show that synthetic monosaccharide-based molecules (FP compounds) bind to the TLR4/MD-2 dimer with submicromolar affinities stabilizing the active receptor conformation. This results in the activation of MyD88- and TRIF-dependent TLR4 signaling and the NLRP3 inflammasome. FP compounds lack in vivo toxicity and exhibit adjuvant activity by stimulating antibody responses with a potency comparable to MPLA

The small satellite NINA-MITA to study galactic and solar cosmic rays in low-altitude polar orbit

Abstract The satellite MITA, carrying on board the scientific payload NINA-2, was launched on July the 15th, 2000 from the cosmodrome of Plesetsk (Russia) with a Cosmos-3M rocket. The satellite and the payload are currently operating within nominal parameters. NINA-2 is the first scientific payload for the technological flight of the Italian small satellite MITA. The detector used in this mission is identical to the one already flying on the Russian satellite Resurs-O1 n.4 in a 840-km sun-synchronous orbit, but makes use of the extensive computer and telemetry capabilities of MITA bus to improve the active data acquisition time. NINA physics objectives are to study cosmic nuclei from hydrogen to iron in the energy range between 10 MeV/n and 1 GeV/n during the years 2000–2003, that is the solar maximum period. The device is capable of charge identification up to iron with isotope sensitivity up to oxigen. The 87.3 degrees, 460 km altitude polar orbit allows investigations of cosmic rays of solar and galactic origin, so to study long and short term solar transient phenomena, and the study of the trapped radiation at higher geomagnetic cutoff