The dielectric constant of PbTe at 4.2 K and ν~\tilde ν=84.15 cm−1^{-1}, 96.97 cm−1^{-1}, 103.60 cm−1^{-1}

The dielectric constant of a PbTe epitaxial layer has been measured by surface wave spectroscopy using an optically pumped far-infrared laser and the technique of attenuated total reflection

INHIBITION OF HERPES SIMPLEX VIRUS TYPE 1 INFECTION BY SOME SELECTED ANTITUMOR TITANIUM(III)-BASED COORDINATION COMPOUNDS

ABSTRAC

The significance of macrophage polarization subtypes for animal models of tissue fibrosis and human fibrotic diseases.

The systemic and organ-specific human fibrotic disorders collectively represent one of the most serious health problems world-wide causing a large proportion of the total world population mortality. The molecular pathways involved in their pathogenesis are complex and despite intensive investigations have not been fully elucidated. Whereas chronic inflammatory cell infiltration is universally present in fibrotic lesions, the central role of monocytes and macrophages as regulators of inflammation and fibrosis has only recently become apparent. However, the precise mechanisms involved in the contribution of monocytes/macrophages to the initiation, establishment, or progression of the fibrotic process remain largely unknown. Several monocyte and macrophage subpopulations have been identified, with certain phenotypes promoting inflammation whereas others display profibrotic effects. Given the unmet need for effective treatments for fibroproliferative diseases and the crucial regulatory role of monocyte/macrophage subpopulations in fibrogenesis, the development of therapeutic strategies that target specific monocyte/macrophage subpopulations has become increasingly attractive. We will provide here an overview of the current understanding of the role of monocyte/macrophage phenotype subpopulations in animal models of tissue fibrosis and in various systemic and organ-specific human fibrotic diseases. Furthermore, we will discuss recent approaches to the design of effective anti-fibrotic therapeutic interventions by targeting the phenotypic differences identified between the various monocyte and macrophage subpopulations

CD28 between tolerance and autoimmunity: The side effects of animal models [version 1; referees: 2 approved]

Regulation of immune responses is critical for ensuring pathogen clearance and for preventing reaction against self-antigens. Failure or breakdown of immunological tolerance results in autoimmunity. CD28 is an important co-stimulatory receptor expressed on T cells that, upon specific ligand binding, delivers signals essential for full T-cell activation and for the development and homeostasis of suppressive regulatory T cells. Many in vivo mouse models have been used for understanding the role of CD28 in the maintenance of immune homeostasis, thus leading to the development of CD28 signaling modulators that have been approved for the treatment of some autoimmune diseases. Despite all of this progress, a deeper understanding of the differences between the mouse and human receptor is required to allow a safe translation of pre-clinical studies in efficient therapies. In this review, we discuss the role of CD28 in tolerance and autoimmunity and the clinical efficacy of drugs that block or enhance CD28 signaling, by highlighting the success and failure of pre-clinical studies, when translated to humans

Interleukin-8 Is Activated in Patients with Chronic Liver Diseases and Associated with Hepatic Macrophage Accumulation in Human Liver Fibrosis

BACKGROUND: Interleukin-8 (IL-8, CXCL8) is a potent chemoattractant for neutrophils and contributes to acute liver inflammation. Much less is known about IL-8 in chronic liver diseases (CLD), but elevated levels were reported from alcoholic and hepatitis C-related CLD. We investigated the regulation of IL-8, its receptors CXCR1 and CXCR2 and possible IL-8 responding cells in CLD patients. METHODOLOGY: Serum IL-8 levels were measured in CLD patients (n = 200) and healthy controls (n = 141). Intrahepatic IL-8, CXCR1 and CXCR2 gene expression was quantified from liver samples (n = 41), alongside immunohistochemical neutrophil (MPO) and macrophage (CD68) stainings. CXCR1 and CXCR2 expression was analyzed on purified monocytes from patients (n = 111) and controls (n = 31). In vitro analyses explored IL-8 secretion by different leukocyte subsets. PRINCIPAL FINDINGS: IL-8 serum levels were significantly increased in CLD patients, especially in end-stage cirrhosis. Interestingly, patients with cholestatic diseases exhibited highest IL-8 serum concentrations. IL-8 correlated with liver function, inflammatory cytokines and non-invasive fibrosis markers. Intrahepatically, IL-8 and CXCR1 expression were strongly up-regulated. However, intrahepatic IL-8 could only be associated to neutrophil infiltration in patients with primary biliary cirrhosis (PBC). In non-cholestatic cirrhosis, increased IL-8 and CXCR1 levels were associated with hepatic macrophage accumulation. In line, CXCR1, but not CXCR2 or CXCR3, expression was increased on circulating monocytes from cirrhotic patients. Moreover, monocyte-derived macrophages from CLD patients, especially the non-classical CD16⁺ subtype, displayed enhanced IL-8 secretion in vitro. CONCLUSIONS: IL-8 is strongly activated in CLD, thus likely contributing to hepatic inflammation. Our study suggests a novel role of IL-8 for recruitment and activation of hepatic macrophages via CXCR1 in human liver cirrhosis

Plasma membrane dynamics and tetrameric organisation of ABCG2 transporters in mammalian cells revealed by single particle imaging techniques

ABCG2 is one of three human ATP binding cassette (ABC) transporters involved in the export from cells of a chemically and structurally diverse range of compounds. This multidrug efflux capability, together with a broad tissue distribution in the body, means that ABCG2 exerts a range of effects on normal physiology such as kidney urate transport, as well as contributing towards the pharmacokinetic profiles of many exogenous drugs. The primary sequence of ABCG2 contains only half the number of domains required for a functioning ABC transporter and so it must oligomerise in order to function, yet its oligomeric state in intact cell membranes remains uncharacterized. We have analysed ABCG2 in living cell membranes using a combination of fluorescence correlation spectroscopy, photon counting histogram analysis, and stepwise photobleaching to demonstrate a predominantly tetrameric structure for ABCG2 in the presence or absence of transport substrates. These results provide the essential basis for exploring pharmacological manipulation of oligomeric state as a strategy to modulate ABCG2 activity in future selective therapeutics

Epithelial response to IFN-γ promotes SARS-CoV-2 infection

SARS-CoV-2, the agent that causes COVID-19, invades epithelial cells, including those of the respiratory and gastrointestinal mucosa, using angiotensin-converting enzyme-2 (ACE2) as a receptor. Subsequent inflammation can promote rapid virus clearance, but severe cases of COVID-19 are characterized by an inefficient immune response that fails to clear the infection. Using primary epithelial organoids from human colon, we explored how the central antiviral mediator IFN-γ, which is elevated in COVID-19, affects epithelial cell differentiation, ACE2 expression, and susceptibility to infection with SARS-CoV-2. In mouse and human colon, ACE2 is mainly expressed by surface enterocytes. Inducing enterocyte differentiation in organoid culture resulted in increased ACE2 production. IFN-γ treatment promoted differentiation into mature KRT20+ enterocytes expressing high levels of ACE2, increased susceptibility to SARS-CoV-2 infection and resulted in enhanced virus production in infected cells. Similarly, infection-induced epithelial interferon signaling promoted enterocyte maturation and enhanced ACE2 expression. We here reveal a mechanism by which IFN-γ-driven inflammatory responses induce a vulnerable epithelial state with robust replication of SARS-CoV-2, which may have an impact on disease outcome and virus transmission

R-spondin-YAP axis promotes gastric oxyntic gland regeneration and Helicobacter pylori-associated metaplasia in mice

The stomach corpus epithelium is organized into anatomical units that consist of glands and pits and contain different specialized secretory cells. Acute and chronic injury of the corpus are associated with characteristic changes of cellular differentiation and proliferation. Processes that control cellular differentiation under homeostatic conditions and upon injury are not well understood. R-spondin 3 (Rspo3) is a Wnt signalling enhancer secreted by gastric stromal cells, which controls stem cell homeostasis in different organs. Here we investigated the function of Rspo3 in the corpus during homeostasis, acute injury, and H. pylori infection.Using organoid culture and conditional mouse models, we demonstrate that RSPO3 is a critical driver of secretory cell differentiation in the corpus gland towards parietal and chief cells, while its absence promoted pit cell differentiation. Acute loss of chief and parietal cells induced by high dose tamoxifen - or merely the depletion of LGR5+ chief cells - caused an upregulation of RSPO3 expression, which was required for the initiation of a coordinated regenerative response via the activation of yes-associated protein (YAP) signaling. This response enabled a rapid recovery of the injured secretory gland cells. However, in the context of chronic H. pylori infection, the R-spondin-driven regeneraton was maintained long-term, promoing severe glandular hyperproliferation and the development of premalignant metaplasia

Soluble urokinase plasminogen activator receptor levels are associated with severity of fibrosis in patients with primary sclerosing cholangitis

The soluble urokinase-type plasminogen activator receptor (suPAR) has evolved as a useful biomarker for different entities of chronic liver disease. However, its role in patients with primary sclerosing cholangitis (PSC) is obscure. We analyzed plasma levels of suPAR in 84 patients with PSC and compared them to 68 patients with inflammatory bowel disease (IBD) without PSC and to 40 healthy controls. Results are correlated with clinical records. suPAR concentrations were elevated in patients with PSC compared to patients with IBD only and to healthy controls ((p) (&)lt; 0.001). Elevated suPAR levels were associated with the presence of liver cirrhosis ((p) (&)lt; 0.001) and signs of portal hypertension ((p) (&)lt; 0.001). suPAR revealed a high accuracy for the discrimination of the presence of liver cirrhosis comparable to previously validated noninvasive fibrosis markers (area under the curve (AUC) 0.802 (95%CI: 0.702-0.902)). Further, we demonstrated that suPAR levels may indicate the presence of acute cholangitis episodes ((p) (&)lt; 0.001). Finally, despite the high proportion of PSC patients with IBD, presence of IBD and its disease activity did not influence circulating suPAR levels. suPAR represents a previously unrecognized biomarker for diagnosis and liver cirrhosis detection in patients with PSC. However, it does not appear to be confounded by intestinal inflammation in the context of IBD