Endothelial cell activation by SARS-CoV-2 spike S1 protein: A crosstalk between endothelium and innate immune cells

Background. Emerging evidences suggest that in severe COVID-19, multi-organ failure is associated with a hyperinflammatory state (the so-called “cytokine storm”) in combination with the development of a prothrombotic state. The central role of endothelial dysfunction in the pathogenesis of the disease is to date accepted, but the precise mechanisms underlying the associated coagulopathy remain unclear. Whether the alterations in vascular homeostasis directly depend upon the SARS-CoV-2 infection of endothelial cells or, rather, occur secondarily to the activation of the inflammatory response is still a matter of debate. Here, we address the effect of the SARS-CoV-2 spike S1 protein on the activation of human lung microvascular endothelial cells (HLMVEC). In particular, the existence of an endothelium-macrophage crosstalk in the response to the spike protein has been explored. Methods and Results. The effect of the spike protein is addressed in human lung microvascular endothelial cells (HLMVEC), either directly or after incubation with a conditioned medium (CM) of human monocyte-derived macrophages (MDM) previously activated by the spike S1 protein (CM-MDM). Both MDM and HLMVEC are activated in response to the S1 protein, with an increased expression of pro-inflammatory mediators. However, when HLMVEC are exposed to CM-MDM, an enhanced cell activation occurs in terms of the expression of adhesion molecules, pro-coagulant markers, and chemokines. Under this experimental condition, ICAM-1 and VCAM-1, the chemokines CXCL8/IL-8, CCL2/MCP1, and CXCL10/IP-10 as well as the protein tissue factor (TF) are markedly induced. Instead, a decrease of thrombomodulin (THBD) is observed. Conclusion. Our data suggest that pro-inflammatory mediators released by spike-activated macrophages amplify the activation of endothelial cells, likely contributing to the impairment of vascular integrity and to the development of a pro-coagulative endothelium

Macroscopic quantum tunnelling in spin filter ferromagnetic Josephson junctions.

The interfacial coupling of two materials with different ordered phases, such as a superconductor (S) and a ferromagnet (F), is driving new fundamental physics and innovative applications. For example, the creation of spin-filter Josephson junctions and the demonstration of triplet supercurrents have suggested the potential of a dissipationless version of spintronics based on unconventional superconductivity. Here we demonstrate evidence for active quantum applications of S-F-S junctions, through the observation of macroscopic quantum tunnelling in Josephson junctions with GdN ferromagnetic insulator barriers. We show a clear transition from thermal to quantum regime at a crossover temperature of about 100 mK at zero magnetic field in junctions, which present clear signatures of unconventional superconductivity. Following previous demonstration of passive S-F-S phase shifters in a phase qubit, our result paves the way to the active use of spin filter Josephson systems in quantum hybrid circuits.We acknowledge financial support from COST Action MP1201 [NanoSC COST], by Progetto FIRB HybridNanoDev RBFR1236VV001 and by Regione Campania through POR Campania FSE 2007/2013, progetto MASTRI CUP B25B09000010007.This is the final version. It was first published by NPG at http://www.nature.com/ncomms/2015/150609/ncomms8376/full/ncomms8376.html#abstract

Electrodynamics of Josephson junctions containing strong ferromagnets

Triplet supercurrents in multilayer ferromagnetic Josephson junctions with misaligned magnetization can penetrate thicker ferromagnetic barriers compared to the singlet component. Although the static properties of these junctions have been extensively studied, the dynamic characteristics remain largely unexplored. Here we report a comprehensive electrodynamic characterization of multilayer ferromagnetic Josephson junctions composed of Co and Ho. By measuring the temperature-dependent current-voltage characteristics and the switching current distributions down to 0.3 K, we show that phase dynamics of junctions with triplet supercurrents exhibits long (in terms of proximity) junction behavior and moderately damped dynamics with renormalized capacitance and resistance. This unconventional behavior possibly provides a different way to dynamically detect triplets. Our results show new theoretical models are required to fully understand the phase dynamics of triplet Josephson junctions for applications in superconducting spintronics.DM, RC, FT would like to thank NANOCOHYBRI project (Cost Action CA 16218). NB acknowledges funding from the British Council through UKIERI programme and Loughborough University. MGB acknowledges funding from EPSRC Programme Grant EP/N017242/1

Macroscopic quantum phenomena in Josephson structures

The Josephson effect is a probe of unparalleled performances in the study of a variety of macroscopic quantum phenomena. In the present article an overview of important achievements and challenging trends is given referring, in particular, to macroscopic quantum tunneling and energy level quantization. The attention is mainly addressed to high-TC superconducting structures and recent investigations concerning nanostructures

High number of circulating CD34+ cells in patients with myelophthisis.

Hematopoietic Stem Cells High number of circulating CD34+ cells in patients with myelophthisis Six patients with bone marrow micrometastases from solid cancers presented with increased numbers of circulating CD34+ cells; the CD34+ cell counts were very high in some cases. By contrast, no patient with metastatic cancer without bone marrow involvement showed raised numbers of circulating hemopoietic progenitors. haematologica 2005; 90:976-977 (http:/

Post-transplant cerebral toxoplasmosis diagnosed by magnetic resonance imaging.

Cerebral toxoplasmosis is a rare late complication in allogeneic bone marrow transplanted patients. Neuroradiological findings may suggest the correct diagnosis. We report a patient in whom cerebral magnetic resonance imaging (MRI) showed a lesion characteristic of toxoplasmosis. Anti- toxoplasma treatment led to clinical and radiological improvement. MRI seems to be a valid tool for detection and follow-up of cerebral toxoplasmosis

Interplay between Static and Dynamic Properties of Semifluxons in YBa2Cu3O7−δ 0−π Josephson Junctions

We have investigated the static and dynamic properties of long YBa2Cu3O7-delta 0-pi Josephson junctions and compared them with those of conventional 0 junctions. Scanning SQUID microscope imaging has revealed the presence of a semifluxon at the phase discontinuity point in 0-pi Josephson junctions. Zero field steps have been detected in the current-voltage characteristics of all junctions. Comparison with simulation allows us to attribute these steps to fluxons traveling in the junction for conventional 0 junctions and to fluxon-semifluxon interactions in the case of 0-pi Josephson junctions

Desmopressin Stimulates Nitric Oxide Production in Human Lung Microvascular Endothelial Cells

Desmopressin (dDAVP) is the best characterized analogue of vasopressin, the endocrine regulator of water balance endowed with potent vasoconstrictive effects. Despite the use of dDAVP in clinical practice, ranging from the treatment of nephrogenic diabetes insipidus to bleeding disorders, much remains to be understood about the impact of the drug on endothelial phenotype. The aim of this study was, thus, to evaluate the effects of desmopressin on the viability and function of human pulmonary microvascular endothelial cells (HLMVECs). The results obtained demonstrate that the vasopressor had no cytotoxic effect on the endothelium; similarly, no sign of endothelial activation was induced by dDAVP, indicated by the lack of effect on the expression of inflammatory cytokines and adhesion molecules. Conversely, the drug significantly stimulated the production of nitric oxide (NO) and the expression of the inducible isoform of nitric oxide synthase, NOS2/iNOS. Since the intracellular level of cAMP also increased, we can hypothesize that NO release is consequent to the activation of the vasopressin receptor 2 (V2R)/guanylate cyclase (Gs)/cAMP axis. Given the multifaceted role of NOS2-deriving NO for many physio-pathological conditions, the meanings of these findings in HLMVECs appears intriguing and deserves to be further addressed

Monocytes from infliximab-resistant patients with Crohn's disease exhibit a disordered cytokine profile

Crohn's disease (CD) is a chronic inflammatory disorder characterized by immune response dysregulation. Tumor necrosis factor-alpha (TNF alpha) is a key cytokine in the pathogenesis of CD, as indicated by the efficacy of anti-TNF-alpha therapy with infliximab (IFX). However, approximately 30-40% of CD patients fail to respond to IFX with still unclear underlying mechanisms. This study compares the inflammatory phenotype of monocytes from CD patients, who respond or non-respond to IFX. Under basal conditions, the mRNA for the cytokines TNF alpha, IL-23, IL-1 beta and the chemokines CXCL8/IL-8, CCL5/RANTES and CCL2/MCP-1 was up-regulated in monocytes from non-responders than responders. The expression of the same cytokines and CCL2/MCP-1 was higher in non-responders also upon LPS treatment. Moreover, higher secretion of TNF alpha, IL-1 beta, IFN gamma and IL-2 proteins occurred in the supernatants of LPS-treated non-responders cells. Resistance to IFX in CD may result from a transcriptional dysregulation of circulating monocytes, leading to hyperactivation of pro-inflammatory pathways. Monocytes' cytokine profile may thus represent a predictive marker of response to IFX. Monocytes were isolated from blood samples of 19 CD patients (11 responders, 8 non-responders) and incubated with or without LPS. Cytokine profiles were assessed by RT-qPCR and, in the supernatants, by ELISA assay