Macroscopic Quantum Tunneling and the "cosmic" Josephson effect

We discuss the possible influence of a cosmic magnetic field on the macroscopic quantum tunneling process associated, in a cosmological context, to the decay of the "false vacuum." We find a close analogy with the effects of an external magnetic field applied to a Josephson junction in the context of low-temperature/high-temperature superconducting devices.Comment: 4 pages, 1 pdf figure. Added references and an inset in Fig. 1, results unchanged. To appear in Phys. Rev. D (Brief Report

Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal non-malignant hematological disease characterized by the expansion of hematopoietic stem cells (HSCs) and progeny mature cells, whose surfaces lack all the proteins linked through the glycosyl-phosphatidyl inositol anchor. This defect arises from an acquired somatic mutation in the X-linked phosphatidylinositol glycan class A gene, with subsequent clonal expansion of the mutated HSCs as a result of a concomitant, likely immune-mediated, selective pressure. The disease is characterized by complement-mediated chronic intravascular hemolysis, resulting in hemolytic anemia and hemosiderinuria; capricious exacerbations lead to recurrent gross hemoglobinuria. Additional cardinal manifestations of PNH are a variable degree of bone marrow failure and an intrinsic propensity to thromboembolic events. The disease is markedly invalidating, with chronic symptoms requiring supportive therapy – usually including periodical transfusions; possible life-threatening complications may also ensue. The biology of PNH has been progressively elucidated in the past few years, but therapeutic strategies remained unsatisfactory for decades, the only exception being stem cell transplantation, which is restricted to selected patients and retains significant morbidity and mortality. Recently, a biological agent to treat PNH has been developed – the terminal complement inhibitor eculizumab – which has been tested in a number of clinical trials, with exciting results. All the data from worldwide clinical trials confirm that eculizumab radically modifies the symptoms, the biology, and the natural history of PNH, strongly improving the quality of life of PNH patients

Cysteine Residues Contribute to the Dimerization and Enzymatic Activity of Human Nuclear dUTP Nucleotidohydrolase (nDut).

dUTPase is an enzyme found in all organisms that have thymine as a constituent of DNA. Through evolution, humans have two major isoforms of dUTPase: a mitochondrial (mDut) and a nuclear (nDut) isoform. The nuclear isoform of dUTPase is a 164-amino-acids-long protein containing three cysteine residues. nDut\u27s starting methionine is post-translationally cleaved, leaving four unique amino acids on its amino-terminus including one cysteine residue (C3). These are not present in the mitochondrial isoform (mDut). Using mass spectrometry analyses of recombinant dUTPase constructs, we have discovered an intermolecular disulfide bridge between cysteine-3 of each nDut monomer. We have found that these two residues stabilize a dimer configuration that is unique to the nDut isoform. We have also uncovered an intramolecular disulfide linkage between cysteine residues C78 and C134, stabilizing the monomeric state of the protein. Of note, both disulfide linkages are essential for nDut\u27s enzymatic activity and dimeric formation can be augmented by the addition of the oxidizing agent, hydrogen peroxide to cells. Analyses of endogenous cellular dUTPase proteins confirm these differences between the two isoforms. We observed that mDut appears to be a mixture of monomer, dimer, and trimer conformations, as well as higher-order subunit interactions. In contrast, nDut appeared to exist only in monomeric and dimeric forms. Cysteine-based redox switches have recently emerged as a distinct class of post-translational modification. In light of this and our results, we propose that nDut possesses a redox switch whereby cysteine interactions regulate nDut\u27s dUTP-hydrolyzing activity

Intravenous itraconazole for treating invasive pulmonary aspergillosis in neutropenic patients with acute lymphoblastic leukemia.

Aspergillus infection is associated with a high mortality rate in immunocompromised hosts; more effective drugs for this infection are needed. Oral itraconazole has been studied in neutropenic fungus-infected patients. Using a novel formulation (intravenous) of itraconazole, we successfully treated severe necrotizing pneumonias due to Aspergillus species occurring during a postchemotherapy prolonged aplastic phase in two patients with acute lymphoblastic leukemia

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

Factors Influencing the Need for and Access to IVF Treatment

Infertility is defined as the inability for a couple to become pregnant after 12 months of regular unprotected sexual intercourse. Infertility can stem from an issue with the female reproductive tract, the male reproductive tract, or both. Individuals struggling with infertility seek medical assistance for a successful reproductive course. However, there are many aspects outside of pathology that may encourage or deter an individual to elect for medical assistance such as in vitro fertilization (IVF). In vitro fertilization is defined as a medical procedure in which an egg is fertilized outside the body. The increased usage of IVF demonstrates the need for equitable access to IVF care. The purpose of this literature review is to consider all the factors and challenges involved in one’s decision to utilize IVF

Observation of a New Fluxon Resonant Mechanism in Annular Josephson Tunnel Structures

A novel dynamical state has been observed in the dynamics of a perdurbed sine-Gordon system. This resonant state, has been experimentally observed as a singularity in the dc current voltage characteristic of an annular Josephson tunnel junction, excited in the presence of a magnetic field. With this respect, it can be assimilated to self-resonances known as Fiske steps. Differently from these, however, we demonstrate, on the basis of numerical simulations, that its detailed dynamics involves rotating fluxon pairs, a mechanism associated, so far, to self-resonances known as zero-field steps.Comment: 4 pages, 2 figures, submitted to Physical Review Letter

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

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:/