Protective Effects of Human and Mouse Soluble Scavenger-Like CD6 Lymphocyte Receptor in a Lethal Model of Polymicrobial Sepsis.

Sepsis still constitutes an unmet clinical need, which could benefit from novel adjunctive strategies to conventional antibiotic therapy. The soluble form of the scavenger-like human CD6 lymphocyte receptor (shCD6) binds to key pathogenic components from Gram-positive and -negative bacteria and shows time- and dose-dependent efficacy in mouse models of monobacterial sepsis. The objective of the present work was to demonstrate the effectiveness of infusing mouse and human sCD6 by different systemic routes, either alone or as adjunctive therapy to gold standard antibiotics, in a lethal model of polymicrobial sepsis.

Free Nano-Object Ramsey Interferometry for Large Quantum Superpositions.

We propose an interferometric scheme based on an untrapped nano-object subjected to gravity. The motion of the center of mass (c.m.

Design and Synthesis of New Cell Penetrating Peptides: Diffusion and Distribution Inside the Cornea.

The role of cell penetrating peptides (CPPs) has been challenged in recent years for drug delivery to ocular tissues for the targeting of both anterior and posterior segments. The enhancement of trans-corneal transport for anterior segment targeting is a very important issue possibly leading to important outcomes on efficacy and to the opportunity of topical administration of molecules with unfavorable penetration properties. The aim of the present work was the design and synthesis of new CPPs, deriving from the structure of PEP-1 peptide.

Identification of an indol-based derivative as potent and selective varicella zoster virus (VZV) inhibitor.

We report the synthesis and antiviral activity of a new family of non-nucleoside antivirals, derived from the indole nucleus. Modifications of this template through Mannich and Friedel-Crafts reactions, coupled with nucleophilic displacement and reductive aminations led to 23 final derivatives, which were pharmacologically tested. Tryptamine derivative 17a was found to have a selective inhibitory activity against human varicella zoster virus (VZV) replication in vitro, being inactive against a variety of other DNA and RNA viruses.

Prevalent role of the insulin receptor isoform A in the regulation of hepatic glycogen metabolism in hepatocytes and in mice.

Aims/hypothesis: In the postprandial state, the liver regulates glucose homeostasis by glucose uptake and conversion to glycogen and lipids. Glucose and insulin signalling finely regulate glycogen synthesis through several mechanisms. Glucose uptake in hepatocytes is favoured by the insulin receptor isoform A (IRA), rather than isoform B (IRB).

Angiogenin Defines Heterogeneity at the Core of the Hematopoietic Niche.

Successful hematopoietic regeneration demands preservation of stemness while enabling expansion and differentiation into blood lineages. Now, Silberstein et al. (2016) and Goncalves et al.

Insulin receptor isoform A ameliorates long-term glucose intolerance in diabetic mice.

Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion. Previous in vitro data showed that insulin receptor isoform A, but not B, favours basal glucose uptake through its specific association with endogenous GLUT1/2 in murine hepatocytes and beta cells. With this background, we hypothesized that hepatic expression of insulin receptor isoform A in a mouse model of type 2 diabetes could potentially increase the glucose uptake of these cells, decreasing the hyperglycaemia and therefore ameliorating the diabetic phenotype.

Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis.

The etiopathogenesis of autoimmune hepatitis (AIH) remains poorly understood. In this study, we sought to develop an animal model of human AIH to gain insight into the immunological mechanisms driving this condition. C57BL/6 mice were i.

Complementary Effects of Interleukin-15 and Alpha Interferon Induce Immunity in Hepatitis B Virus Transgenic Mice.

Unlabelled: In chronic hepatitis B (CHB), failure to control hepatitis B virus (HBV) is associated with T cell dysfunction. HBV transgenic mice mirror many features of the human disease, including T cell unresponsiveness, and thus represent an appropriate model in which to test novel therapeutic strategies. To date, the tolerant state of CD8(+) T cells in these animals could be altered only by strong immunogens or by immunization with HBV antigen-pulsed dendritic cells; however, the effectors induced were unable to suppress viral gene expression or replication.

Development and Identification of a Novel Anti-HIV-1 Peptide Derived by Modification of the N-Terminal Domain of HIV-1 Integrase.

The viral enzyme integrase (IN) is essential for the replication of human immunodeficiency virus type 1 (HIV-1) and represents an important target for the development of new antiretroviral drugs. In this study, we focused on the N-terminal domain (NTD), which is mainly involved into protein oligomerization process, for the development and synthesis of a library of overlapping peptide sequences, with specific length and specific offset covering the entire native protein sequence NTD IN 1-50. The most potent fragment, VVAKEIVAH (peptide 18), which includes a His residue instead of the natural Ser at position 39, inhibits the HIV-1 IN activity with an IC50 value of 4.

Identification of IFN-γ-producing T cells as the main mediators of the side effects associated to mouse interleukin-15 sustained exposure.

Unlabelled: Interleukin-15 (IL-15) is a cell growth-factor that regulates lymphocyte function and homeostasis. Its strong immunostimulatory activity coupled with an apparent lack of toxicity makes IL-15 an exciting candidate for cancer therapy, somehow limited by its short half-life in circulation. To increase IL-15 bioavailability we constructed a recombinant adeno-associated vector expressing murine IL-15 (AAV-mIL15) in the liver.

A RIG-I 2CARD-MAVS200 Chimeric Protein Reconstitutes IFN-β Induction and Antiviral Response in Models Deficient in Type I IFN Response.

RIG-I-like receptors (RLRs) are cellular sensor proteins that detect certain RNA species produced during viral infections. RLRs activate a signaling cascade that results in the production of IFN-β as well as several other cytokines with antiviral and proinflammatory activities. We explored the potential of different constructs based on RLRs to induce the IFN-β pathway and create an antiviral state in type I IFN-unresponsive models.

Liver-directed gene therapy of chronic hepadnavirus infection using interferon alpha tethered to apolipoprotein A-I.

Background & Aims: Current hepatitis B virus (HBV) management is challenging as treatment with nucleos(t)ide analogues needs to be maintained indefinitely and because interferon (IFN)-α therapy is associated with considerable toxicity. Previously, we showed that linking IFNα to apolipoprotein A-I generates a molecule (IA) with distinct antiviral and immunostimulatory activities which lacks the hematological toxicity of IFNα.

Methods: Here, we analyse the antiviral potential of an adeno-associated vector encoding IFNα fused to apolipoprotein A-I (AAV-IA) in comparison to a vector encoding only IFNα (AAV-IFN) in two animal models of chronic hepadnavirus infection.

Chronic exposure to IFNα drives medullar lymphopoiesis towards T-cell differentiation in mice.

Interferon-α is a potent antiviral agent and a vigorous adjuvant in the induction of T-cell responses but its use is limited by hematologic toxicity. Interferon-α alters hematopoietic stem cell dormancy and impairs myelocytic and erythrocytic/megakaryocytic differentiation from hematopoietic progenitors. However, the effect of chronic interferon-α exposure on hematopoietic precursors has still not been well characterized.

Regenerative medicine for the treatment of Teno-desmic injuries of the equine. A series of 150 horses treated with platelet-derived growth factors.

Background/aim: The aim of the present study was to evaluate the safety and the clinical outcome of platelet-rich plasma for the treatment of teno-desmic injures in competition horses.

Patients And Methods: From January 2009 to December 2011, 150 sport horses suffering from teno-desmic injuries were treated with no-gelled platelet-concentrate.

Results: No horse showed any major adverse reaction as a result of the procedure.

Insulin-like growth factor 2 reverses memory and synaptic deficits in APP transgenic mice.

Insulin-like growth factor 2 (IGF2) was recently found to play a critical role in memory consolidation in rats and mice, and hippocampal or systemic administration of recombinant IGF2 enhances memory. Here, using a gene therapy-based approach with adeno-associated virus (AAV), we show that IGF2 overexpression in the hippocampus of aged wild-type mice enhances memory and promotes dendritic spine formation. Furthermore, we report that IGF2 expression decreases in the hippocampus of patients with Alzheimer's disease, and this leads us to hypothesize that increased IGF2 levels may be beneficial for treating the disease.

Splicing regulator SLU7 is essential for maintaining liver homeostasis.

A precise equilibrium between cellular differentiation and proliferation is fundamental for tissue homeostasis. Maintaining this balance is particularly important for the liver, a highly differentiated organ with systemic metabolic functions that is endowed with unparalleled regenerative potential. Carcinogenesis in the liver develops as the result of hepatocellular de-differentiation and uncontrolled proliferation.

The use of platelet-rich plasma gel in patients with mixed tumour undergoing superficial parotidectomy: a randomized study.

Background/aim: Salivary gland tumors are mostly benign tumors. Whether a more conservative surgical approach at greater risk of recurrence, or a more radical intervention with an increased risk of facial paralysis is warranted is still under discussion. Our study addresses the opportunity for improving surgical outcome by employing platelet-rich plasma (PRP) gel at the surgical site.

Matter-wave interferometry of a levitated thermal nano-oscillator induced and probed by a spin.

We show how the interference between spatially separated states of the center of mass (c.m.) of a mesoscopic harmonic oscillator can be evidenced by coupling it to a spin and performing solely spin manipulations and measurements (Ramsey interferometry).

IL12-mediated liver inflammation reduces the formation of AAV transcriptionally active forms but has no effect over preexisting AAV transgene expression.

Recombinant adenoassociated viral vectors (rAAV) have proven to be excellent candidates for gene therapy clinical applications. Recent results showed that cellular immunity to AAV represents a major challenge facing the clinical use of systemic administration of these vectors. Interestingly, no preclinical animal model has previously fully reproduced the clinical findings.

Regenerative Surgery for the Definitive Repair of a Vasculitic Nonhealing Ulcer Using Platelet-derived Growth Factors and Noncultured Autologous Cell Suspension.

Vasculitic ulcers are caused by numerous disorders and may be chronic if not well treated. Various modalities of treatment, both medical and surgical, are available. We describe the case of a 63-year-old patient with a vasculitic ulcer treated with platelet-derived growth factors and noncultured autologous cell suspension collected by an innovative single-use device (ReCell).

Nuclear α1-antichymotrypsin promotes chromatin condensation and inhibits proliferation of human hepatocellular carcinoma cells.

Background & Aims: α1-Antichymotrypsin (α1-ACT), a member of the serpin family (SERPINA3), is an acute-phase protein secreted by hepatocytes in response to cytokines such as oncostatin M. α1-ACT is a protease inhibitor thought to limit tissue damage produced by excessive inflammation-associated proteolysis. However, α1-ACT also is detected in the nuclei of cells, where its activities are unknown.

Clinical Heterogeneity in two patients with Noonan-like Syndrome associated with the same SHOC2 mutation.

Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM #607721) has been recently related to the invariant c.4A > G missense change in SHOC2. It is characterized by features reminiscent of Noonan syndrome.

Fetal vibroacoustic stimulation in computerized cardiotocographic analysis: the role of short-term variability and approximate entropy.

The aim of this study was to evaluate the impact of vibroacoustic stimulation (VAS) on computerized cardiotocography short-term variability (STV) and approximate entropy (ApEn) in both low- and high-risk pregnancies. VAS was performed on 121 high- and 95 low-risk pregnancies after 10 minutes of continuous quiet, while their FHR parameters were monitored and recorded by cCTG analysis. Fetal heart rate was recorded using a computer-assisted equipment.