highlight on the reactivity of phseznx

The first bench stable selenolates, PhSeZnHalides have been synthesized through a completely atom economy oxidative insertion of the elemental zinc on the commercially available PhSeHalides. These reagents showed the characteristic nucleophilic reactivity which will be reviewed in this report. All of the reactions were strongly accelerated when effected in water suspension. Alkyl, aryl, vinyl and acyl substitutions, ring-opening reactions of epoxides and aziridines and Michael type addition will be described including the role of the zinc in the control of the chemoselectivity and stereoselectivity

ultrasound mediated synthesis of ecofriendly zinc chalcogenates in on water conditions

Nucleophilic Selenium is a convenient strategy for the functionalization of organic substrates having electrophilic character. Among all the methods developed for their preparation, the reduction of the corresponding diselenides represents the most versatile procedure. Using these protocols selenolates were usually prepared in situ using atom expensive reducing agents such as NaBH4, LiAlH4, or metals (Na, Li) or metal hydride (NaH). We recently reported that zinc can be efficiently used to reduce Se-halogen bond affording bench stable regents such as PhSeZnCl that showed a strong rate acceleration in "on water" conditions for a number of reactions: alkyl, aryl, vinyl and acyl substitutions, ring-opening reactions of epoxides and aziridines and Michael type addition. We report now the use of Ultrasound irradiation for the oxidative insertion of zinc into Se-Se bond and the formation of the nucleophilic reagent PhSeZnSePh as a green strategy to avoid the use of useless halogen and increase the atom economy of the selenenylating species

Rapamycin Monotherapy in Patients With Type 1 Diabetes Modifies CD4+CD25+FOXP3+ Regulatory T-Cells

OBJECTIVE—Rapamycin is an immunosuppressive drug currently used to prevent graft rejection in humans, which is considered permissive for tolerance induction. Rapamycin allows expansion of both murine and human naturally occurring CD4+CD25+FOXP3+ T regulatory cells (nTregs), which are pivotal for the induction and maintenance of peripheral tolerance. Preclinical murine models have shown that rapamycin enhances nTreg proliferation and regulatory function also in vivo. Objective of this study was to assess whether rapamycin has in vivo effects on human nTregs

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a-/- mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, \u3b3-synuclein and phospho-tau proteins in Vps13a-/- basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a-/- Lyn-/- showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a-/- hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients

Concentration and activity of the soluble form of the interleukin-7 receptor α in type I diabetes identifies an interplay between hyperglycemia and immune function.

Soluble IL-7 receptor alpha (sCD127) is implicated in the pathogenesis of autoimmune diseases. We show that serum sCD127 concentrations are increased at the onset of type 1 diabetes (n=390) as compared to concentrations in age-matched islet autoantibody negative first degree relatives of patients (n=392; P=0.00001). sCD127 Concentration in patients was influenced by islet autoantibody status (P=0.003) and genotype of the rs6897932 single nucleotide polymorphism within theIL-7RA gene (P=0.006). Release of sCD127 in vitro was strongly up-regulated by activation of T lymphocytes, and affected by exposure to cytokines. sCD127 bound IL-7 and was antagonistic to IL-7 signaling and IL-7 mediated T cell proliferation suggesting a regulatory feedback mechanism on T cell expansion. Remarkably, high glucose led to a glycated form of sCD127 that was ineffective as an IL-7 antagonist. The finding of glycated sCD127 in the circulation of patients at onset of type 1 diabetes suggested that physiological regulation of IL-7 mediated T cell survival and expansion by sCD127 may be compromised in type 1 diabetes. The findings indicate that genetic, immunologic and metabolic factors contribute to a dysregulation of the IL-7/IL-7 receptor pathway in type 1 diabetes, and identify a novel hyperglycemia mediated interference of immune regulatory networks

Water and Aqueous Mixtures as Convenient Alternative Media for Organoselenium Chemistry

Even if water is the natural environment for bioorganic reactions, its use in organic chemistry is often severely limited by the high insolubility of the organic derivatives. In this review, we introduce some examples of the use of water to perform organoselenium chemistry. We mainly discuss the advantages of this medium when the recyclability is demonstrated and when the water can control the selectivity of a reaction or enhance the reaction rate

Activation of islet autoreactive naive T cells in infants is influenced by homeostatic mechanisms and antigen presenting capacity.

Islet autoimmunity precedes type 1 diabetes onset. We previously found that islet autoimmunity rarely starts before age six months but reaches its highest incidence already at around 1 year of age. We now examine whether homeostatic expansion and immune competence changes seen in a maturating immune system may account for this marked variation in islet autoimmunity risk in the first year of life. We found naïve proinsulin- and GAD65-responsive T cells in cord blood of healthy newborns, with highest responses observed in children with type 1 diabetes susceptible HLA-DRB1/DQB1 genotypes. Homeostatic expansion characteristics with increased IL-7 concentrations and enhanced T cell responsiveness to IL-7 were observed throughout the first year of life. However, the ability of antigen-presenting cells to activate naïve T cells was compromised at birth, and cord blood monocytes had low surface expression of CD40 and HLA class II. In contrast, antigen presentation and expression of these molecules had reached competent adult levels by the high incidence age of 8 months. We propose that temporal changes in islet autoimmunity seroconversion in infants are a consequence of the changing balance between homeostatic drive and antigen presentation competence. These findings are relevant for early prevention of type 1 diabetes

Beta cell function during rapamycin monotherapy in long-term type 1 diabetes

Type 1 diabetes is considered non-reversible at end-stage disease when there is no measurable insulin production. However, there are indications that insulin-producing beta cells could be present or return if autoimmunity could be controlled. We therefore sought to determine whether immunosuppression therapy can reinstate beta cell function in patients with long-term type 1 diabetes. We examined pancreatic beta cell function in 22 patients with long-term type 1 diabetes (median disease duration 27 years), who had been receiving rapamycin monotherapy (0.1 mg/kg; target trough levels 8-10 ng/ml; 26-314 days) as pre-conditioning for islet transplantation. As control, beta cell function was measured in 14 patients (median disease duration 17 years) who were waiting for an islet transplant without rapamycin pre-conditioning. Fasting C-peptide increased from 0.076 nmol/l (C-peptide responders). Exogenous insulin requirement decreased from 0.64 U/kg daily (IQR 0.56-0.72) to 0.57 U/kg (IQR 0.45-0.70; p = 0.01), but this reduction was significant only in the 12C-peptide-responsive patients. Rapamycin monotherapy was also associated with a decrease in insulin antibody titre (median decrease 110 to 35.9 U/ml; p < 0.001) and fasting serum proinsulin (median decrease 0.51 to 0.28 pmol/l; p = 0.001). All variables remained unchanged in the 14 control patients