Scuola/Università e mercato del lavoro: la transizione che non c’è. Quello che raccontano i percorsi di formazione e le esperienze di lavoro dei nostri studenti

La ricerca di nessi di causalità nella analisi delle dinamiche dei mercati del lavoro è sempre ardua, e ancora di più se ci si concentra sui fenomeni specificamente connessi al rapporto tra studio e lavoro, su cui intervengono molteplici variabili difficilmente inquadrabili negli schemi teorici utilizzati per spiegare i comportamenti legati alle scelte (individuali e politiche) che ruotano intorno al lavoro. Di fronte a tale incertezza emerge l’importanza dell’osservazione del dato di realtà per spiegare, comprendere e valutare anche le diverse opzioni di regolazione, che d’altra parte, almeno nel nostro Paese, raramente discendono da una adeguata base di conoscenza empirica dei fenomeni su cui intervengono

Coupling Osmotic Efficacy with Biocompatibility in Peritoneal Dialysis: A Stiff Challenge

Peritoneal dialysis (PD) is a home-based efficacious modality for the replacement of renal function in end-stage kidney failure patients, but it is still under-prescribed. A major limitation is the durability of the dialytic technique. Continuous exposure of the peritoneum to bioincompatible conventional glucose-based solutions is thought to be the main cause of the long-term morpho-functional peritoneal changes that eventually result in ultrafiltration failure. Poor PD solution biocompatibility is primarily related to the high glucose content, which is not only detrimental to the peritoneal membrane but has many potential metabolic side effects. To improve the clinical outcome and prolong the survival of the treatment, PD-related bioincompatibility urgently needs to be overcome. However, combining dialytic and osmotic efficacy with a satisfactory biocompatible profile is proving to be quite difficult. New approaches targeting the composition of the PD solution include the replacement of glucose with other osmotic agents, and the addition of cytoprotective or osmo-metabolic compounds. Other strategies include the infusion of mesenchymal cells or the administration of orally active agents. In the present article, we review the current evidence on efforts to improve the biocompatible and functional performance of PD, focusing on studies performed in vivo (animal models of PD, human subjects on PD)

Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors

Memory and cognitive functions depend on the cerebral levels of cyclic adenosine monophosphate (cAMP), which are regulated by the phosphodiesterase 4 (PDE4) family of enzymes. Selected rolipram-related PDE4 inhibitors, members of the GEBR library, have been shown to increase hippocampal cAMP levels, providing pro-cognitive benefits with a safe pharmacological profile. In a recent SAR investigation involving a subset of GEBR library compounds, we have demonstrated that, depending on length and flexibility, ligands can either adopt a twisted, an extended or a protruding conformation, the latter allowing the ligand to form stabilizing contacts with the regulatory domain of the enzyme. Here, based on those findings, we describe further chemical modifications of the protruding subset of GEBR library inhibitors and their effects on ligand conformation and potency. In particular, we demonstrate that the insertion of a methyl group in the flexible linker region connecting the catechol portion and the basic end of the molecules enhances the ability of the ligand to interact with both the catalytic and the regulatory domains of the enzyme. (C) 2021 Elsevier Masson SAS. All rights reserved

Molecular bases of PDE4D inhibition by GEBR-library compounds

Selected members of the large rolipram-related GEBR family of phosphodiesterase-4 (PDE4) inhibitors have been shown to facilitate long term potentiation (LTP) and improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, little if any structure-activity relationship studies have so far been carried out in order to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone. Furthermore, we assessed the stability of the observed ligand conformations in the context of the intact enzyme using molecular dynamics simulations. The longer and more flexible ligands appear to be capable of forming contacts with the regulatory portion of the enzyme, thus possibly allowing some degree of selectivity between the different PDE4 isoforms

Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion

International audienceCadherins are a large family of transmembrane calcium-dependent cell adhesion proteins that orchestrate adherens junction formation and are crucially involved in tissue morphogenesis. Due to their important role in cancer development and metastasis, cadherins can be considered attractive targets for drug discovery. A recent crystal structure of the complex of a cadherin extracellular portion and a small molecule inhibitor allowed the identification of a druggable interface, thus providing a viable strategy for the design of cadherin dimerization modulators. Here, we report on a structure-based virtual screening approach that led to the identification of efficient and selective modulators of E-cadherin-mediated cell-cell adhesion. Of all the putative inhibitors that were identified and experimentally tested by cell adhesion assays using human pancreatic tumor BxPC-3 cells expressing both E-cadherin and P-cadherin, two compounds turned out to be effective in inhibiting stable cell-cell adhesion at micromolar concentrations. Moreover, at the same concentrations, one of them also showed anti-invasive properties in cell invasion assays. These results will allow further development of novel and selective cadherin-mediated cell-cell adhesion modulators for the treatment of a variety of cadherin-expressing solid tumors and for improving the efficiency of drug delivery across biological barriers

Effects of hyperprolactinemia on the tibial epiphyseal plate of mice treated with sex hormones

The aim of this study was to evaluate the effects of metoclopramide-induced hyperprolactinemia on the tibial epiphyseal plate of hormone-treated oophorectomized mice. For this purpose, 18 animals with intact ovaries were allocated to two groups, M (metoclopramide) and V (vehicle). One hundred and eight oophorectomized animals were allocated to 12 subgroups: Oophx/V (vehicle)Ooph/M (metoclopramide)Oophx/V+E (vehicle+estradiol)Oophx/M+E (metoclopramide+estradiol)Oophx/V+P (vehicle+progesterone)Oophx/M+P (metoclopramide+progesterone)Oophx/V+T (vehicle+testosterone)Oophx/M+T (metoclopramide+testosterone)Oophx/V+E+P (Vehicle+estradiol+progesterone)Oophx/M+E+P (metoclopramide+estradiol+progesterone)Oophx/V+E+P+T (vehicle+estradiol+progesterone+testosterone)Oophx/M+E+P+T (metoclopramide+estradiol+progesterone+testosterone). After a 50-day treatment was performed histomorphometric and immunohistochemical cell death analysis. In the epiphyseal plate of the hyperprolactinemic and/or oophorectomized animals, cell proliferation and bone formation decreased, inducing intensified cell death. In the sex steroid-treated animals, estrogen boosted cell proliferationprogesterone, bone formation and testosterone, both cell proliferation and bone formation. These findings suggest that oophorectomy and hyperprolactinemia changed epiphyseal plate morphology causing cartilage degeneration. Treatment with combined sex steroids may diminish such deleterious effects.Departamento de Morfologia e Genética, Disciplina de Histologia e Biologia Estrutural, Universidade Federal de São Paulo – UNIFESP, São Paulo (SP), BrazilDepartamento de Obstetrícia e Ginecologia, Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo – USP, São Paulo (SP), BrazilDivision of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa (PI), ItalyInstituto de Ciencias da Saude da Universidade Paulista, UNIP, Sao Paulo (SP), BrazilDepartamento de Morfologia e Genética, Disciplina de Histologia e Biologia Estrutural, Universidade Federal de São Paulo – UNIFESP, São Paulo (SP), BrazilWeb of Scienc

Molecular Bases of PDE4D Inhibition by Memory-Enhancing GEBR Library Compounds

Selected members of the large rolipram-related GEBR family of type 4 phosphodiesterase (PDE4) inhibitors have been shown to facilitate long-term potentiation and to improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, few if any structure–activity relationship studies have been performed to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone. Furthermore, we assessed the stability of the observed ligand conformations in the context of the intact enzyme using molecular dynamics simulations. The longer and more flexible ligands appear to be capable of forming contacts with the regulatory portion of the enzyme, thus possibly allowing some degree of selectivity between the different PDE4 isoforms