Lo spirito e le idee. L'organizzazione della cooperazione intellettuale nella Società delle Nazioni

Il presente studio ricostruisce le tappe che hanno condotto alla costituzione di un’organizzazione internazionale per la cooperazione intellettuale in seno alla Società delle Nazioni. Nello specifico il tema approfondisce le origini e la nascita della Commissione internazionale per la cooperazione intellettuale della Società delle Nazioni (1922), accompagnate dalla creazione di strutture tecniche di supporto come l’Istituto internazionale di cooperazione intellettuale (Parigi); l’Istituto per l’unificazione del diritto privato (Roma); l’Istituto per la cinematografia educativa (Roma). L’opera delle sottocommissioni, tra cui quella per le relazioni interuniversitarie, con relative politiche di mobilità docenti-studenti nell’ambito di specifici progetti, corsi universitari, borse di studio, congressi internazionali. L’impegno dell’Italia nella promozione della cooperazione intellettuale, con un’attenzione particolare rivolta all’esperienza della regia Università di Roma che, soprattutto a metà degli anni Venti, ha ospitato eventi internazionali di rilievo tra cui importanti conferenze di esponenti stranieri della cultura e della politica

Lo spirito e le idee. L'organizzazione della cooperazione intellettuale nella Società delle Nazioni

Il presente studio ricostruisce le tappe che hanno condotto alla costituzione di un’organizzazione internazionale per la cooperazione intellettuale in seno alla Società delle Nazioni. Nello specifico il tema approfondisce le origini e la nascita della Commissione internazionale per la cooperazione intellettuale della Società delle Nazioni (1922), accompagnate dalla creazione di strutture tecniche di supporto come l’Istituto internazionale di cooperazione intellettuale (Parigi); l’Istituto per l’unificazione del diritto privato (Roma); l’Istituto per la cinematografia educativa (Roma). L’opera delle sottocommissioni, tra cui quella per le relazioni interuniversitarie, con relative politiche di mobilità docenti-studenti nell’ambito di specifici progetti, corsi universitari, borse di studio, congressi internazionali. L’impegno dell’Italia nella promozione della cooperazione intellettuale, con un’attenzione particolare rivolta all’esperienza della regia Università di Roma che, soprattutto a metà degli anni Venti, ha ospitato eventi internazionali di rilievo tra cui importanti conferenze di esponenti stranieri della cultura e della politica

Differences in genotype and virulence among four multidrug-resistant <i>Streptococcus pneumoniae</i> isolates belonging to the PMEN1 clone

We report on the comparative genomics and characterization of the virulence phenotypes of four &lt;i&gt;S. pneumoniae&lt;/i&gt; strains that belong to the multidrug resistant clone PMEN1 (Spain&lt;sup&gt;23F&lt;/sup&gt; ST81). Strains SV35-T23 and SV36-T3 were recovered in 1996 from the nasopharynx of patients at an AIDS hospice in New York. Strain SV36-T3 expressed capsule type 3 which is unusual for this clone and represents the product of an in vivo capsular switch event. A third PMEN1 isolate - PN4595-T23 - was recovered in 1996 from the nasopharynx of a child attending day care in Portugal, and a fourth strain - ATCC700669 - was originally isolated from a patient with pneumococcal disease in Spain in 1984. We compared the genomes among four PMEN1 strains and 47 previously sequenced pneumococcal isolates for gene possession differences and allelic variations within core genes. In contrast to the 47 strains - representing a variety of clonal types - the four PMEN1 strains grouped closely together, demonstrating high genomic conservation within this lineage relative to the rest of the species. In the four PMEN1 strains allelic and gene possession differences were clustered into 18 genomic regions including the capsule, the blp bacteriocins, erythromycin resistance, the MM1-2008 prophage and multiple cell wall anchored proteins. In spite of their genomic similarity, the high resolution chinchilla model was able to detect variations in virulence properties of the PMEN1 strains highlighting how small genic or allelic variation can lead to significant changes in pathogenicity and making this set of strains ideal for the identification of novel virulence determinant

An 111In-labelled bis-ruthenium(ii) dipyridophenazine theranostic complex: mismatch DNA binding and selective radiotoxicity towards MMR-deficient cancer cells

Theranostic radionuclides that emit Auger electrons (AE) can generate highly localised DNA damage and the accompanying gamma ray emission can be used for single-photon emission computed tomography (SPECT) imaging. Mismatched DNA base pairs (mismatches) are DNA lesions that are abundant in cells deficient in MMR (mismatch mediated repair) proteins. This form of genetic instability is prevalent in the MMR-deficient subset of colorectal cancers and is a potential target for AE radiotherapeutics. Herein we report the synthesis of a mismatch DNA binding bis-ruthenium(II) dipyridophenazine (dppz) complex that can be radiolabelled with the Auger electron emitting radionuclide indium-111 (111In). Greater stabilisation accompanied by enhanced MLCT (metal to ligand charge-transfer) luminescence of both the bis-Ru(dppz) chelator and non-radioactive indium-loaded complex was observed in the presence of a TT mismatch-containing duplex compared to matched DNA. The radioactive construct [111In]In-bisRu(dppz) ([111In][In-2]4+) targets cell nuclei and is radiotoxic towards MMR-deficient human colorectal cancer cells showing substantially less detrimental effects in a paired cell line with restored MMR function. Additional cell line studies revealed that [111In][In-2]4+ is preferentially radiotoxic towards MMR-deficient colorectal cancer cells accompanied by increased DNA damage due to 111In decay. The biodistribution of [111In][In-2]4+ in live mice was demonstrated using SPECT. These results illustrate how a Ru(II) polypyridyl complex can incorporate mismatch DNA binding and radiometal chelation in a single molecule, generating a DNA-targeting AE radiopharmaceutical that displays selective radiotoxicity towards MMR-deficient cancer cells and is compatible with whole organism SPECT imaging

Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo

Uncontrolled self-association is a major challenge in the exploitation of proteins as therapeutics. Here we describe the development of a structural proteomics approach to identify the amino acids responsible for aberrant self-association of monoclonal antibodies and the design of a variant with reduced aggregation and increased serum persistence in vivo. We show that the human monoclonal antibody, MEDI1912, selected against nerve growth factor binds with picomolar affinity, but undergoes reversible self-association and has a poor pharmacokinetic profile in both rat and cynomolgus monkeys. Using hydrogen/deuterium exchange and cross-linking-mass spectrometry we map the residues responsible for self-association of MEDI1912 and show that disruption of the self-interaction interface by three mutations enhances its biophysical properties and serum persistence, whilst maintaining high affinity and potency. Immunohistochemistry suggests that this is achieved via reduction of non-specific tissue binding. The strategy developed represents a powerful and generic approach to improve the properties of therapeutic proteins

Effects of Anti-VEGF on Predicted Antibody Biodistribution: Roles of Vascular Volume, Interstitial Volume, and Blood Flow

BACKGROUND: The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences. METHODOLOGY/PRINCIPAL FINDINGS: Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naïve or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p>0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p>0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (>25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naïve versus anti-VEGF-administered mice. CONCLUSIONS/SIGNIFICANCE: These observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF

Questions choisies de chevauchement des compétences et responsabilités internationales en droit international public et droit international privé face à la "boat migration méditerranéenne" et à la protection des migrants

The analysis deals with the operation of Treaties and EU laws in determining international jurisdiction in the fields of both Public International Law, including human rights, and Private International Law regarding the implementation of ‘protective measures’, towards the international protection of migrant children and adults. The relevance of different interrelated fields and Treaties within international law towards the determination of State competence and responsibility dealing with boat migration movements towards the protection of migrants may leave complex grey areas potentially jeopardising the certainty and predictability of law. The analysis does not aim to solve general issues of jurisdiction after the arrival of migrants in the territory of a State where an asylum request has already been filed, but it refers to the ‘overlapping’ of international rules of competence and responsibility to determine State ‘protective’ jurisdiction in order to identify which State, or States, should initially deal with asylum requests. In this article, it is advocated for better clarity in the implementation of the – interdependent – mechanisms provided by different Treaties dealing with the determination of international jurisdiction inherent to the international protection of ‘boat migrants’. Therefore, the analysis will focus specifically on the international rules of competence and responsibility applicable to the specific issue of boat migration, where particular attention is given to asylum seekers given their underprivileged vulnerable protection