Study of the RET receptor dysfunctions caused by mutations associated with human neoplastic disorders and developmental diseases

The ret proto-oncogene encodes a membrane spanning glycoprotein which is a member of the receptor tyrosine kinase family (Hanks et al. 1988). RET is the signaling component of multi-subunit receptor complexes for the GDNF of family ligands, including GDNF, neurturin, artemin and persephin. The binding components of these receptor complexes are glycosyl-phosphatidylinositol (GPI)-membrane anchored molecules, known as GDNF family receptor α (GFRαs). Four different GFRαs (GFRα1–4) dictate ligand specificity. Germline point mutations of RET are responsible for the inheritance of MEN2 (Multiple Endocrine Neoplasia type 2) cancer syndromes which are usually divided into three different clinical subtypes: MEN2A, MEN2B and FMTC (familial medullary thyroid carcinoma), which are all autosomal dominant cancer syndromes. Inactivating mutations of RET cause an impaired development of the enteric nervous system which is responsible for the Congenital megacolon or Hirschprung's disease (HSCR). The aim of my work was to study the expression of different RET mutants in order to highlight their biological role in diverse cellular context. In particular, we focused on gain of function cysteine mutations that are responsible for medullary thyroid carcinoma (MTC) by causing covalent RET dimerisation, leading to ligand-independent activation of its tyrosine kinase. In this context, the association of Cys609 and Cys620 activating mutations with HSCR is still an unresolved paradox. To address this issue, we have developed a transgenic model for human diseases (specifically, Multiple Endocrine Neoplasia type 2 and Hirschsprung disease) through the insertion of a gain and loss of function RET mutation, the RETC620R in the mouse genome. We have also studied the in vitro effects of a tyrosine kinase inhibitor PP1, which we propose could represent a potential treatment strategy and merits further testing, using in vivo models such as the one we have generated

Niobic acid nanoparticle catalysts for the aqueous phase transformation of glucose and fructose to 5-hydroxymethylfurfural

A family of bulk and SBA-15 supported peroxo niobic acid sols were prepared by peptisation of niobic acid precipitates with H2O2 as heterogeneous catalysts for aqueous phase glucose and fructose conversion to 5-hydroxymethylfurfural (5-HMF). Niobic acid nanoparticles possess a high density of Brønsted and Lewis acid sites, conferring good activity towards glucose and fructose conversion, albeit with modest 5-HMF yields under mild reaction conditions (100 °C). Thermally-induced niobia crystallisation suppresses solid acidity and activity. Nanoparticulate niobic acid dispersed over SBA-15 exhibits pure Brønsted acidity and an enhanced Turnover Frequency for fructose dehydration

Front-end Electronics and Optimal Ganging Schemes for Single Photon Detection with Large Arrays of SiPMs in Liquid Argon

The operation of large arrays of silicon photomultipliers (SiPM) in tanks of noble liquids requires low noise, low power front-end amplifiers, able to operate reliably in the cryogenic environment. A suitable amplifier needs to be paired with a proper SiPM ganging scheme, meaning the series/parallel combination of SiPMs at its input. This paper presents a simple model to estimate the ganging scheme that gives the best signal to noise ratio once the basic electrical characteristics of the SiPM and amplifier are known. To prove the validity of the model, we used an amplifier based on discrete components, which achieves a white voltage noise in the 0.25-0.37 nV/$\surd$Hz range at liquid nitrogen temperature, while drawing 2-5 mW of power. Combined with the optimal ganging scheme obtained with the model, the amplifier demonstrated excellent single photon sensitivity up to 96 6x6 mm$^2$ SiPMs (total area 34.6 cm$^2$, S/N $\simeq$ 8-11). The measured results are in a good match with calculated values, predicting the possibility to achieve a clear separation of photoelectron peaks also with larger areas