Characterizing Sterol Defect Suppressors Uncovers a Novel Transcriptional Signaling Pathway Regulating Zymosterol Biosynthesis

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The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation

Adequate termination of an immune response is as important as the induction of an appropriate response. CD46, a regulator of complement activity, promotes T cell activation and differentiation towards a regulatory Tr1 phenotype. This Tr1 differentiation pathway is defective in patients with MS, asthma and rheumatoid arthritis, underlying its importance in controlling T cell function and the need to understand its regulatory mechanisms. CD46 has two cytoplasmic tails, Cyt1 and Cyt2, derived from alternative splicing, which are co-expressed in all nucleated human cells. The regulation of their expression and precise functions in regulating human T cell activation has not been fully elucidated.Here, we first report the novel role of CD46 in terminating T cell activation. Second, we demonstrate that its functions as an activator and inhibitor of T cell responses are mediated through the temporal processing of its cytoplasmic tails. Cyt1 processing is required to turn T cell activation on, while processing of Cyt2 switches T cell activation off, as demonstrated by proliferation, CD25 expression and cytokine secretion. Both tails require processing by Presenilin/γSecretase (P/γS) to exert these functions. This was confirmed by expressing wild-type Cyt1 and Cyt2 tails and uncleavable mutant tails in primary T cells. The role of CD46 tails was also demonstrated with T cells expressing CD19 ectodomain-CD46 C-Terminal Fragment (CTF) fusions, which allowed specific triggering of each tail individually.We conclude that CD46 acts as a molecular rheostat to control human T cell activation through the regulation of processing of its cytoplasmic tails

Progress Towards High Performance, Steady-state Spherical Torus

Research on the Spherical Torus (or Spherical Tokamak) is being pursued to explore the scientific benefits of modifying the field line structure from that in more moderate aspect-ratio devices, such as the conventional tokamak. The Spherical Tours (ST) experiments are being conducted in various U.S. research facilities including the MA-class National Spherical Torus Experiment (NSTX) at Princeton, and three medium-size ST research facilities: Pegasus at University of Wisconsin, HIT-II at University of Washington, and CDX-U at Princeton. In the context of the fusion energy development path being formulated in the U.S., an ST-based Component Test Facility (CTF) and, ultimately a Demo device, are being discussed. For these, it is essential to develop high-performance, steady-state operational scenarios. The relevant scientific issues are energy confinement, MHD stability at high beta (B), noninductive sustainment, ohmic-solenoid-free start-up, and power and particle handling. In the confinement area, the NSTX experiments have shown that the confinement can be up to 50% better than the ITER-98-pby2 H-mode scaling, consistent with the requirements for an ST-based CTF and Demo. In NSTX, CTF-relevant average toroidal beta values bT of up to 35% with the near unity central betaT have been obtained. NSTX will be exploring advanced regimes where bT up to 40% can be sustained through active stabilization of resistive wall modes. To date, the most successful technique for noninductive sustainment in NSTX is the high beta-poloidal regime, where discharges with a high noninductive fraction ({approx}60% bootstrap current + neutral-beam-injected current drive) were sustained over the resistive skin time. Research on radio-frequency-based heating and current drive utilizing HHFW (High Harmonic Fast Wave) and EBW (Electron Bernstein Wave) is also pursued on NSTX, Pegasus, and CDX-U. For noninductive start-up, the Coaxial Helicity Injection (CHI), developed in HIT/HIT-II, has been adopted on NSTX to test the method up to Ip {approx} 500 kA. In parallel, start-up using radio-frequency current drive and only external poloidal field coils are being developed on NSTX. The area of power and particle handling is expected to be challenging because of the higher power density expected in the ST relative to that in conventional aspect-ratio tokamaks. Due to its promise for power and particle handling, liquid lithium is being studied in CDX-U as a potential plasma-facing surface for a fusion reactor

Scuola Innovativa Secondaria di Secondo Grado “G. Galilei”, Spadafora (ME)

Il progetto per la Scuola Innovativa Secondaria di Secondo Grado “G. Galilei”, sita a Spadafora (ME), si è collocato al terzo posto nell’ambito del concorso di progettazione in due gradi, Missione 2 – Componente 3 – Investimento 1.1 “Costruzione di nuove scuole mediante sostituzione di edifici” del Piano nazionale di ripresa e resilienza (PNRR), finanziato dall’Unione europea – Next Generation EU (CIG 9297593875, Codice 2° grado A3IA0V3S). Il progetto sposa l’idea di legame con la natura come motore e veicolo di rigenerazione diretta dell’attenzione, per arricchire gli spazi didattici con l’impatto positivo che deriva dalla fruizione di spazi verdi dislocati tra gli ambienti scolastici. Infatti, l’impianto planimetrico della scuola fonde la forma ibrida ad “L” con una ampia corte interna: il fronte più esteso e permeabile si colloca parallelo alla direttrice costiera, mentre il sistema di “green square” arricchisce il lotto conferendo alla scuola anche un valore civico oltre che didattico. Grande attenzione viene data alla sostenibilità, che percorre il progetto nei suoi molteplici aspetti, dalla scelta dei sistemi tecnologici (utilizzo della terra cruda), impiantistici (utilizzo di FER con FV, eolico, PdC) fino ai materiali e agli arredi, atossici, riciclati e riciclabili, con packaging studiati per ridurre gli imballaggi. L’impiantistica della scuola è tale da renderla energeticamente attiva. Soluzioni passive vengono combinate a soluzioni attive. I differenti componenti hanno trasmittanze molto basse, mentre gli involucri opachi realizzati in terra cruda consentono di raggiungere elevate prestazioni termo-igrometriche smorzando efficacemente l’onda termica. L’orientamento, gli aggetti della grande copertura, le schermature della corte interna sagomate in funzione dei percorsi solari e le tende interne, minimizzano i fenomeni di abbagliamento e i carichi termici. La corte interna alberata permette di sfruttare la ventilazione naturale per effetto camino. La riduzione dei carichi termici minimizza la potenza dei generatori (riduzione del 52% dei fabbisogni rispetto all’edificio di riferimento) e garantisce fabbisogni globali di energia primaria inferiori a 75 kWh/(anno m2). Il consumo di energia primaria EPgl,tot è di oltre il 55% inferiore alla soglia fissata per i requisiti degli edifici nZEB (EPgl,tot, lim) mentre l’EPgl,nren è inferiore del 90%. Si è deciso di abbinare al sistema fotovoltaico il microeolico per sfruttare la ventosità del luogo. I due sistemi (installati 58 kWp) generano, su base annua, circa 89.000 kWh superando i fabbisogni richiesti dall’edificio. A ciò si unisce uno studio approfondito sulla contemporaneità tra produzione ed uso dell’energia che implementa un sistema di accumulo a batterie per i cicli di breve durata ed uno di produzione di idrogeno integrato da fuelcell/microcogenerazione per i cicli più lunghi. Così si realizza una scuola che può essere del tutto autosufficiente. Inoltre, viene garantito un comfort ottimale e un controllo distinto per ogni singolo spazio; ciò permette anche di rispondere ai criteri previsti dalla certificazione LEED Platinum. Grazie ad un BMS auto adattativo il controllo può essere gestito sia dall’utenza, con le limitazioni previste dai principi dell’adaptive comfort, che da remoto. Inoltre, l’impianto sfrutta la geotermia attraverso un sistema geotermico ad acqua di falda, associato a sistemi radianti a bassa temperatura, mentre la qualità dell’aria è garantita dalla ventilazione meccanica a portata variabile con possibilità di free cooling notturno (a riduzione ulteriore dei carichi per raffrescamento) e recuperatori ad elevatissima efficienza (>90%), controllo di CO2 e sanificazione continua a ionizzazione. Il progetto garantisce anche il comfort luminoso, grazie a sistemi a LED “blue-hazard-free”. L’illuminazione, invece, è controllata da un sistema DALI per l’integrazione con la luce naturale e la creazione di diversi scenari di luce nelle aule

Access of the substrate to the active site of squalene and oxidosqualene cyclases: comparative inhibition, site-directed mutagenesis and homology-modelling studies

Abstract Substrate access to the active-site cavity of squalene-hopene cyclase from Alicyclobacillus acidocaldarious and lanosterol synthase [OSC (oxidosqualene cyclase)] from Saccharomyces cerevisiae was studied by an inhibition, mutagenesis and homology-modelling approach. Crystal structure and homology modelling indicate that both enzymes possess a narrow constriction that separates an entrance lipophilic channel from the active-site cavity. The role of the constriction as a mobile gate that permits substrate passage was investigated by experiments in which critically located Cys residues, either present in native protein or inserted by site-directed mutagenesis, were labelled with specifically designed thiol-reacting molecules. Some amino acid residues of the yeast enzyme, selected on the basis of sequence alignment and a homology model, were individually replaced by residues bearing side chains of different lengths, charges or hydrophobicities. In some of these mutants, substitution severely reduced enzymatic activity and thermal stability. Homology modelling revealed that in these mutants some critical stabilizing interactions could no longer occur. The possible critical role of entrance channel and constriction in specific substrate recognition by eukaryotic OSC is discussed. In cholesterol and ergosterol biosynthesis, the most significant structural alteration occurring along the pathway, that is generation of the steroid nucleus after assembly of the triterpene backbone, is brought about by lanosterol synthase. Lanosterol synthase belongs to the large family of OSCs (oxidosqualene cyclases), eukaryotic enzymes that catalyse the cyclization of 2,3-oxidosqualene into different cyclic compounds: lanosterol alone in non-photosynthetic organisms (fungi and mammals), cycloartenol, precursor of phytosterols and other tetra-and pentacyclic compounds in plants Prokaryotes possess an enzyme similar to OSCs: SHC (squalene-hopene cyclase) that converts squalene into hopene or diplopterol, pentacyclic precursors of hopanoids Squalene and OSCs catalyse among the most fascinating and complex monoenzymatic reaction

"A factory for a future": Iveruno new school

Here, school is intended as a relational space open to the territory and designed to host public activities accessible to the entire urban community. The new school of Inveruno is, in this sense, the new civic center of the city, a representative building and a place of cultural integration. The school is designed to offer flexible and permeable spaces where innovative education becomes the key principle to provide students with adequate skills. Therefore, the school offers in equal measure individual spaces for education and study, spaces for exploration where students may experiment and as a group practice the skills they have acquired, and group spaces where they may present and discuss the results of their work with the school and city community. Just as important are the open space between the buildings and the central square designed to host open-air events that involve the entire school community