Comparison of the structure-function of five newly members of the calcin family

Calcins are a group of scorpion toxin peptides specifically binding to ryanodine receptors (RyRs) with high affinity, and have the ability to activate and stabilize RyR in a long-lasting subconductance state. Five newly calcins synthesized compounds exhibit typical structural characteristics of a specific family through chemical synthesis and virtual analysis. As the calcins from the same species, Petersiicalcin1 and Petersiicalcin2, Jendekicalcin2 and Jendekicalcin3, have only one residue difference. Both Petersiicalcin1 and Petersiicalcin2 exhibited different affinities in stimulating [3H]ryanodine binding, but the residue mutation resulted in a 2.7 folds difference. Other calcins also exhibited a stimulatory effect on [3H]ryanodine binding to RyR1, however, their affinities were significantly lower than that of Petersiiicalcin1 and Petersiiicalcin2. The channel domain of RyR1 was found to be capable of binding with the basic residues of these calcins, which also exhibited interactions with the S6 helices on RyR1. Dynamic simulations were conducted for Petersiicalcin1 and Petersiicalcin2, which demonstrated their ability to form a highly stable conformation and resulting in an asymmetric tetramer structure of RyR1. The discovery of five newly calcins further enriches the diversity of the natural calcin family, which provides more native peptides for the structure-function analysis between calcin and RyRs

Geant4: A game changer in high energy physics and related applicative fields

Geant4 is an object-oriented toolkit for the simulation of the passage of particles through matter. Its development was initially motivated by the requirements of physics experiments at high energy hadron colliders under construction in the last decade of the 20th century. Since its release in 1998, it has been exploited in many different applicative fields, including space science, nuclear physics, medical physics and archaeology. Its valuable support to scientific discovery is demonstrated by more than 16000 citations received in the past 25 years, including notable citations for main discoveries in different fields. This accomplishment shows that well designed software plays a key role in enabling scientific advancement. In this paper we discuss the key principles and the innovative decisions at the basis of Geant4, which made it a game changer in high energy physics and related fields, and outline some considerations regarding future directions

Sorafenib and Metronomic Capecitabine in Child-Pugh B patients with advanced HCC: A real-life comparison with best supportive care

Background and aims: The efficacy of systemic therapy for unresectable advanced hepatocellular carcinoma (aHCC) has not been proven in patients with Child-Pugh (C-P) B cirrhosis. Nevertheless, in real-world these patients are treated both with tyrosine kinase inhibitors (TKIs) and with metronomic capecitabine (MC). This study aimed to compare sorafenib and MC outcomes versus best supportive care (BSC) in C-P B patients. Method: Between 2008 and 2020, among 774 C-P B patients with aHCC not amenable/responsive to locoregional treatments, 410 underwent sorafenib, 62 MC, and 302 BSC. The propensity score matching method was used to correct the baseline unbalanced prognostic factors. Results: In the unmatched population, median OS was 9.7 months in patients treated with sorafenib, 8.0 with MC, and 3.9 months with BSC. In sorafenib vs. BSC-matched patients (135 couples), median OS was 7.3 (4.9-9.6) vs. 3.9 (2.6-5.2) months (p<0.001). ECOG-Performance Status, tumor size, macrovascular invasion, AFP, treatment-naive, and sorafenib were independent predictors of survival. In MC vs. BSC-matched patients (40 couples), median OS was 9.0 (0.2-17.8) vs.3.0 (2.2-3.8) months (p<0.001). Median OS did not differ (p = 0.283) in sorafenib vs. MC-matched patients (55 couples). Conclusion: C-P B patients with aHCC undergoing BSC have poor survival. Both Sorafenib and MC treatment improve their prognosis

Accordi e disaccordi sulla buona fede oggettiva

l dovere di buona fede contrattuale ha avuto nel corso del tempo un andamento non lineare. Prima ignorata dalla giurisprudenza, in seguito è divenuta uno strumento fondamentale per integrare il contratto e per regolare l'esercizio dei poteri attribuiti alle parti del contratto. Anche di recente il confronto fra una decisione della Suprema Corte di Cassazione e una decisione della Corte Costituzionale italiana rendono evidente che di fronte a casi diversi per materia, ma simili per quanto concerne il ragionamento giuridico da porre a base della decisione, si possono registrare approcci più o meno convincenti