Growth of Sobolev norms in time dependent semiclassical anharmonic oscillators

We consider the semiclassical Schrödinger equation on Rd given by iħ∂tψ=(− [Formula presented] Δ+Wl(x))ψ+V(t,x)ψ, where Wl is an anharmonic trapping of the form Wl(x)= [Formula presented] ∑j=1dxj2l, l≥2 is an integer and ħ is a semiclassical small parameter. We construct a smooth potential V(t,x), bounded in time with its derivatives, and an initial datum such that the Sobolev norms of the solution grow at a logarithmic speed for all times of order log [Formula presented] ⁡(ħ−1). The proof relies on two ingredients: first we construct an unbounded solution to a forced mechanical anharmonic oscillator, then we exploit semiclassical approximation with coherent states to obtain growth of Sobolev norms for the quantum system which are valid for semiclassical time scales

Synthesis and application of isotope-labeled carnosine in LCMS/MS

Carnosine is an endogenous dipeptide, composed of \u3b2-alanine and L-histidine, and is highly concentrated in skeletal muscle and other excitable tissues. Its physiological roles, based on its biochemical properties, include pH-buffering, metal-ion chelation and antioxidant capacity as well as the ability to protect against the formation of advanced glycation and lipoxidation end-products.1 For these reasons, besides its nutritional ergogenic application in the sport community,2 carnosine supplementation offers a therapeutic potential for the treatment of numerous diseases in which ischemic or oxidative stress is involved.1 Quantitation of carnosine in biological matrices appears to be crucial for these applications, and LC-MS procedures with isotope-labeled internal standards are the state-of-the-art approach for this analytical need.3 The use of these standards allows to account for variations during the complex sample preparation process, different matrix effects between patient samples, and variations in instrument performance. Figure 1 In this work, we present a fast and highly efficient synthetic route to obtain a deuterated carnosine analogue (Figure 1) starting from the trideuterated L-histidine (\u3b1-d1, imidazole-2,5-d2). Moreover, the use of Carnosine-d3 in the validation of a multiple reaction monitoring (MRM) LC-MS/MS method for the analytical quantitation of carnosine in a biological matrix will be reported. References 1. Boldyrev, A. A.; Aldini, G.; Derave, W. Physiol. Rev. 2013, 93, 1803\u20131845. 2. Brisola, G.; Zagatto, A. J. Strength Cond. Res. 2019, 33, 253-282. 3. Stokvis, E.; Rosing, H.; L\uf3pez-L\ue1zaro, L.; Schellens, J. H. M.; Beijnen, J. H. Biomed. Chromatogr. 2004, 18, 400-402

Quantum Poincare Recurrences for Hydrogen Atom in a Microwave Field

We study the time dependence of the ionization probability of Rydberg atoms driven by a microwave field, both in classical and in quantum mechanics. The quantum survival probability follows the classical one up to the Heisenberg time and then decays algebraically as P(t) ~ 1/t. This decay law derives from the exponentially long times required to escape from some region of the phase space, due to tunneling and localization effects. We also provide parameter values which should allow to observe such decay in laboratory experiments.Comment: revtex, 4 pages, 4 figure

Design, synthesis and preliminary biological evaluation of 3-cyclopropyl-4-phenoxy-1H-pyrazole derivatives as small molecular ligands of RAGE

Receptor for advanced glycation end products (RAGE) is a multiligand receptor belonging to the immunoglobulin superfamily and plays a crucial role in the development of many human diseases such as neurodegenerative diseases, diabetes, cardiovascular diseases and cancer.1 RAGE is involved in a number of cell processes such as neuroinflammation, apoptosis, proliferation and autophagy, and therefore it is of considerable interest as a promising drug target for innovative therapeutic approaches. It consists of an extracellular region, a short hydrophobic transmembrane spanning region, and a highly charged amino acid cytoplasmatic tail. The extracellular region contains a signal peptide, followed by one N-terminal V-type immunoglobulin domain and two C-type (C1 and C2) immunoglobulin domains.2 RAGE is able to interact with a large number of pro-inflammatory and regulatory molecules, such as advanced glycation end-products (AGEs), quinolinic acid, beta amyloid (A\u3b2), high mobility group box 1 (HMGB1), S100/calgranulin family proteins.3,4 However, due to the structural heterogeneity of these endogenous ligands, little is known about the key pharmacophore elements for ligand-RAGE interaction and the specific mode of binding. On these grounds, we aimed at designing new small molecules able to bind the VC1 extracellular domains of RAGE, in order to clarify the structural features that account for RAGE affinity and activation, and to identify new drug-like compounds. Following a process of structural simplification of known pyrazole-5-carboxamide RAGE ligands,1 we planned a set of novel derivatives characterized by a variously functionalized 3-cyclopropyl-4-phenoxy-1H-pyrazole scaffold (Figure 1). The design and synthesis of the new putative RAGE ligands will be presented and discussed, together with the results of their in vitro screening by means of a surface plasmon resonance (SPR)-based assay to estimate their binding ability to the RAGE extracellular domain. References 1. Bongarzone S., Savickas V., Luzi F., Gee A. D. J. Med. Chem. 2017, 60, 7213-7232. 2. Hudson B. I., Carter A. M., Harja E., Kalea A. Z., Arriero M., Yang H., Grant P. J., Schmidt A. M. FASEB J. 2008, 22, 1572-1580. 3. Xue J., Rai V., Singer D., Chabierski S., Xie J., Reverdatto S., Burz D. S., Schmidt A. M., Hoffmann R., Shekhtman A. Structure 2011, 19, 722\u2013732. 4. Koch M., Chitayat S., Dattilo B. M., Schiefner A., Diez J., Chazin W. J., Fritz, G. Structure 2010, 18, 1342-1352

INTEGRATED DATING OF THE CONSTRUCTION AND RESTORATION OF THE MODENA CATHEDRAL VAULTS (NORTHERN ITALY): PRELIMINARY RESULTS

After the last damaging earthquake in 2012, an anti-seismic reinforcement project of the cathedral of Modena was designed giving us the opportunity to investigate and date the building materials. Radiocarbon (14C), optically stimulated luminescence (OSL), and thermoluminescence (TL) dating techniques were performed on the vaults with the aim to (1) clarify the construction timing, (2) define the history of the restorations, and (3) explore the possible correlation of the main restoration works to the earthquake chronology deduced from the historic catalog. Preliminary results show that medieval older bricks were reused for most of the original construction. Only lime and non-gypsum mortar was used for the original construction in the 15th century and for later repair of damage caused by earthquakes in the 16th and 17th centuries. Gypsum mortar was used for later repair in the 18th century. The results show much stronger damage due to earthquakes than previously thought

Clathrin light chain A drives selective myosin VI recruitment to clathrin-coated pits under membrane tension

Clathrin light chains (CLCa and CLCb) are major constituents of clathrin-coated vesicles. Unique functions for these evolutionary conserved paralogs remain elusive, and their role in clathrin-mediated endocytosis in mammalian cells is debated. Here, we find and structurally characterize a direct and selective interaction between CLCa and the long isoform of the actin motor protein myosin VI, which is expressed exclusively in highly polarized tissues. Using genetically-reconstituted Caco-2 cysts as proxy for polarized epithelia, we provide evidence for coordinated action of myosin VI and CLCa at the apical surface where these proteins are essential for fission of clathrin-coated pits. We further find that myosin VI and Huntingtin-interacting protein 1-related protein (Hip1R) are mutually exclusive interactors with CLCa, and suggest a model for the sequential function of myosin VI and Hip1R in actin-mediated clathrin-coated vesicle budding

Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis for catalytic priming

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Inhibition of Ubc13-mediated ubiquitination by GPS2 regulates multiple stages of B cell development

Non-proteolytic ubiquitin signaling mediated by Lys63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNF signaling and lipid metabolism in the adipose tissue through modulation of Lys63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells