Use of functional imaging across clinical phases in CNS drug development

The use of novel brain biomarkers using nuclear magnetic resonance imaging holds potential of making central nervous system (CNS) drug development more efficient. By evaluating changes in brain function in the disease state or drug effects on brain function, the technology opens up the possibility of obtaining objective data on drug effects in the living awake brain. By providing objective data, imaging may improve the probability of success of identifying useful drugs to treat CNS diseases across all clinical phases (I–IV) of drug development. The evolution of functional imaging and the promise it holds to contribute to drug development will require the development of standards (including good imaging practice), but, if well integrated into drug development, functional imaging can define markers of CNS penetration, drug dosing and target engagement (even for drugs that are not amenable to positron emission tomography imaging) in phase I; differentiate objective measures of efficacy and side effects and responders vs non-responders in phase II, evaluate differences between placebo and drug in phase III trials and provide insights into disease modification in phase IV trials

Molecular dynamics study of the fragmentation of silicon doped fullerenes

Tight binding molecular dynamics simulations, with a non orthogonal basis set, are performed to study the fragmentation of carbon fullerenes doped with up to six silicon atoms. Both substitutional and adsorbed cases are considered. The fragmentation process is simulated starting from the equilibrium configuration in each case and imposing a high initial temperature to the atoms. Kinetic energy quickly converts into potential energy, so that the system oscillates for some picoseconds and eventually breaks up. The most probable first event for substituted fullerenes is the ejection of a C2 molecule, another very frequent event being that one Si atom goes to an adsorbed position. Adsorbed Si clusters tend to desorb as a whole when they have four or more atoms, while the smaller ones tend to dissociate and sometimes interchange positions with the C atoms. These results are compared with experimental information from mass abundance spectroscopy and the products of photofragmentation.Comment: Seven two-column pages, six postscript figures. To be published in Physical Review

The Lie derivative of spinor fields: theory and applications

Starting from the general concept of a Lie derivative of an arbitrary differentiable map, we develop a systematic theory of Lie differentiation in the framework of reductive G-structures P on a principal bundle Q. It is shown that these structures admit a canonical decomposition of the pull-back vector bundle i_P^*(TQ) = P\times_Q TQ over P. For classical G-structures, i.e. reductive G-subbundles of the linear frame bundle, such a decomposition defines an infinitesimal canonical lift. This lift extends to a prolongation Gamma-structure on P. In this general geometric framework the concept of a Lie derivative of spinor fields is reviewed. On specializing to the case of the Kosmann lift, we recover Kosmann's original definition. We also show that in the case of a reductive G-structure one can introduce a "reductive Lie derivative" with respect to a certain class of generalized infinitesimal automorphisms, and, as an interesting by-product, prove a result due to Bourguignon and Gauduchon in a more general manner. Next, we give a new characterization as well as a generalization of the Killing equation, and propose a geometric reinterpretation of Penrose's Lie derivative of "spinor fields". Finally, we present an important application of the theory of the Lie derivative of spinor fields to the calculus of variations.Comment: 28 pages, 1 figur

Spin-polarized oxygen hole states in cation deficient La(1-x)CaxMnO(3+delta)

When holes are doped into a Mott-Hubbard type insulator, like lightly doped manganites of the La(1-x)CaxMnO3 family, the cooperative Jahn-Teller distortions and the appearance of orbital ordering require an arrangement of Mn(3+)/Mn(4+) for the establishment of the insulating canted antiferromagnetic (for x<=0.1), or of the insulating ferromagnetic (for 0.1<x<= 0.2) ground state. In the present work we provide NMR evidence about a novel and at the same time puzzling effect in La(1-x)CaxMnO(3+delta) systems with cation deficience. We show that in the low Ca-doping regime, these systems exhibit a very strong hyperfine field at certain La nuclear sites, which is not present in the stoichiometric compounds. Comparison of our NMR results with recent x-ray absorption data at the Mn K edge, suggests the formation of a spin-polarized hole arrangement on the 2p oxygen orbitals as the origin of this effect.Comment: 10 pages, 4 Figures, submitted to PR

Definition of Naturally Processed Peptides Reveals Convergent Presentation of Autoantigenic Topoisomerase I Epitopes in Scleroderma.

ObjectiveAutoimmune responses to DNA topoisomerase I (topo I) are found in a subset of scleroderma patients who are at high risk for interstitial lung disease (ILD) and mortality. Anti-topo I antibodies (ATAs) are associated with specific HLA-DRB1 alleles, and the frequency of HLA-DR-restricted topo I-specific CD4+ T cells is associated with the presence, severity, and progression of ILD. Although this strongly implicates the presentation of topo I peptides by HLA-DR in scleroderma pathogenesis, the processing and presentation of topo I has not been studied.MethodsWe developed a natural antigen processing assay (NAPA) to identify putative CD4+ T cell epitopes of topo I presented by monocyte-derived dendritic cells (mo-DCs) from 6 ATA-positive patients with scleroderma. Mo-DCs were pulsed with topo I protein, HLA-DR-peptide complexes were isolated, and eluted peptides were analyzed by mass spectrometry. We then examined the ability of these naturally presented peptides to induce CD4+ T cell activation in 11 ATA-positive and 11 ATA-negative scleroderma patients.ResultsWe found that a common set of 10 topo I epitopes was presented by Mo-DCs from scleroderma patients with diverse HLA-DR variants. Sequence analysis revealed shared peptide-binding motifs within the HLA-DRβ chains of ATA-positive patients and a subset of topo I epitopes with distinct sets of anchor residues capable of binding to multiple different HLA-DR variants. The NAPA-derived epitopes elicited robust CD4+ T cell responses in 73% of ATA-positive patients (8 of 11), and the number of epitopes recognized correlated with ILD severity (P = 0.025).ConclusionThese findings mechanistically implicate the presentation of a convergent set of topo I epitopes in the development of scleroderma

Detection of the Cherenkov light diffused by Sea Water with the ULTRA Experiment

The study of Ultra High Energy Cosmic Rays represents one of the most challenging topic in the Cosmic Rays and in the Astroparticle Physics fields. The interaction of primary particles with atmospheric nuclei produces a huge Extensive Air Shower together with isotropic emission of UV fluorescence light and highly directional Cherenkov photons, that are reflected/diffused isotropically by the impact on the Earth's surface or on high optical depth clouds. For space-based observations, detecting the reflected Cherenkov signal in a delayed coincidence with the fluorescence light improves the accuracy of the shower reconstruction in space and in particular the measurement of the shower maximum, giving a strong signature for discriminating hadrons and neutrinos, and helping to estimate the primary chemical composition. Since the Earth's surface is mostly covered by water, the ULTRA (UV Light Transmission and Reflection in the Atmosphere)experiment has been designed to provide the diffusing properties of sea water, overcoming the lack of information in this specific field. A small EAS array, made up of 5 particle detectors, and an UV optical device, have been coupled to detect in coincidence both electromagnetic and UV components. The detector was in operation from May to December, 2005, in a small private harbor in Capo Granitola (Italy); the results of these measurements in terms of diffusion coefficient and threshold energy are presented here.Comment: 4 pages, 3 figures, PDF format, Proceedings of 30th ICRC, International Cosmic Ray Conference 2007, Merida, Yucatan, Mexico, 3-11 July 200

A Cylindrical GEM Inner Tracker for the BESIII experiment at IHEP

The Beijing Electron Spectrometer III (BESIII) is a multipurpose detector that collects data provided by the collision in the Beijing Electron Positron Collider II (BEPCII), hosted at the Institute of High Energy Physics of Beijing. Since the beginning of its operation, BESIII has collected the world largest sample of J/{\psi} and {\psi}(2s). Due to the increase of the luminosity up to its nominal value of 10^33 cm-2 s-1 and aging effect, the MDC decreases its efficiency in the first layers up to 35% with respect to the value in 2014. Since BESIII has to take data up to 2022 with the chance to continue up to 2027, the Italian collaboration proposed to replace the inner part of the MDC with three independent layers of Cylindrical triple-GEM (CGEM). The CGEM-IT project will deploy several new features and innovation with respect the other current GEM based detector: the {\mu}TPC and analog readout, with time and charge measurements will allow to reach the 130 {\mu}m spatial resolution in 1 T magnetic field requested by the BESIII collaboration. In this proceeding, an update of the status of the project will be presented, with a particular focus on the results with planar and cylindrical prototypes with test beams data. These results are beyond the state of the art for GEM technology in magnetic field