Structural and dynamical properties of superfluid helium: a density functional approach

We present a novel density functional for liquid 4He, properly accounting for the static response function and the phonon-roton dispersion in the uniform liquid. The functional is used to study both structural and dynamical properties of superfluid helium in various geometries. The equilibrium properties of the free surface, droplets and films at zero temperature are calculated. Our predictions agree closely to the results of ab initio Monte Carlo calculations, when available. The introduction of a phenomenological velocity dependent interaction, which accounts for backflow effects, is discussed. The spectrum of the elementary excitations of the free surface and films is studied.Comment: 37 pages, REVTeX 3.0, figures on request at [email protected]

Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2)

Inhibitors against Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) and B2 (TbrPDEB2) have gained interest as new treatments for human African trypanosomiasis. The recently reported alkynamide tetrahydrophthalazinones, which show submicromolar activities against TbrPDEB1 and anti-T. brucei activity, have been used as starting point for the discovery of new TbrPDEB1 inhibitors. Structure-based design indicated that the alkynamide-nitrogen atom can be readily decorated, leading to the discovery of 37, a potent TbrPDEB1 inhibitor with submicromolar activities against T. brucei parasites. Furthermore, 37 is more potent against TbrPDEB1 than hPDE4 and shows no cytotoxicity on human MRC-5 cells. The crystal structures of the catalytic domain of TbrPDEB1 co-crystalized with several different alkynamides show a bidentate interaction with key-residue Gln874, but no interaction with the parasite-specific P-pocket, despite being (uniquely) a more potent inhibitor for the parasite PDE. Incubation of blood stream form trypanosomes by 37 increases intracellular cAMP levels and results in the distortion of the cell cycle and cell death, validating phosphodiesterase inhibition as mode of action

Discovery of fragments inducing conformational effects in dynamic proteins using a second-harmonic generation biosensor

Biophysical screening of compound libraries for the identification of ligands that interact with a protein is efficient, but does typically not reveal if (or how) ligands may interfere with its functional properties. For this a biochemical/functional assay is required. But for proteins whose function is dependent on a conformational change, such assays are typically complex or have low throughput. Here we have explored a high-throughput second-harmonic generation (SHG) biosensor to detect fragments that induce conformational changes upon binding to a protein in real time and identify dynamic regions. Multiwell plate format SHG assays were developed for wild-type and six engineered single-cysteine mutants of acetyl choline binding protein (AChBP), a homologue to ligand gated ion channels (LGICs). They were conjugated with second harmonic-active labels via amine or maleimide coupling. To validate the assay, it was confirmed that the conformational changes induced in AChBP by nicotinic acetyl choline receptor (nAChR) agonists and antagonists were qualitatively different. A 1056 fragment library was subsequently screened against all variants and conformational modulators of AChBP were successfully identified, with hit rates from 9–22%, depending on the AChBP variant. A subset of four hits was selected for orthogonal validation and structural analysis. A time-resolved grating-coupled interferometry-based biosensor assay confirmed the interaction to be a reversible 1-step 1 : 1 interaction, and provided estimates of affinities and interaction kinetic rate constants (KD = 0.28–63 μM, ka = 0.1–6 μM−1 s−1, kd = 1 s−1). X-ray crystallography of two of the fragments confirmed their binding at a previously described conformationally dynamic site, corresponding to the regulatory site of LGICs. These results reveal that SHG has the sensitivity to identify fragments that induce conformational changes in a protein. A selection of fragment hits with a response profile different to known LGIC regulators was characterized and confirmed to bind to dynamic regions of the protein.Title in thesis list of papers: Discovery of fragments targeting dynamic proteins using second-harmonic generation</p

[Don Quijote de la Mancha]

Sign.: [ ]4, a-p8, q2, A-I8; [ ]3, A-T8, V7; [2]2, A-R8, S2; [ ]2 , a8, A-Z8, 2A-2E8, 2F4; []3, A-Z8, 2A-2G8, 2H2Las h. de lám. son grab. calc., dibujadas por: Rafael Ximeno, Agustín Navarro, Paret, Monnet, P. Camarón y J. Camarón; y grabadas por: P. Duflos, Moreno Tejada y Femme DuflosFront. calc. con el retrato de Cervantes en t. I y IV, dibujados por Ximeno y Monnet y grabados por DuflosLas h. de mapa pleg. son: "Demostracion de la celebre Cueva de Montesinos citada por Cervantes en su Dn. Quixote", Paret del. y "Plano geografico de las Lagunas de Ruidera y curso que hacen sus aguas sobrantes con el nombre de Rio Guadiana" en t. IV, y "Carta geografica de los viages de Don Quixote y sitios de sus aventuras" delineada por Manuel Antº. Rodriguz. segun las observaciones historicas de Juan Antº. Pellicer en t.

International Large Detector: Interim Design Report

The ILD detector is proposed for an electron-positron collider with collision centre-of-mass energies from 90~\GeV~to about 1~\TeV. It has been developed over the last 10 years by an international team of scientists with the goal to design and eventually propose a fully integrated detector, primarily for the International Linear Collider, ILC. In this report the fundamental ideas and concepts behind the ILD detector are discussed and the technologies needed for the realisation of the detector are reviewed. The document starts with a short review of the science goals of the ILC, and how the goals can be achieved today with the detector technologies at hand. After a discussion of the ILC and the environment in which the experiment will take place, the detector is described in more detail, including the status of the development of the technologies foreseen for each subdetector. The integration of the different sub-systems into an integrated detector is discussed, as is the interface between the detector and the collider. This is followed by a concise summary of the benchmarking which has been performed in order to find an optimal balance between performance and cost. To the end the costing methodology used by ILD is presented, and an updated cost estimate for the detector is presented. The report closes with a summary of the current status and of planned future actions

The ILD detector at the ILC

The International Large Detector, ILD, is a detector concept which has been developed for the electron-positron collider ILC. The detector has been optimized for precision physics in a range of energies between 90 GeV and 1 TeV. ILD features a high precision, large volume combined silicon and gaseous tracking system, together with a high granularity calorimeter, all inside a 3.5 T solenoidal magnetic field. The paradigm of particle flow has been the guiding principle of the design of ILD. In this document the required performance of the detector, the proposed implementation and the readiness of the different technologies needed for the implementation are discussed. This is done in the framework of the ILC collider proposal, now under consideration in Japan, and includes site specific aspects needed to build and operate the detector at the proposed ILC site in Japan