Naturally Occurring PCSK9 Inhibitors

Genetic, epidemiological and pharmacological data have led to the conclusion that antagonizing or inhibiting Proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cardiovascular events. This clinical outcome is mainly related to the pivotal role of PCSK9 in controlling low-density lipoprotein (LDL) cholesterol levels. The absence of oral and affordable anti-PCSK9 medications has limited the beneficial effects of this new therapeutic option. A possible breakthrough in this field may come from the discovery of new naturally occurring PCSK9 inhibitors as a starting point for the development of oral, small molecules, to be used in combination with statins in order to increase the percentage of patients reaching their LDL-cholesterol target levels. In the present review, we have summarized the current knowledge on natural compounds or extracts that have shown an inhibitory effect on PCSK9, either in experimental or clinical settings. When available, the pharmacodynamic and pharmacokinetic profiles of the listed compounds are described

The use of ESEM-EDX as an innovative tool to analyze the mineral structure of peri-implant human bone

This study aimed to investigate the mineralization and chemical composition of the bone-implant interface and peri-implant tissues on human histological samples using an environmental scanning electron microscope as well as energy-dispersive x-ray spectroscopy (ESEM-EDX) as an innovative method. Eight unloaded implants with marginal bone tissue were retrieved after four months from eight patients and were histologically processed and analyzed. Histological samples were observed under optical microscopy (OM) to identify the microarchitecture of the sample and bone morphology. Then, all samples were observed under ESEM-EDX from the coronal to the most apical portion of the implant at 500x magnification. A region of interest with bone tissue of size 750 7 500 microns was selected to correspond to the first coronal and the last apical thread (ROI). EDX microanalysis was used to assess the elemental composition of the bone tissue along the thread interface and the ROI. Atomic percentages of Ca, P, N, and Ti, and the Ca/N, P/N and Ca/P ratios were measured in the ROI. Four major bone mineralization areas were identified based on the different chemical composition and ratios of the ROI. Area 1: A well-defined area with low Ca/N, P/N, and Ca/P was identified as low-density bone. Area 2: A defined area with higher Ca/N, P/N, and Ca/P, identified as new bone tissue, or bone remodeling areas. Area 3: A well-defined area with high Ca/N, /P/N, and Ca/P ratios, identified as bone tissue or bone chips. Area 4: An area with high Ca/N, P/N, and Ca/P ratios, which was identified as mature old cortical bone. Bone Area 2 was the most represented area along the bone-implant interface, while Bone Area 4 was identified only at sites approximately 1.5 mm from the interface. All areas were identified around implant biopsies, creating a mosaic-shaped distribution with well-defined borders. ESEM-EDX in combination with OM allowed to perform a microchemical analysis and offered new important information on the organic and inorganic content of the bone tissue around implants

Reflexive representability and stable metrics

It is well-known that a topological group can be represented as a group of isometries of a reflexive Banach space if and only if its topology is induced by weakly almost periodic functions (see \cite{Shtern:CompactSemitopologicalSemigroups}, \cite{Megrelishvili:OperatorTopologies} and \cite{Megrelishvili:TopologicalTransformations}). We show that for a metrisable group this is equivalent to the property that its metric is uniformly equivalent to a stable metric in the sense of Krivine and Maurey (see \cite{Krivine-Maurey:EspacesDeBanachStables}). This result is used to give a partial negative answer to a problem of Megrelishvili

Large-angle production of charged pions by 3 GeV/c - 12.9 GeV/c protons on beryllium, aluminium and lead targets

Measurements of the double-differential $\pi^{\pm}$ production cross-section in the range of momentum 100 \MeVc \leq p < 800 \MeVc and angle 0.35 \rad \leq \theta < 2.15 \rad in proton--beryllium, proton--aluminium and proton--lead collisions are presented. The data were taken with the HARP detector in the T9 beam line of the CERN PS. The pions were produced by proton beams in a momentum range from 3 \GeVc to 12.9 \GeVc hitting a target with a thickness of 5% of a nuclear interaction length. The tracking and identification of the produced particles was performed using a small-radius cylindrical time projection chamber (TPC) placed inside a solenoidal magnet. Incident particles were identified by an elaborate system of beam detectors. Results are obtained for the double-differential cross-sections at six incident proton beam momenta (3 \GeVc, 5 \GeVc, 8 \GeVc, 8.9 \GeVc (Be only), 12 \GeVc and 12.9 \GeVc (Al only)) and compared to previously available data

Measurement of the production of charged pions by protons on a tantalum target

A measurement of the double-differential cross-section for the production of charged pions in proton--tantalum collisions emitted at large angles from the incoming beam direction is presented. The data were taken in 2002 with the HARP detector in the T9 beam line of the CERN PS. The pions were produced by proton beams in a momentum range from 3 \GeVc to 12 \GeVc hitting a tantalum target with a thickness of 5% of a nuclear interaction length. The angular and momentum range covered by the experiment (100 \MeVc \le p < 800 \MeVc and 0.35 \rad \le \theta <2.15 \rad) is of particular importance for the design of a neutrino factory. The produced particles were detected using a small-radius cylindrical time projection chamber (TPC) placed in a solenoidal magnet. Track recognition, momentum determination and particle identification were all performed based on the measurements made with the TPC. An elaborate system of detectors in the beam line ensured the identification of the incident particles. Results are shown for the double-differential cross-sections ${{\mathrm{d}^2 \sigma}} / {{\mathrm{d}p\mathrm{d}\theta}}$ at four incident proton beam momenta (3 \GeVc, 5 \GeVc, 8 \GeVc and 12 \GeVc). In addition, the pion yields within the acceptance of typical neutrino factory designs are shown as a function of beam momentum. The measurement of these yields within a single experiment eliminates most systematic errors in the comparison between rates at different beam momenta and between positive and negative pion production.Comment: 49 pages, 31 figures. Version accepted for publication on Eur. Phys. J.

Measurement of the production cross-section of positive pions in the collision of 8.9 GeV/c protons on beryllium

The double-differential production cross-section of positive pions, $d^2\sigma^{\pi^{+}}/dpd\Omega$, measured in the HARP experiment is presented. The incident particles are 8.9 GeV/c protons directed onto a beryllium target with a nominal thickness of 5% of a nuclear interaction length. The measured cross-section has a direct impact on the prediction of neutrino fluxes for the MiniBooNE and SciBooNE experiments at Fermilab. After cuts, 13 million protons on target produced about 96,000 reconstructed secondary tracks which were used in this analysis. Cross-section results are presented in the kinematic range 0.75 GeV/c < $p_{\pi}$ < 6.5 GeV/c and 30 mrad < $\theta_{\pi}$ < 210 mrad in the laboratory frame.Comment: 39 pages, 21 figures. Version accepted for publication by Eur. Phys. J.

Forward production of charged pions with incident π±\pi^{\pm} on nuclear targets measured at the CERN PS

Measurements of the double-differential $\pi^{\pm}$ production cross-section in the range of momentum 0.5 \GeVc \leq p \le 8.0 \GeVc and angle 0.025 \rad \leq \theta \le 0.25 \rad in interactions of charged pions on beryllium, carbon, aluminium, copper, tin, tantalum and lead are presented. These data represent the first experimental campaign to systematically measure forward pion hadroproduction. The data were taken with the large acceptance HARP detector in the T9 beam line of the CERN PS. Incident particles, impinging on a 5% nuclear interaction length target, were identified by an elaborate system of beam detectors. The tracking and identification of the produced particles was performed using the forward spectrometer of the HARP detector. Results are obtained for the double-differential cross-sections ${{\mathrm{d}^2 \sigma}}/{{\mathrm{d}p\mathrm{d}\Omega}}$ mainly at four incident pion beam momenta (3 \GeVc, 5 \GeVc, 8 \GeVc and 12 \GeVc). The measurements are compared with the GEANT4 and MARS Monte Carlo simulationComment: to be published on Nuclear Physics

Large-angle production of charged pions by 3 GeV/c - 12 GeV/c protons on carbon, copper and tin targets

A measurement of the double-differential $\pi^{\pm}$ production cross-section in proton--carbon, proton--copper and proton--tin collisions in the range of pion momentum 100 \MeVc \leq p < 800 \MeVc and angle 0.35 \rad \le \theta <2.15 \rad is presented. The data were taken with the HARP detector in the T9 beam line of the CERN PS. The pions were produced by proton beams in a momentum range from 3 \GeVc to 12 \GeVc hitting a target with a thickness of 5% of a nuclear interaction length. The tracking and identification of the produced particles was done using a small-radius cylindrical time projection chamber (TPC) placed in a solenoidal magnet. An elaborate system of detectors in the beam line ensured the identification of the incident particles. Results are shown for the double-differential cross-sections at four incident proton beam momenta (3 \GeVc, 5 \GeVc, 8 \GeVc and 12 \GeVc)

A First Search for coincident Gravitational Waves and High Energy Neutrinos using LIGO, Virgo and ANTARES data from 2007

We present the results of the first search for gravitational wave bursts associated with high energy neutrinos. Together, these messengers could reveal new, hidden sources that are not observed by conventional photon astronomy, particularly at high energy. Our search uses neutrinos detected by the underwater neutrino telescope ANTARES in its 5 line configuration during the period January - September 2007, which coincided with the fifth and first science runs of LIGO and Virgo, respectively. The LIGO-Virgo data were analysed for candidate gravitational-wave signals coincident in time and direction with the neutrino events. No significant coincident events were observed. We place limits on the density of joint high energy neutrino - gravitational wave emission events in the local universe, and compare them with densities of merger and core-collapse events.Comment: 19 pages, 8 figures, science summary page at http://www.ligo.org/science/Publication-S5LV_ANTARES/index.php. Public access area to figures, tables at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=p120000