Successful Dendrimer and Liposome-Based Strategies to Solubilize an Antiproliferative Pyrazole Otherwise Not Clinically Applicable

Water-soluble formulations of the pyrazole derivative 3-(4-chlorophenyl)-5-(4-nitrophenylamino)-1H-pyrazole-4-carbonitrile (CR232), which were proven to have in vitro antiproliferative effects on different cancer cell lines, were prepared by two diverse nanotechnological approaches. Importantly, without using harmful organic solvents or additives potentially toxic to humans, CR232 was firstly entrapped in a biodegradable fifth-generation dendrimer containing lysine (G5K). CR232-G5K nanoparticles (CR232-G5K NPs) were obtained with high loading (DL%) and encapsulation efficiency (EE%), which showed a complex but quantitative release profile governed by Weibull kinetics. Secondly, starting from hydrogenated soy phosphatidylcholine and cholesterol, we prepared biocompatible CR232-loaded liposomes (CR232-SUVs), which displayed DL% and EE% values increasing with the increase in the lipids/CR232 ratio initially adopted and showed a constant prolonged release profile ruled by zero-order kinetics. When relevant, attenuated total reflectance Fourier transformed infrared spectroscopy (ATR-FTIR) and nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy (SEM) and dynamic light scattering (DLS) experiments, as well as potentiometric titrations completed the characterization of the prepared NPs. CR232-G5K NPs were 2311-fold more water-soluble than the pristine CR232, and the CR232-SUVs with the highest DL% were 1764-fold more soluble than the untreated CR232, thus establishing the success of both our strategies

Distant Homology Modeling of LCAT and Its Validation through In Silico Targeting and In Vitro and In Vivo Assays

LCAT (lecithin:cholesterol acyltransferase) catalyzes the transacylation of a fatty acid of lecithin to cholesterol, generating a cholesteryl ester and lysolecithin. The knowledge of LCAT atomic structure and the identification of the amino acids relevant in controlling its structure and function are expected to be very helpful to understand the enzyme catalytic mechanism, as involved in HDL cholesterol metabolism. However - after an early report in the late '90 s - no recent advance has been made about LCAT three-dimensional structure. In this paper, we propose an LCAT atomistic model, built following the most up-to-date molecular modeling approaches, and exploiting newly solved crystallographic structures. LCAT shows the typical folding of the \u3b1/\u3b2 hydrolase superfamily, and its topology is characterized by a combination of \u3b1-helices covering a central 7-strand \u3b2-sheet. LCAT presents a Ser/Asp/His catalytic triad with a peculiar geometry, which is shared with such other enzyme classes as lipases, proteases and esterases. Our proposed model was validated through different approaches. We evaluated the impact on LCAT structure of some point mutations close to the enzyme active site (Lys218Asn, Thr274Ala, Thr274Ile) and explained, at a molecular level, their phenotypic effects. Furthermore, we devised some LCAT modulators either designed through a de novo strategy or identified through a virtual high-throughput screening pipeline. The tested compounds were proven to be potent inhibitors of the enzyme activity

Photon counting with photon number resolution through superconducting nanowires coupled to a multi-channel TDC in FPGA

The paper presents a system for measuring photon statistics and photon timing in the few-photon regime down to the single-photon level. The measurement system is based on superconducting nanowire single photon detectors and a time-to-digital converter implemented into a programmable device. The combination of these devices gives high performance to the system in terms of resolution and adaptability to the actual experimental conditions. As a case of application, we present the measurement of photon statistics for coherent light states. In this measurement, we make use of 8th order single photon correlations to reconstruct with high fidelity the statistics of a coherent state with average photon number up to 4. The processing is performed by means of a tapped-delay-line time-to-digital converter architecture that also hosts an asynchronous-correlated-digital-counter implemented in a field programmable gate array device and specifically designed for performance optimization in multi-channel usage

Exercise for reducing fear of falling in older people living in the community: Cochrane systematic review and meta-analysis

Objective: To determine the effect of exercise interventions on fear of falling in community-living people aged ≥65 years. Design: Systematic review and meta-analysis. Bibliographic databases, trial registers and other sources were searched for randomised or quasi-randomised trials. Data were independently extracted by pairs of reviewers using a standard form. Results: Thirty trials (2878 participants) reported 36 interventions (Tai Chi and yoga (n=9); balance training (n=19); strength and resistance training (n=8)). The risk of bias was low in few trials. Most studies were from high income countries (Australia=8, USA=7). Intervention periods (26 weeks=7) and exercise frequency (1-3 times/week=32; ≥4 times/week=4) varied between studies. Fear of falling was measured by single-item questions (7) and scales measuring falls efficacy (14), balance confidence (9) and concern or worry about falling (2). Meta-analyses showed a small to moderate effect of exercise interventions on reducing fear of falling immediately post intervention (standardised mean difference (SMD) 0.37, 95% CI 0.18, 0.56; 24 studies; low quality evidence). There was a small, but not statistically significant effect in the longer term (<6 months (SMD 0.17, 95% CI -0.05, 0.38 (four studies) and ≥ 6 months post intervention SMD 0.20, 95% CI -0.01, 0.41 (three studies)). Conclusions: Exercise interventions probably reduce fear of falling to a small to moderate degree immediately post-intervention in community-living older people. The high risk of bias in most included trials suggests findings should be interpreted with caution. High quality trials are needed to strengthen the evidence base in this area

Airway management in neonates and infants: European Society of Anaesthesiology and Intensive Care and British Journal of Anaesthesia joint guidelines.

Airway management is required during general anaesthesia and is essential for life-threatening conditions such as cardiopulmonary resuscitation. Evidence from recent trials indicates a high incidence of critical events during airway management, especially in neonates or infants. It is important to define the optimal techniques and strategies for airway management in these groups. In this joint European Society of Anaesthesiology and Intensive Care (ESAIC) and British Journal of Anaesthesia (BJA) guideline on airway management in neonates and infants, we present aggregated and evidence-based recommendations to assist clinicians in providing safe and effective medical care. We identified seven main areas of interest for airway management: i) preoperative assessment and preparation; ii) medications; iii) techniques and algorithms; iv) identification and treatment of difficult airways; v) confirmation of tracheal intubation; vi) tracheal extubation, and vii) human factors. Based on these areas, Population, Intervention, Comparison, Outcomes (PICO) questions were derived that guided a structured literature search. GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was used to formulate the recommendations based on those studies included with consideration of their methodological quality (strong '1' or weak '2' recommendation with high 'A', medium 'B' or low 'C' quality of evidence). In summary, we recommend: 1. Use medical history and physical examination to predict difficult airway management (1С). 2. Ensure adequate level of sedation or general anaesthesia during airway management (1B). 3. Administer neuromuscular blocker before tracheal intubation when spontaneous breathing is not necessary (1С). 4. Use a videolaryngoscope with an age-adapted standard blade as first choice for tracheal intubation (1B). 5. Apply apnoeic oxygenation during tracheal intubation in neonates (1B). 6. Consider a supraglottic airway for rescue oxygenation and ventilation when tracheal intubation fails (1B). 7. Limit the number of tracheal intubation attempts (1C). 8. Use a stylet to reinforce and preshape tracheal tubes when hyperangulated videolaryngoscope blades are used and when the larynx is anatomically anterior (1C). 9. Verify intubation is successful with clinical assessment and end-tidal CO2 waveform (1C). 10. Apply high-flow nasal oxygenation, continuous positive airway pressure or nasal intermittent positive pressure ventilation for postextubation respiratory support, when appropriate (1B)

Measurement of the mass and lifetime of the Ωb−\Omega_b^- baryon

A proton-proton collision data sample, corresponding to an integrated luminosity of 3 fb$^{-1}$ collected by LHCb at $\sqrt{s}=7$ and 8 TeV, is used to reconstruct $63\pm9$ $\Omega_b^-\to\Omega_c^0\pi^-$, $\Omega_c^0\to pK^-K^-\pi^+$ decays. Using the $\Xi_b^-\to\Xi_c^0\pi^-$, $\Xi_c^0\to pK^-K^-\pi^+$ decay mode for calibration, the lifetime ratio and absolute lifetime of the $\Omega_b^-$ baryon are measured to be \begin{align*} \frac{\tau_{\Omega_b^-}}{\tau_{\Xi_b^-}} &= 1.11\pm0.16\pm0.03, \\ \tau_{\Omega_b^-} &= 1.78\pm0.26\pm0.05\pm0.06~{\rm ps}, \end{align*} where the uncertainties are statistical, systematic and from the calibration mode (for $\tau_{\Omega_b^-}$ only). A measurement is also made of the mass difference, $m_{\Omega_b^-}-m_{\Xi_b^-}$, and the corresponding $\Omega_b^-$ mass, which yields \begin{align*} m_{\Omega_b^-}-m_{\Xi_b^-} &= 247.4\pm3.2\pm0.5~{\rm MeV}/c^2, \\ m_{\Omega_b^-} &= 6045.1\pm3.2\pm 0.5\pm0.6~{\rm MeV}/c^2. \end{align*} These results are consistent with previous measurements.Comment: 11 pages, 5 figures, All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-008.htm

Observation of J/ψpJ/\psi p resonances consistent with pentaquark states in Λb0→J/ψK−p{\Lambda_b^0\to J/\psi K^-p} decays

Observations of exotic structures in the $J/\psi p$ channel, that we refer to as pentaquark-charmonium states, in $\Lambda_b^0\to J/\psi K^- p$ decays are presented. The data sample corresponds to an integrated luminosity of 3/fb acquired with the LHCb detector from 7 and 8 TeV pp collisions. An amplitude analysis is performed on the three-body final-state that reproduces the two-body mass and angular distributions. To obtain a satisfactory fit of the structures seen in the $J/\psi p$ mass spectrum, it is necessary to include two Breit-Wigner amplitudes that each describe a resonant state. The significance of each of these resonances is more than 9 standard deviations. One has a mass of $4380\pm 8\pm 29$ MeV and a width of $205\pm 18\pm 86$ MeV, while the second is narrower, with a mass of $4449.8\pm 1.7\pm 2.5$ MeV and a width of $39\pm 5\pm 19$ MeV. The preferred $J^P$ assignments are of opposite parity, with one state having spin 3/2 and the other 5/2.Comment: 48 pages, 18 figures including the supplementary material, v2 after referee's comments, now 19 figure

A new algorithm for identifying the flavour of Bs0B_s^0 mesons at LHCb

A new algorithm for the determination of the initial flavour of $B_s^0$ mesons is presented. The algorithm is based on two neural networks and exploits the $b$ hadron production mechanism at a hadron collider. The first network is trained to select charged kaons produced in association with the $B_s^0$ meson. The second network combines the kaon charges to assign the $B_s^0$ flavour and estimates the probability of a wrong assignment. The algorithm is calibrated using data corresponding to an integrated luminosity of 3 fb$^{-1}$ collected by the LHCb experiment in proton-proton collisions at 7 and 8 TeV centre-of-mass energies. The calibration is performed in two ways: by resolving the $B_s^0$-$\bar{B}_s^0$ flavour oscillations in $B_s^0 \to D_s^- \pi^+$ decays, and by analysing flavour-specific $B_{s 2}^{*}(5840)^0 \to B^+ K^-$ decays. The tagging power measured in $B_s^0 \to D_s^- \pi^+$ decays is found to be $(1.80 \pm 0.19({\rm stat}) \pm 0.18({\rm syst}))$\%, which is an improvement of about 50\% compared to a similar algorithm previously used in the LHCb experiment.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-056.htm