Acyclic Cucurbit[n]uril-Type Containers as Receptors for Neuromuscular Blocking Agents: Structure–Binding Affinity Relationships

Acyclic cucurbit[n]uril molecular containers 1 and 2C3 have previously been shown to strongly bind to the neuromuscular blocking agents rocuronium, vecuronium, pancuronium, and cisatracurium in vitro by optical methods and to reverse neuromuscular block in vivo in rats. In this paper we study the in vitro binding of a panel of acyclic CB[n]-type receptors toward the four neuromuscular blocking agents and acetylcholine to develop structure-binding affinity relationships. The selected variants include those with different aromatic sidewalls (e.g. 1Me4 with dimethyl o-xylylene walls; 3 with 1,8-linked naphthalene walls), with different glycoluril oligomer lengths (e.g. 4 and 5 based on glycoluril trimer), and with different linker lengths between aromatic wall and SO3- solubilizing group (e.g. 2C2–2C4). Based on the analysis of complexation induced changes in 1H NMR chemical shift we conclude that the hydrophobic regions of the guests bind in the hydrophobic cavity of the hosts with the cationic moieties of the guest binding at the ureidyl C=O portals by ion-dipole and ion-ion interactions. The thermodynamic parameters of binding were determined by direct and competition isothermal titration calorimetry experiments. We find that hosts 4 and 5 based on glycoluril trimer form significantly weaker complexes with the streroidal NMBAs than with the analogues hosts based on glycoluril tetramer (1 and 2C3). Similarly, hosts 1Me4 and 3 with different length and height aromatic walls do not exhibit the extreme binding constants displayed by 2C3 but rather behave similarly to 1. Finally, we find that hosts 2C2 and 2C4 bind only slightly more weakly to the NMBAs than 2C3, but retain the ability to discriminate against acetylcholine, and possess higher inherent water solubility than 2C3. Host 2C4, in particular, holds potential for future in vivo applications. This work is licensed under a Creative Commons Attribution 4.0 International License

CHARACTERISTICS AND MECHANISM OF POTENTIAL PROBIOTICS WITH SPECIAL REFERENCE TO LACTIC ACID BACTERIA FROM TRADITIONAL FERMENTED FISH PRODUCTS: A REVIEW

Lactic acid bacteria (LAB) are widely used in the food industry due to their probiotic properties and fermentation activities. Traditional fermented fish products are dominated by a diverse variety of lactic acid bacteria with significant probiotic characteristics. Several in vitro and in vivo studies on lactic acid bacteria from fermented fish products have confirmed LAB strains to possess characteristics to be considered as probiotics that contribute to positive health benefits to the host and are generally regarded as safe (GRAS). This paper presents a review of the characteristics of the LAB strain that is considered as a probiotic. It also presents an overview of the probiotics mechanism of action and specifically highlights the LAB species with potential probiotic characteristics isolated from traditional fermented fish products

School-Based Obesity Interventions: A Literature Review

Childhood obesity is an impending epidemic. This article is an over

The validity of using ICD-9 codes and pharmacy records to identify patients with chronic obstructive pulmonary disease

Background: Administrative data is often used to identify patients with chronic obstructive pulmonary disease (COPD), yet the validity of this approach is unclear. We sought to develop a predictive model utilizing administrative data to accurately identify patients with COPD. Methods: Sequential logistic regression models were constructed using 9573 patients with postbronchodilator spirometry at two Veterans Affairs medical centers (2003-2007). COPD was defined as: 1) FEV1/FVC <0.70, and 2) FEV1/FVC < lower limits of normal. Model inputs included age, outpatient or inpatient COPD-related ICD-9 codes, and the number of metered does inhalers (MDI) prescribed over the one year prior to and one year post spirometry. Model performance was assessed using standard criteria. Results: 4564 of 9573 patients (47.7%) had an FEV1/FVC < 0.70. The presence of ≥1 outpatient COPD visit had a sensitivity of 76% and specificity of 67%; the AUC was 0.75 (95% CI 0.74-0.76). Adding the use of albuterol MDI increased the AUC of this model to 0.76 (95% CI 0.75-0.77) while the addition of ipratropium bromide MDI increased the AUC to 0.77 (95% CI 0.76-0.78). The best performing model included: ≥6 albuterol MDI, ≥3 ipratropium MDI, ≥1 outpatient ICD-9 code, ≥1 inpatient ICD-9 code, and age, achieving an AUC of 0.79 (95% CI 0.78-0.80). Conclusion: Commonly used definitions of COPD in observational studies misclassify the majority of patients as having COPD. Using multiple diagnostic codes in combination with pharmacy data improves the ability to accurately identify patients with COPD.Department of Veterans Affairs, Health Services Research and Development (DHA), American Lung Association (CI- 51755-N) awarded to DHA, the American Thoracic Society Fellow Career Development AwardPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/84155/1/Cooke - ICD9 validity in COPD.pd

Cell-cell contact area affects Notch signaling and Notch-dependent patterning

During development, cells undergo dramatic changes in their morphology. By affecting contact geometry, these morphological changes could influence cellular communication. However, it has remained unclear whether and how signaling depends on contact geometry. This question is particularly relevant for Notch signaling, which coordinates neighboring cell fates through direct cell-cell signaling. Using micropatterning with a receptor trans-endocytosis assay, we show that signaling between pairs of cells correlates with their contact area. This relationship extends across contact diameters ranging from microns to tens of microns. Mathematical modeling predicts that dependence of signaling on contact area can bias cellular differentiation in Notch-mediated lateral inhibition processes, such that smaller cells are more likely to differentiate into signal-producing cells. Consistent with this prediction, analysis of developing chick inner ear revealed that ligand-producing hair cell precursors have smaller apical footprints than non-hair cells. Together, these results highlight the influence of cell morphology on fate determination processes

Quaternary structure independent folding of voltage-gated ion channel pore domain subunits

Every voltage-gated ion channel (VGIC) has a pore domain (PD) made from four subunits, each comprising an antiparallel transmembrane helix pair bridged by a loop. The extent to which PD subunit structure requires quaternary interactions is unclear. Here, we present crystal structures of a set of bacterial voltage-gated sodium channel (BacNaV) 'pore only' proteins that reveal a surprising collection of non-canonical quaternary arrangements in which the PD tertiary structure is maintained. This context-independent structural robustness, supported by molecular dynamics simulations, indicates that VGIC-PD tertiary structure is independent of quaternary interactions. This fold occurs throughout the VGIC superfamily and in diverse transmembrane and soluble proteins. Strikingly, characterization of PD subunit-binding Fabs indicates that non-canonical quaternary PD conformations can occur in full-length VGICs. Together, our data demonstrate that the VGIC-PD is an autonomously folded unit. This property has implications for VGIC biogenesis, understanding functional states, de novo channel design, and VGIC structural origins

2-Benzyloxynaphthalene aminoalkylated chalcone designed as acetylcholinesterase inhibitor: Structural characterisation, in vitro biological activity and molecular docking studies

The design of an acetylcholinesterase inhibitor with multifunctional properties became the perspective for the development of an effective drug against Alzheimer's disease. Towards this target, 1-{4-hydroxy-3-[(piperidin-1-yl)methyl]phenyl}ethan-1-one (chalcone 3) was prepared and studied as an acetylcholinesterase inhibitor. The novel chalcone 3 was synthesised via Claisen-Schmidt condensation reaction with 84% yield and characterized using 1D and 2D NMR spectroscopy. The in vitro bioactivity studies of chalcone 3 demonstrated excellent inhibitory activity against AChE (IC50 1.0 nM) showing 33-fold better inhibition than donepezil, biometal chelating ability and moderate antioxidant activity. Chalcone 3 with these fascinating multifunctional proprieties can be a good candidate for the development of AD treatments. A molecular modelling investigation revealed that chalcone 3 showed dual binding inhibition of AChE enzyme. XRD shows short intra- and inter-molecular interactions with two chalcone 3 molecules per cell. Interesting Hirshfeld Surface Analysis (HSA) was conducted showing explicit agreement with the XRD analysis

Taking the Measure of the Universe: Precision Astrometry with SIM PlanetQuest

Precision astrometry at microarcsecond accuracy has application to a wide range of astrophysical problems. This paper is a study of the science questions that can be addressed using an instrument that delivers parallaxes at about 4 microarcsec on targets as faint as V = 20, differential accuracy of 0.6 microarcsec on bright targets, and with flexible scheduling. The science topics are drawn primarily from the Team Key Projects, selected in 2000, for the Space Interferometry Mission PlanetQuest (SIM PlanetQuest). We use the capabilities of this mission to illustrate the importance of the next level of astrometric precision in modern astrophysics. SIM PlanetQuest is currently in the detailed design phase, having completed all of the enabling technologies needed for the flight instrument in 2005. It will be the first space-based long baseline Michelson interferometer designed for precision astrometry. SIM will contribute strongly to many astronomical fields including stellar and galactic astrophysics, planetary systems around nearby stars, and the study of quasar and AGN nuclei. SIM will search for planets with masses as small as an Earth orbiting in the `habitable zone' around the nearest stars using differential astrometry, and could discover many dozen if Earth-like planets are common. It will be the most capable instrument for detecting planets around young stars, thereby providing insights into how planetary systems are born and how they evolve with time. SIM will observe significant numbers of very high- and low-mass stars, providing stellar masses to 1%, the accuracy needed to challenge physical models. Using precision proper motion measurements, SIM will probe the galactic mass distribution and the formation and evolution of the Galactic halo. (abridged)Comment: 54 pages, 28 figures, uses emulateapj. Submitted to PAS

Reduction of PG:1115+080 Images

The data are three exposures in PC6 through F785LP obtained on March 3, 1991. The exposure times are 120, 400, and 400 seconds. The data are reduced with the "standard" WFPC reduction scheme: A-to-D correction, DC bias subtraction, AC bias subtraction, dark current subtraction, preflash subtraction, and flat field normalization, using the best available calibration data. The exposures are combined into a weighted average normalized to 400 seconds exposure time, so one DN (data number) is about 17.25 electrons. At this step, cosmic rays are removed by intercomparison of the three images