Design and Synthesis of Conformationally Constrained RORγt Inverse Agonists

Retinoic-acid-related orphan receptor γt (RORγt) inverse agonists could be used for the treatment of autoimmune diseases. Previously, we reported a novel quinazolinedione 1 a with a flexible linear linker as a novel RORγt inverse agonist. A U-shaped conformation in the complex structure of 1 a with RORγt protein was confirmed. Further improvement of the pharmacokinetic (PK) profiles was required because of the low drug exposure in mice upon oral administration (mouse AUC of 1 a : 27 ng ⋅ h ⋅ mL⁻¹ at 1 mg ⋅ kg⁻¹, p.o.). To improve the PK profiles, conformationally constrained U-shaped scaffolds were investigated. As a result, morpholine analogues with improved PK profiles and high potency were successfully identified. The substituent at the N1 position of the quinazoline moiety was also modified, leading to an enhancement of reporter activity. Consequently, compound 43 (N²-(3-chloro-4-cyanophenyl)-N⁴-(3-(cyclopropylmethyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)morpholine-2,4-dicarboxamide) exhibited improved drug exposure (mouse AUC: 1289 ng ⋅ h ⋅ mL⁻¹ at 1 mg ⋅ kg⁻¹, p.o.). In addition, suppression of IL-17A gene expression by IL-23 stimulation in a mouse pharmacodynamics model was observed for 43 . The conformation of 43 with RORγt protein was also confirmed as U-shape by X-ray co-crystal structure analysis. The key interaction that boosts potency is also discussed.     

A study of Weibull parameters using long-term wind observations

The two parameters of a Weibull density distribution function were calculated for three different locations; a city area, an extremely exposed area in a city centre and an open sea area in Hong Kong. A long-term data source, consisting of thirty years (1968–1997) of hourly mean wind data, was adopted and analysed. Based on these data, it was found that the numerical values of the shape and scale parameters for these weather stations varied over a wide range. The shape parameter varied from 1.63 to 2.03 and the scale parameter ranged from 2.76 to 8.92. The yearly Weibull probability density function distribution for the city area indicated that the wind data could be grouped into two distinct periods, 1968–1981 and 1982–1997. Seasonal Weibull distribution for the three locations were compared and wider distributions were observed in the more open areas.     

Comparison of different climate regimes: the impact of broadening participation

So-far, most climate mitigation studies look at climate policy strategies in a so-called first-best world, i.e. using the least expensive emission reduction options in all world regions and sectors. To explore the impact of limited participation of countries, we have run a set of scenarios that explore the impact of introducing a carbon tax in OECD, the BRIC countries (Brazil Russia, India and China) and the rest of the world. The results show that carbon taxes can effectively reduce greenhouse gas emissions. However, if low greenhouse gas concentration levels are to be achieved, early participation (in some form) of large developing countries is important to increase reduction potential. It should be noted that global carbon taxes (without additional assumptions) lead to relatively high costs in low-income regions. Cap-and-trade regimes have more flexibility to create a comparable distribution of costs amongst countries.     

Web‐Forming System Design Using CFD Modelling for Complex 3D Nonwoven Shell Structures

Summary: CFD modelling has been used to study the unique problem of airflow containing fibres around 3D porous media in nonwoven web forming systems. The related gas‐solid two‐phase flows were simulated using a commercial CFD package, FLUENT. Simulation results revealed that the uniformity of air velocities and fibre concentration around the moulds, particularly for complex‐shaped moulds, could be improved significantly by means of employing vertically oriented web forming system and moulds with controlled porosity. Experimental results indicated that the distribution of the area densities of the 3D nonwovens produced using polypropylene/polyester bi‐component fibre followed the same patterns of the airflow and fibre distributions simulated using the CFD model. The CFD model is a valuable tool for optimising the web forming systems and improving the uniformity of the 3D nonwovens.

Area density distribution of the 3D products produced using the vertical system.     

Concordance between task and interface rotational and translational control improves ground vehicle performance

Research in various areas of human-system interaction suggests the importance of examining the similarities and dissimilarities between tasks and the interfaces used to complete them. Specifically, the theory of cognitive fit suggests that human problem solvers will perform better when the data and data displays they use to complete a task match some characteristic of that task. An experiment was performed that extends the theory of cognitive fit to the realm of human performance on motor tasks. Participants completed several virtual vehicle control motor tasks that consisted of rotational and translational control components. The tasks were performed with user interfaces that either combined or separated rotational and translational control. The tasks were of two types: control of either rotation or translation changes but not both concurrently, or simultaneous control of combined rotation and translation changes. The results indicate that task performance was better when the characteristics of the interface matched the characteristics of the task. Actual or potential applications of this research include constructing ground vehicle interface controls that are designed specifically based on the characteristics of the task for which they are to be used, such as primarily driving fast and in a straight line (e.g., on a highway) versus primarily driving slowly with much turning (e.g., on a city street).     

Identifizierung von Konservierungsmitteln auf Papierchromatogrammen durch Bestrahlung mit kurzwelligem Ultraviolettlicht

Zusammenfassung Zur routinemäßigen Überwachung von Lebensmitteln auf Vorkommen von einem oder mehreren von 11 verschiedenen Konservierungsmitteln sowie von Saccharin wurde eine papierchromatographische Methode angewandt. Die Identifizierung der Substanzen geschieht durch Beobachtung des mit kurzwelligem Ultraviolettlicht (2537 Å) beleuchteten Papiers vor und nach der Behandlung mit verschiedenen Reagentien.Nach einem Vortrag, der in Malmö anläßlich Svenska Livsmedelstekniska Föreningens Livsmedelsdagar, 9.–9. Februar 1962, genhalten wurde.     

Polyester-polyether block copolymers. I. Wide-angle X-ray diffraction studies of poly(hexamethylene terephthalate)/poly(oxytetramethylene) and related block polymers

The crystallisation and orientation of the individual structural components of poly(hexamethylene terephthalate)/poly(oxytetramethylene) block copolymers have been studied by wide-angle X-ray diffraction. The crystallisation behaviour in the unstretched state is determined by the proportions and molecular weights of the polyether blocks. For copolymers containing less than 60 wt% of polyether of m. w. ≯ 2000, only the polyester segments crystallise spontaneously, but with polyether m. w > 2000 two crystalline phases are formed. Similar behaviour was found in block polymers from other readily crystallising polyesters, but with non-crystallising polyesters the polyether segments crystallised spontaneously. Moderate tensile deformation of the block copolymers from polyether of m. w. 2000 leads to the stress-reversible highly oriented crystallisation of the polyether whilst the polyester remains undeformed. At higher extensions, irreversible orientation of the polyester segments occurs. The observations suggest that the polyester and polyether segments form discrete regions since otherwise homogeneous crystallisation should occur.     

Wear of surface engineered metal-on-metal hip prostheses

The wear of existing metal-on-metal (MOM) hip prostheses (1 mm3/million cycles) is much lower than the more widely used polyethylene-on-metal bearings (30-100 mm3/million cycles). However, there remain some potential concerns about the toxicity of metal wear particles and elevated metal ion levels, both locally and systemically in the human body. The aim of this study was to investigate the wear, wear debris and ion release of fully coated surface engineered MOM bearings for hip prostheses. Using a physiological anatomical hip joint simulator, five different bearing systems involving three thick (8-12 microm) coatings, TiN, CrN and CrCN, and one thin (2 microm) coating diamond like carbon (DLC) were evaluated and compared to a clinically used MOM cobalt chrome alloy bearing couple. The overall wear rates of the surface engineered prostheses were at least 18-fold lower than the traditional MOM prostheses after 2 million cycles and 36-fold lower after 5 million cycles. Consequently, the volume of wear debris and the ion levels in the lubricants were substantially lower. These parameters were also much lower than in half coated (femoral heads only) systems that have been reported previously. The extremely low volume of wear debris and concentration of metal ions released by these surface engineered systems, especially with CrN and CrCN coatings, have considerable potential for the clinical application of this technology.     

Numerical evaluation of heating of the human head due to magnetic resonance imaging

In this paper, we present a numerical model for evaluating tissue heating during magnetic resonance imaging (MRI). Our method, which included a detailed anatomical model of a human head, calculated both the electromagnetic power deposition and the associated temperature elevations during an MRI head examination. Numerical studies were conducted using a realistic birdcage coil excited at frequencies ranging from 63 to 500 MHz. The model was validated both experimentally and analytically. The experimental validation was performed at the MR test facility located at the Food and Drug Administration's Center for Devices and Radiological Health.