Structural and molecular recognition studies with acyclic anion receptors

Acyclic molecules containing amides, ureas, and pyrrole groups have proven to be effective and selective anion-binding agents. In this Account, the structural chemistry of isophthalamide anion complexes, ortho-phenylenediamine based bis-ureas, and amidopyrroles, as well as anion-triggered deprotonation processes in neutral anion receptor systems, are discussed.     

REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors

We describe a drug-design strategy termed REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) in which nonpeptidic surrogates for specific determinants of known peptide ligands are identified in silico by using a core peptide-bound protein structure as a design anchor. In the REPLACE application example, we present the effective replacement of two critical binding motifs in a lead protein-protein interaction inhibitor pentapeptide with more druglike phenyltriazole and diphenyl ether groups. These were identified through docking of fragment libraries into the volume of the cyclin-binding groove of CDK2/cyclin A vacated through truncation of the inhibitor peptide-binding determinants. Proof of concept for this strategy was obtained through the generation of potent peptide-small-molecule hybrids and by the confirmation of inhibitor-binding modes in X-ray crystal structures. This method therefore allows nonpeptide fragments to be identified without the requirement for a high-sensitivity binding assay and should be generally applicable in replacing amino acids as individual residues or groups in peptide inhibitors to generate pharmaceutically acceptable lead molecules.     

Laminar mixing of shear thinning fluids in a SMX static mixer

Flow and mixing of power-law fluids in a standard SMX static mixer were simulated using computational fluid dynamics (CFD). Results showed that shear thinning reduces the ratio of pressure drop in the static mixer to pressure drop in empty tube as compared to Newtonian fluids. The correlations for pressure drop and friction factor were obtained at Re_MR?100. The friction factor is a function of both Reynolds number and power-law index. A proper apparent strain rate, area-weighted average strain rate on the solid surface in mixing section, was proposed to calculate pressure drop for a non-Newtonian fluid. Particle tracking showed that shear thinning fluids exhibit better mixing quality, lower pressure drop and higher mixing efficiency as compared to a Newtonian fluid in the SMX static mixer.     

Synthesis and self-association in aqueous media of poly(ethylene oxide)/poly(ethyl glycidyl carbamate) amphiphilic block copolymers

New temperature sensitive AB, ABA, and BAB amphiphilic block copolymers consisting of hydrophilic poly(ethylene oxide) and hydrophobic poly(ethyl glycidyl carbamate) blocks were synthesized by anionic polymerization followed by chemical modification reactions. The self-association of the block copolymers in aqueous media was studied by UV-vis spectroscopy and dynamic and static light scattering. The obtained block copolymers spontaneously form micelles in aqueous media. The critical micellization concentration varied from 0.5 to 4 g/L depending on the copolymer architecture and composition. The influence of the temperature upon the self-association of the block copolymers was investigated. The increase of temperature did not affect the value of the critical micellization concentration, but led to the formation of better defined micelles with narrow size distribution.     

Pressure effect of growing with electron beam-induced deposition with tungsten hexafluoride and tetraethylorthosilicate precursor

Electron beam-induced deposition (EBID) provides a simple way to fabricate submicron- or nanometer-scale structures from various elements in a scanning electron microscope (SEM). The growth rate and shape of the deposits are influenced by many factors. We have studied the growth rate and morphology of EBID-deposited nanostructures as a function of the tungsten hexafluoride (WF6) and tetraethylorthosilicate (TEOS) precursor gas pressure and growth time, and we have used Monte Carlo simulations to model the growth of tungsten and silicon oxide to elucidate the mechanisms involved in the EBID growth. The lateral radius of the deposit decreases with increasing pressure because of the enhanced vertical growth rate which limits competing lateral broadening produced by secondary and forward-scattered electrons. The morphology difference between the conical SiO(x) and the cylindrical W nanopillars is related to the difference in interaction volume between the two materials. A key parameter is the residence time of the precursor gas molecules. This is an exponential function of the surface temperature; it changes during nanopillar growth and is a function of the nanopillar material and the beam conditions.     

Quantitative31P nuclear magnetic resonance analysis of the phospholipids of erythrocyte membranes using detergent

³¹P Nuclear magnetic resonance (NMR) spectra of human erythrocyte lysates dissolved in sodium cholate were acquired. The narrow resonances of phospholipids were mostly well resolved, allowing identification and accurate quantitative analysis of phospholipid classes of the erythrocyte membranes. The ether-linked phosphatidylethanolamine components of the erythrocyte membranes were identified, based on the removal of plasmalogens by acidolysis and of diacyl phospholipid species by degradation using phospholipase A₁. It was also shown that the introduction of double bonds on the acyl chains of phosphatidylcholine shifted the³¹P NMR resonances to lower frequencies. Quantitative analyses of phospholipids from the spectra were based on their apparent molar concentrations. The recoveries of phospholipids from erythrocytes were significantly higher than those using conventional extraction procedures.     

Isolation of erucic acid from rapeseed oil by lipase-catalyzed hydrolysis

Three lipases were compared for their ability to hydrolyze high erucic acid rapeseed oil, with the objective of concentrating the erucic acid in a single glyceride fraction. Lipase fromPseudomonas cepacia released all fatty acids rapidly and did not result in selective distribution of erucic acid.Geotrichum candidum lipase released C20 and C22 fatty acids extremely slowly, resulting in their accumulation in the di- and triglyceride fractions. Less than 2% of the total erucic acid was found in the free fatty acid (FFA) fraction. Lipase fromCandida rugosa released erucic acid more slowly than C20 and C18 fatty acids at 35°C but only resulted in a limited accumulation of the erucic acid in the di- and triglyceride fractions. However, when hydrolysis catalyzed byC. rugosa lipase was carried out below 20°C, the reaction mixture solidified and was composed solely of FFAs and diglycerides. The diglyceride fraction contained approximately 95% erucic acid while about 20% of the total erucic acid was found in the FFA fraction. It is concluded that hydrolysis at low temperature withC. rugosa lipase results in a higher purity of erucic acid in the glyceride fraction than can be obtained withG. candidum lipase, but with considerable loss of erucic acid to the FFA fraction.     

百格拉直角坐标机器人用于汽车生产

德国百格拉公司是著名的机器人供应商,生产多种规格的直线运动单元／导轨、步进电动机、交流伺服电动机、直线电动机和多轴数控系统。以此为基础,在短时间内可提供各种规格的线性导轨,二维、三维标准机器人及用户专用机器人。这些机器人可以装备焊枪、通用手爪或专用工具,完成焊接、搬运、上下料、包装、码垛、拆垛、检测、探伤、分类、装配、贴标、喷码、打码及喷涂等一系列工作。由于百格拉的导轨、驱动电动机、减速机和控制系统等所有部件一直自己生产,这使得机器人整体性能更加优异。     

Ambient fine particulate air pollution triggers ST-elevation myocardial infarction, but not non-ST elevation myocardial infarction: a case-crossover study

Background

We and others have shown that increases in particulate air pollutant (PM) concentrations in the previous hours and days have been associated with increased risks of myocardial infarction, but little is known about the relationships between air pollution and specific subsets of myocardial infarction, such as ST-elevation myocardial infarction (STEMI) and non ST-elevation myocardial infarction (NSTEMI).

Methods

Using data from acute coronary syndrome patients with STEMI (n?=?338) and NSTEMI (n?=?339) and case-crossover methods, we estimated the risk of STEMI and NSTEMI associated with increased ambient fine particle (<2.5 um) concentrations, ultrafine particle (10-100 nm) number concentrations, and accumulation mode particle (100-500 nm) number concentrations in the previous few hours and days.

Results

We found a significant 18% increase in the risk of STEMI associated with each 7.1 μg/m³ increase in PM_2.5 concentration in the previous hour prior to acute coronary syndrome onset, with smaller, non-significantly increased risks associated with increased fine particle concentrations in the previous 3, 12, and 24 hours. We found no pattern with NSTEMI. Estimates of the risk of STEMI associated with interquartile range increases in ultrafine particle and accumulation mode particle number concentrations in the previous 1 to 96 hours were all greater than 1.0, but not statistically significant. Patients with pre-existing hypertension had a significantly greater risk of STEMI associated with increased fine particle concentration in the previous hour than patients without hypertension.

Conclusions

Increased fine particle concentrations in the hour prior to acute coronary syndrome onset were associated with an increased risk of STEMI, but not NSTEMI. Patients with pre-existing hypertension and other cardiovascular disease appeared particularly susceptible. Further investigation into mechanisms by which PM can preferentially trigger STEMI over NSTEMI within this rapid time scale is needed.     

David Godschalk

David R. Godschalk, professor emeritus in the Department of City and Regional Planning at the University of North Carolina, Chapel Hill, passed away in early 2018. In this essay we reflect on Dave’s planning scholarship and practice. We discuss his main contributions in 4 prominent areas. First is the importance of public participation and collaboration for the planning and governance of communities. He argued for democratizing and recasting public participation, with planners working alongside community members coproducing plans and incorporating uncertainty, new information, and different viewpoints. Second is Dave’s focus on the tenets of the comprehensive plan and its core element, the land use plan. In the plan, central principles of livable urban forms and model planning processes can be integrated and translated to practice. With academic collaborators and practitioners he pioneered theoretical and empirical research on what constitutes a high-quality plan, a fundamental question at the heart of planning. Third is his research demonstrating how spatial planning can be used for hazard mitigation and urban resilience. This work forged a new generation of planning academics and practitioners who focused on hazard plans for predisaster mitigation and postdisaster recovery at multiple governmental levels. Finally, fourth is his personal involvement in planning-related institutions that he helped create, lead, or steer. In his various roles as scholar, teacher, mentor, collaborator, supervisor, planning director, and elected official, Dave touched the lives of many who now build on his contributions in creating better communities.