J. Appl. Cryst.の発刊に際して

Adequate initial configurations for molecular dynamics simulations consist of arrangements of molecules distributed in space in such a way to approximately represent the system's overall structure. In order that the simulations are not disrupted by large van der Waals repulsive interactions, atoms from different molecules must keep safe pairwise distances. Obtaining such a molecular arrangement can be considered a packing problem: Each type molecule must satisfy spatial constraints related to the geometry of the system, and the distance between atoms of different molecules must be greater than some specified tolerance. We have developed a code able to pack millions of atoms, grouped in arbitrarily complex molecules, inside a variety of three-dimensional regions. The regions may be intersections of spheres, ellipses, cylinders, planes, or boxes. The user must provide only the structure of one molecule of each type and the geometrical constraints that each type of molecule must satisfy. Building complex mixtures, interfaces, solvating biomolecules in water, other solvents, or mixtures of solvents, is straightforward. In addition, different atoms belonging to the same molecule may also be restricted to different spatial regions, in such a way that more ordered molecular arrangements can be built, as micelles, lipid double-layers, etc. The packing time for state-of-the-art molecular dynamics systems varies from a few seconds to a few minutes in a personal computer. The input files are simple and currently compatible with PDB, Tinker, Molden, or Moldy coordinate files. The package is distributed as free software and can be downloaded from http://www.ime.unicamp.br/~martinez/packmol/.

/pdf/packmol-a-package-for-building-initial-configurations-for-qsy9r74wrw.pdf

PACKMOL: a package for building initial configurations for molecular dynamics simulations.

基礎講座 電気泳動(Electrophoresis)

It is important that the medical profession plays a significant role in critically evaluating the use of diagnostic procedures and therapies as they are introduced and tested in the detection, management, or prevention of disease states. Rigorous and expert analysis of the available data documenting absolute and relative benefits and risks of those procedures and therapies can produce helpful guidelines that improve the effectiveness of care, optimize patient outcomes, and favorably affect the overall cost of care by focusing resources on the most effective strategies.

The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have jointly engaged in the production of such guidelines in the area of cardiovascular disease since 1980. The ACC/AHA Task Force on Practice Guidelines, whose charge is to develop, update, or revise practice guidelines for important cardiovascular diseases and procedures, directs this effort. The Task Force is pleased to have this guideline developed in conjunction with the European Society of Cardiology (ESC). Writing committees are charged with the task of performing an assessment of the evidence and acting as an independent group of authors to develop or update written recommendations for clinical practice.

Experts in the subject under consideration have been selected from all 3 organizations to examine subject-specific data and write guidelines. The process includes additional representatives from other medical practitioner and specialty groups when appropriate. Writing committees are specifically charged to perform a formal literature review, weigh the strength of evidence for or against a particular treatment or procedure, and include estimates of expected health outcomes where data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that might influence the choice of particular tests or therapies are considered as well as frequency of follow-up and cost effectiveness. When available, information from studies on cost will be considered; however, review …

/pdf/acc-aha-esc-2006-guidelines-for-management-of-patients-with-5a3f1emfzy.pdf

ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death

The concept of metabolite profiling has been around for decades, but technical innovations are now enabling it to be carried out on a large scale with respect to the number of both metabolites measured and experiments carried out. Here we provide a detailed protocol for gas chromatography mass spectrometry (GC-MS)-based metabolite profiling that offers a good balance of sensitivity and reliability, being considerably more sensitive than NMR and more robust than liquid chromatography-linked mass spectrometry. We summarize all steps from collecting plant material and sample handling to derivatization procedures, instrumentation settings and evaluating the resultant chromatograms. We also define the contribution of GC-MS-based metabolite profiling to the fields of diagnostics, gene annotation and systems biology. Using the protocol described here facilitates routine determination of the relative levels of 300-500 analytes of polar and nonpolar extracts in approximately 400 experimental samples per week per machine.

Gas chromatography mass spectrometry–based metabolite profiling in plants

To take advantage of the charged aerosol detector (CAD) for sensitive LC analysis of analytes with weak chromophore, the volatility of the entire mobile phase is a prerequisite. Therefore, it is not feasible to use common non-volatile ion-pairing reagents such as tetrabutylammonium hydroxide for the analysis of polar, acidic amino acids. This case study presents a possible procedure for transferring an ion pair chromatography to an HPLC-CAD method using the example of carbocisteine and its two main degradation products, carbocisteine sulfoxide and carbocisteine lactam. In screening experiments, substitution by various volatile alkylamines resulted in inferior chromatographic separation. As an alternative, mixed-mode chromatography using a column with strong anion exchange functionalities and a mobile phase containing 12 mM formic acid and 2 mM trifluoroacetic acid, led to a selectivity equivalent to ion pair chromatography with tetrabutylammonium hydroxide. A change in the level of background noise generated by non-volatile impurities eluting from the column during measurements – often called column bleeding – invalidated the settings predicted from response surface methodology experiments in terms of modelling chromatographic selectivity and CAD sensitivity, and a reduction of the acetonitrile ratio to 22 % (v/v) was required. At a flow rate of 1.2 mL/min and an evaporation temperature of 65°C, the experimentally determined LOQs of both degradation products were below 50 ng on column. The combination of mixed-mode chromatography with CAD offers a viable alternative to ion pair chromatography with UV detection in the analysis of acidic analytes with a weak chromophore such as amino acids and impurities thereof.

Method transfer from ion pair chromatography to charged aerosol detector-compatible mixed-mode chromatography: a case study using carbocisteine

Monoclonal antibody infusions (mAb-i) are administered for the treatment of various diseases. They are often transported over long distances from the compounding site to the site of administration. However, transport studies are typically carried out with the original drug product but not with compounded mAb-i. To address this gap, the impact of mechanical stress on the formation of subvisible/nanoparticles in mAb-i was investigated by dynamic light scattering and flow imaging microscopy. Different mAb-i concentrations were subjected to vibrational orbital shaking and stored at 2-8°C up to 35 days. The screening revealed that pembrolizumab and bevacizumab infusions show the highest propensity for particle formation. Especially bevacizumab at low concentrations exhibited an increase in particle formation. Because of the unknown health risks associated with the long-term application of subvisible particles (SVPs)/nanoparticles in infusion bags, stability studies carried out in the frame of licensing application procedures should also focus on SVP formation in mAb-i. In general, pharmacists should minimize the time of storage and mechanical stress during transport, especially in the case of low-concentrated mAb-i. Moreover, if siliconized syringes are used, they should be washed once with saline solution to minimize particle entry.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ardp.202300101

An exploratory study on the effect of mechanical stress on particle formation in monoclonal antibody infusions.

Summary.By using microwave irradiation bisammonium-and bispyridinium-type allosteric modulators of muscarinic receptors can be obtained fast and efficiently.

Short Communication A Fast and Efficient Track to Allosteric Modulators of Muscarinic Receptors: Microwave-Assisted Syntheses

Schon lange wird uber den Wirkmechanismus des Analgetikums Paracetamol spekuliert. COX1 und COX2, die durch die nicht-steroidalen Analgetika blockiert werden, kamen bisher als Wirkort fur Paracetamol nicht in Frage. Vor einigen Jahren kam die COX3 ins Gesprach, diese Hypothese konnte aber nicht endgultig bestatigt werden.

Ulrike Holzgrabe

Papers

Method transfer from ion pair chromatography to charged aerosol detector-compatible mixed-mode chromatography: a case study using carbocisteine

An exploratory study on the effect of mechanical stress on particle formation in monoclonal antibody infusions.

Short Communication A Fast and Efficient Track to Allosteric Modulators of Muscarinic Receptors: Microwave-Assisted Syntheses

Wie wirkt Paracetamol? Ein weiterer Mosaikstein zum Wirkmechismus

Nature-inspired synthesis of antibacterial glucovanillin derivatives.