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Darmstadt, Germany

Merck KGaA is a German chemical and pharmaceutical company headquartered in Darmstadt, with around 40,000 employees in around 70 countries. Merck was founded in 1668 and is the world's oldest operating chemical and pharmaceutical company. The company was privately owned until going public in 1995. However, the Merck family still controls a majority of the company's shares.Following World War I, Merck lost possession of some of its foreign assets, including the Merck & Co. subsidiary in the United States. Merck & Co., which operates as Merck Sharp and Dohme outside the U.S. and Canada, is now an independent company. While Merck in Darmstadt is the legal successor of the original Merck and retains the rights to the name "Merck" in all countries except the U.S. and Canada, it is sometimes known as the "German Merck" or "Merck Darmstadt" in North America. The company was formerly also referred to as "E. Merck" .Merck KGaA operates mainly in Europe, Africa, Asia, Oceania and Latin America. Since Merck & Co. holds the rights to the Merck name in the U.S. and Canada, the company operated under the umbrella brand EMD Chemicals in North America, and since 2010 as EMD Millipore , formed from the initials of Emanuel Merck, Darmstadt. Wikipedia.

Samel S.A.,University of Marburg | Czodrowski P.,Merck KGaA | Essen L.-O.,University of Marburg
Acta Crystallographica Section D: Biological Crystallography

Tyrocidine, a macrocyclic decapeptide from Bacillus brevis, is nonribosomally assembled by a set of multimodular peptide synthetases, which condense two d-amino acids and eight l-amino acids to produce this membrane-disturbing antibiotic. d-Phenylalanine, the first amino acid incorporated into tyrocidine, is catalytically derived from enzyme-bound l-Phe by the C-terminal epimerization (E) domain of tyrocidine synthetase A (TycA). The 1.5Å resolution structure of the cofactor-independent TycA E domain reveals an intimate relationship to the condensation (C) domains of peptide synthetases. In contrast to the latter, the TycA E domain uses an enlarged bridge region to plug the active-site canyon from the acceptor side, whereas at the donor side a latch-like floor loop is suitably extended to accommodate the III helix of the preceding peptide-carrier domain. Additionally, E domains exclusively harbour a conserved glutamate residue, Glu882, that is opposite the active-site residue His743. This active-site topology implies Glu882 as a candidate acid-base catalyst, whereas His743 stabilizes in the protonated state a transient enolate intermediate of the l↔d isomerization. © 2014 International Union Of Crystallography. Source

Fiedler K.,Kinderwunsch Centrum Munich Fertility Center Munich | Ezcurra D.,Merck KGaA
Reproductive Biology and Endocrinology

Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of controlled ovarian stimulation (COS) as part of assisted reproductive technologies (ART). While the safety and efficacy of ART is well established, physicians should always be aware of the risk of OHSS in patients undergoing COS, as it can be fatal. This article will briefly present the pathophysiology of OHSS, including the key role of vascular endothelial growth factor (VEGF), to provide the foundation for an overview of current techniques for the prevention of OHSS. Risk factors and predictive factors for OHSS will be presented, as recognizing these risk factors and individualizing the COS protocol appropriately is the key to the primary prevention of OHSS, as the benefits and risks of each COS strategy vary among individuals. Individualized COS (iCOS) could effectively eradicate OHSS, and the identification of hormonal, functional and genetic markers of ovarian response will facilitate iCOS. However, if iCOS is not properly applied, various preventive measures can be instituted once COS has begun, including cancelling the cycle, coasting, individualizing the human chorionic gonadotropin trigger dose or using a gonadotropin-releasing hormone (GnRH) agonist (for those using a GnRH antagonist protocol), the use of intravenous fluids at the time of oocyte retrieval, and cryopreserving/vitrifying all embryos for subsequent transfer in an unstimulated cycle. Some of these techniques have been widely adopted, despite the scarcity of data from randomized clinical trials to support their use. © 2012 Fiedler and Ezcurra; licensee BioMed Central Ltd. Source

Harmonization of diagnostic nomenclature used in the pathology analysis of tissues from rodent toxicity studies will enhance the comparability and consistency of data sets from different laboratories worldwide. The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of four major societies of toxicologic pathology to develop a globally recognized nomenclature for proliferative and nonproliferative lesions in rodents. This article recommends standardized terms for classifying changes observed in tissues of the mouse and rat central (CNS) and peripheral (PNS) nervous systems. Sources of material include academic, government, and industrial histopathology databases from around the world. Covered lesions include frequent, spontaneous, and aging-related changes as well as principal toxicant-induced findings. Common artifacts that might be confused with genuine lesions are also illustrated. The neural nomenclature presented in this document is also available electronically on the Internet at the goRENI website (http://www.goreni.org/). Source

Rogov V.,Goethe University Frankfurt | Dotsch V.,Goethe University Frankfurt | Johansen T.,University of Tromso | Kirkin V.,Merck KGaA
Molecular Cell

Selective autophagy ensures recognition and removal of various cytosolic cargos. Hence, aggregated proteins, damaged organelles, or pathogens are enclosed into the double-membrane vesicle, the autophagosome, and delivered to the lysosome for degradation. This process is mediated by selective autophagy receptors, such as p62/SQSTM1. These proteins recognize autophagic cargo and, via binding to small ubiquitin-like modifiers (UBLs)-Atg8/LC3/GABARAPs and ATG5-mediate formation of selective autophagosomes. Recently, it was found that UBLs can directly engage the autophagosome nucleation machinery. Here, we review recent findings on selective autophagy and propose a model for selective autophagosome formation in close proximity to cargo. © 2014 Elsevier Inc. Source

Czodrowski P.,Merck KGaA
Journal of Chemical Information and Modeling

A detailed analysis of the hERG content inside the ChEMBL database is performed. The correlation between the outcome from binding assays and functional assays is probed. On the basis of descriptor distributions, design paradigms with respect to structural and physicochemical properties of hERG active and hERG inactive compounds are challenged. Finally, classification models with different data sets are trained. All source code is provided, which is based on the Python open source packages RDKit and scikit-learn to enable the community to rerun the experiments. The code is stored on github (https://github.com/pzc/herg-chembl-jcim). © 2013 American Chemical Society. Source

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