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https://www.readbyqxmd.com/read/28109060/morphine-pharmacodynamics-in-mechanically-ventilated-preterm-neonates-undergoing-endotracheal-suctioning
#1
P A Välitalo, Ehj Krekels, M van Dijk, Shp Simons, D Tibboel, Caj Knibbe
To date, morphine pharmacokinetics (PKs) are well quantified in neonates, but results about its efficacy are ambiguous. This work presents an analysis of a previously published study on pain measurements in mechanically ventilated preterm neonates who received either morphine or placebo to improve comfort during invasive ventilation. The research question was whether morphine reduces the pain associated with endotracheal or nasal suctioning before, during, and after suctioning. Because these neonates cannot verbalize their pain levels, pain was assessed on the basis of several validated pain measurement instruments (i...
January 21, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28106709/systemic-pharmacokinetics-and-pharmacodynamics-of-intravitreal-aflibercept-bevacizumab-and-ranibizumab
#2
Robert L Avery, Alessandro A Castellarin, Nathan C Steinle, Dilsher S Dhoot, Dante J Pieramici, Robert See, Stephen Couvillion, Maʼan A Nasir, Melvin D Rabena, Mauricio Maia, Sherri Van Everen, Kha Le, William D Hanley
PURPOSE: To evaluate the systemic pharmacokinetics (PKs) of aflibercept, bevacizumab, and ranibizumab in patients with neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO). METHODS: Prospective, open-label, nonrandomized clinical trial of patients with AMD, DME, or RVO who were antivascular endothelial growth factor (VEGF) naïve or had not received anti-VEGF for ≥4 months. Patients received 3 monthly intravitreal injections of aflibercept 2...
January 18, 2017: Retina
https://www.readbyqxmd.com/read/28106181/in-vitro-kinetic-study-of-the-squalestatin-tetraketide-synthase-dehydratase-reveals-the-stereochemical-course-of-a-fungal-highly-reducing-polyketide-synthase
#3
Emma Liddle, Alan Scott, Li-Chen Han, David Ivison, Thomas J Simpson, Christine L Willis, Russell J Cox
Six potential diketide substrates for the squalestatin tetraketide synthase (SQTKS) dehydratase (DH) domain were synthesised as N-acetyl cysteamine thiolesters (SNAC) and tested in kinetic assays as substrates with an isolated DH domain. 3R-3-hydroxybutyryl SNAC 3R-16 was turned over by the enzyme, but its enantiomer was not. Of the four 2-methyl substrates only 2R,3R-2-methyl-3-hydroxybutyryl SNAC 2R,3R-8 was a substrate. Combined with stereochemical information from the isolated SQTKS enoyl reductase (ER) domain, our results provide a near complete stereochemical description of the first cycle of beta-modification reactions of a fungal highly reducing polyketide synthase (HR-PKS)...
January 20, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28103677/inversion-of-extender-unit-selectivity-in-the-erythromycin-polyketide-synthase-by-acyltransferase-domain-engineering
#4
Irina Koryakina, Christian Kasey, John B McArthur, Andrew N Lowell, Joseph A Chemler, Shasha Li, Douglas A Hansen, David H Sherman, Gavin J Williams
Acyltransferase (AT) domains of polyketide synthases (PKSs) select extender units for incorporation into polyketides and dictate large portions of the structures of clinically relevant natural products. Accordingly, there is significant interest in engineering the substrate specificity of PKS ATs in order to site-selectively manipulate polyketide structure. However, previous attempts to engineer ATs have yielded mutant PKSs with relaxed extender unit specificity, rather than an inversion of selectivity from one substrate to another...
January 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28102686/one-pot-enzymatic-total-synthesis-of-presteffimycinone-an-early-intermediate-of-the-anthracycline-antibiotic-steffimycin-biosynthesis
#5
Guojun Wang, Jing Chen, Haining Zhu, Jürgen Rohr
Early acting cyclases play critical roles in programming the polyketide biosynthesis toward certain, distinguished scaffolds. Starting from acetyl-CoA and malonyl-CoA, a one-pot enzymatic total synthesis of an anthracyclinone scaffold, presteffimycinone, was achieved by mixing polyketide synthase (PKS) and early post-PKS enzymes from the biosynthetic pathways of three different types of type II-PKS driven anticancer antibiotics, namely, the mithramycin (aureolic acid-type), gilvocarcin (rearranged angucycline-type), and steffimycin (anthracycline) pathways...
January 19, 2017: Organic Letters
https://www.readbyqxmd.com/read/28098952/solving-the-puzzle-of-one-carbon-loss-in-ripostatin-biosynthesis
#6
Chengzhang Fu, David Auerbach, Yanyan Li, Ullrich Scheid, Eva Luxenburger, Ronald Garcia, Herbert Irschik, Rolf Müller
Ripostatin is a promising antibiotic that inhibits RNA polymerase by binding to a novel binding site. In this study, the characterization of the biosynthetic gene cluster of ripostatin, which is a peculiar polyketide synthase (PKS) hybrid cluster encoding cis- and trans-acyltransferase PKS genes, is reported. Moreover, an unprecedented mechanism for phenyl acetic acid formation and loading as a starter unit was discovered. This phenyl-C2 unit is derived from phenylpyruvate (phenyl-C3) and the mechanism described herein explains the mysterious loss of one carbon atom in ripostatin biosynthesis from the phenyl-C3 precursor...
January 18, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28098949/identification-of-cellular-targets-involved-in-cardiac-failure-caused-by-pki-in-oncology-an-approach-combining-pharmacovigilance-and-pharmacodynamics
#7
E Patras de Campaigno, E Bondon-Guitton, G Laurent, F Montastruc, J L Montastruc, M Lapeyre-Mestre, F Despas
AIMS: To evaluate the risk of cardiac failure (CF) of 15 anticancer protein kinase inhibitors (PKIs) through a case/non-case analysis and to identify which PK(s) and pathways are involved in PKI-induced CF. METHODS: To evaluate the risk of CF, adjusted reporting odds ratios (aRORs) were calculated for the 15 anticancer PKIs in the WHO safety report database (VigiBase®). We realised a literature review to identify 21 PK possibly involved in CF caused by PKIs. Pearson's correlation coefficients (r) between aROR and affinity data of the 15 PKIs for the 21 PKs were calculated to identify the cellular target most likely involved in PKI-induced CF...
January 18, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28096394/elucidating-the-mechanism-of-fluorinated-extender-unit-loading-for-improved-production-of-fluorine-containing-polyketides
#8
Omer Ad, Benjamin W Thuronyi, Michelle C Y Chang
Polyketides are a large family of bioactive natural products synthesized by polyketide synthase (PKS) enzyme complexes predominantly from acetate and propionate. Given the structural diversity of compounds produced using these two simple building blocks, there has been longstanding interest in engineering the incorporation of alternative extender units. We have been investigating the mechanism of fluorinated monomer insertion by three of the six different modules of the PKS involved in erythromycin biosynthesis (6-deoxyerythronolide B synthase, DEBS) to begin understanding the contribution of different steps, such as enzyme acylation, transacylation, C-C bond formation, and chain transfer, to the overall selectivity and efficiency of this process...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28095865/engineered-biosynthesis-of-milbemycins-in-the-avermectin-high-producing-strain-streptomyces-avermitilis
#9
Myoun-Su Kim, Wan-Je Cho, Myoung Chong Song, Seong-Whan Park, Kaeun Kim, Eunji Kim, Naryeong Lee, Sang-Jip Nam, Ki-Hoon Oh, Yeo Joon Yoon
BACKGROUND: Milbemycins, produced from Streptomyces hygroscopicus subsp. aureolacrimosus and Streptomyces bingchenggensis, are 16-membered macrolides that share structural similarity with avermectin produced from Streptomyces avermitilis. Milbemycins possess strong acaricidal, insecticidal, and anthelmintic activities but low toxicity. Due to the high commercial value of the milbemycins and increasing resistance to the avermectins and their derivatives, it is imperative to develop an efficient combinatorial biosynthesis system exploiting an overproduction host strain to produce the milbemycins and novel analogs in large quantities...
January 17, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/28078214/pharmacology-of-testosterone-replacement-therapy-preparations
#10
REVIEW
Jennifer J Shoskes, Meghan K Wilson, Michael L Spinner
The goal of testosterone replacement therapy (TRT) is to return serum testosterone levels to within physiologic range and improve symptoms in hypogonadal men. Some of the symptoms aimed to improve upon include decreased libido, erectile dysfunction, infertility, hot flashes, depressed mood, and loss of muscle mass or hair. Clinical use of testosterone for replacement therapy began approximately 70 years ago. Over the decades, numerous preparations and formulations have been developed primarily focusing on different routes of delivery and thus pharmacokinetics (PKs)...
December 2016: Translational Andrology and Urology
https://www.readbyqxmd.com/read/28066819/growth-on-chitin-impacts-the-transcriptome-and-metabolite-profiles-of-antibiotic-producing-vibrio-coralliilyticus-s2052-and-photobacterium-galatheae-s2753
#11
Sonia Giubergia, Christopher Phippen, Kristian Fog Nielsen, Lone Gram
Members of the Vibrionaceae family are often associated with chitin-containing organisms, and they are thought to play a major role in chitin degradation. The purpose of the present study was to determine how chitin affects the transcriptome and metabolome of two bioactive Vibrionaceae strains, Vibrio coralliilyticus and Photobacterium galatheae. We focused on chitin degradation genes and secondary metabolites based on the assumption that these molecules in nature confer an advantage to the producer. Growth on chitin caused upregulation of genes related to chitin metabolism and of genes potentially involved in host colonization and/or infection...
January 2017: MSystems
https://www.readbyqxmd.com/read/28054175/directed-accumulation-of-less-toxic-pimaricin-derivatives-by-improving-the-efficiency-of-a-polyketide-synthase-dehydratase-domain
#12
Zhen Qi, Yucong Zhou, Qianjin Kang, Chunyan Jiang, Jianting Zheng, Linquan Bai
Pimaricin is an important polyene antifungal antibiotic that binds ergosterol and extracts it from fungal membranes. In previous work, two pimaricin derivatives (1 and 2) with improved pharmacological activities and another derivative (3) that showed no antifungal activity were produced by the mutant strain of Streptomyces chattanoogensis, in which the P450 monooxygenase gene scnG has been inactivated. Furthermore, inactivation of the DH12 dehydratase domain of the pimaricin polyketide synthases (PKSs) resulted in specific accumulation of the undesired metabolite 3, suggesting that improvement of the corresponding dehydratase activity may reduce or eliminate the accumulation of 3...
January 4, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28040135/pallister-killian-syndrome-cytogenetics-and-molecular-investigations-of-mosaic-tetrasomy-12p-in-prenatal-chorionic-villus-and-in-amniocytes-strategy-of-prenatal-diagnosis
#13
Francesco Libotte, Domenico Bizzoco, Ivan Gabrielli, Alvaro Mesoraca, Pietro Cignini, Salvatore Giovanni Vitale, Ilaria Marilli, Ferdinando Antonio Gulino, Agnese Maria Chiara Rapisarda, Claudio Giorlandino
OBJECTIVE: Pallister-Killian syndrome (PKS) is a rare, sporadic genetic disorder caused by mosaic tetrasomy of the short arm of chromosome 12 (12p). Clinically, PKS is characterized by several systemic abnormalities, such as intellectual impairment, hearing loss, epilepsy, hypotonia, craniofacial dysmorphism, pigmentary skin anomalies, epilepsy, and a variety of congenital malformations. Prenatally, PKS can be suspected in the presence of ultrasound anomalies: diaphragmatic hernia, rhizomelic micromelia, hydrops fetalis, fetal overweight, ventriculomegaly in the central nervous system, congenital heart defects, or absent visualization of the stomach...
December 2016: Taiwanese Journal of Obstetrics & Gynecology
https://www.readbyqxmd.com/read/28032946/population-pharmacokinetics-modeling-of-unbound-efavirenz-atazanavir-and-ritonavir-in-hiv-infected-subjects-with-aging-biomarkers
#14
J B Dumond, J Chen, M Cottrell, C R Trezza, Hma Prince, C Sykes, C Torrice, N White, S Malone, R Wang, K B Patterson, N E Sharpless, A Forrest
Unbound drug is the pharmacodynamically relevant concentration. This study aimed to determine if chronologic age or markers of biologic aging, such as the frailty phenotype and p16(INK4a) gene expression, altered unbound pharmacokinetics (PKs) of efavirenz (EFV) and atazanavir/ritonavir (ATV/RTV). Sixty human immunodeficiency virus (HIV)-infected participants receiving EFV and 31 receiving ATV/RTV provided 1 to 11 samples to quantify total and unbound plasma concentrations. Population PK models with total and unbound concentrations simultaneously described are developed for each drug...
December 29, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28019088/p16-ink4a-a-senescence-marker-influences-tenofovir-emtricitabine-metabolite-disposition-in-hiv-infected-subjects
#15
J B Dumond, J W Collins, M L Cottrell, C R Trezza, Hma Prince, C Sykes, C Torrice, N White, S Malone, R Wang, K B Patterson, N E Sharpless, A Forrest
The goal of this study was to explore the relationships between tenofovir (TFV) and emtricitabine (FTC) disposition and markers of biologic aging, such as the frailty phenotype and p16(INK4a) gene expression. Chronologic age is often explored in population pharmacokinetic (PK) analyses, and can be uninformative in capturing the impact of aging on physiology, particularly in human immunodeficiency virus (HIV)-infected patients. Ninety-one HIV-infected participants provided samples to quantify plasma concentrations of TFV/FTC, as well as peripheral blood mononuclear cell (PBMC) samples for intracellular metabolite concentrations; 12 participants provided 11 samples, and 79 participants provided 4 samples, over a dosing interval...
December 26, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28017636/identification-and-first-characterization-of-smeps8-a-potential-interaction-partner-of-smtk3-and-ser-transcribed-in-the-gonads-of-schistosoma-mansoni
#16
C Buro, C Burmeister, T Quack, C G Grevelding
In eukaryotes the roles of protein kinases (PKs) regulating important biological processes such as growth and differentiation are well known. Molecular, biochemical, and physiological analyses trying to unravel principles of schistosome development have substantiated the importance for PKs also in this parasite. Amongst others the role of SmTK3 was studied, one of the first cellular PKs characterized from Schistosoma mansoni. Its function was demonstrated in mitogenic and differentiation processes in the gonads...
December 22, 2016: Experimental Parasitology
https://www.readbyqxmd.com/read/28010735/several-steps-of-lateral-gene-transfer-followed-by-events-of-birth-and-death-evolution-shaped-a-fungal-sorbicillinoid-biosynthetic-gene-cluster
#17
Irina S Druzhinina, Eva M Kubicek, Christian P Kubicek
BACKGROUND: Sorbicillinoids are a family of complex cyclic polyketides produced by only a small number of distantly related ascomycete fungi such as Trichoderma (Sordariomycetes) and Penicillium (Eurotiomycetes). In T. reesei, they are synthesized by a gene cluster consisting of eight genes including two polyketide synthases (PKS). To reconstruct the evolutionary origin of this gene cluster, we examined the occurrence of these eight genes in ascomycetes. RESULTS: A cluster comprising at least six of them was only found in Hypocreales (Acremonium chrysogenum, Ustilaginoidea virens, Trichoderma species from section Longibrachiatum) and in Penicillium rubens (Eurotiales)...
December 7, 2016: BMC Evolutionary Biology
https://www.readbyqxmd.com/read/28005187/improved-pestalotiollide-b-production-by-deleting-competing-polyketide-synthase-genes-in-pestalotiopsis-microspora
#18
Longfei Chen, Yingying Li, Qian Zhang, Dan Wang, Oren Akhberdi, Dongsheng Wei, Jiao Pan, Xudong Zhu
Pestalotiollide B, an analog of dibenzodioxocinones which are inhibitors of cholesterol ester transfer proteins, is produced by Pestalotiopsis microspora NK17. To increase the production of pestalotiollide B, we attempted to eliminate competing polyketide products by deleting the genes responsible for their biosynthesis. We successfully deleted 41 out of 48 putative polyketide synthases (PKSs) in the genome of NK17. Nine of the 41 PKS deleted strains had significant increased production of pestalotiollide B (P < 0...
December 22, 2016: Journal of Industrial Microbiology & Biotechnology
https://www.readbyqxmd.com/read/28004519/antimicrobial-assay-and-genetic-screening-of-selected-freshwater-cyanobacteria-and-identification-of-a-biomolecule-dihydro-2h-pyran-2-one-derivative
#19
A Srivastava, V K Singh, S Patnaik, J Tripathi, P Singh, G Nath, R K Asthana
AIMS: Explorations of freshwater cyanobacteria as antimicrobial (bacteria, fungi and MRSA strains) drug resource using bioassay, NRPS (non-ribosomal polypeptide synthetase) and PKS (polyketide synthase) genes, as well as in silico approach. METHODS AND RESULTS: We have bioassayed the extracts of Phormidium CCC727, Geitlerinema CCC728, Arthrospira CCC729, Leptolyngbya CCC732, Phormidium CCC730, Phormidium CCC731 against six pathogenic bacteria Gram (+ve): Staphylococcus aureus including seven clinical methicillin-resistant S...
December 22, 2016: Journal of Applied Microbiology
https://www.readbyqxmd.com/read/27976343/biosynthesis-of-mycotoxin-tenuazonic-acid-by-novel-type-of-fungal-pks-nrps-hybrid-enzyme
#20
C S Yun, T Motoyama, H Osada
No abstract text is available yet for this article.
December 2016: Planta Medica
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