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https://www.readbyqxmd.com/read/28207984/structural-basis-of-microtubule-stabilization-by-discodermolide
#1
Andrea E Prota, Katja Bargsten, Mariano Redondo, Amos B Smith Iii, Chia-Ping H Yang, Hayley M McDaid, Ian Paterson, Susan B Horwitz, José Fernando Díaz, Michel O Steinmetz
Microtubule-stabilizing agents (MSAs) are widely used in chemotherapy. Here, using X-ray crystallography we describe the detailed binding modes of two potent MSAs, (+)-discodermolide (DDM) and the DDM-paclitaxel-hybrid KS-1-199-32, in the taxane pocket of ß-tubulin. Both compounds bind in a very similar hairpin conformation as previously observed in solution. However, they differentially stabilize the M-loop of ß-tubulin: KS-1-199-32 induces an M-loop helical conformation that is not observed for DDM. In the context of the microtubule structure, both MSAs connect the ß-tubulin helices H6 and H7 and loop S9-S10 with the M-loop, which is similar to the structural effects elicited by epothilone A, but distinct from paclitaxel...
February 16, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28199769/protein-templated-formation-of-an-inhibitor-of-the-blood-coagulation-factor%C3%A2-xa-through-a-background-free-amidation-reaction
#2
Mike Jaegle, Torsten Steinmetzer, Jörg Rademann
Protein-templated reactions enable the target-guided formation of protein ligands from reactive fragments, ideally with no background reaction. Herein, we investigate the templated formation of amides. A nucleophilic fragment that binds to the coagulation factor Xa was incubated with the protein and thirteen differentially activated dipeptides. The protein induced a non-catalytic templated reaction for the phenyl and trifluoroethyl esters; the latter was shown to be a completely background-free reaction. Starting from two fragments with millimolar affinity, a 29 nm superadditive inhibitor of factor Xa was obtained...
February 15, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28193641/a-method-for-high-throughput-production-of-sequence-verified-dna-libraries-and-strain-collections
#3
Justin D Smith, Ulrich Schlecht, Weihong Xu, Sundari Suresh, Joe Horecka, Michael J Proctor, Raeka S Aiyar, Richard A O Bennett, Angela Chu, Yong Fuga Li, Kevin Roy, Ronald W Davis, Lars M Steinmetz, Richard W Hyman, Sasha F Levy, Robert P St Onge
The low costs of array-synthesized oligonucleotide libraries are empowering rapid advances in quantitative and synthetic biology. However, high synthesis error rates, uneven representation, and lack of access to individual oligonucleotides limit the true potential of these libraries. We have developed a cost-effective method called Recombinase Directed Indexing (REDI), which involves integration of a complex library into yeast, site-specific recombination to index library DNA, and next-generation sequencing to identify desired clones...
February 13, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28192676/crossing-boundaries
#4
Leighton Ku, Erika Steinmetz, Tyler Bysshe, Brian K Bruen
OBJECTIVES: Previous state interagency collaborations have led to successful tobacco cessation initiatives. The objective of this study was to assess the roles and interaction of state Medicaid and public health agency efforts to support tobacco cessation for low-income Medicaid beneficiaries. METHODS: We interviewed Medicaid and state public health agency officials in 8 states in September and October 2015 about collaborations in policy development and implementation for Medicaid tobacco cessation, including Medicaid coverage policies, quitlines, and monitoring...
January 1, 2017: Public Health Reports
https://www.readbyqxmd.com/read/28188208/quantitative-detection-of-burkholderia-pseudomallei-in-soil-samples-using-multiple-gene-targets-in-real-time-pcr
#5
A Göhler, T T Trung, V Hopf, C Kohler, J Hartleib, V Wuthiekanun, S J Peacock, D Limmathurotsakul, A Tuanyok, I Steinmetz
Burkholderia pseudomallei is present in the environment in many parts of the world and causes the often-fatal disease melioidosis. The sensitive detection and quantification of B. pseudomallei in the environment is a prerequisite to assess the risk of infection. We recently reported the direct detection of B. pseudomallei in soil samples using a qPCR targeting a single type three secretion system 1 (TTSS1) gene. Here, we extend the qPCR-based analysis of B. pseudomallei in soil by validating novel qPCR gene targets selected from comparative genomic analysis...
February 10, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28175308/population-pharmacokinetics-and-dosing-simulations-of-ceftazidime-in-critically-ill-patients-receiving-sustained-low-efficiency-dialysis
#6
Christina König, Stephan Braune, Jason A Roberts, Axel Nierhaus, Oliver M Steinmetz, Michael Baehr, Otto R Frey, Claudia Langebrake, Stefan Kluge
No abstract text is available yet for this article.
February 8, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28169959/the-impact-of-preoperative-depression-on-hospital-consumer-assessment-of-healthcare-providers-and-systems-hcahps-survey-results-in-a-lumbar-fusion-population
#7
Jay M Levin, Robert D Winkelman, Gabriel A Smith, Joseph Tanenbaum, Edward C Benzel, Thomas E Mroz, Michael P Steinmetz
STUDY DESIGN: A retrospective cohort study at a single institution. OBJECTIVE: To determine the effect of preoperative depression on Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey scores in a lumbar fusion population. SUMMARY OF BACKGROUND DATA: HCAHPS surveys are used to assess the quality of the patient experience, and directly influences reimbursement for hospital systems and spine surgeons nationwide. Untreated depression has been linked to worse functional outcomes in spine surgery...
February 6, 2017: Spine
https://www.readbyqxmd.com/read/28167371/updating-irradiated-graphite-disposal-project-grapa-and-the-international-decommissioning-network
#8
Anthony Wickham, Hans-Jürgen Steinmetz, Patrick O'Sullivan, Michael I Ojovan
Demonstrating competence in planning and executing the disposal of radioactive wastes is a key factor in the public perception of the nuclear power industry and must be demonstrated when making the case for new nuclear build. This work addresses the particular waste stream of irradiated graphite, mostly derived from reactor moderators and amounting to more than 250,000 tonnes world-wide. Use may be made of its unique chemical and physical properties to consider possible processing and disposal options outside the normal simple classifications and repository options for mixed low or intermediate-level wastes...
February 3, 2017: Journal of Environmental Radioactivity
https://www.readbyqxmd.com/read/28161814/soil-myxobacteria-as-a-potential-source-of-polyketide-peptide-substances
#9
Ivana Charousová, Heinrich Steinmetz, Juraj Medo, Soňa Javoreková, Joachim Wink
Myxobacteria, a group of antimicrobial producing bacteria, have been successfully cultured and characterized from ten soil samples collected from different parts of Slovakia. A total of 79 myxobacteria belonging to four genera (Myxococcus, Corallococcus, Sorangium, and Polyangium) were isolated based on aspects of their life cycle. Twenty-five of them were purified, fermented, and screened for antimicrobial activities against 11 test microorganisms. Results indicated that crude extracts showed more significant activities against Gram-positive than against Gram-negative bacteria or fungi...
February 4, 2017: Folia Microbiologica
https://www.readbyqxmd.com/read/28161286/meg-and-eeg-demonstrate-similar-test-retest-reliability-of-the-40hz-auditory-steady-state-response
#10
Kristina T Legget, Allison K Hild, Sarah E Steinmetz, Steven T Simon, Donald C Rojas
The auditory steady-state response (ASSR) is increasingly being used as a biomarker in neuropsychiatric disorders, but research investigating the test-retest reliability of this measure is needed. We previously reported ASSR reliability, measured by electroencephalography (EEG), to 40Hz amplitude-modulated white noise and click train stimuli. The purpose of the current study was to (a) assess the reliability of the MEG-measured ASSR to 40Hz amplitude-modulated white noise and click train stimuli, and (b) compare test-retest reliability between MEG and EEG measures of ASSR, which has not previously been investigated...
February 1, 2017: International Journal of Psychophysiology
https://www.readbyqxmd.com/read/28144662/potato-virus-x-a-filamentous-plant-viral-nanoparticle-for-doxorubicin-delivery-in-cancer-therapy
#11
Duc H T Le, Karin L Lee, Sourabh Shukla, Ulrich Commandeur, Nicole F Steinmetz
Plant viral nanoparticles (VNPs) are a novel class of nanocarriers with implications for drug delivery in cancer therapy. VNPs are characterized by their highly symmetrical nanoscale structures. Furthermore, plant VNPs are biocompatible, biodegradable, and non-infectious in mammals. VNPs provide a proteinaceous platform technology that can be readily engineered to carry contrast agents and therapies using chemical and genetic modifications. Of particular interest are high aspect ratio, elongated filaments such as the ones formed by potato virus X (PVX, measuring 515 × 13 nm)...
February 9, 2017: Nanoscale
https://www.readbyqxmd.com/read/28128474/mimicking-the-regulation-step-of-fe-monooxygenases-allosteric-modulation-of-fe-iv-oxo-formation-by-guest-binding-in-a-dinuclear-zn-ii-fe-ii-calix-6-arene-based-funnel-complex
#12
Nathalie Ségaud, Constance De Thomasson, Caroline Daverat, Katell Sénéchal-David, Amandine Dos Santos, Vincent Steinmetz, Philippe Maître, Jean-Noël Rebilly, Frédéric Banse, Olivia Reinaud
A heteroditopic ligand associated with a calix[6]arene scaffold bearing a tris(imidazole) coordinating site at its small rim and an amine/pyridine ligand at its large rim has been prepared, and its regioselective coordination to Zn(II) at the small rim and Fe(II) in the amine/pyridine ligand has been achieved. The heterodinuclear complex obtained displays an overall cone conformation capped by the tris(imidazole)Zn(II) moiety and bears a non-heme Fe(II) complex at its base. Each of the metal centers exhibits one labile position, allowing the coordination inside the cavity of a guest alkylamine at Zn(II) and the generation of reaction intermediates (Fe(III) (OOH) and Fe(IV) O) at the large rim...
January 27, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28125793/the-state-of-systems-genetics-in-2017
#13
Nitin S Baliga, Johan L M Björkegren, Jef D Boeke, Michael Boutros, Nigel P S Crawford, Aimée M Dudley, Charles R Farber, Allan Jones, Allan I Levey, Aldons J Lusis, H Craig Mak, Joseph H Nadeau, Marcus B Noyes, Enrico Petretto, Nicholas T Seyfried, Lars M Steinmetz, Sibylle C Vonesch
Cell Systems invited 16 experts to share their views on the field of systems genetics. In questions repeated in the headings, we asked them to define systems genetics, highlight its relevance to researchers outside the field, discuss what makes a strong systems genetics paper, and paint a picture of where the field is heading in the coming years. Their responses, ordered by the journal but otherwise unedited, make it clear that deciphering genotype to phenotype relationships is a central challenge of systems genetics and will require understanding how networks and higher-order properties of biological systems underlie complex traits...
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28121424/polymer-structure-and-conformation-alter-the-antigenicity-of-virus-like-particle-polymer-conjugates
#14
Parker W Lee, Sergey A Isarov, Jaqueline D Wallat, Sudheer K Molugu, Sourabh Shukla, Jessie E P Sun, Jun Zhang, Yi Zheng, Melissa Lucius Dougherty, Dominik Konkolewicz, Phoebe L Stewart, Nicole F Steinmetz, Michael J A Hore, Jonathan K Pokorski
Covalent conjugation of water-soluble polymers to proteins is critical for evading immune surveillance in the field of biopharmaceuticals. The most common and long-standing polymer modification is the attachment of methoxypoly(ethylene glycol) (mPEG), termed PEGylation, which has led to several clinically approved pharmaceuticals. Recent data indicate that brush-type polymers significantly enhance in vitro and in vivo properties. Herein, the polymer conformation of poly(ethylene glycol) is detailed and compared with those of water-soluble polyacrylate and polynorbornene (PNB) when attached to icosahedral virus-like particles...
January 25, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28117813/setting-up-a-stroke-team-algorithm-and-conducting-simulation-based-training-in-the-emergency-department-a-practical-guide
#15
Damla Tahtali, Ferdinand Bohmann, Peter Rostek, Marlies Wagner, Helmuth Steinmetz, Waltraud Pfeilschifter
Time is of the essence when caring for an acute stroke patient. The ultimate goal is to restore blood flow to the ischemic brain. This can be achieved by either thrombolysis with recombinant tissue-plasminogen activator (rt-PA), the standard therapy for stroke patients who present within the first hours of symptom onset without contraindications, or by an endovascular approach, if a proximal brain vessel occlusion is detected. As the efficacy of both therapies declines over time, every minute saved along the way will improve the patient's outcome...
January 15, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28116233/longitudinal-changes-of-cortical-microstructure-in-parkinson-s-disease-assessed-with-t1-relaxometry
#16
Lucas Nürnberger, René-Maxime Gracien, Pavel Hok, Stephanie-Michelle Hof, Udo Rüb, Helmuth Steinmetz, Rüdiger Hilker, Johannes C Klein, Ralf Deichmann, Simon Baudrexel
BACKGROUND: Histological evidence suggests that pathology in Parkinson's disease (PD) goes beyond nigrostriatal degeneration and also affects the cerebral cortex. Quantitative MRI (qMRI) techniques allow the assessment of changes in brain tissue composition. However, the development and pattern of disease-related cortical changes have not yet been demonstrated in PD with qMRI methods. The aim of this study was to investigate longitudinal cortical microstructural changes in PD with quantitative T1 relaxometry...
2017: NeuroImage: Clinical
https://www.readbyqxmd.com/read/28112764/cryo-electron-tomography-investigation-of-serum-albumin-camouflaged-tobacco-mosaic-virus-nanoparticles
#17
Neetu M Gulati, Andrzej S Pitek, Nicole F Steinmetz, Phoebe L Stewart
Nanoparticles offer great potential in drug delivery and imaging, but shielding strategies are necessary to increase circulation time and performance. Structure-function studies are required to define the design rules to achieve effective shielding. With several formulations reaching clinical testing and approval, the ability to assess and detail nanoparticle formulations at the single particle level is becoming increasingly important. To address this need, we use cryo-electron tomography (cryo-ET) to investigate stealth-coated nanoparticles...
January 23, 2017: Nanoscale
https://www.readbyqxmd.com/read/28108987/activation-of-sirt1-by-human-chorionic-gonadotropin-exerts-a-therapeutic-effect-on-hepatic-injury-and-inflammation
#18
Caroline Steinmetz, Anubha Kashyap, Nataliya Zhivkova, Henry Alizor, Isabell Ernst, Daniela Gottfried-Brand, Henning Janssen, Andreas Teufel, Henning Schulze-Bergkamen, Johannes Lotz, Jürgen Kuball, Matthias Theobald, Michael Heise, Hauke Lang, Peter R Galle, Dennis Strand, Susanne Strand
: The incidence and prevalence of inflammatory liver diseases has increased over the last years but therapeutic options are limited. Pregnancy induces a state of immune tolerance, which can result in spontaneous improvement of clinical symptoms of certain autoimmune diseases including autoimmune hepatitis (AIH). We investigated the immune suppressive mechanisms of the human pregnancy hormone chorionic gonadotropin (hCG) in the liver. HCG signaling activates SIRT1, which deacetylates FOXO3a, leading to repression of pro-apoptotic gene expression...
January 21, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28108469/blood-rna-biomarkers-in-prodromal-park4-and-rem-sleep-behavior-disorder-show-role-of-complexin-1-loss-for-risk-of-parkinson-s-disease
#19
Suna Lahut, Suzana Gispert, Özgür Ömür, Candan Depboylu, Kay Seidel, Jorge Antolio Domínguez-Bautista, Nadine Brehm, Hülya Tireli, Karl Hackmann, Caroline Pirkevi, Barbara Leube, Vincent Ries, Kerstin Reim, Nils Brose, Wilfred F den Dunnen, Madrid Johnson, Zsuzsanna Wolf, Marc Schindewolf, Wiebke Schrempf, Kathrin Reetz, Peter Young, David Vadasz, Achilleas S Frangakis, Evelin Schröck, Helmuth Steinmetz, Marina Jendrach, Udo Rüb, Ayşe Nazlı Başak, Wolfgang Oertel, Georg Auburger
Parkinson's disease (PD) is a frequent neurodegenerative process at old age. Accumulation and aggregation of the lipid-binding SNARE complex component alpha-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity are intensely investigated. In view of physiological SNCA roles in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation), to identify effects of SNCA gain-of-function as potential disease biomarkers...
January 20, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28100734/does-the-superior-colliculus-control-perceptual-sensitivity-or-choice-bias-during-attention-evidence-from-a-multialternative-decision-framework
#20
Devarajan Sridharan, Nicholas A Steinmetz, Tirin Moore, Eric I Knudsen
: Distinct networks in the forebrain and the midbrain coordinate to control spatial attention. The critical involvement of the superior colliculus (SC)-the central structure in the midbrain network-in visuospatial attention has been shown by four seminal, published studies in monkeys (Macaca mulatta) performing multialternative tasks. However, due to the lack of a mechanistic framework for interpreting behavioral data in such tasks, the nature of the SC's contribution to attention remains unclear...
January 18, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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