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https://www.readbyqxmd.com/read/29456803/potent-inhibitors-of-hepatitis-c-virus-ns3-protease-employment-of-a-difluoromethyl-group-as-a-hydrogen-bond-donor
#1
Barbara Zheng, Stanley V D'Andrea, Li-Qiang Sun, Alan Xiangdong Wang, Yan Chen, Peter Hrnciar, Jacques Friborg, Paul Falk, Dennis Hernandez, Fei Yu, Amy K Sheaffer, Jay O Knipe, Kathy Mosure, Ramkumar Rajamani, Andrew C Good, Kevin Kish, Jeffrey Tredup, Herbert E Klei, Manjula Paruchuri, Alicia Ng, Qi Gao, Richard A Rampulla, Arvind Mathur, Nicholas A Meanwell, Fiona McPhee, Paul M Scola
The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of 18 with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF2 moiety and the backbone carbonyl of Leu135 of the enzyme. Structure-activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH3 and CF3 analogues, respectively, providing insight into the deployment of this unique amino acid...
February 8, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29456185/human-ips-derived-astroglia-from-a-stable-neural-precursor-state-show-improved-functionality-compared-with-conventional-astrocytic-models
#2
Anders Lundin, Louise Delsing, Maryam Clausen, Piero Ricchiuto, José Sanchez, Alan Sabirsh, Mei Ding, Jane Synnergren, Henrik Zetterberg, Gabriella Brolén, Ryan Hicks, Anna Herland, Anna Falk
In vivo studies of human brain cellular function face challenging ethical and practical difficulties. Animal models are typically used but display distinct cellular differences. One specific example is astrocytes, recently recognized for contribution to neurological diseases and a link to the genetic risk factor apolipoprotein E (APOE). Current astrocytic in vitro models are questioned for lack of biological characterization. Here, we report human induced pluripotent stem cell (hiPSC)-derived astroglia (NES-Astro) developed under defined conditions through long-term neuroepithelial-like stem (ltNES) cells...
February 9, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29454121/complications-of-impulse-generator-exchange-surgery-for-deep-brain-stimulation-a-single-centre-retrospective-study
#3
Ann-Kristin Helmers, Isabel Lübbing, Falk Birkenfeld, Karsten Witt, Michael Synowitz, Hubertus Maximilian Mehdorn, Daniela Falk
OBJECTIVE: Non-rechargeable deep brain stimulation (DBS) impulse generators (IG) with a low or empty battery status require surgical IG exchange several years after initial implantation. Complication rates in patients undergoing DBS surgery range from 7.6% to 25.3%. The aim of this study was to investigate the complication rates after IG exchange surgery and to identify risk factors for complications. METHODS: We retrospectively analysed complications following IG exchange surgery from 2008 to 2015 in a single-centre university hospital setting...
February 14, 2018: World Neurosurgery
https://www.readbyqxmd.com/read/29453429/human-neutrophils-can-mimic-myeloid-derived-suppressor-cells-pmn-mdsc-and-suppress-microbead-or-lectin-induced-t-cell-proliferation-through-artefactual-mechanisms
#4
Dmitri Negorev, Ulf H Beier, Tianyi Zhang, Jon G Quatromoni, Pratik Bhojnagarwala, Steven M Albelda, Sunil Singhal, Evgeniy Eruslanov, Falk W Lohoff, Matthew H Levine, Joshua M Diamond, Jason D Christie, Wayne W Hancock, Tatiana Akimova
We report that human conventional CD15 + neutrophils can be isolated in the peripheral blood mononuclear cell (PBMC) layer during Ficoll gradient separation, and that they can impair T cell proliferation in vitro without concomitant neutrophil activation and killing. This effect was observed in a total of 92 patients with organ transplants, lung cancer or anxiety/depression, and in 18 healthy donors. Although such features are typically associated in the literature with the presence of certain myeloid-derived suppressor cell (PMN-MDSC) populations, we found that commercial centrifuge tubes that contained membranes or gels for PBMC isolation led to up to 70% PBMC contamination by CD15 + neutrophils, with subsequent suppressive effects in certain cellular assays...
February 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29448799/vibrational-treatment-of-the-formic-acid-double-minimum-case-in-valence-coordinates
#5
Falk Richter, P Carbonnière
One single full dimensional valence coordinate HCOOH ground state potential energy surface accurate for both cis and trans conformers for all levels up to 6000 cm -1 relative to trans zero point energy has been generated at CCSD(T)-F12a/aug-cc-pVTZ level. The fundamentals and a set of eigenfunctions complete up to about 3120 and 2660 cm -1 for trans- and cis-HCOOH, respectively, have been calculated and assigned using the improved relaxation method of the Heidelberg multi-configuration time-dependent Hartree package and an exact expression for the kinetic energy in valence coordinates generated by the TANA program...
February 14, 2018: Journal of Chemical Physics
https://www.readbyqxmd.com/read/29448041/vip-changes-during-daytime-in-chicken-intrinsic-choroidal-neurons
#6
Bettina Hohberger, Carmen Jessberger, Matthias Zenkel, Alexandra Kaser-Eichberger, Antonio Bergua, Falk Schrödl, Winfried Neuhuber
PURPOSE: Ocular autonomic control is mediated by sympathetic and parasympathetic nerve fibres. Their interactions are complemented by primary afferent nerve fibers of and intrinsic choroidal neurons (ICN). As the vasodilatative neuropeptide, vasoactive intestinal peptide (VIP), is expressed in extrinsic and intrinsic ocular neurons, it is of special interest in ophthalmic research. Since circadian changes of ocular blood flow are known in humans and birds, this study aimed at investigating VIP expression at different daytimes in chicken choroid, the preferred model species in ICN research...
February 12, 2018: Experimental Eye Research
https://www.readbyqxmd.com/read/29446965/associations-between-coherent-neural-activity-in-the-brain-s-value-system-during-antismoking-messages-and-reductions-in-smoking
#7
Nicole Cooper, Steven Tompson, Matthew B O'Donnell, Jean M Vettel, Danielle S Bassett, Emily B Falk
OBJECTIVE: Worldwide, tobacco use is the leading cause of preventable death and illness. One common strategy for reducing the prevalence of cigarette smoking and other health risk behaviors is the use of graphic warning labels (GWLs). This has led to widespread interest from the perspective of health psychology in understanding the mechanisms of GWL effectiveness. Here we investigated differences in how the brain responds to negative, graphic warning label-inspired antismoking ads and neutral control ads, and we probed how this response related to future behavior...
February 15, 2018: Health Psychology: Official Journal of the Division of Health Psychology, American Psychological Association
https://www.readbyqxmd.com/read/29445001/interventional-treatment-of-severe-tricuspid-regurgitation-early-clinical-experience-in-a-multicenter-observational-first-in-man-study
#8
Alexander Lauten, Hans R Figulla, Axel Unbehaun, Neil Fam, Joachim Schofer, Torsten Doenst, Joerg Hausleiter, Marcus Franz, Christian Jung, Henryk Dreger, David Leistner, Brunilda Alushi, Anja Stundl, Ulf Landmesser, Volkmar Falk, Karl Stangl, Michael Laule
BACKGROUND: Transcatheter caval valve implantation is under evaluation as a treatment option for inoperable patients with severe tricuspid regurgitation (TR). The procedure involves the catheter-based implantation of bioprosthetic valves in the inferior vena cava and superior vena cava to treat symptoms associated with TR. This study is the first to evaluate the feasibility, safety, and efficacy of this interventional concept. METHODS AND RESULTS: Twenty-five patients (mean age, 73...
February 2018: Circulation. Cardiovascular Interventions
https://www.readbyqxmd.com/read/29444606/the-links-between-healthy-problematic-and-addicted-internet-use-regarding-comorbidities-and-self-concept-related-characteristics
#9
Tagrid Leménager, Sabine Hoffmann, Julia Dieter, Iris Reinhard, Karl Mann, Falk Kiefer
Background Addicted Internet users present with higher rates of comorbidities, e.g., attention-deficit hyperactivity disorder (ADHD), depressive, and anxiety disorders. In addition, deficits in self-concept-related characteristics were found in addicted Internet gamers and social network users. The aim of this study was to examine the links between healthy, problematic, and addicted Internet use regarding comorbidities and self-concept-related characteristics. The association between recently developed ADHD-like symptoms without an underlying diagnosis and addictive Internet use was also examined...
February 15, 2018: Journal of Behavioral Addictions
https://www.readbyqxmd.com/read/29441658/host-genetic-variation-strongly-influences-the-microbiome-structure-and-function-in-fungal-fruiting-bodies
#10
Mari Pent, Markus Hiltunen, Kadri Põldmaa, Brendan Furneaux, Falk Hildebrand, Hanna Johannesson, Martin Ryberg, Mohammad Bahram
Despite increasing knowledge on host-associated microbiomes, little is known about mechanisms underlying fungus-microbiome interactions. This study aimed to examine the relative importance of host genetic, geographic and environmental distance in structuring fungus-associated microbiomes. We analyzed the taxonomic composition and function of microbiomes inhabiting fungal fruiting-bodies in relation to host genetic variation, soil pH and geographic distance between samples. For this, we sequenced the metagenomes of 40 fruiting-bodies collected from six fairy rings (i...
February 14, 2018: Environmental Microbiology
https://www.readbyqxmd.com/read/29440750/publisher-correction-enterotypes-in-the-landscape-of-gut-microbial-community-composition
#11
Paul I Costea, Falk Hildebrand, Manimozhiyan Arumugam, Fredrik Bäckhed, Martin J Blaser, Frederic D Bushman, Willem M de Vos, S Dusko Ehrlich, Claire M Fraser, Masahira Hattori, Curtis Huttenhower, Ian B Jeffery, Dan Knights, James D Lewis, Ruth E Ley, Howard Ochman, Paul W O'Toole, Christopher Quince, David A Relman, Fergus Shanahan, Shinichi Sunagawa, Jun Wang, George M Weinstock, Gary D Wu, Georg Zeller, Liping Zhao, Jeroen Raes, Rob Knight, Peer Bork
In the version of this Perspective originally published, the first and last name of co-author Manimozhiyan Arumugam were switched. This has now been corrected in all versions of the Perspective.
February 13, 2018: Nature Microbiology
https://www.readbyqxmd.com/read/29439554/pilot-study-on-mass-spectrometry-based-analysis-of-the-proteome-of-cd34%C3%A2-%C2%BAcd123%C3%A2-%C2%BA-progenitor-cells-for-the-identification-of-potential-targets-for-immunotherapy-in-acute-myeloid-leukemia
#12
Johannes R Schmidt, Elke Rücker-Braun, Katharina Heidrich, Malte von Bonin, Friedrich Stölzel, Christian Thiede, Jan M Middeke, Gerhard Ehninger, Martin Bornhäuser, Johannes Schetelig, Kristin Schubert, Martin von Bergen, Falk Heidenreich
Targeting of leukemic stem cells with specific immunotherapy would be an ideal approach for the treatment of myeloid malignancies, but suitable epitopes are unknown. The comparative proteome-level characterization of hematopoietic stem and progenitor cells from healthy stem cell donors and patients with acute myeloid leukemia has the potential to reveal differentially expressed proteins which can be used as surface-markers or as proxies for affected molecular pathways. We employed mass spectrometry methods to analyze the proteome of the cytosolic and the membrane fraction of CD34 and CD123 co-expressing FACS-sorted leukemic progenitors from five patients with acute myeloid leukemia...
February 12, 2018: Proteomes
https://www.readbyqxmd.com/read/29439343/overactive-brca1-affects-presenilin-1-in-induced-pluripotent-stem-cell-derived-neurons-in-alzheimer-s-disease
#13
Michalina Wezyk, Aleksandra Szybinska, Joanna Wojsiat, Marcelina Szczerba, Kelly Day, Harriet Ronnholm, Malin Kele, Mariusz Berdynski, Beata Peplonska, Jakub Piotr Fichna, Jan Ilkowski, Maria Styczynska, Anna Barczak, Marzena Zboch, Anna Filipek-Gliszczynska, Krzysztof Bojakowski, Magdalena Skrzypczak, Krzysztof Ginalski, Michal Kabza, Izabela Makalowska, Maria Barcikowska-Kotowicz, Urszula Wojda, Anna Falk, Cezary Zekanowski
 The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1)...
2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29434359/surgical-device-enabled-epicardial-laa-closure-to-achieve-safe-complete-and-durable-laa-occlusion
#14
Etem Caliskan, James L Cox, Volkmar Falk, Sacha P Salzberg, Maximilian Y Emmert
No abstract text is available yet for this article.
February 13, 2018: Nature Reviews. Cardiology
https://www.readbyqxmd.com/read/29430299/serum-carotenoids-and-macular-pigment-optical-density-in-patients-with-intestinal-resections-and-healthy-subjects-an-exploratory-study
#15
Jane N Eriksen, August P Prahm, Mads Krüger Falk, Eva Arrigoni, Palle B Jeppesen, Michael Larsen, Lars O Dragsted
Reduced absorption capacity in patients with intestinal resections (IR) could result in malabsorption of fat-soluble components like carotenoids, which are of clinical interest in relation to visual health. In this case cohort, we investigated the association between IR and serum lutein, zeaxanthin, β-carotene and macular pigment optical density, when compared with healthy controls. Ten patients with IR and twelve healthy controls were included in the study. Baseline characteristics were comparable between groups, except for higher serum TAG (P < 0·05) and shorter bowel length (P < 0·0001) in the group with IR...
2018: Journal of Nutritional Science
https://www.readbyqxmd.com/read/29428506/8-year-retrospective-analysis-of-intravenous-arginine-therapy-for-acute-metabolic-strokes-in-pediatric-mitochondrial-disease
#16
Rebecca D Ganetzky, Marni J Falk
BACKGROUND: Intravenous (IV) arginine has been reported to ameliorate acute metabolic stroke symptoms in adult patients with Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes (MELAS) syndrome, where its therapeutic benefit is postulated to result from arginine acting as a nitric oxide donor to reverse vasospasm. Further, reduced plasma arginine may occur in mitochondrial disease since the biosynthesis of arginine's precursor, citrulline, requires ATP. Metabolic strokes occur across a wide array of primary mitochondrial diseases having diverse molecular etiologies that are likely to share similar pathophysiologic mechanisms...
February 2, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29427452/cxcr4-cxcl12-interaction-is-important-for-plasma-cell-homing-and-survival-in-nzb-w-mice
#17
Qingyu Cheng, Laleh Khodadadi, Adriano Taddeo, Jens Klotsche, Bimba F Hoyer, Andreas Radbruch, Falk Hiepe
Antibody-secreting cells (ASCs), including short-lived plasmablasts and long-lived memory plasma cells (LLPCs), contribute to autoimmune pathology. ASCs, particularly LLPCs, refractory to conventional immunosuppressive drugs pose a major therapeutic challenge. Since stromal cells expressing C-X-C motif chemokine-12 (CXCL12) organize survival niches for LLPCs in the bone marrow, we investigated the effects of CXCL12 and its ligand CXCR4 on ASCs in lupus mice (NZB/W). Fewer adoptively transferred splenic ASCs were retrieved from the bone marrow of recipient immunodeficient Rag1-/- mice when the ASCs were pre-treated with the CXCR4 blocker AMD3100...
February 10, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/29425605/2017-esc-eacts-guidelines-for-the-management-of-valvular-heart-disease
#18
Helmut Baumgartner, Volkmar Falk, Jeroen J Bax, Michele De Bonis, Christian Hamm, Per Johan Holm, Bernard Iung, Patrizio Lancellotti, Emmanuel Lansac, Daniel Rodríguez Muñoz, Raphael Rosenhek, Johan Sjögren, Pilar Tornos Mas, Alec Vahanian, Thomas Walther, Olaf Wendler, Stephan Windecker, José Luis Zamorano
No abstract text is available yet for this article.
February 2018: Revista Española de Cardiología
https://www.readbyqxmd.com/read/29425597/quality-improvement-in-anesthesiology-leveraging-data-and-analytics-to-optimize-outcomes
#19
REVIEW
Elizabeth A Valentine, Scott A Falk
Quality improvement is at the heart of practice of anesthesiology. Objective data are critical for any quality improvement initiative; when possible, a combination of process, outcome, and balancing metrics should be evaluated to gauge the value of an intervention. Quality improvement is an ongoing process; iterative reevaluation of data is required to maintain interventions, ensure continued effectiveness, and continually improve. Dashboards can facilitate rapid analysis of data and drive decision making. Large data sets can be useful to establish benchmarks and compare performance against other providers, practices, or institutions...
March 2018: Anesthesiology Clinics
https://www.readbyqxmd.com/read/29423527/a-high-throughput-approach-to-identify-specific-neurotoxicants-developmental-toxicants-in-human-neuronal-cell-function-assays
#20
Johannes Delp, Simon Gutbier, Stefanie Klima, Lisa Hoelting, Kevin Pinto-Gil, Jui-Hua Hsieh, Michael Aichem, Karsten Klein, Falk Schreiber, Raymond R Tice, Manuel Pastor, Mamta Behl, Marcel Leist
The (developmental) neurotoxicity hazard is still unknown for most chemicals. Establishing a test battery covering most of the relevant adverse outcome pathways may close this gap, without requiring a huge animal experimentation program. Ideally, each of the assays would cover multiple mechanisms of toxicity. One candidate test is the human LUHMES cell-based NeuriTox test. To evaluate its readiness for larger-scale testing, a proof of concept library assembled by the U.S. National Toxicology Program (NTP) was screened...
January 21, 2018: ALTEX
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