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https://www.readbyqxmd.com/read/28821859/reduction-of-the-off-pathway-iron-sulphur-cluster-n1a-of-escherichia-coli-respiratory-complex-i-restrains-nad-dissociation
#1
Emmanuel Gnandt, Johannes Schimpf, Caroline Harter, Jo Hoeser, Thorsten Friedrich
Respiratory complex I couples the electron transfer from NADH to ubiquinone with the translocation of protons across the membrane. The reaction starts with NADH oxidation by a flavin cofactor followed by transferring the electrons through a chain of seven iron-sulphur clusters to quinone. An eighth cluster called N1a is located proximally to flavin, but on the opposite side of the chain of clusters. N1a is strictly conserved although not involved in the direct electron transfer to quinone. Here, we show that the NADH:ferricyanide oxidoreductase activity of E...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28821646/location-of-the-mesopontine-neurons-responsible-for-maintanance-of-anesthetic-loss-of-consciousness
#2
Anne Minert, Shai-Lee Yatziv, Marshall Devor
The transition from wakefulness to general anesthesia is widely attributed to suppressive actions of anesthetic molecules distributed by the systemic circulation to the cerebral cortex (for amnesia and loss-of-consciousness) and to the spinal cord (for atonia and antinociception). An alternative hypothesis proposes that anesthetics act on one or more brainstem or diencephalic nuclei, with suppression of cortex and spinal cord mediated by dedicated axonal pathways. We previously documented induction of an anesthesia-like state in rats by microinjection of small amounts of GABAA-R agonists into an upper brainstem region named the mesopontine tegmental anesthesia area(MPTA)...
August 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28818609/multicenter-comparison-of-22c3-pharmdx-agilent-and-sp263-ventana-assays-to-test-pd-l1-expression-for-nsclc-patients-to-be-treated-with-immune-checkpoint-inhibitors
#3
Antonio Marchetti, Massimo Barberis, Renato Franco, Graziano De Luca, Maria Vittoria Pace, Stefania Staibano, Marco Volante, Fiamma Buttitta, Elena Guerini-Rocco, Luisella Righi, Tommaso D'antuono, Giorgio V Scagliotti, Carmine Pinto, Gaetano De Rosa, Mauro Papotti
INTRODUCTION: Among the several agents targeting the programmed cell death 1 (PD-1) pathway, pembrolizumab is currently the only one approved for the treatment of non-small cell lung cancer patients in association with a companion diagnostic assay, the anti-programmed cell death ligand 1 (PD-L1) immunohistochemical (IHC) 22C3 PharmDx (Agilent) using the Dako Autostainer. However, the Dako platform is not present in each pathology department and this technical limitation is a major problem for the diffusion of the PD-L1 IHC predictive test for pembrolizumab...
August 14, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28815504/purification-and-in-vitro-characterization-of-zinc-finger-recombinases
#4
Femi J Olorunniji, Susan J Rosser, W Marshall Stark
Zinc finger recombinases (ZFRs) are designer site-specific recombinases that have been adapted for a variety of genome editing purposes. Due to their modular nature, ZFRs can be customized for targeted sequence recognition and recombination. There has been substantial research on the in vivo properties and applications of ZFRs; however, in order to fully understand and customize them, it will be necessary to study their properties in vitro. Experiments in vitro can allow us to optimize catalytic activities, improve target specificity, measure and minimize off-target activity, and characterize key steps in the recombination pathway that might be modified to improve performance...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28814634/state-dependent-sensorimotor-gating-in-a-rhythmic-motor-system
#5
Rachel S White, Robert M Spencer, Michael P Nusbaum, Dawn M Blitz
Sensory feedback influences motor circuits and/or their projection neuron inputs to adjust ongoing motor activity, but its efficacy varies. Currently, less is known about regulation of sensory feedback onto projection neurons that control downstream motor circuits than about sensory regulation of the motor circuit neurons themselves. Here, we tested whether sensory feedback onto projection neurons is sensitive only to activation of a motor system, or also to the modulatory state underlying that activation, using the crab Cancer borealis stomatogastric nervous system...
August 16, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28814238/structural-insights-for-drugs-developed-for-phospholipase-d-enzymes
#6
Kimberly Stieglitz
BACKGROUND: In recent years human phospholipase D enzymes (PLD1 and PLD2 isozymes) have emerged as drug targets for various diseases such as cardiovascular disease, cancer, infectious diseases and neurodegenerative conditions such as Alzheimer's and Parkinson's disease. The interest in PLD as a drug target is due to the fact that PLD enzymes belong to a superfamily of phospholipases that are essential to intracellular and extracellular signaling. Many bioactive lipid signaling molecules are generated by these enzymes including phosphatidic and lysophosphatidic acid, arachidonic acid, and diacylglycerol (DAG)...
August 15, 2017: Current Drug Discovery Technologies
https://www.readbyqxmd.com/read/28813137/site-a-mediated-partial-unfolding-of-cytochrome-c-on-cardiolipin-vesicles-is-species-dependent-and-does-not-require-lys72
#7
Margaret M Elmer-Dixon, Bruce E Bowler
Measurements at pH 8 allow evaluation of binding of 100% cardiolipin vesicles to site A of cytochrome c without interference from other known binding sites. Site A encompasses Lys72, Lys73, Lys86 and Lys87, located in or adjacent to Ω-loop D (residues 70-85), which positions Met80 for binding to the heme. Binding of cytochrome c to cardiolipin disrupts Met80 heme binding, permitting peroxidase activity. Cardiolipin binding to yeast iso-1-cytochrome c versus human cytochrome c is compared to assess how cardiolipin binding to site A has evolved for cytochrome c from species that do not have a complete intrinsic apoptotic pathway to species that do...
August 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/28812643/a-submarine-volcanic-eruption-leads-to-a-novel-microbial-habitat
#8
Roberto Danovaro, Miquel Canals, Michael Tangherlini, Antonio Dell'Anno, Cristina Gambi, Galderic Lastras, David Amblas, Anna Sanchez-Vidal, Jaime Frigola, Antoni M Calafat, Rut Pedrosa-Pàmies, Jesus Rivera, Xavier Rayo, Cinzia Corinaldesi
Submarine volcanic eruptions are major catastrophic events that allow investigation of the colonization mechanisms of newly formed seabed. We explored the seafloor after the eruption of the Tagoro submarine volcano off El Hierro Island, Canary Archipelago. Near the summit of the volcanic cone, at about 130 m depth, we found massive mats of long, white filaments that we named Venus's hair. Microscopic and molecular analyses revealed that these filaments are made of bacterial trichomes enveloped within a sheath and colonized by epibiotic bacteria...
April 24, 2017: Nature ecology & evolution
https://www.readbyqxmd.com/read/28809941/analysis-of-agoshrna-maturation-and-loading-into-ago2
#9
Alex Harwig, Zita Kruize, Zhenhuang Yang, Tobias Restle, Ben Berkhout
The RNA interference (RNAi) pathway was recently expanded by the discovery of multiple alternative pathways for processing of natural microRNA (miRNA) and man-made short hairpin RNA (shRNA) molecules. One non-canonical pathway bypasses Dicer cleavage and requires instead processing by Argonaute2 (Ago2), which also executes the subsequent silencing step. We named these molecules AgoshRNA, which generate only a single active RNA strand and thus avoid off-target effects that can be induced by the passenger strand of a regular shRNA...
2017: PloS One
https://www.readbyqxmd.com/read/28808589/anti-angiogenic-agents-for-the-treatment-of-solid-tumors-potential-pathways-therapy-and-current-strategies-a-review
#10
REVIEW
Ahmed M Al-Abd, Abdulmohsin J Alamoudi, Ashraf B Abdel-Naim, Thikryat A Neamatallah, Osama M Ashour
Recent strategies for the treatment of cancer, other than just tumor cell killing have been under intensive development, such as anti-angiogenic therapeutic approach. Angiogenesis inhibition is an important strategy for the treatment of solid tumors, which basically depends on cutting off the blood supply to tumor micro-regions, resulting in pan-hypoxia and pan-necrosis within solid tumor tissues. The differential activation of angiogenesis between normal and tumor tissues makes this process an attractive strategic target for anti-tumor drug discovery...
November 2017: Journal of Advanced Research
https://www.readbyqxmd.com/read/28801734/fibrinogen-promotes-malignant-biological-tumor-behavior-involving-epithelial-mesenchymal-transition-via-the-p-akt-p-mtor-pathway-in-esophageal-squamous-cell-carcinoma
#11
Fei Zhang, Yun Wang, Peng Sun, Zhi-Qiang Wang, De-Shen Wang, Dong-Sheng Zhang, Feng-Hua Wang, Jian-Hua Fu, Rui-Hua Xu, Yu-Hong Li
PURPOSE: Hyperfibrinogenemia is associated with unfavorable prognosis and advanced tumor behavior in various malignancies, including esophageal squamous cell carcinoma (ESCC). However, its biological function in ESCC is unknown. The present study was designed to further validate the prognostic value of preoperative plasma hyperfibrinogenemia and evaluate the biological role of fibrinogen, as well as the underlying mechanism in ESCC. METHODS: Data from 452 cases with newly diagnosed ESCC followed by curative surgery between 2006 and 2010 were retrospectively evaluated...
August 11, 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28801684/structural-properties-of-human-iapp-dimer-in-membrane-environment-studied-by-all-atom-molecular-dynamics-simulations
#12
Na Liu, Mojie Duan, Minghui Yang
The aggregation of human islet amyloid polypeptide (hIAPP) can damage the membrane of the β-cells in the pancreatic islets and induce type 2 diabetes (T2D). Growing evidences indicated that the major toxic species are small oligomers of IAPP. Due to the fast aggregation nature, it is hard to characterize the structures of IAPP oligomers by experiments, especially in the complex membrane environment. On the other side, molecular dynamics simulation can provide atomic details of the structure and dynamics of the aggregation of IAPP...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28801274/mannich-base-approach-to-5-methoxyisatin-3-4-isopropylphenyl-hydrazone-a-water-soluble-prodrug-for-a-multitarget-inhibition-of-cholinesterases-beta-amyloid-fibrillization-and-oligomer-induced-cytotoxicity
#13
Leonardo Pisani, Annalisa De Palma, Nicola Giangregorio, Daniela V Miniero, Paolo Pesce, Orazio Nicolotti, Francesco Campagna, Cosimo D Altomare, Marco Catto
Targeting protein aggregation for the therapy of neurodegenerative diseases remains elusive for medicinal chemists, despite a number of small molecules known to interfere in amyloidogenesis, particularly of amyloid beta (Aβ) protein. Starting from previous findings in the antiaggregating activity of a class of indolin-2-ones inhibiting Aβ fibrillization, 5-methoxyisatin 3-(4-isopropylphenyl)hydrazone 1 was identified as a multitarget inhibitor of Aβ aggregation and cholinesterases with IC50s in the low μM range...
August 8, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28798939/orphan-nuclear-receptor-tr3-nur77-is-a-specific-therapeutic-target-for-hepatic-cancers
#14
Yingling Zeng, Xiaoguang Ye, Degui Liao, Shizhang Huang, Huinan Mao, Dezheng Zhao, Huiyan Zeng
OBJECTIVE: Although great success has been achieved in cancer treatment, current cancer therapies, including anti-tumorigenesis and anti-angiogenesis, still face the problems of insufficient efficacy, resistance and intrinsic refractoriness, in addition to their toxic side effects. There is a demand to identify additional targets that can be blocked to turn off the downstream effects of most, if not all, pathways. Our previous studies suggest that orphan nuclear receptor TR3 (human) / Nur77 (mouse) is such a target...
June 2017: Journal of Clinical & Experimental Oncology
https://www.readbyqxmd.com/read/28798270/a-phase-i-dose-escalation-study-of-the-safety-and-pharmacokinetics-of-pictilisib-in-combination-with-erlotinib-in-patients-with-advanced-solid-tumors
#15
Stephen Leong, Rebecca A Moss, Daniel W Bowles, Joseph A Ware, Jing Zhou, Jill M Spoerke, Mark R Lackner, Geetha Shankar, Jennifer L Schutzman, Ruud van der Noll, Emile E Voest, Jan H M Schellens
BACKGROUND: Epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K) are involved in the proliferation and survival of many cancer types. Enhanced antitumor activity may be achieved through combined inhibition of these pathways. We report results for pictilisib (GDC-0941, a class I pan-PI3K inhibitor) plus erlotinib (an EGFR tyrosine kinase inhibitor) in patients with advanced solid tumors. MATERIALS AND METHODS: A 3 + 3 dose-escalation study was carried out at a starting daily dose of 60 mg pictilisib on days 1-21 of a 28-day cycle and 150 mg erlotinib from day 2 of cycle 1...
August 10, 2017: Oncologist
https://www.readbyqxmd.com/read/28797825/mechanisms-underlying-longevity-a-genetic-switch-model-of-aging
#16
REVIEW
Jeremy M Van Raamsdonk
While the questions of "What causes aging?" and "Why do we age?" and "How can we stop it?" remain unanswered, recent advances in aging research have continued to increase our understanding of the aging process. Until the last couple of decades, aging was viewed as an inevitable process of damage accumulation and not a subject for scientific pursuit. This view changed when it was demonstrated that the aging process is in fact malleable and genetically determined: mutations in single genes can have dramatic effects on longevity...
August 7, 2017: Experimental Gerontology
https://www.readbyqxmd.com/read/28797224/the-adaptive-landscape-of-wildtype-and-glycosylation-deficient-populations-of-the-industrial-yeast-pichia-pastoris
#17
Josef W Moser, Iain B H Wilson, Martin Dragosits
BACKGROUND: The effects of long-term environmental adaptation and the implications of major cellular malfunctions are still poorly understood for non-model but biotechnologically relevant species. In this study we performed a large-scale laboratory evolution experiment with 48 populations of the yeast Pichia pastoris in order to establish a general adaptive landscape upon long-term selection in several glucose-based growth environments. As a model for a cellular malfunction the implications of OCH1 mannosyltransferase knockout-mediated glycosylation-deficiency were analyzed...
August 10, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28797070/methyl-pyruvate-protects-a-normal-lung-fibroblast-cell-line-from-irinotecan-induced-cell-death-potential-use-as-adjunctive-to-chemotherapy
#18
Bernice Monchusi, Monde Ntwasa
The Warburg Effect, characterized by increased rate of glycolysis even under normoxic conditions, is one of the hallmarks of cancer. Relatively lower oxidative phosphorylation (OXPHOS) is also a characteristic feature in cancer cells. We hypothesized that interference with this phenomenon, by introducing exogenous pyruvate, would upset this cancer phenotype and boost the energy requirements of normal cells. We find that methyl pyruvate protects irinotecan-treated normal lung fibroblast cell line (MRC-5) probably by turning off the p53/p21 axis of the apoptotic pathways...
2017: PloS One
https://www.readbyqxmd.com/read/28796342/elucidation-of-insulin-assembly-at-acidic-and-neutral-ph-characterization-of-low-molecular-weight-oligomers
#19
Matthew T Mawhinney, Thomas L Williams, James L Hart, Mitra L Taheri, Brigita Urbanc
Deficiency in insulin secretion and function that characterize type 2 diabetes often requires administration of extraneous insulin, leading to injection-site amyloidosis. Insulin aggregation at neutral pH is not well understood. Although oligomer formation is believed to play an important role, insulin oligomers have not been fully characterized yet. Here, we elucidate similarities and differences between in vitro insulin aggregation at acidic and neutral pH for a range of insulin concentrations (2.5-100 μM) by using kinetic thioflavin T fluorescence, circular dichroism, atomic force and electron microscopy imaging...
August 10, 2017: Proteins
https://www.readbyqxmd.com/read/28794158/intracellular-rebinding-of-transition-state-analogues-provides-extended-in-vivo-inhibition-lifetimes-on-human-purine-nucleoside-phosphorylase
#20
Sara T Gebre, Scott A Cameron, Lei Li, Y S Babu, Vern L Schramm
Purine nucleoside phosphorylase (PNP) is part of the human purine salvage pathway. Its deficiency triggers apoptosis of activated T-cells, making it a target for T-cell proliferative disorders. Transition-state analogues of PNP bind with picomolar (pM) dissociation constants. Tight-binding PNP inhibitors show exceptionally long lifetimes on the target enzyme. We solve the mechanism of the target residence time by comparing functional off-rates in vitro and in vivo. We report in vitro PNP-inhibitor dissociation rates (t1/2) from 3 to 31 min for seven Immucillins with dissociation constants of 115 to 6 pM...
August 9, 2017: Journal of Biological Chemistry
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