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https://www.readbyqxmd.com/read/28646182/high-intensity-interval-training-improves-mitochondrial-function-and-suppresses-thrombin-generation-in-platelets-undergoing-hypoxic-stress
#1
Li-Hua Wu, Shao-Chiang Chang, Tieh-Cheng Fu, Ching-Hui Huang, Jong-Shyan Wang
This study elucidates how high-intensity interval training (HIT) and moderate-intensity continuous training (MCT) affect mitochondrial functionality and thrombin generation (TG) in platelets following hypoxic exercise (HE, 100 W under 12% O2 for 30 min). Forty-five healthy sedentary males were randomized to engage either HIT (3-minute intervals at 40% and 80%VO2max, n = 15) or MCT (sustained 60%VO2max, n = 15) for 30 minutes/day, 5 days/week for 6 weeks, or to a control group (CTL, n = 15) that did not received exercise intervention...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28638354/investigating-team-coordination-in-baseball-using-a-novel-joint-decision-making-paradigm
#2
Rob Gray, Nancy J Cooke, Nathan J McNeese, Jaimie McNabb
A novel joint decision making paradigm for assessing team coordination was developed and tested using baseball infielders. Balls launched onto an infield at different trajectories were filmed using four video cameras that were each placed at one of the typical positions of the four infielders. Each participant viewed temporally occluded videos for one of the four positions and were asked to say either "ball" if they would attempt to field it or the name of the bag that they would cover. The evaluation of two experienced coaches was used to assign a group coordination score for each trajectory and group decision times were calculated...
2017: Frontiers in Psychology
https://www.readbyqxmd.com/read/28624695/first-in-human-phase-i-study-of-oral-s49076-a-unique-met-axl-fgfr-inhibitor-in-advanced-solid-tumours
#3
Jordi Rodon, Sophie Postel-Vinay, Antoine Hollebecque, Paolo Nuciforo, Analia Azaro, Valérie Cattan, Lucie Marfai, Isabelle Sudey, Karl Brendel, Audrey Delmas, Stéphanie Malasse, Jean-Charles Soria
BACKGROUND AND OBJECTIVES: S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule. MATERIALS AND METHODS: Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD...
June 15, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28622697/vitamin-c-and-doxycycline-a-synthetic-lethal-combination-therapy-targeting-metabolic-flexibility-in-cancer-stem-cells-cscs
#4
Ernestina Marianna De Francesco, Gloria Bonuccelli, Marcello Maggiolini, Federica Sotgia, Michael P Lisanti
Here, we developed a new synthetic lethal strategy for further optimizing the eradication of cancer stem cells (CSCs). Briefly, we show that chronic treatment with the FDA-approved antibiotic Doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation. The expression of four mitochondrial DNA encoded proteins (MT-ND3, MT-CO2, MT-ATP6 and MT-ATP8) is suppressed, by up to 35-fold. This high selection pressure metabolically synchronizes the surviving cancer cell sub-population towards a predominantly glycolytic phenotype, resulting in metabolic inflexibility...
June 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28589758/identification-of-type-i-and-type-ii-inhibitors-of-c-yes-kinase-using-in-silico-and-experimental-techniques
#5
Chandrasekaran Ramakrishnan, Anthony Mary Thangakani, Devadasan Velmurugan, Dhanabalan Anantha Krishnan, Masakazu Sekijima, Yutaka Akiyama, M Michael Gromiha
c-Yes kinase is considered as one of the attractive targets for anti-cancer drug design. The DFG (Asp-Phe-Gly) motif present in most of the kinases will adopt active and inactive conformations, known as DFG-in and DFG-out and their inhibitors are classified into type I and type II, respectively. In the present study, two screening protocols were followed for identification of c-Yes kinase inhibitors. (i) Structure-based virtual screening (SBVS) and (ii) Structure-based (SB) and Pharmacophore-based (PB) tandem screening...
June 7, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28571491/insights-into-unbound-bound-states-of-gpr142-receptor-in-a-membrane-aqueous-system-using-molecular-dynamics-simulations
#6
Aman Chandra Kaushik, Shakti Sahi
G protein coupled receptors (GPCRs) are source machinery in signal transduction pathways and being one of the major therapeutic targets play a significant in drug discovery. GPR142, an orphan GPCR, has been implicated in the regulation of insulin, thereby having a crucial role in Type II diabetes management. Deciphering of the structures of orphan GPCRs (O-GPCRs) offer better prospects for advancements in research in ion translocation and transduction of extracellular signals. As the crystallographic structure of GPR142 is not available in PDB, therefore, threading and abinitio based approaches were used for 3D modeling of GPR142...
June 1, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28566208/development-of-wnk-signaling-inhibitors-as-a-new-class-of-antihypertensive-drugs
#7
Mari Ishigami-Yuasa, Yuko Watanabe, Takayasu Mori, Hiroyuki Masuno, Shinya Fujii, Eriko Kikuchi, Shinichi Uchida, Hiroyuki Kagechika
Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia and hypertension despite a normal glomerular filtration rate. Abnormal activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress-responsive kinase 1)/SPAK (STE20/SPS1-related proline/alanine-rich kinase) and NCC (NaCl cotransporter) results in characteristic salt-sensitive hypertension. Thus, inhibitors of the WNK-OSR1/SPAK-NCC cascade are candidates for a new class of antihypertensive drugs. In this study, we developed novel inhibitors of this signal cascade from the 9-aminoacridine lead compound 1, one of the hit compounds obtained by screening our chemical library for WNK-SPAK binding inhibitors...
July 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28553255/development-of-the-korean-facial-emotion-stimuli-korea-university-facial-expression-collection-2nd-edition
#8
Sun-Min Kim, Ye-Jin Kwon, Soo-Yun Jung, Min-Ji Kim, Yang Seok Cho, Hyun Taek Kim, Ki-Chun Nam, Hackjin Kim, Kee-Hong Choi, June-Seek Choi
Background: Developing valid emotional facial stimuli for specific ethnicities creates ample opportunities to investigate both the nature of emotional facial information processing in general and clinical populations as well as the underlying mechanisms of facial emotion processing within and across cultures. Given that most entries in emotional facial stimuli databases were developed with western samples, and given that very few of the eastern emotional facial stimuli sets were based strictly on the Ekman's Facial Action Coding System, developing valid emotional facial stimuli of eastern samples remains a high priority...
2017: Frontiers in Psychology
https://www.readbyqxmd.com/read/28544026/immobilization-and-high-platelet-count-are-associated-with-thromboembolic-complications-in-heparin-induced-thrombocytopenia
#9
Juliane Bolbrinker, Edeltraut Garbe, Antonios Douros, Matthias Huber, Elisabeth Bronder, Andreas Klimpel, Frank Andersohn, Oliver Meyer, Abdulgabar Salama, Reinhold Kreutz
PURPOSE: Immune-mediated heparin-induced thrombocytopenia (HIT type II, HIT) is a potentially serious adverse drug reaction characterized by an increased risk of venous and arterial thrombosis. This study aimed to identify risk factors associated with the development of these complications. METHODS: Our study cohort included patients with HIT assembled in our pharmacovigilance center by reports from 51 collaborating hospitals in Berlin, Germany. To identify risk factors for thromboembolic complications, patients with thromboembolic events (cases) were compared to those without thromboembolic events (controls) in a case-control design...
May 24, 2017: Pharmacoepidemiology and Drug Safety
https://www.readbyqxmd.com/read/28489272/fear-learning-alterations-after-traumatic-brain-injury-and-their-role-in-development-of-posttraumatic-stress-symptoms
#10
Daniel E Glenn, Dean T Acheson, Mark A Geyer, Caroline M Nievergelt, Dewleen G Baker, Victoria B Risbrough
BACKGROUND: It is unknown how traumatic brain injury (TBI) increases risk for posttraumatic stress disorder (PTSD). One potential mechanism is via alteration of fear-learning processes that could affect responses to trauma memories and cues. We utilized a prospective, longitudinal design to determine if TBI is associated with altered fear learning and extinction, and if fear processing mediates effects of TBI on PTSD symptom change. METHODS: Eight hundred fifty two active-duty Marines and Navy Corpsmen were assessed before and after deployment...
May 10, 2017: Depression and Anxiety
https://www.readbyqxmd.com/read/28482680/optimal-starting-point-for-fifth-metatarsal-zone-ii-fractures-a-cadaveric-study
#11
Geoffrey I Watson, Sydney C Karnovsky, Gabrielle Konin, Mark C Drakos
BACKGROUND: Identifying the optimal starting point for intramedullary fixation of tibia and femur fractures is well described in the literature using a retrograde or anterograde technique. This technique has not been applied to the fifth metatarsal, where screw trajectory can cause iatrogenic malreduction. The generally accepted starting point for the fifth metatarsal is "high and inside" to accommodate the fifth metatarsal's dorsal apex and medial curvature. We used a retrograde technique to identify the optimal starting position for intramedullary fixation of fifth metatarsal fractures...
April 1, 2017: Foot & Ankle International
https://www.readbyqxmd.com/read/28435527/discovery-of-highly-potent-2-sulfonyl-pyrimidinyl-derivatives-for-apoptosis-inhibition-and-ischemia-treatment
#12
Li Li, Xian Jiang, Shaoqiang Huang, Zhengxin Ying, Zhaolan Zhang, Chenjie Pan, Sisi Li, Xiaodong Wang, Zhiyuan Zhang
A series of 2-sulfonyl-pyrimidinyl derivatives was developed as apoptosis inhibitors. These represent the first class of apoptosis inhibitors that function through stabilizing mitochondrial respiratory complex II. Starting from a phenotypic screen hit with micromolar activity, we optimized the cellular apoptosis inhibition activity of 2-sulfonyl-pyrimidinyl derivatives to picomolar level (compound 42, also named as TC9-305). The therapeutic potential of these new apoptosis inhibitors was further demonstrated by their neuroprotective effect on an ischemic animal model...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28432090/international-variations-in-clinical-practice-guidelines-for-palliative-sedation-a-systematic-review
#13
REVIEW
Ebun Abarshi, Judith Rietjens, Lenzo Robijn, Augusto Caraceni, Sheila Payne, Luc Deliens, Lieve Van den Block
OBJECTIVES: Palliative sedation is a highly debated medical practice, particularly regarding its proper use in end-of-life care. Worldwide, guidelines are used to standardise care and regulate this practice. In this review, we identify and compare national/regional clinical practice guidelines on palliative sedation against the European Association for Palliative Care (EAPC) palliative sedation Framework and assess the developmental quality of these guidelines using the Appraisal Guideline Research and Evaluation (AGREE II) instrument...
April 20, 2017: BMJ Supportive & Palliative Care
https://www.readbyqxmd.com/read/28430158/identification-of-tight-binding-plasmepsin-ii-and-falcipain-2-inhibitors-in-aqueous-extracts-of-marine-invertebrates-by-the-combination-of-enzymatic-and-interaction-based-assays
#14
Emir Salas-Sarduy, Yasel Guerra, Giovanni Covaleda Cortés, Francesc Xavier Avilés, María A Chávez Planes
Natural products from marine origin constitute a very promising and underexplored source of interesting compounds for modern biotechnological and pharmaceutical industries. However, their evaluation is quite challenging and requires specifically designed assays to reliably identify the compounds of interest in a highly heterogeneous and interfering context. In the present study, we describe a general strategy for the confident identification of tight-binding protease inhibitors in the aqueous extracts of 62 Cuban marine invertebrates, using Plasmodium falciparum hemoglobinases Plasmepsin II and Falcipain 2 as model enzymes...
April 21, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28427007/novel-and-revisited-approaches-in-antituberculosis-drug-discovery
#15
REVIEW
Jennifer Herrmann, Jan Rybniker, Rolf Müller
The increasing prevalence of multidrug-resistant Mycobacterium tuberculosis (Mtb) necessitates the discovery and development of novel drugs against tuberculosis. In this review, we focus on two recent approaches that led to the discovery of promising antitubercular compound classes: (I) Hits derived from large compound library screens are increasingly difficult to translate into clinical application; this in turn fostered the development of innovative screening methods. (II) An alternative strategy towards high-quality hits and leads is to evaluate chemically diverse scaffolds which can be found among natural products...
April 17, 2017: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/28425495/the-biglen-gpr171-peptide-receptor-system-within-the-basolateral-amygdala-regulates-anxiety-like-behavior-and-contextual-fear-conditioning
#16
Erin N Bobeck, Ivone Gomes, Darlene Pena, Kirstie A Cummings, Roger L Clem, Mihaly Mezei, Lakshmi A Devi
Studies show that neuropeptide-receptor systems in the basolateral amygdala (BLA) play an important role in the pathology of anxiety and other mood disorders. Since GPR171, a recently deorphanized receptor for the abundant neuropeptide BigLEN, is expressed in the BLA, we investigated its role in fear and anxiety-like behaviors. To carry out these studies we identified small molecule ligands using a homology model of GPR171 to virtually screen a library of compounds. One of the hits, MS0021570_1, was identified as a GPR171 antagonist based on its ability to block (i) BigLEN-mediated activation of GPR171 in heterologous cells, (ii) BigLEN-mediated hyperpolarization of BLA pyramidal neurons, and (iii) feeding induced by DREADD-mediated activation of BigLEN containing AgRP neurons in the arcuate nucleus...
April 20, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28410536/the-influence-of-ball-swing-on-the-timing-and-coordination-of-a-natural-interceptive-task
#17
Vishnu Sarpeshkar, David L Mann, Wayne Spratford, Bruce Abernethy
Successful interception relies on the use of perceptual information to accurately guide an efficient movement strategy that allows performers to be placed at the right place at the right time. Although previous studies have highlighted the differences in the timing and coordination of movement that underpin interceptive expertise, very little is known about how these movement patterns are adapted when intercepting targets that follow a curvilinear flight-path. The aim of this study was to examine how curvilinear ball-trajectories influence movement patterns when intercepting a fast-moving target...
April 11, 2017: Human Movement Science
https://www.readbyqxmd.com/read/28397890/discovery-and-optimization-of-selective-inhibitors-of-protein-arginine-methyltransferase-5-by-docking-based-virtual-screening
#18
Yan Ye, Bidong Zhang, Ruifeng Mao, Chenhua Zhang, Yulan Wang, Jing Xing, Yu-Chih Liu, Xiaomin Luo, Hong Ding, Yaxi Yang, Bing Zhou, Hualiang Jiang, Kaixian Chen, Cheng Luo, Mingyue Zheng
Protein arginine methyltransferase 5 (PRMT5) is a type II PRMT enzyme critical for diverse cellular processes and different types of cancers. Many efforts have been made to discover novel scaffold PRMT5 inhibitors. Herein, we report the discovery of DC_P33 as a hit compound of PRMT5 inhibitor, identified by molecular docking based virtual screening and (3)H-labeled radioactive methylation assays. Structure-activity relationship (SAR) analysis was performed on the analogs of DC_P33 and then structural modifications were done to improve its activity...
May 3, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28390229/discovery-of-4-amino-3-arylsulfoquinolines-a-novel-non-acetylenic-chemotype-of-metabotropic-glutamate-5-mglu5-receptor-negative-allosteric-modulators
#19
János Galambos, Attila Bielik, Gábor Wágner, György Domány, János Kóti, Zoltán Béni, Áron Szigetvári, Zsuzsanna Sánta, Zoltán Orgován, Amrita Bobok, Béla Kiss, Mónika L Mikó-Bakk, Mónika Vastag, Katalin Sághy, Mikhail Krasavin, Krisztina Gál, István Greiner, Zsolt Szombathelyi, György M Keserű
Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) showed efficacy in a number of animal models of different CNS diseases including anxiety and depression. Virtually all of the compounds which reached the clinic belong to the same chemotype having an acetylenic linker that connects (hetero)cyclic moieties. Searching for new chemotypes we identified a morpholino-sulfoquinoline derivative (1) by screening our corporate compound deck. The HTS hit showed reasonable affinity and selectivity towards mGlu5 receptors, however, its inferior metabolic stability prevented its testing in vivo...
March 29, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28388665/dose-response-relationships-for-environmentally-mediated-infectious-disease-transmission-models
#20
Andrew F Brouwer, Mark H Weir, Marisa C Eisenberg, Rafael Meza, Joseph N S Eisenberg
Environmentally mediated infectious disease transmission models provide a mechanistic approach to examining environmental interventions for outbreaks, such as water treatment or surface decontamination. The shift from the classical SIR framework to one incorporating the environment requires codifying the relationship between exposure to environmental pathogens and infection, i.e. the dose-response relationship. Much of the work characterizing the functional forms of dose-response relationships has used statistical fit to experimental data...
April 2017: PLoS Computational Biology
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