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https://www.readbyqxmd.com/read/29326832/at-the-atrioventricular-crossroads-dual-pathway-electrophysiology-in-the-atrioventricular-node-and-its-underlying-heterogeneities
#1
Sharon A George, N Rokhaya Faye, Alejandro Murillo-Berlioz, K Benjamin Lee, Gregory D Trachiotis, Igor R Efimov
The atrioventricular node (AVN) is a complex structure that performs a variety of functions in the heart. The AVN is primarily an electrical gatekeeper between the atria and ventricles and introduces a delay between atrial and ventricular excitation, allowing for efficient ventricular filling. The AVN is composed of several compartments that safely transmit electrical excitation from the atria to the ventricles via the fast or slow pathways. There are many electrophysiological differences between these pathways, including conduction time and electrical refractoriness, that increase the predisposition of the atrioventricular junction to arrhythmias such as atrioventricular nodal re-entrant tachycardia...
December 2017: Arrhythmia & Electrophysiology Review
https://www.readbyqxmd.com/read/29321583/allele-specific-repression-of-sox2-through-the-long-non-coding-rna-sox2ot
#2
Tobias C Messemaker, Selina M van Leeuwen, Patrick R van den Berg, Anke E J 't Jong, Robert-Jan Palstra, Rob C Hoeben, Stefan Semrau, Harald M M Mikkers
The transcription factor Sox2 controls the fate of pluripotent stem cells and neural stem cells. This gatekeeper function requires well-regulated Sox2 levels. We postulated that Sox2 regulation is partially controlled by the Sox2 overlapping long non-coding RNA (lncRNA) gene Sox2ot. Here we show that the RNA levels of Sox2ot and Sox2 are inversely correlated during neural differentiation of mouse embryonic stem cells (ESCs). Through allele-specific enhanced transcription of Sox2ot in mouse Sox2eGFP knockin ESCs we demonstrate that increased Sox2ot transcriptional activity reduces Sox2 RNA levels in an allele-specific manner...
January 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29320302/federal-right-to-try-legislation-threatening-the-fda-s-public-health-mission
#3
Steven Joffe, Holly Fernandez Lynch
The Food and Drug Administration (FDA) is the gatekeeper of the country’s drugs and medical devices. Originally created to prevent the misleading of patients, it was later tasked with ensuring the safety of medical products. In 1962, Congress expanded the FDA’s mandate again, requiring it to..
January 10, 2018: New England Journal of Medicine
https://www.readbyqxmd.com/read/29319191/linaclotide-in-irritable-bowel-syndrome-with-constipation-a-phase-3-randomized-trial-in-china-and-other-regions
#4
Yunsheng Yang, Jingyuan Fang, Xiaozhong Guo, Ning Dai, Xizhong Shen, Youlin Yang, Jing Sun, Bal Raj Bhandari, David S Reasner, Jacquelyn A Cronin, Mark G Currie, Jeffrey M Johnston, Peter Zeng, Niwat Montreewasuwat, George Zhijian Chen, Sam Lim
BACKGROUND AND AIM: Linaclotide is a guanylate cyclase-C agonist approved in multiple countries to treat irritable bowel syndrome with constipation (IBS-C). China has unmet need for well-tolerated therapy that is effective in treating both bowel and abdominal symptoms of IBS-C. This trial evaluated linaclotide's efficacy and safety in IBS-C patients in China and other regions. METHODS: This Phase 3, double-blind trial randomized IBS-C patients to once-daily oral 290-μg linaclotide or placebo at centers in China, North America, and Oceania...
January 10, 2018: Journal of Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/29316858/interdependency-of-construction-safety-hazards-from-a-network-perspective-a-mechanical-installation-case
#5
Pin-Chao Liao, Zhonghua Guo, Tao Wang, Jing Wen, Chung-Han Tsai
The assumption that safety hazards in construction projects are independent leads to a weak foundation for risk assessments, and related management strategies may be biased. Therefore, understanding interdependencies of hazards is critical to risk assessment in construction safety. This study proposed a qualitative-quantitative hybrid approach to delineating hazard associations. Based on the hazard network model for an elevator installation, we identified the characteristics of the hazard network and determined critical hazard types based on the hazard associations...
January 10, 2018: International Journal of Occupational Safety and Ergonomics: JOSE
https://www.readbyqxmd.com/read/29313703/the-use-of-gatekeeping-procedures-in-the-statistical-planning-of-animal-experiments
#6
Benjamin Mayer, Vicky Stahl, Martina Kron
Statistical sample size calculation is essential when planning animal experiments in basic medical research. Usually, such trials involve the testing of multiple hypotheses, and interpreting them in a confirmative manner would require the appropriate adjustment of the Type 1 error. This has to be taken into account as early as possible during sample size estimation - otherwise, all the results obtained would be exploratory, i.e. without cogency. In this paper, the concept of gatekeeping is introduced, along with alternative approaches for Type 1 error adjustment...
December 2017: Alternatives to Laboratory Animals: ATLA
https://www.readbyqxmd.com/read/29290775/nuclear-egfr-and-integrator-super-elongation-complex-concurrently-binds-to-immediate-early-genes-for-gene-transactivation
#7
Victor Chun-Lam Wong
The gene transactivation function of nuclear EGFR (nEGFR) has been studied by investigating the genomic co-occupancies of nEGFR and RNA Polymerase II (RNAPII). However, due to RNAPII pausing, the co-recruitment of RNAPII and nEGFR does not necessarily represent productive transactivation. In this study, we integrated gatekeepers of productive transcriptional elongation such as Integrator and Super Elongation Complex (SEC) to interrogate the function of nEGFR. By analyzing publicly available ChIP-seq and RNA-seq data, we aims to 1) explore the function of nEGFR, 2) unravel nEGFR target genes, and 3) discuss potential mechanisms of nEGFR chromatin recruitment...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29288940/discovery-of-2-4-diarylaminopyrimidines-bearing-a-resorcinol-motif-as-novel-alk-inhibitors-to-overcome-the-g1202r-resistant-mutation
#8
Kaijun Geng, Zongjun Xia, Yinchun Ji, Ruisi Ruthy Zhang, Deqiao Sun, Jing Ai, Zilan Song, Meiyu Geng, Ao Zhang
To address drug resistance caused by ALK kinase mutations, especially the most refractory and predominant mutation G1202R for the second-generation ALK inhibitor, a series of new diarylaminopyrimidine analogues were designed by incorporating a resorcinol moiety (A-ring) to interact the ALK kinase domain where the G1202R is located. Compound 12d turns out as the most potent with IC50 values of 1.7, 3.5, and 1.8 nM against ALK wild type, gatekeeper mutant L1196M, and the G1202R mutant, respectively. More importantly, compound 12d has excellent inhibitory effects against the proliferation of BaF3 cells specifically expressing ALK wild type, gatekeeper L1196M, and the most challenging mutant G1202R, with IC50 values all less than 1...
December 20, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29283310/mixture-based-gatekeeping-procedures-in-adaptive-clinical-trials
#9
George Kordzakhia, Alex Dmitrienko, Eiji Ishida
Clinical trials with data-driven decision rules often pursue multiple clinical objectives such as the evaluation of several endpoints or several doses of an experimental treatment. These complex analysis strategies give rise to "multivariate" multiplicity problems with several components or sources of multiplicity. A general framework for defining gatekeeping procedures in clinical trials with adaptive multistage designs is proposed in this paper. The mixture method is applied to build a gatekeeping procedure at each stage and inferences at each decision point (interim or final analysis) are performed using the combination function approach...
December 28, 2017: Journal of Biopharmaceutical Statistics
https://www.readbyqxmd.com/read/29282826/rational-design-binding-studies-and-crystal-structure-evaluation-of-the-first-ligand-targeting-the-dimerization-interface-of-the-14-3-3%C3%AE-adapter-protein
#10
Carsten Schmuck, Martin Ehlers, Jean-Noel Grad, Sumit Mittal, David Bier, Marcel Mertel, Ludwig Ohl, Maria Bartel, Jeroen Briels, Marius Heimann, Christian Ottmann, Elsa Sanchez-Garcia, Daniel Hoffmann
14-3-3 proteins play a central role in signaling pathways in cells: they interact as gatekeeper proteins with a huge number of binding partners. Their function as hub for intracellular communication can explain why these adapter proteins are associated with a wide range of diseases. How they control the various cellular mechanisms is still unclear, but it is assumed that the dimeric nature of the 14-3-3 proteins plays a key role in their activity. Here we present, to the best of our knowledge, the first example of a small molecule binding to the 14-3-3ζ dimerization interface...
December 28, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29280052/patient-and-provider-perspectives-on-the-development-of-personalized-medicine-a-mixed-methods-approach
#11
Lauren Puryear, Natalie Downs, Andrea Nevedal, Eleanor T Lewis, Kelly E Ormond, Maria Bregendahl, Carlos J Suarez, Sean P David, Steven Charlap, Isabella Chu, Steven M Asch, Neda Pakdaman, Sang-Ick Chang, Mark R Cullen, Latha Palaniappan
While genetic testing gains adoption in specialty services such as oncology, neurology, and cardiology, use of genetic and genomic testing has yet to be adopted as widely in primary care. The purpose of this study is to identify and compare patient and primary care provider (PCP) expectations of genetics services in primary care. Patient and PCP perspectives were assessed through a mixed-method approach combining an online survey and semi-structured interviews in a primary care department of a large academic medical institution...
December 27, 2017: Journal of Community Genetics
https://www.readbyqxmd.com/read/29278263/disrupting-gatekeeping-practices-journalists-source-selection-in-times-of-crisis
#12
Toni G L A van der Meer, Piet Verhoeven, Johannes W J Beentjes, Rens Vliegenthart
As gatekeepers, journalists have the power to select the sources that get a voice in crisis coverage. The aim of this study is to find out how journalists select sources during a crisis. In a survey, journalists were asked how they assess the following sources during an organizational crisis: news agencies, an organization undergoing a crisis, and the general public. The sample consisted of 214 Dutch experienced journalists who at least once covered a crisis. Using structural equation modeling, sources' likelihood of being included in the news was predicted using five source characteristics: credibility, knowledge, willingness, timeliness, and the relationship with the journalist...
October 2017: Journalism (Lond)
https://www.readbyqxmd.com/read/29277965/novel-insights-into-the-mechanism-of-sepl-mediated-control-of-effector-secretion-in-enteropathogenic-escherichia-coli
#13
Meztlli O Gaytán, Julia Monjarás Feria, Eduardo Soto, Norma Espinosa, Julia M Benítez, Dimitris Georgellis, Bertha González-Pedrajo
Type three secretion systems (T3SSs) are virulence determinants employed by several pathogenic bacteria as molecular syringes to inject effector proteins into host cells. Diarrhea-producing enteropathogenic Escherichia coli (EPEC) uses a T3SS to colonize the intestinal tract. T3S is a highly coordinated process that ensures hierarchical delivery of three classes of substrates: early (inner rod and needle subunits), middle (translocators), and late (effectors). Translocation of effectors is triggered upon host-cell contact in response to different environmental cues, such as calcium levels...
December 26, 2017: MicrobiologyOpen
https://www.readbyqxmd.com/read/29275545/application-of-optical-coherence-tomography-for-in-vivo-monitoring-of-the-meningeal-lymphatic-vessels-during-opening-of-blood-brain-barrier-mechanisms-of-brain-clearing
#14
Oxana Semyachkina-Glushkovskaya, Arkady Abdurashitov, Alexander Dubrovsky, Denis Bragin, Olga Bragina, Nataliya Shushunova, Galina Maslyakova, Nikita Navolokin, Alla Bucharskaya, Valery Tuchin, Juergen Kurths, Alexander Shirokov
The meningeal lymphatic vessels were discovered 2 years ago as the drainage system involved in the mechanisms underlying the clearance of waste products from the brain. The blood-brain barrier (BBB) is a gatekeeper that strongly controls the movement of different molecules from the blood into the brain. We know the scenarios during the opening of the BBB, but there is extremely limited information on how the brain clears the substances that cross the BBB. Here, using the model of sound-induced opening of the BBB, we clearly show how the brain clears dextran after it crosses the BBB via the meningeal lymphatic vessels...
December 2017: Journal of Biomedical Optics
https://www.readbyqxmd.com/read/29261277/aiegen-functionalized-mesoporous-silica-gated-by-cyclodextrin-modified-cus-for-cell-imaging-and-chemo-photothermal-cancer-therapy
#15
Qing-Lan Li, Duo Wang, Yuanzheng Cui, Zhiying Fan, Li Ren, Dongdong Li, Jihong Yu
A novel multifunctional drug delivery system has been constructed by assembling per-6-thio-β-cyclodextrin-modified ultrasmall CuS nanoparticles (CD-CuS) onto fluorescent AIEgen-containing mesoporous silica nanoparticles (FMSN). The CD-CuS nanoparticles are anchored on the surface of benzimidazole-grafted FMSN, acting as a gatekeeper and photothermal agent. The prepared blue-emitting nanocomposite (FMSN@CuS) exhibits good biocompatibility and cell imaging capability. Anticancer drug doxorubicin hydrochloride (DOX) molecules are loaded into FMSN@CuS, and zero prerelease at physiological pH (7...
December 20, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/29251717/glycolysis-gatekeeper-pdk1-reprograms-breast-cancer-stem-cells-under-hypoxia
#16
F Peng, J-H Wang, W-J Fan, Y-T Meng, M-M Li, T-T Li, B Cui, H-F Wang, Y Zhao, F An, T Guo, X-F Liu, L Zhang, L Lv, D-K Lv, L-Z Xu, J-J Xie, W-X Lin, E W-F Lam, J Xu, Q Liu
This corrects the article DOI: 10.1038/onc.2017.368.
December 18, 2017: Oncogene
https://www.readbyqxmd.com/read/29249194/multi-functional-magnetic-nanoparticles-as-an-effective-drug-carrier-for-the-controlled-anti-tumor-treatment
#17
Zhi Li, Junya Zhang, Xiaonan Guo, Xinhong Guo, Zhenzhong Zhang
Because of the complications and mutability of cancers, combination of chemotherapy and other therapy with multi-mechanisms would be a bright future for the treatment of cancer. Thus, development of multi-functional tumor-targeted drug delivery systems with two or more than two functions should be of great significance. In the study, the Fe3O4@C nanoparticles linked with thermoresponsive copolymer (MTC-NPs) were synthesized, after that, the magnetic properties and photothermal effects of MTC NPs were evaluated...
January 1, 2017: Journal of Biomaterials Applications
https://www.readbyqxmd.com/read/29246083/researchers-experiences-and-lessons-learned-from-doing-mixed-methods-research-with-a-population-with-intellectual-disabilities-insights-from-the-sophie-study
#18
Deirdre Corby, Mary Rose Sweeney
Researchers are challenged to provide opportunities for people with intellectual disabilities (IDs) and their families to become participants in research. This article explores the processes and procedures involved in conducting a mixed-methods study. The preparation for the study is described and explained. Recruitment is examined by describing the process and analysing phone calls made to potential participants. Reflections of research team members help to develop the analysis and contribute to a discussion of the fieldwork...
January 1, 2017: Journal of Intellectual Disabilities: JOID
https://www.readbyqxmd.com/read/29242113/professionals-knowledge-attitude-and-referral-behaviour-of-preimplantation-genetic-diagnosis-for-hereditary-breast-and-ovarian-cancer
#19
J J G Gietel-Habets, C E M de Die-Smulders, V C G Tjan-Heijnen, I A P Derks-Smeets, R van Golde, E Gomez-Garcia, L A D M van Osch
Hereditary breast and ovarian cancer caused by a BRCA1/2 mutation is the most frequent indication for preimplantation genetic diagnosis (PGD) in the Netherlands. The extent to which involved professionals are informed about this option, however, is unclear. The few available international studies mostly represent a limited range of professionals, and suggest that their knowledge about PGD for hereditary cancer syndromes is sparse and referral for PGD is based on limited understanding. A cross-sectional survey assessing awareness, knowledge, acceptability and PGD-referral for BRCA was completed by 188 professionals involved in the field of breast and ovarian cancer or reproduction...
December 6, 2017: Reproductive Biomedicine Online
https://www.readbyqxmd.com/read/29241542/micu2-restricts-spatial-crosstalk-between-insp3r-and-mcu-channels-by-regulating-threshold-and-gain-of-micu1-mediated-inhibition-and-activation-of-mcu
#20
Riley Payne, Henry Hoff, Anne Roskowski, J Kevin Foskett
Ca2+ entry into mitochondria is mediated by the Ca2+ uniporter-channel complex containing MCU, the Ca2+-selective pore, and associated regulatory proteins. The roles of MICU proteins are controversial. MICU1 was proposed to be necessary for MCU activity, whereas subsequent studies suggested it inhibits the channel in the low-cytoplasmic Ca2+ ([Ca2+]c) regime, a mechanism referred to as "gatekeeping," that imposes a [Ca2+]c threshold for channel activation at ∼1-3 μM. Here, we measured MCU activity over a wide range of quantitatively controlled and recorded [Ca2+]c...
December 12, 2017: Cell Reports
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