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Gatekeeper

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https://www.readbyqxmd.com/read/28228638/pain-a-gatekeeper-circuit
#1
Katherine Whalley
No abstract text is available yet for this article.
February 23, 2017: Nature Reviews. Neuroscience
https://www.readbyqxmd.com/read/28225269/indazole-based-covalent-inhibitors-to-target-drug-resistant-epidermal-growth-factor-receptor
#2
Stefano Tomassi, Jonas Lategahn, Julian Engel, Marina Keul, Hannah Lea Tumbrink, Julia Ketzer, Thomas Mühlenberg, Matthias Baumann, Carsten Schultz-Fademrecht, Sebastian Bauer, Daniel Rauh
The specific targeting of oncogenic mutant epidermal growth factor receptor (EGFR) is a breakthrough in targeted cancer therapy and marks a drastic change in the treatment of non-small cell lung cancer (NSCLC). The recurrent emergence of resistance to these targeted drugs requires the development of novel chemical entities that efficiently inhibit drug-resistant EGFR. Herein, we report the optimization process for a hit compound that has emerged from a phenotypic screen resulting in indazole-based compounds...
February 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28219448/a-computational-protocol-to-evaluate-the-effects-of-protein-mutants-in-the-kinase-gatekeeper-position-on-the-binding-of-atp-substrate-analogues
#3
Valentina Romano, Tjaart A P de Beer, Torsten Schwede
BACKGROUND: The determination of specific kinase substrates in vivo is challenging due to the large number of protein kinases in cells, their substrate specificity overlap, and the lack of highly specific inhibitors. In the late 90s, Shokat and coworkers developed a protein engineering-based method addressing the question of identification of substrates of protein kinases. The approach was based on the mutagenesis of the gatekeeper residue within the binding site of a protein kinase to change the co-substrate specificity from ATP to ATP analogues...
February 20, 2017: BMC Research Notes
https://www.readbyqxmd.com/read/28218627/gata4-dependent-organ-specific-endothelial-differentiation-controls-liver-development-and-embryonic-hematopoiesis
#4
Cyrill Géraud, Philipp-Sebastian Koch, Johanna Zierow, Kay Klapproth, Katrin Busch, Victor Olsavszky, Thomas Leibing, Alexandra Demory, Friederike Ulbrich, Miriam Diett, Sandhya Singh, Carsten Sticht, Katja Breitkopf-Heinlein, Karsten Richter, Sanna-Maria Karppinen, Taina Pihlajaniemi, Bernd Arnold, Hans-Reimer Rodewald, Hellmut G Augustin, Kai Schledzewski, Sergij Goerdt
Microvascular endothelial cells (ECs) are increasingly recognized as organ-specific gatekeepers of their microenvironment. Microvascular ECs instruct neighboring cells in their organ-specific vascular niches through angiocrine factors, which include secreted growth factors (angiokines), extracellular matrix molecules, and transmembrane proteins. However, the molecular regulators that drive organ-specific microvascular transcriptional programs and thereby regulate angiodiversity are largely elusive. In contrast to other ECs, which form a continuous cell layer, liver sinusoidal ECs (LSECs) constitute discontinuous, permeable microvessels...
February 20, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28215463/markers-of-tms-evoked-visual-conscious-experience-in-a-patient-with-altitudinal-hemianopia
#5
Chiara Mazzi, Gaetano Mazzeo, Silvia Savazzi
Transcranial magnetic stimulation (TMS) of the occipital and parietal cortices can induce phosphenes, i.e. visual sensations of light without light entering the eyes. In this paper, we adopted a TMS-EEG interactive co-registration approach with a patient (AM) showing altitudinal hemianopia. Occipital and parietal cortices in both hemispheres were stimulated while concurrently recording EEG signal. Results showed that, for all sites, neural activity differentially encoding for the presence vs. absence of a conscious experience could be found in a cluster of electrodes close to the stimulation site at an early (70ms) time-period after TMS...
February 16, 2017: Consciousness and Cognition
https://www.readbyqxmd.com/read/28214722/when-high-pressure-system-constraints-and-a-social-justice-mission-collide-a-socio-structural-analysis-of-emergency-department-social-work-services
#6
Megan Moore, Margaret Cristofalo, Danae Dotolo, Nicole Torres, Alexandra Lahdya, Leyna Ho, Mia Vogel, Mollie Forrester, Bonnie Conley, Susan Fouts
The emergency department (ED) can be a critical intervention point for many patients with multifaceted needs. Social workers have long been part of interdisciplinary ED teams. This study aimed to contribute to the limited understanding of social worker-patient interactions and factors influencing social work services in this setting. This paper reports a qualitative content analysis of social work medical record notes (N = 1509) of services provided to trauma patients in an urban, public, level 1 trauma center and an in-depth analysis of semi-structured interviews with ED social workers (N = 10)...
February 11, 2017: Social Science & Medicine
https://www.readbyqxmd.com/read/28214634/a-systematic-review-of-help-seeking-and-mental-health-service-utilization-among-military-service-members
#7
REVIEW
Melanie A Hom, Ian H Stanley, Matthew E Schneider, Thomas E Joiner
Research has demonstrated that military service members are at elevated risk for a range of psychiatric problems, and mental health services use is a conduit to symptom reduction and remission. Nonetheless, there is a notable underutilization of mental health services in this population. This systematic review aimed to identify and critically examine: (1) rates of service use; (2) barriers and facilitators to care; and (3) programs and interventions designed to enhance willingness to seek care and increase help-seeking behaviors among current military personnel (e...
February 4, 2017: Clinical Psychology Review
https://www.readbyqxmd.com/read/28210205/the-atp-gated-p2x7-receptor-as-a-target-for-the-treatment-of-drug-resistant-epilepsy
#8
REVIEW
Edward Beamer, Wolfgang Fischer, Tobias Engel
Despite the progress made in the development of new antiepileptic drugs (AEDs), the biggest challenges that epilepsy presents to drug development have remained unchanged for the last 80 years: finding a treatment with potential for modifying disease progression and reducing the percentage of patients resistant to all pharmacological interventions. The mechanism of action of the majority of AEDs is based on blocking Na(+) and/or Ca(2+) channels, promotion of GABA or inhibition of glutamate signaling. In order for further progress to be made, however, a fuller picture of epilepsy will need to be considered, including changes to blood-brain barrier permeability, synaptic plasticity, network reorganization, and gliosis...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28207366/collaborative-partnerships-and-gatekeepers-in-online-research-recruitment
#9
Abbas Rattani, Amelia Johns
No abstract text is available yet for this article.
March 2017: American Journal of Bioethics: AJOB
https://www.readbyqxmd.com/read/28206741/polyketide-bioderivatization-using-the-promiscuous-acyltransferase-kircii
#10
Ewa M Musiol-Kroll, Florian Zubeil, Thomas Schafhauser, Thomas Härtner, Andreas Kulik, John McArthur, Irina Koryakina, Wolfgang Wohlleben, Stephanie Grond, Gavin J Williams, Sang Yup Lee, Tilmann Weber
During polyketide biosynthesis, acyltransferases (ATs) are the essential gatekeepers which provide the assembly lines with precursors and thus contribute greatly to structural diversity. Previously, we demonstrated that the discrete AT KirCII from the kirromycin antibiotic pathway accesses nonmalonate extender units. Here, we exploit the promiscuity of KirCII to generate new kirromycins with allyl- and propargyl-side chains in vivo, the latter were utilized as educts for further modification by "click" chemistry...
February 22, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28205653/phosphorylation-of-zinc-channel-zip7-drives-mapk-pi3k-and-mtor-growth-and-proliferation-signalling
#11
T Nimmanon, S Ziliotto, S Morris, L Flanagan, K M Taylor
Zinc is an essential trace element participating in diverse biological processes. Cellular zinc levels are strictly controlled by two families of transport proteins: ZIP channels (SLC39A) and ZnT transporters (SLC30A). ZIP channels increase cytosolic zinc levels by importing zinc into cells or releasing zinc from intracellular stores such as the ER. Among all the 14 human members of the ZIP family, ZIP7 is a gatekeeper of zinc release from intracellular stores, requiring post-translational activation by phosphorylation on residues S275 and S276, resulting in activation of multiple downstream pathways...
February 16, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28205074/coronary-artery-calcium-scanning-in-symptomatic-patients-ready-for-use-as-a-gatekeeper-for-further-testing
#12
EDITORIAL
Alan Rozanski, Daniel S Berman
No abstract text is available yet for this article.
February 15, 2017: Journal of Nuclear Cardiology: Official Publication of the American Society of Nuclear Cardiology
https://www.readbyqxmd.com/read/28192788/metabolic-gatekeeper-function-of-b-lymphoid-transcription-factors
#13
Lai N Chan, Zhengshan Chen, Daniel Braas, Jae-Woong Lee, Gang Xiao, Huimin Geng, Kadriye Nehir Cosgun, Christian Hurtz, Seyedmehdi Shojaee, Valeria Cazzaniga, Hilde Schjerven, Thomas Ernst, Andreas Hochhaus, Steven M Kornblau, Marina Konopleva, Miles A Pufall, Giovanni Cazzaniga, Grace J Liu, Thomas A Milne, H Phillip Koeffler, Theodora S Ross, Isidro Sánchez-García, Arndt Borkhardt, Keith R Yamamoto, Ross A Dickins, Thomas G Graeber, Markus Müschen
B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply...
February 13, 2017: Nature
https://www.readbyqxmd.com/read/28192746/changing-the-navigator-s-course-how-the-increasing-rationalization-of-healthcare-influences-access-for-undocumented-immigrants-under-the-affordable-care-act
#14
Laura López-Sanders
A number of researchers have shown that brokers (e.g., navigators and street-level bureaucrats) bridge access to healthcare services and information for immigrant patients through rich personal relationships and a mission of ethical care. An open question remains concerning how the increasing rationalization of healthcare over the past few decades influences brokerage for undocumented immigrant patients. Drawing from fieldwork and interviews conducted in California, as the Affordable Care Act (ACA) was implemented, I develop the concept of the "double-embedded-liaison...
February 2, 2017: Social Science & Medicine
https://www.readbyqxmd.com/read/28184964/absorption-metabolism-and-excretion-of-14-c-ponatinib-after-a-single-oral-dose-in-humans
#15
Yihua E Ye, Caroline N Woodward, Narayana I Narasimhan
PURPOSE: Ponatinib is a novel tyrosine kinase inhibitor (TKI) specifically designed to inhibit native and mutated BCR-ABL. In the United States, ponatinib has received accelerated approval for adults with T315I-positive chronic myeloid leukemia (CML) or T315I (gatekeeper mutation)-positive, Philadelphia chromosome-positive, acute lymphoblastic leukemia (Ph + ALL), and patients with CML or Ph + ALL for whom no other TKI therapy is indicated. The objective of this phase 1, mass balance study was to evaluate the absorption, metabolism, and excretion of [(14)C]ponatinib in healthy subjects...
February 9, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28178979/managed-care-and-inpatient-mortality-in-adults-effect-of-primary-payer
#16
Anika L Hines, Susan O Raetzman, Marguerite L Barrett, Ernest Moy, Roxanne M Andrews
BACKGROUND: Because managed care is increasingly prevalent in health care finance and delivery, it is important to ascertain its effects on health care quality relative to that of fee-for-service plans. Some stakeholders are concerned that basing gatekeeping, provider selection, and utilization management on cost may lower quality of care. To date, research on this topic has been inconclusive, largely because of variation in research methods and covariates. Patient age has been the only consistently evaluated outcome predictor...
February 8, 2017: BMC Health Services Research
https://www.readbyqxmd.com/read/28174757/transcriptional-regulation-by-atoh1-and-its-target-spdef-in%C3%A2-the%C3%A2-intestine
#17
Yuan-Hung Lo, Eunah Chung, Zhaohui Li, Ying-Wooi Wan, Maxime M Mahe, Min-Shan Chen, Taeko K Noah, Kristin N Bell, Hari Krishna Yalamanchili, Tiemo J Klisch, Zhandong Liu, Joo-Seop Park, Noah F Shroyer
BACKGROUND & AIMS: The transcription factor atonal homolog 1 (ATOH1) controls the fate of intestinal progenitors downstream of the Notch signaling pathway. Intestinal progenitors that escape Notch activation express high levels of ATOH1 and commit to a secretory lineage fate, implicating ATOH1 as a gatekeeper for differentiation of intestinal epithelial cells. Although some transcription factors downstream of ATOH1, such as SPDEF, have been identified to specify differentiation and maturation of specific cell types, the bona fide transcriptional targets of ATOH1 still largely are unknown...
January 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28174150/involving-children-with-cancer-in-health-promotive-research-a-case-study-describing-why-what-and-how
#18
Jens M Nygren, Susanne Lindberg, Pontus Wärnestål, Petra Svedberg
BACKGROUND: Participatory research approaches have been introduced to meet end-users' needs in the development of health promotion interventions among children. However, whereas children are increasingly involved as passive informants in particular parts of research, they are rarely involved as partners, equal to adult researchers, throughout the research process. This is especially prominent in the context of child health where the child is commonly considered to be vulnerable or when the research concerns sensitive situations...
February 7, 2017: JMIR Research Protocols
https://www.readbyqxmd.com/read/28174081/ingenious-ph-sensitive-dextran-mesoporous-silica-nanoparticles-based-drug-delivery-systems-for-controlled-intracellular-drug-release
#19
Min Zhang, Jia Liu, Ying Kuang, Qilin Li, Di-Wei Zheng, Qiongfang Song, Hui Chen, Xueqin Chen, Yanglin Xu, Cao Li, Bingbing Jiang
In this work, dextran, a polysaccharide with excellent biocompatibility, is applied as the "gatekeeper" to fabricate the pH-sensitive dextran/mesoporous silica nanoparticles (MSNs) based drug delivery systems for controlled intracellular drug release. Dextran encapsulating on the surface of MSNs is oxidized by NaIO4 to obtain three kinds of dextran dialdehydes (PADs), which are then coupled with MSNs via pH-sensitive hydrazone bond to fabricate three kinds of drug carriers. At pH 7.4, PADs block the pores to prevent premature release of anti-cancer drug doxorubicin hydrochloride (DOX)...
February 4, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28168807/hypoxia-induced-hif1%C3%AE-targets-in-melanocytes-reveal-a-molecular-profile-associated-with-poor-melanoma-prognosis
#20
Stacie K Loftus, Laura L Baxter, Julia C Cronin, Temesgen D Fufa, William J Pavan
Hypoxia and HIF1α signaling direct tissue-specific gene responses regulating tumor progression, invasion and metastasis. By integrating HIF1α knockdown and hypoxia-induced gene expression changes, this study identifies a melanocyte-specific, HIF1α-dependent / hypoxia-responsive gene expression signature. Integration of these gene expression changes with HIF1α ChIP-Seq analysis identifies 81 HIF1α direct target genes in melanocytes. The expression levels for ten of the HIF1α direct targets - GAPDH, PKM, PPAT, DARS, DTWD1, SEH1L, ZNF292, RLF, AGTRAP, and GPC6 - are significantly correlated with reduced time of Disease Free Status (DFS) in melanoma by logistic regression (P-value =0...
February 6, 2017: Pigment Cell & Melanoma Research
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