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https://www.readbyqxmd.com/read/28431232/genome-wide-mapping-of-drosha-cleavage-sites-on-primary-micrornas-and-noncanonical-substrates
#1
Baekgyu Kim, Kyowon Jeong, V Narry Kim
MicroRNA (miRNA) maturation is initiated by DROSHA, a double-stranded RNA (dsRNA)-specific RNase III enzyme. By cleaving primary miRNAs (pri-miRNAs) at specific positions, DROSHA serves as a main determinant of miRNA sequences and a highly selective gatekeeper for the canonical miRNA pathway. However, the sites of DROSHA-mediated processing have not been annotated, and it remains unclear to what extent DROSHA functions outside the miRNA pathway. Here, we establish a protocol termed "formaldehyde crosslinking, immunoprecipitation, and sequencing (fCLIP-seq)," which allows identification of DROSHA cleavage sites at single-nucleotide resolution...
April 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28430833/on-the-need-for-quantitative-bias-analysis-in-the-peer-review-process
#2
Matthew P Fox, Timothy L Lash
Peer review is central to the process through which epidemiologists generate evidence to inform public health and medical interventions. Reviewers thereby act as critical gatekeepers to high-quality research. They are asked to carefully consider the validity of the proposed work or research findings by paying careful attention to the methodology and critiquing the importance of the insight gained. However, although many have noted problems with the peer-review system for both manuscripts and grant submissions, few solutions have been proposed to improve the process...
April 18, 2017: American Journal of Epidemiology
https://www.readbyqxmd.com/read/28427098/opa1-in-lipid-metabolism-function-of-opa1-in-lipolysis-and-thermogenesis-of-adipocytes
#3
Dinh-Toi Chu, Yang Tao, Kjetil Taskén
OPA1 (Optic Atrophy 1) is a mitochondrial GTPase known to regulate fission of mitochondria. It was recently also shown to locate on lipid droplets in adipocytes where it functions as an A-kinase anchoring protein (AKAP) that mediates adrenergic control of lipolysis by facilitating PKA phosphorylation of perilipin (Plin1). In brown adipocytes indirect evidence support the notion that OPA1 regulation of fission serves to increase thermogenesis, which thereby contributes to dissipation of energy. In white adipocytes, OPA1 located on lipid droplets serves as a gatekeeper to control lipolysis induced by adrenergic agonists...
April 2017: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
https://www.readbyqxmd.com/read/28427013/the-accelerated-path-of-ceritinib-translating-pre-clinical-development-into-clinical-efficacy
#4
REVIEW
Tony S K Mok, Lucio Crino, Enriqueta Felip, Ravi Salgia, Tommaso De Pas, Daniel S W Tan, Laura Q M Chow
The discovery of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved-ceritinib and alectinib-and others that are in development-brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms...
March 30, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28425639/designing-dual-inhibitors-of-mdm2-mdmx-unexpected-coupling-of-water-with-gatekeeper-y100-99
#5
Xiong An Lee, Chandra Verma, Adelene Y L Sim
Mdm2 and MdmX share high structural similarity in their N-terminal domains, yet dual inhibitors are challenging to design due to differences in the conformations of the binding pockets, and notably of the proposed gatekeeper residue, Y100/99. Analysis of crystal structures and molecular dynamics (MD) simulations of complexes of Mdm2 and MdmX resulted in the identification of a water molecule with a long residence time that appears to be modulated by the conformation of Y100/99. These observations lead us to speculate that dual inhibitors either i) stabilize both Mdm2 and MdmX with Y100/99 in the open conformation typically seen in complexes of Mdm2 with p53, or ii) the dual inhibitors are agnostic to the conformation of Y100/99...
April 20, 2017: Proteins
https://www.readbyqxmd.com/read/28422296/keeping-out-and-getting-in-reframing-emergency-department-gatekeeping-as-structural-competence
#6
Mara Buchbinder
Sociologists have tended to frame medical gatekeeping as an exclusionary social practice, delineating how practitioners and clerical staff police the moral boundaries of medicine by keeping out patients who are categorised as 'bad', 'deviant', or otherwise problematic. Yet medical gatekeeping, understood more broadly, can include not only keeping patients out of particular clinical settings, but also redirecting them to alternative sources of care. In this article, I draw on qualitative analysis of audio-recorded patient-provider interactions in a United States emergency department (ED) to illustrate medical gatekeeping as a two-step process of, first, categorising certain patient complaints as unsuitable for treatment within a particular setting, and second, diverting patients to alternative sites for care...
April 19, 2017: Sociology of Health & Illness
https://www.readbyqxmd.com/read/28415099/p594contrast-transthoracic-echocardiography-as-a-gatekeeper-for-patent-foramen-ovale-closure
#7
M Muratori, G Italiano, E Innocenti, L Fusini, M Mapelli, G Tamborini, S Ghulam Ali, P Gripari, A Maltagliati, F Celeste, M Pepi
Background.: The presence of patent foramen ovale (PFO) has been linked to many illness, including cryptogenic stroke, transient ischemic attack, migraine, platypnea-orthodeoxia syndrome and decompression sickness in scuba divers. Transesophageal echocardiography is the gold standard technique for the visualization of atrial septal anatomy, but it is a secondary level exam, not always available, with additional associated costs and not completely free from procedural risks. Standard transthoracic echocardiography (TTE) has a too low sensitivity for PFO screening...
December 1, 2016: European Heart Journal Cardiovascular Imaging
https://www.readbyqxmd.com/read/28412436/noninvasive-ffr-derived-from-coronary-ct-angiography-management-and-outcomes-in-the-promise-trial
#8
Michael T Lu, Maros Ferencik, Rhonda S Roberts, Kerry L Lee, Alexander Ivanov, Elizabeth Adami, Daniel B Mark, Farouc A Jaffer, Jonathon A Leipsic, Pamela S Douglas, Udo Hoffmann
OBJECTIVES: The purpose of this study was to determine whether noninvasive fractional flow reserve derived from computed tomography (FFRCT) predicts coronary revascularization and outcomes and whether its addition improves efficiency of referral to invasive coronary angiography (ICA) after coronary computed tomography angiography (CTA). BACKGROUND: FFRCT may improve the efficiency of an anatomic CTA strategy for stable chest pain. METHODS: This observational cohort study included patients with stable chest pain in the PROMISE trial (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) referred to ICA within 90 days after CTA...
April 7, 2017: JACC. Cardiovascular Imaging
https://www.readbyqxmd.com/read/28408483/o-glcnac-cycling-and-the-regulation-of-nucleocytoplasmic-dynamics
#9
REVIEW
Moriah Eustice, Michelle R Bond, John A Hanover
The dynamic carbohydrate post-translational modification (PTM) O-linked β-N-acetyl glucosamine (O-GlcNAc) is found on thousands of proteins throughout the nucleus and cytoplasm, and rivals phosphorylation in terms of the number of substrates and pathways influenced. O-GlcNAc is highly conserved and essential in most organisms, with disruption of O-GlcNAc cycling linked to diseases ranging from cancer to neurodegeneration. Nuclear pore proteins were the first identified O-GlcNAc-modified substrates, generating intense and ongoing interest in understanding the role of O-GlcNAc cycling in nuclear pore complex structure and function...
April 15, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28407530/redox-responsive-nanocarriers-for-drug-and-gene-co-delivery-based-on-chitosan-derivatives-modified-mesoporous-silica-nanoparticles
#10
Jian-Tao Lin, Zong-Kun Liu, Qing-Ling Zhu, Xiao-Hui Rong, Cui-Ling Liang, Jie Wang, Dong Ma, Jing Sun, Guan-Hai Wang
Stimuli-responsive nanocarriers for anticancer drug and gene co-delivery are promising strategy in cancer therapy. The ultimate goal is to deliver high local concentration of therapeutic agents with no premature release and result in synergistic effects for combination therapies. In this work, we developed a redox stimuli-responsive and synergistic co-delivery system for anticancer drug DOX and p53 gene for potential cancer therapy. A dendronized chitosan derivative (CP) as a "gatekeeper" to control release the drug was used to modify MSNs via a disulfide linker and improve the gene transfection efficiency...
April 5, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28396416/proteolytic-control-of-the-mitochondrial-calcium-uniporter-complex
#11
Chen-Wei Tsai, Yujiao Wu, Ping-Chieh Pao, Charles B Phillips, Carole Williams, Christopher Miller, Matthew Ranaghan, Ming-Feng Tsai
The mitochondrial calcium uniporter is a Ca(2+)-activated Ca(2+) channel complex mediating mitochondrial Ca(2+) uptake, a process crucial for Ca(2+) signaling, bioenergetics, and cell death. The uniporter is composed of the pore-forming MCU protein, the gatekeeping MICU1 and MICU2 subunits, and EMRE, a single-pass membrane protein that links MCU and MICU1 together. As a bridging subunit required for channel function, EMRE could paradoxically inhibit uniporter complex formation if expressed in excess. Here, we show that mitochondrial mAAA proteases AFG3L2 and SPG7 rapidly degrade unassembled EMRE using the energy of ATP hydrolysis...
April 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28391558/a-survey-of-the-knowledge-of-african-american-women-about-prostate-cancer-screening
#12
Taryn Y Eastland
Prostate cancer is the second most common cancer diagnosed in men. Its incident and mortality rates are generally higher in populations of African descent. The scientific community recommends that men should be informed of the benefits, risks, and limitations of screening in order to make an informed decision regarding participation in prostate cancer screening. Women are known to act as the healthcare gatekeeper for the family. As such, African-American (AA) women could facilitate the informed decision-making process by providing prostate cancer and screening information to AA men...
April 8, 2017: Journal of Cancer Education: the Official Journal of the American Association for Cancer Education
https://www.readbyqxmd.com/read/28390804/open-vs-endoscopic-cricopharyngeal-myotomy-is-there-a-difference
#13
Colin Huntley, Maurits Boon, Joseph Spiegel
INTRODUCTION: The upper esophageal sphincter (UES) is composed largely of the cricopharyngeus muscle (CP) and acts as the gatekeeper to the esophagus. There are multiple methods of treating UES dysfunction, but myotomy has been shown to be the most definitive means. We aim to evaluate the difference between open and endoscopic CP myotomy (CPM). METHODS: A retrospective review of all patients undergoing endoscopic and open CPM was undertaken. We recorded demographic, clinical, operative, hospital, and postoperative data for both groups from January 2010-March 2015...
March 31, 2017: American Journal of Otolaryngology
https://www.readbyqxmd.com/read/28384467/huntington-s-disease-nuclear-gatekeepers-under-attack
#14
Matthew B Veldman, X William Yang
In this issue of Neuron, Gasset-Rosa et al. (2017) and Grima et al. (2017) describe defects in the nuclear pore complex and impaired nucleocytoplasmic transport in Huntington's disease (HD). The findings suggest that erosion of nuclear gatekeeping function, which is found in normal brain aging, may play an important role in the pathogenesis of multiple neurodegenerative disorders, including HD.
April 5, 2017: Neuron
https://www.readbyqxmd.com/read/28379388/prevalence-of-obstructive-coronary-artery-disease-and-prognosis-in-patients-with-stable-symptoms-and-a-zero-coronary-calcium-score
#15
Tarun K Mittal, Alison Pottle, Ed Nicol, Mahmoud Barbir, Ben Ariff, Saeed Mirsadraee, Michael Dubowitz, Diana A Gorog, Piers Clifford, Soroosh Firoozan, Robert Smith, Simon Dubrey, Harmeet Chana, Jaymin Shah, Nigel Stephens, Christopher Travill, Andrew Kelion, Mini Pakkal, Adam Timmis
Aims: CT calcium scoring (CTCS) and CT cardiac angiography (CTCA) are widely used in patients with stable chest pain to exclude significant coronary artery disease (CAD). We aimed to resolve uncertainty about the prevalence of obstructive coronary artery disease and long-term outcomes in patients with a zero-calcium score (ZCS). Methods and results: Consecutive patients with stable cardiac symptoms referred for CTCS or CTCS and CTCA from chest pain clinics to a tertiary cardiothoracic centre were prospectively enrolled...
March 31, 2017: European Heart Journal Cardiovascular Imaging
https://www.readbyqxmd.com/read/28377490/biological-role-and-therapeutic-targeting-of-tgf-%C3%AE-3-in-glioblastoma
#16
Katharina Seystahl, Alexandros Papachristodoulou, Isabel Burghardt, Hannah Schneider, Kathy Hasenbach, Michel Janicot, Patrick Roth, Michael Weller
Transforming growth factor (TGF)-β contributes to the malignant phenotype of glioblastoma by promoting invasiveness and angiogenesis and creating an immunosuppressive microenvironment. So far, TGF-β1 and TGF-β2 isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma. A pathogenic role for TGF-β3 in glioblastoma has not been defined yet. Here we studied the expression and functional role of endogenous and exogenous TGF-β3 in glioblastoma models. TGF-β3 mRNA is expressed in human and murine long-term glioma cell lines as well as in human glioma-initiating cell cultures with expression levels lower than TGF-β1 or TGF-β2 in most cell lines...
April 4, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28374137/the-proliferation-mechanism-of-lactobacillus-plantarum-rb1-stimulated-by-stachyose
#17
Qing Pan, Xiaoqun Zeng, Daodong Pan, Liuyang Peng, Zhen Wu, Yangying Sun, Yan Wei
The proliferation mechanism of Lactobacillus plantarum RB1 promoted by stachyose was investigated in this work. The hydrolysis of stachyose, the glycometabolism, and the cytoactivity of L. plantarum RB1 were detected after proliferation. The specific activity of α-galactosidase of L. plantarum RB1 in the stachyose group was significantly higher than the control group (without stachyose), which indicated that the stachyose induced L. plantarum RB1 and produced more α-galactosidase to hydrolyze stachyose. The glycometabolism which includes glycolysis and tricarboxylic acid (TCA) cycle was significantly enhanced in the stachyose group compared with the control group...
April 4, 2017: Current Microbiology
https://www.readbyqxmd.com/read/28364939/innovations-in-cold-chain-equipment-for-immunization-supply-chains
#18
REVIEW
Joanie Robertson, Lauren Franzel, Denis Maire
BACKGROUND: Since 2010, numerous new technologies have entered the immunization cold chain equipment market. The World Health Organization (WHO) Immunization Devices Programme-Performance, Quality and Safety (PQS)-has played a key role in bringing these to market. In this article, the authors explore the emergence of new cold chain equipment technologies from 2004 to 2016 and the role of PQS in this evolution. METHODS: This review focuses on three major vaccine cold chain technology innovations-solar direct-drive refrigerators, long-term passive cold boxes, and equipment with user-independent freeze prevention...
April 19, 2017: Vaccine
https://www.readbyqxmd.com/read/28359596/-primary-care-in-ireland
#19
T Sánchez-Sagrado
Spanish doctors are still leaving the country to look for quality work. Ireland is not a country with many Spanish professionals but it is interesting to know its particular Health care system. Ireland is one of the countries with a national health care system, although it has a mixture of private health care insurance schemes. People have a right to health care if they have been living in Ireland at least for a year. Access to the primary care health system depends on age and income: free of charge for Category 1 and co-payments for the rest...
March 27, 2017: Semergen
https://www.readbyqxmd.com/read/28356527/chemokine-receptor-ccr7-restricts-fatal-west-nile-virus-encephalitis
#20
Susana V Bardina, Julia A Brown, Daniela Michlmayr, Kevin W Hoffman, Janet Sum, Alexander G Pletnev, Sergio A Lira, Jean K Lim
West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the CNS. Despite an excess of virus-specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates compared to wild-type animals...
March 29, 2017: Journal of Virology
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