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https://www.readbyqxmd.com/read/27923051/electrophysiological-characteristics-of-human-ipsc-derived-cardiomyocytes-for-the-assessment-of-drug-induced-proarrhythmic-potential
#1
Wataru Yamamoto, Keiichi Asakura, Hiroyuki Ando, Tomohiko Taniguchi, Atsuko Ojima, Takaaki Uda, Tomoharu Osada, Seiji Hayashi, Chieko Kasai, Norimasa Miyamoto, Hiroyuki Tashibu, Takashi Yoshinaga, Daiju Yamazaki, Atsushi Sugiyama, Yasunari Kanda, Kohei Sawada, Yuko Sekino
The aims of this study were to (1) characterize basic electrophysiological elements of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that correspond to clinical properties such as QT-RR relationship, (2) determine the applicability of QT correction and analysis methods, and (3) determine if and how these in-vitro parameters could be used in risk assessment for adverse drug-induced effects such as Torsades de pointes (TdP). Field potential recordings were obtained from commercially available hiPSC-CMs using multi-electrode array (MEA) platform with and without ion channel antagonists in the recording solution...
2016: PloS One
https://www.readbyqxmd.com/read/27920024/biology-and-pathobiology-of-tdp-43-and-emergent-therapeutic-strategies
#2
Lin Guo, James Shorter
Cytoplasmic TDP-43 mislocalization and aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is an RNA-binding protein (RBP) with a prion-like domain (PrLD) that promotes TDP-43 misfolding. PrLDs possess compositional similarity to canonical prion domains of various yeast proteins, including Sup35. Strikingly, disease-causing TDP-43 mutations reside almost exclusively in the PrLD and can enhance TDP-43 misfolding and toxicity. Another ∼70 human RBPs harbor PrLDs, including FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2, which have surfaced in the etiology of neurodegenerative diseases...
December 5, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27916654/prion-like-mechanisms-and-potential-therapeutic-targets-in-neurodegenerative-disorders
#3
REVIEW
Masato Hasegawa, Takashi Nonaka, Masami Masuda-Suzukake
Prion-like propagation of abnormal intracytoplasmic proteins, which are the defining features of major neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), has been proposed. A growing body of evidence strongly suggests that abnormal tau, α-synuclein and TDP-43 have prion-like properties, convert the corresponding normal proteins into abnormal forms, and are transmitted from cell to cell, spreading throughout the brain. This idea is extremely important not only for understanding the pathogenesis and progression of these diseases, but also for the development of molecular therapies...
December 1, 2016: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/27915581/ftld-tdp-and-progressive-supranuclear-palsy-in-comorbidity-a-report-of-two-cases-with-different-clinical-presentations
#4
Kateřina Storey, Silvie Johanidesová, Radoslav Matěj, Jiří Keller, Zdeněk Rohan, Robert Rusina
Frontotemporal lobar degeneration with transactive response DNA-binding protein 43 (FTLD-TDP) and progressive supranuclear palsy (PSP) are distinct neurodegenerations with different clinical presentations. We report two cases with FTLD-TDP and PSP in comorbidity: a patient with amnestic dementia developing frontal lobe dementia, Parkinsonism and supranuclear gaze palsy and a patient with cerebellar ataxia and nystagmus developing akinesia, rigidity, and subcortical dementia. Neuropathological examination revealed neuronal and glial tau pathology together with ubiquitin, and phospho-TDP-43-immunoreactivities in the hippocampus, striatum, mesencephalon, and frontal and temporal cortices...
December 3, 2016: Neurocase
https://www.readbyqxmd.com/read/27913405/what-is-the-role-of-tdp-43-in-c9orf72-related-amyotrophic-lateral-sclerosis-and-frontemporal-dementia
#5
Jakub Scaber, Kevin Talbot
No abstract text is available yet for this article.
December 2016: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/27911311/risk-factors-and-pathological-substrates-associated-with-agitation-aggression-in-alzheimer-s-disease-a-preliminary-study-using-nacc-data
#6
Simrin Sennik, Tom A Schweizer, Corinne E Fischer, David G Munoz
BACKGROUND: Neuropsychiatric symptoms are common manifestations of Alzheimer's disease (AD). A number of studies have targeted psychosis, i.e., hallucinations and delusions in AD, but few have assessed agitation/aggression in AD. OBJECTIVE: To investigate the risk factors and pathological substrates associated with presence [A(+)] and absence [A(-)] of agitation/aggression (A) in autopsy-confirmed AD. METHODS: Data was collected from the UDS data as of 2015 on the NACC database...
November 28, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27909398/an-amyloid-like-pathological-conformation-of-tdp-43-is-stabilized-by-hypercooperative-hydrogen-bonds
#7
Miguel Mompeán, Marco Baralle, Emanuele Buratti, Douglas V Laurents
TDP-43 is an essential RNA-binding protein forming aggregates in almost all cases of sporadic amyotrophic lateral sclerosis (ALS) and many cases of frontotemporal lobar dementia (FTLD) and other neurodegenerative diseases. TDP-43 consists of a folded N-terminal domain with a singular structure, two RRM RNA-binding domains, and a long disordered C-terminal region which plays roles in functional RNA regulatory assemblies as well as pernicious aggregation. Evidence from pathological mutations and seeding experiments strongly suggest that TDP-43 aggregates are pathologically relevant through toxic gain-of-harmful-function and/or harmful loss-of-native-function mechanisms...
2016: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/27906075/nuclear-bodies-reorganize-during-myogenesis-in-vitro-and-are-differentially-disrupted-by-expression-of-fshd-associated-dux4
#8
Sachiko Homma, Mary Lou Beermann, Bryant Yu, Frederick M Boyce, Jeffrey Boone Miller
BACKGROUND: Nuclear bodies, such as nucleoli, PML bodies, and SC35 speckles, are dynamic sub-nuclear structures that regulate multiple genetic and epigenetic processes. Additional regulation is provided by RNA/DNA handling proteins, notably TDP-43 and FUS, which have been linked to ALS pathology. Previous work showed that mouse cell line myotubes have fewer but larger nucleoli than myoblasts, and we had found that nuclear aggregation of TDP-43 in human myotubes was induced by expression of DUX4-FL, a transcription factor that is aberrantly expressed and causes pathology in facioscapulohumeral dystrophy (FSHD)...
December 1, 2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27904119/an-autopsy-case-of-amyotrophic-lateral-sclerosis-with-diaphragm-pacing
#9
Hisashi Ito, Tetsumasa Kamei, Sanae Odake, Masayuki Nakano, Riki Okeda, Shunsaku Kohriki, Jun Kawachi, Raymond P Onders, Fumihito Yoshii
Respiratory insufficiency is a critical problem in amyotrophic lateral sclerosis (ALS) patients. We herein present the case of an autopsied patient with sporadic ALS who underwent diaphragm pacing (DP). The pathology showed several localized adhesions with a markedly atrophied diaphragm. A marked loss of motor neurons with Bunina bodies and phosphorylated TDP-43 positive inclusions was found in the spinal cord and primary motor cortex. Mild hyalinization and a few multinucleated giant cells were present around the electrode tracks in the diaphragm...
2016: Internal Medicine
https://www.readbyqxmd.com/read/27897242/cortical-synaptic-and-dendritic-spine-abnormalities-in-a-presymptomatic-tdp-43-model-of-amyotrophic-lateral-sclerosis
#10
Matthew J Fogarty, Paul M Klenowski, John D Lee, Joy R Drieberg-Thompson, Selena E Bartlett, Shyuan T Ngo, Massimo A Hilliard, Mark C Bellingham, Peter G Noakes
Layer V pyramidal neurons (LVPNs) within the motor cortex integrate sensory cues and co-ordinate voluntary control of motor output. In amyotrophic lateral sclerosis (ALS) LVPNs and spinal motor neurons degenerate. The pathogenesis of neural degeneration is unknown in ALS; 10% of cases have a genetic cause, whereas 90% are sporadic, with most of the latter showing TDP-43 inclusions. Clinical and experimental evidence implicate excitotoxicity as a prime aetiological candidate. Using patch clamp and dye-filling techniques in brain slices, combined with high-resolution confocal microscopy, we report increased excitatory synaptic inputs and dendritic spine densities in early presymptomatic mice carrying a TDP-43(Q331K) mutation...
November 29, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27896662/investigating-the-additive-interaction-of-qt-prolonging-drugs-in-older-people-using-claims-data
#11
Andreas D Meid, Anna von Medem, Dirk Heider, Jürgen-Bernhard Adler, Christian Günster, Hanna M Seidling, Renate Quinzler, Hans-Helmut König, Walter E Haefeli
INTRODUCTION: Drugs that potentially prolong the QT interval carry the risk of life-threatening Torsades de pointes (TdP) ventricular arrhythmia. OBJECTIVE: The objective of this study was to investigate the potential additive risk for ventricular arrhythmia with concomitant prescriptions of QT-prolonging drugs. METHODS: Claims data for persons aged ≥65 years between 2010 and 2012 in Germany were analyzed and all cases hospitalized for ventricular arrhythmia were selected...
November 29, 2016: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
https://www.readbyqxmd.com/read/27890430/tar-dna-binding-protein-43-inhibits-inflammatory-response-and-protects-chondrocyte-function-by-modulating-rack1-expression-in-osteoarthritis
#12
Yongming Huang, Qiming Huang, Haitao Su, Xiujun Mai, Enhui Feng, Zhenwu Cao, Xiuyun Zeng
BACKGROUND: TAR DNA-binding protein-43 (TDP-43, transactive response DNA binding protein 43kDa) accumulates in the cytoplasm of affected neurons and glia, as large inclusions of stress granules (SGs). However, the mechanism of TDP-43 interaction with the target genes and its specific role in osteoarthritis (OA) progression is still unknown. The goal of this study was to identify the role of TDP-43 in OA progression by modulating its target genes. METHODS: MSCs were transfected with TDP-43 gene lentivirus...
November 24, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27884524/increasing-phytoplankton-available-phosphorus-and-inhibition-of-macrophyte-on-phytoplankton-bloom
#13
Yanran Dai, Juan Wu, Xiaohang Ma, Fei Zhong, Naxin Cui, Shuiping Cheng
We assembled mesocosms to address the coherent mechanisms that an increasing phosphorus (P) concentration in water columns coupled with the phytoplankton bloom and identify the performance gap of regulating phytoplankton growth between two macrophyte species, Ceratophyllum demersum L. and Vallisneria spiralis L. Intense alkaline phosphatase activities (APA) were observed in the unplanted control, with their predominant part, phytoplankton APA (accounting for up to 44.7% of the total APA), and another large share, bacterial APA...
November 22, 2016: Science of the Total Environment
https://www.readbyqxmd.com/read/27880919/activation-of-g-protein-coupled-receptor-30-by-thiodiphenol-promotes-proliferation-of-estrogen-receptor-%C3%AE-positive-breast-cancer-cells
#14
Bingli Lei, Wei Peng, Gang Xu, Minghong Wu, Yu Wen, Jie Xu, Zhiqiang Yu, Yipei Wang
Many studies have been shown that environmental estrogen bisphenol A (BPA) can activate nuclear receptor (estrogen receptor alpha, ERα) or membrane receptor (G-protein-coupled receptor, GPR30) in breast cancer cells and exerts genomic or nongenomic actions inducing cell proliferation. 4,4'-thiodiphenol (TDP) as one of BPA derivatives exhibits more potent estrogenic activity than BPA does. However, comparatively little is known about the ways in which TDP interferes with these signaling pathways and produces cell biological changes...
November 20, 2016: Chemosphere
https://www.readbyqxmd.com/read/27878411/reckless-administration-of-qt-interval-prolonging-agents-in-elderly-patients-with-drug-induced-torsade-de-pointes
#15
Galia Jackobson, Narin Nard Carmel, Dor Lotan, Anjelika Kremer, Dan Justo
A systematic review was conducted for all published case reports on drug-induced torsade de pointes (TdP) in elderly (≥80 years) patients to study if the administration of the offending agent was reckless. Overall, 61 reports on drug-induced TdP in patients aged 80-97 years were included in the analysis. Non-modifiable risk factors for drug-induced TdP (e.g. acute coronary syndrome, female gender and congestive heart failure), modifiable risk factors (e.g. hypokalemia, severe hypomagnesemia and digitalis toxicity) and reckless administration of a QT interval-prolonging agent (e...
November 22, 2016: Zeitschrift Für Gerontologie und Geriatrie
https://www.readbyqxmd.com/read/27877154/immununochemical-markers-of-the-amyloid-cascade-in-the-hippocampus-in-motor-neuron-diseases
#16
Ulises Gómez-Pinedo, Rocio N Villar-Quiles, Lucia Galán, Jordi A Matías-Guiu, Maria S Benito-Martin, Antonio Guerrero-Sola, Teresa Moreno-Ramos, Jorge Matías-Guiu
BACKGROUND: Several findings suggest that the amyloid precursor protein (APP) and the amyloid cascade may play a role in motor neuron disease (MND). OBJECTIVE: Considering that dementia is one of the most frequent non-motor symptoms in amyotrophic lateral sclerosis (ALS) and that hippocampus is one of the brain areas with greater presence of amyloid-related changes in neurodegenerative diseases, our aim was to analyze the molecular markers of the amyloid cascade of APP in pathology studies of the hippocampus of autopsied patients with ALS and ALS-frontotemporal dementia (FTD)...
2016: Frontiers in Neurology
https://www.readbyqxmd.com/read/27876701/which-tdp-43-aggregates-are-toxic-in-als
#17
EDITORIAL
Cristiana Valle, Maria Teresa Carrì
No abstract text is available yet for this article.
November 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27875990/inverse-relationship-between-alzheimer-s-disease-and-cancer-and-other-factors-contributing-to-alzheimer-s-disease-a-systematic-review
#18
Ovais Shafi
BACKGROUND: The AD etiology is yet not properly known. Interactions among environmental factors, multiple susceptibility genes and aging, contribute to AD. This study investigates the factors that play role in causing AD and how changes in cellular pathways contribute to AD. METHODS: PUBMED database, MEDLINE database and Google Scholar were searched with no date restrictions for published articles involving cellular pathways with roles in cancers, cell survival, growth, proliferation, development, aging, and also contributing to Alzheimer's disease...
November 22, 2016: BMC Neurology
https://www.readbyqxmd.com/read/27867348/better-targeting-better-efficiency-for-wide-scale-neuronal-transduction-with-the-synapsin-promoter-and-aav-php-b
#19
Kasey L Jackson, Robert D Dayton, Benjamin E Deverman, Ronald L Klein
Widespread genetic modification of cells in the central nervous system (CNS) with a viral vector has become possible and increasingly more efficient. We previously applied an AAV9 vector with the cytomegalovirus/chicken beta-actin (CBA) hybrid promoter and achieved wide-scale CNS transduction in neonatal and adult rats. However, this method transduces a variety of tissues in addition to the CNS. Thus we studied intravenous AAV9 gene transfer with a synapsin promoter to better target the neurons. We noted in systematic comparisons that the synapsin promoter drives lower level expression than does the CBA promoter...
2016: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/27858708/cerebrospinal-fluid-biomarkers-as-a-diagnostic-tool-of-the-underlying-pathology-of-primary-progressive-aphasia
#20
George P Paraskevas, Dimitrios Kaselimis, Evie Kourtidou, Vasilios Constantinides, Anastasia Bougea, Costas Potagas, Ioannis Evdokimidis, Elisabeth Kapaki
BACKGROUND: Primary progressive aphasia (PPA) may present with three main clinical variants, namely nonfluent agrammatic (nfaPPA), semantic (sPPA), and logopenic (lPPA) subtypes. Frontotemporal lobar degenerations (FTLD) or Alzheimer's disease (AD) are the most common etiologies. OBJECTIVE: To study the potential of cerebrospinal fluid (CSF) biomarkers for identifying the underlying pathology in patients with PPA. METHODS: CSF levels of total tau protein (τT), amyloid-β peptide (Aβ42), and tau phosphorylated at threonine-181 (τP - 181) were measured by double sandwich, enzyme-linked immunosorbent assay (ELISA) in 43 patients with PPA, 26 patients with AD, and 17 healthy controls...
November 14, 2016: Journal of Alzheimer's Disease: JAD
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