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https://www.readbyqxmd.com/read/29456831/early-afterdepolarisation-tendency-as-a-simulated-pro-arrhythmic-risk-indicator
#1
Beth McMillan, David J Gavaghan, Gary R Mirams
Drug-induced Torsades de Pointes (TdP) arrhythmia is of major interest in predictive toxicology. Drugs which cause TdP block the hERG cardiac potassium channel. However, not all drugs that block hERG cause TdP. As such, further understanding of the mechanistic route to TdP is needed. Early afterdepolarisations (EADs) are a cell-level phenomenon in which the membrane of a cardiac cell depolarises a second time before repolarisation, and EADs are seen in hearts during TdP. Therefore, we propose a method of predicting TdP using induced EADs combined with multiple ion channel block in simulations using biophysically-based mathematical models of human ventricular cell electrophysiology...
November 1, 2017: Toxicology Research
https://www.readbyqxmd.com/read/29449800/robustness-and-vulnerability-of-the-autoregulatory-system-that-maintains-nuclear-tdp-43-levels-a-trade-off-hypothesis-for-als-pathology-based-on-in-silico-data
#2
Akihiro Sugai, Taisuke Kato, Akihide Koyama, Yuka Koike, Sou Kasahara, Takuya Konno, Tomohiko Ishihara, Osamu Onodera
Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm and its disappearance from the nucleus are pathological features of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) and are directly involved in the pathogenesis of these conditions. TDP-43 is an essential nuclear protein that readily aggregates in a concentration-dependent manner. Therefore, cells must strictly maintain an appropriate amount of nuclear TDP-43. In one relevant maintenance mechanism, TDP-43 binds to its pre-mRNA and promotes alternative splicing, resulting in mRNA degradation via nonsense-mediated mRNA decay...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29449089/characterization-of-the-lncrna-transcriptome-in-mesc-derived-motor-neurons-implications-for-fus-als
#3
Silvia Biscarini, Davide Capauto, Giovanna Peruzzi, Lei Lu, Alessio Colantoni, Tiziana Santini, Neil A Shneider, Elisa Caffarelli, Pietro Laneve, Irene Bozzoni
Long non-coding RNAs (lncRNAs) are currently recognized as crucial players in nervous system development, function and pathology. In Amyotrophic Lateral Sclerosis (ALS), identification of causative mutations in FUS and TDP-43 or hexanucleotide repeat expansion in C9ORF72 point to the essential role of aberrant RNA metabolism in neurodegeneration. In this study, by taking advantage of an in vitro differentiation system generating mouse motor neurons (MNs) from embryonic stem cells, we identified and characterized the long non-coding transcriptome of MNs...
January 31, 2018: Stem Cell Research
https://www.readbyqxmd.com/read/29448169/molecular-spectroscopic-features-of-protein-in-newly-developed-chickpea-relationship-with-protein-chemical-profile-and-metabolism-in-the-rumen-and-intestine-of-dairy-cows
#4
Baoli Sun, Nazir Ahmad Khan, Peiqiang Yu
The first aim of this study was to investigate the nutritional value of crude protein (CP) in CDC [Crop Development Centre (CDC), University of Saskatchewan] chickpea varieties (Frontier kabuli and Corinne desi) in comparison with a CDC barley variety in terms of: 1) CP chemical profile and subfractions; (2) in situ rumen degradation kinetics and intestinal digestibility of CP; 2) metabolizable protein (MP) supply to dairy cows; and (3) protein molecular structure characteristics using advanced molecular spectroscopy...
February 6, 2018: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
https://www.readbyqxmd.com/read/29438978/a-single-n-terminal-phosphomimic-disrupts-tdp-43-polymerization-phase-separation-and-rna-splicing
#5
Ailin Wang, Alexander E Conicella, Hermann Broder Schmidt, Erik W Martin, Shannon N Rhoads, Ashley N Reeb, Amanda Nourse, Daniel Ramirez Montero, Veronica H Ryan, Rajat Rohatgi, Frank Shewmaker, Mandar T Naik, Tanja Mittag, Yuna M Ayala, Nicolas L Fawzi
TDP-43 is an RNA-binding protein active in splicing that concentrates into membraneless ribonucleoprotein granules and forms aggregates in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Although best known for its predominantly disordered C-terminal domain which mediates ALS inclusions, TDP-43 has a globular N-terminal domain (NTD). Here, we show that TDP-43 NTD assembles into head-to-tail linear chains and that phosphomimetic substitution at S48 disrupts TDP-43 polymeric assembly, discourages liquid-liquid phase separation (LLPS) in vitro , fluidizes liquid-liquid phase separated nuclear TDP-43 reporter constructs in cells, and disrupts RNA splicing activity...
February 9, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29432563/traumatic-injury-induces-stress-granule-formation-and-enhances-motor-dysfunctions-in-als-ftd-models
#6
Eric N Anderson, Lauren Gochenaur, Aditi Singh, Rogan Grant, Krishani Patel, Simon Watkins, Jane Y Wu, Udai Bhan Pandey
Traumatic brain injury (TBI) has been predicted to be a predisposing factor for Amyotrophic lateral sclerosis (ALS) and other neurological disorders. Despite the importance of TBI in ALS progression, the underlying cellular and molecular mechanisms are still an enigma. Here, we examined the contribution of TBI as an extrinsic factor and investigated if TBI influences the susceptibility of developing neurodegenerative symptoms. To evaluate the effects of TBI in vivo, we applied mild to severe trauma to Drosophila and found that TBI leads to the induction of stress granules (SGs) in the brain...
February 8, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29431050/tdp-43-post-translational-modifications-in-health-and-disease
#7
Emanuele Buratti
Nuclear factor TDP-43 is a ubiquitously expressed RNA binding protein that plays a key causative role in several neurodegenerative diseases, especially in the ALS/FTD spectrum. In addition, its aberrant aggregation and expression has been recently observed in other type of diseases, such as myopathies and Niemann-Pick C, a lysosomal storage disease. Areas Covered. This review aims to specifically cover the post-translational modifications (PTMs) that can affect TDP-43 function and cellular status both in health and disease...
February 10, 2018: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29427819/significance-of-t-wave-inversion-triggered-by-spontaneous-atrial-premature-beats-in-patients-with-long-qt-syndrome
#8
Nobuhiro Takasugi, Mieko Takasugi, Hiroko Goto, Takashi Kuwahara, Takashi Nakashima, Tomoki Kubota, Hiromitsu Kanamori, Masanori Kawasaki, Kazuhiko Nishigaki, Shinya Minatoguchi, Richard L Verrier
BACKGROUND: In patients with long QT syndrome (LQTS), a sudden increase in heart rate can cause T-wave alternans (TWA) with beat-to-beat alternating polarity of T wave. We hypothesized that LQTS patients at a high risk of Torsade de Pointes (TdP) may exhibit momentary atrial or sinoatrial premature beat-induced T-wave inversion (APB-TWI). OBJECTIVE: To assess the association of APB-TWI with TdP history and with microvolt TWA. METHODS: 24-h continuous 12-lead electrocardiograms (ECGs) were recorded in 18 healthy subjects and 39 consecutive patients with LQTS types 1 (n=21), 2 (n=4), 3 (n=4), and unidentified (n=10)...
February 7, 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/29421661/caspase-independent-cleavages-of-tdp-43-generates-35kd-fragment-that-cause-apoptosis-of-breast-cancer-cells
#9
Yinan Nan, Shaoqing Wang, William Jia
Transactive response DNA-binding protein 43kD (TDP-43) is a major component of tau-negative and ubiquitin-positive inclusions that characterize ALS (amyotrophic lateral sclerosis) and FTLD (frontotemporal lobar degeneration). Due to its central role in neurodegenerative disease pathogenesis, most research recently has focused on its role associated with neurodegeneration disease, research on neuron and glial cell showed that pathological TDP-43 is associated with cell apoptosis which lead to loss of functional neurons and glial cells...
February 5, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29417336/prion-like-properties-of-disease-relevant-proteins-in-amyotrophic-lateral-sclerosis
#10
REVIEW
S Bräuer, V Zimyanin, A Hermann
The hallmark of age-related neurodegenerative diseases is the appearance of cellular protein deposits and spreading of this pathology throughout the central nervous system. Growing evidence has shown the involvement and critical role of proteins with prion-like properties in the formation of these characteristic cellular aggregates. Prion-like domains of such proteins with their proposed function in the organization of membraneless organelles are prone for misfolding and promoting further aggregation. Spreading of these toxic aggregates between cells and across tissues can explain the progression of clinical phenotypes and pathology in a stereotypical manner, characteristic for almost every neurodegenerative disease...
February 8, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29409526/pathological-phosphorylation-of-tau-and-tdp-43-by-ttbk1-and-ttbk2-drives-neurodegeneration
#11
Laura M Taylor, Pamela J McMillan, Nicole F Liachko, Timothy J Strovas, Bernardino Ghetti, Thomas D Bird, C Dirk Keene, Brian C Kraemer
BACKGROUND: Progressive neuron loss in the frontal and temporal lobes of the cerebral cortex typifies frontotemporal lobar degeneration (FTLD). FTLD sub types are classified on the basis of neuronal aggregated protein deposits, typically containing either aberrantly phosphorylated TDP-43 or tau. Our recent work demonstrated that tau tubulin kinases 1 and 2 (TTBK1/2) robustly phosphorylate TDP-43 and co-localize with phosphorylated TDP-43 in human postmortem neurons from FTLD patients...
February 6, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29409023/erp57-is-protective-against-mutant-sod1-induced-cellular-pathology-in-amyotrophic-lateral-sclerosis
#12
Sonam Parakh, Cyril J Jagaraj, Marta Vidal, Audrey M G Ragagnin, Emma R Perri, Anna Konopka, Reka Toth, Jasmin Galper, Ian P Blair, Colleen J Thomas, Adam K Walker, Shu Yang, Damian M Spencer, Julie D Atkin
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and mutations in superoxide dismutase1 (SOD1) account for 20% of familial ALS cases. The aetiology of ALS remains unclear, but protein misfolding, endoplasmic reticulum (ER) stress and neuronal apoptosis are implicated. We previously established that protein disulphide isomerase (PDIA1) is protective against ER stress and apoptosis in neuronal cells expressing mutant SOD1, recently mutations in PDIA1 and related PDI family member endoplasmic reticulum protein 57 (ERp57/PDIA), were associated with ALS...
February 1, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29408984/postnatal-changes-in-testicular-position-are-associated-with-igf-i-and-function-of-sertoli-and-leydig-cells
#13
Jaakko J Koskenniemi, Helena E Virtanen, Christine Wohlfahrt-Veje, Eliisa Löyttyniemi, Niels E Skakkebaek, Anders Juul, Anna-Maria Andersson, Katharina M Main, Jorma Toppari
Context: Despite clinical guidelines calling for repetitive examination of testicular position during childhood, little is known of normal changes in testicular position during childhood, let alone factors that control it. Objective: To assess changes in, and factors associated with testicular position during childhood. Design: Testicular position (the distance from the pubic bone to the upper pole of the testes) at birth, 3 months, 18 months, 36 months, 7 years and reproductive hormones at three months were measured...
February 1, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29405316/acquired-long-qt-syndrome-and-torsade-de-pointes
#14
REVIEW
Nabil El-Sherif, Gioia Turitto, Mohamed Boutjdir
Since its initial description by Jervell and Lange-Nielsen in 19571 , the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. Although congenital LQTS continues to remain the domain of cardiologists, cardiac electrophysiologists, and specialized centers, the by far more frequent acquired drug-induced LQTS is the domain of all physicians and other members of the health care team who are required to make therapeutic decisions. This report will review the electrophysiological mechanisms of LQTS and TdP, electrocardiographic (ECG) characteristics of acquired LQTS, its clinical presentation, management, and future directions in the field...
February 6, 2018: Pacing and Clinical Electrophysiology: PACE
https://www.readbyqxmd.com/read/29405032/the-multisystem-degeneration-amyotrophic-lateral-sclerosis-neuropathological-staging-and-clinical-translation
#15
Federico Verde, Kelly Del Tredici, Heiko Braak, Albert Ludolph
Amyotrophic lateral sclerosis (ALS) is traditionally considered a disease affecting exclusively motor neurons. However, much evidence points towards additional involvement of brain systems other than the motor. As much as half of ALS patients display cognitive-behavioral disturbances. ALS shares with a considerable proportion of FTD cases the same neuropathological substrate, namely, inclusions of abnormally phosphorylated protein TDP-43 (pTDP-43). In analogy with pathological staging systems elaborated in the past decades for Alzheimer's disease (AD) and Parkinson's disease (PD), a model of staging of pTDP-43 pathology in sporadic ALS (sALS) has been recently proposed...
December 1, 2017: Archives Italiennes de Biologie
https://www.readbyqxmd.com/read/29404783/neuropathology-and-biochemistry-of-early-onset-familial-alzheimer-s-disease-caused-by-presenilin-1-missense-mutation-thr116asn
#16
Stanislav Sutovsky, Tomas Smolek, Peter Turcani, Robert Petrovic, Petra Brandoburova, Santosh Jadhav, Petr Novak, Johannes Attems, Norbert Zilka
The majority (~ 55%) of early onset familial Alzheimer disease (FAD) is caused by mutations in the presenilin 1 gene (PSEN1). Here, we describe a family with early onset FAD with a missense mutation in the PSEN1 gene (Thr116Asn). Five family members developed dementia in the third decade of life. One subject underwent autopsy. The onset of clinical symptoms was at the age of 37 years and the disease progressed rapidly. The clinical picture was characterised by progressive memory impairment, amnestic aphasia, and gait disturbances...
February 5, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29396541/tdp-43-self-interaction-is-modulated-by-redox-active-compounds-auranofin-chelerythrine-and-riluzole
#17
Moritz Oberstadt, Jens Stieler, David Larbi Simpong, Ute Römuß, Nicole Urban, Michael Schaefer, Thomas Arendt, Max Holzer
Amyotrophic lateral sclerosis (ALS) represents a fatal neurodegenerative disease, which is characterized by a rapid loss of lower and upper motor neurons. As a major neuropathological hallmark, protein aggregates containing the Transactivating Response Region (TAR) DNA Binding Protein (TDP-43) are detectable in about 95% of sporadic ALS patients. TDP-43 interacts with itself physiologically to form liquid droplets, which may progress to pathological aggregates. In this study, we established the NanoBit luciferase complementation assay to measure TDP-43 self-interaction and found the fusion of the split luciferase subunits to the N-terminus of the protein as the strongest interacting partners...
February 2, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29383655/autophagic-modulation-by-trehalose-reduces-accumulation-of-tdp-43-in-a-cell-model-of-amyotrophic-lateral-sclerosis-via-tfeb-activation
#18
Ying Wang, Feng-Tao Liu, Yi-Xuan Wang, Rong-Yuan Guan, Chen Chen, Da-Ke Li, Lu-Lu Bu, Jie Song, Yu-Jie Yang, Yi Dong, Yan Chen, Jian Wang
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease characterized by the formation of protein inclusion and progressive loss of motor neurons, finally leading to muscle weakness and respiratory failure. So far, the effective drugs for ALS are yet to be developed. Impairment of transcriptional activator transcription factor EB (TFEB) has been demonstrated as a key element in the pathogenesis of ALS. Trehalose is an mechanistic target of rapamycin-independent inducer for autophagy, which showed autophagic activation and neuroprotective effect in a variety of neurodegenerative diseases...
January 30, 2018: Neurotoxicity Research
https://www.readbyqxmd.com/read/29382817/targeting-tyro3-ameliorates-a-model-of-pgrn-mutant-ftld-tdp-via-tau-mediated-synaptic-pathology
#19
Kyota Fujita, Xigui Chen, Hidenori Homma, Kazuhiko Tagawa, Mutsuki Amano, Ayumu Saito, Seiya Imoto, Hiroyasu Akatsu, Yoshio Hashizume, Kozo Kaibuchi, Satoru Miyano, Hitoshi Okazawa
Mutations in the progranulin (PGRN) gene cause a tau pathology-negative and TDP43 pathology-positive form of frontotemporal lobar degeneration (FTLD-TDP). We generated a knock-in mouse harboring the R504X mutation (PGRN-KI). Phosphoproteomic analysis of this model revealed activation of signaling pathways connecting PKC and MAPK to tau prior to TDP43 aggregation and cognitive impairments, and identified PKCα as the kinase responsible for the early-stage tau phosphorylation at Ser203. Disinhibition of Gas6 binding to Tyro3 due to PGRN reduction results in activation of PKCα via PLCγ, inducing tau phosphorylation at Ser203, mislocalization of tau to dendritic spines, and spine loss...
January 30, 2018: Nature Communications
https://www.readbyqxmd.com/read/29382228/primary-fibroblasts-derived-from-sporadic-amyotrophic-lateral-sclerosis-patients-do-not-show-als-cytological-lesions
#20
Philippe Codron, Julien Cassereau, Patrick Vourc'h, Charlotte Veyrat-Durebex, Hélène Blasco, Selma Kane, Vincent Procaccio, Franck Letournel, Christophe Verny, Guy Lenears, Pascal Reynier, Arnaud Chevrollier
OBJECTIVE: Sporadic amyotrophic lateral sclerosis (sALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons. In view of the heterogeneous presentation of the disease, one of the current challenges is to identify diagnostic and prognostic markers in order to diagnose sALS at early stage and to stratify patients in trials. In this study, we sought to identify cytological hallmarks of sALS in patient-derived fibroblasts with the aim of finding new clinical-related markers of the disease...
January 31, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
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