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Renato De Vecchis, Carmelina Ariano, Giuseppina Di Biase, Michel Noutsias
Background: Several drug classes (antiarrhythmics, antimicrobials, antidepressants, phenothiazines, opiates, prokinetics of digestive tract, etc.) have been related to ventricular hyperkinetic arrhythmias such as torsade de pointes (TdP). TdPs are usually heralded by an abnormal prolongation of heart rate-corrected QT interval on the electrocardiogram, so-called drug-induced long heart rate-corrected QT (diLQTc). We don't know to what extent the drug-induced QTc prolongation is able to predict malignant arrhythmias...
July 2018: Journal of Clinical Medicine Research
Ernesto Manzo, Abigail G O'Conner, Jordan M Barrows, Dakotah D Shreiner, Gabriel J Birchak, Daniela C Zarnescu
ALS patients exhibit dyslipidemia, hypermetabolism and weight loss; in addition, cellular energetics deficits have been detected prior to denervation. Although evidence that metabolism is altered in ALS is compelling, the mechanisms underlying metabolic dysregulation and the contribution of altered metabolic pathways to disease remain poorly understood. Here we use a Drosophila model of ALS based on TDP-43 that recapitulates hallmark features of the disease including locomotor dysfunction and reduced lifespan...
2018: Frontiers in Molecular Neuroscience
Jessica Mandrioli, Roberto D'Amico, Elisabetta Zucchi, Annalisa Gessani, Nicola Fini, Antonio Fasano, Claudia Caponnetto, Adriano Chiò, Eleonora Dalla Bella, Christian Lunetta, Letizia Mazzini, Kalliopi Marinou, Gianni Sorarù, Sara de Biasi, Domenico Lo Tartaro, Marcello Pinti, Andrea Cossarizza
INTRODUCTION: Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions...
June 2018: Medicine (Baltimore)
Xin Lin Tan, Mujun Sun, Rhys D Brady, Shijie J Liu, Roxana Llanos, Steve Cheung, David K Wright, Pablo M Casillas-Espinosa, Maithili Sashindranath, Stuart John McDonald, Bradley J Turner, Terence John O'Brien, Sandy Richard Shultz
Initial studies have found some evidence for transactive response DNA-binding protein 43 (TDP-43) abnormalities after traumatic brain injury (TBI), and the presence of protein inclusions consisting of TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis, a condition associated with TBI. However, no study has characterized changes in TDP-43 phosphorylation, mislocalization, and fragmentation (i.e., abnormalities linked to hallmark TDP-43 pathology) after TBI, and how these relate to functional outcomes...
June 14, 2018: Journal of Neurotrauma
Oscar Ramos-Campoy, Rainiero Ávila-Polo, Oriol Grau-Rivera, Anna Antonell, Jordi Clarimón, Ricardo Rojas-García, Sara Charif, Veronica Santiago-Valera, Isabel Hernandez, Miquel Aguilar, Consuelo Almenar, Dolores Lopez-Villegas, Lorena Bajo, Pau Pastor, Julie Van der Zee, Albert Lladó, Raquel Sanchez-Valle, Ellen Gelpi
The neuropathological hallmark of the C9orf72 intronic hexanucleotide expansion in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) is the presence of small ubiquitin/p62-positive and transactive response DNA binding protein 43 kDa (TDP-43)-negative cytoplasmic inclusions in several brain areas. The identification of this histopathological signature is highly predictive of an underlying mutation. In this study, we screened 1800 cases of the Barcelona IDIBAPS Brain Bank, independently of the clinical and final neuropathological diagnosis of the brain donor, for the presence of ubiquitin/p62-positive inclusions in the cerebellum (UPPI)...
June 7, 2018: Journal of Neuropathology and Experimental Neurology
Yifan Dai, Chunlai Wang, Liang-Yuan Chiu, Kevin Abbasi, Blanton S Tolbert, Geneviève Sauvé, Yun Yen, Chung-Chiun Liu
A simple-prepare, single-use and cost-effective, in vitro biosensor for the detection of TAR DNA-binding protein 43 (TDP-43), a biomarker of neuro-degenerative disorders, was designed, manufactured and tested. This study reports the first biosensor application for the detection of TDP-43 using a novel biosensor fabrication methodology. Bioconjugation mechanism was applied by conjugating anti-TDP 43 with N-succinimidyl S-acetylthioacetate (SATA) producing a thiol-linked anti-TDP 43, which was used to directly link with gold electrode surface, minimizing the preparation steps for biosensor fabrication and simplifying the biosensor surface...
June 1, 2018: Biosensors & Bioelectronics
Xuhui Zheng, Lei Liu, Jinzhong Sun, Gao Li, Fubiao Zhou, Jiemin Xu
Geological and hydrogeological conditions in karst areas are complicated from the viewpoint of engineering. The construction of underground structures in these areas is often disturbed by the gushing of karst water, which may delay the construction schedule, result in economic losses, and even cause heavy casualties. In this paper, an innovative method of multichannel transient Rayleigh wave detecting is proposed by introducing the concept of arrival time difference phase between channels (TDP). Overcoming the restriction of the space-sampling law, the proposed method can extract the phase velocities of different frequency components from only two channels of transient Rayleigh wave recorded on two adjacent detecting points...
2018: PloS One
Elena Tomaselli Muensterman, James E Tisdale
Prolongation of the heart rate-corrected QT (QTc) interval increases the risk for torsades de pointes (TdP), a potentially fatal arrhythmia. The likelihood of TdP is higher in patients with risk factors, which include female sex, older age, heart failure with reduced ejection fraction, hypokalemia, hypomagnesemia, concomitant administration of ≥ 2 QTc interval-prolonging medications, among others. Assessment and quantification of risk factors may facilitate prediction of patients at highest risk for developing QTc interval prolongation and TdP...
June 8, 2018: Pharmacotherapy
Florian Krach, Ranjan Batra, Emily C Wheeler, Anthony Q Vu, Ruth Wang, Kasey Hutt, Stuart J Rabin, Michael W Baughn, Ryan T Libby, Sandra Diaz-Garcia, Jennifer Stauffer, Elaine Pirie, Shahram Saberi, Maria Rodriguez, Assael A Madrigal, Zacharias Kohl, Beate Winner, Gene W Yeo, John Ravits
Sporadic amyotrophic lateral sclerosis (sALS) is the most common form of ALS, however, the molecular mechanisms underlying cellular damage and motor neuron degeneration remain elusive. To identify molecular signatures of sALS we performed genome-wide expression profiling in laser capture microdissection-enriched surviving motor neurons (MNs) from lumbar spinal cords of sALS patients with rostral onset and caudal progression. After correcting for immunological background, we discover a highly specific gene expression signature for sALS that is associated with phosphorylated TDP-43 (pTDP-43) pathology...
June 7, 2018: Acta Neuropathologica
John L Robinson, Edward B Lee, Sharon X Xie, Lior Rennert, EunRan Suh, Colin Bredenberg, Carrie Caswell, Vivianna M Van Deerlin, Ning Yan, Ahmed Yousef, Howard I Hurtig, Andrew Siderowf, Murray Grossman, Corey T McMillan, Bruce Miller, John E Duda, David J Irwin, David Wolk, Lauren Elman, Leo McCluskey, Alice Chen-Plotkin, Daniel Weintraub, Steven E Arnold, Johannes Brettschneider, Virginia M-Y Lee, John Q Trojanowski
Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72)...
June 5, 2018: Brain: a Journal of Neurology
Martina Bocchetta, Elizabeth Gordon, M Jorge Cardoso, Marc Modat, Sebastien Ourselin, Jason D Warren, Jonathan D Rohrer
Background: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder associated with frontal and temporal atrophy. Subcortical involvement has been described as well, with early thalamic atrophy most commonly associated with the C9orf72 expansion. However thalamic involvement has not been comprehensively investigated across the FTD spectrum. Methods: We investigated thalamic volumes in a sample of 341 FTD patients (age: mean(standard deviation) 64...
2018: NeuroImage: Clinical
Jialin Duan, Jingwen Tao, Maocai Zhai, Chengpeng Li, Ning Zhou, Jiagao Lv, Lin Wang, Li Lin, Rong Bai
Anticancer drugs may have proarrhythmic effects including drug-induced QT interval prolongation, which is of particular importance because it can lead to a fatal polymorphic ventricular tachycardia termed torsade de pointes (TdP). QT interval prolongation and TdP are rare life-threatening untoward effects of anticancer therapy, particularly with arsenic trioxides and anthracyclines, and even some novel molecular targeted drugs touted as 'tumor specific'. Several factors that affect myocardial repolarization can further increase the risk of TdP...
May 22, 2018: Oncotarget
Akira Kitamura, Ai Shibasaki, Kayo Takeda, Ryoji Suno, Masataka Kinjo
Normal function and abnormal aggregation of transactivation response (TAR) DNA/RNA-binding protein 43 kDa (TDP-43) are directly associated with the lethal genetic diseases: cystic fibrosis, amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration (FTLD). The binding of TDP-43 to single-stranded DNA (ssDNA) or RNA is involved in transcriptional repression, regulation of RNA splicing, and RNA stabilization. Equilibrium dissociation constants ( K d ) of TDP-43 and ssDNA or RNA have been determined using various methods; however, methods that can measure K d with high sensitivity in a short time using a small amount of TDP-43 in solution would be advantageous...
July 2018: Biochemistry and Biophysics Reports
Matthew A White, Eosu Kim, Amanda Duffy, Robert Adalbert, Benjamin U Phillips, Owen M Peters, Jodie Stephenson, Sujeong Yang, Francesca Massenzio, Ziqiang Lin, Simon Andrews, Anne Segonds-Pichon, Jake Metterville, Lisa M Saksida, Richard Mead, Richard R Ribchester, Youssef Barhomi, Thomas Serre, Michael P Coleman, Justin R Fallon, Timothy J Bussey, Robert H Brown, Jemeen Sreedharan
In the version of this article initially published, the footnote number 17 was missing from the author list for the two authors who contributed equally. Also, the authors have added a middle initial for author Justin R. Fallon and an acknowledgement to the Babraham Institute Imaging Facility and Sequencing Core Facility. The errors have been corrected in the HTML and PDF versions of the article.
June 5, 2018: Nature Neuroscience
Jason P Estes, Danh V Nguyen, Yanjun Chen, Lorien S Dalrymple, Connie M Rhee, Kamyar Kalantar-Zadeh, Damla Şentürk
Standard profiling analysis aims to evaluate medical providers, such as hospitals, nursing homes, or dialysis facilities, with respect to a patient outcome. The outcome, for instance, may be mortality, medical complications, or 30-day (unplanned) hospital readmission. Profiling analysis involves regression modeling of a patient outcome, adjusting for patient health status at baseline, and comparing each provider's outcome rate (e.g., 30-day readmission rate) to a normative standard (e.g., national "average")...
June 5, 2018: Biometrics
Federico Floris, Lionel Chiron, Alice M Lynch, Mark P Barrow, Marc-André Delsuc, Peter B O'Connor
Two-dimensional mass spectrometry (2DMS) involves simultaneous acquisition of the fragmentation patterns of all the analytes in a mixture by correlating their precursor and fragment ions by modulating precursor ions systematically through a fragmentation zone. Tandem two-dimensional mass spectrometry (MS/2DMS) unites the ultra-high accuracy of Fourier transform ion cyclotron resonance (FT-ICR) MS/MS and the simultaneous data-independent fragmentation of 2DMS to achieve extensive inter-residue fragmentation of entire proteins...
June 4, 2018: Journal of the American Society for Mass Spectrometry
Maria D Purice, J Paul Taylor
Following years of rapid progress identifying the genetic underpinnings of amyotrophic lateral sclerosis (ALS) and related diseases such as frontotemporal dementia (FTD), remarkable consistencies have emerged pointing to perturbed biology of heterogeneous nuclear ribonucleoproteins (hnRNPs) as a central driver of pathobiology. To varying extents these RNA-binding proteins are deposited in pathological inclusions in affected tissues in ALS and FTD. Moreover, mutations in hnRNPs account for a significant number of familial cases of ALS and FTD...
2018: Frontiers in Neuroscience
Farahnaz Rezaei Makhouri, Jahan B Ghasemi
BACKGROUND: The acetylated inclusions containing TDP-43 are found in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, suggesting that aberrant TDP-43 acetylation and resulting disruption of RNA binding are linked to onset and progression of TDP-43 proteinopathy. METHODS: Here, the consequences of TDP-43 acetylation at Lys145 within the RRM1 domain and Lys192 within the RRM2 domain were studied using experimentally verifiable molecular models, in which lysine residues (K) were substituted with glutamine (Q) as an acetylation mimic (K→Q) and with arginine (R) as a non-mimic (K→R) mutant...
June 4, 2018: Combinatorial Chemistry & High Throughput Screening
Andrew C Robinson, Yvonne S Davidson, Michael A Horan, Neil Pendleton, David M A Mann
The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation...
May 28, 2018: Journal of Alzheimer's Disease: JAD
Tatyana A Shelkovnikova, Michail S Kukharsky, Haiyan An, Pasquale Dimasi, Svetlana Alexeeva, Osman Shabir, Paul R Heath, Vladimir L Buchman
BACKGROUND: Paraspeckles are subnuclear bodies assembled on a long non-coding RNA (lncRNA) NEAT1. Their enhanced formation in spinal neurons of sporadic amyotrophic lateral sclerosis (ALS) patients has been reported but underlying mechanisms are unknown. The majority of ALS cases are characterized by TDP-43 proteinopathy. In current study we aimed to establish whether and how TDP-43 pathology may augment paraspeckle assembly. METHODS: Paraspeckle formation in human samples was analysed by RNA-FISH and laser capture microdissection followed by qRT-PCR...
June 1, 2018: Molecular Neurodegeneration
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