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Aaron Held, Paxton Major, Asli Sahin, Robert Reenan, Diane Lipscombe, Kristi A Wharton
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose origin and underlying cellular defects are not fully understood. While motor neuron degeneration is the signature feature of ALS, it is not clear if motor neurons, or other cells of the motor circuit, are the site of disease initiation. To better understand the contribution of multiple cell types in ALS, we made use of a Drosophila Sod1G85R knock-in model, in which all cells harbor the disease allele. End-stage dSod1G85R animals of both sexes exhibit severe motor deficits with clear degeneration of motor neurons...
January 18, 2019: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Anthony M Crown, Brittany L Roberts, Keith Crosby, Hilda Brown, Jacob I Ayers, P John Hart, David R Borchelt
Mutations in more than 80 different positions in superoxide dismutase 1 (SOD1) have been associated with amyotrophic lateral sclerosis (fALS). There is substantial evidence that a common consequence of these mutations is to induce the protein to misfold and aggregate. How these mutations perturb native structure to heighten the propensity to misfold and aggregate is unclear. In the present study, we have mutagenized Glu residues at positions 40 and 133 that are involved in stabilizing the beta-barrel structure of the native protein and a critical Zn binding domain, respectively, to examine how specific mutations may cause SOD1 misfolding and aggregation...
January 8, 2019: G3: Genes—Genomes—Genetics
Ravinder Malik, Helen Meng, Piriya Wongkongkathep, Christian I Corrales, Niki Sepanj, Ryan S Atlasi, Frank-Gerrit Klärner, Thomas Schrader, Melissa J Spencer, Joseph A Loo, Martina Wiedau, Gal Bitan
Mutations in superoxide dismutase 1 (SOD1) cause 15%-20% of familial amyotrophic lateral sclerosis (fALS) cases. The resulting amino-acid substitutions destabilize SOD1's protein structure, leading to its self-assembly into neurotoxic oligomers and aggregates, a process hypothesized to cause the characteristic motor-neuron degeneration in affected individuals. Currently, effective disease-modifying therapy is not available for ALS. Molecular tweezers prevent formation of toxic protein assemblies, yet their protective action has not been tested previously on SOD1 or in the context of ALS...
January 2, 2019: Journal of Biological Chemistry
Julius F Kögel, Alexey Y Timoshkin, Artem Schröder, Enno Lork, Jens Beckmann
The adduct free Lewis superacid Al(OCArF3)3 was obtained by the reaction of ArF3COH with AlEt3 and fully characterized (ArF = C6 F5 ). It comprises a high thermal stability up to 180 °C and a distinct reactivity towards Lewis bases, as exemplified by the isolation of the neutral adducts Al(OCArF3)·D (D = MeCN, THF, Et2 O, pyridine, OPEt3 ), the fluoride complexes [Q][FAl(OCArF )3 ] (Q+ = Cs+ , Ag+ , Tl+ , [S(NMe2 )3 ]+ , [Ph3 C]+ , Li+ , [NBu4 ]+ , [FeCp2 ]+ ) and the chloride complex [Ph3 C][ClAl(OCArF )3 ]...
November 21, 2018: Chemical Science
Georgios Pampalakis, Konstantinos Mitropoulos, Georgia Xeromerisiou, Efthymios Dardiotis, Georgia Deretzi, Maria Anagnostouli, Theodora Katsila, Michail Rentzos, George P Patrinos
Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disorder. Two forms are recognized, familial (FALS) that accounts for 5-10% of ALS cases, and sporadic (SALS) that accounts for the rest. Early diagnosis of ALS is important since it improves their therapeutic efficacy. Current diagnosis is based on clinical assessment and requires approximately 12 months, leading to a significant delay in drug administration. Therefore, new methods are required for the earlier diagnosis of ALS. Screening for pathogenic variants in known ALS-associated genes is already exploited as a diagnostic tool in ALS but cannot be applied for population-based screening...
December 17, 2018: Human Mutation
Sebastian Vogel, Pranav Murthy, Xiangdong Cui, Michael T Lotze, Herbert J Zeh, Ulka Sachdev
Platelets play a critical role in the pathophysiology of peripheral arterial disease (PAD). The mechanisms by which muscle ischemia regulates aggregation of platelets are poorly understood. We have recently identified the Nod-like receptor nucleotide-binding domain leucine rich repeat containing protein 3 (NLRP3) expressed by platelets as a critical regulator of platelet activation and aggregation, which may be triggered by activation of toll-like receptor 4 (TLR4). In this study, we performed femoral artery ligation (FAL) in transgenic mice with platelet-specific ablation of TLR4 (TLR4 PF4) and in NLRP3 knockout (NLRP3-/- ) mice...
December 3, 2018: Biochemical and Biophysical Research Communications
Lidia Moraes Ribeiro Jordão, Deborah Carvalho Malta, Maria do Carmo Matias Freire
OBJECTIVE: To investigate the prevalence of simultaneous oral health risk behaviors and associated factors among Brazilian adolescents. METHODS: The study comprised data of 109,104 adolescents participating in the Brazilian National School-based Student Health Survey. The simultaneous presence of less frequent toothbrushing (E), current smoking (C), no visits to the dentist (D), low fruit intake (F), and high sugar intake (A) was assessed by comparison of observed/expected prevalence (OP/EP)...
November 29, 2018: Revista Brasileira de Epidemiologia, Brazilian Journal of Epidemiology
Claudia Consales, Martina Panatta, Alessio Butera, Giuseppe Filomeni, Caterina Merla, Maria Teresa Carrì, Carmela Marino, Barbara Benassi
PURPOSE: we characterized the response to the extremely low frequency magnetic field (ELF-MF) in an in vitro model of familial Amyotrophic Lateral Sclerosis (fALS), carrying two mutant variants of the superoxide dismutase 1 (SOD1) gene. MATERIALS AND METHODS: SH-SY5Y human neuroblastoma cells, stably over-expressing the wild type, the G93A or the H46R mutant SOD1 cDNA, were exposed to either the ELF-MF (50 Hz, 1 mT) or the sham control field, up to 72 hours...
December 4, 2018: International Journal of Radiation Biology
Aswathy Joseph, Marylin Mary Xavier, Jacek Fal, Gaweł Żyła, Soorya Sasi, P Radhakrishnan Nair, A S Padmanabhan, Suresh Mathew
An iron oxide based-electroactive IoNanofluid with a high dielectric constant, high stability and low viscosity was synthesized from ferrous sulphate heptahydrate via a facile microwave assisted one-step route in 1-butyl-4-methylpyridinium chloride. The IoNanofluid exhibited CE coupled faradaic redox reactions involving reversible chemical reaction and reversible electron transfer steps. A transition from diffusion controlled to surface controlled capacitive processes was observed at varying scan rates. The efficiency of the charge-discharge process was greater than 94% even after 100 cycles...
December 4, 2018: Chemical Communications: Chem Comm
Neetu Soni, Karthika Srindharan, Sunil Kumar, Kamlesh Singh Bhaisora, Jayantee Kalita, Anant Mehrotra, Prabhakar Mishra
Purpose: To evaluate the role of diffusion tensor imaging (DTI) in the differentiation of neoplastic and non-neoplastic brain lesions, on the basis of DTI parameters, fractional anisotropy (FA) and mean diffusivity (MD) from the lesion (L) and the perilesional edema (PE). Material and Methods: Patients with newly diagnosed 25 neoplastic [10 high grade gliomas (HGG), 11 metastases, 4 low grade glioma (LGG)] and 25 non-neoplastic [13 tuberculomas and 12 neurocysticercosis (NCC)] brain lesions underwent an MRI, including the DTI sequences...
November 2018: Neurology India
Natalie E Farrawell, Maddison R Yerbury, Steven S Plotkin, Luke McAlary, Justin J Yerbury
Mutations in the SOD1 gene are associated with some forms of familial ALS (fALS). There are over 150 different mutations in the SOD1 gene which cause various effects to the SOD1 enzyme structure, including loss of metal binding and a decrease in dimer affinity. The copper-based therapeutic CuATSM has been proven to be effective at rescuing neuronal cells from SOD1 mutant toxicity, and has also increased the life expectancy of mice expressing the human transgenes SOD1G93A and SOD1G37R. Furthermore, CuATSM is currently the subject of a phase I/II clinical trial in Australia as a treatment for ALS...
November 21, 2018: ACS Chemical Neuroscience
Shenghe Zhao, Jiangsheng Xie, Guanghui Cheng, Yuren Xiang, Houyu Zhu, Wenyue Guo, Han Wang, Minchao Qin, Xinhui Lu, Junle Qu, Jiannong Wang, Jianbin Xu, Keyou Yan
Hybrid perovskite thin films are prone to producing surface vacancies during the film formation, which degrade the stability and photovoltaic performance. Passivation via post-treatment can heal these defects, but present methods are slightly destructive to the bulk of 3D perovskite due to the solvent effect, which hinders fabrication reproducibility. Herein, nondestructive surface/interface passivation using 4-fluoroaniline (FAL) is established. FAL is not only an effective antisolvent candidate for surface modification, but also a large dipole molecule (2...
December 2018: Small
Keith Crosby, Anthony M Crown, Brittany L Roberts, Hilda Brown, Jacob I Ayers, David R Borchelt
Mutations in superoxide dismutase 1 (SOD1) associated with familial amyotrophic lateral sclerosis (fALS) induce the protein to misfold and aggregate. Missense mutations at more than 80 different amino acid positions have been associated with disease. How these mutations heighten the propensity of SOD1 to misfold and aggregate is unclear. With so many mutations, it is possible that more than one mechanism of aggregation may be involved. Of many possible mechanisms to explain heightened aggregation, one that has been suggested is that mutations that eliminate charged amino acids could diminish repulsive forces that would inhibit aberrant protein:protein interactions...
2018: PloS One
Neetu Soni, Sunil Kumar, Karthika Srindharan, Prabhakar Mishra, Nishant Gupta, Girish Bathla, Jyantee Kalita, Sanjay Behari
PURPOSE: To differentiate intra-axial tuberculomas (TB) from metastases based on quantitative differences in the perfusion and diffusion indices of lesion and perilesional edema using arterial spin labeling (ASL) and diffusion tensor imaging (DTI) techniques. MATERIALS AND METHODS: This prospective study included newly diagnosed untreated 12 patients of TB and 13 of metastases who underwent routine magnetic resonance imaging including DTI and ASL sequences. A region of interest analysis was performed and cerebral blood flow (CBF) values of lesion (L), perilesional edema (PE), and normal contralateral white matter (CWM) were calculated...
October 9, 2018: Current Problems in Diagnostic Radiology
E Srinivasan, R Rajasekaran
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that has been associated with mutations in metalloenzyme superoxide dismutase (SOD1) causing protein structural destabilization and aggregation. However, the mechanistic action and the cure for the disease still remain obscure. Herein, we initially studied the conformational preferences of SOD1 protein structures upon substitution of Ala at Gly93 in comparison with that of wild type. Our results corroborated with the previous experimental studies on the aggregation and the destabilizing activity of mutant SOD1 protein G93A...
October 28, 2018: Journal of Computer-aided Molecular Design
Hiroya Naruse, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Takashi Matsukawa, Masaki Tanaka, Koichiro Doi, Jun Yoshimura, Shinichi Morishita, Jun Goto, Tatsushi Toda, Shoji Tsuji
OBJECTIVES: To evaluate the burden of rare variants in the causative genes for amyotrophic lateral sclerosis (ALS) on the age at onset of ALS in a Japanese case series. METHODS: We conducted whole-exome sequencing analysis of 89 families with familial ALS (FALS) and 410 patients with sporadic ALS (SALS) to identify known pathogenic mutations or rare functionally predicted deleterious variants in the causative genes for ALS. Rare variants (minor allele frequency <1%) with scaled Combined Annotation-Dependent Depletion score >20 were defined as rare functionally predicted deleterious variants...
October 24, 2018: Journal of Neurology, Neurosurgery, and Psychiatry
Edward Pokrishevsky, Luke McAlary, Natalie E Farrawell, Beibei Zhao, Mine Sher, Justin J Yerbury, Neil R Cashman
Over 160 mutations in superoxide dismutase 1 (SOD1) are associated with familial amyotrophic lateral sclerosis (fALS), where the main pathological feature is deposition of SOD1 into proteinaceous cytoplasmic inclusions. We previously showed that the tryptophan residue at position 32 (W32) mediates the prion-like propagation of SOD1 misfolding in cells, and that a W32S substitution blocks this phenomenon. Here, we used in vitro protein assays to demonstrate that a W32S substitution in SOD1-fALS mutants significantly diminishes their propensity to aggregate whilst paradoxically decreasing protein stability...
October 22, 2018: Scientific Reports
David Brenner, Kathrin Müller, Regina Gastl, Martin Gorges, Markus Otto, Elmar H Pinkhardt, Jan Kassubek, Jochen H Weishaupt, Albert C Ludolph
Intermediate-length ATXN2 CAG repeats are a risk factor for amyotrophic lateral sclerosis (ALS). Here we report on a female patient with heterozygous repeat expansion mutation in the CACNA1A gene presenting with a pure ALS syndrome while her father, who also carries that CACNA1A mutation, suffers from a classical spinocerebellar ataxia type 6. Hypothesizing that CACNA1A CAG repeat expansions could be a monogenic cause for familial ALS (fALS), we analyzed the CAG repeat lengths in CACNA1A in a large cohort of genetically unexplained patients with fALS...
September 22, 2018: Neurobiology of Aging
Bin Qi, Xin Li, Liang Sun, Bo Chen, Hao Chen, Chenchen Wu, Haibo Zhang, Xiaohai Zhou
Supramolecular nano-assemblies with tunable morphology have attracted extensive attention in composite material manufacturing and many other fields. Herein, a new class of shape-controlled dodecaborate-based supramolecular organic frameworks (BOFs), decorated with diverse ultrafine noble metal clusters (Au, Pd, Pt, Ag), has been successfully fabricated via the tunable host-guest assembly of cucurbit[n = 5,6,7,8]uril and Cs2[closo-B12H12]. Due to the unique dodecaborate-cucurbit[n]uril chaotropic effect, a breakthrough has been made in modulating the supramolecular frameworks in the urchin-like, network-like or octahedron-like structures without tedious chemical modifications or additional additives...
November 1, 2018: Nanoscale
Mehdi Elsayed Moussa, Martin Piesch, Martin Fleischmann, Andrea Schreiner, Michael Seidl, Manfred Scheer
The synthesis of the air-stable and highly soluble Cu(i)-acetonitrile salts [Cu(CH3CN)3.5][FAl] (1) ([FAl] = FAl{OC(C6F10)(C6F5)}3) and [Cu(CH3CN)4][TEF] (2) ([TEF] = Al{OC(CF3)3}4) is presented. Compound 1 reacts with the organometallic polyphosphorus complexes [Cp2Mo2(CO)4(η2-P2)] (A) and [(Cp*Fe(η5-P5)] (B) and salt 2 reacts with B to form one new (3) and three unprecedented (4-6) phosphorus-rich Cu(i) dimers with the general formulas [Cu2(μ,η1:η1-A)2(η2-A)2][FAl]2 (3), [Cu2(μ,η1:η1-A)2(η1-CH3CN)4][FAl]2 (4), [Cu2(μ,η1:η1-B)2(η1-CH3CN)4][FAl]2 (5) and [Cu2(μ,η1:η1-B)2(η1-CH3CN)4][TEF]2 (6)...
November 22, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
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