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https://www.readbyqxmd.com/read/27894420/structural-basis-for-the-recognition-of-spliceosomal-smn-b-b-proteins-by-the-rbm5-ocre-domain-in-splicing-regulation
#1
André Mourão, Sophie Bonnal, Komal Soni, Lisa Warner, Rémy Bordonné, Juan Valcárcel, Michael Sattler
The multi-domain splicing factor RBM5 regulates the balance between antagonistic isoforms of the apoptosis-control genes FAS/CD95, Caspase-2 and AID. An OCRE (OCtamer REpeat of aromatic residues) domain found in RBM5 is important for alternative splicing regulation and mediates interactions with components of the U4/U6.U5 tri-snRNP. We show that the RBM5 OCRE domain adopts a unique β-sheet fold. NMR and biochemical experiments demonstrate that the OCRE domain directly binds to the proline-rich C-terminal tail of the essential snRNP core proteins SmN/B/B'...
November 29, 2016: ELife
https://www.readbyqxmd.com/read/27894243/spinal-muscular-atrophy-more-than-a-disease-of-motor-neurons
#2
L A Nash, J K Burns, J W Chardon, R Kothary, R J Parks
Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease resulting in infant mortality. SMA is caused by genetic deletion or mutation in the survival motor neuron 1 (SMN1) gene, which results in reduced levels of the survival of motor neuron (SMN) protein. SMN protein deficiency preferentially affects α- motor neurons, leading to their degeneration and subsequent atrophy of limb and trunk muscles, progressing to death in severe forms of the disease. More recent studies have shown that SMN protein depletion is detrimental to the functioning of other tissues including skeletal muscle, heart, autonomic and enteric nervous systems, metabolic/endocrine (e...
November 28, 2016: Current Molecular Medicine
https://www.readbyqxmd.com/read/27893852/a-comparative-study-of-smn-protein-and-mrna-in-blood-and-fibroblasts-in-patients-with-spinal-muscular-atrophy-and-healthy-controls
#3
Renske I Wadman, Marloes Stam, Marc D Jansen, Yana van der Weegen, Camiel A Wijngaarde, Oliver Harschnitz, Peter Sodaar, Kees P J Braun, Dennis Dooijes, Henny H Lemmink, Leonard H van den Berg, W Ludo van der Pol
BACKGROUND: Clinical trials to test safety and efficacy of drugs for patients with spinal muscular atrophy (SMA) are currently underway. Biomarkers that document treatment-induced effects are needed because disease progression in childhood forms of SMA is slow and clinical outcome measures may lack sensitivity to detect meaningful changes in motor function in the period of 1-2 years of follow-up during randomized clinical trials. OBJECTIVE: To determine and compare SMN protein and mRNA levels in two cell types (i...
2016: PloS One
https://www.readbyqxmd.com/read/27891608/compensatory-axon-sprouting-for-very-slow-axonal-die-back-in-a-transgenic-model-of-spinal-muscular-atrophy-type-iii
#4
Esther Udina, Charles Putman, Luke Harris, N Tyreman, Victoria Cook, Tessa Gordon
Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and is the leading genetic cause of infantile death. Patients lack the SMN1 gene with the severity of the disease depending on the number of copies of the highly homologous SMN2 gene. Although motoneuron death in the Smn+/- transgenic mouse model of mildest form of SMA, SMA type III, has been reported, we have used retrograde tracing of sciatic and femoral motoneurons in the hindlimb with recording of muscle and motor unit isometric forces to count the number of motoneurons with intact neuromuscular connections...
November 28, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27882347/ml372-blocks-smn-ubiquitination-and-improves-spinal-muscular-atrophy-pathology-in-mice
#5
Mahlet B Abera, Jingbo Xiao, Jonathan Nofziger, Steve Titus, Noel Southall, Wei Zheng, Kasey E Moritz, Marc Ferrer, Jonathan J Cherry, Elliot J Androphy, Amy Wang, Xin Xu, Christopher Austin, Kenneth H Fischbeck, Juan J Marugan, Barrington G Burnett
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease and one of the leading inherited causes of infant mortality. SMA results from insufficient levels of the survival motor neuron (SMN) protein, and studies in animal models of the disease have shown that increasing SMN protein levels ameliorates the disease phenotype. Our group previously identified and optimized a new series of small molecules, with good potency and toxicity profiles and reasonable pharmacokinetics, that were able to increase SMN protein levels in SMA patient-derived cells...
November 17, 2016: JCI Insight
https://www.readbyqxmd.com/read/27881601/structural-basis-for-snrna-recognition-by-the-double-wd40-repeat-domain-of-gemin5
#6
Wenxing Jin, Yi Wang, Chao-Pei Liu, Na Yang, Mingliang Jin, Yao Cong, Mingzhu Wang, Rui-Ming Xu
Assembly of the spliceosomal small nuclear ribonucleoparticle (snRNP) core requires the participation of the multisubunit SMN (survival of motor neuron) complex, which contains SMN and several Gemin proteins. The SMN and Gemin2 subunits directly bind Sm proteins, and Gemin5 is required for snRNP biogenesis and has been implicated in snRNA recognition. The RNA sequence required for snRNP assembly includes the Sm site and an adjacent 3' stem-loop, but a precise understanding of Gemin5's RNA-binding specificity is lacking...
November 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27881600/structural-insights-into-gemin5-guided-selection-of-pre-snrnas-for-snrnp-assembly
#7
Chao Xu, Hideaki Ishikawa, Keiichi Izumikawa, Li Li, Hao He, Yuko Nobe, Yoshio Yamauchi, Hanief M Shahjee, Xian-Hui Wu, Yi-Tao Yu, Toshiaki Isobe, Nobuhiro Takahashi, Jinrong Min
In cytoplasm, the survival of motor neuron (SMN) complex delivers pre-small nuclear RNAs (pre-snRNAs) to the heptameric Sm ring for the assembly of the ring complex on pre-snRNAs at the conserved Sm site [A(U)4-6G]. Gemin5, a WD40 protein component of the SMN complex, is responsible for recognizing pre-snRNAs. In addition, Gemin5 has been reported to specifically bind to the m(7)G cap. In this study, we show that the WD40 domain of Gemin5 is both necessary and sufficient for binding the Sm site of pre-snRNAs by isothermal titration calorimetry (ITC) and mutagenesis assays...
November 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27864217/risk-of-second-malignant-neoplasms-in-women-and-girls-with-germ-cell-tumors
#8
Z Liao, M C Rodrigues, J N Poynter, J F Amatruda, C Rodriguez-Galindo, A L Frazier
Background While an elevated risk of second malignant neoplasms (SMNs) has been observed in men treated for germ cell tumors (GCTs), risk of SMNs have not been quantified in adult women nor in girls treated for GCTs.Patients and Methods One-year survivors of primary GCTs diagnosed between January 1980 and December 2012 were identified from Surveillance, Epidemiology, and End Results registries (SEER 9). Risk of SMNs were calculated using SEER*Stat.Results Among 1,507 patients, a total of 47 SMNs were identified...
November 17, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27847148/sulfamethazine-degradation-in-water-by-the-vuv-uv-process-kinetics-mechanism-and-antibacterial-activity-determination-based-on-a-mini-fluidic-vuv-uv-photoreaction-system
#9
Mengkai Li, Chen Wang, Miaoling Yau, James R Bolton, Zhimin Qiang
A mini-fluidic VUV/UV photoreaction system (MVPS) was developed in our previous study, and it was demonstrated as a powerful tool for studies on pollutant degradation by the VUV/UV process. In this study, we investigated the VUV/UV photodegradation of sulfamethazine (SMN), one of the most frequently detected antibiotics in the environment. The determination methods of photochemical kinetic parameters (e.g., photon fluence-based rate constant and quantum yield) were developed based on the MVPS. The photon fluence-based reaction rate constants for SMN degradation by UV alone and VUV/UV processes were determined as 0...
November 4, 2016: Water Research
https://www.readbyqxmd.com/read/27843464/molecular-genetic-analysis-of-survival-motor-neuron-gene-in-460-turkish-cases-with-suspicious-spinal-muscular-atrophy-disease
#10
Afrooz Rashnonejad, Huseyin Onay, Tahir Atik, Ozlem Atan Sahin, Sarenur Gokben, Hasan Tekgul, Ferda Ozkinay
OBJECTIVE: To describe 12 yr experience of molecular genetic diagnosis of Spinal Muscular Atrophy (SMA) in 460 cases of Turkish patients. MATERIALS & METHODS: A retrospective analysis was performed on data from 460 cases, referred to Medical Genetics Laboratory, Ege University's Hospital, Izmir, Turkey, prediagnosed as SMA or with family history of SMA between 2003 and 2014. The PCR-restriction fragment length polymorphism (RFLP) and the Multiplex ligation-dependent probe amplification (MLPA) analysis were performed to detect the survival motor neuron (SMN)1 deletions and to estimate SMN1 and SMN2 gene copy numbers...
2016: Iranian Journal of Child Neurology
https://www.readbyqxmd.com/read/27830828/corrigendum-survival-motor-neuron-smn-protein-is-required-for-normal-mouse-liver-development
#11
Eva Szunyogova, Haiyan Zhou, Gillian K Maxwell, Rachael A Powis, Francesco Muntoni, Thomas H Gillingwater, Simon H Parson
No abstract text is available yet for this article.
November 10, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27785391/the-role-of-rna-metabolism-in-neurological-diseases
#12
A M Alaqeel, H Abou Al-Shaar, R K Shariff, A Albakr
Neurodegenerative disorders are commonly encountered in medical practices. Such diseases can lead to major morbidity and mortality among the affected individuals. The molecular pathogenesis of these disorders is not yet clear. Recent literature has revealed that mutations in RNA-binding proteins are a key cause of several human neuronal-based diseases. This review discusses the role of RNA metabolism in neurological diseases with specific emphasis on roles of RNA translation and microRNAs in neurodegeneration, RNA-mediated toxicity, repeat expansion diseases and RNA metabolism, molecular pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia, and neurobiology of survival motor neuron (SMN) and spinal muscular atrophy...
December 1, 2015: Balkan Journal of Medical Genetics: BJMG
https://www.readbyqxmd.com/read/27736905/altered-mrna-splicing-in-smn-depleted-motor-neuron-like-cells
#13
Sara K Custer, Timra D Gilson, Hongxia Li, A Gary Todd, Jacob W Astroski, Hai Lin, Yunlong Liu, Elliot J Androphy
Spinal muscular atrophy (SMA) is an intractable neurodegenerative disease afflicting 1 in 6-10,000 live births. One of the key functions of the SMN protein is regulation of spliceosome assembly. Reduced levels of the SMN protein that are observed in SMA have been shown to result in aberrant mRNA splicing. SMN-dependent mis-spliced transcripts in motor neurons may cause stresses that are particularly harmful and may serve as potential targets for the treatment of motor neuron disease or as biomarkers in the SMA patient population...
2016: PloS One
https://www.readbyqxmd.com/read/27726134/survival-of-motor-neurone-protein-is-required-for-normal-postnatal-development-of-the-spleen
#14
Alison K Thomson, Eilidh Somers, Rachael A Powis, Hannah K Shorrock, Kelley Murphy, Kathryn J Swoboda, Thomas H Gillingwater, Simon H Parson
Spinal muscular atrophy (SMA), traditionally described as a predominantly childhood form of motor neurone disease, is the leading genetic cause of infant mortality. Although motor neurones are undoubtedly the primary affected cell type, the severe infantile form of SMA (Type I SMA) is now widely recognised to represent a multisystem disorder where a variety of organs and systems in the body are also affected. Here, we report that the spleen is disproportionately small in the 'Taiwanese' murine model of severe SMA (Smn(-/-) ;SMN2(tg/0) ), correlated to low levels of cell proliferation and increased cell death...
October 11, 2016: Journal of Anatomy
https://www.readbyqxmd.com/read/27711914/second-malignant-neoplasms-and-cause-of-death-in-patients-with-germ-cell-cancer-a-danish-nationwide-cohort-study
#15
Maria G Kier, Merete K Hansen, Jakob Lauritsen, Mette S Mortensen, Mikkel Bandak, Mads Agerbaek, Niels V Holm, Susanne O Dalton, Klaus K Andersen, Christoffer Johansen, Gedske Daugaard
Importance: Patients given systemic treatment for testicular germ cell cancer (GCC) are at increased risk for a second malignant neoplasm (SMN). Previous studies on SMN and causes of death lacked information on the exact treatment applied or were based on patients receiving former treatment options. Objective: To evaluate the treatment-specific risks for SMN and death in a nationwide population-based cohort of patients with GCC treated with current standard regimens...
October 6, 2016: JAMA Oncology
https://www.readbyqxmd.com/read/27699224/systemic-restoration-of-uba1-ameliorates-disease-in-spinal-muscular-atrophy
#16
Rachael A Powis, Evangelia Karyka, Penelope Boyd, Julien Côme, Ross A Jones, Yinan Zheng, Eva Szunyogova, Ewout J N Groen, Gillian Hunter, Derek Thomson, Thomas M Wishart, Catherina G Becker, Simon H Parson, Cécile Martinat, Mimoun Azzouz, Thomas H Gillingwater
The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA...
July 21, 2016: JCI Insight
https://www.readbyqxmd.com/read/27698380/survival-motor-neuron-smn-protein-is-required-for-normal-mouse-liver-development
#17
Eva Szunyogova, Haiyan Zhou, Gillian K Maxwell, Rachael A Powis, Muntoni Francesco, Thomas H Gillingwater, Simon H Parson
Spinal Muscular Atrophy (SMA) is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Decreased levels of, cell-ubiquitous, SMN protein is associated with a range of systemic pathologies reported in severe patients. Despite high levels of SMN protein in normal liver, there is no comprehensive study of liver pathology in SMA. We describe failed liver development in response to reduced SMN levels, in a mouse model of severe SMA. The SMA liver is dark red, small and has: iron deposition; immature sinusoids congested with blood; persistent erythropoietic elements and increased immature red blood cells; increased and persistent megakaryocytes which release high levels of platelets found as clot-like accumulations in the heart...
October 4, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27687523/second-malignant-neoplasm-following-childhood-cancer-a-nested-case-control-study-of-a-recent-cohort-1987-2004-from-the-childhood-cancer-registry-of-the-rh%C3%A3-ne-alpes-region-in-france
#18
L Casagranda, M Oriol, F Freycon, D Frappaz, Y Bertrand, C Bergeron, D Plantaz, J L Stephan, C Freycon, F Gomez, C Berger, B Trombert-Paviot
From a population-based cohort of cases of first cancers diagnosed between 1987 and 2004, before the patient's age of 15 years, the authors conducted a nested case-control study, matching 64 patients who experienced a second malignant neoplasm (SMN) with 190 controls. SMNs comprised 10 leukemia or myelodysplastic syndromes, 5 lymphomas induced by Epstein-Barr virus after allograft, and 49 solid tumors, including mainly 25 carcinomas (17 of the thyroid), 9 bone sarcomas, and 7 central nervous system (CNS) tumors...
September 29, 2016: Pediatric Hematology and Oncology
https://www.readbyqxmd.com/read/27683180/somatic-and-germline-tp53-alterations-in-second-malignant-neoplasms-from-pediatric-cancer-survivors
#19
Amy Sherborne, Vincent Lavergne, Katharine Yu, Leah Lee, Philip Davidson, Tali Mazor, Ivan V Smirnov, Andrew E Horvai, Mignon Loh, Steven G Dubois, Robert Goldsby, Joseph P Neglia, Sue Hammond, Leslie L Robison, Rosanna Wustrack, Joseph F Costello, Alice Nakamura, Kevin M Shannon, Smita Bhatia, Jean L Nakamura
PURPOSE: Second malignant neoplasms (SMNs) are severe late complications that occur in pediatric cancer survivors exposed to radiotherapy and other genotoxic treatments. To characterize the mutational landscape of treatment-induced sarcomas and to identify candidate SMN-predisposing variants we analyzed germline and SMN tumor samples from pediatric cancer survivors. EXPERIMENTAL DESIGN: We performed whole exome sequencing (WES) and RNA sequencing on radiation-induced sarcomas arising from two pediatric cancer survivors...
September 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27663930/estimating-the-excess-lifetime-risk-of-radiation-induced-secondary-malignancy-smn-in-pediatric-patients-treated-with-craniospinal-irradiation-csi-conventional-radiation-therapy-versus-helical-intensity-modulated-radiation-therapy
#20
Jordan A Holmes, Bhishamjit S Chera, David J Brenner, Igor Shuryak, Adam K Wilson, Misty Lehman-Davis, David V Fried, Vivek Somasundaram, Jun Lian, Tim Cullip, Lawrence B Marks
PURPOSE: To quantify the risk of radiation-induced second malignancies (SMN) in pediatric patients receiving craniospinal irradiation (CSI) either with 3-dimensional conformal radiation therapy (Conv CSI) or tomotherapy helical intensity modulated radiation therapy (Tomo CSI). METHODS AND MATERIALS: A novel predictive model that accounts for short- and long-term carcinogenesis was incorporated into our institutional treatment planning system to quantify the lifetime risk of SMN in incidentally irradiated organs...
July 8, 2016: Practical Radiation Oncology
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