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https://www.readbyqxmd.com/read/28815863/decoding-fmri-events-in-sensorimotor-motor-network-using-sparse-paradigm-free-mapping-and-activation-likelihood-estimates
#1
Francisca M Tan, César Caballero-Gaudes, Karen J Mullinger, Siu-Yeung Cho, Yaping Zhang, Ian L Dryden, Susan T Francis, Penny A Gowland
Most functional MRI (fMRI) studies map task-driven brain activity using a block or event-related paradigm. Sparse paradigm free mapping (SPFM) can detect the onset and spatial distribution of BOLD events in the brain without prior timing information, but relating the detected events to brain function remains a challenge. In this study, we developed a decoding method for SPFM using a coordinate-based meta-analysis method of activation likelihood estimation (ALE). We defined meta-maps of statistically significant ALE values that correspond to types of events and calculated a summation overlap between the normalized meta-maps and SPFM maps...
August 16, 2017: Human Brain Mapping
https://www.readbyqxmd.com/read/28811488/deregulation-of-zpr1-causes-respiratory-failure-in-spinal-muscular-atrophy
#2
Naresh K Genabai, Annapoorna Kannan, Saif Ahmad, Xiaoting Jiang, Kanchan Bhatia, Laxman Gangwani
Spinal muscular atrophy (SMA) is caused by the low levels of survival motor neuron (SMN) protein and is characterized by motor neuron degeneration and muscle atrophy. Respiratory failure causes death in SMA but the underlying molecular mechanism is unknown. The zinc finger protein ZPR1 interacts with SMN. ZPR1 is down regulated in SMA patients. We report that ZPR1 functions downstream of SMN to regulate HoxA5 levels in phrenic motor neurons that control respiration. Spatiotemporal inactivation of Zpr1 gene in motor neurons down-regulates HoxA5 and causes defects in the function of phrenic motor neurons that results in respiratory failure and perinatal lethality in mice...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28808928/regulation-of-survival-motor-neuron-protein-by-the-nuclear-factor-kappa-b-pathway-in-mouse-spinal-cord-motoneurons
#3
Saravanan Arumugam, Stefka Mincheva-Tasheva, Ambika Periyakaruppiah, Sandra de la Fuente, Rosa M Soler, Ana Garcera
Survival motor neuron (SMN) protein deficiency causes the genetic neuromuscular disorder spinal muscular atrophy (SMA), characterized by spinal cord motoneuron degeneration. Since SMN protein level is critical to disease onset and severity, analysis of the mechanisms involved in SMN stability is one of the central goals of SMA research. Here, we describe the role of several members of the NF-κB pathway in regulating SMN in motoneurons. NF-κB is one of the main regulators of motoneuron survival and pharmacological inhibition of NF-κB pathway activity also induces mouse survival motor neuron (Smn) protein decrease...
August 14, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28799578/nusinersen-antisense-oligonucleotide-to-increase-smn-protein-production-in-spinal-muscular-atrophy
#4
D M Paton
Patients with spinal muscular atrophy (SMA) have an autosomal recessive disease that limits their ability to produce survival motor neuron (SMN) protein in the CNS resulting in progressive wasting of voluntary muscles. Detailed studies over several years have demonstrated that phosphorothioate and 2'-O-methoxyethyl- modified antisense oligonucleotides (ASOs) targeting the ISS-N1 site increase SMN2 exon 7 inclusion, thus increasing levels of SMN protein in a dose- and time-dependent manner in liver, kidney and skeletal muscle, and CNS tissues only when administered intrathecally...
June 2017: Drugs of Today
https://www.readbyqxmd.com/read/28775379/tia1-is-a-gender-specific-disease-modifier-of-a-mild-mouse-model-of-spinal-muscular-atrophy
#5
Matthew D Howell, Eric W Ottesen, Natalia N Singh, Rachel L Anderson, Joonbae Seo, Senthilkumar Sivanesan, Elizabeth M Whitley, Ravindra N Singh
Spinal muscular atrophy (SMA) is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. The nearly identical SMN2 cannot compensate for SMN1 loss due to exon 7 skipping. The allele C (C (+/+)) mouse recapitulates a mild SMA-like phenotype and offers an ideal system to monitor the role of disease-modifying factors over a long time. T-cell-restricted intracellular antigen 1 (TIA1) regulates SMN exon 7 splicing. TIA1 is reported to be downregulated in obese patients, although it is not known if the effect is gender-specific...
August 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28768735/therapeutic-strategies-for-spinal-muscular-atrophy-smn-and-beyond
#6
REVIEW
Melissa Bowerman, Catherina G Becker, Rafael J Yáñez-Muñoz, Ke Ning, Matthew J A Wood, Thomas H Gillingwater, Kevin Talbot
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) due to inactivating mutations in the encoding gene SMN1 A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO) therapy has recently been licensed...
August 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28766049/usnrnp-biogenesis-mechanisms-and-regulation
#7
REVIEW
Oliver J Gruss, Rajyalakshmi Meduri, Maximilian Schilling, Utz Fischer
Macromolecular complexes composed of proteins or proteins and nucleic acids rather than individual macromolecules mediate many cellular activities. Maintenance of these activities is essential for cell viability and requires the coordinated production of the individual complex components as well as their faithful incorporation into functional entities. Failure of complex assembly may have fatal consequences and can cause severe diseases. While many macromolecular complexes can form spontaneously in vitro, they often require aid from assembly factors including assembly chaperones in the crowded cellular environment...
August 1, 2017: Chromosoma
https://www.readbyqxmd.com/read/28758620/antibodies-against-the-mono-methylated-arginine-glycine-repeat-mma-rg-of-the-epstein-barr-virus-nuclear-antigen-2-ebna2-identify-potential-cellular-proteins-targeted-in-viral-transformation
#8
Hiresh Ayoubian, Thomas Fröhlich, Dagmar Pogodski, Andrew Flatley, Elisabeth Kremmer, Aloys Schepers, Regina Feederle, Georg J Arnold, Friedrich A Grässer
The Epstein-Barr virus is a human herpes virus with oncogenic potential. The virus-encoded nuclear antigen 2 (EBNA2) is a key mediator of viral tumorigenesis. EBNA2 features an arginine-glycine (RG) repeat at amino acids (aa)339-354 that is essential for the transformation of lymphocytes and contains symmetrically (SDMA) and asymmetrically (ADMA) di-methylated arginine residues. The SDMA-modified EBNA2 binds the survival motor neuron protein (SMN), thus mimicking SMD3, a cellular SDMA-containing protein that interacts with SMN...
July 28, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28745812/neuronal-control-of-experimental-colitis-occurs-via-sympathetic-intestinal-innervation
#9
R A Willemze, O Welting, H P van Hamersveld, S L Meijer, J H A Folgering, H Darwinkel, J Witherington, A Sridhar, M J Vervoordeldonk, J Seppen, W J de Jonge
BACKGROUND: Vagus nerve stimulation is currently clinically evaluated as a treatment for inflammatory bowel disease. However, the mechanism by which this therapeutic intervention can have an immune-regulatory effect in colitis remains unclear. We determined the effect of intestine-specific vagotomy or intestine-specific sympathectomy of the superior mesenteric nerve (SMN) on dextran sodium sulfate (DSS)-induced colitis in mice. Furthermore, we tested the efficacy of therapeutic SMN stimulation to treat DSS-induced colitis in rats...
July 26, 2017: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
https://www.readbyqxmd.com/read/28733834/long-term-intensive-gymnastic-training-induced-changes-in-intra-and-inter-network-functional-connectivity-an-independent-component-analysis
#10
Huiyuan Huang, Junjing Wang, Carol Seger, Min Lu, Feng Deng, Xiaoyan Wu, Yuan He, Chen Niu, Jun Wang, Ruiwang Huang
Long-term intensive gymnastic training can induce brain structural and functional reorganization. Previous studies have identified structural and functional network differences between world class gymnasts (WCGs) and non-athletes at the whole-brain level. However, it is still unclear how interactions within and between functional networks are affected by long-term intensive gymnastic training. We examined both intra- and inter-network functional connectivity of gymnasts relative to non-athletes using resting-state fMRI (R-fMRI)...
July 21, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/28728573/splicing-arrays-reveal-novel-rbm10-targets-including-smn2-pre-mrna
#11
Leslie C Sutherland, Philippe Thibault, Mathieu Durand, Elvy Lapointe, Jose M Knee, Ariane Beauvais, Irina Kalatskaya, Sarah C Hunt, Julie J Loiselle, Justin G Roy, Sarah J Tessier, Gustavo Ybazeta, Lincoln Stein, Rashmi Kothary, Roscoe Klinck, Benoit Chabot
BACKGROUND: RBM10 is an RNA binding protein involved in message stabilization and alternative splicing regulation. The objective of the research described herein was to identify novel targets of RBM10-regulated splicing. To accomplish this, we downregulated RBM10 in human cell lines, using small interfering RNAs, then monitored alternative splicing, using a reverse transcription-PCR screening platform. RESULTS: RBM10 knockdown (KD) provoked alterations in splicing events in 10-20% of the pre-mRNAs, most of which had not been previously identified as RBM10 targets...
July 20, 2017: BMC Molecular Biology
https://www.readbyqxmd.com/read/28721394/interhemispheric-disconnectivity-in-the-sensorimotor-network-in-bipolar-disorder-revealed-by-functional-connectivity-and-diffusion-tensor-imaging-analysis
#12
Takuya Ishida, Tomohiro Donishi, Jun Iwatani, Shinichi Yamada, Shun Takahashi, Satoshi Ukai, Kazuhiro Shinosaki, Masaki Terada, Yoshiki Kaneoke
BACKGROUND: Little is known regarding interhemispheric functional connectivity (FC) abnormalities via the corpus callosum in subjects with bipolar disorder (BD), which might be a key pathophysiological basis of emotional processing alterations in BD. METHODS: We performed tract-based spatial statistics (TBSS) using diffusion tensor imaging (DTI) in 24 healthy control (HC) and 22 BD subjects. Next, we analyzed the neural networks with independent component analysis (ICA) in 32HC and 25 BD subjects using resting-state functional magnetic resonance imaging...
June 2017: Heliyon
https://www.readbyqxmd.com/read/28712791/radiotherapy-for-stage-i-and-ii-testicular-seminomas-secondary-malignancies-and-survival
#13
Hiten D Patel, Arnav Srivastava, Ridwan Alam, Gregory A Joice, Zeyad R Schwen, Alice Semerjian, Mohamad E Allaf, Phillip M Pierorazio
INTRODUCTION: Testicular seminoma affects relatively young men with excellent survival outcomes. There has been increasing concern that radiotherapy (RT) leads to secondary malignant neoplasms (SMNs) and subsequent mortality. We evaluated the effect of RT on incidence of SMNs and quantified cancer-related mortality and other causes of death for patients with stage I and II testicular seminoma. MATERIAL AND METHODS: A national sample of men (1988-2013) diagnosed with stage IA/IB/IS/IIA/IIB/IIC testicular seminomas from Surveillance, Epidemiology, and End Results were evaluated...
July 13, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28712387/srsf2-directly-inhibits-intron-splicing-to-suppresses-cassette-exon-inclusion
#14
Heegyum Moon, Sunghee Cho, Tiing Jen Loh, Ha Na Jang, Yongchao Liu, Namjeong Choi, Jagyeong Oh, Jiyeon Ha, Jianhua Zhou, Sungchan Cho, Dong-Eun Kim, Michael B Ye, Xuexiu Zheng, Haihong Shen
SRSF2, a Serine-Arginine rich (SR) protein, is a splicing activator that mediates exon inclusion and exclusion events equally well. Here we show SRSF2 directly suppresses intron splicing to suppress cassette exon inclusion in SMN pre-mRNA. Through a serial mutagenesis, we demonstrate that a 10 nt RNA sequence surrounding the branch-point (BP), is important for SRSF2-mediated inhibition of cassette exon inclusion through directly interacting with SRSF2. We conclude that SRSF2 inhibits intron splicing to promote exon exclusion...
July 17, 2017: BMB Reports
https://www.readbyqxmd.com/read/28697656/impact-of-liver-transplantation-on-the-risk-of-second-malignant-tumors-among-hepatocellular-carcinoma-patients
#15
Hani Oweira, Jan Schmidt, Daniel Helbling, Ulf Petrausch, Othmar Schöb, Arianeb Mehrabi, Anwar Giryes, Hazem Elhadedy, Omar Abdel-Rahman
BACKGROUND: Population-based data on the development of second malignant neoplasms (SMNs) following the diagnosis of hepatocellular carcinoma (HCC) are uncommon. We evaluated this clinical vignette in HCC patients within the Surveillance, Epidemiology and End Results (SEER) database. METHODS: The SEER database (1973-2012) was queried using the SEER*Stat program to determine the clinico-pathological features of HCC patients with more than one year survival who developed SMNs...
July 18, 2017: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28684086/modifier-genes-moving-from-pathogenesis-to-therapy
#16
Edward R B McCabe
This commentary will focus on how we can use our knowledge about the complexity of human disease and its pathogenesis to identify novel approaches to therapy. We know that even for single gene Mendelian disorders, patients with identical mutations often have different presentations and outcomes. This lack of genotype-phenotype correlation led us and others to examine the roles of modifier genes in the context of biological networks. These investigations have utilized vertebrate and invertebrate model organisms...
May 30, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28666123/splicing-correcting-therapy-for-sma
#17
Lili Wan, Gideon Dreyfuss
Spinal muscular atrophy (SMA) is caused by deficiency of SMN protein, which is crucial for spliceosome subunits biogenesis. Most SMA patients have SMN1 deletions, leaving SMN2 as sole SMN source; however, a C→T substitution converts an exonic-splicing enhancer (ESE) to a silencer (ESS), causing frequent exon7 skipping in SMN2 pre-mRNA and yielding a truncated protein. Antisense treatment to SMN2 intron7-splicing silencer (ISS) improves SMN expression and motor function. To view this Bench to Bedside, open or download the PDF...
June 29, 2017: Cell
https://www.readbyqxmd.com/read/28662219/the-effects-of-c5-substituted-2-4-diaminoquinazolines-on-selected-transcript-expression-in-spinal-muscular-atrophy-cells
#18
Cinsley Gentillon, Andrew J Connell, Ryan W Kirk, Matthew E R Butchbach
C5-substituted 2,4-diaminoquinazolines (2,4-DAQs) ameliorate disease severity in SMA mice. It is uncertain, however, that these compounds increase SMN protein levels in vivo even though they were identified as activators of the SMN2 promoter. These compounds also regulate the expression of other transcripts in neuroblastoma cells. In this study, we investigate the mechanism by which the 2,4-DAQs regulate the expression of SMN2 as well as other targets. D156844, D158872, D157161 and D157495 (RG3039) increased SMN2 promoter-driven reporter gene activity by at least 3-fold in NSC-34 cells...
2017: PloS One
https://www.readbyqxmd.com/read/28648462/cyclic-tetrapeptide-hdac-inhibitors-as-potential-therapeutics-for-spinal-muscular-atrophy-screening-with-ipsc-derived-neuronal-cells
#19
Jiun-I Lai, Luke J Leman, Sherman Ku, Chris J Vickers, Christian A Olsen, Ana Montero, M Reza Ghadiri, Joel M Gottesfeld
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is caused by inactivating mutations in the Survival of motor neuron 1 (SMN1) gene, resulting in decreased SMN protein expression. Humans possess a paralog gene, SMN2, which contains a splicing defect in exon 7 leading to diminished expression of full-length, fully functional SMN protein. Increasing SMN2 expression has been a focus of therapeutic development for SMA. Multiple studies have reported the efficacy of histone deacetylase inhibitors (HDACi) in this regard...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28644430/the-clinical-landscape-for-sma-in-a-new-therapeutic-era
#20
REVIEW
K Talbot, E F Tizzano
Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy, due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy...
June 23, 2017: Gene Therapy
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