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https://www.readbyqxmd.com/read/28441483/discovery-of-a-novel-class-of-survival-motor-neuron-2-splicing-modifiers-for-the-treatment-of-spinal-muscular-atrophy
#1
Emmanuel Pinard, Luke Green, Michael Reutlinger, Marla Weetall, Nikolai N Naryshkin, John Baird, Karen S Chen, Sergey V Paushkin, Friedrich Metzger, Hasane Ratni
Spinal muscular atrophy (SMA) is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene, resulting in low levels of functional SMN protein. We have reported recently the identification of small molecules (coumarins, iso-coumarins and pyrido-pyrimidinones) that modify the alternative splicing of SMN2, a paralogous gene to SMN1, restoring the survival motor neuron (SMN) protein level in mouse models of SMA. Herein, we report our efforts to identify a novel chemotype as one strategy to potentially circumvent safety concerns from earlier derivatives, such as in-vitro phototoxicity and in-vitro mutagenicity associated with compounds 1 and 2 or the in-vivo retinal findings observed in a long term chronic tox study with 3 at high exposures only...
April 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28426667/bioenergetic-status-modulates-motor-neuron-vulnerability-and-pathogenesis-in-a-zebrafish-model-of-spinal-muscular-atrophy
#2
Penelope J Boyd, Wen-Yo Tu, Hannah K Shorrock, Ewout J N Groen, Roderick N Carter, Rachael A Powis, Sophie R Thomson, Derek Thomson, Laura C Graham, Anna A L Motyl, Thomas M Wishart, J Robin Highley, Nicholas M Morton, Thomas Becker, Catherina G Becker, Paul R Heath, Thomas H Gillingwater
Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles...
April 20, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28412171/gender-specific-amelioration-of-sma-phenotype-upon-disruption-of-a-deep-intronic-structure-by-an-oligonucleotide
#3
Matthew D Howell, Eric W Ottesen, Natalia N Singh, Rachel L Anderson, Ravindra N Singh
Spinal muscular atrophy (SMA), the leading genetic disease of children, is caused by low levels of survival motor neuron (SMN) protein. Here, we employ A15/283, an antisense oligonucleotide targeting a deep intronic sequence/structure, to examine the impact of restoration of SMN in a mild SMA mouse model. We show gender-specific amelioration of tail necrosis upon subcutaneous administrations of A15/283 into SMA mice at postnatal days 1 and 3. We also demonstrate that a modest increase in SMN due to early administrations of A15/283 dramatically improves testicular development and spermatogenesis...
April 13, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28399889/cardiac-pathology-in-spinal-muscular-atrophy-a-systematic-review
#4
REVIEW
C A Wijngaarde, A C Blank, M Stam, R I Wadman, L H van den Berg, W L van der Pol
BACKGROUND: Hereditary proximal spinal muscular atrophy (SMA) is a severe neuromuscular disease of childhood caused by homozygous loss of function of the survival motor neuron (SMN) 1 gene. The presence of a second, nearly identical SMN gene (SMN2) in the human genome ensures production of residual levels of the ubiquitously expressed SMN protein. Alpha-motor neurons in the ventral horns of the spinal cord are most vulnerable to reduced SMN concentrations but the development or function of other tissues may also be affected, and cardiovascular abnormalities have frequently been reported both in patients and SMA mouse models...
April 11, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28394494/high-frequency-continuous-pulsed-magnetic-stimulation-does-not-adversely-affect-development-on-whole-body-organs-in-female-sprague-dawley-rats
#5
Eiichi Sato, Tomonori Yamanishi, Yasuo Imai, Masashi Kobayashi, Taku Sakamoto, Yuko Ono, Akiko Fujii, Takehiko Yamaguchi, Tsukasa Nakamura, Yoshihiko Ueda
OBJECTIVES: To conduct histopathological studies on various organs in three different groups of female rats for adverse effects of pulsed magnetic stimulation (MS). Blood tests and body and organ weights were also studied. METHODS: A high-frequency continuous magnetic stimulator was used (SMN-X, Nihon Kohden, Tokyo). Thirty-four female Sprague-Dawley rats (SPF) were randomly divided into three groups: treatment (MS) groups with 12 and 36 stimulations (seven rats in each); sham groups exposed only to sounds of stimulation for 12 and 36 times; (seven rats in each); and control groups with no stimulation or sound during the same periods of 12 and 36 stimulations (five rats in each)...
May 2017: Lower Urinary Tract Symptoms
https://www.readbyqxmd.com/read/28389270/combination-of-valproic-acid-and-morpholino-splice-switching-oligonucleotide-produces-improved-outcomes-in-spinal-muscular-atrophy-patient-derived-fibroblasts
#6
Anna Farrelly-Rosch, Chew Ling Lau, Nitin Patil, Bradley J Turner, Fazel Shabanpoor
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality worldwide, is characterised by the homozygous loss of the survival motor neuron 1 (SMN1) gene. The consequent degeneration of spinal motor neurons and progressive atrophy of voluntary muscle groups results in paralysis and eventually premature infantile death. Humans possess a second nearly identical copy of SMN1, known as SMN2. However, SMN2 produces only 10-20% functional SMN protein due to aberrant splicing of its pre-mRNA that leads to the exclusion of exon 7...
April 4, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28387446/polymorphisms-in-the-srnpn-gene-are-associated-with-obesity-susceptibility-among-spanish-population
#7
David Albuquerque, Licínio Manco, Luz M González, Guillermo Gervasini, Goitzane Marcaida Benito, Juan R González, Raquel Rodríguez-López
BACKGROUND: SNRPN, which codes for the RNA-binding SmN protein, is a candidate gene for Prader-Willi syndrome. One characteristic of this neuroendocrine disorder is hyperphagia resulting in extreme obesity later in life. In this study we aim to assess whether variability within this gene could be implicated in obesity susceptibility. MATERIAL AND METHODS: A case-control study was performed including 265 unrelated patients with non-syndromic and early-onset severe obesity, belonging to high risk obesity families from Spanish ancestry; 184 healthy control individuals were included representative of the same genetic background and sex-matched...
April 7, 2017: Journal of Gene Medicine
https://www.readbyqxmd.com/read/28379354/motor-neuronal-repletion-of-the-nmj-organizer-agrin-modulates-the-severity-of-the-spinal-muscular-atrophy-disease-phenotype-in-model-mice
#8
Jeong-Ki Kim, Charlotte Caine, Tomoyuki Awano, Ruth Herbst, Umrao R Monani
Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure...
March 31, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28378408/cancer-recurrence-and-mortality-after-pediatric-heart-transplantation-for-anthracycline-cardiomyopathy-a-report-from-the-pediatric-heart-transplant-study-phts-group
#9
Matthew J Bock, Elfriede Pahl, Paolo G Rusconi, Gerard J Boyle, John J Parent, Clare J Twist, James K Kirklin, Elizabeth Pruitt, Daniel Bernstein
We aimed to determine whether malignancy after pediatric HTx for ACM affects overall post-HTx survival. Patients <18y listed for HTx for ACM in the PHTS database between 1993 and 2014 were compared to those with DCM. A 2:1 matched DCM cohort was also compared. Wait-list and post-HTx survival, along with freedom from common HTx complications, were compared. Eighty subjects were listed due to ACM, whereas 1985 were listed for DCM. Although wait-list survival was higher in the ACM group, post-HTx survival was lower for the ACM cohort...
April 4, 2017: Pediatric Transplantation
https://www.readbyqxmd.com/read/28377606/a-longitudinal-study-of-the-effect-of-short-term-meditation-training-on-functional-network-organization-of-the-aging-brain
#10
Francesca A Cotier, Ruibin Zhang, Tatia M C Lee
The beneficial effects of meditation on preserving age-related changes in cognitive functioning are well established. Yet, the neural underpinnings of these positive effects have not been fully unveiled. This study employed a prospective longitudinal design, and graph-based analysis, to study how an eight-week meditation training vs. relaxation training shaped network configuration at global, intermediate, and local levels using graph theory in the elderly. At the intermediate level, meditation training lead to decreased intra-connectivity in the default mode network (DMN), salience network (SAN) and somatomotor network (SMN) modules post training...
April 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28372746/uptake-and-translocation-of-sulfamethazine-by-alfalfa-grown-under-hydroponic-conditions
#11
Sudarshan Kurwadkar, Garrett Struckhoff, Kameron Pugh, Om Singh
Antibiotics are routinely used in intensive animal agriculture operations collectively known as Concentrated Animal Feed Operations (CAFO) which include dairy, poultry and swine farms. Wastewater generated by CAFOs often contains low levels of antibiotics and is typically managed in an anaerobic lagoon. The objective of this research is to investigate the uptake and fate of aqueous sulfamethazine (SMN) antibiotic by alfalfa (Medicago sativa) grass grown under hydroponic conditions. Uptake studies were conducted using hydroponically grown alfalfa in a commercially available nutrient solution supplemented with 10mg/L of SMN antibiotic...
March 2017: Journal of Environmental Sciences (China)
https://www.readbyqxmd.com/read/28366534/sma-mutations-in-smn-tudor-and-c-terminal-domains-destabilize-the-protein
#12
Toru Takarada, Mawaddah Ar Rochmah, Nur Imma Fatimah Harahap, Masakazu Shinohara, Toshio Saito, Kayoko Saito, Poh San Lai, Yoshihiro Bouike, Yasuhiro Takeshima, Hiroyuki Awano, Ichiro Morioka, Kazumoto Iijima, Hisahide Nishio, Atsuko Takeuchi
BACKGROUND AND PURPOSE: Most spinal muscular atrophy (SMA) patients are homozygous for survival of motor neuron 1 gene (SMN1) deletion. However, some SMA patients carry an intragenic SMN1 mutation. Such patients provide a clue to understanding the function of the SMN protein and the role of each domain of the protein. We previously identified mutations in the Tudor domain and C-terminal region of the SMN protein in three Japanese SMA patients. To clarify the effect of these mutations on protein stability, we conducted expression assays of SMN with mutated domains...
March 30, 2017: Brain & Development
https://www.readbyqxmd.com/read/28359223/epileptic-discharge-related-functional-connectivity-within-and-between-networks-in-benign-epilepsy-with-centrotemporal-spikes
#13
Rong Li, Gong-Jun Ji, Yangyang Yu, Yang Yu, Mei-Ping Ding, Ye-Lei Tang, Huafu Chen, Wei Liao
Benign epilepsy with centrotemporal spikes (BECTS) is a common childhood epilepsy syndrome associated with abnormalities in neurocognitive domains, particularly during interictal epileptiform discharges (IEDs). Here, we investigated the effects of IEDs on brain's intrinsic connectivity networks in 43 BECTS patients and 28 matched healthy controls (HCs). Patients were further divided into IED and non-IED subgroups based on simultaneous EEG-fMRI recordings. Functional connectivity within and between five networks, corresponding to seizure origination and cognitive processes, were analyzed to measure IED effects...
January 10, 2017: International Journal of Neural Systems
https://www.readbyqxmd.com/read/28355945/late-life-depression-modifications-of-brain-resting-state-activity
#14
Filippo Cieri, Roberto Esposito, Nicoletta Cera, Valentina Pieramico, Armando Tartaro, Massimo di Giannantonio
Late-life depression (LLD) is a common emotional and mental disability in the elderly population characterized by the presence of depressed mood, the loss of interest or pleasure in daily activities, and other depression symptoms. It has a serious effect on the quality of life of elderly individuals and increases their risk of developing physical and mental diseases. It is an important area of research, given the growing elderly population. Brain functional connectivity modifications represent one of the neurobiological biomarker for LLD even if to date remains poorly understood...
May 2017: Journal of Geriatric Psychiatry and Neurology
https://www.readbyqxmd.com/read/28350532/urethral-proteomic-analysis-in-ovariectomized-mice-administered-17%C3%AE-oestradiol-replacement-therapy
#15
Huey-Yi Chen, Yu-Ning Lin, Wen-Chi Chen, Shih-Jing Wang, Chao-Jung Chen, Yung-Hsiang Chen
The molecular mechanism by which 17β-oestradiol (E2) increases urethral tone is unclear. As human tissue is limited in availability, we explored changes in the urethras of ovariectomized (OVX) mice. Twenty-four virgin female mice were randomised into three groups: mice with a sham operation only (control), OVX mice without E2 replacement (OVX), and OVX mice with E2 replacement (OVX + E2). Two weeks after the ovariectomy, mice received either E2 or placebo for 4 weeks. Leak point pressure (LPP) and maximum urethral closure pressure (MUCP) were assessed in these mice at 6 weeks after OVX, under anaesthesia...
March 28, 2017: Journal of Obstetrics and Gynaecology: the Journal of the Institute of Obstetrics and Gynaecology
https://www.readbyqxmd.com/read/28337249/cellular-homeostasis-and-antioxidant-response-in-epithelial-ht29-cells-on-titania-nanotube-arrays-surface
#16
Rabiatul Basria Smn Mydin, Srimala Sreekantan, Roshasnorlyza Hazan, Mustafa Fadzil Farid Wajidi, Ishak Mat
Cell growth and proliferative activities on titania nanotube arrays (TNA) have raised alerts on genotoxicity risk. Present toxicogenomic approach focused on epithelial HT29 cells with TNA surface. Fledgling cell-TNA interaction has triggered G0/G1 cell cycle arrests and initiates DNA damage surveillance checkpoint, which possibly indicated the cellular stress stimuli. A profound gene regulation was observed to be involved in cellular growth and survival signals such as p53 and AKT expressions. Interestingly, the activation of redox regulator pathways (antioxidant defense) was observed through the cascade interactions of GADD45, MYC, CHECK1, and ATR genes...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28289706/plastin-3-extends-survival-and-reduces-severity-in-mouse-models-of-spinal-muscular-atrophy
#17
Kevin A Kaifer, Eric Villalón, Erkan Y Osman, Jacqueline J Glascock, Laura L Arnold, D D W Cornelison, Christian L Lorson
Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death and is caused by the loss of survival motor neuron-1 (SMN1). Importantly, a nearly identical gene is present called SMN2; however, the majority of SMN2-derived transcripts are alternatively spliced and encode a truncated, dysfunctional protein. Recently, several compounds designed to increase SMN protein have entered clinical trials, including antisense oligonucleotides (ASOs), traditional small molecules, and gene therapy. Expanding beyond SMN-centric therapeutics is important, as it is likely that the breadth of the patient spectrum and the inherent complexity of the disease will be difficult to address with a single therapeutic strategy...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28285376/association-of-podocyte-autophagosome-numbers-with-idiopathic-membranous-nephropathy-and-secondary-membranous-nephropathy
#18
Juan Jin, Huifang Zhan, Bo Lin, Yiwen Li, Wei Zhang, Qiang He
PURPOSE: This study was to investigate the relation between the number of autophagosomes in podocytes and the syndromes of idiopathic membranous nephropathy (IMN) and secondary membranous nephropathy (sMN). METHODS: The pathological changes in the kidney tissues of patients were detected with the hematoxylin and eosin staining, the periodic acid-Schiff reagent treatment, the Masson's trichrome staining and the immunofluorescence detection (IF). Meanwhile, the autophagosomes in podocyte were analyzed by transmission electron microscopy and the IF assay pointing to LC3-II, an autophagic marker...
March 11, 2017: International Urology and Nephrology
https://www.readbyqxmd.com/read/28271991/new-therapy-for-spinal-muscular-atrophy-offers-modest-bang-for-pharamaceutical-buck
#19
Thomas Morrow
Spinraza is a breakthrough, no doubt. It is a survival SMN-2-directed antisense oligonucleotide indicated for the treatment of SMA in pediatric and adult patients and is administered by injections into the spinal fluid (intrathecally). But it is another ultraexpensive drug, and the evidence so far points to a modest improvement in motor milestones.
February 2017: Managed Care
https://www.readbyqxmd.com/read/28271621/first-characterization-of-human-amniotic-fluid-stem-cell-extracellular-vesicles-as-a-powerful-paracrine-tool-endowed-with-regenerative-potential
#20
Carolina Balbi, Martina Piccoli, Lucio Barile, Andrea Papait, Andrea Armirotti, Elisa Principi, Daniele Reverberi, Luisa Pascucci, Pamela Becherini, Luigi Varesio, Massimo Mogni, Domenico Coviello, Tiziano Bandiera, Michela Pozzobon, Ranieri Cancedda, Sveva Bollini
Human amniotic fluid stem cells (hAFS) have shown a distinct secretory profile and significant regenerative potential in several preclinical models of disease. Nevertheless, little is known about the detailed characterization of their secretome. Herein we show for the first time that hAFS actively release extracellular vesicles (EV) endowed with significant paracrine potential and regenerative effect. c-KIT(+) hAFS were isolated from leftover samples of amniotic fluid from prenatal screening and stimulated to enhance EV release (24 hours 20% O2 versus 1% O2 preconditioning)...
March 8, 2017: Stem Cells Translational Medicine
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