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https://www.readbyqxmd.com/read/28335032/allele-specific-ablation-rescues-electrophysiological-abnormalities-in-a-human-ips-cell-model-of-long-qt-syndrome-with-a-calm2-mutation
#1
Yuta Yamamoto, Takeru Makiyama, Takeshi Harita, Kenichi Sasaki, Yimin Wuriyanghai, Mamoru Hayano, Suguru Nishiuchi, Hirohiko Kohjitani, Sayako Hirose, Jiarong Chen, Fumika Yokoi, Taisuke Ishikawa, Seiko Ohno, Kazuhisa Chonabayashi, Hideki Motomura, Yoshinori Yoshida, Minoru Horie, Naomasa Makita, Takeshi Kimura
Background: Calmodulin is a ubiquitous Ca 2+ sensor molecule encoded by three distinct calmodulin genes, CALM1-3 . Recently, mutations in CALM1-3 have been reported to be associated with severe early-onset long-QT syndrome (LQTS). However, the underlying mechanism through which heterozygous calmodulin mutations lead to severe LQTS remains unknown, particularly in human cardiomyocytes. Objectives: We aimed to establish an LQTS disease model associated with a CALM2 mutation (LQT15) using human induced pluripotent stem cells (hiPSCs) and to assess mutant allele-specific ablation by genome editing for the treatment of LQT15...
March 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28335020/znhit3-is-defective-in-peho-syndrome-a-severe-encephalopathy-with-cerebellar-granule-neuron-loss
#2
Anna-Kaisa Anttonen, Anni Laari, Maria Kousi, Yawei J Yang, Tiina Jääskeläinen, Mirja Somer, Eija Siintola, Eveliina Jakkula, Mikko Muona, Saara Tegelberg, Tuula Lönnqvist, Helena Pihko, Leena Valanne, Anders Paetau, Melody P Lun, Johanna Hästbacka, Outi Kopra, Tarja Joensuu, Nicholas Katsanis, Maria K Lehtinen, Jorma J Palvimo, Anna-Elina Lehesjoki
Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing...
March 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28334952/dnmt1-mutations-found-in-hsanie-patients-affect-interaction-with-uhrf1-and-neuronal-differentiation
#3
Martha Smets, Stephanie Link, Patricia Wolf, Katrin Schneider, Veronica Solis, Joel Ryan, Daniela Meilinger, Weihua Qin, Heinrich Leonhardt
DNMT1 is recruited to substrate sites by PCNA and UHRF1 to maintain DNA methylation after replication. The cell cycle dependent recruitment of DNMT1 is mediated by the PCNA-binding domain (PBD) and the targeting sequence (TS) within the N-terminal regulatory domain. The TS domain was found to be mutated in patients suffering from hereditary sensory and autonomic neuropathies with dementia and hearing loss (HSANIE) and autosomal dominant cerebellar ataxia deafness and narcolepsy (ADCA-DN) and is associated with global hypomethylation and site specific hypermethylation...
March 3, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28334865/structure-of-human-pofut1-its-requirement-in-ligand-independent-oncogenic-notch-signaling-and-functional-effects-of-dowling-degos-mutations
#4
Brian J McMillan, Brandon Zimmerman, Emily D Egan, Michael Lofgren, Xiang Xu, Anthony Hesser, Stephen C Blacklow
Protein O-fucosyltransferase-1 (POFUT1), which transfers fucose residues to acceptor sites on serine and threonine residues of epidermal growth factor-like repeats of recipient proteins, is essential for Notch signal transduction in mammals. Here, we examine the consequences of POFUT1 loss on the oncogenic signaling associated with certain leukemia-associated mutations of human Notch1, report the structures of human POFUT1 in free and GDP-fucose bound states, and assess the effects of Dowling-Degos mutations on human POFUT1 function...
March 17, 2017: Glycobiology
https://www.readbyqxmd.com/read/28334862/the-wilms-tumor-protein-wt1-contributes-to-female-fertility-by-regulating-oviductal-proteostasis
#5
Abinaya Nathan, Peter Reinhardt, Dagmar Kruspe, Tjard Jörß, Marco Groth, Hendrik Nolte, Andreas Habenicht, Jörg Herrmann, Verena Holschbach, Bettina Toth, Marcus Krüger, Zhao-Qi Wang, Matthias Platzer, Christoph Englert
Although the zinc finger transcription factor Wt1 has been linked to female fertility, its precise role in this process has not yet been understood. We have sequenced the WT1 exons in a panel of patients with idiopathic infertility and have identified a missense mutation in WT1 in one patient out of eight. This mutation leads to an amino acid change within the zinc finger domain and results in reduced DNA binding. We utilized Wt1+/- mice as a model to mechanistically pinpoint the consequences of reduced Wt1 levels for female fertility...
March 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28334793/compound-heterozygous-mutations-in-the-gene-pigp-are-associated-with-early-infantile-epileptic-encephalopathy
#6
Devon L Johnstone, Thi Tuyet-Mai Nguyen, Yoshiko Murakami, Kristin D Kernohan, Martine Tétreault, Claire Goldsmith, Asif Doja, Justin D Wagner, Lijia Huang, Taila Hartley, Anik St-Denis, Françoise le Deist, Jacek Majewski, Dennis E Bulman, Taroh Kinoshita, David A Dyment, Kym M Boycott, Philippe M Campeau
There are over 150 known human proteins which are tethered to the cell surface via glycosylphosphatidylinositol (GPI) anchors. These proteins play a variety of important roles in development, and particularly in neurogenesis. Not surprisingly, mutations in the GPI anchor biosynthesis and remodeling pathway cause a number of developmental disorders. This group of conditions has been termed inherited GPI deficiencies (IGDs), a subgroup of congenital disorders of glycosylation; they present with variable phenotypes, often including seizures, hypotonia and intellectual disability...
March 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28334762/missense-uros-mutations-causing-congenital-erythropoietic-porphyria-reduce-uros-homeostasis-that-can-be-rescued-by-proteasome-inhibition
#7
Jean-Marc Blouin, Ganeko Bernardo-Seisdedos, Emma Sasso, Julie Esteve, Cécile Ged, Magalie Lalanne, Arantza Sanz-Parra, Pedro Urquiza, Hubert de Verneuil, Oscar Millet, Emmanuel Richard
Congenital erythropoietic porphyria (CEP) is an inborn error of heme biosynthesis characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in deleterious porphyrin accumulation in blood cells responsible for hemolytic anemia and cutaneous photosensitivity. We analyzed here the molecular basis of UROS impairment associated with twenty nine UROS missense mutations actually described in CEP patients. Using a computational and biophysical joint approach we predicted that most disease-causing mutations would affect UROS folding and stability...
February 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28334751/atp13a2-park9-regulates-endo-lysosomal-cargo-sorting-and-proteostasis-through-a-novel-pi-3-5-p2-mediated-scaffolding-function
#8
S Demirsoy, S Martin, S Motamedi, S van Veen, T Holemans, C Van den Haute, A Jordanova, V Baekelandt, P Vangheluwe, P Agostinis
ATP13A2 (also called PARK9), is a transmembrane endo-/lysosomal-associated P5 type transport ATPase. Loss-of-function mutations in ATP13A2 result in the Kufor-Rakeb Syndrome (KRS), a form of autosomal Parkinson's disease (PD). In spite of a growing interest in ATP13A2, very little is known about its physiological role in stressed cells. Recent studies suggest that the N-terminal domain of ATP13A2 may hold key regulatory functions, but their nature remains incompletely understood. To this end, we generated a set of melanoma and neuroblastoma cell lines stably overexpressing wild-type (WT), catalytically inactive (D508N) and N-terminal mutants, or shRNA against ATP13A2...
February 22, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28334683/combined-metformin-and-insulin-treatment-reverses-metabolically-impaired-omental-adipogenesis-and-accumulation-of-4-hydroxynonenal-in-obese-diabetic-patients
#9
Morana Jaganjac, Shamma Almuraikhy, Fatima Al-Khelaifi, Mashael Al-Jaber, Moataz Bashah, Nayef A Mazloum, Kamelija Zarkovic, Neven Zarkovic, Georg Waeg, Wael Kafienah, Mohamed A Elrayess
OBJECTIVE: Obesity-associated impaired fat accumulation in the visceral adipose tissue can lead to ectopic fat deposition and increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). This study investigated whether impaired adipogenesis of omental (OM) adipose tissues and elevated 4-hydroxynonenal (4-HNE) accumulation contribute to this process, and if combined metformin and insulin treatment in T2DM patients could rescue this phenotype. METHODS: OM adipose tissues were obtained from forty clinically well characterized obese individuals during weight reduction surgery...
March 16, 2017: Redox Biology
https://www.readbyqxmd.com/read/28334226/loss-of-cannabinoid-cb-1-receptors-induces-cortical-migration-malformations-and-increases-seizure-susceptibility
#10
Javier Díaz-Alonso, Adán de Salas-Quiroga, Juan Paraíso-Luna, Daniel García-Rincón, Patricia P Garcez, Maddy Parsons, Clara Andradas, Cristina Sánchez, François Guillemot, Manuel Guzmán, Ismael Galve-Roperh
Neuronal migration is a fundamental process of brain development, and its disruption underlies devastating neurodevelopmental disorders. The transcriptional programs governing this process are relatively well characterized. However, how environmental cues instruct neuronal migration remains poorly understood. Here, we demonstrate that the cannabinoid CB 1 receptor is strictly required for appropriate pyramidal neuron migration in the developing cortex. Acute silencing of the CB 1 receptor alters neuronal morphology and impairs radial migration...
October 5, 2016: Cerebral Cortex
https://www.readbyqxmd.com/read/28334166/grk5-regulates-social-behavior-via-suppression-of-mtorc1-signaling-in-medial-prefrontal-cortex
#11
Bing Niu, Peipei Liu, Minjie Shen, Cao Liu, Li Wang, Feifei Wang, Lan Ma
Impairments in social behaviors are features of a number of psychiatric diseases associated with subtle alterations in the medial prefrontal cortex (mPFC) circuitry. G protein-coupled receptor kinase (GRK) 5 is widely expressing in the cortex, however, its role in regulation of the mPFC activity and the development of social behaviors and psychiatric disorders is unclear. Here, we found that GRK5 dificiency in mice caused social behavior impairments. Further morphological, electrophysiological, and biochemical analyses showed abnormal postsynaptic ultrastructure, impaired excitatory synaptic transmission, the increased association of raptor with mTOR, and overactivated mTORC1-S6K signaling in the mPFC of Grk5-/- mice...
February 27, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/28334111/g%C3%AE-2-regulates-the-multipolar-bipolar-transition-of-newborn-neurons-in-the-developing-neocortex
#12
Ye Guo, Xiaoxiao He, Lu Zhao, Lin Liu, Huifang Song, Xudong Wang, Jiahui Xu, Xingda Ju, Weixiang Guo, Xiaojuan Zhu
Proper neuronal migration is critical for the formation of the six-layered neocortex in the mammalian brain. However, the precise control of neuronal migration is not well understood. Heterotrimeric guanine nucleotide binding proteins (G proteins), composed of Gα and Gβγ, transduce signals from G protein-coupled receptors to downstream effectors and play crucial roles in brain development. However, the functions of individual subunits of G proteins in prenatal brain development remain unclear. Here, we report that Gβ2 is expressed in the embryonic neocortex, with abundant expression in the intermediate zone, and is significantly upregulated in differentiated neurons...
February 23, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/28333576/epstein-barr-virus-lytic-reactivation-activates-b-cells-polyclonally-and-induces-activation-induced-cytidine-deaminase-expression-a-mechanism-underlying-autoimmunity-and-its-contribution-to-graves-disease
#13
Keiko Nagata, Keisuke Kumata, Yuji Nakayama, Yukio Satoh, Hirotsugu Sugihara, Sayuri Hara, Michiko Matsushita, Satoshi Kuwamoto, Masako Kato, Ichiro Murakami, Kazuhiko Hayashi
Graves' disease is an autoimmune disease that results in and is the most common cause of hyperthyroidism, and the reactivation of persisting Epstein-Barr virus (EBV) in B lymphocytes induces the differentiation of host B cells into plasma cells. We previously reported that some EBV-infected B cells had thyrotropin receptor antibodies (TRAbs) as surface immunoglobulins (Igs), and EBV reactivation induced these TRAb+EBV+ cells to produce TRAbs. EBV reactivation induces Ig production from host B cells. The purpose of the present study was to examine total Ig productions from B cell culture fluids and to detect activation-induced cytidine deaminase (AID), nuclear factor kappa B (NF-κB), and EBV latent membrane protein (LMP) 1 in culture B cells during EBV reactivation induction and then we discussed the mechanisms of EBV reactivation-induced Ig production in relation to autoimmunity...
March 23, 2017: Viral Immunology
https://www.readbyqxmd.com/read/28333176/efficacy-of-retrobulbar-hyaluronidase-injection-for-vision-loss-resulting-from-hyaluronic-acid-filler-embolization
#14
Guo-Zhang Zhu, Zhong-Sheng Sun, Wen-Xiong Liao, Bing Cai, Chun-Lin Chen, Hui-Hui Zheng, Li Zeng, Sheng-Kang Luo
Background: Vision loss is a rare but serious complication of facial hyaluronic acid (HA) filler injection, for which there is no proven rescue therapy. Retrobulbar hyaluronidase injection is advocated by many plastic surgeons as an emergency treatment, but has not been carefully assessed for its efficacy. Objectives: To evaluate the efficacy of retrobulbar hyaluronidase injection as a rescue treatment for vision loss caused by HA filler embolization. Methods: Patients with vision loss caused by HA filler embolization were treated with retrobulbar hyaluronidase injection...
January 20, 2017: Aesthetic Surgery Journal
https://www.readbyqxmd.com/read/28333069/environmental-enrichment-in-kennelled-pit-bull-terriers-canis-lupus-familiaris
#15
Jenna Kiddie, Anna Bodymore, Alex Dittrich
Although social enrichment can be considered beneficial in helping dogs cope with the kennel environment, when taking individual needs into account, it places a large demand on the carers and may not be appropriate in under-resourced kennels. Some kennels are also designed in such a way that there is too much social interaction, in that individuals cannot choose to distance themselves from conspecifics. This study therefore aimed to assess the effects of easily accessible enrichment on the behaviour of kennelled Pit Bull Terrier type dogs rescued from a dog-fighting ring in the Philippines...
March 23, 2017: Animals: An Open Access Journal From MDPI
https://www.readbyqxmd.com/read/28332616/long-acting-protein-drugs-for-the-treatment-of-ocular-diseases
#16
Joy G Ghosh, Andrew A Nguyen, Chad E Bigelow, Stephen Poor, Yubin Qiu, Nalini Rangaswamy, Richard Ornberg, Brittany Jackson, Howard Mak, Tucker Ezell, Vania Kenanova, Elisa de la Cruz, Ana Carrion, Bijan Etemad-Gilbertson, Roxana Garcia Caro, Kan Zhu, Vinney George, Jirong Bai, Radhika Sharma-Nahar, Siyuan Shen, Yiqin Wang, Kulandayan K Subramanian, Elizabeth Fassbender, Michael Maker, Shawn Hanks, Joanna Vrouvlianis, Barrett Leehy, Debby Long, Melissa Prentiss, Viral Kansara, Bruce Jaffee, Thaddeus P Dryja, Michael Roguska
Protein drugs that neutralize vascular endothelial growth factor (VEGF), such as aflibercept or ranibizumab, rescue vision in patients with retinal vascular diseases. Nonetheless, optimal visual outcomes require intraocular injections as frequently as every month. Here we report a method to extend the intravitreal half-life of protein drugs as an alternative to either encapsulation or chemical modifications with polymers. We combine a 97-amino-acid peptide of human origin that binds hyaluronan, a major macromolecular component of the eye's vitreous, with therapeutic antibodies and proteins...
March 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/28332554/fucoidan-induces-toll-like-receptor-4-regulated-reactive-oxygen-species-and-promotes-endoplasmic-reticulum-stress-mediated-apoptosis-in-lung-cancer
#17
Hsien-Yeh Hsu, Tung-Yi Lin, Mei-Kuang Lu, Pei-Ju Leng, Shu-Ming Tsao, Yu-Chung Wu
Fucoidan, a sulfated polysaccharide extracted from brown algae, exhibits anti-cancer activity. However, the effects and mechanism of fucoidan-induced apoptosis via endoplasmic reticulum (ER) stress is unclear. In this study, we demonstrated that fucoidan prevents tumorigenesis and reduces tumor size in LLC1-xenograft male C57BL/6 mice. Fucoidan induces an ER stress response by activating the PERK-ATF4-CHOP pathway, resulting in apoptotic cell death in vitro and in vivo. Furthermore, ATF4 knockdown abolishes fucoidan-induced CHOP expression and rescues cell viability...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28332374/comparison-of-dexmedetomidine-and-fentanyl-as-an-adjuvant-to-ropivacaine-for-postoperative-epidural-analgesia-in-pediatric-orthopedic-surgery
#18
Sang Jun Park, Seokyung Shin, Shin Hyung Kim, Hyun Woo Kim, Seung Hyun Kim, Hae Yoon Do, Yong Seon Choi
PURPOSE: Opioids are commonly used as an epidural adjuvant to local anesthetics, but are associated with potentially serious side effects, such as respiratory depression. The aim of this study was to compare the efficacy and safety of dexmedetomidine with that of fentanyl as an adjuvant to epidural ropivacaine in pediatric orthopedic surgery. MATERIALS AND METHODS: This study enrolled 60 children (3-12 years old) scheduled for orthopedic surgery of the lower extremities and lumbar epidural patient-controlled analgesia (PCA)...
May 2017: Yonsei Medical Journal
https://www.readbyqxmd.com/read/28331970/disease-modeling-in-genetic-kidney-diseases-zebrafish
#19
REVIEW
Heiko Schenk, Janina Müller-Deile, Mark Kinast, Mario Schiffer
Growing numbers of translational genomics studies are based on the highly efficient and versatile zebrafish (Danio rerio) vertebrate model. The increasing types of zebrafish models have improved our understanding of inherited kidney diseases, since they not only display pathophysiological changes but also give us the opportunity to develop and test novel treatment options in a high-throughput manner. New paradigms in inherited kidney diseases have been developed on the basis of the distinct genome conservation of approximately 70 % between zebrafish and humans in terms of existing gene orthologs...
March 22, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/28331951/failure-to-rescue-the-elderly-a-superior-quality-metric-for-trauma-centers
#20
G Barmparas, E J Ley, M J Martin, A Ko, M Harada, D Weigmann, K R Catchpole, B L Gewertz
BACKGROUND: Trauma centers require reliable metrics to better compare the quality of care delivered. We compared mortality after a reported complication, termed failure to rescue (FTR), and FTR in the elderly (age >65 years) (FTRE) to determine which is a superior metric to assess quality of care delivered by trauma centers. METHODS: This was a retrospective review of the National Trauma Databank (NTDB) research data sets 2010 and 2011. Patients ≥16 years admitted to centers reporting ≥80% of AIS and/or ≥ 20% of comorbidities with > 200 subjects in the NTDB were selected...
March 22, 2017: European Journal of Trauma and Emergency Surgery: Official Publication of the European Trauma Society
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