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adeno associated virus

Dacheng Ma, Shuguang Peng, Weiren Huang, Zhiming Cai, Zhen Xie
Nuclease dead Cas9 (dCas9) has been widely used for modulating gene expression by fusing with different activation or repression domains. However, delivery of the CRISPR/Cas system fused with variant effector domains in a single adeno-associated virus (AAV) remains challenging due to the payload limit. Here, we engineered a set of downsized variants of Cas9 including Staphylococcus aureus Cas9 (SaCas9) that retained DNA binding activity by deleting conserved functional domains. We demonstrated that fusing FokI nuclease domain to the N-terminal of the minimal SaCas9 (mini-SaCas9) or to the middle of the split mini-SaCas9 can trigger efficient DNA cleavage...
March 21, 2018: ACS Synthetic Biology
Dina A Schneider, Soo-Ho Choi, Colin Agatisa-Boyle, Laurence Zhu, Jungsu Kim, Jennifer Pattison, Dorothy D Sears, Philip L S M Gordts, Longhou Fang, Yury I Miller
Apolipoprotein A-I Binding Protein (AIBP) has been shown to augment cholesterol efflux from endothelial cells and macrophages. In zebrafish and mice, AIBP-mediated regulation of cholesterol levels in the plasma membrane of endothelial cells controls angiogenesis. The goal of this work was to evaluate metabolic changes and atherosclerosis in AIBP loss-of-function and gain-of-function animal studies. Here we show that Apoa1bp-/-Ldlr-/- mice fed a high-cholesterol, high-fat diet had exacerbated weight gain, liver steatosis, glucose intolerance, hypercholesterolemia and hypertriglyceridemia, and larger atherosclerotic lesions compared to Ldlr-/- mice...
March 20, 2018: Journal of Lipid Research
Yun-Ting Su, Meng-Yang Gu, Xi Chu, Xiang Feng, Yan-Qin Yu
The GABAergic neurons in the parafacial zone (PZ) play an important role in sleep-wake regulation and have been identified as part of a sleep-promoting center in the brainstem, but the long-range connections mediating this function remain poorly characterized. Here, we performed whole-brain mapping of both the inputs and outputs of the GABAergic neurons in the PZ of the mouse brain. We used the modified rabies virus EnvA-ΔG-DsRed combined with a Cre/loxP gene-expression strategy to map the direct monosynaptic inputs to the GABAergic neurons in the PZ, and found that they receive inputs mainly from the hypothalamic area, zona incerta, and parasubthalamic nucleus in the hypothalamus; the substantia nigra, pars reticulata and deep mesencephalic nucleus in the midbrain; and the intermediate reticular nucleus and medial vestibular nucleus (parvocellular part) in the pons and medulla...
March 20, 2018: Neuroscience Bulletin
Xing He, Jun Xie, Yange Wang, Xiaobin Fan, Qin Su, Yue Sun, Nanhang Lei, Dongmei Zhang, Guangping Gao, Weiqing Pan
The type 2 immune response is the central mechanism of disease progression in schistosomiasis, but the signals that induce it after infection remain elusive. Aberrant microRNA (miRNA) expression is a hallmark of human diseases including schistosomiasis, and targeting the deregulated miRNA can mitigate disease outcomes. Here, we demonstrate that efficient and sustained elevation of miR-203-3p in liver tissues, using the highly hepatotropic recombinant adeno-associated virus serotype 8 (rAAV8), protects mice against lethal schistosome infection by alleviating hepatic fibrosis...
March 19, 2018: PLoS Pathogens
Florentina Soto, Lei Zhao, Daniel Kerschensteiner
Synaptic cell adhesion molecules (CAMs) promote synapse formation in the developing nervous system. To what extent they maintain and can restore connections in the mature nervous system is unknown. Furthermore, how synaptic CAMs affect the growth of synapse-bearing neurites is unclear. Here, we use adeno-associated viruses (AAVs) to delete, re-, and overexpress the synaptic CAM NGL2 in individual retinal horizontal cells. When we removed NGL2 from horizontal cells, their axons overgrew and formed fewer synapses, irrespective of whether Ngl2 was deleted during development or in mature circuits...
March 19, 2018: ELife
Aziza Alrafiah, Evangelia Karyka, Ian Coldicott, Kayleigh Iremonger, Katherin E Lewis, Ke Ning, Mimoun Azzouz
Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease. SMA is caused by mutations in the survival motor neuron gene ( SMN1 ), leading to reduced levels of SMN protein in the CNS. The actin-binding protein plastin 3 (PLS3) has been reported as a modifier for SMA, making it a potential therapeutic target. Here, we show reduced levels of PLS3 protein in the brain and spinal cord of a mouse model of SMA. Our study also revealed that lentiviral-mediated PLS3 expression restored axonal length in cultured Smn-deficient motor neurons...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Silvana Konermann, Peter Lotfy, Nicholas J Brideau, Jennifer Oki, Maxim N Shokhirev, Patrick D Hsu
Class 2 CRISPR-Cas systems endow microbes with diverse mechanisms for adaptive immunity. Here, we analyzed prokaryotic genome and metagenome sequences to identify an uncharacterized family of RNA-guided, RNA-targeting CRISPR systems that we classify as type VI-D. Biochemical characterization and protein engineering of seven distinct orthologs generated a ribonuclease effector derived from Ruminococcus flavefaciens XPD3002 (CasRx) with robust activity in human cells. CasRx-mediated knockdown exhibits high efficiency and specificity relative to RNA interference across diverse endogenous transcripts...
March 8, 2018: Cell
Dongxia Fu, Haibin Cui, Yunna Zhang
BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. This study aims to investigate whether chloride channel 2 (ClC-2) is involved in high fat diet (HFD)-induced NAFLD and possible molecular mechanisms. METHODS: ClC-2 expression was liver-specifically downregulated using adeno-associated virus in C57BL/6 mice treated with a chow diet or HFD for 12 weeks. Peripheral blood and liver tissues were collected for biochemical and pathological estimation respectively...
March 10, 2018: Cellular Physiology and Biochemistry
Sang-Won Min, Peter Dongmin Sohn, Yaqiao Li, Nino Devidze, Jeffrey R Johnson, Nevan J Krogan, Eliezer Masliah, Sue-Ann Mok, Jason E Gestwicki, Li Gan
Hyperacetylation of tau has been implicated in neurodegeneration and cognitive decline in tauopathy brains. The NAD-dependent class III protein deacetylase SIRT1 is one of major enzymes involved in removal of acetyl groups from tau in vitro However, whether SIRT1 regulates acetylation of pathogenic tau and ameliorates tau-mediated pathogenesis remains unclear. Here, we report deacetylating activity of SIRT1 for acetylated Lys174 (K174) of tau in tauP301S transgenic mice with a brain-specific SIRT1 deletion...
March 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Dario Presutti, Manuela Ceccarelli, Laura Micheli, Giuliana Papoff, Simonetta Santini, Simone Samperna, Cristiana Lalli, Lorena Zentilin, Giovina Ruberti, Felice Tirone
Medulloblastoma (MB), the tumor of the cerebellum, is the most frequent brain cancer in childhood and a major cause of pediatric mortality. Based on gene profiling, four MB subgroups have been identified, i.e., Wnt or Sonic Hedgehog (Shh) types, and subgroup 3 or 4. The Shh-type MB has been shown to arise from the cerebellar precursors of granule neurons (GCPs), where a hyperactivation of the Shh pathway leads to their neoplastic transformation. We have previously shown that the gene Tis21 (PC3/Btg2) inhibits the proliferation and promotes the differentiation and migration of GCPs...
2018: PloS One
Juan Xu, Haiqing Wu, Songwen Chen, Baozhen Qi, Genqing Zhou, Lidong Cai, Liqun Zhao, Yong Wei, Shaowen Liu
Atrial fibrosis serves as an important contributor to atrial fibrillation (AF). Recent data have suggested that microRNA-30c (miR-30c) is involved in fibrotic remodelling and cancer development, but the specific role of miR-30c in atrial fibrosis remains unclear. The purpose of this study was to investigate the role of miR-30c in atrial fibrosis and its underlying mechanisms through in vivo and in vitro experiments. Our results indicate that miR-30c is significantly down-regulated in the rat abdominal aortic constriction (AAC) model and in the cellular model of fibrosis induced by transforming growth factor-β1 (TGF-β1)...
March 13, 2018: Journal of Cellular and Molecular Medicine
Lei Liu, Wataru Ito, Alexei Morozov
Region and cell-type restricted expression of light-activated ion channels is the indispensable tool to study properties of synapses in specific circuits and to monitor synaptic alterations by various stimuli including neuromodulators and behaviors, both ex vivo and in vivo . These analyses require the light-activated proteins or viral vectors for their delivery that do not interfere with the phenomenon under study. Here, we report a case of such interference in which the high-level expression of channelrhodopsin-2 introduced in the somatostatin-positive GABAergic neurons of the dorsomedial prefrontal cortex by an adeno-associated virus vector weakens the presynaptic GABAb receptor-mediated suppression of GABA release...
April 2018: Neurophotonics
Dandan Huang, Baoqing Liu, Kai Huang, Kun Huang
Metabolic disorders, including obesity, non-alcoholic fatty liver disease (NAFLD), metabolic syndrome and diabetes, are complex and progressive diseases. Enoyl coenzyme A hydratase 1 (Ech1) is an enzyme that participates in mitochondrial fatty acid β-oxidation; however, little is known regarding the significance of Ech1 in the pathogenesis of metabolic disorders. Here, we report that high-fat-diet (HFD)-induced and genetic obesity could increase Ech1 expression in mouse liver. The overexpression of Ech1 using adeno-associated virus (AAV2/8) ameliorated HFD-induced liver lipid accumulation and accompanying liver injury...
March 8, 2018: Biochemical and Biophysical Research Communications
Peter J Hamilton, Carissa J Lim, Eric J Nestler, Elizabeth A Heller
Delivery of molecular tools for targeted epigenome editing in rodent brain can be facilitated by the use of viral vector-mediated gene transfer coupled with stereotaxic surgery techniques. Here, we describe the surgical protocol utilized by our group, which is optimized for herpes simplex virus (HSV)-mediated delivery into mouse brain. The protocol outlined herein could also be applied for delivery of adeno-associated viruses (AAV) or lentiviruses in both mice and rats. This method allows for efficient viral transgene expression and subsequent epigenome editing in rodent brain with excellent spatiotemporal control...
2018: Methods in Molecular Biology
Melvin Y Rincon, Filip de Vin, Sandra I Duqué, Shelly Fripont, Stephanie A Castaldo, Jessica Bouhuijzen-Wenger, Matthew G Holt
Until recently, adeno-associated virus 9 (AAV9) was considered the AAV serotype most effective in crossing the blood-brain barrier (BBB) and transducing cells of the central nervous system (CNS), following systemic injection. However, a newly engineered capsid, AAV-PHP.B, is reported to cross the BBB at even higher efficiency. We investigated how much we could boost CNS transgene expression by using AAV-PHP.B carrying a self-complementary (sc) genome. To allow comparison, 6 weeks old C57BL/6 mice received intravenous injections of scAAV2/9-GFP or scAAV2/PHP...
March 9, 2018: Gene Therapy
Tian Li, Yafeng Shen, Li Su, Xiaoyan Fan, Fangxing Lin, Xuting Ye, Dianer Ding, Ying Tang, Yang Yongji, Changhai Lei, Shi Hu
Post-ischemic heart failure is a major cause of death worldwide. Reperfusion of infarcted heart tissue after myocardial infarction has been an important medical intervention to improve outcomes. However, disturbances in Ca2+ and redox homeostasis at the cellular level caused by ischemia/reperfusion remain major clinical challenges. In this study, we investigated the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of a Type-2 ryanodine receptor (RyR2) degradation-associated gene, Presenilin 1 (PSEN1), to combat post-ischemic heart failure...
March 9, 2018: Journal of Drug Targeting
Shannan D Washington, Samantha I Edenfield, Caroline Lieux, Zachary L Watson, Sean M Taasan, Adit Dhummakupt, David C Bloom, Donna M Neumann
Herpes Simplex Virus 1 (HSV-1) establishes a lifelong latent infection in host peripheral neurons including the neurons of the trigeminal ganglia (TG). HSV-1 can reactivate from neurons to cause recurrent infection. During latency, the insulator protein CTCF occupies DNA binding sites on the HSV-1 genome and these sites have been previously characterized as functional enhancer-blocking insulators. Previously, CTCF was found to be dissociated from wild type virus post-reactivation but not in mutants that do not reactivate, indicating that CTCF eviction may also be an important component of reactivation...
March 7, 2018: Journal of Virology
Mychal S Grames, Robert D Dayton, Kasey L Jackson, Adam D Richard, Xiaohong Lu, Ronald L Klein
Recombinant adeno-associated virus (AAV) vectors are a popular genetic approach in neuroscience because they confer such efficient transgene expression in the brain and spinal cord. A number of studies have used AAV to express pathological disease-related proteins in the dopaminergic neurons of the substantia nigra in situ ( e.g., α-synuclein to model aspects of Parkinson's disease). The neuropathology and neurodegeneration of Parkinson's disease occur in a circumscribed pattern in the brain, and one of the most important goals of any gene transfer study is accurate, pinpoint targeting...
March 7, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Beiyun Wang, Jing Huang, Jingbo Li, Yuan Zhong
The molecular development of diabetic encephalopathy remains ill-defined. Recently, we reported that elimination of inflammatory macrophages alleviated the progress and severity of diabetic encephalopathy. Here, we studied the underlying mechanism. Inflammatory macrophages were isolated from the brain of the mice that received i.p. injection of streptozotocin (STZ) to develop diabetes 6 weeks before, and showed enhanced autophagy activity, seemingly through augmentation of Beclin-1 levels. However, the increases in Beclin-1 levels did not result from enhanced gene transcription, but appeared to result from suppression of a Beclin-1-inhibitory microRNA, miR-384-5p...
2018: American Journal of Translational Research
Karina E Guziewicz, Artur V Cideciyan, William A Beltran, András M Komáromy, Valerie L Dufour, Malgorzata Swider, Simone Iwabe, Alexander Sumaroka, Brian T Kendrick, Gordon Ruthel, Vince A Chiodo, Elise Héon, William W Hauswirth, Samuel G Jacobson, Gustavo D Aguirre
Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. The pathophysiology of the interaction between RPE and PR cells preceding the formation of retinal detachment remains not well-understood. Our studies of molecular pathology in the canine BEST1 disease model revealed retina-wide abnormalities at the RPE-PR interface associated with defects in the RPE microvillar ensheathment and a cone PR-associated insoluble interphotoreceptor matrix...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
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