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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
Harrison C Brown, Philip M Zakas, Stephan N George, Ernest T Parker, H Trent Spencer, Christopher B Doering
Potency is a key optimization parameter for hemophilia A gene therapy product candidates. Optimization strategies include promoter engineering to increase transcription, codon optimization of mRNA to improve translation, and amino-acid substitution to promote secretion. Herein, we describe both rational and empirical design approaches to the development of a minimally sized, highly potent AAV-fVIII vector that incorporates three unique elements: a liver-directed 146-nt transcription regulatory module, a target-cell-specific codon optimization algorithm, and a high-expression bioengineered fVIII variant...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Bertrand Jordan
Recent efforts at gene therapy for haemophilia A and B using AAV-derived vectors show durable expression of coagulation factors at significant levels, resulting in almost complete correction of the phenotype. This is the first success of gene therapy for a major hereditary disorder, and shows how continuous improvement of many components of the system has finally succeeded. Although these results must be confirmed with more patients and longer durations, they constitute a significant accomplishment for this approach after decades of frustration...
March 2018: Médecine Sciences: M/S
Shelby Meier, Assaf A Gilad, J Anthony Brandon, Chenghao Qian, Erhe Gao, Jose F Abisambra, Moriel Vandsburger
Research into gene therapy for heart failure has gained renewed interest as a result of improved safety and availability of adeno-associated viral vectors (AAV). While magnetic resonance imaging (MRI) is standard for functional assessment of gene therapy outcomes, quantitation of gene transfer/expression relies upon tissue biopsy, fluorescence or nuclear imaging. Imaging of gene expression through the use of genetically encoded chemical exchange saturation transfer (CEST)-MRI reporter genes could be combined with clinical cardiac MRI methods to comprehensively probe therapeutic gene expression and subsequent outcomes...
March 15, 2018: Scientific Reports
Maria Prendecki, Leyre Martin, Anisha Tanna, Marilina Antonelou, Charles D Pusey
OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) has been linked with thyroid disease as a result of antithyroid medications. We assessed the prevalence of thyroid disease in our patients with AAV. METHODS: Clinical records of 279 patients with AAV diagnosed between 1991 and 2014 were analyzed. RESULTS: Thyroid disease was identified in 21.5% of patients, but only 2 had previously received propylthiouracil...
March 15, 2018: Journal of Rheumatology
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
Hengchao Chen, Yazhi Xing, Li Xia, Zhengnong Chen, Shankai Yin, Jian Wang
The synapse between inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs) has been identified as a sensitive structure to noise-induced damage in the mammalian cochlea. Since this synapse provides the major information pathway from the cochlea to the auditory brain, it is important to maintain its integrity. Neurotrophin-3 (NT-3) has been known to play an important role in the development and the functional maintenance of this synapse. Application of exogenous NT-3, or overexpression of this gene in a transgenic animal model, have shown the value to protect this synapse from noise-induced damage...
March 13, 2018: Gene Therapy
Kharen L Doyle, Carla Cunha, Yvonne Hort, Ramon Tasan, Günther Sperk, John Shine, Herbert Herzog
The mouse olfactory neuroepithelium (ON) is comprised of anatomically distinct populations of cells in separate regions; apical (sustentacular and microvillar), neuronal (olfactory sensory neurons) and basal (horizontal and globose basal cells). The existence of microvillar cells (MVCs) is well documented but their nature and function remains unclear. An important transcription factor for the differentiation of MVCs is Skn-1a, with loss of function of Skn-1a in mice resulting in a complete loss of Trpm-5 expressing MVCs, while olfactory sensory neuron differentiation is normal...
March 1, 2018: Neuropeptides
Eli M Miloslavsky, John L Niles, Zachary S Wallace, Frank B Cortazar, Ana Fernandes, Karen Laliberte, John H Stone
OBJECTIVE: Therapeutic advances in ANCA-associated vasculitis (AAV) have improved patient survival, but mortality rates remain higher than the general population. Glucocorticoids contribute to AAV morbidity and mortality. We examined whether an 8-week glucocorticoid course in combination with rituximab (RTX) would induce disease remission in patients with AAV. METHODS: Patients with active AAV received an 8-week prednisone taper and RTX 375mg/m2 weekly for 4 weeks...
February 3, 2018: Seminars in Arthritis and Rheumatism
Supaporn Suwanchote, Muanpetch Rachayon, Pongsawat Rodsaward, Jongkonnee Wongpiyabovorn, Tawatchai Deekajorndech, Helen L Wright, Steven W Edwards, Michael W Beresford, Pawinee Rerknimitr, Direkrit Chiewchengchol
Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of autoantibodies that cause systemic vascular inflammation by binding to target antigens of neutrophils. These autoantibodies can be found in serum from patients with systemic small-vessel vasculitis and they are considered as a biomarker for ANCA-associated vasculitis (AAV). A conventional screening test to detect ANCA in the serum is indirect immunofluorescence study, and subsequently confirmed by enzyme-linked immunosorbent assay. A positive staining of ANCA can be classified into three main categories based on the staining patterns: cytoplasmic, perinuclear, and atypical...
March 10, 2018: Clinical Rheumatology
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
Mehmet E Yalvac, Jakkrit Amornvit, Lei Chen, Kimberly M Shontz, Sarah Lewis, Zarife Sahenk
Neurotrophin 3 (NT-3) has well-recognized effects on peripheral nerve and Schwann cells, promoting axonal regeneration and associated myelination. In this study, we assessed the effects of AAV.NT-3 gene therapy on the oxidative state of the neurogenic muscle from the TremblerJ (TrJ ) mice at 16 weeks post-gene injection and found that the muscle fiber size increase was associated with a change in the oxidative state of muscle fibers towards normalization of the fiber type ratio seen in the wild type. NT-3-induced fiber size increase was most prominent for the fast twitch glycolytic fiber population...
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
H Marco, J Draibe, J Villacorta, L F Quintana, N Martin, R Garcia-Osuna, C Cabre, M A Martín-Gómez, A Balius, A Saurina, M Picazo, I Gich-Saladich, M Navarro-Díaz, M Praga, T Cavero, J Ballarin, M M Díaz-Encarnación
The classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) remains controversial. The main objective of this study was to define the respective values of ANCA serotype-based classification, clinicopathological classification, and histopathological classification in predicting patient and renal outcomes in a Spanish cohort of patients with ANCA with specificity for myeloperoxidase, MPO-ANCA, versus ANCA with specificity for proteinase 3, PR3-ANCA. Two hundred and forty-five patients with ANCA-AAV and biopsy-proven renal involvement diagnosed between 2000 and 2104 were recruited in 12 nephrology services...
March 9, 2018: Clinical Rheumatology
Bharat Kumar, Jennifer Strouse, Melissa Swee, Petar Lenert, Manish Suneja
INTRODUCTION: Hydralazine is an antihypertensive medication that has been associated with drug-induced lupus erythematosus (DIL) as well as ANCA-associated vasculitis (AAV). Although rare, early diagnosis is critical since drug cessation is the mainstay of therapy. This retrospective study aims to characterize the clinical, laboratory, and histopathologic features of this disease. METHODS: Once approval was obtained from the Institutional Review Board at the University of Iowa, all patients carrying a diagnosis of vasculitis (ICD9 code: 447...
January 12, 2018: Seminars in Arthritis and Rheumatism
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
Jiawei Li, Qingqing Wang, Hanxiao Cai, Zili He, Haoli Wang, Jian Chen, Zengming Zheng, Jiayu Yin, Zhiyong Liao, Huazi Xu, Jian Xiao, Fanghua Gong
Fibroblast growth factor 1 (FGF1) is thought to exert protective and regenerative effects on neurons following spinal cord injury (SCI), although the mechanism of these effects is not well understood. The use of FGF1 as a therapeutic agent is limited by its lack of physicochemical stability and its limited capacity to cross the blood-spinal cord barrier. Here, we demonstrated that overexpression of FGF1 in spinal cord following SCI significantly reduced tissue loss, protected neurons in the ventricornu, ameliorated pathological morphology of the lesion, dramatically improved tissue recovery via neuroprotection, and promoted axonal regeneration and remyelination both in vivo and in vivo...
March 7, 2018: Journal of Cellular and Molecular Medicine
Ishita Bakshi, Eurwin Suryana, Lewin Small, Lake Ee Quek, Amanda Brandon, Nigel Turner, Gregory J Cooney
Skeletal muscle is a major tissue for glucose metabolism and can store glucose as glycogen, convert glucose to lactate via glycolysis and fully oxidise glucose to CO2. Muscle has a limited capacity for gluconeogenesis but can convert lactate and alanine to glycogen. Gluconeogenesis requires FBP2, a muscle specific form of fructose bisphosphatase that converts fructose-1,6-bisphosphate (F-1,6-bisP) to fructose-6-phosphate (F-6-P) opposing the activity of the ATP-consuming enzyme phosphofructokinase (PFK). In mammalian muscle, the activity of PFK is normally 100 times higher than FBP2 and therefore energy wasting cycling between PFK and FBP2 is low...
March 5, 2018: Journal of Endocrinology
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