排序方式: 共有13条查询结果,搜索用时 15 毫秒
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Paymaan Jafar-nejad Berit Powers Armand Soriano Hien Zhao Daniel A Norris John Matson Beatrice DeBrosse-Serra Jamie Watson Padmakumar Narayanan Seung
J Chun Curt Mazur Holly Kordasiewicz Eric E Swayze Frank Rigo 《Nucleic acids research》2021,49(2):657
Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available. 相似文献
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D Yu H Pendergraff J Liu HB Kordasiewicz DW Cleveland EE Swayze WF Lima ST Crooke TP Prakash DR Corey 《Cell》2012,150(5):895-908
Mutant huntingtin (HTT) protein causes Huntington disease (HD), an incurable neurological disorder. Silencing mutant HTT using nucleic acids would eliminate the root cause of HD. Developing nucleic acid drugs is challenging, and an ideal clinical approach to gene silencing would combine the simplicity of single-stranded antisense oligonucleotides with the efficiency of RNAi. Here, we describe RNAi by single-stranded siRNAs (ss-siRNAs). ss-siRNAs are potent (>100-fold more than unmodified RNA) and allele-selective (>30-fold) inhibitors of mutant HTT expression in cells derived from HD patients. Strategic placement of mismatched bases mimics micro-RNA recognition and optimizes discrimination between mutant and wild-type alleles. ss-siRNAs require Argonaute protein and function through the RNAi pathway. Intraventricular infusion of ss-siRNA produced selective silencing of the mutant HTT allele throughout the brain in a mouse HD model. These data demonstrate that chemically modified ss-siRNAs function through the RNAi pathway and provide allele-selective compounds for clinical development. 相似文献
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Large, rapidly evolving intergenic spacers in the mitochondrial DNA of the salamander family Ambystomatidae (Amphibia: Caudata) 总被引:5,自引:2,他引:3
We report the presence, in the mitochondrial DNA (mtDNA) of all of the
sexual species of the salamander family Ambystomatidae, of a shared 240- bp
intergenic spacer between tRNAThr and tRNAPro. We place the intergenic
spacer in context by presenting the sequence of 1,746 bp of mtDNA from
Ambystoma tigrinum tigrinum, describe the nucleotide composition of the
intergenic spacer in all of the species of Ambystomatidae, and compare it
to other coding and noncoding regions of Ambystoma and several other
vertebrate mtDNAs. The nucleotide substitution rate of the intergenic
spacer is approximately three times faster than the substitution rate of
the control region, as shown by comparisons among six Ambystoma
macrodactylum sequences and eight members of the Ambystoma tigrinum
complex. We also found additional inserts within the intergenic spacers of
five species that varied from 87-444 bp in length. The presence of the
intergenic spacer in all sexual species of Ambystomatidae suggests that it
arose at least 20 MYA and has been a stable component of the ambystomatid
mtDNA ever since. As such, it represents one of the few examples of a large
and persistent intergenic spacer in the mtDNA of any vertebrate clade.
相似文献
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A simple, fast and sensitive method was developed to verify the presence of
the sialyl Lewis(x) antigen on an N-linked glycoprotein. High performance
liquid chromatography-electrospray mass spectrometry (HPLC-ESI/MS) was used
to identify which of the five N-linked glycosylation sites of human plasma
alpha1-acid-glycoprotein (orosomucoid, OMD) contain the sialyl Lewis(x)
antigen. OMD was digested with proteolytic enzymes and analyzed by reversed
phase chromatography coupled with on-line ESI/MS. A tandem mass
spectrometry experiment was designed to detect the presence of the sialyl
Lewis(x) antigen based on the observation of an 803 mass to charge ratio (
m/z ) ion produced in the intermediate pressure region of the ESI
interface. The ESI/MS signal at m/z 803 is consistent with an oxonium ion
for a glycan structure containing NeuAc, Gal, GlcNAc, and Fuc. The identity
of the m/z 803 ion was confirmed by ESI/MS/MS analysis of the m/z 803
fragment ion and comparison with a sialyl Lewis(x) standard. The
stereochemistry and linkage positions were assigned using previous NMR
analysis but could be determined with permethylation analysis if necessary.
The analysis of OMD gave a pattern showing signal for the sialyl Lewis(x)
antigen coeluting with each of the five N-linked glycopeptides. The ability
to monitor sialyl Lewis(x) expression at each of the five sites is of
interest in the study of OMD's role in inflammatory diseases.
相似文献
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Survival of vegetation on soil-capped mining wastes is often impaired during dry seasons due to the limited amount of water stored in the shallow soil capping. Growth and survival of Rhodes grass (Chloris gayana) during soil drying on various layered capping sequences constructed of combinations of topsoil, subsoil, seawater-neutralised residue sand and low grade bauxite was determined in a glasshouse. The aim was to describe the survival of Rhodes grass in terms of plant and soil water relationships. The soil water characteristic curve and soil texture analysis was a good predictor of plant survival. The combination of soil with a high water holding capacity and low soil water diffusivity (e.g. subsoil with high clay contents) with soil having a high water holding capacity and high diffusivity (e.g. residue sand) gave best survival during drying down (up to 88 days without water), whereas topsoil and low grade bauxite were unsuitable (plants died within 18–39 days). Clayey soil improved plant survival by triggering a water stress response during peak evaporative water demand once residue sand dried down and its diffusivity fell below a critical range. Thus, for revegetation in seasonally dry climates, soil capping should combine one soil with low diffusivity and one or more soils with high total water holding capacity and high diffusivity. 相似文献
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Kordasiewicz HB Stanek LM Wancewicz EV Mazur C McAlonis MM Pytel KA Artates JW Weiss A Cheng SH Shihabuddin LS Hung G Bennett CF Cleveland DW 《Neuron》2012,74(6):1031-1044
The primary cause of Huntington's disease (HD) is expression of huntingtin with a polyglutamine expansion. Despite an absence of consensus on the mechanism(s) of toxicity, diminishing the synthesis of mutant huntingtin will abate toxicity if delivered to the key affected cells. With antisense oligonucleotides (ASOs) that catalyze RNase H-mediated degradation of huntingtin mRNA, we demonstrate that transient infusion into the cerebrospinal fluid of symptomatic HD mouse models not only delays disease progression but mediates a sustained reversal of disease phenotype that persists longer than the huntingtin knockdown. Reduction of wild-type huntingtin, along with mutant huntingtin, produces the same sustained disease reversal. Similar ASO infusion into nonhuman primates is shown to effectively lower huntingtin in many brain regions targeted by HD pathology. Rather than requiring continuous treatment, our findings establish a therapeutic strategy for sustained HD disease reversal produced by transient ASO-mediated diminution of huntingtin synthesis. 相似文献
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Osorio-Córdoba J LL Rodriguez-Verástegui F Díaz de León-Sánchez E Bosquez-Molina JR Verde-Calvo HB Escalona-Buendía LJ Pérez-F lores C Pelayo-Zaldívar 《Phyton》2015,84(2):375-384
Cactus stems, the cladodes of Opuntia spp. cacti, are consumed in Mexico and other countries due to their fresh and herbaceous flavor, and because of their widely known nutraceutical benefits. In order to extend the postharvest life of this vegetable, the effect of a modified atmosphere packaging (MAP) was studied in cactus stems of the cultivar Atlixco stored at 4 ± 1 °C for 20 days under three types of atmospheres: (1) air (passive atmosphere), (2) 5 kPa O2 + 4 kPa CO2, and (3) N2. During storage, the titratable acidity decreased and the color of cladodes became darker and less green; however, the 5 kPa O2 + 4 kPa CO2 atmosphere was able to preserve both quality characteristics. All modified atmospheres reduced weight loss (from 8 to <2%) and the symptoms of chilling injury, and this physiological disorder appeared earlier in controls than in MAP-stored cladodes. The levels of fermentation metabolites were low in all three evaluated atmospheres. Because of this, only cladodes stored under the N2 atmosphere were selected for furthersensory analysis of the MAP effect on odor perception as evaluated by a trained panel. Results indicated that there was no detrimental effect (atypical odors) of MAP on this sensory characteristic. We conclude that cultivar Atlixco is suitable for preservation using MAP technology. 相似文献