Allele-Specific Silencing of Dominant Disease Genes Miller, Victor M.; Xia, Haibin; Marrs, Ginger L. ...
Proceedings of the National Academy of Sciences - PNAS,
06/2003, Volume:
100, Issue:
12
Journal Article
Peer reviewed
Open access
Small interfering RNA (siRNA) holds therapeutic promise for silencing dominantly acting disease genes, particularly if mutant alleles can be targeted selectively. In mammalian cell models we ...demonstrate that allele-specific silencing of disease genes with siRNA can be achieved by targeting either a linked single-nucleotide polymorphism (SNP) or the disease mutation directly. For a polyglutamine neurodegenerative disorder in which we first determined that selective targeting of the disease-causing CAG repeat is not possible, we took advantage of an associated SNP to generate siRNA that exclusively silenced the mutant Machado-Joseph disease/spinocerebellar ataxia type 3 allele while sparing expression of the WT allele. Allele-specific suppression was accomplished with all three approaches currently used to deliver siRNA: in vitro-synthesized duplexes as well as plasmid and viral expression of short hairpin RNA. We further optimized siRNA to specifically target a missense Tau mutation, V337M, that causes frontotemporal dementia. These studies establish that siRNA can be engineered to silence disease genes differing by a single nucleotide and highlight a key role for SNPs in extending the utility of siRNA in dominantly inherited disorders.
Dual EGFR/erbB2 inhibition is an attractive therapeutic strategy for epithelial tumors, as ligand-induced erbB2/EGFR heterodimerization triggers potent proliferative and survival signals. Here we ...show that a small molecule, GW572016, potently inhibits both EGFR and erbB2 tyrosine kinases leading to growth arrest and/or apoptosis in EGFR and erbB2-dependent tumor cell lines. GW572016 markedly reduced tyrosine phosphorylation of EGFR and erbB2, and inhibited activation of Erk1/2 and AKT, downstream effectors of proliferation and cell survival, respectively. Complete inhibition of activated AKT in erbB2 overexpressing cells correlated with a 23-fold increase in apoptosis compared with vehicle controls. EGF, often elevated in cancer patients, did not reverse the inhibitory effects of GW572016. These observations were reproduced in vivo, where GW572016 treatment inhibited activation of EGFR, erbB2, Erk1/2 and AKT in human tumor xenografts. Erk1/2 and AKT represent potential biomarkers to assess the clinical activity of GW572016. Inhibition of activated AKT in EGFR or erbB2-dependent tumors by GW572016 may lead to tumor regressions when used as a monotherapy, or may enhance the anti-tumor activity of chemotherapeutics, since constitutive activation of AKT has been linked to chemo-resistance.
Alloys exhibiting table-like magnetic entropy change (−ΔSm) profiles are regarded as ideal magnetic refrigerants for the Ericsson magnetic refrigeration cycle. In this work, we fabricated two ...Gd-Co-based amorphous hybrids using various combinations of Gd50Co50, Gd50Co48Fe2, Gd50Co48Mn2 and Gd50Co45Mn5 amorphous ribbons with Curie temperatures ranging from 245 K to 278 K, and obtained table-like −ΔSm profiles across the ice point of water within different temperature ranges. The maximum −ΔSm and refrigeration capacity of the amorphous hybrids were higher than those of other amorphous alloys or composites with flattened −ΔSm values near room temperature, indicating that amorphous hybrids are good candidates for magnetic refrigerants in house-hold magnetic refrigerators.
•We fabricated amorphous hybrids with table-like -ΔSm near room temperature.•The amorphous hybrids exhibit rather high maximum -ΔSm and refrigeration capacity.•The amorphous hybrids are good candidates for house-hold magnetic refrigerants.
The blast fungus Magnaporthe oryzae gains entry to its host plant by means of a specialized pressure-generating infection cell called an appressorium, which physically ruptures the leaf cuticle
. ...Turgor is applied as an enormous invasive force by septin-mediated reorganization of the cytoskeleton and actin-dependent protrusion of a rigid penetration hypha
. However, the molecular mechanisms that regulate the generation of turgor pressure during appressorium-mediated infection of plants remain poorly understood. Here we show that a turgor-sensing histidine-aspartate kinase, Sln1, enables the appressorium to sense when a critical turgor threshold has been reached and thereby facilitates host penetration. We found that the Sln1 sensor localizes to the appressorium pore in a pressure-dependent manner, which is consistent with the predictions of a mathematical model for plant infection. A Δsln1 mutant generates excess intracellular appressorium turgor, produces hyper-melanized non-functional appressoria and does not organize the septins and polarity determinants that are required for leaf infection. Sln1 acts in parallel with the protein kinase C cell-integrity pathway as a regulator of cAMP-dependent signalling by protein kinase A. Pkc1 phosphorylates the NADPH oxidase regulator NoxR and, collectively, these signalling pathways modulate appressorium turgor and trigger the generation of invasive force to cause blast disease.
We designed a novel haploidentical hematopoietic stem cell transplantation (haplo-HSCT) system using idarubicin (IDA) intensified conditioning regimens and combination of antithymocyte globulin and ...basiliximab for GvHD prophylaxis. The outcomes of 110 high-risk acute leukemia patients undergoing haplo-HSCT were compared with 69 contemporaneous high-risk patients receiving HLA-matched sibling transplantation using uniform IDA-intensified regimens. The relapse incidence of haplo-HSCT was 23.4%, and 3-year overall survival (OS) and disease-free survival (DFS) achieved 62.9%, 59.1%, respectively. The cumulative incidences of II-IV and III-IV aGvHD were 28.6 and 14.3%, while limited and extensive cGvHD were 19.4, 13.8%. All these results were equivalent to those of concurrent identical sibling transplantation. Three-year OS and DFS for patients in advance stage reached 48.5, 47.3%. Furthermore, the relapse, 3-year OS of positive minimal residual disease (MRD) patients did not differ from negative MRD patients (18.9% vs 11.5%, 63.6% vs 69.6%), indicating our intensified haplo-HSCT technique could circumvent the dismal prognosis of MRD. These data provide reinforcing evidence that our haplo-HSCT system could dramatically improve the survival of high-risk acute leukemia with low relapse and acceptable transplantation-related mortality, and might be a promising therapeutic option for high-risk patients.
The objective of this study was to understand the drinking water quality state in the Inner Mongolia Autonomous Region from 2014 to 2018 and to derive information that will provide a basis for ...improving the drinking water quality in the region. Monitoring data for drinking water from the Inner Mongolia Autonomous Region for 2014 to 2018 were analyzed and the results were compared with GB 5749-2006, the Standard Test Method for Drinking Water, and GB 5749-2006, the Drinking Water Quality Standards. Data for a total of 30,613 water samples were assessed. Of the data for the microbiological index, sensory trait and general chemical index, and toxicological index, 89, 80, and 69% were qualified, respectively. For the toxicological index, the fluoride and nitrate nitrogen data were the least compliant. The water quality in all the cities was generally very suitable for drinking. However, there were marked differences in the qualified rates of drinking water in different areas and the qualified rates of the data for the three indexes were lower in rural areas than in urban areas. Given the varied issues with the drinking water quality, the relevant departments of League cities should implement appropriate and effective treatment measures to improve the drinking water quality and ensure it is safe for residents.
Lithium-selenium (Li–Se) and sodium-selenium (Na–Se) batteries have recently attracted increasing interest because of their high volumetric specific capacity. However, the practical application of ...the Se cathode is still hindered by volumetric expansion, slow redox reaction kinetics, low area Se-loading, and shuttle effect in ether electrolyte. In this work, we present hierarchically micro/meso/macroporous nitrogen-doped Murray carbon fibers (MCFs) inspired by generalized Murray's law with the engineered quasi-optimal Se/C interface as a free-standing high–Se-loading host for high-performance Li/Na–Se batteries at elevated temperature. Such a hierarchically porous framework not only provides adequate space to accommodate Se for reaction with structural stability but also ensures the rapid electron and ion transport to improve the redox reaction kinetics and to form uniform catholyte electrolyte interphase. At a high area Se-loading of 4 mg/cm2, the Se@MCF cathode maintains a discharge capacity of 425 mAh/g at 5 C after 200 cycles for the Li–Se battery and a discharge capacity of 490 mAh/g at 0.5 C after 200 cycles for the Na–Se battery. Even at high temperatures of 50 and 80 °C, the Se@MCF cathodes demonstrate stable cycling performance and decreased polarization. Our work here not only presents significant progress in the development of the high–Se-loading cathode for ultra-stable and high-capacity Li/Na–Se batteries but also sheds some light on the preparation of advanced free-standing electrodes for other energy storage systems.
Generalized Murray's law–inspired hierarchically micro/meso/macroporous nitrogen-doped Murray carbon fibers (MCFs) with the engineered quasi-optimal Se/C interface as the free-standing high–Se-loading host for high-performance Li/Na–Se batteries at elevated temperature. Display omitted
•Generalized Murray's law inspired carbon fibers (MCFs) with the engineered quasi-optimal Se/C interface are designed.•The quasi-optimal Se/C interface largely enhances the affinity of the carbon matrix with active materials and electrolytes.•The N-doped MCFs effectively anchor the short-chain selenium and Li2Se.•The N-doped MCFs ensure the rapid electron and Li/Na ion transport.•The interwoven porous framework effectively improves the structural stability.
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