Alzheimer’s disease is initially thought to be caused by age-associated accumulation of plaques,in recent years,research has increasingly associated Alzheimer’s disease with lysosomal storage and metabolic disorders...Alzheimer’s disease is initially thought to be caused by age-associated accumulation of plaques,in recent years,research has increasingly associated Alzheimer’s disease with lysosomal storage and metabolic disorders,and the explanation of its pathogenesis has shifted from amyloid and tau accumulation to oxidative stress and impaired lipid and glucose metabolism aggravated by hypoxic conditions.However,the underlying mechanisms linking those cellular processes and conditions to disease progression have yet to be defined.Here,we applied a disease similarity approach to identify unknown molecular targets of Alzheimer’s disease by using transcriptomic data from congenital diseases known to increase Alzheimer’s disease risk,namely Down syndrome,Niemann-Pick type C disease,and mucopolysaccharidoses I.We uncovered common pathways,hub genes,and miRNAs across in vitro and in vivo models of these diseases as potential molecular targets for neuroprotection and amelioration of Alzheimer’s disease pathology,many of which have never been associated with Alzheimer’s disease.We then investigated common molecular alterations in brain samples from a Niemann-Pick type C disease mouse model by juxtaposing them with brain samples of both human and mouse models of Alzheimer’s disease.Detailed phenotypic,molecular,chronological,and biological aging analyses revealed that the Npc1tm(I1061T)Dso mouse model can serve as a potential short-lived in vivo model for brain aging and Alzheimer’s disease research.This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on Alzheimer’s disease research while highlighting shortcomings and lack of correlation in diverse in vitro models.Considering the lack of an Alzheimer’s disease mouse model that recapitulates the physiological hallmarks of brain aging,the short-lived Npc1^(tm(I1061T)Dso) mouse model can further accelerate the research in these fields and offer a unique model for understanding the molecular mechanisms of Alzheimer’s disease from a perspective of accelerated brain aging.展开更多
Background:The precise insertion of large DNA fragments(>3–5 kb)remains one of the key obstacles in establishment of genetically modified murine models.Methods:A 21 kb large DNA fragment containing three tandemly ...Background:The precise insertion of large DNA fragments(>3–5 kb)remains one of the key obstacles in establishment of genetically modified murine models.Methods:A 21 kb large DNA fragment containing three tandemly linked copies of the human HRAS gene was inserted into the genome of C57BL/6J mouse,generating a mouse model designated as KI.C57-ras(or named NF-h HRAS).Whole-genome sequencing and Sanger sequencing were utilized to it confirm precise insertion and copy number.The stability of transgene expression among different generations was verified from multiple aspects using by digital PCR,western blot and DNA sequencing.To assess tumor susceptibility in the mouse model,N-Nitroso-N-methylurea(MNU)was administered at a dosage of 75 mg/kg.Histopathological examinations were conducted using hematoxylin and eosin(H&E)staining.Results:The HRAS DNA fragment was inserted into mouse chromosome 15E1 site,locating between 80623202 bp and 80625020 bp.NF-h HRAS mice exhibited stable inheritance and displayed consistent phenotypes across individuals.Moreover,this mouse model exhibited a high susceptibility to carcinogens.Upon administration of MNU the earliest mortality onset was earlier than that of wild-type littermates(day 65 vs.day 78 for male and day 56 vs.day 84 for female).Notably,100%of the NF-h HRAS transgenic mice developed tumors,with approximately 84%of male NF-h HRAS mice exhibiting specific tumor types,such as squamous cell carcinoma or squamous cell papilloma,which was consistent with the previously reported carcinogenic rasH2 mouse model.The types of tumors and the target organs exhibited diversity in NFh HRAS mice,while the spontaneous tumor incidence remained low(1/50).Conclusions:The NF-h HRAS mice demonstrated excellent genetic stability,a reproducible phenotype,and high susceptibility to carcinogens,indicating their potential utility in non-clinical safety evaluations of drugs as per the S1B guidelines issued by the ICH(The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use).展开更多
The Varzaghan district at the northwestern margin of the Urumieh–Dokhtar magmatic arc, is considered a promising area for the exploration of porphyry Cu deposits in Iran. In this study we identified mono-and multi-el...The Varzaghan district at the northwestern margin of the Urumieh–Dokhtar magmatic arc, is considered a promising area for the exploration of porphyry Cu deposits in Iran. In this study we identified mono-and multi-element geochemical anomalies associated with Cu–Au–Mo–Bi mineralization in the central parts of the Varzaghan district by applying the concentration–area fractal method. After mono-element geochemical investigations, principal component analysis was applied to ten selected elements in order to acquire a multi-element geochemical signature based on the mineralization-related component. Quantitative comparisons of the obtained fractal-based populations were carried out in accordance with known Cu occurrences using Student's t-values. Then,significant mono-and multi-element geochemical layers were separately combined with related geologic and structural layers to generate prospectivity models, using the fuzzy GAMMA approach. For quantitative evaluation of the effectiveness of different geochemical signatures in final prospectivity models, a prediction-area plot was adapted. The results show that the multi-element geochemical signature of principal component one(PC1) is more effective than mono-element layers in delimiting exploration targets related to porphyry Cu deposits.展开更多
α_(s1)-Casein is a potential allergen to induce hypersensitivity in cow milk.We had identifiedα_(s1)-casein and its epitopes in previous studies.The present study aimed to evaluate the allergic mechanism ofα_(s1)-c...α_(s1)-Casein is a potential allergen to induce hypersensitivity in cow milk.We had identifiedα_(s1)-casein and its epitopes in previous studies.The present study aimed to evaluate the allergic mechanism ofα_(s1)-casein in a BALB/c mouse model.The levels of specific IgE,mast cell proteinase,histamine and cytokines in sensitized mice were determined,and the clinical and pathological observation were evaluated.Results showed that the levels of specific IgE,mast cell proteinase,histamine,IL-4,IL-5,IL-10 increased significantly with a dose-dependent trend.The local alveolar septum collapsed or thickened,and lymphatic foci were produced in the spleen and thymus,and the inflammatory cells infiltrated in small intestinal mucosa mesenchyme.In conclusion,the levels of specific IgE,mast cell proteinase,histamine,IL-4,IL-5,IL-10 and some inflammatory factors could possibly serve as allergic biomarkers ofα_(s1)-casein,however,additional studies on signal transduction and gene expression are necessary in future.展开更多
An experimental advanced superconducting tokamak （EAST） operation window with the lower hybrid current drive （LHCD） in H-mode is estimated by using a eore-SOL-divertor （C-S-D） model validated by the present EAST...An experimental advanced superconducting tokamak （EAST） operation window with the lower hybrid current drive （LHCD） in H-mode is estimated by using a eore-SOL-divertor （C-S-D） model validated by the present EAST divertor experiments. The operation window consists of four limits including two usual limits, one of which is the maximum allowable heat load onto the divertor plate, and two additional limits associated with the LHCD. The predictive EAST operation window is not qualified to fulfill its mission for high input power. To extend the operation window, gas puffing and impurity seeding are presented as two effective methods. In addition, the effect of the LHCD current on the operation window is also discussed. Our numerical analysis results provide a reference for the safe operation of EAST experiments with LHCD in future.展开更多
在对软件构架和B/S应用程序体系结构的研究过程中,提出了如何运用构架和构件组装技术,通过对可复用构件的组装进行B/S应用程序的设计和快速开发。文章拟以C2构架风格作为在整合应用系统的业务逻辑的基础设施,以B/S Model 2作为表示层的...在对软件构架和B/S应用程序体系结构的研究过程中,提出了如何运用构架和构件组装技术,通过对可复用构件的组装进行B/S应用程序的设计和快速开发。文章拟以C2构架风格作为在整合应用系统的业务逻辑的基础设施,以B/S Model 2作为表示层的框架原型,提出一种基于构架和构件的B/S结构模型,称为CB Model。并且介绍在研究过程中开发的组装支持工具BSAppBuilder。展开更多
基金supported by the NIA/NIH(1K01AG060040).Studies performed by JN were funded by the NICHD/NIH(5R00HD096117)Microscopy Core Facility supported,in part,with funding from NIH-NCI Cancer Center Support Grant P30 CA016059.
文摘Alzheimer’s disease is initially thought to be caused by age-associated accumulation of plaques,in recent years,research has increasingly associated Alzheimer’s disease with lysosomal storage and metabolic disorders,and the explanation of its pathogenesis has shifted from amyloid and tau accumulation to oxidative stress and impaired lipid and glucose metabolism aggravated by hypoxic conditions.However,the underlying mechanisms linking those cellular processes and conditions to disease progression have yet to be defined.Here,we applied a disease similarity approach to identify unknown molecular targets of Alzheimer’s disease by using transcriptomic data from congenital diseases known to increase Alzheimer’s disease risk,namely Down syndrome,Niemann-Pick type C disease,and mucopolysaccharidoses I.We uncovered common pathways,hub genes,and miRNAs across in vitro and in vivo models of these diseases as potential molecular targets for neuroprotection and amelioration of Alzheimer’s disease pathology,many of which have never been associated with Alzheimer’s disease.We then investigated common molecular alterations in brain samples from a Niemann-Pick type C disease mouse model by juxtaposing them with brain samples of both human and mouse models of Alzheimer’s disease.Detailed phenotypic,molecular,chronological,and biological aging analyses revealed that the Npc1tm(I1061T)Dso mouse model can serve as a potential short-lived in vivo model for brain aging and Alzheimer’s disease research.This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on Alzheimer’s disease research while highlighting shortcomings and lack of correlation in diverse in vitro models.Considering the lack of an Alzheimer’s disease mouse model that recapitulates the physiological hallmarks of brain aging,the short-lived Npc1^(tm(I1061T)Dso) mouse model can further accelerate the research in these fields and offer a unique model for understanding the molecular mechanisms of Alzheimer’s disease from a perspective of accelerated brain aging.
基金National Key R&D Program of China,Grant/Award Number:2023YFC3402000National Institutes for Food and Drug Control,State Key Laboratory of Drug Regulatory Science,Grant/Award Number:2023SKLDRS0124。
文摘Background:The precise insertion of large DNA fragments(>3–5 kb)remains one of the key obstacles in establishment of genetically modified murine models.Methods:A 21 kb large DNA fragment containing three tandemly linked copies of the human HRAS gene was inserted into the genome of C57BL/6J mouse,generating a mouse model designated as KI.C57-ras(or named NF-h HRAS).Whole-genome sequencing and Sanger sequencing were utilized to it confirm precise insertion and copy number.The stability of transgene expression among different generations was verified from multiple aspects using by digital PCR,western blot and DNA sequencing.To assess tumor susceptibility in the mouse model,N-Nitroso-N-methylurea(MNU)was administered at a dosage of 75 mg/kg.Histopathological examinations were conducted using hematoxylin and eosin(H&E)staining.Results:The HRAS DNA fragment was inserted into mouse chromosome 15E1 site,locating between 80623202 bp and 80625020 bp.NF-h HRAS mice exhibited stable inheritance and displayed consistent phenotypes across individuals.Moreover,this mouse model exhibited a high susceptibility to carcinogens.Upon administration of MNU the earliest mortality onset was earlier than that of wild-type littermates(day 65 vs.day 78 for male and day 56 vs.day 84 for female).Notably,100%of the NF-h HRAS transgenic mice developed tumors,with approximately 84%of male NF-h HRAS mice exhibiting specific tumor types,such as squamous cell carcinoma or squamous cell papilloma,which was consistent with the previously reported carcinogenic rasH2 mouse model.The types of tumors and the target organs exhibited diversity in NFh HRAS mice,while the spontaneous tumor incidence remained low(1/50).Conclusions:The NF-h HRAS mice demonstrated excellent genetic stability,a reproducible phenotype,and high susceptibility to carcinogens,indicating their potential utility in non-clinical safety evaluations of drugs as per the S1B guidelines issued by the ICH(The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use).
文摘The Varzaghan district at the northwestern margin of the Urumieh–Dokhtar magmatic arc, is considered a promising area for the exploration of porphyry Cu deposits in Iran. In this study we identified mono-and multi-element geochemical anomalies associated with Cu–Au–Mo–Bi mineralization in the central parts of the Varzaghan district by applying the concentration–area fractal method. After mono-element geochemical investigations, principal component analysis was applied to ten selected elements in order to acquire a multi-element geochemical signature based on the mineralization-related component. Quantitative comparisons of the obtained fractal-based populations were carried out in accordance with known Cu occurrences using Student's t-values. Then,significant mono-and multi-element geochemical layers were separately combined with related geologic and structural layers to generate prospectivity models, using the fuzzy GAMMA approach. For quantitative evaluation of the effectiveness of different geochemical signatures in final prospectivity models, a prediction-area plot was adapted. The results show that the multi-element geochemical signature of principal component one(PC1) is more effective than mono-element layers in delimiting exploration targets related to porphyry Cu deposits.
基金supported by National Science and Technology Project in Rural Areas(China,2018YFC1604205)the National Natural Science Foundation of China(Beijing,China31872886)。
文摘α_(s1)-Casein is a potential allergen to induce hypersensitivity in cow milk.We had identifiedα_(s1)-casein and its epitopes in previous studies.The present study aimed to evaluate the allergic mechanism ofα_(s1)-casein in a BALB/c mouse model.The levels of specific IgE,mast cell proteinase,histamine and cytokines in sensitized mice were determined,and the clinical and pathological observation were evaluated.Results showed that the levels of specific IgE,mast cell proteinase,histamine,IL-4,IL-5,IL-10 increased significantly with a dose-dependent trend.The local alveolar septum collapsed or thickened,and lymphatic foci were produced in the spleen and thymus,and the inflammatory cells infiltrated in small intestinal mucosa mesenchyme.In conclusion,the levels of specific IgE,mast cell proteinase,histamine,IL-4,IL-5,IL-10 and some inflammatory factors could possibly serve as allergic biomarkers ofα_(s1)-casein,however,additional studies on signal transduction and gene expression are necessary in future.
基金supported by National Natural Science Foundation of China(Nos.11105176 and 11105224)
文摘An experimental advanced superconducting tokamak （EAST） operation window with the lower hybrid current drive （LHCD） in H-mode is estimated by using a eore-SOL-divertor （C-S-D） model validated by the present EAST divertor experiments. The operation window consists of four limits including two usual limits, one of which is the maximum allowable heat load onto the divertor plate, and two additional limits associated with the LHCD. The predictive EAST operation window is not qualified to fulfill its mission for high input power. To extend the operation window, gas puffing and impurity seeding are presented as two effective methods. In addition, the effect of the LHCD current on the operation window is also discussed. Our numerical analysis results provide a reference for the safe operation of EAST experiments with LHCD in future.
文摘在对软件构架和B/S应用程序体系结构的研究过程中,提出了如何运用构架和构件组装技术,通过对可复用构件的组装进行B/S应用程序的设计和快速开发。文章拟以C2构架风格作为在整合应用系统的业务逻辑的基础设施,以B/S Model 2作为表示层的框架原型,提出一种基于构架和构件的B/S结构模型,称为CB Model。并且介绍在研究过程中开发的组装支持工具BSAppBuilder。
