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Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

Neural Regeneration research 2025年第1期20卷 174-180页

作者： Yinglong Miao Michael S.Wolfe Computational Medicine Program and Department of Pharmacology University of North Carolina–Chapel HillChapel HillNCUSA Department of Medicinal Chemistry University of KansasLawrenceKSUSA

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

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Evaluation of genotoxicity of Trois through Ames and in vitro chromosomal aberration tests

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Asian Pacific Journal of Tropical Biomedicine 2013年第11期3卷 902-906页

作者： Manu Chaudhary Anurag Payasi Venus Medicine research Centre Hill Top Industrial Estate

Objective:To investigate the mutagenic potential of Trois using the bacterial reverse mutation assay(Ames test)and in vitro chromosomal aberration ***:The ability of Trois to induce reverse mutations was evaluated in Salmonella lyphimurium(TA 98,TA100,TAI535 and TA1537)and Escherichia coli(WP2 uvrA)with and without metabolic activation system(S9 mix)at the dose range of 313 to 5000μg/*** aberrations were evaluated in Chinese hamster lung(CHL)cell line at the dose levels of 15,7.5,3.7,1.9 and 0.9 mg/mL in the absence and presence of S9 ***:There were no increases in the number of revertant colonies at any concentrations of Trois used in the study with and without S9 mix in all tester *** did not produce any structural aberration in CHL cells in the presence or absence of S9 ***:Results of this study suggest that Trois is non-mutagenic.

关键词： Trois Ames test Chromosomal aberration test

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Software-defined process-near-memory architecture using 3D hybrid bonding integration

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Science China(Information Sciences) 2025年第1期68卷 366-378页

作者： Anlin XU Chenchen DENG Jianfeng ZHU Yao WANG Shaojun WEI Leibo LIU School of Integrated Circuits Tsinghua University Beijing Institution of Tracking and Communication Technology Beijing National research Center for Information Science and Technology Tsinghua University

With the unprecedented explosive growing amount of global data, the development of computing chips, which encounter bottlenecks such as power wall and memory wall, cannot satisfy the demanding requirement. This work proposes a software-defined process-near-memory(SDPNM) computing architecture implemented using 3D hybrid bonding *** software-defined chip architecture, featuring spatial computations and dynamic reconfiguration, innovates in a top-down manner to achieve high energy efficiency while maintaining flexibility after fabrication. The process-near-memory integration further advances the SDNPM chip in a bottom-up way to reduce the energy consumption of data movement while improving the bandwidth. Utilizing a relatively mature fabrication and bonding process can result in feasible solutions for both data-intensive and compute-intensive applications including digital signal processing and artificial intelligence. The logic die is fabricated in the SMIC 40 nm process and the DRAM die is fabricated in the PSMC 25 nm process. The hybrid bonding is implemented by XMC. The experimental results show that the energy efficiency of the proposed SDPNM chip is 33.1× better than the state-of-the-art FPGA ranging from 8.2× to 104.1×.

关键词： software-defined chips process near memory energy efficiency dynamic reconfiguration domain specific

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A peptide containing the receptor binding site of insulin-like growth factor binding protein-2 enhances bone mass in ovariectomized rats

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Bone research 2018年第3期6卷 280-288页

作者： Gang Xi Christine Wai Clifford J.Rosen David R.Clemmons Department of Medicine University of North Carolina at Chapel HillChapel HillUSA Maine Medical Center research Institute ScarboroughUSA

Male Igfbp2-/-mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in these animals. Female Igfbp2-/-mice do not have this phenotype but following ovariectomy(OVX) lose more bone than OVX wild-type mice. This suggests that in the absence of estrogen, IGFBP-2 is required to maintain bone mass. Therefore these studies were undertaken to determine if this peptide could stimulate bone acquisition in OVX rats. OVX rats were divided into seven treatment groups: sham animals, OVX animals, OVX animals receiving a control scrambled peptide, or one of three doses of the active peptide termed PEG-HBD-1(0.7, 2,and 6 mg·kg^(-1)) and an OVX group receiving parathyroid hormone(PTH)(50 μg·kg-1 per day). The peptides were administered for8 weeks. DXA revealed a significant reduction in femoral and tibial areal bone mineral density(aBMD) after OVX, whereas treatment with the high-dose peptide increased aBMD by 6.2% ± 2.4%(P < 0.01) compared to control peptide; similar to the increase noted with PTH(5.6% ± 3.0%, P < 0.01). Similar increases were noted with two lower doses of the peptide(3.8% ± 1.5%, P < 0.05 for low dose; 3.1% ± 1.6%, P = 0.07 for middle dose). Micro CT showed that the OVX control peptide animals had reductions of 41% and64% in femoral trabecular BV/TV and trabecular number, respectively. All three doses of the peptide increased bone volume/total volume(BV/TV) significantly, while the low and middle doses increased trabecular number. Cortical BV/TV and thickness at the midshaft increased significantly with each dose of peptide(18.9% ± 9.8%, P < 0.01 and 14.2% ± 7.9%, P < 0.01 for low dose; 23.7% ±10.7%, P < 0.001 and 15.8% ± 6.1%, P < 0.001 for middle dose; 19.0% ± 6.9%, P < 0.01 and 16.2% ± 9.7%, P < 0.001 for high dose)and with PTH(25.8% ± 9.2%, P < 0.001 and 19.4% ± 8.8%, P < 0.001). Histomorphometry showed that the low

关键词： insulin-like growth factor binding protein-2 OVX wild-type mice

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Experimental investigation on the movement mechanism of top coal in steeply inclined ultra-thick coal seams

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Acta Mechanica Sinica 2021年第4期37卷 631-648,I0003页

作者： Jiachen Wang Fei Liu Zhaohui Wang School of Energy and Mining Engineering China University of Mining&TechnologyBeijing 100083China Coal Industry Engineering research Center of top-Coal Caving Mining Beijing 100083China

The pre-blasting zones have a significant influence on the coal broken and the recovery rate of the top coal caving *** paper explores the coal movement mechanism in the top coal with pre-blasting zones based on the geological parameters of Jiangcang No.1 mine in the western of *** steeply inclined ultra-thick coal seam was mined by using the sublevel top-coal caving mining *** geo-image process system(GIPS)software was used to track the mark points on the coal and *** support was used to record the load on the top of the support during the caving mining *** results show that the horizontal coal is moved to the shield window and the vertical coal is moved downward in the first level,while that in the second level shows consistency for the integrity of the *** vertical displacements of the corresponding points in the first level are lairger than that in the second ***,the load on the top of the support in the first level is smaller than that in the second *** indicated that the pre-blasting zones will give a more loosen top-coal and a small degree of difficulty in the top coal caving.

关键词： Sublevel top coal caving Pre-blasting Physical modeling Movement mechanism

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Genetic Diversity Analysis of Rice Germplasm in Tripura State of Northeast India Using Drought and Blast Linked Markers

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Rice science 2017年第1期24卷 10-20页

作者： Alpana ANUPAM Jahangir IMAM Syed Mohammad QUATADAH Anantha SIDDAIAH Shankar Prasad DAS Mukund VARIAR Nimai Prasad MANDAL Central Rainfed Upland Rice research Station ICAR research Complex for North Eastern hill Region Tripura Centre

We genotyped 74 rice germplasms including Tripura＇s local landraces, improved varieties, cultivars and breeding lines and other rice varieties using molecular markers for genetic diversity, drought QTLs, and blast resistance genes. The number of alleles per locus ranged from 2 to 5 with an average of 2.9. The polymorphic information content value per locus ranged from 0.059（RM537） to 0.755（RM252） with an average of 0.475. Cluster analysis based on 30 simple sequence repeat markers revealed 5 clusters and also indicated the presence of variability within the rice accessions. The drought QTL q DTY2.1 was found in 56.0% of germplasms and q DTY1.1 was detected in only 6.8% of the germplasms. Out of seven rice blast resistance genes screened, only two rice varieties, RCPL-1-82 and Buh Vubuk（Lubuk）, were positive for four blast resistance genes while only Releng possessed two blast resistance genes. Among 74 rice germplasms, only three accessions, Releng, RCPL1-82 and Buh Vubuk（Lubuk）, possessed both drought-related QTLs and blast resistance genes. Overall, the 74 indigenous rice genotypes showed low level of genetic diversity, which is in contrast to high level of genetic diversity among rice varieties in northeast India, where highlights the good farming practice, conservation of germplasms and the limitation of molecular markers employed in this study. The presence of both drought related QTLs and blast resistance genes in some of the germplasms can be useful in future breeding programmes.

关键词： drought blast alleles breeding ranged polymorphic Northeast screened upland germplasm

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Barnyard millet global core collection evaluation in the submontane Himalayan region of India using multivariate analysis

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The Crop Journal 2015年第6期3卷 517-525页

作者： Salej Sood Rajesh K.Khulbe Arun Kumar R. Pawan K. Agrawal Hari D.Upadhyaya Indian Council of Agricultural research-Vivekananda Institute of hill Agriculture International Crop research Institute for the Semi-Arid Tropics (ICRISAT)

Barnyard millet(Echinochloa spp.) is one of the most underresearched crops with respect to characterization of genetic resources and genetic enhancement. A total of 95 germplasm lines representing global collection were evaluated in two rainy seasons at Almora,Uttarakhand, India for qualitative and quantitative traits and the data were subjected to multivariate analysis. High variation was observed for days to maturity, five-ear grain weight, and yield components. The first three principal component axes explained 73% of the total multivariate variation. Three major groups were detected by projection of the accessions on the first two principal components. The separation of accessions was based mainly on trait morphology. Almost all Indian and origin-unknown accessions grouped together to form an Echinochloa frumentacea group. Japanese accessions grouped together except for a few outliers to form an Echinochloa esculenta group. The third group contained accessions from Russia, Japan, Cameroon, and Egypt. They formed a separate group on the scatterplot and represented accessions with lower values for all traits except basal tiller number. The interrelationships between the traits indicated that accessions with tall plants, long and broad leaves, longer inflorescences, and greater numbers of racemes should be given priority as donors or parents in varietal development initiatives. Cluster analysis identified two main clusters based on agro-morphological characters.

关键词： Agro-morphological variation Barnyard millet core germplasm Cluster analysis Echinochloa spp Principal component analysis

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SAR of tricyclic sulfones as γ-secretase inhibitors

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Science China Chemistry 2011年第11期54卷 1688-1701页

作者： COLE David ASBEROM Ted BARA Tom BENNETT Chad BURNETT Duane A. CLADER John DOMALSKI Martin GREENLEE William J. HYDE Lynn JOSIEN Hubert McBRIAR Mark McKITTRICK Brian PISSARNITSKI Dmitri RAJAGOPALAN Murali SASIKUMAR Thavalakulamgara Merck research Laboratories 2015 Galloping Hill RoadKenilworth New Jersey 07033 USA

Novel tricyclic sulfones as γ-secretase inhibitors have been reported by this laboratory for the treatment of Alzheimer's disease. Compounds in this series have comparable or better in vitro activities and in vivo efficacies than sulfonamide analogues re- ported previously by this laboratory. Based on the previously reported tricyclic sulfone scaffold, additional SAR studies of C ring were carried out. Various C-ring structures including cyclohexane, pyran, and piperidine were tolerated. Additionally, the 7- and 8- positions of the C-ring were identified as the best sites to introduce substituent for modulating the pharmacokinetic properties of compounds from this series.

关键词： tricyclic sulfones T-secretase Alzheimer's disease inhibitors

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COMPrompter: reconceptualized segment anything model with multiprompt network for camouflaged object detection

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Science China(Information Sciences) 2025年第1期68卷 189-203页

作者： Xiaoqin ZHANG Zhenni YU Li ZHAO Deng-Ping FAN Guobao XIAO Zhejiang Province Key Laboratory of Intelligent Informatics for Safety and Emergency Wenzhou University Nankai International Advanced research Institute (SHENZHEN FUTIAN) College of Computer Science Nankai University School of Computer Science and Technology Tongji University

We rethink the segment anything model(SAM) and propose a novel multiprompt network called COMPrompter for camouflaged object detection(COD). SAM has zero-shot generalization ability beyond other models and can provide an ideal framework for COD. Our network aims to enhance the single prompt strategy in SAM to a multiprompt strategy. To achieve this, we propose an edge gradient extraction module, which generates a mask containing gradient information regarding the boundaries of camouflaged objects. This gradient mask is then used as a novel boundary prompt, enhancing the segmentation process. Thereafter, we design a box-boundary mutual guidance module, which fosters more precise and comprehensive feature extraction via mutual guidance between a boundary prompt and a box prompt. This collaboration enhances the model's ability to accurately detect camouflaged objects. Moreover, we employ the discrete wavelet transform to extract high-frequency features from image embeddings. The high-frequency features serve as a supplementary component to the multiprompt ***, our COMPrompter guides the network to achieve enhanced segmentation results, thereby advancing the development of SAM in terms of COD. Experimental results across COD benchmarks demonstrate that COMPrompter achieves a cutting-edge performance, surpassing the current leading model by an average positive metric of 2.2% in COD10K. In the specific application of COD, the experimental results in polyp segmentation show that our model is superior to top-tier methods as well. The code will be made available at https://***/guobaoxiao/COMPrompter.

关键词： segment anything model camouflaged object detection boundary prompt

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A fiducial approach to the nonparametric deconvolution problem:The discrete case

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Science China Mathematics 2024年第11期67卷 2653-2670页

作者： Yifan Cui Jan Hannig Center for Data Science Zhejiang UniversityHangzhou 310058China Department of Statistics and Operations research University of North Carolina at Chapel HillChapel HillNC 27599USA

Fiducial inference is applied to nonparametric g-modeling in the discrete *** propose a computationally efficient algorithm to sample from the fiducial distribution and use the generated samples to construct point estimates and confidence *** study the theoretical properties of the fiducial distribution and perform extensive simulations in various *** proposed approach gives rise to good statistical performance in terms of the mean squared error of point estimators and coverage of confidence ***,we apply the proposed fiducial method to estimate the probability of each satellite site being malignant using gastric adenocarcinoma data with 844 patients.

关键词： confidence intervals empirical Bayes fiducial inference nonparametric deconvolution

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