Fault diagnosis on large-scale and complex networks is a challenging task, as it requires efficient and accurate inference from huge data volumes. Active probing is a cost-efficient tool for fault diagnosis. However a...Fault diagnosis on large-scale and complex networks is a challenging task, as it requires efficient and accurate inference from huge data volumes. Active probing is a cost-efficient tool for fault diagnosis. However almost all existing probing-based techniques face the following problems: 1) performing inaccurately in noisy networks; 2) generating additional traffic to the network; 3) high cost computation. To address these problems, we propose an efficient probe selection algorithm for fault diagnosis based on Bayesian network. Moreover, two approaches which could significantly reduce the computational complexity of the probe selection process are provided. Finally, we implement the new proposed algorithm and a former representative probing-based algorithm (BPEA algorithm) on different settings of networks. The results show that, the new algorithm performs much faster than BPEA does without sacrificing the diagnostic quality, especially in large, noisy and multiple-fault networks.展开更多
In Internet service fault management based on active probing, uncertainty and noises will affect service fault management. In order to reduce the impact, challenges of Internet service fault management are analyzed in...In Internet service fault management based on active probing, uncertainty and noises will affect service fault management. In order to reduce the impact, challenges of Internet service fault management are analyzed in this paper. Bipartite Bayesian network is chosen to model the dependency relationship between faults and probes, binary symmetric channel is chosen to model noises, and a service fault management approach using active probing is proposed for such an environment. This approach is composed of two phases： fault detection and fault diagnosis. In first phase, we propose a greedy approximation probe selection algorithm （GAPSA）, which selects a minimal set of probes while remaining a high probability of fault detection. In second phase, we propose a fault diagnosis probe selection algorithm （FDPSA）, which selects probes to obtain more system information based on the symptoms observed in previous phase. To deal with dynamic fault set caused by fault recovery mechanism, we propose a hypothesis inference algorithm based on fault persistent time statistic （FPTS）. Simulation results prove the validity and efficiency of our approach.展开更多
To relieve traliic overhead induced by active probing based methods, a new fault detection method, whose key is to divide the detection process into multiple stages, is proposed in this paper. During each stage, only ...To relieve traliic overhead induced by active probing based methods, a new fault detection method, whose key is to divide the detection process into multiple stages, is proposed in this paper. During each stage, only a small region of the network is detected by using a small set of probes. Meanwhile, it also ensures that the entire network can be covered alter multiple detection stages. This method can guarantee that the traffic used by probes during each detection stage is small sufficiently so that the network can operate without severe disturbance from probes. Several simulation results verify the effectiveness of the proposed method.展开更多
DMAKO-05,a novel dimethylation of alkannin oxime derivative,exhibits remarkable anticancer activity as well as excellent cellular selectivity and thus has been considered as a promising antineoplastic agent for colore...DMAKO-05,a novel dimethylation of alkannin oxime derivative,exhibits remarkable anticancer activity as well as excellent cellular selectivity and thus has been considered as a promising antineoplastic agent for colorectal carcinoma and melanoma.However,its potent cytotoxicity is not closely associated with reactive oxygen species（ROS） and bioreductive alkylation.Its specific antitumor target（s） has still remained elusive.To recognize the molecular target（s） of DMAKO-05 and its analogs,four biotinylated DMAKO derivatives were designed and prepared.The biotin moiety was successfully introduced in the molecule through a modified Mitsunobu reaction,which kept its anticancer activity.Moreover,the cellbased investigation demonstrated that replacement of the linker C4 chain with another alkyl chain（C6 or C8） gave rise to the enhancement of cytotoxicity.Among these biotinyl derivatives,both compound 16 and 8c exhibited more potent anticancer activity than DMAKO-05 against MCF-7 cells and were comparatively effective to alkannin toward HCT-15 cells.As expected,they might be thought as ideal chemical probes.Collectively,our present work could provide an available approach for the identification of the potential antineoplastic target（s） of DMAKO derivatives.展开更多
Fluorescent DNA probes commonly used for in situ imaging of cell surface glycans are“always-on”probes(AOPs),which produce high background noise and lack spatial specificity.Molecular dynamics simulations indicate th...Fluorescent DNA probes commonly used for in situ imaging of cell surface glycans are“always-on”probes(AOPs),which produce high background noise and lack spatial specificity.Molecular dynamics simulations indicate that single-stranded DNA(ssDNA)can stably associate with the cell membrane,contributing to persistent background signals in AOPs.To overcome this challenge,a stepwise activated probe(SAP)is developed for in situ imaging of cell surface glycans.In SAP,the cell surface glycan is labeled by rolling circle amplification product through metabolic glycan labeling strategies.The product hybridizes a fluorophore and quencher-labeled ssDNA reporter to form a double strand producing primary enhancement of fluorescence signal.Nicking enzyme(Nb.BbvCI)cleaves the double strand and releases the quencher,further enhancing the signal.Nonspecific absorption of the reporter on the cellular membrane does not increase the fluorophore-quencher distance in SAP or trigger Nb.BbvCI cleavage.As a result,only the glycan sites are illuminated.SAP not only exhibits high imaging specificity but also greatly simplifies the imaging procedure by reducing the washing steps.SAP offers a considerable improvement in detection specificity and sensitivity by employing a two-step activation and amplification process,making it a powerful method for in situ fluorescence imaging.展开更多
Fluorescence-guided surgery(FGS)with tumor-targeted imaging agents,particularly those using the near-infrared wavelength,has emerged as a real-time technique to highlight the tumor location and margins during a surgic...Fluorescence-guided surgery(FGS)with tumor-targeted imaging agents,particularly those using the near-infrared wavelength,has emerged as a real-time technique to highlight the tumor location and margins during a surgical procedure.For accurate visualization of prostate cancer(PCa)boundary and lymphatic metastasis,we developed a new approach involving an efficient self-quenched near-infrared fluorescence probe,Cy-KUE-OA,with dual PCa-membrane affinity.Cy-KUE-OA specifically targeted the prostate-specific membrane antigen(PSMA),anchored into the phospholipids of the cell membrane of PCa cells and consequently showed a strong Cy7-de-quenching effect.This dual–membrane-targeting probe allowed us to detect PSMA-expressing PCa cells both in vitro and in vivo and enabled clear visualization of the tumor boundary during fluorescence-guided laparoscopic surgery in PCa mouse models.Furthermore,the high PCa preference of Cy-KUE-OA was confirmed on surgically resected patient specimens of healthy tissues,PCa,and lymph node metastases.Taken together,our results serve as a bridge between preclinical and clinical research in FGS of PCa and lay a solid foundation for further clinical research.展开更多
ISG15 is a ubiquitin-like(Ubl) protein attached to substrate proteins by ISG15 conjugating enzymes whose dysregulation is implicated in a multitude of disease processes, but the probing of these enzymes remains to be ...ISG15 is a ubiquitin-like(Ubl) protein attached to substrate proteins by ISG15 conjugating enzymes whose dysregulation is implicated in a multitude of disease processes, but the probing of these enzymes remains to be accomplished. Here, we describe the development of a new activity-based probe ISG15-Dha(dehydroalanine) through protein semi-synthesis. In vitro crosslinking and cell lysate proteomic profiling experiments showed that this probe can sequentially capture ISG15 conjugating enzymes including E1 enzyme UBA7, E2 enzyme UBE2L6, E3 enzyme HERC5, the previously known ISG15 deconjugating enzyme(USP18), as well as some other enzymes(USP5 and USP14) which we additionally confirmed to impart deISGylation activity. Collectively, ISG15-Dha provides a new tool that can simultaneously capture ISG15 conjugating and deconjugating enzymes for biochemical or pharmacological studies.展开更多
基金supported by National Key Basic Research Program of China (973 program) under Grant No.2007CB310703Funds for Creative Research Groups of China under Grant No.60821001+1 种基金National Natural Science Foundation of China under Grant No. 60973108National S&T Major Project under Grant No.2011ZX03005-004-02
文摘Fault diagnosis on large-scale and complex networks is a challenging task, as it requires efficient and accurate inference from huge data volumes. Active probing is a cost-efficient tool for fault diagnosis. However almost all existing probing-based techniques face the following problems: 1) performing inaccurately in noisy networks; 2) generating additional traffic to the network; 3) high cost computation. To address these problems, we propose an efficient probe selection algorithm for fault diagnosis based on Bayesian network. Moreover, two approaches which could significantly reduce the computational complexity of the probe selection process are provided. Finally, we implement the new proposed algorithm and a former representative probing-based algorithm (BPEA algorithm) on different settings of networks. The results show that, the new algorithm performs much faster than BPEA does without sacrificing the diagnostic quality, especially in large, noisy and multiple-fault networks.
基金the National Basic Research Program of China (973 Program) (Grant No. 2003CB314806)the National High-Tech Research & Development Program of China (863 Program) (Grant Nos. 2007AA12Z321 and 2007AA01Z206)the National Natural Science Foundation of China (Grant Nos. 60603060, 60502037 and 90604019)
文摘In Internet service fault management based on active probing, uncertainty and noises will affect service fault management. In order to reduce the impact, challenges of Internet service fault management are analyzed in this paper. Bipartite Bayesian network is chosen to model the dependency relationship between faults and probes, binary symmetric channel is chosen to model noises, and a service fault management approach using active probing is proposed for such an environment. This approach is composed of two phases： fault detection and fault diagnosis. In first phase, we propose a greedy approximation probe selection algorithm （GAPSA）, which selects a minimal set of probes while remaining a high probability of fault detection. In second phase, we propose a fault diagnosis probe selection algorithm （FDPSA）, which selects probes to obtain more system information based on the symptoms observed in previous phase. To deal with dynamic fault set caused by fault recovery mechanism, we propose a hypothesis inference algorithm based on fault persistent time statistic （FPTS）. Simulation results prove the validity and efficiency of our approach.
文摘To relieve traliic overhead induced by active probing based methods, a new fault detection method, whose key is to divide the detection process into multiple stages, is proposed in this paper. During each stage, only a small region of the network is detected by using a small set of probes. Meanwhile, it also ensures that the entire network can be covered alter multiple detection stages. This method can guarantee that the traffic used by probes during each detection stage is small sufficiently so that the network can operate without severe disturbance from probes. Several simulation results verify the effectiveness of the proposed method.
基金supported by National Natural Science Foundation of China (No. 81373274)Ph.D. Programs Foundation of Ministry of Education China (No. 20120073110068)Shanghai Biomedical Supporting Funding (No. 15431900600)
文摘DMAKO-05,a novel dimethylation of alkannin oxime derivative,exhibits remarkable anticancer activity as well as excellent cellular selectivity and thus has been considered as a promising antineoplastic agent for colorectal carcinoma and melanoma.However,its potent cytotoxicity is not closely associated with reactive oxygen species（ROS） and bioreductive alkylation.Its specific antitumor target（s） has still remained elusive.To recognize the molecular target（s） of DMAKO-05 and its analogs,four biotinylated DMAKO derivatives were designed and prepared.The biotin moiety was successfully introduced in the molecule through a modified Mitsunobu reaction,which kept its anticancer activity.Moreover,the cellbased investigation demonstrated that replacement of the linker C4 chain with another alkyl chain（C6 or C8） gave rise to the enhancement of cytotoxicity.Among these biotinyl derivatives,both compound 16 and 8c exhibited more potent anticancer activity than DMAKO-05 against MCF-7 cells and were comparatively effective to alkannin toward HCT-15 cells.As expected,they might be thought as ideal chemical probes.Collectively,our present work could provide an available approach for the identification of the potential antineoplastic target（s） of DMAKO derivatives.
基金supported by the National Natural Science Foundation of China(32271521,31971361,and 82170763)the State Key Research Development Program of China(2022YFC2603902)+2 种基金the Natural Science Foundation of Beijing Municipality(5212013)the Fundamental Research Funds for the Central Universities(PT2406)the Talent Cultivation of State Key Laboratory of Organic-Inorganic Composites,Beijing University of Chemical Technology(oic-2024020007)。
文摘Fluorescent DNA probes commonly used for in situ imaging of cell surface glycans are“always-on”probes(AOPs),which produce high background noise and lack spatial specificity.Molecular dynamics simulations indicate that single-stranded DNA(ssDNA)can stably associate with the cell membrane,contributing to persistent background signals in AOPs.To overcome this challenge,a stepwise activated probe(SAP)is developed for in situ imaging of cell surface glycans.In SAP,the cell surface glycan is labeled by rolling circle amplification product through metabolic glycan labeling strategies.The product hybridizes a fluorophore and quencher-labeled ssDNA reporter to form a double strand producing primary enhancement of fluorescence signal.Nicking enzyme(Nb.BbvCI)cleaves the double strand and releases the quencher,further enhancing the signal.Nonspecific absorption of the reporter on the cellular membrane does not increase the fluorophore-quencher distance in SAP or trigger Nb.BbvCI cleavage.As a result,only the glycan sites are illuminated.SAP not only exhibits high imaging specificity but also greatly simplifies the imaging procedure by reducing the washing steps.SAP offers a considerable improvement in detection specificity and sensitivity by employing a two-step activation and amplification process,making it a powerful method for in situ fluorescence imaging.
基金supported by the National Natural Science Foundation of China(NSFC)projects(22122705,22077139 and 81972400)CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-054 and 2021-I2M-1-015)Beijing Outstanding Young Scientist Program(BJJWZYJH01201910023028,China).
文摘Fluorescence-guided surgery(FGS)with tumor-targeted imaging agents,particularly those using the near-infrared wavelength,has emerged as a real-time technique to highlight the tumor location and margins during a surgical procedure.For accurate visualization of prostate cancer(PCa)boundary and lymphatic metastasis,we developed a new approach involving an efficient self-quenched near-infrared fluorescence probe,Cy-KUE-OA,with dual PCa-membrane affinity.Cy-KUE-OA specifically targeted the prostate-specific membrane antigen(PSMA),anchored into the phospholipids of the cell membrane of PCa cells and consequently showed a strong Cy7-de-quenching effect.This dual–membrane-targeting probe allowed us to detect PSMA-expressing PCa cells both in vitro and in vivo and enabled clear visualization of the tumor boundary during fluorescence-guided laparoscopic surgery in PCa mouse models.Furthermore,the high PCa preference of Cy-KUE-OA was confirmed on surgically resected patient specimens of healthy tissues,PCa,and lymph node metastases.Taken together,our results serve as a bridge between preclinical and clinical research in FGS of PCa and lay a solid foundation for further clinical research.
基金supported by the National Key Research&Development Program of China(2021YFA1200104,2022YFC3401500)the National Natural Science Foundation of China(21621003,22137005,21971133,22027807,22034004,92253302,22227810)the Tsinghua University Spring Breeze Fund(2020Z99CFY043,2021Z99CFZ002)。
文摘ISG15 is a ubiquitin-like(Ubl) protein attached to substrate proteins by ISG15 conjugating enzymes whose dysregulation is implicated in a multitude of disease processes, but the probing of these enzymes remains to be accomplished. Here, we describe the development of a new activity-based probe ISG15-Dha(dehydroalanine) through protein semi-synthesis. In vitro crosslinking and cell lysate proteomic profiling experiments showed that this probe can sequentially capture ISG15 conjugating enzymes including E1 enzyme UBA7, E2 enzyme UBE2L6, E3 enzyme HERC5, the previously known ISG15 deconjugating enzyme(USP18), as well as some other enzymes(USP5 and USP14) which we additionally confirmed to impart deISGylation activity. Collectively, ISG15-Dha provides a new tool that can simultaneously capture ISG15 conjugating and deconjugating enzymes for biochemical or pharmacological studies.
