Consensus theory and noncooperative game theory respectively deal with cooperative and noncooperative interactions among multiple players/agents. They provide a natural framework for road pricing design, since each mo...Consensus theory and noncooperative game theory respectively deal with cooperative and noncooperative interactions among multiple players/agents. They provide a natural framework for road pricing design, since each motorist may myopically optimize his or her own utility as a function of road price and collectively communicate with his or her friends and neighbors on traffic situation at the same time. This paper considers the road pricing design by using game theory and consensus theory. For the case where a system supervisor broadcasts information on the overall system to each agent, we present a variant of standard fictitious play called average strategy fictitious play(ASFP) for large-scale repeated congestion games.Only a weighted running average of all other players actions is assumed to be available to each player. The ASFP reduces the burden of both information gathering and information processing for each player. Compared to the joint strategy fictitious play(JSFP) studied in the literature, the updating process of utility functions for each player is avoided. We prove that there exists at least one pure strategy Nash equilibrium for the congestion game under investigation, and the players actions generated by the ASFP with inertia(players reluctance to change their previous actions) converge to a Nash equilibrium almost surely. For the case without broadcasting, a consensus protocol is introduced for individual agents to estimate the percentage of players choosing each resource, and the convergence property of players action profile is still ensured. The results are applied to road pricing design to achieve socially local optimal trip timing. Simulation results are provided based on the real traffic data for the Singapore case study.展开更多
The heterogeneous integration of III-V devices with Si-CMOS on a common Si platform has shown great promise in the new generations of electrical and optical systems for novel applications,such as HEMT or LED with inte...The heterogeneous integration of III-V devices with Si-CMOS on a common Si platform has shown great promise in the new generations of electrical and optical systems for novel applications,such as HEMT or LED with integrated control circuitry.For heterogeneous integration,direct wafer bonding(DWB)techniques can overcome the materials and thermal mismatch issues by directly bonding dissimilar materials systems and device structures together.In addition,DWB can perform at wafer-level,which eases the requirements for integration alignment and increases the scalability for volume production.In this paper,a brief review of the different bonding technologies is discussed.After that,three main DWB techniques of single-,double-and multi-bonding are presented with the demonstrations of various heterogeneous integration applications.Meanwhile,the integration challenges,such as micro-defects,surface roughness and bonding yield are discussed in detail.展开更多
OBJECTIVE To investigate the genome protective effects of anti-malaria drug,artesunate in an experimental allergic asthma model.METHODS Mice were sensitized on day 0 and 7 and challenged on day 14 with 100μg house du...OBJECTIVE To investigate the genome protective effects of anti-malaria drug,artesunate in an experimental allergic asthma model.METHODS Mice were sensitized on day 0 and 7 and challenged on day 14 with 100μg house dust mite(HDM)via intratracheal administration.Artesunate(30mg·kg-1)was administered intra-peritoneally on day 6,7,8,13,14 and 15.Samples were collected on day 1,3 and 5 post last HDM-challenge for analysis of air way inflammation and DNA damage.Lung sections were immunofluorescence(IF)-stained for DNA double strand breaks(DSBs)markers,γH2AX and 53BP1.Levels of DNA repair proteins Ku70 and Rad51,which are involved in non-homologous end joining(NHEJ)and homologous recombination(HR)DNA DSB repair pathways respectively,were measured.To quantify cell death in asthmatic lung,TUNEL staining was performed.Comet assay,a single cell gel electrophoresis was employed to detect DNA damage induced by HDM in BEAS-2Bhuman bronchial epithelial cell line,in vitro.RESULTS Artesunate treatment significantly reduces immune cells infiltration in BAL fluid of asthmatic mice,collected on day 3 and 5 post-challenge.Importantly,artesuante is able to protect bronchial epithelium from DNA DSBs induced by asthma,as detected by the reduced level of γH2AX and 53BP1 foci formation in the nucleus.This genome protective effect is evident even on day 1 post-challenge,when immune cells infiltration remained high.This indicates that artesunate confers protection on bronchial epithelium in the presence of inflammation.Additionally,artesunate is also able to reduce cell death in asthmatic lung revealed by TUNEL assay and cleaved caspase 3 level.Interestingly,the levels of DNA repair proteins in artesuante-treated asthmatic mice are unchanged as compared to HDM-only mice,suggesting that artesunate treatment does not augment the level of DNA repair proteins.When human bronchial epithelial BEAS-2 Bcells were exposed to HDMin vitro,we observed an increase in the levels of DNA damage.Artesunate(60μmol·L-1)co-incubated with HDM is not able to prevent direct DNA damage induced by the allergen.Together,these studies suggest that the genome protective effect of artesunate in vivo may be attributed to physiological effects(such as its anti-inflammatory effects)rather than serving to directly prevent DNA damage.CONCULSION This study highlights a novel role for artesunate in protecting bronchial epithelial cells from asthma-induced DNA damage.展开更多
During the onset of a disease a cell may experience alterations in both the composition and organization of its cellular and molecular structures.These alterations may eventually lead to changes in its geometrical and...During the onset of a disease a cell may experience alterations in both the composition and organization of its cellular and molecular structures.These alterations may eventually lead to changes in its geometrical and mechanical properties such as cell size and shape,deformability and adhesion.As such,knowing how diseased cells respond to mechanical forces can reveal ways by which they differ from healthy ones.Here,we will present biomechanistic insights into red blood cell related diseases that manifest...展开更多
LiMn_2O_4 powder as a cathode materials for rechargeable lithium-ion batteries was prepared by solid-state reaction from Li_2CO_3 and electrolytic MnO_2 at different sintering periods(2,6,18,and 32 h).X-ray diffractio...LiMn_2O_4 powder as a cathode materials for rechargeable lithium-ion batteries was prepared by solid-state reaction from Li_2CO_3 and electrolytic MnO_2 at different sintering periods(2,6,18,and 32 h).X-ray diffraction(XRD)patterns of the prepared samples are identified as the spinel structure with a space group of Fd(?)m.The lattice parameters almost remain the same as the sin- tering periods increase.The sample with a sintering period of 32 h shows good cycling performance at both low and high current densities,and also elevated temperature.It is believed that the excellent electrochemical behavior of this sample results from its good crystallinity and large grain size compared with other samples.Different electrochemical measurements were conducted to investi- gate the electrochemical properties of spinel LiMn_2O_4.展开更多
In order to enhance the effect of corneal grafting, an assisting microsurgical robot has beendeveloped. As one of principal issues for the robotic system design, type and size synthesis of therobotic mechanism is disc...In order to enhance the effect of corneal grafting, an assisting microsurgical robot has beendeveloped. As one of principal issues for the robotic system design, type and size synthesis of therobotic mechanism is discussed. For this purpose, timeline subtask is analyzed with surgicalcomponent motion in manual corneal grafting microsurgery, as the reference of robotic mechanismsynthesis. On the basis of study on the kinematic correlation between the arm structures and the wriststructures, configuration of joint is determined for the surgical task and motion in type synthesis of themechanism. The objective for size synthesis of robotic mechanism is optimization of the mechanismdexterity as a manipulation capability. The condition number based on Jacob matrix is chosen asdexterity measure of the mechanism. The prototype is developed.展开更多
OBJECTIVE Cigarette smoke-induced chronic obstructive pulmonary disease(COPD)is a leading cause of death,where inflammation and oxidative stress are involved in the pathogenesis.Vitamin E isoformγ-tocotrienol possess...OBJECTIVE Cigarette smoke-induced chronic obstructive pulmonary disease(COPD)is a leading cause of death,where inflammation and oxidative stress are involved in the pathogenesis.Vitamin E isoformγ-tocotrienol possesses both anti-oxidative and anti-inflammatory properties.We hypothesized thatγ-tocotrienol may have protective effects against COPD.METHODS BALB/c mice were exposedto cigarette smoke daily for 2 weeks with oralγ-tocotrienol treatment in the second week.Bronchoalveolar lavage(BAL)fluid was assessed for total and differential cell counts,oxidative damage biomarkers,and cytokine levels.Lung tissues were examined for the expression of antioxidants and pro-inflammatory biomarkers.In order to measure changes in lung functions in COPD,another set of mice was exposed to cigarette smoke for 2 months with oralγ-tocotrienol treatment in the last 2 weeks.RESULTSγ-Tocotrienol dose-dependently abated cigarette smoke-induced elevation of BAL fluid total and neutrophil cell counts,cytokine and chemokine(IL-1β,IL-6,IL-17,LIX,G-CSF,KC,RANTES and VEGF)levels,as well as oxidative/nitrosative damage biomarker(advanced oxidation of protein products,8-isoprostane,8-hydroxy-2-deoxyguanosine and 3-nitrotyrosine)levels.γ-Tocotrienol promoted total lung antioxidant capacity and endogenous antioxidant activities of superoxide dismutase,catalase and glutathione peroxidase.More importantly,γ-tocotrienol markedly restored work of breathing and lung functions(total lung capacity,static compliance and FEV100/FVC)in chronic experimental COPD.Furthermore,γ-tocotrienol demonstrated better anti-oxidative,anti-inflammatory,and restoration of lung functions in COPD than prednisolone.CONCLUSION We have shown for the first time the efficacy of vitamin E isomerγ-tocotrienol in protection against cigarette smoke-induced COPD by direct neutralization of free radicals,abating oxidative damage,and restoring antioxidants activities,coupled with anti-inflammatory actions in the inflamed airways.展开更多
The turbulent flows through the channels with abrupt cross-sectional changes are common and importantphysical process in nature.For a better prediction of the mean flow and turbulent characteristics for this problem,a...The turbulent flows through the channels with abrupt cross-sectional changes are common and importantphysical process in nature.For a better prediction of the mean flow and turbulent characteristics for this problem,atwo-dimensional depth-averaged numerical model is developed.The model is robust and accurate in reproducing therecirculation flow behind a groyne and turbulent flows in channels with abrupt cross-sectional changes,when com-pared to the available experimental data of mean velocities and turbulence kinetic energy.Our results reveal that theabrupt cross-sectional change of a channel can affect the flow pattern significantly and introduces the complex turbu-lence characteristics.In particular,when the channel has an abrupt expansion,the mean flow pattern is mainly in lon-gitudinal direction with rather small transverse component.Meanwhile,a recirculating region forms behind the expan-sion position and the turbulence has very strong intensity within this region.For the flow in the channel with an ab-rupt contraction,the longitudinal component of the flow is decreased by the obstruction on one side and accelerated onthe other side,whereas the transverse velocity is small.The turbulence is extraordinarily strong in the regions adja-cent to the contraction wall in the narrow channel.In both cases of abrupt cross-sectional changes,the TKE is genera-ted dominantly by the shear of the longitudinal velocities.展开更多
OBJECTIVE To develop a 2-week cigarette smoke(CS)acute lung injury model exacerbated by haemophilus influenzae(NTHi)and study the protective effect of andrographolide in this COPD model.METHODS Female BALB/c mice,6-8-...OBJECTIVE To develop a 2-week cigarette smoke(CS)acute lung injury model exacerbated by haemophilus influenzae(NTHi)and study the protective effect of andrographolide in this COPD model.METHODS Female BALB/c mice,6-8-week-old,were exposed to 4% 3R4 FCS delivered using aperistaltic pump daily for 2 weeks to induce an acute lung injury model.After 2 weeks of smoking,mice were inoculated intratracheally with NTHi to induce exacerbation on the model.Mice were sacrificed 48 h after last bacteria challenge and lung samples were collected for various analyses.RESULTS After developing a 2-week CS acute lung injury model exacerbated by NTHi,the CS+NTHi group was shown to have a higher inflammatory response,higher bacterial clearance,an upregulation of MMP12 mRNA levels and decrease in TIMP1 mRNA levels in the lungs.Administration of Andrographolide suppressed BALF lung cellular infiltrates,TNF-α,CXCL1/KC,IL-1βand 8-OHdG protein levels,together with increased HO-1 and GR mRNA levels and decreased MMP-8 and MMP-9 mRNA levels.Andrographolide was able to ameliorate lung histopathology as observed with H&E staining and inflammation scoring.Andrographolide was also shown to reduce Keap-1 level in lungs without affecting DJ-1 level.CONCLUSION This study demonstrates the protective effect of andrographolide in a novel 2-week CS acute lung injury model exacerbated by NTHi and presents it as a potential therapeutic for COPD.展开更多
This paper deals with the problem of finding solutions to the Picard boundary problem. In our approacn, by means of the homotopy method, the equation considered is linked to a simpler equation by introducing a paramet...This paper deals with the problem of finding solutions to the Picard boundary problem. In our approacn, by means of the homotopy method, the equation considered is linked to a simpler equation by introducing a parameter. We first find the solutions of the simpler equation, and give a priori estimates of the equation we considered, and then one can obtain the solutions of Picard boundary problem by following the path of solutions of Cauchy problem.展开更多
Salicylic acid(SA),a defense hormone produced after pathogen challenge,is critical for plant immunity.Arabidopsis NONEXPRESSER OF PR GENES 1(NPR1)and its paralogs NPR3 and NPR4 can bind SA and mediate SA signal transd...Salicylic acid(SA),a defense hormone produced after pathogen challenge,is critical for plant immunity.Arabidopsis NONEXPRESSER OF PR GENES 1(NPR1)and its paralogs NPR3 and NPR4 can bind SA and mediate SA signal transduction.NPR1 functions as a transcriptional co-activator to promote defense gene expression,whereas NPR3 and NPR4 have been shown to function as negative regulators in the SA signaling pathway.Although the mechanism about NPR1 regulation has been well studied,how NPR3/NPR4 proteins are regulated in immune responses remains largely unknown.Here,we show that the stability of NPR3/NPR4 is enhanced by SA.In the absence of pathogen challenge,NPR3/NPR4 are unstable and degraded by the 26S proteasome,whereas the increase in cellular SA levels upon pathogen infection suppresses NPR3/NPR4 degradation.We found that UBP12 and UBP13,two homologous deubiquitinases from a ubiquitin-specific protease subfamily,negatively regulate plant immunity by promoting NPR3/NPR4 stability.Our genetic results further showed that UBP12/UBP13-mediated immunity suppression is partially dependent on NPR3/NPR4 functions.By interacting with NPR3 in the nucleus in an SA-dependent manner,UBP12 and UBP13 remove ubiquitin from polyubiquitinated NPR3 to protect it from being degraded.The stabilization of NPR3/NPR4 promoted by UBP12/UBP13 is essential for negative regulation of basal and SA-induced immunity.展开更多
Secretome derived from mesenchymal stem cells (MSCs) have profound effects on tissue regeneration, which could become the basis of future MSCs therapies. Hypoxia, as the physiologic environment of MSCs, has great pote...Secretome derived from mesenchymal stem cells (MSCs) have profound effects on tissue regeneration, which could become the basis of future MSCs therapies. Hypoxia, as the physiologic environment of MSCs, has great potential to enhance MSCs paracrine therapeutic effect. In our study, the paracrine effects of secretome derived from MSCs preconditioned in normoxia and hypoxia was compared through both in vitro functional assays and an in vivo rat osteochondral defect model. Specifically, the paracrine effect of total EVs were compared to that of soluble factors to characterize the predominant active components in the hypoxic secretome. We demonstrated that hypoxia conditioned medium, as well as the corresponding EVs, at a relatively low dosage, were efficient in promoting the repair of critical-sized osteochondral defects and mitigated the joint inflammation in a rat osteochondral defect model, relative to their normoxia counterpart. In vitro functional test shows enhancement through chondrocyte proliferation, migration, and matrix deposition, while inhibit IL-1β-induced chondrocytes senescence, inflammation, matrix degradation, and pro-inflammatory macrophage activity. Multiple functional proteins, as well as a change in EVs’ size profile, with enrichment of specific EV-miRNAs were detected with hypoxia preconditioning, implicating complex molecular pathways involved in hypoxia pre-conditioned MSCs secretome generated cartilage regeneration.展开更多
Rapid and accurate chemical composition identification is critically important in chemistry.While it can be achieved with optical absorption spectrometry by comparing the experimental spectra with the reference data w...Rapid and accurate chemical composition identification is critically important in chemistry.While it can be achieved with optical absorption spectrometry by comparing the experimental spectra with the reference data when the chemical compositions are simple,such application is limited in more complicated scenarios especially in nano-scale research.This is due to the difficulties in identifying optical absorption peaks(i.e.,from“featureless”spectra)arose from the complexity.In this work,using the ultraviolet-visible(UV-Vis)absorption spectra of metal nanoclusters(NCs)as a demonstration,we develop a machine-learningbased method to unravel the compositions of metal NCs behind the“featureless”spectra.By implementing a one-dimensional convolutional neural network,good matches between prediction results and experimental results and low mean absolute error values are achieved on these optical absorption spectra that human cannot interpret.This work opens a door for the identification of nanomaterials at molecular precision from their optical properties,paving the way to rapid and high-throughput characterizations.展开更多
Needle-in-a-Haystack problems exist across a wide range of applications including rare disease prediction,ecological resource management,fraud detection,and material property optimization.A Needle-in-a-Haystack proble...Needle-in-a-Haystack problems exist across a wide range of applications including rare disease prediction,ecological resource management,fraud detection,and material property optimization.A Needle-in-a-Haystack problem arises when there is an extreme imbalance of optimum conditions relative to the size of the dataset.However,current state-of-the-art optimization algorithms are not designed with the capabilities to find solutions to these challenging multidimensional Needle-in-a-Haystack problems,resulting in slow convergence or pigeonholing into a local minimum.In this paper,we present a Zooming Memory-Based Initialization algorithm,entitled ZoMBI,that builds on conventional Bayesian optimization principles to quickly and efficiently optimize Needle-in-a-Haystack problems in both less time and fewer experiments.The ZoMBI algorithm demonstrates compute time speed-ups of 400×compared to traditional Bayesian optimization as well as efficiently discovering optima in under 100 experiments that are up to 3×more highly optimized than those discovered by similar methods.展开更多
Noninvasive X-ray imaging of nanoscale three-dimensional objects,such as integrated circuits(ICs),generally requires two types of scanning:ptychographic,which is translational and returns estimates of the complex elec...Noninvasive X-ray imaging of nanoscale three-dimensional objects,such as integrated circuits(ICs),generally requires two types of scanning:ptychographic,which is translational and returns estimates of the complex electromagnetic field through the IC;combined with a tomographic scan,which collects these complex field projections from multiple angles.Here,we present Attentional Ptycho-Tomography(APT),an approach to drastically reduce the amount of angular scanning,and thus the total acquisition time.APT is machine learning-based,utilizing axial self-Attention for Ptycho-Tomographic reconstruction.APT is trained to obtain accurate reconstructions of the ICs,despite the incompleteness of the measurements.The training process includes regularizing priors in the form of typical patterns found in IC interiors,and the physics of X-ray propagation through the IC.We show that APT with×12 reduced angles achieves fidelity comparable to the gold standard Simultaneous Algebraic Reconstruction Technique(SART)with the original set of angles.When using the same set of reduced angles,then APT also outperforms Filtered Back Projection(FBP),Simultaneous Iterative Reconstruction Technique(SIRT)and SART.The time needed to compute the reconstruction is also reduced,because the trained neural network is a forward operation,unlike the iterative nature of these alternatives.Our experiments show that,without loss in quality,for a 4.48×93.2×3.92µm^(3) IC(≃6×10^(8) voxels),APT reduces the total data acquisition and computation time from 67.96 h to 38 min.We expect our physics-assisted and attention-utilizing machine learning framework to be applicable to other branches of nanoscale imaging,including materials science and biological imaging.展开更多
Liquid biopsy of cancers,detecting tumor-related information from liquid samples,has attracted wide attentions as an emerging technology.Our previously reported large-area PERFECT(Precise-Efficient-Robust-Flexible-Eas...Liquid biopsy of cancers,detecting tumor-related information from liquid samples,has attracted wide attentions as an emerging technology.Our previously reported large-area PERFECT(Precise-Efficient-Robust-Flexible-Easy-ControllableThin)filter has demonstrated competitive sensitivity in recovering rare tumor cells from clinical samples.However,it is time-consuming and easily biased to manually inspect rare target cells among numerous background cells distributed in a large area(Φ≥13 mm).This puts forward an urgent demand for rapid and bias-free inspection.Hereby,this paper implemented deep learning-based object detection for the inspection of rare tumor cells from large-field images of PERFECT filters with hematoxylin-eosin(HE)-stained cells recovered from bronchoalveolar lavage fluid(BALF).CenterNet,EfficientDet,and YOLOv5 were trained and validated with 240 and 60 image blocks containing tumor and/or background cells,respectively.YOLOv5 was selected as the basic network given the highest mAP@0.5 of 92.1%,compared to those of CenterNet and EfficientDet at 85.2%and 91.6%,respectively.Then,tricks including CIoU loss,image flip,mosaic,HSV augmentation and TTA were applied to enhance the performance of the YOLOv5 network,improving mAP@0.5 to 96.2%.This enhanced YOLOv5 network-based object detection,named as BALFilter Reader,was tested and cross-validated on 24 clinical cases.The overall diagnosis performance(~2 min)with sensitivity@66.7%±16.7%,specificity@100.0%±0.0%and accuracy@75.0%±12.5%was superior to that from two experienced pathologists(10–30 min)with sensitivity@61.1%,specificity@16.7%and accuracy@50.0%,with the histopathological result as the gold standard.The AUC of the BALFilter Reader is 0.84±0.08.Moreover,a customized Web was developed for a user-friendly interface and the promotion of wide applications.The current results revealed that the developed BALFilter Reader is a rapid,bias-free and easily accessible AI-enabled tool to promote the transplantation of the BALFilter technique.This work can easily expand to other cytopathological diagnoses and improve the application value of micro/nanotechnology-based liquid biopsy in the era of intelligent pathology.展开更多
Wound healing is a dynamic process that involves a series of molecular and cellular events aimed at replacing devitalized and missing cellular components and/or tissue layers.Recently,extracellular vesicles(EVs),natur...Wound healing is a dynamic process that involves a series of molecular and cellular events aimed at replacing devitalized and missing cellular components and/or tissue layers.Recently,extracellular vesicles(EVs),naturally cell-secreted lipid membrane-bound vesicles laden with biological cargos including proteins,lipids,and nucleic acids,have drawn wide attention due to their ability to promote wound healing and tissue regeneration.However,current exploitation of EVs as therapeutic agents is limited by their low isolation yields and tedious isolation processes.To circumvent these challenges,bioinspired cell-derived nanovesicles(CDNs)that mimic EVs were obtained by shearing mesenchymal stem cells(MSCs)through membranes with different pore sizes.Physical characterisations and highthroughput proteomics confirmed that MSC-CDNs mimicked MSC-EVs.Moreover,these MSC-CDNs were efficiently uptaken by human dermal fibroblasts and demonstrated a dose-dependent activation of MAPK signalling pathway,resulting in enhancement of cell proliferation,cell migration,secretion of growth factors and extracellular matrix proteins,which all promoted tissue regeneration.Of note,MSC-CDNs enhanced angiogenesis in human dermal microvascular endothelial cells in a 3D PEGfibrin scaffold and animal model,accelerating wound healing in vitro and in vivo.These findings suggest that MSC-CDNs could replace both whole cells and EVs in promoting wound healing and tissue regeneration.展开更多
文摘Consensus theory and noncooperative game theory respectively deal with cooperative and noncooperative interactions among multiple players/agents. They provide a natural framework for road pricing design, since each motorist may myopically optimize his or her own utility as a function of road price and collectively communicate with his or her friends and neighbors on traffic situation at the same time. This paper considers the road pricing design by using game theory and consensus theory. For the case where a system supervisor broadcasts information on the overall system to each agent, we present a variant of standard fictitious play called average strategy fictitious play(ASFP) for large-scale repeated congestion games.Only a weighted running average of all other players actions is assumed to be available to each player. The ASFP reduces the burden of both information gathering and information processing for each player. Compared to the joint strategy fictitious play(JSFP) studied in the literature, the updating process of utility functions for each player is avoided. We prove that there exists at least one pure strategy Nash equilibrium for the congestion game under investigation, and the players actions generated by the ASFP with inertia(players reluctance to change their previous actions) converge to a Nash equilibrium almost surely. For the case without broadcasting, a consensus protocol is introduced for individual agents to estimate the percentage of players choosing each resource, and the convergence property of players action profile is still ensured. The results are applied to road pricing design to achieve socially local optimal trip timing. Simulation results are provided based on the real traffic data for the Singapore case study.
文摘The heterogeneous integration of III-V devices with Si-CMOS on a common Si platform has shown great promise in the new generations of electrical and optical systems for novel applications,such as HEMT or LED with integrated control circuitry.For heterogeneous integration,direct wafer bonding(DWB)techniques can overcome the materials and thermal mismatch issues by directly bonding dissimilar materials systems and device structures together.In addition,DWB can perform at wafer-level,which eases the requirements for integration alignment and increases the scalability for volume production.In this paper,a brief review of the different bonding technologies is discussed.After that,three main DWB techniques of single-,double-and multi-bonding are presented with the demonstrations of various heterogeneous integration applications.Meanwhile,the integration challenges,such as micro-defects,surface roughness and bonding yield are discussed in detail.
基金The project supported by a NMRC grant NMRC/CBRG/0027/2012from the National Medical Research Council of Singapore,with additional support from the Singapore-MIT Alliance for Research and Technology
文摘OBJECTIVE To investigate the genome protective effects of anti-malaria drug,artesunate in an experimental allergic asthma model.METHODS Mice were sensitized on day 0 and 7 and challenged on day 14 with 100μg house dust mite(HDM)via intratracheal administration.Artesunate(30mg·kg-1)was administered intra-peritoneally on day 6,7,8,13,14 and 15.Samples were collected on day 1,3 and 5 post last HDM-challenge for analysis of air way inflammation and DNA damage.Lung sections were immunofluorescence(IF)-stained for DNA double strand breaks(DSBs)markers,γH2AX and 53BP1.Levels of DNA repair proteins Ku70 and Rad51,which are involved in non-homologous end joining(NHEJ)and homologous recombination(HR)DNA DSB repair pathways respectively,were measured.To quantify cell death in asthmatic lung,TUNEL staining was performed.Comet assay,a single cell gel electrophoresis was employed to detect DNA damage induced by HDM in BEAS-2Bhuman bronchial epithelial cell line,in vitro.RESULTS Artesunate treatment significantly reduces immune cells infiltration in BAL fluid of asthmatic mice,collected on day 3 and 5 post-challenge.Importantly,artesuante is able to protect bronchial epithelium from DNA DSBs induced by asthma,as detected by the reduced level of γH2AX and 53BP1 foci formation in the nucleus.This genome protective effect is evident even on day 1 post-challenge,when immune cells infiltration remained high.This indicates that artesunate confers protection on bronchial epithelium in the presence of inflammation.Additionally,artesunate is also able to reduce cell death in asthmatic lung revealed by TUNEL assay and cleaved caspase 3 level.Interestingly,the levels of DNA repair proteins in artesuante-treated asthmatic mice are unchanged as compared to HDM-only mice,suggesting that artesunate treatment does not augment the level of DNA repair proteins.When human bronchial epithelial BEAS-2 Bcells were exposed to HDMin vitro,we observed an increase in the levels of DNA damage.Artesunate(60μmol·L-1)co-incubated with HDM is not able to prevent direct DNA damage induced by the allergen.Together,these studies suggest that the genome protective effect of artesunate in vivo may be attributed to physiological effects(such as its anti-inflammatory effects)rather than serving to directly prevent DNA damage.CONCULSION This study highlights a novel role for artesunate in protecting bronchial epithelial cells from asthma-induced DNA damage.
文摘During the onset of a disease a cell may experience alterations in both the composition and organization of its cellular and molecular structures.These alterations may eventually lead to changes in its geometrical and mechanical properties such as cell size and shape,deformability and adhesion.As such,knowing how diseased cells respond to mechanical forces can reveal ways by which they differ from healthy ones.Here,we will present biomechanistic insights into red blood cell related diseases that manifest...
基金the National Natural Science Foundation of China(No.50272012).
文摘LiMn_2O_4 powder as a cathode materials for rechargeable lithium-ion batteries was prepared by solid-state reaction from Li_2CO_3 and electrolytic MnO_2 at different sintering periods(2,6,18,and 32 h).X-ray diffraction(XRD)patterns of the prepared samples are identified as the spinel structure with a space group of Fd(?)m.The lattice parameters almost remain the same as the sin- tering periods increase.The sample with a sintering period of 32 h shows good cycling performance at both low and high current densities,and also elevated temperature.It is believed that the excellent electrochemical behavior of this sample results from its good crystallinity and large grain size compared with other samples.Different electrochemical measurements were conducted to investi- gate the electrochemical properties of spinel LiMn_2O_4.
基金This project is supported by National Hi-tech Research and DevelopmentProgram of China (863 Program, No.2002AA420110).
文摘In order to enhance the effect of corneal grafting, an assisting microsurgical robot has beendeveloped. As one of principal issues for the robotic system design, type and size synthesis of therobotic mechanism is discussed. For this purpose, timeline subtask is analyzed with surgicalcomponent motion in manual corneal grafting microsurgery, as the reference of robotic mechanismsynthesis. On the basis of study on the kinematic correlation between the arm structures and the wriststructures, configuration of joint is determined for the surgical task and motion in type synthesis of themechanism. The objective for size synthesis of robotic mechanism is optimization of the mechanismdexterity as a manipulation capability. The condition number based on Jacob matrix is chosen asdexterity measure of the mechanism. The prototype is developed.
基金The project supported in part by NMRC/CBRG/0027/2012from the National Medical Research Council of Singapore and by NUHS Seed Fund R-184-000-238-112
文摘OBJECTIVE Cigarette smoke-induced chronic obstructive pulmonary disease(COPD)is a leading cause of death,where inflammation and oxidative stress are involved in the pathogenesis.Vitamin E isoformγ-tocotrienol possesses both anti-oxidative and anti-inflammatory properties.We hypothesized thatγ-tocotrienol may have protective effects against COPD.METHODS BALB/c mice were exposedto cigarette smoke daily for 2 weeks with oralγ-tocotrienol treatment in the second week.Bronchoalveolar lavage(BAL)fluid was assessed for total and differential cell counts,oxidative damage biomarkers,and cytokine levels.Lung tissues were examined for the expression of antioxidants and pro-inflammatory biomarkers.In order to measure changes in lung functions in COPD,another set of mice was exposed to cigarette smoke for 2 months with oralγ-tocotrienol treatment in the last 2 weeks.RESULTSγ-Tocotrienol dose-dependently abated cigarette smoke-induced elevation of BAL fluid total and neutrophil cell counts,cytokine and chemokine(IL-1β,IL-6,IL-17,LIX,G-CSF,KC,RANTES and VEGF)levels,as well as oxidative/nitrosative damage biomarker(advanced oxidation of protein products,8-isoprostane,8-hydroxy-2-deoxyguanosine and 3-nitrotyrosine)levels.γ-Tocotrienol promoted total lung antioxidant capacity and endogenous antioxidant activities of superoxide dismutase,catalase and glutathione peroxidase.More importantly,γ-tocotrienol markedly restored work of breathing and lung functions(total lung capacity,static compliance and FEV100/FVC)in chronic experimental COPD.Furthermore,γ-tocotrienol demonstrated better anti-oxidative,anti-inflammatory,and restoration of lung functions in COPD than prednisolone.CONCLUSION We have shown for the first time the efficacy of vitamin E isomerγ-tocotrienol in protection against cigarette smoke-induced COPD by direct neutralization of free radicals,abating oxidative damage,and restoring antioxidants activities,coupled with anti-inflammatory actions in the inflamed airways.
基金supported,in part,by the National Natural Science Foundation of China(51061130547 and51279120)
文摘The turbulent flows through the channels with abrupt cross-sectional changes are common and importantphysical process in nature.For a better prediction of the mean flow and turbulent characteristics for this problem,atwo-dimensional depth-averaged numerical model is developed.The model is robust and accurate in reproducing therecirculation flow behind a groyne and turbulent flows in channels with abrupt cross-sectional changes,when com-pared to the available experimental data of mean velocities and turbulence kinetic energy.Our results reveal that theabrupt cross-sectional change of a channel can affect the flow pattern significantly and introduces the complex turbu-lence characteristics.In particular,when the channel has an abrupt expansion,the mean flow pattern is mainly in lon-gitudinal direction with rather small transverse component.Meanwhile,a recirculating region forms behind the expan-sion position and the turbulence has very strong intensity within this region.For the flow in the channel with an ab-rupt contraction,the longitudinal component of the flow is decreased by the obstruction on one side and accelerated onthe other side,whereas the transverse velocity is small.The turbulence is extraordinarily strong in the regions adja-cent to the contraction wall in the narrow channel.In both cases of abrupt cross-sectional changes,the TKE is genera-ted dominantly by the shear of the longitudinal velocities.
基金The project supported by National Medical Research Council(NMRC/CBRG/0027/2012)
文摘OBJECTIVE To develop a 2-week cigarette smoke(CS)acute lung injury model exacerbated by haemophilus influenzae(NTHi)and study the protective effect of andrographolide in this COPD model.METHODS Female BALB/c mice,6-8-week-old,were exposed to 4% 3R4 FCS delivered using aperistaltic pump daily for 2 weeks to induce an acute lung injury model.After 2 weeks of smoking,mice were inoculated intratracheally with NTHi to induce exacerbation on the model.Mice were sacrificed 48 h after last bacteria challenge and lung samples were collected for various analyses.RESULTS After developing a 2-week CS acute lung injury model exacerbated by NTHi,the CS+NTHi group was shown to have a higher inflammatory response,higher bacterial clearance,an upregulation of MMP12 mRNA levels and decrease in TIMP1 mRNA levels in the lungs.Administration of Andrographolide suppressed BALF lung cellular infiltrates,TNF-α,CXCL1/KC,IL-1βand 8-OHdG protein levels,together with increased HO-1 and GR mRNA levels and decreased MMP-8 and MMP-9 mRNA levels.Andrographolide was able to ameliorate lung histopathology as observed with H&E staining and inflammation scoring.Andrographolide was also shown to reduce Keap-1 level in lungs without affecting DJ-1 level.CONCLUSION This study demonstrates the protective effect of andrographolide in a novel 2-week CS acute lung injury model exacerbated by NTHi and presents it as a potential therapeutic for COPD.
文摘This paper deals with the problem of finding solutions to the Picard boundary problem. In our approacn, by means of the homotopy method, the equation considered is linked to a simpler equation by introducing a parameter. We first find the solutions of the simpler equation, and give a priori estimates of the equation we considered, and then one can obtain the solutions of Picard boundary problem by following the path of solutions of Cauchy problem.
基金National Research Foundation(NRF),Prime Minister's Office,Singapore under its Campus for Research Excel-lence and Technological Enterprise(CREATE)programThe Disruptive and Sustainable Technologies for Agricultural Precision(DiSTAP)is an interdisciplinary research group(IRG)of the Singapore-MIT Alliance for Research and Technology Centre(SMART)+1 种基金National Research Foundation(NRF)Prime Minister's Office,Singapore,under its Campus for Research Excellence and Technological Enterprise(CREATE)program.
文摘Salicylic acid(SA),a defense hormone produced after pathogen challenge,is critical for plant immunity.Arabidopsis NONEXPRESSER OF PR GENES 1(NPR1)and its paralogs NPR3 and NPR4 can bind SA and mediate SA signal transduction.NPR1 functions as a transcriptional co-activator to promote defense gene expression,whereas NPR3 and NPR4 have been shown to function as negative regulators in the SA signaling pathway.Although the mechanism about NPR1 regulation has been well studied,how NPR3/NPR4 proteins are regulated in immune responses remains largely unknown.Here,we show that the stability of NPR3/NPR4 is enhanced by SA.In the absence of pathogen challenge,NPR3/NPR4 are unstable and degraded by the 26S proteasome,whereas the increase in cellular SA levels upon pathogen infection suppresses NPR3/NPR4 degradation.We found that UBP12 and UBP13,two homologous deubiquitinases from a ubiquitin-specific protease subfamily,negatively regulate plant immunity by promoting NPR3/NPR4 stability.Our genetic results further showed that UBP12/UBP13-mediated immunity suppression is partially dependent on NPR3/NPR4 functions.By interacting with NPR3 in the nucleus in an SA-dependent manner,UBP12 and UBP13 remove ubiquitin from polyubiquitinated NPR3 to protect it from being degraded.The stabilization of NPR3/NPR4 promoted by UBP12/UBP13 is essential for negative regulation of basal and SA-induced immunity.
基金supported by National Medical Research Council of Singapore(MOH-000371-00)the National Research Foundation,Prime Minister’s Office,Singapore under its Campus for Research Excellence and Technological Enterprise(CREATE)program,through Singapore-MIT Alliance for Research and Technology(SMART):Critical Analytics for Manufacturing Personalized-Medicine(CAMP)Inter-Disciplinary Research Group.YY was supported by NUS Research Scholarship.
文摘Secretome derived from mesenchymal stem cells (MSCs) have profound effects on tissue regeneration, which could become the basis of future MSCs therapies. Hypoxia, as the physiologic environment of MSCs, has great potential to enhance MSCs paracrine therapeutic effect. In our study, the paracrine effects of secretome derived from MSCs preconditioned in normoxia and hypoxia was compared through both in vitro functional assays and an in vivo rat osteochondral defect model. Specifically, the paracrine effect of total EVs were compared to that of soluble factors to characterize the predominant active components in the hypoxic secretome. We demonstrated that hypoxia conditioned medium, as well as the corresponding EVs, at a relatively low dosage, were efficient in promoting the repair of critical-sized osteochondral defects and mitigated the joint inflammation in a rat osteochondral defect model, relative to their normoxia counterpart. In vitro functional test shows enhancement through chondrocyte proliferation, migration, and matrix deposition, while inhibit IL-1β-induced chondrocytes senescence, inflammation, matrix degradation, and pro-inflammatory macrophage activity. Multiple functional proteins, as well as a change in EVs’ size profile, with enrichment of specific EV-miRNAs were detected with hypoxia preconditioning, implicating complex molecular pathways involved in hypoxia pre-conditioned MSCs secretome generated cartilage regeneration.
基金the Singapore RIE2020 Advanced Manufacturing and Engineering Programmatic grant“Accelerated Materials Development for Manufacturing”by the Agency for Science,Technology and Research under No.A1898b0043.
文摘Rapid and accurate chemical composition identification is critically important in chemistry.While it can be achieved with optical absorption spectrometry by comparing the experimental spectra with the reference data when the chemical compositions are simple,such application is limited in more complicated scenarios especially in nano-scale research.This is due to the difficulties in identifying optical absorption peaks(i.e.,from“featureless”spectra)arose from the complexity.In this work,using the ultraviolet-visible(UV-Vis)absorption spectra of metal nanoclusters(NCs)as a demonstration,we develop a machine-learningbased method to unravel the compositions of metal NCs behind the“featureless”spectra.By implementing a one-dimensional convolutional neural network,good matches between prediction results and experimental results and low mean absolute error values are achieved on these optical absorption spectra that human cannot interpret.This work opens a door for the identification of nanomaterials at molecular precision from their optical properties,paving the way to rapid and high-throughput characterizations.
基金acknowledges support from the National Research Foundation,Singapore(project No.NRF-NRFF13-2021-0005)the Ministry of Education,Singapore,under its Research Centre of Excellence award to I-FIM(project No.EDUNC-33-18-279-V12).
文摘Needle-in-a-Haystack problems exist across a wide range of applications including rare disease prediction,ecological resource management,fraud detection,and material property optimization.A Needle-in-a-Haystack problem arises when there is an extreme imbalance of optimum conditions relative to the size of the dataset.However,current state-of-the-art optimization algorithms are not designed with the capabilities to find solutions to these challenging multidimensional Needle-in-a-Haystack problems,resulting in slow convergence or pigeonholing into a local minimum.In this paper,we present a Zooming Memory-Based Initialization algorithm,entitled ZoMBI,that builds on conventional Bayesian optimization principles to quickly and efficiently optimize Needle-in-a-Haystack problems in both less time and fewer experiments.The ZoMBI algorithm demonstrates compute time speed-ups of 400×compared to traditional Bayesian optimization as well as efficiently discovering optima in under 100 experiments that are up to 3×more highly optimized than those discovered by similar methods.
基金We are grateful to Jung Ki Song,Mo Deng,Baoliang Ge,William Harrod,Ed Cole,Zachary Levine,Bradley Alpert,Nina Weisse-Bernstein,Lee Oesterling,and Antonio Orozco for helpful discussions and comments.Funding from the Intelligence Advanced Research Projects Activity,Office of the Director of National Intelligence(IARPA-ODNI),contract FA8650-17-C-9113 is gratefully acknowledged.The MIT SuperCloud and Lincoln Laboratory Supercomputing Center provided resources(high performance computing,database,consultation)that have contributed to the research results reported within this paperI.Kang acknowledges support from Korea Foundation for Advanced Studies(KFAS).This research used resources of the Advanced Photon Source,a U.S.Department of Energy(DOE)Office of Science User Facility,operated for the DOE Office of Science by Argonne National Laboratory under Contract No.DE-AC02-06CH11357.The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements,either expressed or implied,of the ODNI,IARPA,or the US Government.
文摘Noninvasive X-ray imaging of nanoscale three-dimensional objects,such as integrated circuits(ICs),generally requires two types of scanning:ptychographic,which is translational and returns estimates of the complex electromagnetic field through the IC;combined with a tomographic scan,which collects these complex field projections from multiple angles.Here,we present Attentional Ptycho-Tomography(APT),an approach to drastically reduce the amount of angular scanning,and thus the total acquisition time.APT is machine learning-based,utilizing axial self-Attention for Ptycho-Tomographic reconstruction.APT is trained to obtain accurate reconstructions of the ICs,despite the incompleteness of the measurements.The training process includes regularizing priors in the form of typical patterns found in IC interiors,and the physics of X-ray propagation through the IC.We show that APT with×12 reduced angles achieves fidelity comparable to the gold standard Simultaneous Algebraic Reconstruction Technique(SART)with the original set of angles.When using the same set of reduced angles,then APT also outperforms Filtered Back Projection(FBP),Simultaneous Iterative Reconstruction Technique(SIRT)and SART.The time needed to compute the reconstruction is also reduced,because the trained neural network is a forward operation,unlike the iterative nature of these alternatives.Our experiments show that,without loss in quality,for a 4.48×93.2×3.92µm^(3) IC(≃6×10^(8) voxels),APT reduces the total data acquisition and computation time from 67.96 h to 38 min.We expect our physics-assisted and attention-utilizing machine learning framework to be applicable to other branches of nanoscale imaging,including materials science and biological imaging.
基金supported by the National Key R&D Program of China(Grant No.2020YFC2005405)the National Natural Science Foundation of China(Grant No.61904004 and Grant No.82027805)+2 种基金the Seeding Grant for Medicine and Information on Sciences awarded by Peking University(Grant No.BMU2018MI003)Dr.Yaoping Liu thanks the Postdoctoral Science Foundation of China(Grant Nos.2018M631261 and 2019T20018)supported by the 111 Project(B18001).
文摘Liquid biopsy of cancers,detecting tumor-related information from liquid samples,has attracted wide attentions as an emerging technology.Our previously reported large-area PERFECT(Precise-Efficient-Robust-Flexible-Easy-ControllableThin)filter has demonstrated competitive sensitivity in recovering rare tumor cells from clinical samples.However,it is time-consuming and easily biased to manually inspect rare target cells among numerous background cells distributed in a large area(Φ≥13 mm).This puts forward an urgent demand for rapid and bias-free inspection.Hereby,this paper implemented deep learning-based object detection for the inspection of rare tumor cells from large-field images of PERFECT filters with hematoxylin-eosin(HE)-stained cells recovered from bronchoalveolar lavage fluid(BALF).CenterNet,EfficientDet,and YOLOv5 were trained and validated with 240 and 60 image blocks containing tumor and/or background cells,respectively.YOLOv5 was selected as the basic network given the highest mAP@0.5 of 92.1%,compared to those of CenterNet and EfficientDet at 85.2%and 91.6%,respectively.Then,tricks including CIoU loss,image flip,mosaic,HSV augmentation and TTA were applied to enhance the performance of the YOLOv5 network,improving mAP@0.5 to 96.2%.This enhanced YOLOv5 network-based object detection,named as BALFilter Reader,was tested and cross-validated on 24 clinical cases.The overall diagnosis performance(~2 min)with sensitivity@66.7%±16.7%,specificity@100.0%±0.0%and accuracy@75.0%±12.5%was superior to that from two experienced pathologists(10–30 min)with sensitivity@61.1%,specificity@16.7%and accuracy@50.0%,with the histopathological result as the gold standard.The AUC of the BALFilter Reader is 0.84±0.08.Moreover,a customized Web was developed for a user-friendly interface and the promotion of wide applications.The current results revealed that the developed BALFilter Reader is a rapid,bias-free and easily accessible AI-enabled tool to promote the transplantation of the BALFilter technique.This work can easily expand to other cytopathological diagnoses and improve the application value of micro/nanotechnology-based liquid biopsy in the era of intelligent pathology.
基金the National University of Singapore(Nano Nash Program A-0004336-00-00&A-000850400-00,Singapore)Nanyang Technological University,Singapore(grant number 001487-00001)+4 种基金the Industry Alignment Fund—Pre-Positioning(IAF-PP)grant(A20G1a0046 and R-148-000-307-305/A0004345-00-00)the Singapore Ministry of Education,under its Singapore Ministry of Education Academic Research Fund Tier 1(10051-MOE AcRF Tier 1:Thematic Call 2020)from Bertrand Czarnythe National University of Singapore Nano-NASH Program(NUHSRO/2020/002/Nano Nash/LOA)the National University of Singapore Yong Loo Lin School of Medicine Nanomedicine Translational Research Program(NUHSRO/2021/034/TRP/09/Nanomedicine)the financial supports from Agency for Science,Technology,and Research(A~*STAR,Singapore)Advanced Manufacturing and Engineering Individual Research Grant(AME IRG)(Project ID:A1883c0013,Singapore)。
文摘Wound healing is a dynamic process that involves a series of molecular and cellular events aimed at replacing devitalized and missing cellular components and/or tissue layers.Recently,extracellular vesicles(EVs),naturally cell-secreted lipid membrane-bound vesicles laden with biological cargos including proteins,lipids,and nucleic acids,have drawn wide attention due to their ability to promote wound healing and tissue regeneration.However,current exploitation of EVs as therapeutic agents is limited by their low isolation yields and tedious isolation processes.To circumvent these challenges,bioinspired cell-derived nanovesicles(CDNs)that mimic EVs were obtained by shearing mesenchymal stem cells(MSCs)through membranes with different pore sizes.Physical characterisations and highthroughput proteomics confirmed that MSC-CDNs mimicked MSC-EVs.Moreover,these MSC-CDNs were efficiently uptaken by human dermal fibroblasts and demonstrated a dose-dependent activation of MAPK signalling pathway,resulting in enhancement of cell proliferation,cell migration,secretion of growth factors and extracellular matrix proteins,which all promoted tissue regeneration.Of note,MSC-CDNs enhanced angiogenesis in human dermal microvascular endothelial cells in a 3D PEGfibrin scaffold and animal model,accelerating wound healing in vitro and in vivo.These findings suggest that MSC-CDNs could replace both whole cells and EVs in promoting wound healing and tissue regeneration.
