Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism rem...Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism remains unknown.Therefore,experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets.Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4,which is highly expressed on the membrane of astrocyte endfeet,most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes.These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders,such as aquaporin-4 loss,astrocytopathy,granulocyte and macrophage infiltration,complement activation,demyelination,and neuronal loss;however,they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders.In this review,we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro,ex vivo,and in vivo for neuromyelitis optica spectrum disorders,suggest potential pathogenic mechanisms for further investigation,and provide guidance on experimental model choices.In addition,this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders,offering further therapeutic targets and a theoretical basis for clinical trials.展开更多
Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein functio...Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.展开更多
To investigate the mechanisms underlying the onset and progression of ischemic stroke,some methods have been proposed that can simultaneously monitor and create embolisms in the animal cerebral cortex.However,these me...To investigate the mechanisms underlying the onset and progression of ischemic stroke,some methods have been proposed that can simultaneously monitor and create embolisms in the animal cerebral cortex.However,these methods often require complex systems and the effect of age on cerebral embolism has not been adequately studied,although ischemic stroke is strongly age-related.In this study,we propose an optical-resolution photoacoustic microscopy-based visualized photothrombosis methodology to create and monitor ischemic stroke in mice simultaneously using a 532 nm pulsed laser.We observed the molding process in mice of different ages and presented age-dependent vascular embolism differentiation.Moreover,we integrated optical coherence tomography angiography to investigate age-associated trends in cerebrovascular variability following a stroke.Our imaging data and quantitative analyses underscore the differential cerebrovascular responses to stroke in mice of different ages,thereby highlighting the technique's potential for evaluating cerebrovascular health and unraveling age-related mechanisms involved in ischemic strokes.展开更多
Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen r...Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.展开更多
安全生产事故往往由多组织交互、多因素耦合造成,事故原因涉及多个组织。为预防和遏制多组织生产安全事故的发生,基于系统理论事故建模与过程模型(Systems-Theory Accident Modeling and Process,STAMP)、24Model,构建一种用于多组织事...安全生产事故往往由多组织交互、多因素耦合造成,事故原因涉及多个组织。为预防和遏制多组织生产安全事故的发生,基于系统理论事故建模与过程模型(Systems-Theory Accident Modeling and Process,STAMP)、24Model,构建一种用于多组织事故分析的方法,并以青岛石油爆炸事故为例进行事故原因分析。结果显示:STAMP-24Model可以分组织,分层次且有效、全面、详细地分析涉及多个组织的事故原因,探究多组织之间的交互关系;对事故进行动态演化分析,可得到各组织不安全动作耦合关系与形成的事故失效链及管控失效路径,进而为预防多组织事故提供思路和参考。展开更多
Thermal rectification is an exotic thermal transport phenomenon,an analog to electrical rectification,in which heat flux along one direction is larger than that in the other direction and is of significant interest in...Thermal rectification is an exotic thermal transport phenomenon,an analog to electrical rectification,in which heat flux along one direction is larger than that in the other direction and is of significant interest in electronic device applications.However,achieving high thermal rectification efficiency or rectification ratio is still a scientific challenge.In this work,we performed a systematic simulation of thermal rectification by considering both efforts of thermal conductivity asymmetry and geometrical asymmetry in a multi-segment thermal rectifier.It is found that the high asymmetry of thermal conductivity and the asymmetry of the geometric structure of multi-segment thermal rectifiers can significantly enhance the thermal rectification,and the combination of both thermal conductivity asymmetry and geometrical asymmetry can further improve thermal rectification efficiency.This work suggests a possible way for improving thermal rectification devices by asymmetry engineering.展开更多
Through the analysis to the DDoS(distributed denial of service) attack, it will conclude that at different time segments, the arrive rate of normal SYN (Synchronization) package are similar, while the abnormal pac...Through the analysis to the DDoS(distributed denial of service) attack, it will conclude that at different time segments, the arrive rate of normal SYN (Synchronization) package are similar, while the abnormal packages are different with the normal ones. Toward this situation a DDoS defense algorithm based on multi-segment timeout technology is presented, more than one timeout segment are set to control the net flow. Experiment results show that in the case of little flow, multi-segment timeout has the ability dynamic defense, so the system performance is improved and the system has high response rate.展开更多
Complex product development will inevitably face the design planning of the multi-coupled activities, and overlapping these activities could potentially reduce product development time, but there is a risk of the addi...Complex product development will inevitably face the design planning of the multi-coupled activities, and overlapping these activities could potentially reduce product development time, but there is a risk of the additional cost. Although the downstream task information dependence to the upstream task is already considered in the current researches, but the design process overall iteration caused by the information interdependence between activities is hardly discussed; especially the impact on the design process' overall iteration from the valid information accumulation process. Secondly, most studies only focus on the single overlapping process of two activities, rarely take multi-segment and multi-ply overlapping process of multi coupled activities into account; especially the inherent link between product development time and cost which originates from the overlapping process of multi coupled activities. For the purpose of solving the above problems, as to the insufficiency of the accumulated valid information in overlapping process, the function of the valid information evolution (VIE) degree is constructed. Stochastic process theory is used to describe the design information exchange and the valid information accumulation in the overlapping segment, and then the planning models of the single overlapping segment are built. On these bases, by analyzing overlapping processes and overlapping features of multi-coupling activities, multi-segment and multi-ply overlapping planning models are built; by sorting overlapping processes and analyzing the construction of these planning models, two conclusions are obtained: (1) As to multi-segment and multi-ply overlapping of multi coupled activities, the total decrement of the task set development time is the sum of the time decrement caused by basic overlapping segments, and minus the sum of the time increment caused by multiple overlapping segments; (2) the total increment of development cost is the sum of the cost increment caused by all overlapping process. And then, based on overlapping degree analysis of these planning models, by the V1E degree function, the four lemmas theory proofs are represented, and two propositions are finally proved: (1) The multi-ply overlapping of the multi coupled activities will weaken the basic overlapping effect on the development cycle time reduction (2) Overlapping the multi coupled activities will decrease product development cycle, but increase product development cost. And there is trade-off between development time and cost. And so, two methods are given to slacken and eliminate multi-ply overlapping effects. At last, an example about a vehicle upper subsystem design illustrates the application of the proposed models; compared with a sequential execution pattern, the decreasing of development cycle (22%) and the increasing of development cost (3%) show the validity of the method in the example The proposed research not only lays a theoretical foundation for correctly planning complex product development process, but also provides specific and effective operation methods for overlapping multi coupled activities.展开更多
Understanding the anisotropic creep behaviors of shale under direct shearing is a challenging issue.In this context,we conducted shear-creep and steady-creep tests on shale with five bedding orientations (i.e.0°,...Understanding the anisotropic creep behaviors of shale under direct shearing is a challenging issue.In this context,we conducted shear-creep and steady-creep tests on shale with five bedding orientations (i.e.0°,30°,45°,60°,and 90°),under multiple levels of direct shearing for the first time.The results show that the anisotropic creep of shale exhibits a significant stress-dependent behavior.Under a low shear stress,the creep compliance of shale increases linearly with the logarithm of time at all bedding orientations,and the increase depends on the bedding orientation and creep time.Under high shear stress conditions,the creep compliance of shale is minimal when the bedding orientation is 0°,and the steady-creep rate of shale increases significantly with increasing bedding orientations of 30°,45°,60°,and 90°.The stress-strain values corresponding to the inception of the accelerated creep stage show an increasing and then decreasing trend with the bedding orientation.A semilogarithmic model that could reflect the stress dependence of the steady-creep rate while considering the hardening and damage process is proposed.The model minimizes the deviation of the calculated steady-state creep rate from the observed value and reveals the behavior of the bedding orientation's influence on the steady-creep rate.The applicability of the five classical empirical creep models is quantitatively evaluated.It shows that the logarithmic model can well explain the experimental creep strain and creep rate,and it can accurately predict long-term shear creep deformation.Based on an improved logarithmic model,the variations in creep parameters with shear stress and bedding orientations are discussed.With abovementioned findings,a mathematical method for constructing an anisotropic shear creep model of shale is proposed,which can characterize the nonlinear dependence of the anisotropic shear creep behavior of shale on the bedding orientation.展开更多
Precipitous Arctic sea-ice decline and the corresponding increase in Arctic open-water areas in summer months give more space for sea-ice growth in the subsequent cold seasons. Compared to the decline of the entire Ar...Precipitous Arctic sea-ice decline and the corresponding increase in Arctic open-water areas in summer months give more space for sea-ice growth in the subsequent cold seasons. Compared to the decline of the entire Arctic multiyear sea ice,changes in newly formed sea ice indicate more thermodynamic and dynamic information on Arctic atmosphere–ocean–ice interaction and northern mid–high latitude atmospheric teleconnections. Here, we use a large multimodel ensemble from phase 6 of the Coupled Model Intercomparison Project(CMIP6) to investigate future changes in wintertime newly formed Arctic sea ice. The commonly used model-democracy approach that gives equal weight to each model essentially assumes that all models are independent and equally plausible, which contradicts with the fact that there are large interdependencies in the ensemble and discrepancies in models' performances in reproducing observations. Therefore, instead of using the arithmetic mean of well-performing models or all available models for projections like in previous studies, we employ a newly developed model weighting scheme that weights all models in the ensemble with consideration of their performance and independence to provide more reliable projections. Model democracy leads to evident bias and large intermodel spread in CMIP6 projections of newly formed Arctic sea ice. However, we show that both the bias and the intermodel spread can be effectively reduced by the weighting scheme. Projections from the weighted models indicate that wintertime newly formed Arctic sea ice is likely to increase dramatically until the middle of this century regardless of the emissions scenario.Thereafter, it may decrease(or remain stable) if the Arctic warming crosses a threshold(or is extensively constrained).展开更多
This paper presents an enhanced version of the standard shooting method that enables problems with two unknown parameters to be solved.A novel approach is applied to the analysis of the natural vibrations of Euler-Ber...This paper presents an enhanced version of the standard shooting method that enables problems with two unknown parameters to be solved.A novel approach is applied to the analysis of the natural vibrations of Euler-Bernoulli beams.The proposed algorithm,named as two-parameter multiple shooting method,is a new powerful numerical tool for calculating the natural frequencies and modes of multi-segment prismatic and non-prismatic beams with different boundary conditions.The impact of the axial force and additional point masses is also taken into account.Due to the fact that the method is based directly on the fourth-order ordinary differential equation,the structures do not have to be divided into many small elements to obtain an accurate enough solution,even though the geometry is very complex.To verify the proposed method,three different examples are considered,i.e.,a three-segment non-prismatic beam,a prismatic column subject to non-uniformly distributed compressive loads,and a two-segment beam with an additional point mass.Numerical analyses are carried out with the software MATHEMATICA.The results are compared with the solutions computed by the commercial finite element program SOFiSTiK.Good agreement is achieved,which confirms the correctness and high effectiveness of the formulated algorithm.展开更多
A vortex domain wall's(VW) magnetic racetrack memory's high performance depends on VW structural stability,high speed, low power consumption and high storage density. In this study, these critical parameters w...A vortex domain wall's(VW) magnetic racetrack memory's high performance depends on VW structural stability,high speed, low power consumption and high storage density. In this study, these critical parameters were investigated in magnetic multi-segmented nanowires using micromagnetic simulation. Thus, an offset magnetic nanowire with a junction at the center was proposed for this purpose. This junction was implemented by shifting one portion of the magnetic nanowire horizontally in the x-direction(l) and vertically(d) in the y-direction. The VW structure became stable by manipulating magnetic properties, such as magnetic saturation(M_(4)) and magnetic anisotropy energy(K_(u)). In this case, increasing the values of M_(4) ≥ 800 kA/m keeps the VW structure stable during its dynamics and pinning and depinning in offset nanowires,which contributes to maintenance of the storage memory's lifetime for a longer period. It was also found that the VW moved with a speed of 500 m/s, which is desirable for VW racetrack memory devices. Moreover, it was revealed that the VW velocity could be controlled by adjusting the offset area dimensions(l and d), which helps to drive the VW by using low current densities and reducing the thermal-magnetic spin fluctuations. Further, the depinning current density of the VW(J_(d)) over the offset area increases as d increases and l decreases. In addition, magnetic properties, such as the M_(4) and K_(u),can affect the depinning process of the VW through the offset area. For high storage density, magnetic nanowires(multisegmented) with four junctions were designed. In total, six states were found with high VW stability, which means three bits per cell. Herein, we observed that the depinning current density(J_(d)) for moving the VW from one state to another was highly influenced by the offset area geometry(l and d) and the material's magnetic properties, such as the M_(4) and K_(u).展开更多
Since the 1950s,when the Turing Test was introduced,there has been notable progress in machine language intelligence.Language modeling,crucial for AI development,has evolved from statistical to neural models over the ...Since the 1950s,when the Turing Test was introduced,there has been notable progress in machine language intelligence.Language modeling,crucial for AI development,has evolved from statistical to neural models over the last two decades.Recently,transformer-based Pre-trained Language Models(PLM)have excelled in Natural Language Processing(NLP)tasks by leveraging large-scale training corpora.Increasing the scale of these models enhances performance significantly,introducing abilities like context learning that smaller models lack.The advancement in Large Language Models,exemplified by the development of ChatGPT,has made significant impacts both academically and industrially,capturing widespread societal interest.This survey provides an overview of the development and prospects from Large Language Models(LLM)to Large Multimodal Models(LMM).It first discusses the contributions and technological advancements of LLMs in the field of natural language processing,especially in text generation and language understanding.Then,it turns to the discussion of LMMs,which integrates various data modalities such as text,images,and sound,demonstrating advanced capabilities in understanding and generating cross-modal content,paving new pathways for the adaptability and flexibility of AI systems.Finally,the survey highlights the prospects of LMMs in terms of technological development and application potential,while also pointing out challenges in data integration,cross-modal understanding accuracy,providing a comprehensive perspective on the latest developments in this field.展开更多
BACKGROUND Colorectal cancer(CRC)is a serious threat worldwide.Although early screening is suggested to be the most effective method to prevent and control CRC,the current situation of early screening for CRC is still...BACKGROUND Colorectal cancer(CRC)is a serious threat worldwide.Although early screening is suggested to be the most effective method to prevent and control CRC,the current situation of early screening for CRC is still not optimistic.In China,the incidence of CRC in the Yangtze River Delta region is increasing dramatically,but few studies have been conducted.Therefore,it is necessary to develop a simple and efficient early screening model for CRC.AIM To develop and validate an early-screening nomogram model to identify individuals at high risk of CRC.METHODS Data of 64448 participants obtained from Ningbo Hospital,China between 2014 and 2017 were retrospectively analyzed.The cohort comprised 64448 individuals,of which,530 were excluded due to missing or incorrect data.Of 63918,7607(11.9%)individuals were considered to be high risk for CRC,and 56311(88.1%)were not.The participants were randomly allocated to a training set(44743)or validation set(19175).The discriminatory ability,predictive accuracy,and clinical utility of the model were evaluated by constructing and analyzing receiver operating characteristic(ROC)curves and calibration curves and by decision curve analysis.Finally,the model was validated internally using a bootstrap resampling technique.RESULTS Seven variables,including demographic,lifestyle,and family history information,were examined.Multifactorial logistic regression analysis revealed that age[odds ratio(OR):1.03,95%confidence interval(CI):1.02-1.03,P<0.001],body mass index(BMI)(OR:1.07,95%CI:1.06-1.08,P<0.001),waist circumference(WC)(OR:1.03,95%CI:1.02-1.03 P<0.001),lifestyle(OR:0.45,95%CI:0.42-0.48,P<0.001),and family history(OR:4.28,95%CI:4.04-4.54,P<0.001)were the most significant predictors of high-risk CRC.Healthy lifestyle was a protective factor,whereas family history was the most significant risk factor.The area under the curve was 0.734(95%CI:0.723-0.745)for the final validation set ROC curve and 0.735(95%CI:0.728-0.742)for the training set ROC curve.The calibration curve demonstrated a high correlation between the CRC high-risk population predicted by the nomogram model and the actual CRC high-risk population.CONCLUSION The early-screening nomogram model for CRC prediction in high-risk populations developed in this study based on age,BMI,WC,lifestyle,and family history exhibited high accuracy.展开更多
Flow units(FU)rock typing is a common technique for characterizing reservoir flow behavior,producing reliable porosity and permeability estimation even in complex geological settings.However,the lateral extrapolation ...Flow units(FU)rock typing is a common technique for characterizing reservoir flow behavior,producing reliable porosity and permeability estimation even in complex geological settings.However,the lateral extrapolation of FU away from the well into the whole reservoir grid is commonly a difficult task and using the seismic data as constraints is rarely a subject of study.This paper proposes a workflow to generate numerous possible 3D volumes of flow units,porosity and permeability below the seismic resolution limit,respecting the available seismic data at larger scales.The methodology is used in the Mero Field,a Brazilian presalt carbonate reservoir located in the Santos Basin,who presents a complex and heterogenic geological setting with different sedimentological processes and diagenetic history.We generated metric flow units using the conventional core analysis and transposed to the well log data.Then,given a Markov chain Monte Carlo algorithm,the seismic data and the well log statistics,we simulated acoustic impedance,decametric flow units(DFU),metric flow units(MFU),porosity and permeability volumes in the metric scale.The aim is to estimate a minimum amount of MFU able to calculate realistic scenarios porosity and permeability scenarios,without losing the seismic lateral control.In other words,every porosity and permeability volume simulated produces a synthetic seismic that match the real seismic of the area,even in the metric scale.The achieved 3D results represent a high-resolution fluid flow reservoir modelling considering the lateral control of the seismic during the process and can be directly incorporated in the dynamic characterization workflow.展开更多
文摘Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism remains unknown.Therefore,experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets.Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4,which is highly expressed on the membrane of astrocyte endfeet,most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes.These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders,such as aquaporin-4 loss,astrocytopathy,granulocyte and macrophage infiltration,complement activation,demyelination,and neuronal loss;however,they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders.In this review,we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro,ex vivo,and in vivo for neuromyelitis optica spectrum disorders,suggest potential pathogenic mechanisms for further investigation,and provide guidance on experimental model choices.In addition,this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders,offering further therapeutic targets and a theoretical basis for clinical trials.
基金supported by Warren Alpert Foundation and Houston Methodist Academic Institute Laboratory Operating Fund(to HLC).
文摘Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.
基金supported by University of Macao,China,Nos.MYRG2022-00054-FHS and MYRG-GRG2023-00038-FHS-UMDF(to ZY)the Macao Science and Technology Development Fund,China,Nos.FDCT0048/2021/AGJ and FDCT0020/2019/AMJ and FDCT 0011/2018/A1(to ZY)Natural Science Foundation of Guangdong Province of China,No.EF017/FHS-YZ/2021/GDSTC(to ZY)。
文摘To investigate the mechanisms underlying the onset and progression of ischemic stroke,some methods have been proposed that can simultaneously monitor and create embolisms in the animal cerebral cortex.However,these methods often require complex systems and the effect of age on cerebral embolism has not been adequately studied,although ischemic stroke is strongly age-related.In this study,we propose an optical-resolution photoacoustic microscopy-based visualized photothrombosis methodology to create and monitor ischemic stroke in mice simultaneously using a 532 nm pulsed laser.We observed the molding process in mice of different ages and presented age-dependent vascular embolism differentiation.Moreover,we integrated optical coherence tomography angiography to investigate age-associated trends in cerebrovascular variability following a stroke.Our imaging data and quantitative analyses underscore the differential cerebrovascular responses to stroke in mice of different ages,thereby highlighting the technique's potential for evaluating cerebrovascular health and unraveling age-related mechanisms involved in ischemic strokes.
基金supported by the National Key R&D Program of China,No.2021YFA0805200(to SY)the National Natural Science Foundation of China,No.31970954(to SY)two grants from the Department of Science and Technology of Guangdong Province,Nos.2021ZT09Y007,2020B121201006(both to XJL)。
文摘Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.
文摘安全生产事故往往由多组织交互、多因素耦合造成,事故原因涉及多个组织。为预防和遏制多组织生产安全事故的发生,基于系统理论事故建模与过程模型(Systems-Theory Accident Modeling and Process,STAMP)、24Model,构建一种用于多组织事故分析的方法,并以青岛石油爆炸事故为例进行事故原因分析。结果显示:STAMP-24Model可以分组织,分层次且有效、全面、详细地分析涉及多个组织的事故原因,探究多组织之间的交互关系;对事故进行动态演化分析,可得到各组织不安全动作耦合关系与形成的事故失效链及管控失效路径,进而为预防多组织事故提供思路和参考。
基金Project supported by the National Natural Science Foundation of China(Grant No.12274355)Xiamen University Malaysia Research Fund(Grant Nos.XMUMRF/2022C9/IORI/003 and XMUMRF/2022-C10/IORI/004)。
文摘Thermal rectification is an exotic thermal transport phenomenon,an analog to electrical rectification,in which heat flux along one direction is larger than that in the other direction and is of significant interest in electronic device applications.However,achieving high thermal rectification efficiency or rectification ratio is still a scientific challenge.In this work,we performed a systematic simulation of thermal rectification by considering both efforts of thermal conductivity asymmetry and geometrical asymmetry in a multi-segment thermal rectifier.It is found that the high asymmetry of thermal conductivity and the asymmetry of the geometric structure of multi-segment thermal rectifiers can significantly enhance the thermal rectification,and the combination of both thermal conductivity asymmetry and geometrical asymmetry can further improve thermal rectification efficiency.This work suggests a possible way for improving thermal rectification devices by asymmetry engineering.
基金Supported by the Natural Science Foundation ofHebei Province (F2004000133)
文摘Through the analysis to the DDoS(distributed denial of service) attack, it will conclude that at different time segments, the arrive rate of normal SYN (Synchronization) package are similar, while the abnormal packages are different with the normal ones. Toward this situation a DDoS defense algorithm based on multi-segment timeout technology is presented, more than one timeout segment are set to control the net flow. Experiment results show that in the case of little flow, multi-segment timeout has the ability dynamic defense, so the system performance is improved and the system has high response rate.
基金sponsored by Jiangsu Provincial Colleges and Universities Natural Science Foundation of China (Grant No.08KJD410001)Humanities and Social Sciences Planning Fund of Ministry of Education of China (Grant No. 12YJAZH151)Humanities and Social Sciences Youth Fund of Ministry of Education of China (Grant No. 12YJCZH209)
文摘Complex product development will inevitably face the design planning of the multi-coupled activities, and overlapping these activities could potentially reduce product development time, but there is a risk of the additional cost. Although the downstream task information dependence to the upstream task is already considered in the current researches, but the design process overall iteration caused by the information interdependence between activities is hardly discussed; especially the impact on the design process' overall iteration from the valid information accumulation process. Secondly, most studies only focus on the single overlapping process of two activities, rarely take multi-segment and multi-ply overlapping process of multi coupled activities into account; especially the inherent link between product development time and cost which originates from the overlapping process of multi coupled activities. For the purpose of solving the above problems, as to the insufficiency of the accumulated valid information in overlapping process, the function of the valid information evolution (VIE) degree is constructed. Stochastic process theory is used to describe the design information exchange and the valid information accumulation in the overlapping segment, and then the planning models of the single overlapping segment are built. On these bases, by analyzing overlapping processes and overlapping features of multi-coupling activities, multi-segment and multi-ply overlapping planning models are built; by sorting overlapping processes and analyzing the construction of these planning models, two conclusions are obtained: (1) As to multi-segment and multi-ply overlapping of multi coupled activities, the total decrement of the task set development time is the sum of the time decrement caused by basic overlapping segments, and minus the sum of the time increment caused by multiple overlapping segments; (2) the total increment of development cost is the sum of the cost increment caused by all overlapping process. And then, based on overlapping degree analysis of these planning models, by the V1E degree function, the four lemmas theory proofs are represented, and two propositions are finally proved: (1) The multi-ply overlapping of the multi coupled activities will weaken the basic overlapping effect on the development cycle time reduction (2) Overlapping the multi coupled activities will decrease product development cycle, but increase product development cost. And there is trade-off between development time and cost. And so, two methods are given to slacken and eliminate multi-ply overlapping effects. At last, an example about a vehicle upper subsystem design illustrates the application of the proposed models; compared with a sequential execution pattern, the decreasing of development cycle (22%) and the increasing of development cost (3%) show the validity of the method in the example The proposed research not only lays a theoretical foundation for correctly planning complex product development process, but also provides specific and effective operation methods for overlapping multi coupled activities.
基金funded by the National Natural Science Foundation of China(Grant Nos.U22A20166 and 12172230)the Guangdong Basic and Applied Basic Research Foundation(Grant No.2023A1515012654)+1 种基金funded by the National Natural Science Foundation of China(Grant Nos.U22A20166 and 12172230)the Guangdong Basic and Applied Basic Research Foundation(Grant No.2023A1515012654)。
文摘Understanding the anisotropic creep behaviors of shale under direct shearing is a challenging issue.In this context,we conducted shear-creep and steady-creep tests on shale with five bedding orientations (i.e.0°,30°,45°,60°,and 90°),under multiple levels of direct shearing for the first time.The results show that the anisotropic creep of shale exhibits a significant stress-dependent behavior.Under a low shear stress,the creep compliance of shale increases linearly with the logarithm of time at all bedding orientations,and the increase depends on the bedding orientation and creep time.Under high shear stress conditions,the creep compliance of shale is minimal when the bedding orientation is 0°,and the steady-creep rate of shale increases significantly with increasing bedding orientations of 30°,45°,60°,and 90°.The stress-strain values corresponding to the inception of the accelerated creep stage show an increasing and then decreasing trend with the bedding orientation.A semilogarithmic model that could reflect the stress dependence of the steady-creep rate while considering the hardening and damage process is proposed.The model minimizes the deviation of the calculated steady-state creep rate from the observed value and reveals the behavior of the bedding orientation's influence on the steady-creep rate.The applicability of the five classical empirical creep models is quantitatively evaluated.It shows that the logarithmic model can well explain the experimental creep strain and creep rate,and it can accurately predict long-term shear creep deformation.Based on an improved logarithmic model,the variations in creep parameters with shear stress and bedding orientations are discussed.With abovementioned findings,a mathematical method for constructing an anisotropic shear creep model of shale is proposed,which can characterize the nonlinear dependence of the anisotropic shear creep behavior of shale on the bedding orientation.
基金supported by the Chinese–Norwegian Collaboration Projects within Climate Systems jointly funded by the National Key Research and Development Program of China (Grant No.2022YFE0106800)the Research Council of Norway funded project,MAPARC (Grant No.328943)+2 种基金the support from the Research Council of Norway funded project,COMBINED (Grant No.328935)the National Natural Science Foundation of China (Grant No.42075030)the Postgraduate Research and Practice Innovation Program of Jiangsu Province (KYCX23_1314)。
文摘Precipitous Arctic sea-ice decline and the corresponding increase in Arctic open-water areas in summer months give more space for sea-ice growth in the subsequent cold seasons. Compared to the decline of the entire Arctic multiyear sea ice,changes in newly formed sea ice indicate more thermodynamic and dynamic information on Arctic atmosphere–ocean–ice interaction and northern mid–high latitude atmospheric teleconnections. Here, we use a large multimodel ensemble from phase 6 of the Coupled Model Intercomparison Project(CMIP6) to investigate future changes in wintertime newly formed Arctic sea ice. The commonly used model-democracy approach that gives equal weight to each model essentially assumes that all models are independent and equally plausible, which contradicts with the fact that there are large interdependencies in the ensemble and discrepancies in models' performances in reproducing observations. Therefore, instead of using the arithmetic mean of well-performing models or all available models for projections like in previous studies, we employ a newly developed model weighting scheme that weights all models in the ensemble with consideration of their performance and independence to provide more reliable projections. Model democracy leads to evident bias and large intermodel spread in CMIP6 projections of newly formed Arctic sea ice. However, we show that both the bias and the intermodel spread can be effectively reduced by the weighting scheme. Projections from the weighted models indicate that wintertime newly formed Arctic sea ice is likely to increase dramatically until the middle of this century regardless of the emissions scenario.Thereafter, it may decrease(or remain stable) if the Arctic warming crosses a threshold(or is extensively constrained).
文摘This paper presents an enhanced version of the standard shooting method that enables problems with two unknown parameters to be solved.A novel approach is applied to the analysis of the natural vibrations of Euler-Bernoulli beams.The proposed algorithm,named as two-parameter multiple shooting method,is a new powerful numerical tool for calculating the natural frequencies and modes of multi-segment prismatic and non-prismatic beams with different boundary conditions.The impact of the axial force and additional point masses is also taken into account.Due to the fact that the method is based directly on the fourth-order ordinary differential equation,the structures do not have to be divided into many small elements to obtain an accurate enough solution,even though the geometry is very complex.To verify the proposed method,three different examples are considered,i.e.,a three-segment non-prismatic beam,a prismatic column subject to non-uniformly distributed compressive loads,and a two-segment beam with an additional point mass.Numerical analyses are carried out with the software MATHEMATICA.The results are compared with the solutions computed by the commercial finite element program SOFiSTiK.Good agreement is achieved,which confirms the correctness and high effectiveness of the formulated algorithm.
文摘A vortex domain wall's(VW) magnetic racetrack memory's high performance depends on VW structural stability,high speed, low power consumption and high storage density. In this study, these critical parameters were investigated in magnetic multi-segmented nanowires using micromagnetic simulation. Thus, an offset magnetic nanowire with a junction at the center was proposed for this purpose. This junction was implemented by shifting one portion of the magnetic nanowire horizontally in the x-direction(l) and vertically(d) in the y-direction. The VW structure became stable by manipulating magnetic properties, such as magnetic saturation(M_(4)) and magnetic anisotropy energy(K_(u)). In this case, increasing the values of M_(4) ≥ 800 kA/m keeps the VW structure stable during its dynamics and pinning and depinning in offset nanowires,which contributes to maintenance of the storage memory's lifetime for a longer period. It was also found that the VW moved with a speed of 500 m/s, which is desirable for VW racetrack memory devices. Moreover, it was revealed that the VW velocity could be controlled by adjusting the offset area dimensions(l and d), which helps to drive the VW by using low current densities and reducing the thermal-magnetic spin fluctuations. Further, the depinning current density of the VW(J_(d)) over the offset area increases as d increases and l decreases. In addition, magnetic properties, such as the M_(4) and K_(u),can affect the depinning process of the VW through the offset area. For high storage density, magnetic nanowires(multisegmented) with four junctions were designed. In total, six states were found with high VW stability, which means three bits per cell. Herein, we observed that the depinning current density(J_(d)) for moving the VW from one state to another was highly influenced by the offset area geometry(l and d) and the material's magnetic properties, such as the M_(4) and K_(u).
基金We acknowledge funding from NSFC Grant 62306283.
文摘Since the 1950s,when the Turing Test was introduced,there has been notable progress in machine language intelligence.Language modeling,crucial for AI development,has evolved from statistical to neural models over the last two decades.Recently,transformer-based Pre-trained Language Models(PLM)have excelled in Natural Language Processing(NLP)tasks by leveraging large-scale training corpora.Increasing the scale of these models enhances performance significantly,introducing abilities like context learning that smaller models lack.The advancement in Large Language Models,exemplified by the development of ChatGPT,has made significant impacts both academically and industrially,capturing widespread societal interest.This survey provides an overview of the development and prospects from Large Language Models(LLM)to Large Multimodal Models(LMM).It first discusses the contributions and technological advancements of LLMs in the field of natural language processing,especially in text generation and language understanding.Then,it turns to the discussion of LMMs,which integrates various data modalities such as text,images,and sound,demonstrating advanced capabilities in understanding and generating cross-modal content,paving new pathways for the adaptability and flexibility of AI systems.Finally,the survey highlights the prospects of LMMs in terms of technological development and application potential,while also pointing out challenges in data integration,cross-modal understanding accuracy,providing a comprehensive perspective on the latest developments in this field.
基金Supported by the Project of NINGBO Leading Medical Health Discipline,No.2022-B11Ningbo Natural Science Foundation,No.202003N4206Public Welfare Foundation of Ningbo,No.2021S108.
文摘BACKGROUND Colorectal cancer(CRC)is a serious threat worldwide.Although early screening is suggested to be the most effective method to prevent and control CRC,the current situation of early screening for CRC is still not optimistic.In China,the incidence of CRC in the Yangtze River Delta region is increasing dramatically,but few studies have been conducted.Therefore,it is necessary to develop a simple and efficient early screening model for CRC.AIM To develop and validate an early-screening nomogram model to identify individuals at high risk of CRC.METHODS Data of 64448 participants obtained from Ningbo Hospital,China between 2014 and 2017 were retrospectively analyzed.The cohort comprised 64448 individuals,of which,530 were excluded due to missing or incorrect data.Of 63918,7607(11.9%)individuals were considered to be high risk for CRC,and 56311(88.1%)were not.The participants were randomly allocated to a training set(44743)or validation set(19175).The discriminatory ability,predictive accuracy,and clinical utility of the model were evaluated by constructing and analyzing receiver operating characteristic(ROC)curves and calibration curves and by decision curve analysis.Finally,the model was validated internally using a bootstrap resampling technique.RESULTS Seven variables,including demographic,lifestyle,and family history information,were examined.Multifactorial logistic regression analysis revealed that age[odds ratio(OR):1.03,95%confidence interval(CI):1.02-1.03,P<0.001],body mass index(BMI)(OR:1.07,95%CI:1.06-1.08,P<0.001),waist circumference(WC)(OR:1.03,95%CI:1.02-1.03 P<0.001),lifestyle(OR:0.45,95%CI:0.42-0.48,P<0.001),and family history(OR:4.28,95%CI:4.04-4.54,P<0.001)were the most significant predictors of high-risk CRC.Healthy lifestyle was a protective factor,whereas family history was the most significant risk factor.The area under the curve was 0.734(95%CI:0.723-0.745)for the final validation set ROC curve and 0.735(95%CI:0.728-0.742)for the training set ROC curve.The calibration curve demonstrated a high correlation between the CRC high-risk population predicted by the nomogram model and the actual CRC high-risk population.CONCLUSION The early-screening nomogram model for CRC prediction in high-risk populations developed in this study based on age,BMI,WC,lifestyle,and family history exhibited high accuracy.
文摘Flow units(FU)rock typing is a common technique for characterizing reservoir flow behavior,producing reliable porosity and permeability estimation even in complex geological settings.However,the lateral extrapolation of FU away from the well into the whole reservoir grid is commonly a difficult task and using the seismic data as constraints is rarely a subject of study.This paper proposes a workflow to generate numerous possible 3D volumes of flow units,porosity and permeability below the seismic resolution limit,respecting the available seismic data at larger scales.The methodology is used in the Mero Field,a Brazilian presalt carbonate reservoir located in the Santos Basin,who presents a complex and heterogenic geological setting with different sedimentological processes and diagenetic history.We generated metric flow units using the conventional core analysis and transposed to the well log data.Then,given a Markov chain Monte Carlo algorithm,the seismic data and the well log statistics,we simulated acoustic impedance,decametric flow units(DFU),metric flow units(MFU),porosity and permeability volumes in the metric scale.The aim is to estimate a minimum amount of MFU able to calculate realistic scenarios porosity and permeability scenarios,without losing the seismic lateral control.In other words,every porosity and permeability volume simulated produces a synthetic seismic that match the real seismic of the area,even in the metric scale.The achieved 3D results represent a high-resolution fluid flow reservoir modelling considering the lateral control of the seismic during the process and can be directly incorporated in the dynamic characterization workflow.