Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is ...Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is considerable heterogeneity,including clinical presentation,progression,and the underlying triggers for disease initiation.Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations,it has become apparent that overt disease is preceded by a prodromal phase,possibly in years,where compensatory mechanisms delay symptom onset.Since 85-90%of amyotrophic lateral sclerosis is sporadic,there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration.Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease.Skeletal muscle,including the neuromuscular junction,manifests abnormalities at the earliest stages of the disease,before motor neuron loss,making it a promising source for identifying biomarkers of the prodromal phase.The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time.The advent of“omics”technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle,ranging from coding and non-coding RNAs to proteins and metabolites.This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms.A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease.There are two major goals of this review.The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity,evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages,and evidence of progressive change during disease progression.The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression,and as such,their potential as therapeutic targets in amyotrophic lateral sclerosis.展开更多
By studying the spectral properties of the underlying operator corresponding to the M/G/1 queueing model with optional second service we obtain that the time-dependent solution of the model strongly converges to its s...By studying the spectral properties of the underlying operator corresponding to the M/G/1 queueing model with optional second service we obtain that the time-dependent solution of the model strongly converges to its steady-state solution. We also show that the time-dependent queueing size at the departure point converges to the corresponding steady-state queueing size at the departure point.展开更多
Partial drainage often occurs during piezocone penetration testing on Yellow River Delta silt because of its intermediate physical and mechanical properties between those of sand and clay.Yet,there is no accurate unde...Partial drainage often occurs during piezocone penetration testing on Yellow River Delta silt because of its intermediate physical and mechanical properties between those of sand and clay.Yet,there is no accurate understanding for the range of penetra-tion rates to trigger the partial drainage of silt soils.In order to fully investigate cone penetration rate effects under partial drainage condi-tions,indoor 1 g penetration model tests and numerical simulations of cavity expansion at variable penetration rates were carried out on the Yellow River Delta silt.The boundary effect of the model tests and the variation of key parameters at the different cavity ex-pansion rates were analyzed.The 1 g penetration model test results and numerical simulations results consistently indicated that the penetration rate to trigger the partially drainage of typical silt varied at least three orders of magnitude.The numerical simulations also provide the reference values for the penetration resistance corresponding to zero dilation and zero viscosity at any given normalized penetration rate for silt in Yellow River Delta.These geotechnical properties can be used for the design of offshore platforms in Yel-low River Delta,and the understanding of cone penetration rate effects under the partially drained conditions would provide some technical support for geohazard evaluation of offshore platforms.展开更多
By studying the spectrum of the underlying operator corresponding to the exhaustive-service M/G/1 queueing model with single vacations we prove that the time-dependent solution of the model strongly converges to its s...By studying the spectrum of the underlying operator corresponding to the exhaustive-service M/G/1 queueing model with single vacations we prove that the time-dependent solution of the model strongly converges to its steady-state solution.展开更多
A novel anchorage for long-span suspension bridges,called pile-caisson composite structures,was recently proposed by the authors in an attempt to reduce the construction period and costs.This study aims to investigate...A novel anchorage for long-span suspension bridges,called pile-caisson composite structures,was recently proposed by the authors in an attempt to reduce the construction period and costs.This study aims to investigate the displacement and force behavior of piles in a pile-caisson composite structure under eccentric inclined loading considering different stratum features.To this end,both 1g model tests and three-dimensional numerical simulations were performed.Two groups of 1g model tests were used to validate the finite-element(FE)method.Parametric studies were then performed to investigate the effects of groundwater level,burial depth of the pile-caisson composite structure,and distribution of soil layers on the performance of the pile-caisson composite structure.The numerical analyses indicated that the influence of the groundwater level on the stability of the caisson was much greater than that of the piles.In addition,increasing the burial depth of the pile-caisson composite structure can assist in reducing the displacements and improving the stability of the pile-caisson composite structure.In addition,the distribution of soil layers can significantly affect the stability of the pile-caisson composite structure,especially the soil layer around the caisson.展开更多
Let {Xn} be a Markov chain with transition probability pij =： aj-（i-1）＋,i,j ≥ 0, where aj=0 providedj 〈 0, a0 〉 0, a0＋a1〈 1 and ∑∞n=0 an= 1. Let μ∑∞n=1nan. It is known that {Xn} is positive recurrent wh...Let {Xn} be a Markov chain with transition probability pij =： aj-（i-1）＋,i,j ≥ 0, where aj=0 providedj 〈 0, a0 〉 0, a0＋a1〈 1 and ∑∞n=0 an= 1. Let μ∑∞n=1nan. It is known that {Xn} is positive recurrent when μ 〈 1; is null recurrent when μ= 1; and is transient when μ 〉 1. In this paper, the integrability of the first returning time and the last exit time are discussed. Keywords Geom/G/1 queuing model, first returning time, last exit time, Markov chain展开更多
基金supported by NIH Grants R01NS092651 and R21NS111275-01the Department of Veterans Affairs,BX001148 and BX005899(to PHK)。
文摘Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is considerable heterogeneity,including clinical presentation,progression,and the underlying triggers for disease initiation.Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations,it has become apparent that overt disease is preceded by a prodromal phase,possibly in years,where compensatory mechanisms delay symptom onset.Since 85-90%of amyotrophic lateral sclerosis is sporadic,there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration.Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease.Skeletal muscle,including the neuromuscular junction,manifests abnormalities at the earliest stages of the disease,before motor neuron loss,making it a promising source for identifying biomarkers of the prodromal phase.The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time.The advent of“omics”technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle,ranging from coding and non-coding RNAs to proteins and metabolites.This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms.A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease.There are two major goals of this review.The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity,evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages,and evidence of progressive change during disease progression.The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression,and as such,their potential as therapeutic targets in amyotrophic lateral sclerosis.
基金supported by the National Natural Science Foundation of China(11371303)Natural Science Foundation of Xinjiang(2012211A023)Science Foundation of Xinjiang University(XY110101)
文摘By studying the spectral properties of the underlying operator corresponding to the M/G/1 queueing model with optional second service we obtain that the time-dependent solution of the model strongly converges to its steady-state solution. We also show that the time-dependent queueing size at the departure point converges to the corresponding steady-state queueing size at the departure point.
基金supported by the National Natural Science Foundation of China(Nos.U1806230,U2006213),and the Fundamental Research Funds for the Central Univer-sities(No.201962011).
文摘Partial drainage often occurs during piezocone penetration testing on Yellow River Delta silt because of its intermediate physical and mechanical properties between those of sand and clay.Yet,there is no accurate understanding for the range of penetra-tion rates to trigger the partial drainage of silt soils.In order to fully investigate cone penetration rate effects under partial drainage condi-tions,indoor 1 g penetration model tests and numerical simulations of cavity expansion at variable penetration rates were carried out on the Yellow River Delta silt.The boundary effect of the model tests and the variation of key parameters at the different cavity ex-pansion rates were analyzed.The 1 g penetration model test results and numerical simulations results consistently indicated that the penetration rate to trigger the partially drainage of typical silt varied at least three orders of magnitude.The numerical simulations also provide the reference values for the penetration resistance corresponding to zero dilation and zero viscosity at any given normalized penetration rate for silt in Yellow River Delta.These geotechnical properties can be used for the design of offshore platforms in Yel-low River Delta,and the understanding of cone penetration rate effects under the partially drained conditions would provide some technical support for geohazard evaluation of offshore platforms.
基金supported by National Natural Science Foundation of China (GrantNo. 10861011)
文摘By studying the spectrum of the underlying operator corresponding to the exhaustive-service M/G/1 queueing model with single vacations we prove that the time-dependent solution of the model strongly converges to its steady-state solution.
基金support from the National Natural Science Foundation of China(Grant Nos.51778575,52078457).
文摘A novel anchorage for long-span suspension bridges,called pile-caisson composite structures,was recently proposed by the authors in an attempt to reduce the construction period and costs.This study aims to investigate the displacement and force behavior of piles in a pile-caisson composite structure under eccentric inclined loading considering different stratum features.To this end,both 1g model tests and three-dimensional numerical simulations were performed.Two groups of 1g model tests were used to validate the finite-element(FE)method.Parametric studies were then performed to investigate the effects of groundwater level,burial depth of the pile-caisson composite structure,and distribution of soil layers on the performance of the pile-caisson composite structure.The numerical analyses indicated that the influence of the groundwater level on the stability of the caisson was much greater than that of the piles.In addition,increasing the burial depth of the pile-caisson composite structure can assist in reducing the displacements and improving the stability of the pile-caisson composite structure.In addition,the distribution of soil layers can significantly affect the stability of the pile-caisson composite structure,especially the soil layer around the caisson.
基金Supported by National Natural Science Foundation of China(Grant Nos.11001070,11101113)Zhejiang Provincial Natural Science Foundation(Grant No.R6090034)
文摘Let {Xn} be a Markov chain with transition probability pij =： aj-（i-1）＋,i,j ≥ 0, where aj=0 providedj 〈 0, a0 〉 0, a0＋a1〈 1 and ∑∞n=0 an= 1. Let μ∑∞n=1nan. It is known that {Xn} is positive recurrent when μ 〈 1; is null recurrent when μ= 1; and is transient when μ 〉 1. In this paper, the integrability of the first returning time and the last exit time are discussed. Keywords Geom/G/1 queuing model, first returning time, last exit time, Markov chain
