Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis:a narrative review

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.

Multiple sclerosis：integration of modeling with biology,clinical and imaging measures to provide better monitoring of disease progression and prediction of outcome

Multiple Sclerosis（MS） is a major cause of neurological disability in adults and has an annual cost of approximately $28 billion in the United States. MS is a very complex disorder as demyelination can happen in a variety of locations throughout the brain; therefore, this disease is never the same in two patients making it very hard to predict disease progression. A modeling approach which combines clinical, biological and imaging measures to help treat and fight this disorder is needed. In this paper, I will outline MS as a very heterogeneous disorder, review some potential solutions from the literature, demonstrate the need for a biomarker and will discuss how computational modeling combined with biological, clinical and imaging data can help link disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism.

Emulating a System Dynamics Model with Agent-Based Models: A Methodological Case Study in Simulation of Diabetes Progression

An agent-based simulation model hierarchy emulating disease states and behaviors critical to progression of diabetes type 2 was designed and implemented in the DEVS framework. This model was built to approximately reproduce some essential findings that were previously reported for a rather complex model of diabetes progression. Our models are translations of basicelements of this previously reported system dynamics model of diabetes. The system dynamics model, which mimics diabetes progression over an aggregated US population, was disaggregated and reconstructed bottom-up at the individual (agent) level. Four levels of model complexity were defined in order to systematically evaluate which parameters are needed to mimic outputs of the system dynamics model. The four estimated models attempted to replicate stock counts representing disease states in the system dynamics model while estimating impacts of an elderliness factor, obesity factor and health-related behavioral parameters. Health-related behavior was modeled as a simple realization of the Theory of Planned Behavior, a joint function of individual attitude and diffusion of social norms that spread over each agent’s social network. Although the most complex agent-based simulation model contained 31 adjustable parameters, all models were considerably less complex than the system dynamics model which required numerous time series inputs to make its predictions. All three elaborations of the baseline model provided significantly improved fits to the output of the system dynamics model, although behavioral factors appeared to contribute more than the elderliness factor. The results illustrate a promising approach to translate complex system dynamics models into agent-based model alternatives that are both conceptually simpler and capable of capturing main effects of complex local agent-agent interactions.

Prediction for risk of disease progression among hospitalized COVID-19 patients

Objective:The COVID-19 pandemic poses a significant threat to global health.Given the lack of studies on risk factors for COVID-19 progression at present,this study aimed to build a predictive model to predict the progression risk among hospitalized COVID-19 patients.Methods:We extracted data from 1074 mild and moderate COVID-19 patients from Electronic Health Records(EHRs)in a designated Wuhan hospital including demographic characteristics and clinical and laboratory information.Disease progression was defined as progressing to severe critical illness after admission.The LASSO regression was used to select the predicted variables and a logistic regression model was applied to build the predictive model.Nomogram was used to show the results.Results:Seven variables were included in the predictive model:age per 10 years(OR,1.15;95%CI,1.03-1.29),lactate dehydrogenase(OR,1.73;95%CI,1.14-2.62),neutrophil-to-lymphocyte ratio(OR,2.07;95%CI,1.42-3.02),eosinophil count(OR,2.10;95%CI,1.20-3.69),albumin(OR,2.37;95%CI,1.65-3.45),hemoglobin(OR,1.50;95%CI,1.10-2.05),D-dimer(OR,1.63;95%CI,1.19-2.23).The mean area under the receiver operating characteristic curve of the predictive model was 0.72(95%CI,0.69-0.76).Conclusions:This study built a predictive model that could effectively predict the progression risk among hospitalized COVID-19 patients.

Pressure stimulated current in progressive failure process of combined coal-rock under uniaxial compression:Response and mechanism

Effective monitoring of the structural health of combined coal-rock under complex geological conditions by pressure stimulated currents(PSCs)has great potential for the understanding of dynamic disasters in underground engineering.To reveal the effect of this way,the uniaxial compression experiments with PSC monitoring were conducted on three types of coal-rock combination samples with different strength combinations.The mechanism explanation of PSCs are investigated by resistivity test,atomic force microscopy(AFM)and computed tomography(CT)methods,and a PSC flow model based on progressive failure process is proposed.The influence of strength combinations on PSCs in the progressive failure process are emphasized.The results show the PSC responses between rock part,coal part and the two components are different,which are affected by multi-scale fracture characteristics and electrical properties.As the rock strength decreases,the progressive failure process changes obviously with the influence range of interface constraint effect decreasing,resulting in the different responses of PSC strength and direction in different parts to fracture behaviors.The PSC flow model is initially validated by the relationship between the accumulated charges of different parts.The results are expected to provide a new reference and method for mining design and roadway quality assessment.

Practical Progress of SBAR Communication Model-Related Teaching in Clinical Teaching

This paper elaborates the core and essence of situation,background,assessment,recommendation(SBAR)communication model,clarify the application status of SBAR communication model in the clinical teaching of nursing students,and describe its effectiveness and limitations,so as to provide reference for improving clinical nursing teaching ability.

Study on Theme-Rheme Pattern Model of English Advertisement Discourse

Theme-rheme pattern model is the principle base for analyzing English advertisement discourse.We find the discourse of English advertisements,by analysis,in such ways of developing as parallel model,continuous model,alternative model and concentrated model,has reflected the ad owner's expectation to change the law of audiences' cognition.This kind of law and the advertising function is closely connected with the same purpose,which contributes to affect potential consumers.

Fuzzy Modelling for Predicting the Risk of Recurrence and Progression of Superficial Bladder Tumors

Nowadays, bladder cancer is the fourth most common cancer in adults and the second most frequent urogenital tumor. Predicting recurrence and progression of superficial bladder tumors, with available clinical information to decide the therapy to be used is a difficult task. In this work, two mathematical models were developed to help specialists on the decision process. The mathematical tool used to formulate the model was the fuzzy sets theory, due to its capacity in dealing with uncertainties inherent in medical concepts. In the first model, Stage, Grade and Size of the tumor were also considered input variables and Risk of Recurrence of a superficial bladder tumor as output variable of the first Fuzzy Rule-Based Systems (FRBS). In the second model, in addition to the Stage, Grade and Size of the tumor, it was also considered as input variable of a second FRBS Carcinoma in situ and, the Risk of Progression of superficial tumors as an output variable. For each model, simulations were made with data originated from of patients of the Clinics Hospital/ UNICAMP and A. C. Camargo Hospital of São Paulo, with the aim to verify the reliability of results generated by the two systems. From a database and the possibility found by FRBS, after the possibility-probability transformation, we can generate the real probability of each fuzzy output set.

Progress in biological research on Tupaia belangeri

Tupaia belangeri,as a typical tropical species,has high value in biological research.It has the characteristics of small body size,high brain to body mass ratio,short reproductive cycle,short lifespan,and low maintenance cost.In biomedical research,experimental animals considered as substitutes for primates.This review discusses the systematic classification,distribution,and research progress of Scandentia.Emphasis was focus on the research progress,developmental status,and basic biological research in T.belangeri.Believing that the T.belangeri,as the closest species to humans,has many advantages as an experimental animal,and it can be further widely applied in human disease research.Therefore,how to create a clear and stable strain of T.belangeri with a clear genetic background is crucial for the development of the national economy and scientific research.

On the Application of Theme-Rheme Theory in College English Writing

Writing is one of the four basic skills students are required to master in foreign language studies,and an important way of language output.However,the teaching of English writing in college is deficient.In the English writings of college students,the lack of structural cohesion and semantic coherence is common.The theme-rheme theory is about discourse cohesion.Proper use of themes and thematic progession patterns qualifies cohesion and clear thoughts of a discourse and the variety of sentence patterns.Therefore,the theme-rheme theory plays an important role in writing teaching.

NUMERICAL MODELLING OF PROGRESSIVE FAILURE IN PARTICULATE COMPOSITES LIKE SANDSTONE

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Modeling of anisotropic polydispersed composites by progressive micromechanical approach

A progressive micromechanical method is presented in order to predict the elastic constants of polydispersed composites including multi-directional or randomly ori- ented reinforcement particles. Heterogeneities of various types are introduced into the matrices in a gradual manner. At each step, the Mori-Tanaka method is used to ob- tain the stiffness tensor of the intermediate medium used as a matrix of the following step. The proposed method is capable of introducing any kind of heterogeneities based on their dimensions, orientations, mechanical properties, and volume fractions to the ma- trix. Furthermore, suitable probability density functions can be defined for physical and structural parameters of the composite, including the level of the filler-matrix interfacial bonding, the aspect ratio, and the orientation of reinforcement particles. The efficiency of the iterative approach and the convergence of the solution are studied by computing the stiffness tensors of unidirectional and bidirectional particulate composites. The results of the present study are also compared with the literature data for a randomly oriented particulate composite.

Disturbed bone remodelling activity varies in different stages of experimental, gradually progressive apical periodontitis in rats

Bone remodelling keeps going through the lifespan of human by bone formation and bone resorption.In the craniofacial region,mandibles act as the main force for biting and chewing,and also become susceptible to a common bone-loss disease,namely,apical periodontitis,once infected dental pulp is not treated timely,during which bone resorption occurs from the apical foramen to the apical bone area.Although conventional root canal treatment(RCT)can remove the most of the infection,chronical apical periodontitis due to incomplete removal of dental pulp and subsequent microleakage will become refractory and more challenging,and this process has scarcely been specifically studied as a bone remodelling issue in rat models.Therefore,to study chronical and refractory apical periodontitis owing to incomplete cleaning of infected dental pulp and microleackage in vivo,we establish a modified rat model of gradually progressive apical periodontitis by sealing residual necrotic dental pulp and introducing limited saliva,which simulates gradually progressive apical periodontitis,as observed in the clinical treatment of chronical and refractory apical periodontitis.We show that bone-loss is inevitable and progressive in this case of apical periodontitis,which confirms again that complete and sound root canal treatment is crucial to halt the progression of chronical and refractory apical periodontitis and promote bone formation.Interestingly,bone remodelling was enhanced at the initial stage of apical periodontitis in this model while reduced with a high osteoblast number afterwards,as shown by the time course study of the modified model.Suggesting that the pathological apical microenvironment reserve its hard tissue formation ability to some degree but in a disturbed manner.Hopefully,our findings can provide insights for future bone regenerative treatment for apical periodontitisassociated bone loss.

A progressive processing method for breast cancer detection via UWB based on an MRI-derived model

Ultra-wideband （UWB） microwave imaging is a promising method for breast cancer detection based on the large contrast of electric parameters between the malignant tumor and its surrounded normal breast organisms. In the case of multiple tumors being present, the conventional imaging approaches may be ineffective to detect all the tumors clearly. In this paper, a progressive processing method is proposed for detecting more than one tumor. The method is divided into three stages： primary detection, refocusing and image optimization. To test the feasibility of the approach, a numerical breast model is developed based on the realistic magnetic resonance image （MRI）. Two tumors are assumed embedded in different positions. Successful detection of a 3.6 mm-diameter tumor at a depth of 42 mm is achieved. The correct information of both tumors is shown in the reconstructed image, suggesting that the progressive processing method is promising for multi-tumor detection.

PROGRESSIVE FRACTURE MODELING OF THE FAILURE WAVE IN IMPACTED GLASS

The failure wave has been observed propagating in glass under impact loading since 1991. It is a continuous fracture zone which may be associated with the damage accumulation process during the propagation of shock waves. A progressive fracture model was proposed to describe the failure wave formation and propagation in shocked glass considering its heterogeneous meso-structures. The original and. nucleated microcracks will expand along the pores and other defects with concomitant dilation when shock loading is below the Hugoniot Elastic Limit. The governing equation of the failure wave is characterized by inelastic bulk strain with material damage and fracture. And the inelastic bulk strain consists of dilatant strain from nucleation and expansion of microcracks and condensed strain from the collapse of the original pores. Numerical simulation of the free surface velocity was performed and found in good agreement with planar impact experiments on K9 glass at China Academy of Engineering Physics. And the longitudinal, lateral and shear stress histories upon the arrival of the failure wave were predicted, which present the diminished shear strength and lost spall strength in the failed layer.

PROGRESSIVE FRAGMENT MODELING OF FAILURE WAVE IN CERAMICS UNDER PLANAR IMPACT LOADING

Polycrystalline ceramics have heterogeneous meso-structures which result in high singularity in stress distribution. Based on this, a progressive fragment model was proposed which describes the failure wave formation and propagation in shocked ceramics. The governing equation of the failure wave was characterized by inelastic bulk strain with material damage and fracture. And the inelastic bulk strain consists of dilatant strain from nucleation and expansion of microcracks and condensed strain from collapse of original pores. Numerical simulation of the free surface velocity was performed in good agreement with planar impact experiments on 92.93% aluminas at China Academy of Engineering Physics. And the longitudinal, lateral and shear stress histories upon the arrival of the failure wave were predicted, which present the diminished shear strength and lost spall strength in the failed layer.

Predicting Simplified Thematic Progression Pattern for Discourse Analysis

The pattern of thematic progression,reflecting the semantic relationships between contextual two sentences,is an important subject in discourse analysis.We introduce a new corpus of Chinese news discourses annotated with thematic progression information and explore some computational methods to automatically extracting the discourse structural features of simplified thematic progression pattern(STPP)between contextual sentences in a text.Furthermore,these features are used in a hybrid approach to a major discourse analysis task,Chinese coreference resolution.This novel approach is built up via heuristic sieves and a machine learning method that comprehensively utilizes both the top-down STPP features and the bottom-up semantic features.Experimental results on the intersection of the CoNLL-2012 task shared dataset and the CDTC corpus demonstrate the effectiveness of our proposed approach.

INPUT-OUTPUT MODELS OF SCIENCE AND TECHNOLOGY AND ITS APPLICATION IN EVALUATING PROGRESS OF ENTERPRISE SCIENCE AND TECHNOLOGY

The method of compiling input-output models of science and technology was studied,and the application of input-output techniques in evaluating the progress of enterprise science and technology was discussed.And the models for determining direct,indirect and full contributions of the progress of enterprise science and technology have been set up which can be used to analyse and evaluate the direct,indirect and full benefits of the progress of enterprise science and technology.

Modelling of heat transfer for progressive freeze concentration process by spiral finned crystallizer

This study presents a novel design for a spiral finned crystallizer which is the primary element of progressive freeze concentration(PFC) system, which simplifies the setup of the conventional system. After the crystallizer has been designed, the research experiments have been conducted and evaluated through a thorough analysis of its performance by developing a mathematical model that can be used to predict the productivity of ice crystal at a range of coolant temperature. The model is developed based on the basic heat transfer equation, and by considering the solution's and the coolant's convective heat transfer coefficient(h) under the forced flow condition.The model's accuracy is verified by making comparison between the ice crystal mass' experimental value and the values predicted by the model. Consequently, the study found that the model helps in enhancing the PFC system.

Research progress and comparison of the establishment of animal models of radiotherapy or chemotherapy-induced oral mucositis

The mechanism of radiotherapy or chemotherapy-induced oral mucositis is not yet clear.And model establishment is needed in further study.In order to summarize the methods of model establishment and make a comparison,literature databases including Web of Science、Pubmed and CNKI were searched for related researches from January 2015 to January 2021.Hamsters,mice,rats,guinea pigs and miniature pigs were chosen to be modeling animals and modeling methods could be classified into:chemotherapy,chemotherapy combined with superficial mucosal irritation,radiotherapy,radiotherapy combined with superficial mucosal irritation and chemoradiotherapy.Advantages and disadvantages had been analyzed in this study to provide reference for following studies.