Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology

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.

A bounding surface visco-plasticity model considering generalized spacing ratio of soils

The non-unique critical state of soils with time-dependent behaviors is a significant issue in geotechnical engineering problems.However,previous bounding surface plasticity models cannot predict accurately the non-unique critical state of soils,because the distance between the compression line and critical state line charged by strain-rate effect is basically neglected.To fill this gap,a generalized spacing ratio of soils is defined in the elasto-viscoplastic framework,and a bounding surface visco-plasticity model is formulated and verified,which can consider the generalized spacing ratio.Specifically,the generalized spacing ratio of soils reflects the distance between the compression line and the critical state line of soils with time-dependent behaviors.Then,the generalized spacing ratio is introduced into an improved anisotropic bounding surface.A new expression of the visco-plastic multiplier is derived by solving the consistency equation of an anisotropic bounding surface.In the expression,a strain rate index is proposed to account for the strain-rate effect on visco-plastic strain increment,and a visco-plastic hardening modulus is derived to predict the visco-plastic response of soils in overconsolidation conditions.The model is then verified through constant strain rate tests and creep tests.Notably,it can capture the non-unique critical states of soils with time-dependent behaviors due to the generalized spacing ratio and the creep rupture of soils due to the visco-plastic multiplier that considers the stress ratio and visco-plastic strain rate.

Generalized Height-Diameter Models for Pinus montezumae Lamb. and Pinus pseudostrobus Lindl. Plantations in Michoacan, Mexico

Tree height (H) in a natural stand or forest plantation is a fundamental variable in management, and the use of mathematical expressions that estimate H as a function of diameter at breast height (d) or variables at the stand level is a valuable support tool in forest inventories. The objective was to fit and propose a generalized H-d model for Pinus montezumae and Pinus pseudostrobus established in forest plantations of Nuevo San Juan Parangaricutiro, Michoacan, Mexico. Using nonlinear least squares (NLS), 10 generalized H-d models were fitted to 883 and 1226 pairs of H-d data from Pinus montezumae and Pinus pseudostrobus, respectively. The best model was refitted with the maximum likelihood mixed effects model (MEM) approach by including the site as a classification variable and a known variance structure. The Wang and Tang equation was selected as the best model with NLS;the MEM with an additive effect on two of its parameters and an exponential variance function improved the fit statistics for Pinus montezumae and Pinus pseudostrobus, respectively. The model validation showed equality of means among the estimates for both species and an independent subsample. The calibration of the MEM at the plot level was efficient and might increase the applicability of these results. The inclusion of dominant height in the MEM approach helped to reduce bias in the estimates and also to better explain the variability among plots.

A generalized viscoelastic Biot/squirt model for clay-bearing sandstones in a wide range of permeabilities

To simultaneously take into account the Biot-flow mechanism, the squirt-flow mechanism, and the frame-viscoelasticity mechanism, a generalized viscoelastic BISQ （Biot/squirt） model is developed for wave propagation in clay-bearing sandstones based on Dvorkin＇s elastic BISQ model. The present model is extended to a wide range of permeabilities （k 〉 0.05 mD） by introducing a dimensionless correction factor for viscoelastic parameters, defined as a function of the permeability and the clay content. We describe the frame＇s stress-strain relationship of the clay-bearing sandstones by the differential constitutive equations of generalized viscoelasticity and then derive the viscoelastic-wave dynamic equations. With the assumption of a plane-wave solution, we finally yield the phase velocities and the attenuation coefficients by solving the dynamic wave equations in the frequency and wave number domain. The comparison of numerical results and experimental data shows that the generalized viscoelastic BISQ model is applicable for modeling the wave propagation in most of the sandstones mainly bearing kaolinite clay.

Generalized functional model of maximum and minimum detectable deformation gradient for PALSAR interferometry

Empirical functional models for the maximum and minimum detectable deformation gradient of PALSAR interferometry were established based on coherence and discrete look numbers. Then, a least square regression method was used to fit the model coefficients and thus obtain the generalized functional models for both coherence and look numbers. The experimental results with ALOS PALSAR data of Wenchuan earthquake of China show that the new model works well for judging whether the deformation gradient can be detected by the D-InSAR technology or not. The results can help researchers to choose PALSAR data and to configure processing parameters, and also benefit the interpretation of the measured surface deformation.

Study upon Modeling and Visualization of 3D Geologic Body Based on Generalized Tri-Prism

According to the characteristics of bore data,a model of 3D geologic body with generalized tri-prism as the primitive modeling element is constructed while the modeling process and key algorithms of modeling are presented here in detail.Using this method,the original bore data go through Delaunay triangulation to generate irregular triangular network on the surface,and then links stratum segments on the adjoining bores in session to form tri-prisms which would be pinched out.Finally stratified 3D geologic body model is built by an iterated search which searches for consecutive layer of the same property.The result shows that this method can effectively simulate stratified stratum modeling.

Diagnostics in generalized nonlinear models based on maximum L_q-likelihood estimation

In order to detect whether the data conforms to the given model, it is necessary to diagnose the data in the statistical way. The diagnostic problem in generalized nonlinear models based on the maximum Lq-likelihood estimation is considered. Three diagnostic statistics are used to detect whether the outliers exist in the data set. Simulation results show that when the sample size is small, the values of diagnostic statistics based on the maximum Lq-likelihood estimation are greater than the values based on the maximum likelihood estimation. As the sample size increases, the difference between the values of the diagnostic statistics based on two estimation methods diminishes gradually. It means that the outliers can be distinguished easier through the maximum Lq-likelihood method than those through the maximum likelihood estimation method.

Genetically modified non-human primate models for research on neurodegenerative diseases

Neurodegenerative diseases(NDs)are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease(AD),Parkinson's disease(PD),Huntington's disease(HD),and amyotrophic lateral sclerosis(ALS).Currently,there are no therapies available that can delay,stop,or reverse the pathological progression of NDs in clinical settings.As the population ages,NDs are imposing a huge burden on public health systems and affected families.Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments.While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms,the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap.Old World nonhuman primates(NHPs),such as rhesus,cynomolgus,and vervet monkeys,are phylogenetically,physiologically,biochemically,and behaviorally most relevant to humans.This is particularly evident in the similarity of the structure and function of their central nervous systems,rendering such species uniquely valuable for neuroscience research.Recently,the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms.This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained,as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.

Correcting Climate Model Sea Surface Temperature Simulations with Generative Adversarial Networks:Climatology,Interannual Variability,and Extremes

Climate models are vital for understanding and projecting global climate change and its associated impacts.However,these models suffer from biases that limit their accuracy in historical simulations and the trustworthiness of future projections.Addressing these challenges requires addressing internal variability,hindering the direct alignment between model simulations and observations,and thwarting conventional supervised learning methods.Here,we employ an unsupervised Cycle-consistent Generative Adversarial Network(CycleGAN),to correct daily Sea Surface Temperature(SST)simulations from the Community Earth System Model 2(CESM2).Our results reveal that the CycleGAN not only corrects climatological biases but also improves the simulation of major dynamic modes including the El Niño-Southern Oscillation(ENSO)and the Indian Ocean Dipole mode,as well as SST extremes.Notably,it substantially corrects climatological SST biases,decreasing the globally averaged Root-Mean-Square Error(RMSE)by 58%.Intriguingly,the CycleGAN effectively addresses the well-known excessive westward bias in ENSO SST anomalies,a common issue in climate models that traditional methods,like quantile mapping,struggle to rectify.Additionally,it substantially improves the simulation of SST extremes,raising the pattern correlation coefficient(PCC)from 0.56 to 0.88 and lowering the RMSE from 0.5 to 0.32.This enhancement is attributed to better representations of interannual,intraseasonal,and synoptic scales variabilities.Our study offers a novel approach to correct global SST simulations and underscores its effectiveness across different time scales and primary dynamical modes.

Evaluating Privacy Leakage and Memorization Attacks on Large Language Models (LLMs) in Generative AI Applications

The recent interest in the deployment of Generative AI applications that use large language models (LLMs) has brought to the forefront significant privacy concerns, notably the leakage of Personally Identifiable Information (PII) and other confidential or protected information that may have been memorized during training, specifically during a fine-tuning or customization process. We describe different black-box attacks from potential adversaries and study their impact on the amount and type of information that may be recovered from commonly used and deployed LLMs. Our research investigates the relationship between PII leakage, memorization, and factors such as model size, architecture, and the nature of attacks employed. The study utilizes two broad categories of attacks: PII leakage-focused attacks (auto-completion and extraction attacks) and memorization-focused attacks (various membership inference attacks). The findings from these investigations are quantified using an array of evaluative metrics, providing a detailed understanding of LLM vulnerabilities and the effectiveness of different attacks.

Recent developments of generalized plasticity models for saturated and unsaturated soils

Soil undergoes both elastic and plastic deformations under different loading conditions. A relatively accurate constitutive model of soil behaviors should be capable of predicting the elastic and plastic deformations properly. Among a large number of elastoplastic constitutive models developed over the last several decades, constitutive models based on generalized plasticity have been successfully utilized in modeling the mechanical behavior of various soils. This paper attempts to present a review of the most recent developments of generalized plasticity models for geotechnical problems. After a brief review of generalized plasticity theories and constitutive models, limitations of the original Pastor-Zienkiewicz model in practical application are summarized. Afterwards, recent achievements in the generalized plasticity models for both saturated and unsaturated soils and their applicability are analyzed, and a general approach for modification of generalized plasticity models is highlighted.

Application of the Improved Generalized Autoregressive Conditional Heteroskedast Model Based on the Autoregressive Integrated Moving Average Model in Data Analysis

This study firstly improved the Generalized Autoregressive Conditional Heteroskedast model for the issue that financial product sales data have singular information when applying this model, and the improved outlier detection method was used to detect the location of outliers, which were processed by the iterative method. Secondly, in order to describe the peak and fat tail of the financial time series, as well as the leverage effect, this work used the skewed-t Asymmetric Power Autoregressive Conditional Heteroskedasticity model based on the Autoregressive Integrated Moving Average Model to analyze the sales data. Empirical analysis showed that the model considering the skewed distribution is effective.

Incorporating shape constraints in generalized additive modelling of the height-diameter relationship for Norway spruce

Background： Measurements of tree heights and diameters are essential in forest assessment and modelling. Tree heights are used for estimating timber volume, site index and other important variables related to forest growth and yield, succession and carbon budget models. However, the diameter at breast height （dbh） can be more accurately obtained and at lower cost, than total tree height. Hence, generalized height-diameter （h-d） models that predict tree height from dbh, age and other covariates are needed. For a more flexible but biologically plausible estimation of covariate effects we use shape constrained generalized additive models as an extension of existing h-d model approaches. We use causal site parameters such as index of aridity to enhance the generality and causality of the models and to enable predictions under projected changeable climatic conditions. Methods： We develop unconstrained generalized additive models （GAM） and shape constrained generalized additive models （SCAM） for investigating the possible effects of tree-specific parameters such as tree age, relative diameter at breast height, and site-specific parameters such as index of aridity and sum of daily mean temperature during vegetation period, on the h-d relationship of forests in Lower Saxony, Germany. Results： Some of the derived effects, e.g. effects of age, index of aridity and sum of daily mean temperature have significantly non-linear pattern. The need for using SCAM results from the fact that some of the model effects show partially implausible patterns especially at the boundaries of data ranges. The derived model predicts monotonically increasing levels of tree height with increasing age and temperature sum and decreasing aridity and social rank of a tree within a stand, The definition of constraints leads only to marginal or minor decline in the model statistics like AIC An observed structured spatial trend in tree height is modelled via 2-dimensional surface fitting. Conclusions： We demonstrate that the SCAM approach allows optimal regression modelling flexibility similar to the standard GAM but with the additional possibility of defining specific constraints for the model effects. The longitudinal character of the model allows for tree height imputation for the current status of forests but also for future tree height prediction.

A Simplified Scheme of the Generalized Layered Radiative Transfer Model

In this paper, firstly, a simplified version （SGRTM） of the generalized layered radiative transfer model （GRTM） within the canopy, developed by us, is presented. It reduces the information requirement of inputted sky diffuse radiation, as well as of canopy morphology, and in turn saves computer resources. Results from the SGRTM agree perfectly with those of the GRTM. Secondly, by applying the linear superposition principle of the optics and by using the basic solutions of the GRTM for radiative transfer within the canopy under the condition of assumed zero soil reflectance, two sets of explicit analytical solutions of radiative transfer within the canopy with any soil reflectance magnitude are derived： one for incident diffuse, and the other for direct beam radiation. The explicit analytical solutions need two sets of basic solutions of canopy reflectance and transmittance under zero soil reflectance, run by the model for both diffuse and direct beam radiation. One set of basic solutions is the canopy reflectance αf （written as α1 for direct beam radiation） and transmittance βf （written as β1 for direction beam radiation） with zero soil reflectance for the downward radiation from above the canopy （i.e. sky）, and the other set is the canopy reflectance （αb） and transmittance βb for the upward radiation from below the canopy （i.e., ground）. Under the condition of the same plant architecture in the vertical layers, and the same leaf adaxial and abaxial optical properties in the canopies for the uniform diffuse radiation, the explicit solutions need only one set of basic solutions, because under this condition the two basic solutions are equal, i.e., αf = αb and βf = βb. Using the explicit analytical solutions, the fractions of any kind of incident solar radiation reflected from （defined as surface albedo, or canopy reflectance）, transmitted through （defined as canopy transmittance）, and absorbed by （defined as canopy absorptance） the canopy and other properties pertinent to the radiative transfer within the canopy can be estimated easily on the ground surface below the canopy （soil or snow surface） with any reflectance magnitudes. The simplified transfer model is proven to have a similar accuracy compared to the detailed model, as well as very efficient computing.

Local and generalized height-diameter models with random parameters for mixed,uneven-aged forests in Northwestern Durango,Mexico

Background:We used mixed models with random components to develop height-diameter(h-d) functions for mixed,uneven-aged stands in northwestern Durango(Mexico),considering the breast height diameter(d) and stand variables as predictors.Methods:The data were obtained from 44 permanent plots used to monitor stand growth under forest management in the study area.Results:The generalized Bertalanffy-Richards model performed better than the other generalized models in predicting the total height of the species under study.For the genera Pinus and Quercus,the models were successfully calibrated by measuring the height of a subsample of three randomly selected trees close to the mean d,whereas for species of the genera Cupressus,Arbutus and Alnus,three trees were also selected,but they are specifically the maximum,minimum and mean d trees.Conclusions:The presented equations represent a new tool for the evaluation and management of natural forest in the region.

Baroclinic Instability in the Generalized Phillips' Model Part Ⅱ:Three-layer Model

The nonlinear stability of the three-layer generalized Phillips model, for which the velocity in each layeris constant and the top and bottom surfaces are either rigid or free, is studied by employing Arnol'd'svariational principle and a prior estimate method. The nonlinear stability criteria are established. For comparison, the linear instability criteria are also obtained by using normal mode method. and the influences ofthe free parameter, β parameter and curvature in vertical profile of the horizontal velocity on the linear instability are discussed by use of the growth rate curves. The comparison between the nonlinear stability criterion and the linear one is made. It is shown that insome cases the two criteria are exactly the same in form, but in other cases, they are different. This phenomenon, which reveals the nonlinear property of the linear instability features. is explained by the explosiveresonant interaction (ERI). When there exists the ERI, i.e., the nonlinear mechanisms play a leading role inthe dynamical system. the nonlinear stability criterion is different from the linear one, on the other hand.when there does not exist the ERI. the nonlinear stability criterion is the same as the linear one in form.

Gamma generalized linear model to investigate the effects of climate variables on the area burned by forest fire in northeast China

The purpose of this study was to determine a suitable model for investigating the effects of climate factors on the area burned by forest fire in the Tahe forest region, Daxing＇an Mountains, in northeast China. The response variables were the area burned by lightning- caused fire, human-caused fire, and total burned area. The predictor variables were nine climate variables collected from the local weather station. Three regression models were utilized, including multiple linear regression, log- linear model （log-transformation on both response and predictor variables）, and gamma-generalized linear model. The goodness-of-fit of the models were compared based on model fitting statistics such as R2, AIC, and RMSE. The results revealed that the gamma-generalized linear model was generally superior to both multiple linear regressionmodel and log-linear model for fitting the fire data. Further, the best models were selected based on the criteria that the climate variables were statistically significant at at = 0.05. The gamma best models indicated that maximum wind speed, precipitation, and days that rainfall greater than 0.1 mm had significant impacts on the area burned by the lightning-caused fire, while the mean temperature and minimum relative humidity were the .main drivers of the burned area caused by human activities. Overall, the total burned area by forest fire was significantly influenced by days that rainfall greater than 0.1 mm and minimum rela- tive humidity, indicating that the moisture condition of forest stands determine the burned area by forest fire.

GENERALIZED SIMULATION MODEL FOR MILLED SURFACE TOPOGRAPHY-APPLICATION TO PERIPHERAL MILLING

Based on analyzing various factors influencing milled surface topography, firstly, a generalized model for milled surface topography is proposed. Secondly, using the principles of transformation matrix and vector operation, the trajectory equation of cutting edge relative to workpiece is derived. Then, a three dimensional topography simulation algorithm is constructed through dividing the workpiece into regular grids. Finally, taking the peripheral milling process as an example, the generalized model is simplified, and the corresponding simulation examples are given. The results indicate that it is very efficient for the generalized model to be used to analyze and simulate the peripherally milled surface topography.

Seepage simulation of high concrete-faced rockfill dams based on generalized equivalent continuum model

This research focused on the three-dimensional(3 D) seepage field simulation of a high concrete-faced rockfill dam(CFRD) under complex hydraulic conditions. A generalized equivalent continuum model of fractured rock mass was used for equivalent continuous seepage field analysis based on the improved node virtual flow method. Using a high CFRD as an example, the generalized equivalent continuum range was determined, and a finite element model was established based on the terrain and geological conditions, as well as structural face characteristics of the dam area. The equivalent seepage coefficients of different material zones or positions in the dam foundation were calculated with the Snow model or inverse analysis. Then, the 3 D seepage field in the dam area was calculated under the normal water storage conditions, and the corresponding water head distribution, seepage flow, seepage gradient, and seepage characteristics in the dam area were analyzed. The results show that the generalized equivalent continuum model can effectively simulate overall seepage patterns of the CFRD under complex hydraulic conditions and provide a reference for seepage analysis of similar CFRDs.

The Survival Probability in Generalized Poisson Risk Model

In this paper we generalize the aggregated premium income process from a constant rate process to a poisson process for the classical compound Poinsson risk model,then for the generalized model and the classical compound poisson risk model ,we respectively get its survival probability in finite time period in case of exponential claim amounts.