Strategies for translating proteomics discoveries into drug discovery for dementia

Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing population.As such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development.In this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired populations.We highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this field.We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.

Identification of partial differential equations from noisy data with integrated knowledge discovery and embedding using evolutionary neural networks

Identification of underlying partial differential equations(PDEs)for complex systems remains a formidable challenge.In the present study,a robust PDE identification method is proposed,demonstrating the ability to extract accurate governing equations under noisy conditions without prior knowledge.Specifically,the proposed method combines gene expression programming,one type of evolutionary algorithm capable of generating unseen terms based solely on basic operators and functional terms,with symbolic regression neural networks.These networks are designed to represent explicit functional expressions and optimize them with data gradients.In particular,the specifically designed neural networks can be easily transformed to physical constraints for the training data,embedding the discovered PDEs to further optimize the metadata used for iterative PDE identification.The proposed method has been tested in four canonical PDE cases,validating its effectiveness without preliminary information and confirming its suitability for practical applications across various noise levels.

Sensing and Communication Integrated Fast Neighbor Discovery for UAV Networks

In unmanned aerial vehicle(UAV)networks,the high mobility of nodes leads to frequent changes in network topology,which brings challenges to the neighbor discovery(ND)for UAV networks.Integrated sensing and communication(ISAC),as an emerging technology in 6G mobile networks,has shown great potential in improving communication performance with the assistance of sensing information.ISAC obtains the prior information about node distribution,reducing the ND time.However,the prior information obtained through ISAC may be imperfect.Hence,an ND algorithm based on reinforcement learning is proposed.The learning automaton(LA)is applied to interact with the environment and continuously adjust the probability of selecting beams to accelerate the convergence speed of ND algorithms.Besides,an efficient ND algorithm in the neighbor maintenance phase is designed,which applies the Kalman filter to predict node movement.Simulation results show that the LA-based ND algorithm reduces the ND time by up to 32%compared with the Scan-Based Algorithm(SBA),which proves the efficiency of the proposed ND algorithms.

Prediction model for corrosion rate of low-alloy steels under atmospheric conditions using machine learning algorithms

This work constructed a machine learning(ML)model to predict the atmospheric corrosion rate of low-alloy steels(LAS).The material properties of LAS,environmental factors,and exposure time were used as the input,while the corrosion rate as the output.6 dif-ferent ML algorithms were used to construct the proposed model.Through optimization and filtering,the eXtreme gradient boosting(XG-Boost)model exhibited good corrosion rate prediction accuracy.The features of material properties were then transformed into atomic and physical features using the proposed property transformation approach,and the dominant descriptors that affected the corrosion rate were filtered using the recursive feature elimination(RFE)as well as XGBoost methods.The established ML models exhibited better predic-tion performance and generalization ability via property transformation descriptors.In addition,the SHapley additive exPlanations(SHAP)method was applied to analyze the relationship between the descriptors and corrosion rate.The results showed that the property transformation model could effectively help with analyzing the corrosion behavior,thereby significantly improving the generalization ability of corrosion rate prediction models.

Pulse rate estimation based on facial videos:an evaluation and optimization of the classical methods using both self-constructed and public datasets

Pulse rate is one of the important characteristics of traditional Chinese medicine pulse diagnosis,and it is of great significance for determining the nature of cold and heat in diseases.The prediction of pulse rate based on facial video is an exciting research field for getting palpation information by observation diagnosis.However,most studies focus on optimizing the algorithm based on a small sample of participants without systematically investigating multiple influencing factors.A total of 209 participants and 2,435 facial videos,based on our self-constructed Multi-Scene Sign Dataset and the public datasets,were used to perform a multi-level and multi-factor comprehensive comparison.The effects of different datasets,blood volume pulse signal extraction algorithms,region of interests,time windows,color spaces,pulse rate calculation methods,and video recording scenes were analyzed.Furthermore,we proposed a blood volume pulse signal quality optimization strategy based on the inverse Fourier transform and an improvement strategy for pulse rate estimation based on signal-to-noise ratio threshold sliding.We found that the effects of video estimation of pulse rate in the Multi-Scene Sign Dataset and Pulse Rate Detection Dataset were better than in other datasets.Compared with Fast independent component analysis and Single Channel algorithms,chrominance-based method and plane-orthogonal-to-skin algorithms have a more vital anti-interference ability and higher robustness.The performances of the five-organs fusion area and the full-face area were better than that of single sub-regions,and the fewer motion artifacts and better lighting can improve the precision of pulse rate estimation.

Dynamic interactive bitwise meta-holography with ultra-high computational and display frame rates

Interactive holography offers unmatched levels of immersion and user engagement in the field of future display.Despite of the substantial progress has been made in dynamic meta-holography,the realization of real-time,highly smooth interactive holography remains a significant challenge due to the computational and display frame rate limitations.In this study,we introduced a dynamic interactive bitwise meta-holography with ultra-high computational and display frame rates.To our knowledge,this is the first reported practical dynamic interactive metasurface holographic system.We spa-tially divided the metasurface device into multiple distinct channels,each projecting a reconstructed sub-pattern.The switching states of these channels were mapped to bitwise operations on a set of bit values,which avoids complex holo-gram computations,enabling an ultra-high computational frame rate.Our approach achieves a computational frame rate of 800 kHz and a display frame rate of 23 kHz on a low-power Raspberry Pi computational platform.According to this methodology,we demonstrated an interactive dynamic holographic Tetris game system that allows interactive gameplay,color display,and on-the-fly hologram creation.Our technology presents an inspiration for advanced dynamic meta-holography,which is promising for a broad range of applications including advanced human-computer interaction,real-time 3D visualization,and next-generation virtual and augmented reality systems.

The Probability Density Function Related to Shallow Cumulus Entrainment Rate and Its Influencing Factors in a Large-Eddy Simulation

The process of entrainment-mixing between cumulus clouds and the ambient air is important for the development of cumulus clouds.Accurately obtaining the entrainment rate(λ)is particularly important for its parameterization within the overall cumulus parameterization scheme.In this study,an improved bulk-plume method is proposed by solving the equations of two conserved variables simultaneously to calculateλof cumulus clouds in a large-eddy simulation.The results demonstrate that the improved bulk-plume method is more reliable than the traditional bulk-plume method,becauseλ,as calculated from the improved method,falls within the range ofλvalues obtained from the traditional method using different conserved variables.The probability density functions ofλfor all data,different times,and different heights can be well-fitted by a log-normal distribution,which supports the assumed stochastic entrainment process in previous studies.Further analysis demonstrate that the relationship betweenλand the vertical velocity is better than other thermodynamic/dynamical properties;thus,the vertical velocity is recommended as the primary influencing factor for the parameterization ofλin the future.The results of this study enhance the theoretical understanding ofλand its influencing factors and shed new light on the development ofλparameterization.

Experimental study on the effect of unloading rate on gneiss rockburst

Rockburst are often encountered in tunnel construction due to the complex geological conditions.To study the influence of unloading rate on rockburst,gneiss rockburst experiments were conducted under three groups of unloading rates.A high-speed photography system and acoustic emission(AE)system were used to monitor the entire process of rockburst process in real-time.The results show that the intensity of gneiss rockburst decreases with decrease of unloading rate,which is manifested as the reduction of AE energy and fragments ejection velocity.The mechanisms are proposed to explain this effect:(i)The reduction of unloading rate changes the crack propagation mechanism in the process of rockburst.This makes the rockbursts change from the tensile failure mechanism at high unloading rate to the tension-shear mixed failure mechanism at low unloading rate,and more energy released in the form of shear crack propagation.Then,less strain energy is converted into kinetic energy of fragments ejection.(ii)Less plate cracking degree of gneiss has taken shape due to decrease of unloading rate,resulting in the destruction of rockburst incubation process.The enlightenments of reducing the unloading rate for the project are also described quantitatively.The rockburst magnitude is reduced from the medium magnitude at the unloading rate of 0.1 MPa/s to the slight magnitude at the unloading rate of 0.025 MPa/s,which was judged by the ejection velocity.

A new era of mutation rate analyses: Concepts and methods

The mutation rate is a pivotal biological characteristic,intricately governed by natural selection and historically garnering considerable attention.Recent advances in high-throughput sequencing and analytical methodologies have profoundly transformed our understanding in this domain,ushering in an unprecedented era of mutation rate research.This paper aims to provide a comprehensive overview of the key concepts and methodologies frequently employed in the study of mutation rates.It examines various types of mutations,explores the evolutionary dynamics and associated theories,and synthesizes both classical and contemporary hypotheses.Furthermore,this review comprehensively explores recent advances in understanding germline and somatic mutations in animals and offers an overview of experimental methodologies,mutational patterns,molecular mechanisms,and driving forces influencing variations in mutation rates across species and tissues.Finally,it proposes several potential research directions and pressing questions for future investigations.

Present-day Upper-crustal Strain Rate Field in Southeastern Tibet and its Geodynamic Implications:Constraints from GPS Measurements with ABIC Method

The Earth’s surface kinematics and deformation are fundamental to understanding crustal evolution.An effective research approach is to estimate regional motion field and deformation fields based on modern geodetic networks.If the discrete observed velocity field is obtained,the velocity related fields,such as dilatation rate and maximum shear strain rate,can be estimated by applying varied mathematical approaches.This study applied Akaike's Bayesian Information Criterion(ABIC)method to calculate strain rate fields constrained by GPS observations in the southeast Tibetan Plateau.Comparison with results derived from other three methods revealed that our ABIC-derived strain rate fields were more precise.The maximum shear strain rate highlighted the Xianshuihe–Xiaojiang fault system as the main boundary for the outward migration of material in southeastern Tibet,indicating rotation of eastern Tibet material around the eastern Himalaya rather than whole extrusion along a fixed channel.Additionally,distinct dilatation rate patterns in the northeast and southwest regions of the fault system were observed.The northeast region,represented by the Longmenshan area,exhibited negative dilatational anomalies;while the southwest region,represented by the Jinsha River area north of 29°N,displayed positive dilatational anomalies.This indicates compression in the former and extension in the latter.Combined with deep geophysical observations,we believe that the upper and lower crusts of the Jinsha River area north of 29°N are in an entire expanding state,probably caused by the escape-drag effect of material.The presence of a large,low-viscosity region south of 29°N may not enable the entire escape of the crust,but instead result in a differential escape of the lower crust faster than the upper crust.

Federated Learning Model for Auto Insurance Rate Setting Based on Tweedie Distribution

In the assessment of car insurance claims,the claim rate for car insurance presents a highly skewed probability distribution,which is typically modeled using Tweedie distribution.The traditional approach to obtaining the Tweedie regression model involves training on a centralized dataset,when the data is provided by multiple parties,training a privacy-preserving Tweedie regression model without exchanging raw data becomes a challenge.To address this issue,this study introduces a novel vertical federated learning-based Tweedie regression algorithm for multi-party auto insurance rate setting in data silos.The algorithm can keep sensitive data locally and uses privacy-preserving techniques to achieve intersection operations between the two parties holding the data.After determining which entities are shared,the participants train the model locally using the shared entity data to obtain the local generalized linear model intermediate parameters.The homomorphic encryption algorithms are introduced to interact with and update the model intermediate parameters to collaboratively complete the joint training of the car insurance rate-setting model.Performance tests on two publicly available datasets show that the proposed federated Tweedie regression algorithm can effectively generate Tweedie regression models that leverage the value of data fromboth partieswithout exchanging data.The assessment results of the scheme approach those of the Tweedie regressionmodel learned fromcentralized data,and outperformthe Tweedie regressionmodel learned independently by a single party.

A performance-based hybrid deep learning model for predicting TBM advance rate using Attention-ResNet-LSTM

The technology of tunnel boring machine(TBM)has been widely applied for underground construction worldwide;however,how to ensure the TBM tunneling process safe and efficient remains a major concern.Advance rate is a key parameter of TBM operation and reflects the TBM-ground interaction,for which a reliable prediction helps optimize the TBM performance.Here,we develop a hybrid neural network model,called Attention-ResNet-LSTM,for accurate prediction of the TBM advance rate.A database including geological properties and TBM operational parameters from the Yangtze River Natural Gas Pipeline Project is used to train and test this deep learning model.The evolutionary polynomial regression method is adopted to aid the selection of input parameters.The results of numerical exper-iments show that our Attention-ResNet-LSTM model outperforms other commonly-used intelligent models with a lower root mean square error and a lower mean absolute percentage error.Further,parametric analyses are conducted to explore the effects of the sequence length of historical data and the model architecture on the prediction accuracy.A correlation analysis between the input and output parameters is also implemented to provide guidance for adjusting relevant TBM operational parameters.The performance of our hybrid intelligent model is demonstrated in a case study of TBM tunneling through a complex ground with variable strata.Finally,data collected from the Baimang River Tunnel Project in Shenzhen of China are used to further test the generalization of our model.The results indicate that,compared to the conventional ResNet-LSTM model,our model has a better predictive capability for scenarios with unknown datasets due to its self-adaptive characteristic.

Construction of a Computational Scheme for the Fuzzy HIV/AIDS Epidemic Model with a Nonlinear Saturated Incidence Rate

This work aimed to construct an epidemic model with fuzzy parameters.Since the classical epidemic model doesnot elaborate on the successful interaction of susceptible and infective people,the constructed fuzzy epidemicmodel discusses the more detailed versions of the interactions between infective and susceptible people.Thenext-generation matrix approach is employed to find the reproduction number of a deterministic model.Thesensitivity analysis and local stability analysis of the systemare also provided.For solving the fuzzy epidemic model,a numerical scheme is constructed which consists of three time levels.The numerical scheme has an advantage overthe existing forward Euler scheme for determining the conditions of getting the positive solution.The establishedscheme also has an advantage over existing non-standard finite difference methods in terms of order of accuracy.The stability of the scheme for the considered fuzzy model is also provided.From the plotted results,it can beobserved that susceptible people decay by rising interaction parameters.

Machine learning-based comparison of factors influencing estimated glomerular filtration rate in Chinese women with or without nonalcoholic fatty liver

BACKGROUND The prevalence of non-alcoholic fatty liver(NAFLD)has increased recently.Subjects with NAFLD are known to have higher chance for renal function impairment.Many past studies used traditional multiple linear regression(MLR)to identify risk factors for decreased estimated glomerular filtration rate(eGFR).However,medical research is increasingly relying on emerging machine learning(Mach-L)methods.The present study enrolled healthy women to identify factors affecting eGFR in subjects with and without NAFLD(NAFLD+,NAFLD-)and to rank their importance.AIM To uses three different Mach-L methods to identify key impact factors for eGFR in healthy women with and without NAFLD.METHODS A total of 65535 healthy female study participants were enrolled from the Taiwan MJ cohort,accounting for 32 independent variables including demographic,biochemistry and lifestyle parameters(independent variables),while eGFR was used as the dependent variable.Aside from MLR,three Mach-L methods were applied,including stochastic gradient boosting,eXtreme gradient boosting and elastic net.Errors of estimation were used to define method accuracy,where smaller degree of error indicated better model performance.RESULTS Income,albumin,eGFR,High density lipoprotein-Cholesterol,phosphorus,forced expiratory volume in one second(FEV1),and sleep time were all lower in the NAFLD+group,while other factors were all significantly higher except for smoking area.Mach-L had lower estimation errors,thus outperforming MLR.In Model 1,age,uric acid(UA),FEV1,plasma calcium level(Ca),plasma albumin level(Alb)and T-bilirubin were the most important factors in the NAFLD+group,as opposed to age,UA,FEV1,Alb,lactic dehydrogenase(LDH)and Ca for the NAFLD-group.Given the importance percentage was much higher than the 2nd important factor,we built Model 2 by removing age.CONCLUSION The eGFR were lower in the NAFLD+group compared to the NAFLD-group,with age being was the most important impact factor in both groups of healthy Chinese women,followed by LDH,UA,FEV1 and Alb.However,for the NAFLD-group,TSH and SBP were the 5th and 6th most important factors,as opposed to Ca and BF in the NAFLD+group.

Prediction of corrosion rate for friction stir processed WE43 alloy by combining PSO-based virtual sample generation and machine learning

The corrosion rate is a crucial factor that impacts the longevity of materials in different applications.After undergoing friction stir processing(FSP),the refined grain structure leads to a notable decrease in corrosion rate.However,a better understanding of the correlation between the FSP process parameters and the corrosion rate is still lacking.The current study used machine learning to establish the relationship between the corrosion rate and FSP process parameters(rotational speed,traverse speed,and shoulder diameter)for WE43 alloy.The Taguchi L27 design of experiments was used for the experimental analysis.In addition,synthetic data was generated using particle swarm optimization for virtual sample generation(VSG).The application of VSG has led to an increase in the prediction accuracy of machine learning models.A sensitivity analysis was performed using Shapley Additive Explanations to determine the key factors affecting the corrosion rate.The shoulder diameter had a significant impact in comparison to the traverse speed.A graphical user interface(GUI)has been created to predict the corrosion rate using the identified factors.This study focuses on the WE43 alloy,but its findings can also be used to predict the corrosion rate of other magnesium alloys.

Floating Waste Discovery by Request via Object-Centric Learning

Discovering floating wastes,especially bottles on water,is a crucial research problem in environmental hygiene.Nevertheless,real-world applications often face challenges such as interference from irrelevant objects and the high cost associated with data collection.Consequently,devising algorithms capable of accurately localizing specific objects within a scene in scenarios where annotated data is limited remains a formidable challenge.To solve this problem,this paper proposes an object discovery by request problem setting and a corresponding algorithmic framework.The proposed problem setting aims to identify specified objects in scenes,and the associated algorithmic framework comprises pseudo data generation and object discovery by request network.Pseudo-data generation generates images resembling natural scenes through various data augmentation rules,using a small number of object samples and scene images.The network structure of object discovery by request utilizes the pre-trained Vision Transformer(ViT)model as the backbone,employs object-centric methods to learn the latent representations of foreground objects,and applies patch-level reconstruction constraints to the model.During the validation phase,we use the generated pseudo datasets as training sets and evaluate the performance of our model on the original test sets.Experiments have proved that our method achieves state-of-the-art performance on Unmanned Aerial Vehicles-Bottle Detection(UAV-BD)dataset and self-constructed dataset Bottle,especially in multi-object scenarios.

Fluorinated semi-interpenetrating polymer networks for enhancing the mechanical performance and storage stability of polymer-bonded explosives by controlling curing and phase separation rates

Herein, the effect of fluoropolymer binders on the properties of polymer-bonded explosives(PBXs) was comprehensively investigated. To this end, fluorinated semi-interpenetrating polymer networks(semiIPNs) were prepared using different catalyst amounts(denoted as F23-CLF-30-D). The involved curing and phase separation processes were monitored using Fourier-transform infrared spectroscopy, differential scanning calorimetry, a haze meter and a rheometer. Curing rate constant and activation energy were calculated using a theoretical model and numerical method, respectively. Results revealed that owing to its co-continuous micro-phase separation structure, the F23-CLF-30-D3 semi-IPN exhibited considerably higher tensile strength and elongation at break than pure fluororubber F2314 and the F23-CLF-30-D0 semi-IPN because the phase separation and curing rates matched in the initial stage of curing.An arc Brazilian test revealed that F23-CLF-30-D-based composites used as mock materials for PBXs exhibited excellent mechanical performance and storage stability. Thus, the matched curing and phase separation rates play a crucial role during the fabrication of high-performance semi-IPNs;these factors can be feasibly controlled using an appropriate catalyst amount.

Towards cultivar-oriented gene discovery for better crops

The continued expansion of the world population,increasingly inconsistent climate and shrinking agricultural resources present major challenges to crop breeding.Fortunately,the increasing ability to discover and manipulate genes creates new opportunities to develop more productive and resilient cultivars.Many genes have been described in papers as being beneficial for yield increase.However,few of them have been translated into increased yield on farms.In contrast,commercial breeders are facing gene decidophobia,i.e.,puzzled about which gene to choose for breeding among the many identified,a huge chasm between gene discovery and cultivar innovation.The purpose of this paper is to draw attention to the shortfalls in current gene discovery research and to emphasise the need to align with cultivar innovation.The methodology dictates that genetic studies not only focus on gene discovery but also pay good attention to the genetic backgrounds,experimental validation in relevant environments,appropriate crop management,and data reusability.The close of the gaps should accelerate the application of molecular study in breeding and contribute to future global food security.

A Multi-Token Sector Antenna Neighbor Discovery Protocol for Directional Ad Hoc Networks

In this paper,we propose a Multi-token Sector Antenna Neighbor Discovery(M-SAND)protocol to enhance the efficiency of neighbor discovery in asynchronous directional ad hoc networks.The central concept of our work involves maintaining multiple tokens across the network.To prevent mutual interference among multi-token holders,we introduce the time and space non-interference theorems.Furthermore,we propose a master-slave strategy between tokens.When the master token holder(MTH)performs the neighbor discovery,it decides which 1-hop neighbor is the next MTH and which 2-hop neighbors can be the new slave token holders(STHs).Using this approach,the MTH and multiple STHs can simultaneously discover their neighbors without causing interference with each other.Building on this foundation,we provide a comprehensive procedure for the M-SAND protocol.We also conduct theoretical analyses on the maximum number of STHs and the lower bound of multi-token generation probability.Finally,simulation results demonstrate the time efficiency of the M-SAND protocol.When compared to the QSAND protocol,which uses only one token,the total neighbor discovery time is reduced by 28% when 6beams and 112 nodes are employed.

Recent Advances of Bioactive Marine Natural Products in Drug Discovery

Marine natural products(MNPs)are valuable resources for drug development.To date,17 drugs from marine sources are in clinical use,and 33 pharmaceutical compounds are in clinical trials.Presently the success of drug development from the marine resources is higher than the industry average.It is a feasible strategy to conduct the discovery of druglead compounds based on marine chemical ecology by fully exploiting the pharmacological potential of marine chemical defense matters.In the search for bioactive MNPs,our group has constructed a biological resources library including more than 1500 strains of fungi.Focusing on the strategy of Blue Drug Library,we have discovered a series of novel MNPs with abundant biological functions.Highly efficient and scalable total synthesis of(+)-aniduquinolone A(44)and pesimquinolone I(48)have been completed,which will facilitate access to sufficient quantities of candidates for in vivo pharmacological and toxicological studies.As a nucleoprotein(NP)inhibitor,QLA(75)possesses significant anti-influenza A virus(IAV)activities both in vitro and in vivo.CHNQD-00803(76)is a potent and selective AMP-activated kinase(AMPK)activator that can effectively inhibit metabolic disorders and metabolic dysfunction-associated steatohepatitis(MASH)progression.Moreover,we identified two new candidate molecules with potent anti-hepatocellular carcinoma effects.Particularly,as a natural guanine-nucleotide exchange factors for ADP-ribosylation factor GTPases(Arf-GEFs)inhibitor prodrug,CHNQD-01255(78)is qualified to be developed as a targeted candidate anticancer drug,which may be promising to apply for cancer immunotherapy.Hence,it is evident that MNPs play an important role in drug development.