Large animal models for Huntington's disease research

Huntington'sdisease(HD)isahereditary neurodegenerative disorder for which there is currently no effectivetreatmentavailable.Consequently,the development of appropriate disease models is critical to thoroughly investigate disease progression.The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin(HTT)gene,leading to the expansion of a polyglutamine repeat in the HTT protein.Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain,which precipitate selective neuronal loss in specific brain regions.Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets.Due to the marked species differences between rodents and larger animals,substantial efforts have been directed toward establishing large animal models for HD research.These models are pivotal for advancing the discovery of novel therapeutic targets,enhancing effective drug delivery methods,and improving treatment outcomes.We have explored the advantages of utilizing large animal models,particularly pigs,in previous reviews.Since then,however,significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD.In the current review,we provide a comprehensive overview of large animal models of HD,incorporating recent findings regarding the establishment of HD knock-in(KI)pigs and their genetic therapy.We also explore the utilization of large animal models in HD research,with a focus on sheep,non-human primates(NHPs),and pigs.Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

Shallow Convection Dataset Simulated by Three Different Large Eddy Models

Shallow convection plays an important role in transporting heat and moisture from the near-surface to higher altitudes,yet its parameterization in numerical models remains a great challenge,partly due to the lack of high-resolution observations.This study describes a large eddy simulation(LES)dataset for four shallow convection cases that differ primarily in inversion strength,which can be used as a surrogate for real data.To reduce the uncertainty in LES modeling,three different large eddy models were used,including SAM(System for Atmospheric Modeling),WRF(Weather Research and Forecasting model),and UCLA-LES.Results show that the different models generally exhibit similar behavior for each shallow convection case,despite some differences in the details of the convective structure.In addition to grid-averaged fields,conditionally sampled variables,such as in-cloud moisture and vertical velocity,are also provided,which are indispensable for calculation of the entrainment/detrainment rate.Considering the essentiality of the entraining/detraining process in the parameterization of cumulus convection,the dataset presented in this study is potentially useful for validation and improvement of the parameterization of shallow convection.

Optimization of Fixture Number in Large Thin-Walled Parts Assembly Based on IPSO

There are lots of researches on fixture layout optimization for large thin-walled parts.Current researches focus on the positioning problem,i.e.,optimizing the positions of a constant number of fixtures.However,how to determine the number of fixtures is ignored.In most cases,the number of fixtures located on large thin-walled parts is determined based on engineering experience,which leads to huge fixture number and extra waste.Therefore,this paper constructs an optimization model to minimize the number of fixtures.The constraints are set in the optimization model to ensure that the part deformation is within the surface profile tolerance.In addition,the assembly gap between two parts is also controlled.To conduct the optimization,this paper develops an improved particle swarm optimization(IPSO)algorithm by integrating the shrinkage factor and adaptive inertia weight.In the algorithm,particles are encoded according to the fixture position.Each dimension of the particle is assigned to a sub-region by constraining the optional position range of each fixture to improve the optimization efficiency.Finally,a case study on ship curved panel assembly is provided to prove that our method can optimize the number of fixtures while meeting the assembly quality requirements.This research proposes a method to optimize the number of fixtures,which can reduce the number of fixtures and achieve deformation control at the same time.

Features of sampling stream sediments of large river valleys under cryolithogenesis conditions in the Balygychan-Sugoy trough,North-East of Russia

Comprehensive research has been implemented to raise the efficiency of the geochemical survey of stream sediments(SSs)that formed under the cryolithogenesis conditions.The authors analysed the composition,structure and specific features of the formation of exogenous anomalous geochemical fields(AGFs)identified through SSs of large river valleys of IV order.In our case,these were the valleys of Maly Ken,Ken and Tap Rivers.These rivers are located in the central and southern parts of the Balygychan-Sugoy trough enclosed in the Magadan region,North-East of Russia.The authors proposed a new technique to sample loose alluvium of SSs in the large river valleys along the profiles.The profiles were located across the valleys.The AGFs of Au,Ag,Pb,Zn,Sn,Bi,Mo and W were studied.Correlations between elements have been established.These elements are the main indicator elements of Au-Ag,Ag-Pb,Sn-Ag,Mo-W and Sn-W mineralization occurring on the sites under study.The results obtained were compared with the results of geochemical surveys of SSs.It is concluded that the AGFs recognized along the profiles reflect the composition and structure of eroded and drained ore zones,uncover completely and precisely the pattern of element distribution in loose sediments of large water flows.The alluvium fraction<0.25 mm seems to be most significant in a practical sense,as it concentrated numerous ore elements.Sampling of this fraction in the river valleys of IV order does not cause any difficulty,for this kind of material is plentiful.The developed technique of alluvium sampling within large river valleys is efficient in searching for diverse mineralization at all stages of prognostic prospecting.It is applicable for geochemical survey of SSs performed at different scales both in the North-East of Russia,as well as other regions with similar climatic conditions,where the SSs are formed under the cryolithogenesis conditions.

The influence of inter-band rock on rib spalling in longwall panel with large mining height

In order to improve rib stability,failure criteria and instability mode of a thick coal seam with inter-band rock layer are analysed in this study.A three-dimensional mechanical model is established for the rib by considering the rock layer.A safety factor is defined foy the rib,and it is observed that the safety factor exhibits a positive correlation with the thickness and strength of the inter-band rock.A calculation method for determining critical parameters of the rock layer is presented to ensure the rib stability.It is revealed that incomplete propagation of the fracture at the hard rock constitutes a fundamental prerequisite for ensuring the rib stability.The influence of the position of the inter-band rock in the coal seam on failure mechanism of the rib was thoroughly investigated by developing a series of physical models for the rib at the face area.The best position for the inter-band rock in the coal seam is at a height of 1.5 m away from the roof line,which tends to provide a good stability state for the rib.For different inter-band rock positions,two ways of controlling rib by increasing supports stiffness and flexible grouting reinforcement are proposed.

Improvement in Tol2 transposon for efficient large-cargo capacity transgene applications in cultured cells and zebrafish(Danio rerio)

Most viruses and transposons serve as effective carriers for the introduction of foreign DNA up to 11 kb into vertebrate genomes.However,their activity markedly diminishes with payloads exceeding 11 kb.Expanding the payload capacity of transposons could facilitate more sophisticated cargo designs,improving the regulation of expression and minimizing mutagenic risks associated with molecular therapeutics,metabolic engineering,and transgenic animal production.In this study,we improved the Tol2 transposon by increasing protein expression levels using a translational enhancer(QBI SP163,ST)and enhanced the nuclear targeting ability using the nuclear localization protein H2B(SHT).The modified Tol2 and ST transposon efficiently integrated large DNA cargos into human cell cultures(H1299),comparable to the well-established super PiggyBac system.Furthermore,mRNA from ST and SHT showed a significant increase in transgene delivery efficiency of large DNA payloads(8 kb,14 kb,and 24 kb)into zebrafish(Danio rerio).This study presents a modified Tol2 transposon as an enhanced nonviral vector for the delivery of large DNA payloads in transgenic applications.

Multi-blade rubbing characteristics of the shaft-disk-blade-casing system with large rotation

Blade rubbing faults cause detrimental impact on the operation of aeroengines. Most of the existing studies on blade rubbing in the shaft-disk-blade-casing(SDBC) system have overlooked the elastic deformation of the blade, while some only consider the whirl of the rotor, neglecting its spin. To address these limitations, this paper proposes a dynamic model with large rotation for the SDBC system. The model incorporates the spin and whirl of the rotor, enabling the realistic reproduction of multiblade rubbing faults. To verify the accuracy of the SDBC model with large rotation and demonstrate its capability to effectively consider the rotational effects such as the centrifugal stiffening and gyroscopic effects, the natural characteristics and dynamic responses of the proposed model are compared with those obtained from reported research and experimental results. Furthermore, the effects of the rotating speed, contact stiffness,and blade number on the dynamic characteristics of the SDBC system with multi-blade rubbing are investigated. The results indicate that the phase angle between the rotor deflection and the unbalance excitation force increases with the increasing rotating speed,which significantly influences the rubbing penetration of each blade. The natural frequency of the SDBC system with rubbing constrain can be observed in the acceleration response of the casing and the torsional response of the shaft, and the frequency is related to the contact stiffness. Moreover, the vibration amplitude increases significantly with the product of the blade number under rubbing, and the rotating frequency approaches the natural frequency of the SDBC system. The proposed model can provide valuable insight for the fault diagnosis of rubbing in bladed rotating machinery.

Frontogenesis and Frontolysis of a Cold Filament Driven by the Cross-Filament Wind and Wave Fields Simulated by a Large Eddy Simulation

The variations of the frontogenetic trend of a cold filament induced by the cross-filament wind and wave fields are studied by a non-hydrostatic large eddy simulation. Five cases with different strengths of wind and wave fields are studied.The results show that the intense wind and wave fields further break the symmetries of submesoscale flow fields and suppress the levels of filament frontogenesis. The changes of secondary circulation directions—that is, the conversion between the convergence and divergence of the surface cross-filament currents with the downwelling and upwelling jets in the filament center—are associated with the inertial oscillation. The filament frontogenesis and frontolysis caused by the changes of secondary circulation directions may periodically sharpen and smooth the gradient of submesoscale flow fields.The lifecycle of the cold filament may include multiple stages of filament frontogenesis and frontolysis.

DeBERTa-GRU: Sentiment Analysis for Large Language Model

Modern technological advancements have made social media an essential component of daily life.Social media allow individuals to share thoughts,emotions,and ideas.Sentiment analysis plays the function of evaluating whether the sentiment of the text is positive,negative,neutral,or any other personal emotion to understand the sentiment context of the text.Sentiment analysis is essential in business and society because it impacts strategic decision-making.Sentiment analysis involves challenges due to lexical variation,an unlabeled dataset,and text distance correlations.The execution time increases due to the sequential processing of the sequence models.However,the calculation times for the Transformer models are reduced because of the parallel processing.This study uses a hybrid deep learning strategy to combine the strengths of the Transformer and Sequence models while ignoring their limitations.In particular,the proposed model integrates the Decoding-enhanced with Bidirectional Encoder Representations from Transformers(BERT)attention(DeBERTa)and the Gated Recurrent Unit(GRU)for sentiment analysis.Using the Decoding-enhanced BERT technique,the words are mapped into a compact,semantic word embedding space,and the Gated Recurrent Unit model can capture the distance contextual semantics correctly.The proposed hybrid model achieves F1-scores of 97%on the Twitter Large Language Model(LLM)dataset,which is much higher than the performance of new techniques.

Multi-environment BSA-seq using large F3 populations is able to achieve reliable QTL mapping with high power and resolution: An experimental demonstration in rice

Bulked-segregant analysis by deep sequencing(BSA-seq) is a widely used method for mapping QTL(quantitative trait loci) due to its simplicity, speed, cost-effectiveness, and efficiency. However, the ability of BSA-seq to detect QTL is often limited by inappropriate experimental designs, as evidenced by numerous practical studies. Most BSA-seq studies have utilized small to medium-sized populations, with F2populations being the most common choice. Nevertheless, theoretical studies have shown that using a large population with an appropriate pool size can significantly enhance the power and resolution of QTL detection in BSA-seq, with F_(3)populations offering notable advantages over F2populations. To provide an experimental demonstration, we tested the power of BSA-seq to identify QTL controlling days from sowing to heading(DTH) in a 7200-plant rice F_(3)population in two environments, with a pool size of approximately 500. Each experiment identified 34 QTL, an order of magnitude greater than reported in most BSA-seq experiments, of which 23 were detected in both experiments, with 17 of these located near41 previously reported QTL and eight cloned genes known to control DTH in rice. These results indicate that QTL mapping by BSA-seq in large F_(3)populations and multi-environment experiments can achieve high power, resolution, and reliability.

Computing large deviation prefactors of stochastic dynamical systems based on machine learning

We present a large deviation theory that characterizes the exponential estimate for rare events in stochastic dynamical systems in the limit of weak noise.We aim to consider a next-to-leading-order approximation for more accurate calculation of the mean exit time by computing large deviation prefactors with the aid of machine learning.More specifically,we design a neural network framework to compute quasipotential,most probable paths and prefactors based on the orthogonal decomposition of a vector field.We corroborate the higher effectiveness and accuracy of our algorithm with two toy models.Numerical experiments demonstrate its powerful functionality in exploring the internal mechanism of rare events triggered by weak random fluctuations.

Customized scaffolds for large bone defects using 3D‑printed modular blocks from 2D‑medical images

Additive manufacturing(AM)has revolutionized the design and manufacturing of patient-specific,three-dimensional(3D),complex porous structures known as scaffolds for tissue engineering applications.The use of advanced image acquisition techniques,image processing,and computer-aided design methods has enabled the precise design and additive manufacturing of anatomically correct and patient-specific implants and scaffolds.However,these sophisticated techniques can be timeconsuming,labor-intensive,and expensive.Moreover,the necessary imaging and manufacturing equipment may not be readily available when urgent treatment is needed for trauma patients.In this study,a novel design and AM methods are proposed for the development of modular and customizable scaffold blocks that can be adapted to fit the bone defect area of a patient.These modular scaffold blocks can be combined to quickly form any patient-specific scaffold directly from two-dimensional(2D)medical images when the surgeon lacks access to a 3D printer or cannot wait for lengthy 3D imaging,modeling,and 3D printing during surgery.The proposed method begins with developing a bone surface-modeling algorithm that reconstructs a model of the patient’s bone from 2D medical image measurements without the need for expensive 3D medical imaging or segmentation.This algorithm can generate both patient-specific and average bone models.Additionally,a biomimetic continuous path planning method is developed for the additive manufacturing of scaffolds,allowing porous scaffold blocks with the desired biomechanical properties to be manufactured directly from 2D data or images.The algorithms are implemented,and the designed scaffold blocks are 3D printed using an extrusion-based AM process.Guidelines and instructions are also provided to assist surgeons in assembling scaffold blocks for the self-repair of patient-specific large bone defects.

An improved algorithm based on equivalent sound velocity profile method at large incident angle

With the development of ultra-wide coverage technology,multibeam echo-sounder(MBES)system has put forward higher requirements for localization accuracy and computational efficiency of ray tracing method.The classical equivalent sound speed profile(ESSP)method replaces the measured sound velocity profile(SVP)with a simple constant gradient SVP,reducing the computational workload of beam positioning.However,in deep-sea environment,the depth measurement error of this method rapidly increases from the central beam to the edge beam.By analyzing the positioning error of the ESSP method at edge beam,it is discovered that the positioning error increases monotonically with the incident angle,and the relationship between them could be expressed by polynomial function.Therefore,an error correction algorithm based on polynomial fitting is obtained.The simulation experiment conducted on an inclined seafloor shows that the proposed algorithm exhibits comparable efficiency to the original ESSP method,while significantly improving bathymetry accuracy by nearly eight times in the edge beam.

Plume-lithosphere interaction in the Comei Large Igneous Province: Evidence from two types of mafic dykes in Gyangze, south Tibet, China

Two suites of mafic dykes,T1193-A and T1194-A,outcrop in Gyangze area,southeast Tibet.They are in the area of Comei LIP and have indistinguishable field occurrences with two other dykes in Gyangze,T0902 dyke with 137.7±1.3 Ma zircon age and T0907 dyke with 142±1.4 Ma zircon age reported by Wang YY et al.(2016),indicating coeval formation time.Taking all the four diabase dykes into consideration,two different types,OIB-type and weak enriched-type,can be summarized.The“OIB-type”samples,including T1193-A and T0907 dykes,show OIB-like geochemical features and have initial Sr-Nd isotopic values similar with most mafic products in Comei Large Igneous Provinces(LIP),suggesting that they represent melts directly generated from the Kerguelen mantle plume.The“weak enriched-type”samples,including T1194-A and T0902 dykes,have REEs and trace element patterns showing withinplate affinity but have obvious Nb-Ta-Ti negative anomalies.They show uniform lowerεNd(t)values(−6‒−2)and higher 87Sr/86Sr(t)values(0.706‒0.709)independent of their MgO variation,indicating one enriched mantle source.Considering their closely spatial and temporal relationship with the widespread Comei LIP magmatic products in Tethyan Himalaya,these“weak enriched-type”samples are consistent with mixing of melts from mantle plume and the above ancient Tethyan Himalaya subcontinental lithospheric mantle(SCLM)in different proportions.These weak enriched mafic rocks in Comei LIP form one special rock group and most likely suggest large scale hot mantle plume-continental lithosphere interaction.This process may lead to strong modification of the Tethyan Himalaya lithosphere in the Early Cretaceous.

An improved positioning model of deep-seafloor datum point at large incidence angle

The inhomogeneous sound speed in seawater causes refraction of sound waves,and the elimination of the refraction effect is essential to the accuracy of underwater acoustic positioning.The raytracing method is an indispensable tool for effectively handling problems.However,this method has a conflict between localization accuracy and computational quantity.The equivalent sound speed profile(ESSP)method uses a simple sound speed profile(SSP)instead of the actual complex SSP,which can improve positioning precision but with residual error.The residual error is especially non-negligible in deep water and at large beam incidence angles.By analyzing the residual error of the ESSP method through a simulation,an empirical formula of error is presented.The data collected in the sailing circle mode(large incidence angle)of the South China Sea are used for verification.The experiments show that compared to the ESSP method,the improved algorithm has higher positioning precision and is more efficient than the ray-tracing method.

Enhancing Relational Triple Extraction in Specific Domains:Semantic Enhancement and Synergy of Large Language Models and Small Pre-Trained Language Models

In the process of constructing domain-specific knowledge graphs,the task of relational triple extraction plays a critical role in transforming unstructured text into structured information.Existing relational triple extraction models facemultiple challenges when processing domain-specific data,including insufficient utilization of semantic interaction information between entities and relations,difficulties in handling challenging samples,and the scarcity of domain-specific datasets.To address these issues,our study introduces three innovative components:Relation semantic enhancement,data augmentation,and a voting strategy,all designed to significantly improve the model’s performance in tackling domain-specific relational triple extraction tasks.We first propose an innovative attention interaction module.This method significantly enhances the semantic interaction capabilities between entities and relations by integrating semantic information fromrelation labels.Second,we propose a voting strategy that effectively combines the strengths of large languagemodels(LLMs)and fine-tuned small pre-trained language models(SLMs)to reevaluate challenging samples,thereby improving the model’s adaptability in specific domains.Additionally,we explore the use of LLMs for data augmentation,aiming to generate domain-specific datasets to alleviate the scarcity of domain data.Experiments conducted on three domain-specific datasets demonstrate that our model outperforms existing comparative models in several aspects,with F1 scores exceeding the State of the Art models by 2%,1.6%,and 0.6%,respectively,validating the effectiveness and generalizability of our approach.

Hydromassage of macular hole edges for large and persistent full-thickness macular holes

●AIM:To introduce the macular hole(MH)hydromassage technique as a potentially beneficial approach for the treatment of large or persistent MH.●METHODS:This retrospective observational case series comprised 16 consecutive patients(17 eyes)diagnosed with MH.Inclusion criteria involved a hole aperture diameter larger than 600μm or the presence of an unclosed MH larger than 600μm following the previous vitrectomy.Standard MH repair procedures were administered in all cases,involving the manipulation and aspiration of the hole margin through the application of water flow with a soft-tip flute needle.A comprehensive assessment was conducted for each case before and after surgery,and optical coherence tomography(OCT)images were captured at every follow-up point.●RESULTS:The mean preoperative aperture diameter was 747±156μm(range 611-1180μm),with a mean base diameter of 1390±435μm(range 578-2220μm).Following surgery,all cases achieved complete anatomical closure of MH,with 13 cases(76.5%)exhibiting type 1 closure and 4 cases(23.5%)demonstrating type 2 closure.No significant differences were observed in the preoperative OCT variables between the two closure types.Eyes with type 1 closure showed a significantly improved visual acuity(0.70±0.10,range 0.50-0.80)compared to those with type 2 closure(0.90±0.12,range 0.80-1.00,P=0.014).●CONCLUSION:The MH hydromassage technique demonstrates promising results,achieving acceptable closure rates in cases of large or persistent MH.This technique may serve as an effective adjunctive maneuver during challenging MH surgery.

The environmental analysis and site selection of mussel and large yellow croaker aquaculture areas based on high resolution remote sensing

Mussel aquaculture and large yellow croaker aquaculture areas and their environmental characteristics in Zhoushan were analyzed using satellite data and in-situ surveys.A new two-step remote sensing method was proposed and applied to determine the basic environmental characteristics of the best mussel and large yellow croaker aquaculture areas.This methodology includes the first step of extraction of the location distribution and the second step of the extraction of internal environmental factors.The fishery ranching index(FRI1,FRI2)was established to extract the mussel and the large yellow croaker aquaculture area in Zhoushan,using Gaofen-1(GF-1)and Gaofen-6(GF-6)satellite data with a special resolution of 2 m.In the second step,the environmental factors such as sea surface temperature(SST),chlorophyll a(Chl-a)concentration,current and tide,suspended sediment concentration(SSC)in mussel aquaculture area and large yellow croaker aquaculture area were extracted and analyzed in detail.The results show the following three points.(1)For the extraction of the mussel aquaculture area,FRI1 and FRI2 are complementary,and the combination of FRI1 and FRI2 is suitable to extract the mussel aquaculture area.As for the large yellow croaker aquaculture area extraction,FRI2 is suitable.(2)Mussel aquaculture and the large yellow croaker aquaculture area in Zhoushan are mainly located on the side near the islands that are away from the eastern open waters.The water environment factor template suitable for mussel and large yellow croaker aquaculture was determined.(3)This two-step remote sensing method can be used for the preliminary screening of potential site selection for the mussels and large yellow croaker aquaculture area in the future.the fishery ranching index(FRI1,FRI2)in this paper can be applied to extract the mussel and large yellow croaker aquaculture areas in coastal waters around the world.

The Turbulent Schmidt Number for Transient Contaminant Dispersion in a Large Ventilated Room Using a Realizable k-εModel

Buildings with large open spaces in which chemicals are handled are often exposed to the risk of explosions.Computational fluid dynamics is a useful and convenient way to investigate contaminant dispersion in such large spaces.The turbulent Schmidt number(Sc_(t))concept has typically been used in this regard,and most studies have adopted a default value.We studied the concentration distribution for sulfur hexafluoride(SF_(6))assuming different emission rates and considering the effect of Sc_(t).Then we examined the same problem for a light gas by assuming hydrogen gas(H_(2))as the contaminant.When SF_(6) was considered as the contaminant gas,a variation in the emission rate completely changed the concentration distribution.When the emission rate was low,the gravitational effect did not take place.For both low and high emission rates,an increase in S_(ct) accelerated the transport rate of SF_(6).In contrast,for H_(2) as the contaminant gas,a larger S_(ct) could induce a decrease in the H_(2) transport rate.

Percutaneous antegrade management of large proximal ureteral stones using non-papillary puncture

Objective:To evaluate the feasibility and the safety of medial non-papillary percutaneous nephrolithotomy(npPCNL)for the management of large proximal ureteral stones.Methods:We evaluated prospectively collected data of 37 patients with large proximal ureteral stones more than 1.5 cm in diameter treated by prone npPCNL.Depending on stone size,in-toto stone removal or lithotripsy using the Lithoclast®Trilogy(EMS Medical,Nyon,Switzerland)was performed.Perioperative parameters including operative time(from start of puncture to the skin suturing),stone extraction time(from the first insertion of the nephroscope to the extraction of all stone fragments),and the stone-free rate were evaluated.Results:Twenty-one males and 16 females underwent npPCNL for the management of large upper ureteral calculi.The median age and stone size of treated patients were 58(interquartile range[IQR]:51-69)years and 19.3(IQR:18.0-22.0)mm,respectively.The median operative time and stone extraction time were 25(IQR:21-29)min and 8(IQR:7-10)min,respectively.One case(2.7%)of postoperative bleeding and two cases(5.4%)of prolonged fever were managed conservatively.The stone-free rate at a 1-month follow-up was 94.6%.Conclusion:The npPCNL provides a straight route to the ureteropelvic junction and proximal ureter.Approaching from a dilated portion of the ureter under low irrigation pressure with larger diameter instruments results in effective and safe stone extraction within a few minutes.