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Abstract During early embryonic development, the transition from totipotency to pluripotency is a fundamental and critical process for proper development. However, the regulatory mechanisms governing this transition remain elusive. Here, we conducted a comprehensive genome-wide CRISPR/Cas9 screen to investigate the 2-cell-like cells (2CLCs) phenotype in mouse embryonic stem cells (mESCs). This effort led to the identification of ten regulators that play a pivotal role in determining cell fate during this transition. Notably, our study revealed Mdm2 as a significant negative regulator of 2CLCs, as perturbation of Mdm2 resulted in a higher proportion of 2CLCs. Mdm2 appears to influence cell fate through its impact on cell cycle progression and H3K27me3 epigenetic modifications. In summary, the results of our CRISPR/Cas9 screen have uncovered several genes with distinct functions in regulating totipotency and pluripotency at various levels, offering a valuable resource for potential targets in future molecular studies.

IntroductionOver the past decades, immune dysregulation has been consistently demonstrated being common charactoristics of endometriosis (EM) and Inflammatory Bowel Disease (IBD) in numerous studies. However, the underlying pathological mechanisms remain unknown. In this study, bioinformatics techniques were used to screen large-scale gene expression data for plausible correlations at the molecular level in order to identify common pathogenic pathways between EM and IBD.MethodsBased on the EM transcriptomic datasets GSE7305 and GSE23339, as well as the IBD transcriptomic datasets GSE87466 and GSE126124, differential gene analysis was performed using the limma package in the R environment. Co-expressed differentially expressed genes were identified, and a protein-protein interaction (PPI) network for the differentially expressed genes was constructed using the 11.5 version of the STRING database. The MCODE tool in Cytoscape facilitated filtering out protein interaction subnetworks. Key genes in the PPI network were identified through two topological analysis algorithms (MCC and Degree) from the CytoHubba plugin. Upset was used for visualization of these key genes. The diagnostic value of gene expression levels for these key genes was assessed using the Receiver Operating Characteristic (ROC) curve and Area Under the Curve (AUC) The CIBERSORT algorithm determined the infiltration status of 22 immune cell subtypes, exploring differences between EM and IBD patients in both control and disease groups. Finally, different gene expression trends shared by EM and IBD were input into CMap to identify small molecule compounds with potential therapeutic effects.Results113 differentially expressed genes (DEGs) that were co-expressed in EM and IBD have been identified, comprising 28 down-regulated genes and 86 up-regulated genes. The co-expression differential gene of EM and IBD in the functional enrichment analyses focused on immune response activation, circulating immunoglobulin-mediated humoral immune response and humoral immune response. Five hub genes (SERPING1、VCAM1、CLU、C3、CD55) were identified through the Protein-protein Interaction network and MCODE.High Area Under the Curve (AUC) values of Receiver Operating Characteristic (ROC) curves for 5hub genes indicate the predictive ability for disease occurrence.These hub genes could be used as potential biomarkers for the development of EM and IBD. Furthermore, the CMap database identified a total of 9 small molecule compounds (TTNPB、CAY-10577、PD-0325901 etc.) targeting therapeutic genes for EM and IBD.DiscussionOur research revealed common pathogenic mechanisms between EM and IBD, particularly emphasizing immune regulation and cell signalling, indicating the significance of immune factors in the occurence and progression of both diseases. By elucidating shared mechanisms, our study provides novel avenues for the prevention and treatment of EM and IBD.

Abstract Esophageal carcinoma (EC), one of the most lethal human malignancies, lacks effective targeted therapies. Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in a variety of cancers, but its role and mechanism in EC are still unclear. Immunohistochemistry and qRT-PCR were used to analyze the expression of IDO1 in EC, and the prognostic value of IDO1 in EC was evaluated by Kaplan-Meier test. The in vitro and in vivo function loss/acquisition tests were performed to evaluate the biological effects of IDO1 in EC. The mechanism of action of IDO1-regulation EC was explored through Firefly luciferase & Renilla luciferase activity reporter, chromatin immunoprecipitation (ChIP) and immunofluorescence (IF) assays. Clinically, IDO1 expression was abnormally elevated in EC and positively correlated with overall survival. Functionally, IDO1 was contributed to the proliferation and migration of EC cells. Mechanically, IDO1 regulated the expression of chemokine C-X-C ligand 10 (CXCL10) by promoting the entry of NF-κB into the nucleus to combine with the promoter of CXCL10. Consistently, IDO1 facilitated EC progression may dependent on the presence of CXCL10. Moreover, NF-κB alleviated the inhibitory effect of IDO1 knockdown on EC. IDO1 drove the progression of EC by directly binding NF-κB and CXCL10, the finding that may provide an effective theoretical basis for precise therapies for EC.

The interaction between foot-and-mouth disease virus (FMDV) and the host is extremely important for virus infection, but there are few researches on it, which is not conducive to vaccine development and FMD control. In this study, we designed a porcine genome-scale CRISPR/Cas9 knockout library containing 93,859 single guide RNAs targeting 16,886 protein-coding genes, 25 long ncRNAs, and 463 microRNAs. Using this library, several previously unreported genes required for FMDV infection are highly enriched post-FMDV selection in IBRS-2 cells. Follow-up studies confirmed the dependency of FMDV on these genes, and we identified a functional role for one of the FMDV-related host genes: TOB1 (Transducer of ERBB2.1). TOB1-knockout significantly inhibits FMDV infection by positively regulating the expression of RIG-I and MDA5. We further found that TOB1-knockout led to more accumulation of mRNA transcripts of transcription factor CEBPA, and thus its protein, which further enhanced transcription of RIG-I and MDA5 genes. In addition, TOB1-knockout was shown to inhibit FMDV adsorption and internalization mediated by EGFR/ERBB2 pathway. Finally, the FMDV lethal challenge on TOB1-knockout mice confirmed that the deletion of TOB1 inhibited FMDV infection in vivo. These results identify TOB1 as a key host factor involved in FMDV infection in pigs.

Jiajin Mountain, where the giant pandas reside, is an essential nature reserve in China. To comprehend the land use classification of the habitat, this article proposes a remote sensing interpretation algorithm based on spatial case reasoning, known as spatial case-based reasoning (SCBR). The algorithm incorporates specific spatial factors into its framework and does not require an extensive amount of domain knowledge and eliminates the need for a complex model training process, making it capable of completing land use classification in the study area. SCBR comprises a spatial case expression model and a spatial case similarity reasoning model. The paper conducted comparative experiments between the proposed algorithm and support vector machine (SVM), U-Net, vision transformer (ViT), and Trans-Unet, and the results demonstrate that spatial case-based reasoning produces superior classification outcomes. The land use classification experiment based on spatial case-based reasoning at the Jiajinshan giant panda habitat produced satisfactory experimental results. In the comparative experiments, the overall accuracy of SCBR classification reached 95%, and the Kappa coefficient reached 90%. The paper further analyzed the changes in land use classification from 2018 to 2022, and the average accuracy consistently exceeds 80%. We discovered that the ecological environment in the region where the giant pandas reside has experienced significant improvement, particularly in forest protection and restoration. This study provides a theoretical basis for the ecological environment protection of the area.

Tangeretin (Tan), a citrus flavonoid, possesses a strong anti-tumor efficacy in various human cancers. However, the precise role of Tan in the development of esophageal squamous cell carcinoma (ESCC) remains unclear. RNA sequencing (RNA-seq) analysis was performed to observe the Tan-related genes in Tan-treated TE-1 cells. The direct relationship between GLI family zinc finger 2 (GLI2) and the promoter of glycoprotein non-metastatic melanoma protein B (GPNMB) was predicted by bioinformatics analysis and validated by luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Cell survival after Tan treatment was assessed by CCK8 assay. Gene expression levels were evaluated by a qRT-PCR, western blot, or immunofluorescence method. Cell migration and invasion were detected by wound-healing and transwell assays. The function of Tan in vivo was examined using xenograft studies. Our data indicated anti-migration and anti-invasion functions of Tan in ESCC cells in vitro. Tan also diminished tumor growth in vivo. Mechanistically, Tan diminished the expression and transcriptional activity of GLI2 in ESCC cells. Silencing of GLI2 resulted in decreased expression of GPNMB by inhibiting GPNMB transcription via the binding site at the GPNMB promoter at position +(1539-1550). Moreover, Tan down-regulated GPNMB expression in ESCC cells, and re-expression of GPNMB reversed anti-migration and anti-invasion functions of Tan in ESCC cells. Our findings uncover anti-migration and anti-invasion effects of Tan in ESCC cells by down-regulating GPNMB by suppressing GLI2-mediated GPNMB transcription, providing new evidence that Tan can function as a therapeutic agent against ESCC.

The present study was an 8-week feeding trial investigating the effects of lysine and threonine supplementation in vegetable-based diets on growth, antioxidative capacity, and gut microbiota of juvenile redclaw crayfish, Cherax quadricarinatus (initial weight 11.52 ± 0.23 g). The lysine and threonine were supplemented to formulate five isonitrogenous (37%) and isolipidic (9%) diets containing 0% (control), 0.2% lysine (L0.2), 0.2% threonine (T0.2), 0.4% lysine (L0.4), and 0.4% threonine (T0.4), respectively. Compared to the control, weight gain rate (WGR) and specific growth rate (SGR) of C. quadricarinatus significantly increased with increasing dietary lysine and threonine supplementation from 0.2% to 0.4% (P0.05). Compared with the control, crayfish in T0.4 and L0.4 showed significantly higher glutathione peroxidase (GPx) activity (P

Spermatogenesis in mammalian testes is essential for male fertility, ensuring a continuous supply of mature sperm. The testicular microenvironment finely tunes this process, with retinoic acid, an active metabolite of vitamin A, serving a pivotal role. Retinoic acid is critical for various stages, including the differentiation of spermatogonia, meiosis in spermatogenic cells, and the production of mature spermatozoa. Vitamin A deficiency halts spermatogenesis, leading to the degeneration of numerous germ cells, a condition reversible with retinoic acid supplementation. Although retinoic acid can restore fertility in some males with reproductive disorders, it does not work universally. Furthermore, high doses may adversely affect reproduction. The inconsistent outcomes of retinoid treatments in addressing infertility are linked to the incomplete understanding of the molecular mechanisms through which retinoid signaling governs spermatogenesis. In addition to the treatment of male reproductive disorders, the role of retinoic acid in spermatogenesis also provides new ideas for the development of male non-hormone contraceptives. This paper will explore three facets: the synthesis and breakdown of retinoic acid in the testes, its role in spermatogenesis, and its application in male reproduction. Our discussion aims to provide a comprehensive reference for studying the regulatory effects of retinoic acid signaling on spermatogenesis and offer insights into its use in treating male reproductive issues.

Considering the requirements pertaining to the trafficability of off-road vehicles on rough roads, and since their roll stability deteriorates rapidly when turning violently or passing slant roads due to a high center of gravity (CG), an efficient anti-slip control (ASC) method with superior instantaneity and robustness, in conjunction with a rollover prevention algorithm, was proposed in this study. A nonlinear 14 DOF vehicle model was initially constructed in order to explain the dynamic coupling mechanism among the lateral motion, yaw motion and roll motion of vehicles. To acquire physical state changes and friction forces of the tires in real time, corrected LuGre tire models were utilized with the aid of resolvers and inertial sensors, and an adaptive sliding mode controller (ASMC) was designed to suppress each wheel’s slip ratio. In addition, a model predictive controller (MPC) was established to forecast rollover risk and roll moment in reaction to the change in the lateral forces as well as the different ground heights of the opposite wheels. During experimentation, the mutations of tire adhesion capacity were quickly discerned and the wheel-hub drive motors (WHDM) and ASC maintained the drive efficiency under different adhesion conditions. Finally, a hardware-in-the-loop (HIL) platform made up of the vehicle dynamic model in the dSPACE software, semi-active suspension (SAS), a vehicle control unit (VCU) and driver simulator was constructed, where the prediction and moving optimization of MPC was found to enhance roll stability effectively by reducing the length of roll arm when necessary.

Geological disasters such as rockfalls and landslides are common in the Tibet region due to its complex topography, strong tectonic movements, and diverse climate conditions. These disasters have an increasingly significant impact on the region's economic construction and social development. In order to assess the susceptibility of rockfalls and landslides in a quantitative manner, this study selected eight factors, including slope, aspect, topographic relief, slope shape, elevation, distance to fault, river density, and engineering geological group, to conduct the sensitivity analysis of the influencing factors by applying GIS and certainty factor analysis methods. The research shows that there is a direct correlation between rockfall, landslide and influencing factors, and the susceptibility of these hazards is high in the areas with: (1) a slope greater than 30°, (2) aspect facing southeast, south, or southwest direction, (3) topographic relief of 200～800 m/km2, (4) concave slope, (5) elevation between 1500 and 4500 m, (6) distance between 0 and 3 km to fault, (7) river density greater than 0.5 km/km2, (8) lithologies identified by the codes of YJ2, TS1, TS2, and BZ1. The susceptibility of the factors is ranked in descending order as slope > engineering geological group > elevation > slope shape > river density > topographic relief > aspect > distance to fault. These results can be used as a reference for assessing the susceptibility of rockfalls and landslides in Tibet.

Nanowires have emerged as promising one-dimensional materials with which to construct various nanocircuits and nanosensors. However, measuring the electrical properties of individual nanowires directly remains challenging because of their small size, thereby hindering the comprehensive understanding of nanowire-based device performance. A crucial factor in achieving reliable electrical characterization is establishing well-determined contact conditions between the nanowire sample and the electrodes, which becomes particularly difficult for soft nanowires. Introduced here is a novel technique for measuring the conductivity of an individual nanowire with the aid of automated nanomanipulation using an atomic force microscope. In this method, two nanowire segments cut from the same silver nanowire are positioned onto a pair of gold electrodes, serving as flexible nanoprobes to establish controllable contact with the sample. By changing the contact points along the nanowire sample, conductivity measurements can be performed on different regions, thereby eliminating the influence of contact resistance by analyzing multiple current–voltage curves. Using this approach, the resistivity of a 100-nm-diameter silver nanowire is determined to be 3.49 × 10−8 Ω m.

CRISPR-Cas9-mediated genome editing in sheep is of great use in both agricultural and biomedical applications. While targeted gene knockout by CRISPR-Cas9 through non-homologous end joining (NHEJ) has worked efficiently, the knockin efficiency via homology-directed repair (HDR) remains lower, which severely hampers the application of precise genome editing in sheep. Here, in sheep fetal fibroblasts (SFFs), we optimized several key parameters that affect HDR, including homology arm (HA) length and the amount of double-stranded DNA (dsDNA) repair template; we also observed synchronization of SFFs in G2/M phase could increase HDR efficiency. Besides, we identified three potent small molecules, RITA, Nutlin3, and CTX1, inhibitors of p53-MDM2 interaction, that caused activation of the p53 pathway, resulting in distinct G2/M cell-cycle arrest in response to DNA damage and improved CRISPR-Cas9-mediated HDR efficiency by 1.43- to 4.28-fold in SFFs. Furthermore, we demonstrated that genetic knockout of p53 could inhibit HDR in SFFs by suppressing the expression of several key factors involved in the HDR pathway, such as BRCA1 and RAD51. Overall, this study offers an optimized strategy for the usage of dsDNA repair template, more importantly, the application of MDM2 antagonists provides a simple and efficient strategy to promote CRISPR/Cas9-mediated precise genome editing in sheep primary cells.

Credit customer subdivisions and borrower characteristics are essential tools for banks and lending companies to evaluate credit risk and make profits. This study proposes a Multi-Level Default Risk Rating (MLDRR) strategy based on a heterogeneous ensemble learning method. Further, a novel Eight Subdivisions Model (ESM) of credit customers is constructed. Through the model, the credit customers are subdivided into eight important categories, such as the defaulting customers that are easily missed, the customers with the highest risk, customers with the potential risk, and target customers, etc. Moreover, we describe the risk characteristics of the customer subdivisions and find deficiencies in the agency's existing risk ratings. Finally, the explored strategies are validated on one hundred thousand real credit data, demonstrating the effectiveness of ESM. Compared with the traditional customer segmentation and characteristics research, this paper develops a new credit customer segmentation method based on the perspective of default risk and describes the risk characteristics more comprehensively through eight customer subdivisions.

Adipogenesis involves complex interactions between transcription and metabolic signalling. Exploration of the developmental characteristics of intramuscular adipocyte will provide targets for enhancing beef cattle marbling without increasing obesity. Few reports have compared bovine perirenal and intramuscular adipocyte transcriptomes using the combined analysis of transcriptomes and lipid metabolism to explore differences in adipogenic characteristics. We identified perirenal preadipocytes (PRA) and intramuscular preadipocytes (IMA) in Qinchuan cattle. We found that IMA were highly prolific in the early stages of adipogenesis, while PRA shows a stronger adipogenic ability in the terminal differentiation. Bovine perirenal and intramuscular adipocytes were detected through the combined analysis of the transcriptome and metabolome. More triglyceride was found to be upregulated in perirenal adipocytes; however, more types and amounts of unsaturated fatty acids were detected in intramuscular adipocytes, including eicosapentaenoic acid (20:5 n-3; EPA) and docosahexaenoic acid (22:6 n-3; DHA). Furthermore, differentially expressed genes in perirenal and intramuscular adipocytes were positively correlated with the eicosanoid, phosphatidylcholine (PC), phosphatidyl ethanolamine (PE), and sphingomyelin contents. Associated differential metabolic pathways included the glycerolipid and glycerophospholipid metabolisms. Our research findings provide a basis for the screening of key metabolic pathways or genes and metabolites involved in intramuscular fat production in cattle.

We designed and synthesized two new ionic thermally activated delayed fluorescent (TADF) emitters that are charged analogues of a known multiresonant TADF (MR-TADF) compound, DiKTa. The emission of the charged derivatives is red-shifted compared to the parent compound. For instance, DiKTa-OBuIm emits in the green (λPL = 499 nm, 1 wt % in mCP) while DiKTa-DPA-OBuIm emits in the red (λPL = 577 nm, 1 wt % in mCP). In 1 wt % mCP films, both emitters showed good photoluminescence quantum yields of 71% and 61%, and delayed lifetimes of 316.6 μs and 241.7 μs, respectively, for DiKTa-OBuIm and DiKTa-DPA-OBuIm, leading to reverse intersystem crossing rates of 2.85 × 103 s−1 and 3.04 × 103 s−1. Light-emitting electrochemical cells were prepared using both DiKTa-OBuIm and DiKTa-DPA-OBuIm as active emitters showing green (λmax = 534 nm) and red (λmax = 656 nm) emission, respectively.

Currently, most routes of the oil and gas pipelines in mountainous areas are selected in a traditional manual manner, with the quality greatly depending on the experience and technical level of the route selection personnel. Thus, the result of route selection is often not scientific and reasonable enough. Therefore, a route selection method of oil and gas pipelines in mountainous areas based on geological information atlas was put forward. Specifically, the regional geological information atlas is established in terms of landform, geological risk, high consequence area and sensitive area, the cost grid map for route selection through the quantification of factor cost is built with consideration to the routing cost of pipeline, and thus the optimal route is obtained through the analysis with optimal route algorithm. In addition, this method was applied to a pipeline in the mountainous area in Southwest China. By comparing the calculated route and the existing route, it is found that the route analyzed by this method of pipelines in mountainous areas based on the geological information atlas could effectively avoid the complex terrain, poor geological environment, high consequence area and environment sensitive area, and the distance cost could be considered comprehensively, thus solving the problem of inadequate consideration to the comprehensive factors in manual route selection. In general, the route selected by this method could be used as a reference for the pipeline route designers.

Abstract Animal models of human diseases play a critical role in medical research. Pigs are anatomically and physiologically more like humans than are small rodents such as mice, making pigs an attractive option for modeling human diseases. Advances in recent years in genetic engineering have facilitated the rapid rise of pig models for use in studies of human disease. In the present review, we summarize the current status of pig models for human cardiovascular, metabolic, neurodegenerative, and various genetic diseases. We also discuss areas that need to be improved. Animal models of human diseases play a critical role in medical research. Advances in recent years in genetic engineering have facilitated the rapid rise of pig models for use in studies of human disease. In the present review, we summarize the current status of pig models for human cardiovascular, metabolic, neurodegenerative, various genetic diseases and xenotransplantation.

The geothermal resource has become the significant constitution of renewable and clean energies in the world. This study focuses on the genetic mechanism of a high-temperature geothermal system and its engineering impact in the Woka graben, southern Tibet, via hydrochemical and isotopic analyses. The hydrochemical types are mainly SO4-Na type, SO4-Cl-Na type, and HCO3-SO4-Na type. Geothermal water is characterized as medium to alkaline affinity with low total dissolved solids. D-O isotopes indicate that geothermal water is recharged by atmospheric precipitation at the elevation of 5193–5247 m. Na-K-Mg equilibrium diagram shows partial equilibrium or mixed water, and the proportion of cold water mixing is 73–83%. The temperature ranges of shallow and deep geothermal reservoirs are from 96.85°C to 119.57°C and from 120°C to 200°C, respectively. Geothermal water is heated by melting crust and controlled by deep faults. For major construction projects in the Woka graben, detailed investigation and demonstration should be conducted to avoid the geothermal water channel as much as possible, or to divert the geothermal water and reasonably arrange the construction sequence to overcome the problem.

Abstract Background A considerable number of muscle development-related genes were differentially expressed in the early stage of avian adipocyte differentiation. However, the functions of them in adipocyte differentiation remain largely known. In this study, the myoblast determination protein 1 (MYOD1) was selected as a representative of muscle development. We investigated its expression, function, and regulation in avian adipocyte differentiation. Results The expression of MYOD1 decreased significantly in the early stage of avian adipocyte differentiation. CRISPR/Cas9-mediated deletion of MYOD1 induced adipocyte differentiation, whereas over-expression of MYOD1 inhibited adipogenesis. The mRNA-seq data showed that MYOD1 could perturb the lipid biosynthetic process during differentiation. Our results showed that MYOD1 directly up-regulates the miR-206 expression by binding the upstream 1200 bp region of miR-206. Then, over-expression of miR-206 can inhibit the adipogenesis. Furthermore, MYOD1 affected the expression of endogenous miR-206 and its target gene Kruppel-like factor 4 (KLF4), which is an important activator of adipogenesis. Accordingly, the inhibition of miR-206 or over-expression of KLF4 could counteract the inhibitory effect of MYOD1 on adipocyte differentiation. Conclusions Our results establish that MYOD1 inhibits adipocyte differentiation by up-regulating miR-206 to suppress the KLF4 expression. These findings identify a novel function of MYOD1 in adipocyte differentiation, suggesting a potential role in body-fat distribution regulation.

Parameter setting is an essential factor affecting algorithm performance in data mining techniques. CABOSFV is an efficient clustering algorithm which can cluster binary data with sparse features, but it is challenging to specify the threshold parameter. To solve the difficulty of parameter decision, a clustering algorithm based on sparse feature vector without specifying parameter (CASP) is proposed in this paper. The calculation method of an upper limit of threshold is firstly defined to determine the range of threshold. Furthermore, we use the sparseness index to sort the data and conduct the clustering process based on the adjusted sparse feature vector after data sorting. An interval search strategy is adopted to find a suitable threshold within the defined threshold range, and the clustering result with the selected suitable parameter is the outcome. Experiments on 7 UCI datasets demonstrate that the clustering results of the CASP algorithm are superior to other baselines in terms of both effectiveness and efficiency. CASP not only simplifies the parameter decision process, but also obtains desirable clustering results quickly and stably, which shows the practicability of the algorithm.

Evaluating internal Cluster Validity Index (CVI) is a critical task in clustering research. Existing studies mainly employ the number of clusters (NC-based method) or external CVIs (external CVIs-based method) to evaluate internal CVIs, which are not always reasonable in all scenarios. Additionally, there is no guideline of choosing appropriate methods to evaluate internal CVIs in different cases. In this paper, we focus on the evaluation abilities of external CVIs to internal CVIs, and propose a novel approach, named external CVI's evaluation Ability MEasurement approach through Ranking consistency (CAMER), to measure the evaluation abilities of external CVIs quantitatively, for assisting in selecting appropriate external CVIs to evaluate internal CVIs. Specifically, we formulate the evaluation ability measurement problem as a ranking consistency task, by measuring the consistency between the evaluation results of external CVIs to internal CVIs and the ground truth performance of internal CVIs. Then, the superiority of CAMER is validated through a real-world case. Moreover, the evaluation abilities of seven popular external CVIs to internal CVIs in six different scenarios are explored by CAMER. Finally, these explored evaluation abilities are validated on four real-world datasets, demonstrating the effectiveness of CAMER.

BackgroundIncreasing researches have been reported that epigenetic alterations play critical roles in ESCC development. However, the role of the histone demethylase KDM4D in ESCC tumorigenesis is poorly investigated. This study aims to discover the underlying mechanisms between KDM4D and ESCC progression.MethodsCCK-8 assays, clone formation assay and soft-agar assays were performed to assess cell proliferation. Transwell assay was utilized to assess cell migration efficiency, while sphere formation assay was used to evaluate the cell self-renewal ability. Bioinformatic analysis was conducted to identify prognostic factors and predict the potential E3 ubiquitin ligases. In vitro ubiquitination assay was conducted to confirm the regulations between SYVN1 and HMGB1. The mRNA levels or protein levels of genes were detected by real-time PCR and western blot analysis. In vivo tumor xenograft models were used to determine whether the HMGB1 inhibition affected the malignant features of ESCC cells.ResultEpigenome screening and low-throughput validations highlighted that KDM4D is a tumor suppressor in ESCC. KDM4D expressed lowly in tumors that predicts poor prognosis. KDM4D deficiency significantly enhanced tumor growth, migration and stemness. Mechanistically, KDM4D transcriptionally activates SYVN1 expressions via H3K9me3 demethylation at the promoter region, thereby triggering the ubiquitin-dependent degradation of HMGB1. Low KDM4D depended on accumulated HMGB1 to drive ESCC progression and aggressiveness. Targeting HMGB1 (Glycyrrhizin) could remarkably suppress ESCC tumor growth in vitro and in vivo, especially in KDM4D-deficient cells.ConclusionsWe systematically identified KDM4D/SYVN1/HMGB1 axis in ESCC progression, proving novel biomarkers and potential therapeutic targets.

Recommending loan products to applicants would benefit many financial businesses and individuals. Nevertheless, many loan products suffer from the cold start problem; i.e., there are no available historical data for training the recommendation model. Considering the delayed feedback and the complex semantic properties of loans, methods for general cold start recommendation cannot be directly used. Moreover, existing loan recommendation methods ignore the default risk, which should be evaluated along with the approval rate. To solve these challenges, we propose CSRLoan for cold start loan recommendation. CSRLoan employs pretraining techniques to learn the embeddings of statements, which captures the intrinsic semantic information of different loans. For recommendation, we design a dual neural matrix factorization (NMF) model, which can not only capture the semantic information of both loan products and applicants but also generate the recommendation results and default risk at the same time. Extensive experiments have been conducted on real-world datasets to evaluate the effectiveness and efficiency of the proposed CSRLoan.

Wear debris in lubrication oil provides important information for marine engine condition monitoring and faults diagnosis. Inductive sensors have been widely used to detect wear debris in lubrication oil. To improve the sensitivity, the inductive coil is always connected with a capacitor in parallel to form parallel LC resonance-sensing circuit. A previous study optimized the parallel resonance circuit by adjusting the excitation frequency. However, multiple parameters (namely, excitation signal, signal detection circuits, and signal-processing program, etc.) need to be adjusted accordingly for a series of the testing frequencies. To simplify the optimization, we propose a method based on adjusting the parallel capacitance in this work. The impedance (inductance and internal resistance) of the sensing coil and its variation induced by particles are first measured, which are the necessary parameters for establishing the function relationship between the parallel capacitance and the relative impedance variation. With the function relationship, the relative impedance variation is calculated directly, and the optimal capacitance is located at the highest absolute value of it. The experimental results for the ferrous and nonferrous particles match the calculation results well. Interestingly, the optimal capacitance for the nonferrous particle was larger than that of the ferrous particle. We speculate that the difference is generated due to the increased resistance induced by the eddy current effect.

Selenoprotein V (SELENOV) is a new and the least conserved member of the selenoprotein family. Herein we generated Selenov knockout (KO) mice to determine its in vivo function. The KO led to 16–19% increases (P

Pluripotency maintenance and exit in embryonic stem cells is a focal topic in stem cell biology. However, the effects of screening under very stringent culture conditions (e.g., differentiation medium, no leukemia inhibitory factor, no chemical inhibitors such as PD0325901 and CHIR99021, and no feeder cells) and of prolonging culture for key factors that regulate pluripotency exit, have not yet been reported. Here, we used a genome-wide CRISPR library to perform such a screen in mouse embryonic stem cells. Naïve NANOG-GFP mESCs were first transfected with a mouse genome-wide CRISPR knockout library to obtain a mutant mESCs library, followed by screening for two months in a strict N2B27 differentiation medium. The clones that survived our stringent screening were analyzed to identify the inserted sgRNAs. In addition to identifying the enriched genes that were reported in previous studies (Socs3, Tsc1, Trp53, Nf2, Tcf7l1, Csnk1a1, and Dhx30), we found 17 unreported genes, among which Zfp771 and Olfr769 appeared to be involved in pluripotency exit. Furthermore, Zfp771 knockout ESCs showed a differentiation delay in embryonic chimera experiments, indicating Zfp771 played an important role in pluripotency exit. Our results show that stringent screening with the CRISPR library can reveal key regulators of pluripotency exit.

Internal cluster validity index is a powerful tool for evaluating clustering performance. The study on internal cluster validity indices for categorical data has been a challenging task due to the difficulty in measuring distance between categorical attribute values. While some efforts have been made, they ignore the relationship between different categorical attribute values and the detailed distribution information between data objects. To solve these problems, we propose a novel index called Categorical data cluster Utility Based On Silhouette (CUBOS). Specifically, we first make clear the superiority of the paradigm of Silhouette index in exploring the details of clustering results. Then, we raise the Improved Distance metric for Categorical data (IDC) inspired by Category Distance to measure distance between categorical data exactly. Finally, the paradigm of Silhouette index and IDC are combined to construct the CUBOS, which can overcome the aforementioned shortcomings and produce more accurate evaluation results than other baselines, as shown by the experimental results on several UCI datasets.

In this paper, we deal with the vibration control problem of a flexible spacecraft system with unknown external disturbance and uncertain input backlash nonlinearity. The considered system is described by two partial differential equations and an ordinary differential equation as governing equations, and by ordinary differential equations as boundary conditions. The backlash nonlinearity is reformulated into the desired control input associated with an extra input nonlinear error. This input error and the external disturbance are combined into an unknown “disturbance-like” item. Two boundary control inputs are designed at the center body of the spacecraft, compensating for the unknown upper-bound of such items by applying proper online updating laws. As a result, the vibration of both solar panels of the flexible spacecraft is suppressed and their angle positions are regulated in the desired region. The numerical simulations are provided to verify the control performance of the proposed controls by the choice of proper parameters.

Inductance detection is an important method for detecting wear debris in ship lubricating oil. Presently, an LCR (inductance, resistance, capacitance) meter is generally used to detect wear debris by measuring the inductance change of the sensing coil. When ferromagnetic debris passes through the sensing coil, a pulse will appear in the inductance signal. Previous studies have shown that the amplitude of the inductance pulse decreases significantly with the increase in the particles’ velocity. Therefore, it is difficult to detect ferromagnetic debris with a high flow velocity using an LCR meter. In this paper, a novel method, high-frequency voltage acquisition (HFVA), is proposed to detect ferromagnetic debris. Different from previous methods, the wear debris was detected directly by measuring the voltage change of the sensing coil, while the synchronized sampling method was utilized to ensure the higher-frequency acquisition of the sensor output signal. The experimental results show that when the velocity of particles increased from 6 mm/s to 62 mm/s, the amplitude of the signal pulse obtained by HFVA decreased by only 13%, which was much lower than the 85% obtained by utilizing the LCR method.

Porcine epidemic diarrhea virus (PEDV) is a burdensome coronavirus for the global pig industry. Although its fecal-oral route has been well-recognized, increasing evidence suggests that PEDV can also spread through airborne routes, indicating that the infection may also occur in the respiratory tract. N6-methyladenosine (m6A) has been known to regulate viral replication and host immunity, yet its regulatory role and molecular mechanism regarding PEDV infection outside the gastrointestinal tract remain unexplored. In this study, we demonstrate that PEDV can infect porcine lung tissue and the 3D4/21 alveolar macrophage cell line, and the key m6A demethylase ALKBH5 is remarkably induced after PEDV infection. Interestingly, the disruption of ALKBH5 expression remarkably increases the infection’s capacity for PEDV. Transcriptome profiling identified dozens of putative targets of ALKBH5, including GAS6, which is known to regulate virus infectivity. Further, MeRIP-qPCR and mRNA stability analyses suggest that ALKBH5 regulates the expression of GAS6 via an m6A-YTHDF2-dependent mechanism. Overall, our study demonstrates that PEDV can infect porcine lung tissue and 3D4/21 cells and reveals the crucial role of ALKBH5 in restraining PEDV infections, at least partly, by influencing GAS6 through an m6A-YTHDF2-dependent mechanism.

Animal cloning is of great importance to the production of transgenic and genome-edited livestock. Especially for multiple gene-editing operations, recloning is one of the most feasible methods for livestock. In addition, a multiple-round cloning method is practically necessary for animal molecular breeding. However, cloning efficiency remains extremely low, especially for serial cloning, which seriously impedes the development of livestock breeding based on genome editing technology. The incomplete reprogramming and failure in oocyte activation of some pluripotent factors were deemed to be the main reason for the low efficiency of animal recloning. Here, to overcome this issue, which occurred frequently in the process of animal recloning, we established a reporter system in which fluorescent proteins were driven by pig OCT4 or SOX2 promoter to monitor the reprogramming process in cloned and recloned pig embryos. We studied the effect of different histone deacetylase (HDAC) inhibitors on incomplete reprogramming. Our results showed that Trichostatin A (TSA) could activate pluripotent factors and significantly enhance the development competence of recloned pig embryos, while the other two inhibitors, valproic acid (VPA) and Scriptaid, had little effect on that. Furthermore, we found no difference in OCT4 mRNA abundance between TSA-treated and untreated embryos. These findings suggest that TSA remarkably improves the reprogramming state of pig recloned embryos by restoring the expression of incompletely activated pluripotent genes OCT4 and SOX2.

Atomic force microscope (AFM)-based nanomanipulation has been proved to be a possible method for assembling various nanoparticles into complex patterns and devices. To achieve efficient and fully automated nanomanipulation, nanoparticles on the substrate must be identified precisely and automatically. This work focuses on an autodetection method for flexible nanowires using a deep learning technique. An instance segmentation network based on You Only Look Once version 3 (YOLOv3) and a fully convolutional network (FCN) is applied to segment all movable nanowires in AFM images. Combined with follow-up image morphology and fitting algorithms, this enables detection of postures and positions of nanowires at a high abstraction level. Benefitting from these algorithms, our program is able to automatically detect nanowires of different morphologies with nanometer resolution and has over 90% reliability in the testing dataset. The detection results are less affected by image complexity than the results of existing methods and demonstrate the good robustness of this algorithm.

Investor recommendation is a critical and challenging task for startups, which can assist startups in locating suitable investors and enhancing the possibility of obtaining investment. While some efforts have been made for investor recommendation, few of them explore the impact of startups’ features, including partners, rounds, and fields, to investor recommendation performance. Along this line, in this paper, with the help of the heterogeneous information network, we propose a FEatures’ COntribution Measurement approach of startups on investor recommendation, named FECOM. Specifically, we construct the venture capital heterogeneous information network at first. Then, we define six venture capital metapaths to represent the features of startups that we focus on. In this way, we can measure the contribution of startups’ features on the investor recommendation task by validating the recommendation performance based on different metapaths. Finally, we extract four practical rules to assist in further investment tasks by using our proposed FECOM approach.

Sensitive on-line detection of Cu2+ in lubricating oil of marine power plant is important for displaying equipment wear status and fault pre-judgment in real time. However, there are few reports on in-situ, portable and highly sensitive Cu2+ detection devices in organic media before. In this report, CsPbBr3 perovskite quantum dots (PQDs) are employed as fluorescence probe for Cu2+ detection in microfluidic chip. The size effect of the CsPbBr3 QDs on the detection performances is firstly investigated. To obtain preferable sensitivity and detection limit, polymethyl methacrylate opal photonic crystals (PMMA OPCs) film is developed as microfluidic sensor substrate, which can tremendously improve the fluorescence intensity of PQDs as high as 26-fold. The enhancement effect can be attributed to the coupling between photonic crystal stopband effect and the excitation light field. Moreover, the use of photomultiplier module for fluorescence signal measurement enables the detection device to be portable. The novel strategy offers the advantages of higher sensitivity (8.62 μM–1) and lower detection limit (0.40 nM). Otherwise, this sensor also provides wide detection range and good selectivity, thus, it will have potential in oil quality in-situ detection and mechanical wear prediction in the future.

ABSTRACT: Blind tip reconstruction (BTR) method is one of the favorable methods to estimate the atomic force microscopy (AFM) probe shape. The exact shape of the characterizer is not required for BTR, while the geometry of the sample may affect the reconstruction significantly. A cone-shaped array sample was chosen as a characterizer to be evaluated. The target AFM probe to be reconstructed was a diamond triangular pyramid probe with two feature angles, namely front angle (FA) and back angle (BA). Four conical structures with different semi-angles were dilated by the pyramid probe. Simulation of scanning process demonstrates that it is easy to judge from the images of the isolated rotary structure, cone-shaped, the suitability of the sample to be a tip characterizer for a pyramid probe. The cone-shaped array sample was repeatedly scanned 50 times by the diamond probe using an AFM. The series of scanning images shrank gradually and more information of the probe was exhibited in the images, indicating that the characterizer has been more suitable for BTR. The feature angle FA of the characterizer increasingly reduces during the scanning process. A self-adaptive grinding between the probe and the characterizer contributes to BTR of the diamond pyramid probe. Keywords: AFM diamond probe, BTR, Cone characterizer, Self-adaptive, Grinding

Customer segmentation is critical for auto insurance companies to gain competitive advantage by mining useful customer related information. While some efforts have been made for customer segmentation to support auto insurance decision making, their customer segmentation results tend to be affected by the characteristics of the algorithm used and lack multiple validation from multiple algorithms. To this end, we propose an auto insurance business analytics approach that segments customers by using three mixed-type data clustering algorithms including k-prototypes, improved k-prototypes and similarity-based agglomerative clustering. The customer segmentation results of these algorithms can complement and reinforce each other and demonstrate as much information as possible to support decision-making. To confirm its practical value, the proposed approach extracts seven rules for an auto insurance company that may support the company to make customer related decisions and develop insurance products.

A combined tip-sample scanning architecture can improve the imaging speed of atomic force microscopy (AFM). However, the nonorthogonality between the three scanners and the nonideal response of each scanner cause measurement errors. In this article, the authors systematically analyze the influence of the installation and response errors of the combined scanning architecture. The experimental results show that when the probe in the homemade high-speed AFM moves with the Z-scanner, the spot position on the four-quadrant detector changes, thus introducing measurement error. Comparing the experimental results with the numerical and theoretical results shows that the undesired motion of the Z-scanner introduces a large error. The authors believe that this significant error occurs because the piezoelectric actuator not only stretches along the polarization direction but also swings under nonuniform multifield coupling. This article proposes a direction for further optimizing the instrument and provides design ideas for similar high-speed atomic force microscopes.

Having a basic understanding of non-Newtonian fluid flow through porous media, which usually consist of series of expansions and contractions, is of importance for enhanced oil recovery, groundwater remediation, microfluidic particle manipulation, etc. The flow in contraction and/or expansion microchannel is unbounded in the primary direction and has been widely studied before. In contrast, there has been very little work on the understanding of such flow in an expansion–contraction microchannel with a confined cavity. We investigate the flow of five types of non-Newtonian fluids with distinct rheological properties and water through a planar single-cavity microchannel. All fluids are tested in a similarly wide range of flow rates, from which the observed flow regimes and vortex development are summarized in the same dimensionless parameter spaces for a unified understanding of the effects of fluid inertia, shear thinning, and elasticity as well as confinement. Our results indicate that fluid inertia is responsible for developing vortices in the expansion flow, which is trivially affected by the confinement. Fluid shear thinning causes flow separations on the contraction walls, and the interplay between the effects of shear thinning and inertia is dictated by the confinement. Fluid elasticity introduces instability and asymmetry to the contraction flow of polymers with long chains while suppressing the fluid inertia-induced expansion flow vortices. However, the formation and fluctuation of such elasto-inertial fluid vortices exhibit strong digressions from the unconfined flow pattern in a contraction–expansion microchannel of similar dimensions.

The global incidence of cancer is rapidly rising, and despite an improved understanding of cancer molecular biology, immune landscapes, and advancements in cytotoxic, biologic, and immunologic anti-cancer therapeutics, cancer remains a leading cause of death worldwide. Cancer is caused by the accumulation of a series of gene mutations called driver mutations that confer selective growth advantages to tumor cells. As cancer therapies move toward personalized medicine, predictive modeling of the role driver mutations play in tumorigenesis and therapeutic susceptibility will become essential. The development of next-generation sequencing technology has made the evaluation of mutated genes possible in clinical practice, allowing for identification of driver mutations underlying cancer development in individual patients. This, combined with recent advances in gene editing technologies such as CRISPR-Cas9 enables development of personalized tumor models for prediction of treatment responses for mutational profiles observed clinically. Pigs represent an ideal animal model for development of personalized tumor models due to their similar size, anatomy, physiology, metabolism, immunity, and genetics compared to humans. Such models would support new initiatives in precision medicine, provide approaches to create disease site tumor models with designated spatial and temporal clinical outcomes, and create standardized tumor models analogous to human tumors to enable therapeutic studies. In this review, we discuss the process of utilizing genomic sequencing approaches, gene editing technologies, and transgenic porcine cancer models to develop clinically relevant, personalized large animal cancer models for use in co-clinical trials, ultimately improving treatment stratification and translation of novel therapeutic approaches to clinical practice.

Abstract MYD88 plays an important role in the immune response against infections. To analyze MYD88 gene expression during different stages of pig development, we used real-time PCR. MYD88 was seen expressed in all tissues examined. MYD88 expression in spleen, lungs, and thymus reached its highest value from 7 to 14 days of age and decreased thereafter. Expression in lymph nodes was high until 28 days of age and then it declined after weaning, with stable low levels in adult pigs. MYD88 expression was high before 35 days of age in the small intestine (duodenum, jejunum, and ileum), where it reached its highest value from 7 to 14 days of age. MYD88 expression in the small intestine declined post-weaning and remained relatively low during adulthood. The results of this study suggest that weaning stress and development of the immune system might be positively correlated with MYD88 expression regulation. Moreover, this study provided evidence that the high expression of MYD88 may diminish weaning stress and increase disease resistance in Meishan pigs.

Purpose: In order to investigate community structure of the component stocks of SSE (Shanghai Stock Exchange) 180-index, a stock correlation network is built to find the intra-community and inter-community relationship. Design/methodology/approach: The stock correlation network is built taking the vertices as stocks and edges as correlation coefficients of logarithm returns of stock price. It is built as undirected weighted at first. GN algorithm is selected to detect community structure after transferring the network into un-weighted with different thresholds. Findings: The result of the network community structure analysis shows that the stock market has obvious industrial characteristics. Most of the stocks in the same industry or in the same supply chain are assigned to the same community. The correlation of the internal stock prices’ fluctuation is closer than in different communities. The result of community structure detection also reflects correlations among different industries. Originality/value: Based on the analysis of the community structure in Shanghai stock market, the result reflects some industrial characteristics, which has reference value to relationship among industries or sub-sectors of listed companies.

Measurement of force on a micro- or nano-Newton scale is important when exploring the mechanical properties of materials in the biophysics and nanomechanical fields. The atomic force microscope (AFM) is widely used in microforce measurement. The cantilever probe works as an AFM force sensor, and the spring constant of the cantilever is of great significance to the accuracy of the measurement results. This paper presents a normal spring constant calibration method with the combined use of an electromagnetic balance and a homemade AFM head. When the cantilever presses the balance, its deflection is detected through an optical lever integrated in the AFM head. Meanwhile, the corresponding bending force is recorded by the balance. Then the spring constant can be simply calculated using Hooke’s law. During the calibration, a feedback loop is applied to control the deflection of the cantilever. Errors that may affect the stability of the cantilever could be compensated rapidly. Five types of commercial cantilevers with different shapes, stiffness, and operating modes were chosen to evaluate the performance of our system. Based on the uncertainty analysis, the expanded relative standard uncertainties of the normal spring constant of most measured cantilevers are believed to be better than 2%.

Precision measurements of a nanoscale sample surface using an atomic force microscope (AFM) require a precise quantitative knowledge of the 3D tip shape. Blind tip reconstruction (BTR), established by Villarrubia, gives an outer bound with larger errors if the tip characterizer is not appropriate. In order to explore the errors of BTR, a series of simulation experiments based on a conical model were carried out. The results show that, to reconstruct the tip precisely, the cone angle of the tip characterizer must be smaller than that of the tip. Furthermore, the errors decrease as a function of the tip cone angle and increase linearly with the sample radius of curvature, irrespective of the tip radius of curvature. In particular, for sharp (20 nm radius) and blunt (80 nm radius) tips, the radius of curvature of the tip characterizer must be smaller than 5 nm. Based on these simulation results, a local error model of BTR was established. The maximum deviation between the errors derived from the model and the simulated experiments is 1.22 nm. Compared with the lateral resolution used in the above simulated experiments (4 nm/pixel), it is valid to ignore the deviations and consider the local error model of BTR is indeed in quantitative agreement with the simulation results. Finally, two simulated ideal structures are proposed here, together with their corresponding real samples. The simulation results show they are suitable for BTR.

Induced pluripotent stem cells (iPSCs) generated from somatic cells by ectopic expression of reprogramming factors, e.g., POU5F1 (OCT4), KLF4, and SOX2, have great potential for regenerative medicine. However, before they can be used in a clinical setting, the mechanism of reprogramming needs to be better understood. Here, by engineering reprogramming factors to a destabilizing protein domain, we achieved inducible generation of mouse and pig iPSCs. Stability of the fusion protein was precisely regulated by the addition of the cell-permeable small molecule trimethoprim (TMP) in a dose-dependent manner. With these tools, we found that during the early and middle stages of reprogramming, exogenous OCT4 or KLF4 could be omitted, whereas exogenous SOX2 expression at early and middle stages was required for successful reprogramming. Our TMP reprogramming system is useful for defining the stoichiometry and temporal requirements of transcription factors for reprogramming.