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Objectives: Colistin is known as the last resort antibiotic to treat the infections caused by multidrug resistant foodborne pathogens. The emergence and widespread dissemination of plasmid-mediated colistin resistance gene mcr-1 in the Escherichia coli (E. coli) incurs potential threat to public health. Here, we investigated the epidemiology, transmission dynamics, and genetic characterization of mcr-1 harbouring E. coli isolates from poultry originated in Hebei Province, China. Methods: A total of 297 faecal samples were collected from the two large poultry farms in Hebei Province, China. The samples were processed for E. coli identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry and 16S rDNA sequencing. Then, the mcr-1 gene harbouring E. coli strains were identified by polymerase chain reaction and subjected to antimicrobial susceptibility testing by broth microdilution assay. The genomic characterization of the isolates was done by whole genome sequencing using the various bioinformatics tools, and multi-locus sequence typing was done by sequence analysis of the seven housekeeping genes. The conjugation experiment was done to check the transferability of mcr-1 along with the plasmid stability testing. Results: A total of six mcr-1 E. coli isolates with minimum inhibitory concentration of 4 μg/mL were identified from 297 samples (2.02%). The mcr-1 harbouring E. coli were identified as multidrug resistant and belonged to ST101 (n = 4) and ST410 (n = 2). The genetic environment of mcr-1 presented its position on IncHI2 plasmid in 4 isolates and p0111 in 2 isolates, which is a rarely reported plasmid type for mcr-1. Moreover, both type of plasmids was transferable to recipient J53, and mcr-1 was flanked by 3 mobile elements ISApl1, Tn3, and IS26 forming a novel backbone Tn3–IS26-mcr-1– pap2-ISApl1 on the p0111 plasmid. The phylogenetic analysis shared a common lineage with mcr-1 harbouring isolates from the environment, humans, and animals, which indicate its horizontal spread among the diverse sources, species, and hosts. Conclusion: This study recommends the one health approach for future surveillance across multiple sources and bacterial species to adopt relevant measures and reduce global resistance crises.

Accurate measurement of urban sprawl is vital for urban planning and management. Urban planning-induced internal structure complexity affects the extent of urban sprawl. In addition, urban sprawl is closely linked to economic development. The study attempts to explore the impact of urban sprawl from an economic-dominated perspective. Thus a City-Ring road-County (CRC) scale framework based on top-down administrative divisions for urban sprawl measurement is proposed: 1) the single-index measurement based on economic activity is applied to calculate urban sprawl; 2) the spatiotemporal pattern of urban sprawl is investigated through a case study in 31 economy-dominated provincial capital cities across China from 2005 to 2015; 3) the impact of economy and land on urban sprawl is explored using correlation analysis. The results indicate that the degree of urban sprawl at the city scale shows an “inverted U-shaped” curve from 2005 to 2015, which represents that the phenomenon of urban sprawl was most severe in 2010. It finds that urban sprawl was more severe in the east and central regions relative to the provincial capitals in the western region, with the situation being most severe in the northeast region. Regions that have been transformed from suburban to urban built-up areas need to be given priority attention by the local government, including population movement, land layout, and fiscal policy, to meet the criteria of the urbanization process. Through correlation analysis, we also found that urban sprawl was influenced by the industry structure and the form of built-up area. The outcome of the study suggests that the data scale is sufficiently small in granularity to provide geographic boundaries for systematic analysis of urban sprawl in multiple administrative regions. Thus, the study helps provide a reference for differential planning policy formulation by governments at diverse economic levels.

Bisphenol H (BPH) has emerged as a potential alternative to bisphenol A (BPA), which has been curtailed for use due to concerns over its reproductive and endocrine toxicity. This study investigates whether BPH exerts antiandrogenic effects by impairing Leydig cell function, a critical component in testosterone production. We administered orally BPH to adult male rats at doses of 0, 1, 10, and 100 mg/kg/day for 7 days. Notably, BPH treatment resulted in a dose-dependent reduction in testicular testosterone levels, with significant decreases observed at ≥ 1 mg/kg/day. Additionally, BPH affected the expression of key genes involved in steroidogenesis and cholesterol metabolism, including Nr5a1, Nr3c4, Lhcgr, Scarb1, and Star, at higher doses (10 and/or 100 mg/kg/day). The study also revealed alterations in antioxidant gene expression (Sod2 and Cat) and modulation of m6A-related genes (Ythdf1–3 and Foxo3) and their proteins. Through MeRIP-qPCR analysis, we identified increased m6A modifications in Scarb1 and Star genes following BPH exposure. In vitro experiments with primary Leydig cells confirmed that BPH enhanced oxidative stress and diminished testosterone production, which were partially mitigated by antioxidant vitamin E supplementation and Ythdf3 knockdown. Meanwhile, simultaneous administration of BPH and vitamin E to primary Leydig cells partially counteracted BPH-induced alterations in the Ythdf3 expression. Our findings underscore a novel mechanism by which BPH disrupts Leydig cell function through the oxidative stress-m6A modification-autophagy pathway, raising concerns about its potential reproductive toxicity.

Background: Primary synovial sarcoma originating in the pelvis is an extremely rare malignancy, and only a few cases have been reported. Usually, the tumor is detected at an advanced stage, making treatment more difficult. Lacking high-quality research, there are no consensus guidelines for the systemic treatment of the disease. Case presentation: We admitted a 32-year-old male patient with an MRI suggestive of an 8.2 × 7.7 x 8.9 cm mass in the pelvis with bleeding. After a comprehensive evaluation, the patient underwent surgery, and postoperative pathology suggested biphasic synovial sarcoma. Once the diagnosis was clear, the patient was treated with chemotherapy, radiotherapy, and targeted therapy. Unfortunately, the patient died due to a recurrence of pelvic synovial sarcoma with multiple metastases throughout the body, with a survival period of 28 months. Conclusion: Synovial sarcoma, a highly malignant soft tissue tumor, and primary intrapelvic synovial sarcoma are even rarer, with a poor prognosis. Ultrasound, Computed Tomography, and MRI can help doctors detect the tumor at an early stage and treat it aggressively, especially with surgical treatment, which can effectively improve the survival rate. Combined with the course of diagnosis and treatment of this case, it is possible to deepen the understanding of primary pelvic synovial sarcoma and discuss appropriate treatment strategies for this rare disease.

With the development of dynamic acquisition technology for satellite video data, significant progress in target tracking has been made in recent years. This progress plays an important role in monitoring rapidly changing events. Different from targets in ordinary videos, targets in satellite videos usually demonstrate the phenomenon of a small size occupation pattern (small) and weak feature capture (dim) due to occlusion, illumination variation, and confusion with the surroundings. To the best of our knowledge, while some review work has been proposed for satellite videos object tracking, it has primarily concentrated on new datasets or has simply applied target tracking algorithms designed for ordinary videos directly to satellite videos for review. There is a lack of a comprehensive overview of satellite videos data sources and previous satellite video target tracking algorithms. Hence, there is a need for a systematic summary and in-depth exploration of the theory and the present state of satellite video object tracking. We provide an overview as well as a meta-analysis of satellite video targets, data sources, performance metrics, state-of-art models, and the trend of the target-specific comparative methods. To identify emerging research trends and opportunities, we classify established and emerging algorithms into three main categories and evaluate their performance on typical satellite videos. By providing comprehensive comparisons from both experimental (qualitative and quantitative) and theoretical perspectives, we demonstrate the tracking effects of several popular methods in various situations to show their strengths and weaknesses. In addition, this paper also collects the latest open-source datasets and predicts promising future research directions. Our collections of satellite videos benchmark datasets are available at: https://zenodo.org/record/8425369.

Accurate detection of changes in buildings is crucial for the understanding of urban development. The growing accessibility of remote sensing imagery has enabled urban scale change detection (CD) in both 2D and 3D. However, existing methods have not yet fully exploited the fusion of feature information in multi-temporal images, resulting in insufficient accuracy in 2D changed regions or in elevation changes. To this end, a Cross-temporal and Spatial Context Learning Network (CSCLNet) aimed at multi-task building CD from dual-temporal optical images is proposed, capturing both 2D and 3D changes simultaneously. It leverages a CNN network to extract multi-layer semantic features. Subsequently, two modules, Cross-temporal Transformer Semantic Enhancement (CTSE) and Multi-layer Feature Fusion (MFF), are developed to refine the feature representations. CTSE enhances temporal information by cross attention of dual-temporal features to enable interactions and MFF fuses multi-layer features and enhances attention to global and local spatial context. Finally, two prediction heads are introduced to separately handle 2D and 3D change prediction, identifying changed building objects and their elevation changes. Experiments conducted with two public datasets, 3DCD and SMARS, show that the CSCLNet achieves state-of-the-art for both 2D and 3D CD tasks. In particular, the change-specific RMSE of elevation changes has been reduced to 4.52 m in real world scenes. The code is available at: https://github.com/Geo3DSmart/CSCLNet.

Prenatal exposure to diethylhexyl phthalate (DEHP) has been linked with a decline in testosterone levels in adult male rats, but the underlying mechanism remains unclear. We investigated the potential epigenetic regulation, particularly focusing on N6-methyladenosine (m6A) modification, as a possible mechanism. Dams were gavaged with DEHP (0, 10, 100, and 750 mg/kg/day) from gestational day 14 to day 21. The male offspring were examined at the age of 56 days. Prenatal DEHP administration at 750 mg/kg/day caused a decline in testosterone concentrations, an elevation in follicle-stimulating hormone, a downregulated expression of CYP11A1 HSD3B2, without affecting Leydig cell numbers. Interestingly, Methyltransferase Like 4 (METTL4), an m6A methyltransferase, was downregulated, while there were no changes in METTL3 and METTL14. Moreover, CYP11A1 showed m6A reduction in response to prenatal DEHP exposure. Additionally, METTL4 expression increased postnatally, peaking in adulthood. Knockdown of METTL4 resulted in the downregulation of CYP11A1 and HSD3B2 and an increase in SCARB1 expression. Furthermore, the increase in autophagy protection in adult Leydig cells induced by prenatal DEHP exposure was not affected by 3-methyladenosine (3MA) treatment, indicating a potential protective role of autophagy in response to DEHP exposure. In conclusion, prenatal DEHP exposure reduces testosterone by downregulating CYP11A1 and HSD3B2 via m6A epigenetic regulation and induction of autophagy protection in adult Leydig cells as a response to DEHP exposure.

Abstract Background Overexpression of T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is related to the exhaustion of CD8+ tumor-infiltrating lymphocytes (TILs) in diffuse large B-cell lymphoma (DLBCL). However, the mechanism of TIM3-mediated CD8+TILs exhaustion in DLBCL remains poorly understood. Therefore, we aimed to clarify the potential pathway involved in TIM3-mediated CD8+TILs exhaustion and its significance in DLBCL. Methods The expression of TIM3 and its correlation with CD8+TILs exhaustion, the key ligand of TIM3, and the potential pathway of TIM3-mediated CD8+TILs exhaustion in DLBCL were analyzed using single-cell RNA sequencing and validated by RNA sequencing. The biological significance of TIM3-related pathway in DLBCL was investigated based on RNA sequencing, immunohistochemistry, and reverse transcription-quantitative polymerase chain reaction data. Finally, the possible regulatory mechanism of TIM3-related pathway in DLBCL was explored using single-cell RNA sequencing and RNA sequencing. Results Our results demonstrated that CD8+TILs, especially the terminally exhausted state, were the major clusters that expressed TIM3 in DLBCL. Galectin-9, mainly expressed in M2 macrophages, is the key ligand of TIM3 and can induce the exhaustion of CD8+TILs through TIM3/Galectin-9 pathway. Meanwhile, high TIM3/Galectin-9 enrichment is related to immunosuppressive tumor microenvironment, severe clinical manifestations, inferior prognosis, and poor response to CHOP-based chemotherapy, and can predict the clinical efficacy of immune checkpoint blockade therapy in DLBCL. Furthermore, the TIM3/Galectin-9 enrichment in DLBCL may be regulated by the IFN-γ signaling pathway. Conclusions Our study highlights that TIM3/Galectin-9 pathway plays a crucial role in CD8+TILs exhaustion and the immune escape of DLBCL, which facilitates further functional studies and could provide a theoretical basis for the development of novel immunotherapy in DLBCL.

Abstract The purpose of this study was to determine the level of horizontal transmission of the bla CTX-M-65 gene and the role of its associated mobile genetic elements (MGEs) in the bovine-derived Escherichia coli. After PCR identification, two plasmids carrying bla CTX-M-65 were successfully transferred to the recipient E. coli J53 Azr through conjugation assays and subsequently selected for Whole-Genome sequencing (WGS) analysis. The resistance profiles of these two positive strains and their transconjugants were also determined through antimicrobial susceptibility tests. Whole genome data were acquired using both the PacBio sequencing platform and the Illumina data platform. The annotated results were then submitted to the Genbank database for accession number recording. For comparison, the genetic environment of plasmids carrying the resistance gene bla CTX-M-65 was mapped using the Easyfig software. WGS analysis revealed Tn3-like composite transposons bearing bla CTX-M-65 , bla TEM-1 , and bla OXA-10 in the IncHI2-type plasmids of these two E. coli ST1508 strains. A phylogenetic tree was generated from all 48 assembled E. coli isolates bla CTX-M-65 , bla TEM-1 , and bla OXA-10 from the NCBI Pathogen Detection database with our two isolates, showing the relationships and the contribution of SNPs to the diversity between genetic samples. This study suggests that the transmissibility of bla CTX-M-65 on Tn3-like composite transposons contributes to an increased risk of its transmission in E. coli derived from dairy cattle.

IntroductionSince the first report, primary mediastinal seminoma has a low incidence in the population, and it mainly affects young and middle-aged men, is clinically rare, and accounts for a very small proportion of mediastinal tumors. In this study, we describe the first case of primary mediastinal seminoma with azoospermia and hypothesize that the coexistence of the two disorders may not be a coincidence.Case reportA 16-year-old man presented with chest tightness and chest pain, a mediastinal mass on chest CT, and abnormal 18F-fluoro-deoxyglucose uptake on a PET-CT scan. By biopsy of the mass, the pathological diagnosis was a primary mediastinal seminoma. Because chemotherapy is included in the treatment of the tumor, the patient underwent sperm freezing before treatment, considering that chemotherapy can affect fertility, but the patient was diagnosed with azoospermia. Finally, the patient underwent tumor resection and postoperative chemotherapy. No tumor recurrence was observed at the current follow-up.ConclusionPrimary mediastinal seminoma is mainly confirmed by histopathological examination, and surgery and chemoradiotherapy are the current treatments. In patients with mediastinal seminoma or azoospermia, doctors should be aware that the two disorders may coexist, especially in men who have fertility requirements or long-term infertility, and that examination of the mediastinum and semen may lead to unexpected findings in the diagnosis and treatment. For mediastinal germ cell tumors, genetic testing is of great value in the treatment of tumors and the prediction of associated diseases. Future studies exploring the potential correlation between mediastinal seminoma and azoospermia will be prospective.

Satellite video object tracking has become an emerging technology for dynamically observing the earth, providing the possibility for tracking moving objects in a short time. Deep learning methods such as CNN-based trackers and transformer-based trackers have been widely applied for single object tracking in natural videos. The target in natural videos is captured by ground sensors, whereas satellite sensors come from high altitudes of hundreds of kilometers or more, the trackers designed for natural videos may suffer the influence of complex background, especially small targets with weak features in view of remote sensing platforms. Furtherly, the confusion of visually similar objects with the target and the deformation of target in satellite videos can also lead to incorrect positioning. To address these problems, we proposed a target-aware bilateral CNN-Transformer network (TabCtNet). In TabCtNet, the bilateral CNN-Transformer architecture with the aggregation and interaction of local spatial information and global temporal context is designed to tackle the challenge of small target with weak features in complex and clutter background in satellite videos. To effectively reduce the impact of similar objects, the target-aware block-erasing strategy (TAS) is constructed to generate weakened heatmaps from the template target mask in a data-driven manner. Moreover, a pixel-wise refinement module with corner-based box estimation (PE) is designed to extract more fine-grained spatial information for more accurate box estimation and reduce the effect of target deformation. Experimental results show that TabCtNet quantitatively and qualitatively outperforms advanced single object tracking methods on two different satellite video datasets with four categories of targets from different scenarios. Furthermore, to investigate the generalizability of the TabCtNet framework, satellite videos sourced from different countries captured by various satellite platforms were used for evaluation, and the results reveal its robust performance across various scenarios.

ObjectiveOur network meta-analysis aimed to ascertain the effect of physical activity on the visual–spatial working memory of individuals with mild cognitive impairment and Alzheimer’s disease as well as to propose tailored exercise interventions for each group.MethodsEmploying a frequentist approach, we performed a network meta-analysis to compare the effectiveness of different exercise interventions in improving the visual–spatial working memory of individuals with mild cognitive impairment and Alzheimer’s disease. Subsequently, we explored the moderating variables influencing the effectiveness of the exercise interventions through a subgroup analysis.ResultsWe included 34 articles involving 3,074 participants in the meta-analysis, comprised of 1,537 participants from studies on mild cognitive impairment and 1,537 participants from studies on Alzheimer’s disease. The articles included exhibited an average quality score of 6.6 (score studies) and 6.75 (reaction time [RT] studies), all passing the inconsistency test (p > 0.05). In the mild cognitive impairment literature, mind–body exercise emerged as the most effective exercise intervention (SMD = 0.61, 95% CI: 0.07–1.14). In Alzheimer’s disease research, aerobic exercise was identified as the optimal exercise intervention (SMD = 0.39, 95% CI: 0.06–0.71).ConclusionThe results of the subgroup analysis suggest that the most effective approach to enhancing the visual–spatial working memory of individuals with mild cognitive impairment entails exercising at a frequency of three or more times per week for over 60 min each time and at a moderate intensity for more than 3 months. Suitable exercise options include mind–body exercise, multicomponent exercise, resistance exercise, and aerobic exercise. For individuals with Alzheimer’s disease, we recommend moderately intense exercise twice per week for over 90 min per session and for a duration of 3 months or longer, with exercise options encompassing aerobic exercise and resistance exercise.

Abstract Background RNASET2 has been identified as an oncogene with anti-angiogenic and immunomodulatory effects in a variety of cancers, but its function in clear cell renal cell carcinoma (ccRCC) is still not well understood. Methods The RNASET2 expression matrix was extracted from the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets and analyzed for diagnostic and prognostic value. RNASET2 mRNA expression was detected by quantitative polymerase chain reaction (qPCR) in ccRCC patients and renal cancer cell lines. Wound healing assay, transwell assay, western blotting, and tube formation assays were used to evaluate the function of RNASET2 in renal cancer in vitro. In addition, transcriptome sequencing was performed on knockdown RNASET2 kidney cancer cells to analyze their potential signaling pathways. Moreover, the immune microenvironment and mutational status were evaluated to predict the potential mechanisms of RNASET2 involvement in renal cancer progression. Sensitivity to common chemotherapeutic and targeted agents was assessed according to the Genomics of Drug Sensitivity in Cancer (GDSC) database. Results RNASET2 expression was significantly upregulated in ccRCC tissues and renal cancer cell lines, predicting poor prognosis for patients. In vitro experiments showed that silencing RNASET2 inhibited the migration and pro-angiogenic ability of renal cancer cells. Transcriptome sequencing suggested its possible involvement in the remodeling of the immune microenvironment in renal cell carcinoma. Furthermore, bioinformatics analysis and immunohistochemical staining showed that RNASET2 was positively correlated with the infiltration abundance of regulatory T cells. Finally, we mapped the mutational landscape of RNASET2 in ccRCC and found its predictive value for drug sensitivity. Conclusions Our results suggest that RNASET2 is a promising biomarker and therapeutic target in ccRCC.

Background Tumor mutational burden (TMB) is a valuable prognostic biomarker. This study explored the predictive value of TMB and the potential association between TMB and immune infiltration in diffuse large B-cell lymphoma (DLBCL). Methods We downloaded the gene expression profile, somatic mutation, and clinical data of DLBCL patients from The Cancer Genome Atlas (TCGA) database. We classified the samples into high-and low-TMB groups to identify differentially expressed genes (DEGs). Functional enrichment analyses were performed to determine the biological functions of the DEGs. We utilized the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm to estimate the abundance of 22 immune cells, and the significant difference was determined by the Wilcoxon rank-sum test between the high- and low-TMB group. Hub gene had been screened as the prognostic TMB-related immune biomarker by the combination of the Immunology Database and Analysis Portal (ImmPort) database and the univariate Cox analysis from the Gene Expression Omnibus (GEO) database including six DLBCL datasets. Various database applications such as Tumor Immune Estimation Resource (TIMER), CellMiner, konckTF, and Genotype-Tissue Expression (GTEx) verified the functions of the target gene. Wet assay confirmed the target gene expression at RNA and protein levels in DLBCL tissue and cell samples. Results Single nucleotide polymorphism (SNP) occurred more frequently than insertion and deletion, and C > T was the most common single nucleotide variant (SNV) in DLBCL. Survival analysis showed that the high-TMB group conferred poor survival outcomes. A total of 62 DEGs were obtained, and 13 TMB-related immune genes were identified. Univariate Cox analysis results illustrated that CD1c mutation was associated with lower TMB and manifested a satisfactory clinical prognosis by analysis of large samples from the GEO database. In addition, infiltration levels of immune cells in the high-TMB group were lower. Using the TIMER database, we systematically analyzed that the expression of CD1c was positively correlated with B cells, neutrophils, and dendritic cells and negatively correlated with CD8+ T cells, CD4+ T cells, and macrophages. Drug sensitivity showed a significant positive correlation between CD1c expression level and clinical drug sensitivity from the CellMiner database. CREB1, AHR, and TOX were used to comprehensively explore the regulation of CD1c-related transcription factors and signaling pathways by the KnockTF database. We searched the GETx database to compare the mRNA expression levels of CD1c between DLBCL and normal tissues, and the results suggested a significant difference between them. Moreover, wet experiments were conducted to verify the high expression of CD1c in DLBCL at the RNA and protein levels. Conclusions Higher TMB correlated with poor survival outcomes and inhibited the immune infiltrates in DLBCL. Our results suggest that CD1c is a TMB-related prognostic biomarker.

Despite the unprecedented success of super-resolution (SR) development for natural images, achieving hyperspectral image (HSI) SR with rich spectral characteristics remains a challenging task. Typically, HSI SR is accomplished by fusing low-resolution HSI (LR HSI) with the corresponding high-resolution multispectral image (HR MSI). However, due to the significant spectral difference between MSI and HSI, it is difficult to retain the spatial characteristics of MSI during image fusion. In addition, the spectral response function (SRF) used for simulating MSI is often unknown or unavailable in hyperspectral remote sensing images, further complicating the problem. To address the above issues, a local-aware coupled network (LCNet) is proposed in this paper. In LCNet, the SRF and point spread function (PSF) are adaptively learned in the primary stage of the network to address the issue of unknown prior information. By coupling two reconstruction networks, LCNet effectively preserves both the texture details of MSI and the spectral characteristics of HSI. Furthermore, the spatial local-aware block selectively emphasizes the texture features of MSI. Experimental results on three publicly available HSIs demonstrate whether the proposed LCNet is superior to the state-of-the-art methods with respect to both stability and quality.

Abstract Background Debates exist on the treatment decision of the stage II/III colorectal cancer (CRC) due to the insufficiency of the current TNM stage‐based risk stratification system. Epithelial–mesenchymal transition (EMT) and tumor microenvironment (TME) have both been linked to CRC progression in recent studies. We propose to improve the prognosis prediction of CRC by integrating TME and EMT. Methods In total, 2382 CRC patients from seven datasets and one in‐house cohort were collected, and 1640 stage II/III CRC patients with complete survival information and gene expression profiles were retained and divided into a training cohort and three independent validation cohorts. Integrated analysis of 398 immune, stroma, and epithelial‐mesenchymal transition (ISE)‐related genes identified an ISE signature independently associated with the recurrence of CRC. The underlying biological mechanism of the ISE signature and its influence on adjuvant chemotherapy was further explored. Results We constructed a 26‐gene signature which was significantly associated with poor outcome in Training cohort (p

BackgroundExhaustion of CD8+ tumor-infiltrating lymphocytes (TILs), characterized by the overexpression of immune checkpoints (IC), is a major impediment to anti-tumor immunity. However, the exhaustion status of CD8+TILs in angioimmunoblastic T cell lymphoma (AITL) remains unclear. Therefore, we aimed to elucidate the exhaustion status of CD8+TILs in AITL and its influence on prognosis.MethodsThe correlation between CD8+TILs and IC expression in AITL was analyzed using single-cell RNA sequencing (n = 2), flow cytometry (n = 20), and RNA sequencing (n = 20). Biological changes related to CD8+TILs exhaustion at different cytotoxic T lymphocyte (CTL) levels (mean expression levels of CD8A, CD8B, GZMA, GZMB, and PRF1) in AITL were evaluated using RNA sequencing (n = 20) and further validated using the GEO dataset (n = 51). The impact of CD8 protein expression and CTL levels on patient prognosis was analyzed using flow cytometry and RNA sequencing, respectively.ResultsOur findings demonstrated that the higher the infiltration of CD8+TILs, the higher was the proportion of exhausted CD8+TILs characterized by the overexpression of multiple IC. This was accompanied by extensive exhaustion-related biological changes, which suggested severe exhaustion in CD8+TILs and may be one of the main reasons for the poor prognosis of patients with high CD8+TILs and CTL.ConclusionOur study comprehensively reveals the exhaustion status of CD8+TILs and their potential negative impact on AITL prognosis, which facilitates further mechanistic studies and is valuable for guiding immunotherapy strategies.

Dock is a significant site in the shipbuilding industry. The detection of docks contributes to many important fields. With the abundant methods and datasets, the deep learning-based object detection in remote sensing images has received wide attention. However, there is no dataset that includes the dock class. This article first proposes a dock dataset to build a benchmark and advance dock detection research. Further, object detection of docks using existing methods cannot yield convincing results due to the characteristics of docks. To meet the challenges in dock detection, a novel deformable spatial attention module (DSAM) is proposed to enhance the feature representation and localization of docks. Based on the DSAM, a novel network architecture is proposed to perform accurate and efficient dock detection. The ablation and comparison experiments reveal that the proposed methods are accurate and effective, which are superior to the existing methods.

Abstract Background This study aimed to develop a radiogenomic prognostic prediction model for colorectal cancer (CRC) by investigating the biological and clinical relevance of intratumoural heterogeneity. Methods This retrospective multi-cohort study was conducted in three steps. First, we identified genomic subclones using unsupervised deconvolution analysis. Second, we established radiogenomic signatures to link radiomic features with prognostic subclone compositions in an independent radiogenomic dataset containing matched imaging and gene expression data. Finally, the prognostic value of the identified radiogenomic signatures was validated using two testing datasets containing imaging and survival information collected from separate medical centres. Results This multi-institutional retrospective study included 1601 patients (714 females and 887 males; mean age, 65 years ± 14 [standard deviation]) with CRC from 5 datasets. Molecular heterogeneity was identified using unsupervised deconvolution analysis of gene expression data. The relative prevalence of the two subclones associated with cell cycle and extracellular matrix pathways identified patients with significantly different survival outcomes. A radiogenomic signature-based predictive model significantly stratified patients into high- and low-risk groups with disparate disease-free survival (HR = 1.74, P = 0.003). Radiogenomic signatures were revealed as an independent predictive factor for CRC by multivariable analysis (HR = 1.59, 95% CI:1.03–2.45, P = 0.034). Functional analysis demonstrated that the 11 radiogenomic signatures were predominantly associated with extracellular matrix and immune-related pathways. Conclusions The identified radiogenomic signatures might be a surrogate for genomic signatures and could complement the current prognostic strategies.

Change Detection (CD) provides a research basis for environmental monitoring, urban expansion and reconstruction as well as disaster assessment, by identifying the changes of ground objects in different time periods. Traditional CD focused on the Binary Change Detection (BCD), focusing solely on the change and no-change regions. Due to the dynamic progress of earth observation satellite techniques, the spatial resolution of remote sensing images continues to increase, Multi-class Change Detection (MCD) which can reflect more detailed land change has become a hot research direction in the field of CD. Although many scholars have reviewed change detection at present, most of the work still focuses on BCD. This paper focuses on the recent progress in MCD, which includes five major aspects: challenges, datasets, methods, applications and future research direction. Specifically, the background of MCD is first introduced. Then, the major difficulties and challenges in MCD are discussed and delineated. The benchmark datasets for MCD are described, and the available open datasets are listed. Moreover, MCD is further divided into three categories and the specific techniques are described, respectively. Subsequently, the common applications of MCD are described. Finally, the relevant literature in the main journals of remote sensing in the past five years are analyzed and the development and future research direction of MCD are discussed. This review will help researchers understand this field and provide a reference for the subsequent development of MCD. Our collections of MCD benchmark datasets are available at: https://zenodo.org/record/6809804#.YsfvxXZByUk

Abstract Background Anastomotic blood supply is vital to anastomotic healing. The aim of this study was to demonstrate the effect of the left colic artery (LCA) on blood supply in the anastomotic area, explore the relationship between individual differences in the LCA and blood supply in the anastomotic area, and elucidate the relevant indications for LCA retention during radical resection for sigmoid or rectal cancer. Method Radical sigmoid or rectal cancer resection with LCA retention was performed in 40 patients with colorectal cancer who participated in this study. Systemic pressure, LCA diameter, and the distance from the root of the LCA to the root of the inferior mesenteric artery were measured and recorded. The marginal artery stump pressure in the anastomotic colon before and after the LCA clamping was measured, respectively. Results There is a significant difference between the marginal artery stump pressure before LCA ligation and after ligation (53.1 ± 12.38 vs 42.76 ± 12.71, p < 0.001). The anastomotic blood supply positively and linearly correlated with body mass index and systemic pressure. Receiver-operating curve analysis revealed that LCA diameter (area under the curve 0.971, cutoff 1.95 mm) was an effective predictor of LCA improving anastomosis blood supply. No relationship was found between the LCA root location and anastomotic blood supply. Conclusion Preserving the LCA is effective in improving blood supply in the anastomotic area, and larger LCA diameters result in a better blood supply to the anastomotic area.

Elevated detection rates of the blaCTX-M-55 gene in animals have been reported as a result of antibiotic misuse in clinics. To investigate the horizontal transfer mechanism of blaCTX-M-55 and its associated mobile genetic elements (MGEs), we isolated 318 nonrepetitive strains of Escherichia coli (E. coli) from bovine samples in Xinjiang and Gansu provinces, China. All E. coli strains were screened for the CTX-M-55 gene using PCR. The complete genomic data were sequenced using the PacBio triplet sequencing platform and corrected using the Illumina data platform. The genetic environment of the plasmids carrying the resistance blaCTX-M-55 gene was mapped using the software Easyfig2.2.3 for comparison. The results showed that all blaCTX-M-55-positive strains were resistant to multiple antibiotics. Five strains of Escherichia coli carry the blaCTX-M-55 gene, which is adjacent to other resistance genes and is located on the IncHI2-type plasmid. Four of the five blaCTX-M-55-harbor strains carried translocatable units (TUs). All the donor bacteria carrying the blaCTX-M-55 genes could transfer horizontally to the recipient (E. coli J53 Azr). This study demonstrates that the transmission of blaCTX-M-55 is localized on IS26-flanked composite transposons. The cotransmission and prevalence of blaCTX-M-55 with other MDR resistance genes on epidemic plasmids require enhanced monitoring and control.

IntroductionPhysical activity interventions improve cognitive performance, especially visuospatial working memory (VSWM). However, evidence on the effects of these interventions in children, adolescents, and older adults remains scant. This meta-analysis aimed to identify the effects of physical activity on VSWM improvement in healthy individuals and the best exercise intervention program to improve VSWM capacity.MethodsWe searched for randomized controlled trials (RCTs) of exercise interventions targeting VSWM in healthy individuals from Web of Science, MEDLINE, BIOSIS Previews, PubMed, China National Knowledge Infrastructure, and Wanfang Data (Chinese) databases, from inception to August 20, 2022.ResultsAmong 21 articles (1,595 healthy participants), the heterogeneity test statistic was I2 = 32.3%, p = 0.053. The mean quality scores of the included articles were 6.9 points (reaction time [RT] studies) and 7.5 points (Score studies). Moreover, 28 RCTs were included (10 RT studies and 18 Score studies), and the subgroup analysis found significant effects for elderly participants, children, interventions involving a higher level of cognitive engagement, low and moderate exercise intensity, chronic exercise, exercise duration ≥60 min, and exercise period ≥90 days. Physical activity had a small but significant positive impact on VSWM in healthy individuals. Current evidence confirms the effects of physical activity on VSWM capacity only in children and seniors but not in young adults. Other age groups, including adolescents and middle-aged adults, have not been studied. Prescription of interventions involving high-level cognitive engagement, low and moderate exercise intensity, chronic exercise, exercise for >30 min per session, and exercise for more than 3 months is recommended for children and seniors.DiscussionFuture RCTs would be to fill the gap in studies on adolescents and middle-aged adults, and report detailed exercise intervention programs about different age groups.Systematic Review Registration: PROSPERO (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022354737). INPLASY (https://doi.org/10.37766/inplasy2022.8.0053).

BackgroundAngioimmunoblastic T-cell lymphoma (AITL) has a rich tumor microenvironment (TME) that typically harbors plenty of CD4+tumor infiltrating lymphocytes, (TIL)-T-cells (so called common AITL). Nonetheless, AITL with large numbers of CD8+TIL-Ts that outnumber CD4+cells have been observed (CD8-predominant AITL). However, detailed comparison of CD8-predominant AITL and common AITL are still lacking.MethodsWe compared clinicopathological features, TIL subsets, TME T cell receptor-β (TRB), and immunoglobulin heavy chain (IGH) repertoires, and gene expression profiles in six CD8-predominant and 12 common AITLs using case-control matching (2014 to 2019).ResultsComparing with common AITLs, CD8-predominant AITLs showed more frequent edema (P = 0.011), effusion (P = 0.026), high elevated plasma EBV-DNA (P = 0.008), and shorter survival (P = 0.034). Moreover, they had more pronounced eosinophil increase (P = 0.004) and a higher Ki67 index (P = 0.041). Flow cytometry revealed an inverted CD4/CD8 ratio in TIL-Ts and lower TIL-B proportions (P = 0.041). TRB repertoire metrics deteriorated, including lower productive clones (P = 0.014) and higher clonality score (P = 0.019). The IGH repertoire was also narrowed, showing a higher proportion of the top 10 clones (P = 0.002) and lower entropy (P = 0.027). Gene expression analysis showed significant enrichment for upregulated negative regulation of immune system processes and downregulated T-cell activation and immune cell differentiation.ConclusionOur findings demonstrated that CD8-predominant AITL is a distinct immune pattern of AITL characterized by anti-tumor immunity impairment and an immunosuppressive microenvironment. These characteristics can interpret its severe clinical manifestations and poor outcomes.

Bisphenol A (BPA) analogues substituted on the benzene ring are widely used in a variety of industrial and consumer materials. However, their effects on the glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) remain unclear. The inhibitory effects of 6 BPA analogues on the inhibition of human and rat 11β-HSD1 were investigated. The potencies of inhibition on human 11β-HSD1 were bisphenol H (IC50, 0.75 µM) > bisphenol G (IC50, 5.06 µM) > diallyl bisphenol A (IC50, 13.36 µM) > dimethyl bisphenol A (IC50, 30.18 µM) > bisphenol A dimethyl ether (IC50, 33.08 µM) > tetramethyl bisphenol A (>100 µM). The inhibitory strength of these chemicals on rat 11β-HSD1 was much weaker than that on the human enzyme, ranging from 74.22 to 205.7 µM. All BPA analogues are mixed/competitive inhibitors of both human and rat enzymes. Molecular docking studies predict that bisphenol H and bisphenol G both bind to the active site of human 11β-HSD1, forming a hydrogen bond with catalytic residue Ser170. The bivariate correlation of IC50 values with LogP (lipophilicity), molecular weight, heavy atoms, and molecular volume revealed a significant inverse regression and the correlation of IC50 values with ΔG (low binding energy) revealed a positive regression. In conclusion, the lipophilicity, molecular weight, heavy atoms, molecular volume, and binding affinity of a BPA analogue determine the inhibitory strength of human and rat 11β-HSD isoforms.

Abstract Background The natural hosts of Shigella are typically humans and other primates, but it has been shown that the host range of Shigella has expanded to many animals. Although Shigella is becoming a major threat to animals, there is limited information on the genetic background of local strains. The purpose of this study was to assess the presence of virulence factors and the molecular characteristics of S. flexneri isolated from calves with diarrhea. Results Fifty-four S. flexneri isolates from Gansun, Shanxi, Qinghai, Xinjiang and Tibet obtained during 2014 to 2016 possessed four typical biochemical characteristics of Shigella. The prevalences of ipaH, virA, ipaBCD, ial, sen, set1A, set1B and stx were 100 %, 100 %, 77.78 %, 79.63 %, 48.15 %, 48.15 and 0 %, respectively. Multilocus variable number tandem repeat analysis (MLVA) based on 8 variable number of tandem repeat (VNTR) loci discriminated the isolates into 39 different MLVA types (MTs), pulsed field gel electrophoresis (PFGE) based on NotI digestion divided the 54 isolates into 31 PFGE types (PTs), and multilocus sequence typing (MLST) based on 15 housekeeping genes differentiated the isolates into 7 MLST sequence types (STs). Conclusions The findings from this study enrich our knowledge of the molecular characteristics of S. flexneri collected from calves with diarrhea, which will be important for addressing clinical and epidemiological issues regarding shigellosis.

High spatial resolution (HSR) imagery scene classification has become a hot research topic in remote sensing. Scene classification method based on the handcrafted features, such as the bag-of-visual-words (BoVW) model, describes an image by extracting local features of the scene and mapping them to the dictionary space, but usually uses a shallow structure and loses the spatial distribution characteristics of the scene. The method based on deep learning extracts hierarchical features to describe the scene, which can maintain the spatial position information well. However, deep features in different levels have scale recognition restrictions for multi-scale ground objects, and cannot understand complex scenes well. In this paper, the multi-level convolutional pyramid semantic fusion (MCPSF) framework is proposed for HSR imagery scene classification. Differing from previous scene classification methods, which integrate the feature of different levels directly, of which the fusion features have large differences in both sparsity and eigenvalue magnitude, MCPSF integrates multi-level semantic features extracted by BoVW model and convolutional neural network (CNN) model. In MCPSF, two convolution pyramid feature expression strategies are proposed to enhance the ability of capturing multi-scale land objects, i.e., local and convolutional pyramid based BoVW (LCPB) model and local and convolutional pyramid based pooling-stretched (LCPP) model. The effectiveness of the proposed method is verified on 21-class UC Merced (UCM) dataset and 30-class Aerial Image Dataset (AID). The framework was also transferred toa case study of scene annotation in Wuhan. The proposed framework significantly improves the performance when compared with other state-of-the-art methods.

Hyperspectral unmixing (HU) has been a hot research topic in the field of hyperspectral remote sensing. In recent years, the employment of the probabilistic topic model to acquire the latent topics of hyperspectral images has been an effective method for spectral unmixing. However, such methods fail to fully exploit the potential of topic models in uncovering image semantics, and they need extra sparsity constraints, which greatly increases the complexity of the model. To solve these problems, a sparse topic relaxion and group clustering model for HU (STRGC) is proposed. In STRGC, the sparse prior constraints implied by the sparse topic model are introduced, which means that the sparse characteristics of the model are used to capture the semantic representation of the spectrum. Through the relaxation of the model, the possible spectral representations of ground features can be obtained, and this further alleviates the influence caused by endmember variability on the accuracy of the unmixing process. Then, fuzzy clustering is used to locate the position of the endmember quickly and accurately. Furthermore, unmixing models with different characteristics are united to alleviate the ill-posed nature of the model, thereby improving the fractional abundance. Experimental results obtained with one simulated dataset and three well-known real hyperspectral datasets confirm the effectiveness and advantages of the proposed method.

High-spatial resolution urban scenes, which contain ecological, social, and environmental zones, are composed of diverse functional areas. Depicting urban scenes from both qualitative and quantitative aspects, i.e., scene classification and scene unmixing, are increasingly important tasks. The purpose of scene classification is to mark a scene as a separate category, and this approach is widely applied to qualitatively define scenes. However, with the rapid development of cities, urban scenes usually show a mixed nature, resulting in urban mixed scenes (UMSs). Traditional scene classification cannot describe the mix of urban scenes. Few studies have focused on the quantitative measurements of UMSs, which aim at discovering and analyzing the proportion of different subscenes. In this article, a scene unmixing framework based on nonnegative matrix factorization for UMSs (UnUMS) is proposed to estimate the mixing ratio of urban scenes. In the UnUMS, a deep feature representation is used for the high-dimensional representation of the image, and then a nonnegative matrix factorization strategy is used to estimate the proportion of UMSs. Finally, the UMS can be described by the proportion of each subscene. To confirm the robust generalizability of UnUMS, the WH-center Mix dataset with a set of small mixed scenes and the WH-hy LMix dataset with a large UMS image are utilized. The root-mean-square error and the newly proposed vector angular distance are utilized to quantitatively evaluate the effect of scene unmixing from different aspects. Experiments with the two datasets demonstrate that UnUMS can accurately estimate the proportions of different scenes for UMS.

Background: Preoperative and postoperative evaluation of colorectal cancer (CRC) patients is crucial for subsequent treatment guidance. Our study aims to provide a timely and rapid assessment of the prognosis of CRC patients with deep learning according to non-invasive preoperative computed tomography (CT) and explore the underlying biological explanations.Methods: A total of 808 CRC patients with preoperative CT (development cohort: n = 426, validation cohort: n = 382) were enrolled in our study. We proposed a novel end-to-end Multi-Size Convolutional Neural Network (MSCNN) to predict the risk of CRC recurrence with CT images (CT signature). The prognostic performance of CT signature was evaluated by Kaplan-Meier curve. An integrated nomogram was constructed to improve the clinical utility of CT signature by combining with other clinicopathologic factors. Further visualization and correlation analysis for CT deep features with paired gene expression profiles were performed to reveal the molecular characteristics of CRC tumors learned by MSCNN in radiographic imaging.Results: The Kaplan-Meier analysis showed that CT signature was a significant prognostic factor for CRC disease-free survival (DFS) prediction [development cohort: hazard ratio (HR): 50.7, 95% CI: 28.4–90.6, p < 0.001; validation cohort: HR: 2.04, 95% CI: 1.44–2.89, p < 0.001]. Multivariable analysis confirmed the independence prognostic value of CT signature (development cohort: HR: 30.7, 95% CI: 19.8–69.3, p < 0.001; validation cohort: HR: 1.83, 95% CI: 1.19–2.83, p = 0.006). Dimension reduction and visualization of CT deep features demonstrated a high correlation with the prognosis of CRC patients. Functional pathway analysis further indicated that CRC patients with high CT signature presented down-regulation of several immunology pathways. Correlation analysis found that CT deep features were mainly associated with activation of metabolic and proliferative pathways.Conclusions: Our deep learning based preoperative CT signature can effectively predict prognosis of CRC patients. Integration analysis of multi-omic data revealed that some molecular characteristics of CRC tumor can be captured by deep learning in CT images.

Background: Increasing evidence have depicted that DNA repair–related genes (DRGs) are associated with the prognosis of colorectal cancer (CRC) patients. Thus, the aim of this study was to evaluate the impact of DNA repair–related gene signature (DRGS) in predicting the prognosis of CRC patients.Method: In this study, we retrospectively analyzed the gene expression profiles from six CRC cohorts. A total of 1,768 CRC patients with complete prognostic information were divided into the training cohort (n = 566) and two validation cohorts (n = 624 and 578, respectively). The LASSO Cox model was applied to construct a prediction model. To further validate the clinical significance of the model, we also validated the model with Genomics of Drug Sensitivity in Cancer (GDSC) and an advanced clear cell renal cell carcinoma (ccRCC) immunotherapy data set.Results: We constructed a prognostic DRGS consisting of 11 different genes to stratify patients into high- and low-risk groups. Patients in the high-risk groups had significantly worse disease-free survival (DFS) than those in the low-risk groups in all cohorts [training cohort: hazard ratio (HR) = 2.40, p < 0.001, 95% confidence interval (CI) = 1.67–3.44; validation-1: HR = 2.20, p < 0.001, 95% CI = 1.38–3.49 and validation-2 cohort: HR = 2.12, p < 0.001, 95% CI = 1.40–3.21). By validating the model with GDSC, we could see that among the chemotherapeutic drugs such as oxaliplatin, 5-fluorouracil, and irinotecan, the IC50 of the cell line in the low-risk group was lower. By validating the model with the ccRCC immunotherapy data set, we can clearly see that the overall survival (OS) of the objective response rate (ORR) with complete response (CR) and partial response (PR) in the low-risk group was the best.Conclusions: DRGS is a favorable prediction model for patients with CRC, and our model can predict the response of cell lines to chemotherapeutic agents and potentially predict the response of patients to immunotherapy.

Methyl tert-butyl ether (MTBE) is a widely used gasoline additive. It is considered an endocrine-disrupting chemical. Whether MTBE affects the development of Leydig cells in late puberty of males and its underlying mechanism remains unclear. Twenty-four male Sprague-Dawley rats (35 days old) were randomly allocated into four groups and were orally given MTBE (0, 300, 600, and 1200 mg/kg/day) from postnatal day (PND) 35–56. MTBE markedly reduced serum testosterone levels at 300 mg/kg and higher doses without altering the serum levels of luteinizing hormone and follicle-stimulating hormone. It mainly inhibited cell proliferation, induced mitochondrial autophagy and apoptosis, and indirectly stimulated Sertoli cells to secrete anti-Müllerian hormones, thereby significantly reducing the number of Leydig cells at 1200 mg/kg. MTBE also markedly down-regulated the expression of mature Leydig cell biomarker Cyp11a1 and Hsd3b1 and their proteins, while up-regulating the expression of immature Leydig cell biomarker Akr1c14 and its protein at 600 mg/kg and higher. MTBE significantly down-regulated the expression of cell cycle gene Ccnd1, antioxidant gene Gpx1, and anti-apoptotic gene Bcl2, while increasing pro-apoptotic gene Bax level at 1200 mg/kg. In vitro study further confirmed that MTBE can inhibit testosterone synthesis by inducing reactive oxygen species (ROS) generation, mitophagy, and apoptosis at 200 and 300 mM. In conclusion, exposure to MTBE compromises the development of Leydig cells in late puberty in male rats.

Anomaly detection for large scale cellular networks can be used by network operators to optimize network performance and enhance mobile user experience. This paper aims at detecting user anomalies from spatio-temporal cell phone activity data. We design an approach combining time series analysis and machine learning to extract the traffic patterns of areal units. This approach can cluster areal units with similar traffic patterns and segment a city into distinct groups. Then, in grouped-areas, we use a clustering technique to detect anomalous behaviors of the cellular network and verify the accuracy of the results using ground truth information collected from online sources. The results indicate that anomalies are associated with abruptly high or unexpected traffic demand at a specific location and time. In addition, we obtain anomaly-free data by removing anomalous data and train a decomposed traffic prediction model. It is observed that the prediction model trained with anomaly-free data can achieve lower normalized mean square error (NMSE), i.e., higher prediction accuracy, than the model trained with anomalous data.

Glucocorticoid hormone might cause intrauterine growth restriction. The glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase 2 (HSD11B2) in the placenta eliminates excess levels of glucocorticoids during pregnancy. The aim of the current study was to define the effects of diethylstilbestrol (DES) on HS D11B2 activity in the mammalian placentas and identify its mode of action. Rat and human placental microsomal HSD11B2 were incubated with different concentrations of DES, and IC50 values were determined. The mode of action was analyzed by incubation of DES together with substrates, glucocorticoid and NAD+. DES suppressed rat and human HSD11B2 with IC50 values of 5.33 and 12.62 μM, respectively. DES was a competitive inhibitor of rat and human HSD11B2 when steroid substrates were added, while it was an uncompetitive inhibitor when cofactor NAD+ was exposed. Oral administration of DES (0.5 mg/kg) to the rat delayed the cortisol metabolism in adult female Sprague–Daw ley rats, as indicated by the increases in cortisol’s elimination half-life, maximum concentration and area under the curve. In conclusion, DES is a potent HSD11B2 inhibitor, possibly contributing to the intrauterine growth restriction.

Background: 11β-Hydroxysteroid dehydrogenase one is responsible for activating inert glucocorticoid cortisone into biologically active cortisol in humans and may be a novel target for the treatment of nonalcoholic fatty liver disease.Methods: A series of benzylidene cyclopentanone derivatives were synthesized, and the selective inhibitory effects on rat, mouse and human 11β-hydroxysteroid dehydrogenase one and two were screened. The most potent compound [5-bis-(2,6-difluoro-benzylidene)-cyclopentanone] (WZS08), was used to treat nonalcoholic fatty liver disease in mice fed a high-fat-diet for 100 days.Results: WZS08 was the most potent inhibitor of rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, with half maximum inhibitory concentrations of 378.0, 244.1, and 621.1 nM, respectively, and it did not affect 11β-hydroxysteroid dehydrogenase two at 100 μM. When mice were fed WZS08 (1, 2, and 4 mg/kg) for 100 days, WZS08 significantly lowered the serum insulin levels and insulin index at 4 mg/kg. WZS08 significantly reduced the levels of serum triglycerides, cholesterol, low-density lipoprotein, and hepatic fat ratio at low concentration of 1 mg/kg. It down-regulated Plin2 expression and up-regulated Fabp4 expression at low concentration of 1 mg/kg. It significantly improved the morphology of the non-alcoholic fatty liver.Conclusion: WZS08 selectively inhibits rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, and can treat non-alcoholic fatty liver disease in a mouse model.

Background: Diisoheptyl phthalate (DIHP) is a phthalate plasticizer, which is a branched phthalate. Here, we reported the effects of gestational exposure to DIHP on testis development in male rats.Methods: Pregnant Sprague-Dawley rats were orally fed with vehicle (corn oil, control) or DIHP (10, 100, 500, and 1,000 mg/kg) from gestational day (GD) 12–21. At GD21, serum testosterone levels, the number and distribution of fetal Leydig cells, and testicular mRNA and protein levels, the incidence of multinucleated gonocytes, and focal testicular hypoplasia in the neonatal testis were measured.Results: DIHP increased the fetal Leydig cell cluster size and decreased the fetal Leydig cell size with LOAEL of 10 mg/kg. DIHP did not affect the fetal Leydig cell number. DIHP significantly lowered serum testosterone levels, down-regulated the expression of steroidogenesis-related genes (Lhcgr, Star, Cyp11a1, Hsd3b1, Cyp17a1, and Hsd17b3) and testis descent-related gene (Insl3) as well as protein levels of cholesterol side-chain cleavage enzyme (CYP11A1) and insulin-like 3 (INSL3). DIHP dose-dependently increased the percentage of multinucleated gonocytes with the low observed adverse-effect level (LOAEL) of 100 mg/kg. DIHP induced focal testicular hypoplasia.Conclusion: Gestational exposure to DIHP causes testis dysgenesis in rats.

The function of immature Leydig cells is regulated by hormones, such as androgen and luteinizing hormone (LH). However, the regulation of this process is still unclear. The objective of this study was to determine whether luteinizing hormone (LH) or androgens contribute to this process. Immature Leydig cells were purified from 35-day-old male Sprague Dawley rats and cultured with LH (1 ng/ml) or androgen (7α-methyl-19- nortestosterone, MENT, 100 nM) for 2 days. LH or MENT treatment significantly increased the androgens produced by immature Leydig cells in rats. Microarray and qPCR and enzymatic tests showed that LH up-regulated the expression of Scarb1, Cyp11a1, Cyp17a1, and Srd5a1 while down-regulated the expression of Sult2a1 and Akr1c14. On the contrary, the expression of Cyp17a1 was up-regulated by MENT. LH and MENT regulate Leydig cell function through different sets of transcription factors. We conclude that LH and androgens participate in the regulation of rat immature Leydig cell function through different transcriptional pathways.

Background: Radiomics refers to the extraction of a large amount of image information from medical images, which can provide decision support for clinicians. In this study, we developed and validated a radiomics-based nomogram to predict the prognosis of colorectal cancer (CRC).Methods: A total of 381 patients with colorectal cancer (primary cohort: n = 242; validation cohort: n = 139) were enrolled and radiomic features were extracted from the vein phase of preoperative computed tomography (CT). The radiomics score was generated by using the least absolute shrinkage and selection operator algorithm (LASSO). A nomogram was constructed by combining the radiomics score with clinicopathological risk factors for predicting the prognosis of CRC patients. The performance of the nomogram was evaluated by the calibration curve, receiver operating characteristic (ROC) curve and C-index statistics. Functional analysis and correlation analysis were used to explore the underlying association between radiomic feature and the gene-expression patterns.Results: Five radiomic features were selected to calculate the radiomics score by using the LASSO regression model. The Kaplan-Meier analysis showed that radiomics score was significantly associated with disease-free survival (DFS) [primary cohort: hazard ratio (HR): 5.65, 95% CI: 2.26–14.13, P < 0.001; validation cohort: HR: 8.49, 95% CI: 2.05–35.17, P < 0.001]. Multivariable analysis confirmed the independent prognostic value of radiomics score (primary cohort: HR: 5.35, 95% CI: 2.14–13.39, P < 0.001; validation cohort: HR: 5.19, 95% CI: 1.22–22.00, P = 0.026). We incorporated radiomics signature with the TNM stage to build a nomogram, which performed better than TNM stage alone. The C-index of the nomogram achieved 0.74 (0.69–0.80) in the primary cohort and 0.82 (0.77–0.87) in the validation cohort. Functional analysis and correlation analysis found that the radiomic signatures were mainly associated with metabolism related pathways.Conclusions: The radiomics score derived from the preoperative CT image was an independent prognostic factor and could be a complement to the current staging strategies of colorectal cancer.

Cadmium is a heavy metal, and people are exposed to it through contaminated foods and smoking. In humans and other mammals, cadmium causes damage to male testis. In this review, we summarize the effects of cadmium on the development and function of the testis. Cadmium causes severe structural damage to the seminiferous tubules, Sertoli cells, and blood-testis barrier, thus leading to the loss of sperm. Cadmium hinders Leydig cell development, inhibits Leydig cell function, and induces Leydig cell tumors. Cadmium also disrupts the vascular system of the testis. Cadmium is a reactive oxygen species inducer and possibly induces DNA damage, thus epigenetically regulating somatic cell and germ cell function, leading to male subfertility/infertility.

Background: The purpose of this study was to investigate cytochrome P450-7B1 (CYP7B1) in the human and rat testes to regulate 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity. We hypothesized that dehydroepiandrosterone (DHEA) and its product 7α-hydroxydehydroepiandrosterone (7αOHD) after catalysis of CYP7B1 played a critical role in driving the direction of 11β-HSD1, because 7αOHD is an alternative substrate for 11β-HSD1.Methods: We examined the influence of DHEA and 7αOHD on 11β-HSD1 activities in both intact Leydig cells and microsomes using radioactive substrates and identified the location of CYP7B1 in Leydig cells using immunohistochemical staining, Western blot, and qPCR.Results: We found that DHEA stimulated 11β-HSD1 oxidase activity in intact cells (EC50 = 0.97 ± 0.11 μM) and inhibited its reductase activity (IC50 = 1.04 ± 0.06 μM). In microsomes, DHEA was a competitive inhibitor of the reductase activity. The 11β-HSD1 oxidase activity in intact cells was inhibited by 7αOHD (IC50 = 1.18 ± 0.12 μM), and the reductase activity was enhanced (EC50 = 0.7 ± 0.04 μM). 7αOHD was a competitive inhibitor of 11β-HSD1 oxidase. CYP7B1 was present in rat Leydig cells, as shown by immunohistochemistry, Western blotting, and qPCR analysis.Conclusion: Our results are consistent with a conclusion that DHEA in the circulation driving 11β-HSD1 toward an oxidase in Leydig cells mainly through inhibiting the reductase of the enzyme, while 7αOHD (CYP7B1 catalytic product of DHEA) drives the enzyme toward the opposite direction.

11β-Hydroxysteroid dehydrogenase 1 (HSD11B1) is an NADPH-dependent oxidoreductase that elevates cortisol (in human beings) or corticosterone (in rats) locally via metabolically activating 11 keto-glucocorticoids. Taxifolin is a flavonoid in food plants. The present study investigated the effects of taxifolin on rat and human liver microsomal HSD11B1. Taxifolin competitively inhibited rat and human HSD11B1 against steroid cortisone or 11-dehydrocorticosterone, with IC50 values of 37,833 and 4981 nM, respectively. Oral administration of 5 and 10 mg/kg taxifolin for 30 min significantly inhibited rat liver HSD11B1 ex vivo and suppressed cortisone metabolism as shown by the significant increase of T1/2, Cmax, Tmax, and the area under curve (AUC) after exogenous injection of cortisone in vivo. This result shows that taxifolin is a potent inhibitor of both rat and human HSD11B1, being a possible supplement to treat the metabolic syndrome.

By labelling high spatial resolution (HSR) images with specific semantic classes according to geographical properties, scene classification has been proven to be an effective method for HSR remote sensing image semantic interpretation. Deep learning is widely applied in HSR remote sensing scene classification. Most of the scene classification methods based on deep learning assume that the training datasets and the test datasets come from the same datasets or obey similar feature distributions. However, in practical application scenarios, it is difficult to guarantee this assumption. For new datasets, it is time-consuming and labor-intensive to repeat data annotation and network design. The neural architecture search (NAS) can automate the process of redesigning the baseline network. However, traditional NAS lacks the generalization ability to different settings and tasks. In this paper, a novel neural network search architecture framework—the spatial generalization neural architecture search (SGNAS) framework—is proposed. This model applies the NAS of spatial generalization to cross-domain scene classification of HSR images to bridge the domain gap. The proposed SGNAS can automatically search the architecture suitable for HSR image scene classification and possesses network design principles similar to the manually designed networks. To obtain a simple and low-dimensional search space, the traditional NAS search space was optimized and the human-the-loop method was used. To extend the optimized search space to different tasks, the search space was generalized. The experimental results demonstrate that the network searched by the SGNAS framework with good generalization ability displays its effectiveness for cross-domain scene classification of HSR images, both in accuracy and time efficiency.

Male fetal Leydig cells in the testis secrete androgen and insulin-like 3, determining the sexual differentiation. The abnormal development of fetal Leydig cells could lead to the reduction of androgen and insulin-like 3, thus causing the male reproductive tract anomalies in male neonates, including cryptorchidism and hypospadias. Environmental pollutants, such as phthalic acid esters (phthalates), can perturb the development and differentiated function of Leydig cells, thereby contributing to the reproductive toxicity in the male. Here, we review the epidemiological studies in humans and experimental investigations in rodents of various phthalates. Most of phthalates disturb the expression of various genes encoded for steroidogenesis-related proteins and insulin-like 3 in fetal Leydig cells and the dose-additive effects are exerted after exposure in a mixture.

Because of the advantages of facile and fast preparation process, screen printing technology shows great potentials in the prospective large-scale production of thermoelectric materials. Herein, rGO/Sb _2 Te _3 composite powders have been prepared by a hydrothermal process, and then flexible rGO/Sb _2 Te _3 /SV4/PEDOT:PSS composite films with different weights of rGO/Sb _2 Te _3 composite powders have been prepared via a screen printing process. The effects of the contents of rGO/Sb _2 Te _3 composite powders on thermoelectric properties of the rGO/Sb _2 Te _3 /SV4/PEDOT:PSS composite films have been studied. The Seebeck coefficients of the achieved composite films was basically unchanged with the content of rGO/Sb _2 Te _3 composite powders increasing, whereas the electrical conductivities decrease, resulting in a maximal power factor of 2.96 μW/mK ^2 at 375 K for the composite film containing 85 wt.% rGO/Sb _2 Te _3 composite powders. The cold pressing combining annealing process has been employed to improve the thermoelectric properties of the composite films. After the treatment, the electrical conductivity of the composite film with 85 wt.% rGO/Sb _2 Te _3 powders has been significantly improved, while the corresponding Seebeck coefficient has slightly decreased. An optimal power factor of 14.13 μW/mK ^2 has been acquired at 375 K, which is ∼ 5 times higher when compared to the untreated composite film (2.96 μW/mK ^2 at 375 K).

Building extraction is a binary classification task that separates the building area from the background in remote sensing images. The conditional random field (CRF) is directly modelled by the maximum posterior probability, which can make full use of the spatial neighbourhood information of both labelled and observed images. CRF is widely used in building footprint extraction. However, edge oversmoothing still exists when CRF is directly used to extract buildings from high spatial resolution (HSR) remote sensing images. Based on a computer vision multi-scale semantic segmentation network (D-LinkNet), a novel building extraction framework is proposed, named multiscale-aware and segmentation-prior conditional random fields (MSCRF). To solve the problem of losing building details in the downsampling process, D-LinkNet connecting the encoder and decoder is correspondingly used to generate the unary potential. By integrating multi-scale building features in the central module, D-LinkNet can integrate multiscale contextual information without loss of resolution. For the pairwise potential, the segmentation prior is fused to alleviate the influence of spectral diversity between the building and the background area. Moreover, the local class label cost term is introduced. The clear boundaries of the buildings are obtained by using the larger-scale context information. The experimental results demonstrate that the proposed MSCRF framework is superior to the state-of-the-art methods and performs well for building extraction of complex scenes.

Triphenyltin chloride (TPT) is present in a wide range of human foods. TPT could disrupt testis function as a potential endocrine disruptor of Leydig cells. However, the effect of TPT on pubertal Leydig cell development is still unclear. The objective of the current study was to explore whether exposure to TPT affected Leydig cell developmental process and to clarify the underlying mechanisms. Male Sprague-Dawley rats at 35 days of age were randomly divided into four groups and received normal corn oil (control), 0.5, 1, or 2 mg/kg/day TPT for 18 days. Immature Leydig cells isolated from 35-day-old rat testes were treated with TPT (10 and 100 nM) for 24 h in vitro. In vivo exposure to ≥0.5 mg/kg TPT lowered serum testosterone levels and lowered Star mRNA. TPT at 2 mg/kg also lowered Lhcgr, Cyp11a1, Hsd3b1, Hsd17b3 as well as pAKT1/AKT1, pAKT2/AKT2, and pERK1/2/ERK1/2 ratios. In vitro exposure to TPT (100 nM) increased ROS production and induced cell apoptosis rate in rat immature Leydig cells. In conclusion, TPT exposure disrupts Leydig cell development possibly via interfering with the phosphorylation of AKT1, AKT2, and ERK1/2 kinases.

Background: Leydig cells secrete the steroid hormone, testosterone, which is essential for male fertility and reproductive health. Stress increases the secretion of glucocorticoid [corticosterone, (CORT) in rats] that decreases circulating testosterone levels in part through a direct action on its receptors in Leydig cells. Intratesticular CORT level is dependent on oxidative inactivation of CORT by 11β-hydroxysteroid dehydrogenase 1 (HSD11B1) in rat Leydig cells. Pain may cause the stress, thus affecting testosterone production in Leydig cells.Methods: Adult male Sprague–Dawley rats orally received vehicle control or 5 or 10 mg/kg dehydroepiandrosterone (DHEA) 0.5 h before being subjected to pain stimulation for 1, 3, and 6 h. In the present study, we investigated the time-course changes of steroidogenic gene expression levels after acute pain-induced stress in rats and the possible mechanism of DHEA that prevented it. Plasma CORT, luteinizing hormone (LH), and testosterone (T) levels were measured, and Leydig cell gene expression levels were determined. The direct regulation of HSD11B1 catalytic direction by DHEA was detected in purified rat Leydig, liver, and rat Hsd11b1-transfected COS1 cells.Results: Plasma CORT levels were significantly increased at hour 1, 3, and 6 during the pain stimulation, while plasma T levels were significantly decreased starting at hour 3 and 6. Pain-induced stress also decreased Star, Hsd3b1, and Cyp17a1 expression levels at hour 3. When 5 and 10 mg/kg DHEA were orally administered to rats 0.5 h before starting pain stimulation, DHEA prevented pain-mediated decrease in plasma T levels and the expression of Star, Hsd3b1, and Cyp17a1 without affecting plasma CORT levels. DHEA was found to modulate HSD11B1 activities by increasing its oxidative activity and decreasing its reductive activity, thus decreasing the intracellular CORT levels in Leydig cells.Conclusion: Stress induced by acute pain can inhibit Leydig cell T production by upregulation of corticosterone. DHEA can prevent the negative effects of excessive corticosterone by modulating HSD11B1 activity.

Background: Piperine is the primary pungent alkaloid isolated from the fruit of black peppercorns. Piperine is used frequently in dietary supplements and traditional medicines. The objective of the present study was to investigate the effects of piperine on the testis development in the pubertal rat.Methods: Piperine (0 or 5 or 10 mg/kg) was gavaged to 35-day-old male Sprague-Dawley rats for 30 days. Serum levels of testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured. The development of adult Leydig cell population was also analyzed 65 days postpartum. For in vitro studies, immature Leydig cells were isolated from 35-day-old male rats and treated with 50 μM piperine in the presence of different steroidogenic stimulators/substrates for 24 h.Results: Thirty-day treatment of rats with piperine significantly increased serum T levels without affecting LH concentrations. However, piperine treatment reduced serum FSH levels. Consistent with increase in serum T, piperine increased Leydig cell number, cell size, and multiple steroidogenic pathway proteins, including steroidogenic acute regulatory protein, cholesterol side-chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase 1, 17α-hydroxylase/20-lyase, and steroidogenic factor 1 expression levels. Piperine significantly increased the ratio of phospho-AKT1 (pAKT1)/AKT1, phosphos-AKT2 (pAKT2)/AKT2, and phospho-ERK1/2 (pERK1/2)/ERK1/2 in the testis. Interestingly, piperine inhibited spermatogenesis. Piperine in vitro also increased androgen production and stimulated cholesterol side-chain cleavage enzyme and 17α-hydroxylase/20-lyase activities in immature Leydig cells.Conclusion: Piperine stimulates pubertal Leydig cell development by increasing Leydig cell number and promoting its maturation while it inhibits spermatogenesis in the rat. ERK1/2 and AKT pathways may involve in the piperine-mediated stimulation of Leydig cell development.

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease which has been previously shown to be associated with type 2 diabetes mellitus (T2DM). Recent research has indicated that type 1 diabetes mellitus (T1DM) is also involved in the development of nonalcoholic fatty liver disease, whereas the underlying mechanisms are largely unknown. Forkhead box O1 (FoxO1) and adiponectin (APN) have been proposed to play an important role in the processes in NAFLD in T1DM. We herein investigated the effects of FoxO1 and APN on the development of NAFLD and the underlying mechanism in streptozotocin-induced T1DM. Serum liver enzymes AST, ALT, and triglyceride (TG) were determined by commercially available kits. Blood glucose levels were measured by the OneTouch Ultra glucose meter. Relevant protein expression was tested by Western blot analysis. Results showed that serum AST, ALT, and TG were all significantly increased in T1DM rats, which was ameliorated by application of APN or selective inhibition of FoxO1 with AS1842856. Moreover, APN and AS1842856 both decreased the expression of liver nuclear FoxO1 which was significantly increased in diabetic rats. However, the inhibition of FoxO1 did not alter the expression of APN and its receptors. We also found that Akt1 expression was significantly declined in diabetic rat which was restored by APN and moderately and significantly increased by FoxO1 inhibition. It is concluded that APN ameliorates NAFLD via inhibition of FoxO1 through Akt1/FoxO1 signaling pathway.

Background. Sepsis leads to severe acute lung injury/acute respiratory distress syndrome (ALI/ARDS) that is associated with enhanced endoplasmic reticulum (ER) stress. Heme oxygenase-1 (HO-1), an ER-anchored protein, exerts antioxidant and protective functions under ALI. However, the role of HO-1 activation in the development of endoplasmic reticulum (ER) stress during sepsis remains unknown. Methods. Cecal ligation and puncture (CLP) model was created to induce septic ALI. Lung tissue ER stress was measured 18 hours after CLP. The effects of HO-1 on ER stress during septic ALI were investigated in vivo using HO-1 agonist hemin and antagonist ZnPP. Results. Compared with the sham group, ER stress in septic lung increased significantly 18 hours after CLP, which was significantly reduced by pretreatment with the ER inhibitor 4-phenylbutyrate (4-PBA). The lung injury score and the lung wet to dry (W/D) ratio in lungs were significantly reduced in septic rats after ER stress inhibition. Similarly, lung ER stress-related genes’ (PERK, eIF2-α, ATF4, and CHOP) levels were attenuated after ER stress inhibition. Furthermore, HO-1 activation by hemin reduced p-PERK, p-eIF2-α, ATF4, and CHOP protein expression and oxidative stress and lung cell apoptosis. Additionally, HO-1 antagonist could aggregate the ER stress-related ALI. Conclusions. ER stress was activated during CLP-induced ALI, which may represent a mechanism by which CLP induces ALI. HO-1 activation could inhibit CLP-induced lung ER stress and attenuate CLP-induced ALI.