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Cyprinus acutidorsalis (Wang, 1979) is an endemic fish in China that is sparsely distributed in the Hainan provinces and Guangxi Zhuang Autonomous Region (GZAR). In this study, the complete mitochondrial genome of C. acutidorsalis from the Hainan population from the Wanquan River was sequenced, and its phylogenetic relationship was analyzed. The circular mtDNA was 16,581 bp in length, and the overall base composition was A (32.0%), C (27.5%), T (24.8%), and G (15.70%), with a slight bias toward A + T. The complete mitogenome encoded 13 protein-coding genes (PCGs), 22 tRNA genes, two rRNA genes, and a control region. Phylogenetic analysis indicated that the most closely related fish to C. acutidorsalis from the Hainan population was C. acutidorsalis from the Guangxi population. These findings offer basic molecular data and a better understanding of the phylogenetic relationships among the Cyprinus species.

Abstract Prunus conradinae, a valuable flowering cherry belonging to the Rosaceae family subgenus Cerasus and endemic to China, has high economic and ornamental value. However, a high-quality P. conradinae genome is unavailable, which hinders our understanding of its genetic relationships and phylogenesis, and ultimately, the possibility of mining of key genes for important traits. Herein, we have successfully assembled a chromosome-scale P. conradinae genome, identifying 31,134 protein-coding genes, with 98.22% of them functionally annotated. Furthermore, we determined that repetitive sequences constitute 46.23% of the genome. Structural variation detection revealed some syntenic regions, inversions, translocations, and duplications, highlighting the genetic diversity and complexity of Cerasus. Phylogenetic analysis demonstrated that P. conradinae is most closely related to P. campanulata, from which it diverged ~ 19.1 million years ago (Mya). P. avium diverged earlier than P. cerasus and P. conradinae. Similar to the other Prunus species, P. conradinae underwent a common whole-genome duplication event at ~ 138.60 Mya. Furthermore, 79 MADS-box members were identified in P. conradinae, accompanied by the expansion of the SHORT VEGETATIVE PHASE subfamily. Our findings shed light on the complex genetic relationships, and genome evolution of P. conradinae and will facilitate research on the molecular breeding and functions of key genes related to important horticultural and economic characteristics of subgenus Cerasus.

Abstract Background Southwest China is one of the largest karst regions in the world. Karst environment is relatively fragile and vulnerable to human activities. Due to the discharge of sewage and domestic garbage, the karst system may be polluted by pathogenic bacteria. The detection of bacterial distribution and identification of phage capable of infecting them is an important approach for environmental assessment and resource acquisition. Methods Bacteria and phages were isolated from karst water in southwest China using the plate scribing and double plate method, respectively. Isolated phage was defined by transmission electron microscopy, one-step growth curve and optimal multiplicity of infection (MOI). Genomic sequencing, phylogenetic analysis, comparative genomic and proteomic analysis were performed. Results A Klebsiella quasipneumoniae phage was isolated from 32 isolates and named KL01. KL01 is morphologically identified as Caudoviricetes with an optimal MOI of 0.1, an incubation period of 10 min, and a lysis period of 60 min. The genome length of KL01 is about 45 kb, the GC content is 42.5%, and it contains 59 open reading frames. The highest average nucleotide similarity between KL01 and a known Klebsiella phage 6939 was 83.04%. Conclusions KL01 is a novel phage, belonging to the Autophagoviridae, which has strong lytic ability. This study indicates that there were not only some potential potentially pathogenic bacteria in the karst environment, but also phage resources for exploration and application.

Aims: Cellular dormancy is a state of quiescence subpopulation of tumor cells, characterized by low differentiation and lack of mitotic activity. They could evade chemotherapy and targeted therapy, leading to drug resistance and disease recurrence. Recent studies have shown a correlation between dormant cancer cells and unique extracellular matrix (ECM) composition, which is critical in regulating cell behavior. However, their interacting roles in TNBC patients remains to be characterized. Main methods: Dormant cancer cells in MDA-MB-231 cell line with highest PKH26 dye-retaining were FACS-sorted and gene expression was then analyzed. Dormant associated ECM (DA-ECM) signature was characterized by pathway analysis. Unsupervised hierarchical clustering was used to define distinct ECM features for TNBC patients. ECM-specific tumor biology was defined by integration of bulk RNA-seq with single-cell RNA-seq data, analysis of ligand-receptor interactions and enriched biological pathways, and in silico drug screening. We validated the sensitivity of dormant cancer cells to MAPK inhibitors by flow cytometry in vitro. Key findings: We observed that dormant TNBC cells preferentially expressed ∼10 % DA-ECM genes. The DA-ECM High subtype defined by unsupervised hierarchical clustering analysis was associated with immunosuppressive tumor microenvironment. Moreover, ligand-receptor interaction and pathway analysis revealed that the DA-ECM High subtype may likely help maintain tumor cell dormancy through MAPK, Hedgehog and Notch signaling pathways. Finally, in silico drug screening against the DA-ECM signature and in vitro assay showed dormant cancer cells were relatively sensitive to the MAPK pathway inhibitors, which may represent a potential therapeutic strategy for treating TNBC. Significance: Collectively, our research revealed that dormancy-associated ECM characterized tumor cells possess significant ECM remodeling capacity, and treatment strategies towards these cells could improve TNBC patient outcome.

Understanding public emotion on social media about community wellness is crucial for enhancing health awareness and guiding policy-making. In order to more fully mine the deep contextual semantical information of short texts and further enhance the effectiveness of emotion prediction in social media, we propose the Deep Parallel Contextual Analysis Framework (DPCAF) in the community wellness domain, specifically addressing the challenges of limited text length and available semantical features in social media text. Specifically, at the embedding layer, we first utilize two different word embedding techniques to generate high-quality vector representations, aiming to achieve more comprehensive semantical capture, stronger generalization ability, and more robust model performance. Subsequently, in the deep contextual layer, the obtained representations are fused with POS and locational representations, and processed through a deep parallel layer composed of Convolutional Neural Networks and Bidirectional Long Short-Term Memory Network. An attention model is then used to further extract semantical features of social media texts. Finally, these deep parallel contextual representations are post-integrated for emotion prediction. Experiments on a dataset collected from social media regarding community wellness demonstrate that compared to benchmark models, DPCAF achieves at least a 4.81 % increase in Precision, a 3.44 % increase in Recall, and a 10.81 % increase in F1-score. Relative to the most advanced models, DPCAF shows a minimum improvement of 2.65 % in Precision, 3.02 % in Recall, and 2.53 % in F1-score.

Abstract In histopathology, doctors identify diseases by characterizing abnormal cells and their spatial organization within tissues. Polarization microscopy and supervised learning have been proved as an effective tool for extracting polarization parameters to highlight pathological features. Here, we present an alternative approach based on unsupervised learning to group polarization-pixels into clusters, which correspond to distinct pathological structures. For pathological samples from different patients, it is confirmed that such unsupervised learning technique can decompose the histological structures into a stable basis of characteristic microstructural clusters, some of which correspond to distinctive pathological features for clinical diagnosis. Using hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) samples, we demonstrate how the proposed framework can be utilized for segmentation of histological image, visualization of microstructure composition associated with lesion, and identification of polarization-based microstructure markers that correlates with specific pathology variation. This technique is capable of unraveling invisible microstructures in non-polarization images, and turn them into visible polarization features to pathologists and researchers.

Abstract Background Osteosarcoma (OSA) presents a clinical challenge and has a low 5‐year survival rate. Currently, the lack of advanced stratification models makes personalized therapy difficult. This study aims to identify novel biomarkers to stratify high‐risk OSA patients and guide treatment. Methods We combined 10 machine‐learning algorithms into 101 combinations, from which the optimal model was established for predicting overall survival based on transcriptomic profiles for 254 samples. Alterations in transcriptomic, genomic and epigenomic landscapes were assessed to elucidate mechanisms driving poor prognosis. Single‐cell RNA sequencing (scRNA‐seq) unveiled genes overexpressed in OSA cells as potential therapeutic targets, one of which was validated via tissue staining, knockdown and pharmacological inhibition. We characterized changes in multiple phenotypes, including proliferation, colony formation, migration, invasion, apoptosis, chemosensitivity and in vivo tumourigenicity. RNA‐seq and Western blotting elucidated the impact of squalene epoxidase (SQLE) suppression on signalling pathways. Results The artificial intelligence‐derived prognostic index (AIDPI), generated by our model, was an independent prognostic biomarker, outperforming clinicopathological factors and previously published signatures. Incorporating the AIDPI with clinical factors into a nomogram improved predictive accuracy. For user convenience, both the model and nomogram are accessible online. Patients in the high‐AIDPI group exhibited chemoresistance, coupled with overexpression of MYC and SQLE, increased mTORC1 signalling, disrupted PI3K–Akt signalling, and diminished immune infiltration. ScRNA‐seq revealed high expression of MYC and SQLE in OSA cells. Elevated SQLE expression correlated with chemoresistance and worse outcomes in OSA patients. Therapeutically, silencing SQLE suppressed OSA malignancy and enhanced chemosensitivity, mediated by cholesterol depletion and suppression of the FAK/PI3K/Akt/mTOR pathway. Furthermore, the SQLE‐specific inhibitor FR194738 demonstrated anti‐OSA effects in vivo and exhibited synergistic effects with chemotherapeutic agents. Conclusions AIDPI is a robust biomarker for identifying the high‐risk subset of OSA patients. The SQLE protein emerges as a metabolic vulnerability in these patients, providing a target with translational potential.

Background: Osteosarcoma, the most common primary malignant bone tumor, is currently treated with surgery combined with chemotherapy, but the limited availability of targeted drugs contributes to a poor prognosis. Identifying effective therapeutic targets is crucial for improving the prognosis of osteosarcoma patients. Methods: We screened the DepMap database to identify essential genes as potential therapeutic targets for osteosarcoma. Gene Set Enrichment Analysis (GSEA) was employed to elucidate the biological roles of these essential genes. Promising candidates were filtered through univariate and multivariate Cox analyses, as well as Kaplan-Meier survival analyses using the GSE21257-OSA and TARGET-OSA datasets. The functional role of the target gene was assessed through cell experiments. Additionally, an in situ nude mice model was established to observe the gene's function, and RNA sequencing was utilized to explore the underlying molecular mechanism. Results: A total of 934 essential genes were identified based on their effects (Chronos) using the DepMap database. These genes were primarily enriched in the ribosome pathway according to GSEA analysis. Among them, 195 genes were associated with the ribosome pathway. Rps28, Rps7, and Rps25 were validated as promising candidates following univariate and multivariate Cox analyses of the TARGET-OSA and GSE21257-OSA datasets. Kaplan-Meier survival analyses indicated Rps28 represented an especially promising target, with high expression correlating with poor prognosis. Knockdown of small ribosomal subunit protein eS28, the protein of Rps28, inhibited proliferation, migration, and invasion in both in vitro and in vivo experiments. Silencing RPS28 affected the MAPK signaling pathway in osteosarcoma. Conclusion: In summary, Rps28 has been identified as an essential gene for osteosarcoma cell survival and eS28 may serve as a potential vulnerability in osteosarcoma.

Amidst the framework of dual circulation, innovation emerges as a pivotal strategy for realizing high-quality economic development. Concurrently, digital finance, serving as a potent complement to traditional financial systems, significantly influences regional innovation enhancement. This research employs a spatial panel methodology to thoroughly investigate the inherent mechanisms through which digital finance development shapes regional innovation. Empirical testing is conducted using panel data derived from 283 mainland Chinese prefecture-level cities spanning from 2013 to 2020. The findings underscore that digital inclusive finance plays a crucial role in amplifying regional innovation output, unveiling a distinct spatial impact on innovation. The progression of each facet of digital finance contributes to mitigating supply-side financing constraints, thereby directly fostering heightened regional innovation. The study delves into a Chinese regional sub-sample, revealing a prevalent driving effect with conspicuous heterogeneity across the major regions—East > Central > West. As scientific and technological innovation stands as the primary driving force, its profound interplay with the evolution of financial inclusion in China is evident. This study provides valuable insights to fortify regional modernization efforts and serves as a reference for policymakers and researchers navigating the complex intersection of finance and innovation in the Chinese context.

AbstractMacropodus hongkongensis (Freyhof & Herder, 2002), is sparsely distributed in Hong Kong and Guangdong provinces. Recently, a new geographical population of M. hongkongensis was discovered in the Wanquan River in the Hainan province. Therefore, this study focused on sequencing the complete mitochondrial genome of the new geographical population of Macropodus hongkongensis from the Wanquan River. The circular mtDNA molecule was 16,492 bp in size, and the overall base compositions were A (30.30%), C (24.90%), T (29.80%), and G (15.00%), with a slight bias toward A + T. The complete mitogenome encoded 13 protein-coding genes (PCGs), 22 tRNA genes, 2 rRNA genes, and a control region. Phylogenetic analysis indicated that M. hongkongensis of the Hainan Wanquan River was most closely related to the M. hongkongensis of the Gongdong population. These results provide useful genetic information for species identification and phylogenetic studies of Macropodus species.

Abstract Background The purpose of this study is to explore the related factors of precocious puberty in children. Methods 1239 children who underwent physical examination in our hospital from January 2020 to December 2022 were analyzed, including 198 precocious children and 1041 normal children. According to the age of 198 precocious children and 1041 normal children, 205 normal children were selected, and the remaining 836 normal children were excluded. They were divided into precocious group and normal group. The general data of the two groups were recorded. Logistic regression was used to analyze the influencing factors of precocious puberty in children. Results There were statistically significant differences (P 10 years old), and daily exercise time (

External magnetic field has been employed to improve appearance and suppress defects in the single laser or arc welding, and its physical mechanism in magnetic-field-assisted single laser or arc welding has been clearly clarified. However, few studies on the physical processes in magnetic-field-assisted laser-arc hybrid welding (MFA-LAHW) are conducted and its influencing mechanism is unclear. In this research, a comprehensive three-dimension numerical model is established to investigate the keyhole dynamics and weld pool behaviors in MFA-LAHW under the effect of different magnetic flux density. The results suggest that the interaction between a lower magnetic flux density (≤30 mT) and welding current is induced due to the existence of arc. Compared to the magnetic-field-assisted laser beam welding (MFA-LBW), this interaction induces a stronger Lorentz force up to the order of magnitude of 105 N/m3. The weld pool width is reduced while its length and height are increased because the Lorentz force facilitates the backward flow of thermal fluid, increasing the heat transfer from the keyhole and droplet to the rear weld pool edge. Moreover, the steady magnetic field improves the keyhole stability. The deform on keyhole rear wall brought by the droplet and vortex is suppressed, and keyhole size is widened under steady magnetic field, which reduced keyhole collapse. Furthermore, the comparative analysis with the case in MFA-LBW is carried out and the MFA-LAHW is verified to be more valuable for medium-thickness aluminum alloy. This work provides the underlying physics understanding of MFA-LAHW, which will broaden the application value of LAHW.

High speed cutting is an effective technique to achieve high efficiency and high quality machining of titanium alloy and other difficult materials. The high speed cutting process of titanium alloy has the nonlinear dynamic characteristics of high temperature, high strain and high strain rate. In order to accurately describe the dynamic mechanical behavior of titanium alloy in high speed cutting, the research on dynamic constitutive model of titanium alloy is reviewed. The application conditions, advantages and disadvantages of Johnson-Cook model, Zerilli-Armstrong model and Bammann model are analyzed from the perspective of phenomenological model and physical model with Ti-6Al-4V as the research object. After comprehensive comparison, the Johnson-Cook model is selected for further exploration, and the Johnson-Cook modified model is classified based on the influence of temperature and competition mechanism. The prediction accuracy of the Johnson-Cook modified model is improved compared with that of the classical model. At the same time, it is proposed that the construction of phenomenology-physics composite constitutive model can be taken as the key direction to explore the dynamic constitutive model of titanium alloy, and the method of experiment and computer synchronization can be used to obtain the optimal solution of constitutive model parameters, so as to improve the prediction accuracy of dynamic constitutive model.

A staggered vane-shaped slot-line slow-wave structure (SV-SL SWS) for application in W-band traveling wave tubes (TWTs) is proposed in this article. In contrast to the conventional slot-line SWSs with dielectric substrates, the proposed SWS consists only of a thin metal sheet inscribed with periodic grooves and two half-metal enclosures, which means it can be easily manufactured and assembled and has the potential for mass production. This SWS not only solves the problem of the dielectric loading effect but also improves the heat dissipation capability of such structures. Meanwhile, the SWS design presented here covers a −15 dB S11 frequency range from 87.5 to 95 GHz. The 3-D simulation for a TWT based on the suggested SWS is also investigated. Under dual-electron injection conditions with a total voltage of 17.2 kV and a total current of 0.3 A, the maximum output power at 90 GHz is 200 W, with a 3 dB bandwidth up to 4 GHz. With a good potential for fabrication using microfabrication techniques, this structure can be a good candidate for millimeter-wave TWT applications.

AbstractRapid urbanization currently poses a threat to cropland areas. Therefore, exploring the pattern of change in cropland areas and its driving mechanism is of great significance in safeguarding regional economic development and food security. In this study, data regarding cropland in the Changsha-Zhuzhou-Xiangtan city group (CZTCG) from 2000 to 2020 were collected, and dynamic changes in cropland in the past 20 years were analyzed. Based on this, the mechanisms that drive cropland change were explored in the context of multiple dimensions. Furthermore, an Inertial Development Scenario and a Cropland Priority Scenario were designed to simulate land use/land cover (LULC) changes in the CZTCG in 2025 and 2035, and, in particular, to analyze the characteristics of future spatiotemporal changes of cropland. The results demonstrated that the cropland area in the CZTCG in the past 20 years has shown a two-stage trend of increasing (2000–2015, increase of 8.25%) and decreasing (2015–2020, decrease of 2.91%), and the main reasons for cropland loss in the whole process of change were forest and building, with serious loss of cropland area in Changsha County and Wangcheng District. Between 2000 and 2020, socio-economic factors (GDP, total agricultural output), topography (elevation, slope), and climate change (average annual temperature, annual precipitation) were highly correlated with changes in cropland area, exhibiting significant temporal and regional variability. The simulation results indicate that until 2035, the Cropland Priority Scenario shows a significant increase in the area of cropland in the study area compared to the Inertial Development Scenario. Consequently, the implementation of a strategy that prioritizes cropland can effectively protect it, while helping to promote ecological development and regional socio-economic development.

Blockchain technology has become more common in the audit industry, posing new problems for traditional audit work. Researchers have been studying the effect of customers’ use of blockchain technology on audits, especially on audit risk and audit methods. This paper examines audit cases of Chinese enterprises that use blockchain technology. It analyzes the effect of the use of blockchain technology on the audit and the new audit problems. It also examines an Australian blockchain audit case using a questionnaire. This case study showed that the application of new technologies to the audit industry may lead to increased inherent risks and control risks. The audit methodology is uncertain and there are two possible approaches: (1) a combination of direct, indirect, account-level, and entity-level evidence and (2) an increase in indirect and entity-level evidence. This paper puts forward the reference case of the Australian blockchain audit experience and suggestions for developing blockchain audits in China.

Background: Presbycusis/Age-related hearing loss is a sensorineural hearing loss caused by age-related deterioration of the auditory system that poses a risk to the physical and mental health of older people, including social and cognitive decline. It is also associated with frailty, falls and depression. There are currently no specific medications for the treatment of presbycusis, and early detection and intervention are key to its prevention and management. Traditional Chinese medicine interventions may offer opportunities in the prevention and treatment of presbycusis, but there is no relevant review. Methods: Literature searches was conducted using PubMed, Cochrane Library, Web of Science, and China National Knowledge Infrastructure (CNKI) databases for review articles, research articles, clinical trials, meta-analyses, and case studies in animal models and clinical trials. Results: We summarized the pathological mechanisms associated with presbycusis, related to genetic factors, environment, lifestyle, and molecular mechanisms related to oxidative stress, mitochondrial dysfunction, and inflammatory pathways. It is suggested that traditional Chinese medicine interventions may offer opportunities in the prevention and treatment of presbycusis using active ingredients of herbs or formulas, acupuncture, and exercise such as Tai Chi Chuan or Ba Duan Jin. The active ingredients of herbs or formulas may exert ear protection through Nrf2-mediated antioxidant pathways, NF-kB and NLRP3-related anti-inflammatory signaling, and regulation of autophagy. Conclusions: Here, we review the pathogenetic factors and pathological mechanisms involved in presbycusis, as well as traditional Chinese medicine interventions and treatments, with the aim of providing a new perspective for the prevention and treatment of hearing loss in the elderly and further improving their quality of life.

Summary: In vitro embryonic analogue models, such as gastruloids, trunk-like structures and embryoids, have been developed to understand principles of early development and morphogenesis. However, models that can fully mimic head formation are still missing. Here, we present a protocol for generating the head-like structure (HLS) in zebrafish embryonic explants. We describe steps for dissection and constructing cell and patterning landscapes. We then detail assessment of this structure through axis induction.For complete details on the use and execution of this protocol, please refer to Cheng et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Summary: The role of alternative polyadenylation (APA) in tumor development is becoming increasingly evident, but the impact of APA events on the prognosis of LUAD patients is unclear. Therefore, in the present study, we aimed to analyze specific APA events in LUAD to identify novel prognostic biomarkers for LUAD. We first identified prognostic candidate genes for LUAD associated with APA events and validated them in both the East Asian and the USA cohorts, finding that five genes (DCUN1D5, PSMC4, TFAM, THRA, and TMEM100) were of prognostic significance in both populations. Based on this, an APA-based prognostic signature was constructed for the East Asian population. The predictive accuracy of the prognostic signature was further evaluated by the time-dependent ROC, with 1-, 2-, and 3-year AUCs of 0.86, 0.81, and 0.71, respectively. This study may provide new markers for individualized diagnosis and prognostic assessment of LUAD and potential targets for precision treatment.

Abstract Point cloud registration is of great significance to the reconstruction of high‐precision 3D city models. There are some challenges when aligning aerial and close‐range photogrammetric point clouds, such as huge view differences caused by the different sights of the sensors, massive noisy points due to the error in dense matching, and scale uncertainty since there are no control points for absolute orientation. To achieve complementary advantages of aerial and close‐range point clouds, in this paper, a robust cross‐source point clouds registration method is proposed using image visual context features and scale consistency. First, a cross‐view image matching method based on image visual context features is proposed to obtain corresponding points. Second, to overcome the challenges of noisy points and scale differences, an outlier filtering method is designed based on scale consistency. Finally, the dual quaternions model considering the scale factor is introduced to solve the spatial transformation model. To analyze the feasibility of this method qualitatively and quantitatively, experiments are conducted using the public scene dataset of Dortmund, Germany, and the scene dataset of Zhengzhou City, China. Three kinds of cross‐source point clouds registration experiments are conducted in this paper, including aerial and close‐range point clouds registration in Dortmund, and aerial and ground point clouds registrations in both Dortmund and Zhengzhou. The chamfer distances of the three sets of experiments are 4.48 m, 5.97 m and 4.78 m, respectively. The ablation study shows that the outlier filtering method and the dual quaternions model improve the accuracy by at least 14% and 25%, respectively. The experiments demonstrate that the method accomplishes the cross‐source point clouds registration in large‐scale scenes accurately and efficiently, providing a solid foundation for subsequent fine 3D reconstruction.

Abstract Background Urinary bladder cancer (UBC) is a common malignancy of the urinary tract; however, the mechanism underlying its high recurrence and responses to immunotherapy remains unclear, making clinical outcome predictions difficult. Epigenetic alterations, especially DNA methylation, play important roles in bladder cancer development and are increasingly being investigated as biomarkers for diagnostic or prognostic predictions. However, little is known about hydroxymethylation since previous studies based on bisulfite-sequencing approaches could not differentiate between 5mC and 5hmC signals, resulting in entangled methylation results. Methods Tissue samples of bladder cancer patients who underwent laparoscopic radical cystectomy (LRC), partial cystectomy (PC), or transurethral resection of bladder tumor (TURBT) were collected. We utilized a multi-omics approach to analyze both primary and recurrent bladder cancer samples. By integrating various techniques including RNA sequencing, oxidative reduced-representation bisulfite sequencing (oxRRBS), reduced-representation bisulfite sequencing (RRBS), and whole exome sequencing, a comprehensive analysis of the genome, transcriptome, methylome, and hydroxymethylome landscape of these cancers was possible. Results By whole exome sequencing, we identified driver mutations involved in the development of UBC, including those in FGFR3, KDMTA, and KDMT2C. However, few of these driver mutations were associated with the down-regulation of programmed death-ligand 1 (PD-L1) or recurrence in UBC. By integrating RRBS and oxRRBS data, we identified fatty acid oxidation-related genes significantly enriched in 5hmC-associated transcription alterations in recurrent bladder cancers. We also observed a series of 5mC hypo differentially methylated regions (DMRs) in the gene body of NFATC1, which is highly involved in T-cell immune responses in bladder cancer samples with high expression of PD-L1. Since 5mC and 5hmC alternations are globally anti-correlated, RRBS-seq-based markers that combine the 5mC and 5hmC signals, attenuate cancer-related signals, and therefore, are not optimal as clinical biomarkers. Conclusions By multi-omics profiling of UBC samples, we showed that epigenetic alternations are more involved compared to genetic mutations in the PD-L1 regulation and recurrence of UBC. As proof of principle, we demonstrated that the combined measurement of 5mC and 5hmC levels by the bisulfite-based method compromises the prediction accuracy of epigenetic biomarkers.

Quantum sensors based on NV centers in diamond are well established, however the sensitivity of detection of high-frequency radio signals has been limited. Here the authors use nanoscale field-focusing to enhance sensitivity and demonstrate ranging for GHz radio signals in an interferometer set-up.

Abstract Despite the success of targeted therapies in cancer treatment, therapy-induced resistance remains a major obstacle to a complete cure. Tumor cells evade treatments and relapse via phenotypic switching driven by intrinsic or induced cell plasticity. Several reversible mechanisms have been proposed to circumvent tumor cell plasticity, including epigenetic modifications, regulation of transcription factors, activation or suppression of key signaling pathways, as well as modification of the tumor environment. Epithelial-to-mesenchymal transition, tumor cell and cancer stem cell formation also serve as roads towards tumor cell plasticity. Corresponding treatment strategies have recently been developed that either target plasticity-related mechanisms or employ combination treatments. In this review, we delineate the formation of tumor cell plasticity and its manipulation of tumor evasion from targeted therapy. We discuss the non-genetic mechanisms of targeted drug-induced tumor cell plasticity in various types of tumors and provide insights into the contribution of tumor cell plasticity to acquired drug resistance. New therapeutic strategies such as inhibition or reversal of tumor cell plasticity are also presented. We also discuss the multitude of clinical trials that are ongoing worldwide with the intention of improving clinical outcomes. These advances provide a direction for developing novel therapeutic strategies and combination therapy regimens that target tumor cell plasticity.

Abstract Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease that can be treated with revascularization. Surgery increases the risk of poor wound healing (PWH) due to the impact on the blood supply to the flap. We aimed to analyze risk factors for PWH in MMD with a complete Y-shaped incision. A total of 125 patients with MMD were enrolled in this prospective observational study. The wounds were assessed and measured on the third and seventh days after surgery. The mean age of these patients was 43.3 ± 10.0 years. The ratio of male to female was 1:1.3. 15 (12.0%) patients had incision complications. 5 patients (4.0%) had redness; 2 patients (1.6%) had swelling; 2 patients (1.6%) had fat necrosis; 3 patients (2.4%) had incision infection; and 3 patients (2.4%) had flap necrosis. Student’s t test showed significant differences in BMI (P = 0.040) and fever time (P = 0.050). The standard chi-squared test showed significant differences in incision infection (P = 0.010), suture mode (P = 0.047), and cutting off large branch vessels in the flap (P

Mueller matrix imaging is emerging for the quantitative characterization of pathological microstructures and is especially sensitive to fibrous structures. Liver fibrosis is a characteristic of many types of chronic liver diseases. The clinical diagnosis of liver fibrosis requires time-consuming multiple staining processes that specifically target on fibrous structures. The staining proficiency of technicians and the subjective visualization of pathologists may bring inconsistency to clinical diagnosis. Mueller matrix imaging can reduce the multiple staining processes and provide quantitative diagnostic indicators to characterize liver fibrosis tissues. In this study, a fiber-sensitive polarization feature parameter (PFP) was derived through the forward sequential feature selection (SFS) and linear discriminant analysis (LDA) to target on the identification of fibrous structures. Then, the Pearson correlation coefficients and the statistical T-tests between the fiber-sensitive PFP image textures and the liver fibrosis tissues were calculated. The results show the gray level run length matrix (GLRLM)-based run entropy that measures the heterogeneity of the PFP image was most correlated to the changes of liver fibrosis tissues at four stages with a Pearson correlation of 0.6919. The results also indicate the highest Pearson correlation of 0.9996 was achieved through the linear regression predictions of the combination of the PFP image textures. This study demonstrates the potential of deriving a fiber-sensitive PFP to reduce the multiple staining process and provide textures-based quantitative diagnostic indicators for the staging of liver fibrosis.

ObjectiveThis study aimed to explore the hemodynamic changes before and after anastomosis in patients with Moyamoya disease (MMD) using multiple models.MethodsWe prospectively enrolled 42 MMD patients who underwent combined revascularization. Intraoperative FLOW800 was performed before and after anastomosis, and parameters was collected, including maximum intensity, delay time, rise time, slope, blood flow index, and microvascular transit time (MVTT). Additionally, preoperative and postoperative hemodynamic parameters were measured using color Doppler ultrasonography (CDUS), including peak systolic velocity, end-diastolic velocity, resistance index (RI), pulsatility index (PI), and flow volume. Subsequently, the correlation between FLOW800 and CDUS parameters was explored.ResultsA total of 42 participants took part with an average age of 46.5 years, consisting of 19 men and 23 women. The analysis of FLOW800 indicated that both the delay time and rise time experienced a substantial decrease in both the recipient artery and vein. Additionally, the MVTT was found to be significantly reduced after the surgery (5.7 ± 2.2 s vs. 4.9 ± 1.6, p = 0.021). However, no statistically significant differences were observed among the other parameters. Similarly, all postoperative parameters in CDUS hemodynamics exhibited significant alterations in comparison to the preoperative values. The correlation analysis between FLOW800 and CDUS parameters indicated a significant association between MVTT and RI and PI, no significant relationships were found among the other parameters in the two groups.ConclusionThe hemodynamic outcomes of the donor and recipient arteries demonstrated significant changes following bypass surgery. The parameter of time appears to be more precise and sensitive in assessing hemodynamics using FLOW800. Multiple evaluations of hemodynamics could offer substantial evidence for perioperative management.

IntroductionAccurate delineation of tumor targets is crucial for stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC). This study aims to develop a deep learning-based segmentation approach to accurately and efficiently delineate NSCLC targets using diagnostic PET-CT and SBRT planning CT (pCT).MethodsThe diagnostic PET was registered to pCT using the transform matrix from registering diagnostic CT to the pCT. We proposed a 3D-UNet-based segmentation method to segment NSCLC tumor targets on dual-modality PET-pCT images. This network contained squeeze-and-excitation and Residual blocks in each convolutional block to perform dynamic channel-wise feature recalibration. Furthermore, up-sampling paths were added to supplement low-resolution features to the model and also to compute the overall loss function. The dice similarity coefficient (DSC), precision, recall, and the average symmetric surface distances were used to assess the performance of the proposed approach on 86 pairs of diagnostic PET and pCT images. The proposed model using dual-modality images was compared with both conventional 3D-UNet architecture and single-modality image input.ResultsThe average DSC of the proposed model with both PET and pCT images was 0.844, compared to 0.795 and 0.827, when using 3D-UNet and nnUnet. It also outperformed using either pCT or PET alone with the same network, which had DSC of 0.823 and 0.732, respectively.DiscussionTherefore, our proposed segmentation approach is able to outperform the current 3D-UNet network with diagnostic PET and pCT images. The integration of two image modalities helps improve segmentation accuracy.

Abstract Objective Standard medical treatment for early non‐small cell lung cancer (NSCLC) is surgery; however, stereotactic body radiotherapy (SBRT) can be a viable substitute for elderly patients who can no longer tolerate or refuse surgery. The unsurpassed care for elderly patients with early NSCLC remains inconclusive. We conducted a propensity‐score matching analysis to compare the efficacy and side‐effects of SBRT and video‐assisted thoracic surgery (VATS) in elderly patients with pathologically‐proven early NSCLC. Methods This single‐institution retrospective study included 310 elderly patients who underwent VATS (n = 180) or SBRT (n = 130) from January 2011 to November 2018 at the Tianjin Medical University Cancer Institute and Hospital. Sex, performance status, pathology type, Charlson Comorbidity Index, and T‐stage according to the eighth tumor node metastasis classification were considered when performing propensity‐score matching. Results After propensity‐score matching, 71 patients were included in each group for analysis. A median follow‐up period of 53.5 months was observed for all patients; 72 and 53 months for patients undergoing VATS and SBRT, respectively. Overall survival (p = 0.492), progression‐free survival (p = 0.294), locoregional recurrence‐free survival (p = 0.866), and distant metastasis‐free survival (p = 0.452) did not differ significantly between the VATS and SBRT groups. Multivariate analysis showed a significant correlation between the T‐stage and overall survival. However, treatment‐related toxicity was lower in the SBRT group than in the VATS group. Conclusions SBRT is an option comparable with surgery for elderly patients with pathologically‐proven early‐stage NSCLC.

Context Yi-Qi Cong-Ming (YQCM) decoction has been widely used to prevent age-related hearing loss (ARHL), the most prevalent neurodegenerative disease in the elderly.Objective To explore the mechanism of YQCM decoction in the treatment of ARHL.Materials and methods The chemical constituents of YQCM were screened from the Traditional Chinese Medicine Systems Pharmacology Database. Potential targets of YQCM against ARHL were predicted by DrugBank, GeneCards, and OMIM database. Protein-protein network and enrichment analysis were used for exploring possible molecular mechanisms. Molecular docking and an in vitro model of ARHL by exposing auditory cells with 100 μM H2O2 for 3 h were applied. Cell viability and mitochondrial membrane potential (ΔΨM) were detected by CCK-8 and high-content analysis. γH2AX and cleaved caspase-3 were detected by Western blot.Results The main compounds have good affinities with hub targets, especially AKT1, PTGS2, and CASP3. GO and KEGG analysis showed that the main biological process and key targets were related to negative regulation of the apoptotic process. H2O2 treatment could reduce the cell viability by 68% and impaired ΔΨM, while 90 μg/mL YQCM pre-treatment could restore the cell viability by 97.45% and increase ΔΨM (2-fold higher). YQCM pre-treatment also reduced γH2AX and cleaved caspase-3 protein levels.Conclusions Our study suggested that YQCM prevents ARHL by modulating the apoptosis process in auditory hair cells. Moreover, this study proved that bioinformatics analysis combined with molecular docking and cell model is a promising method to explore other possible pharmacological interventions of ARHL.

Abstract Background Recurrent bladder cancer is the most common type of urinary tract malignancy; nevertheless, the mechanistic basis for its recurrence is uncertain. Innovative technologies such as single‐cell transcriptomics and spatial transcriptomics (ST) offer new avenues for studying recurrent tumour progression at the single‐cell level while preserving spatial data. Method This study integrated single‐cell RNA (scRNA) sequencing and ST profiling to examine the tumour microenvironment (TME) of six bladder cancer tissues (three from primary tumours and three from recurrent tumours). Findings scRNA data‐based ST deconvolution analysis revealed a much higher tumour heterogeneity along with TME in recurrent tumours than in primary tumours. High‐resolution ST analysis further identified that while the overall natural killer/T cell and malignant cell count or the ratio of total cells was similar or even lower in the recurrent tumours, a higher interaction between epithelial and immune cells was detected. Moreover, the analysis of spatial communication reveals a marked increase in activity between cancer‐associated fibroblasts (CAFs) and malignant cells, as well as other immune cells in recurrent tumours. Interpretation We observed an enhanced interplay between CAFs and malignant cells in bladder recurrent tumours. These findings were first observed at the spatial level.

Objectives: Plasmacytoid dendritic cells (pDCs) play a crucial role in the microenvironment of tumor. Evidences has been shown that chemokine receptor 9 (CCR9) is an important molecule that attracts pDCs homing to the digestive tract and the latter are involved in the formation of digestive tract immune tolerance. The aim of this study was to explore the role of CCR9-CCL25 interaction in pDC-mediated immunosuppression microenvironment of gastric cancer (GC). Materials and methods: Regulatory T cells (Tregs) and pDCs were detected by immunohistochemistry. CCR9, which expressed on pDC was visualized by immunofluorescence. Western Blot was applied to evaluate the expression of CCL-25. Total pDCs, CCR9+pDCs, CCR9−pDCs, total Tregs, inducible costimulator + (ICOS) Tregs and ICOS−Tregs in peripheral blood and draining lymph nodes were analyzed by flow cytometry. Plasma concentration of the cytokines were measured by enzyme-linked immunosorbent assay Results: Total Tregs, pDCs and CCR9+pDCs were higher in GC tissue. CCL-25 was over-expressed in carcinoma tissue. Peripheral total pDCs, CCR9−pDCs, total Tregs, ICOS+ Tregs, ICOS− Tregs were significantly increased in GC patients. More total pDCs, CCR9+ pDCs, total Tregs, ICOS+ Tregs were found in metastatic lymph nodes. Plasma concentrations of IL-6 and IL-10 were significantly higher in GC patients. More CCR9+ pDCs were found infiltrating carcinoma tissue in patients with later T staging and lymph node metastasis and conferred a poor prognosis. Conclusion: CCR9-CCL25 interaction might play an important role in mediating PDC homing to metastatic lymph nodes and carcinoma tissue, which contributed to the formation of tumor immunosuppressive microenvironment and poor prognosis.

In clinic, controlling acute coagulation after small-diameter vessel grafts transplantation is considered a primary problem. The combination of heparin with high anticoagulant efficiency and polyurethane fiber with good compliance is a good choice for vascular materials. However, blending water-soluble heparin with fat-soluble poly (ester-ether-urethane) urea elastomer (PEEUU) uniformly and preparing nanofibers tubular grafts with uniform morphology is a huge challenge. In this research, we have compounded PEEUU with optimized constant concentration of heparin by homogeneous emulsion blending, then spun into the hybrid PEEUU/heparin nanofibers tubular graft (H-PHNF) for replacing rats’ abdominal aorta in situ for comprehensive performance evaluation. The in vitro results demonstrated that H-PHNF was of uniform microstructure, moderate wettability, matched mechanical properties, reliable cytocompatibility, and strongest ability to promote endothelial growth. Replacement of resected abdominal artery with the H-PHNF in rat showed that the graft was capable of homogeneous hybrid heparin and significantly promoted the stabilization of vascular smooth muscle cells (VSMCs) as well as stabilizing the blood microenvironment. This research demonstrates the H-PHNF with substantial patency, indicating their potential for vascular tissue engineering.

Objective: This study aimed to identify immune infiltration characteristics and new immunological diagnostic biomarkers in the cerebrovascular tissue of moyamoya disease (MMD) using bioinformatics analysis.Methods: GSE189993 and GSE141022 were downloaded from the GEO database. Differentially expressed gene and PPI analysis were performed. After performing WGCNA, the most significant module associated with MMD was obtained. Next, functional pathways according to GSEA, GO, and KEGG were enriched for the aforementioned core genes obtained from PPI and WGCNA. Additionally, immune infiltration, using the CIBERSORT deconvolution algorithm, immune-related biomarkers, and the relationship between these genes, was further explored. Finally, diagnostic accuracy was verified with ROC curves in the validation dataset GSE157628.Results: A total of 348 DEGs were screened, including 89 downregulated and 259 upregulated genes. The thistlel module was detected as the most significant module associated with MMD. Functional analysis of the core genes was chiefly involved in the immune response, immune system process, protein tyrosine kinase activity, secretory granule, and so on. Among 13 immune-related overlapping genes, 4 genes (BTK, FGR, PTPN11, and SYK) were identified as potential diagnostic biomarkers, where PTPN11 showed the highest specificity and sensitivity. Meanwhile, a higher proportion of eosinophils, not T cells or B cells, was demonstrated in the specific immune infiltration landscape of MMD.Conclusion: Immune activities and immune cells were actively involved in the progression of MMD. BTK, FGR, PTPN11, and SYK were identified as potential immune diagnostic biomarkers. These immune-related genes and cells may provide novel insights for immunotherapy in the future.

Ischemic stroke (IS), resulting from the occlusion of the cerebral artery and subsequent interruption of blood flow, represents a major and critical threat to public health. Oxidative stress (OS) has been confirmed to play a role in the IS pathological process and neural death. Understanding the essential role of OS-related genes in ischemic stroke is critical to understanding the current perception of the pathophysiological process in IS. Herein, by integrating three IS datasets (GSE16561, GSE22255, and GSE58294), we divided IS samples into the low- and high-OS groups by calculating the OS score identified by the oxidative stress gene set. The functional enrichment analysis of differentially expressed genes (DEGs) between the low- and high-OS groups indicated that DEGs were associated with hypoxia, the inflammatory response, and oxidative phosphorylation pathways. Furthermore, nine hub genes (namely TLR1, CXCL1, MMP9, TLR4, IL1R2, EGR1, FOS, CXCL10, and DUSP1) were identified through the Girvan–Newman algorithm and cytoHubba algorithms. Nine hub genes were highly expressed in IS samples and positively related to neutrophils and macrophages. Drug-sensitive analysis targeting hub genes defined allopurinol and nickel sulfate as potential candidates for impairing the neural death caused by oxidative stress in IS. Finally, we employed five machine learning methods to check the efficacy of the predictive model identified by nine hub genes. The results showed that our model had superior power for predicting the OS activity of IS patients. TLR4 was found to have excellent diagnostic value and a wide-spectrum interaction with other hub genes. Our research emphasized the impact of oxidative stress on ischemic stroke, which supports the idea that antioxidants hold great promise in ischemic stroke therapy.

Abstract To investigate the value of the radiomic models for differentiating parasellar cavernous hemangiomas from meningiomas and to compare the classification performance with different MR sequences and classifiers. A total of 96 patients with parasellar tumors (40 cavernous hemangiomas and 56 meningiomas) were enrolled in this retrospective multiple-center study. Univariate and multivariate analyses were performed to identify the clinical factors and semantic features of MRI scans. Radiomics features were extracted from five MRI sequences using radiomics software. Three feature selection methods and six classifiers were evaluated in the training cohort to construct favorable radiomic machine-learning classifiers. The performance of different classifiers was evaluated using the AUC and compared to neuroradiologists. The detection rates of T1WI, T2WI, and CE-T1WI for parasellar cavernous hemangiomas and meningiomas were approximately 100%. In contrast, the ADC maps had the detection rate of 18/22 and 19/25, respectively, (AUC, 0.881) with 2.25 cm as the critical value diameter. Radiomics models with the SVM and KNN classifiers based on T2WI and ADC maps had favorable predictive performances (AUC > 0.90 and F-score value > 0.80). These models outperformed MRI model (AUC 0.805) and neuroradiologists (AUC, 0.756 and 0.545, respectively). Radiomic models based on T2WI and ADC and combined with SVM and KNN classifiers have the potential to be a viable method for differentiating parasellar hemangiomas from meningiomas. T2WI is more universally applicable than ADC values due to its higher detection rate for parasellar tumors.

Abstract Background Bladder cancer (BC) seriously endangers public health, but effective biomarkers for BC diagnosis, particularly in the early stage, are still lacking. Identification of reliable biomarkers associated with early-stage BC is of great importance to early treatment and an improved outcome. Methods Differentially expressed genes (DEGs) were identified using four publicly available early-stage BC gene-expression profiles. Protein–protein interaction (PPI) and survival analysis for hub genes was evaluated. The correlation between methylation of genes and prognosis was evaluated using the MethSurv database. Co-expressed genes were explored using Cancer Cell Line Encyclopedia database and the corresponding expression were assessed in vitro. The competing endogenous RNA network and the immune cell infiltration in BC were generated using data of The Cancer Genome Atlas. Results Ten hub genes of the 213 integrated DEGs were identified, including CDH1, IGFBP3, PPARG, SDC1, EPCAM, ACTA2, COL3A1, TPM1, ACTC1, and ACTN1. CDH1 appeared to increase from tumor initiation stage and negatively correlated with methylation. Six methylated sites in CDH1 indicated a good prognosis and one site indicated an aberrant prognosis. High CDH1 expression was negatively correlated with infiltrations by most immune cells, such as plasmacytoid dendritic cells (pDCs), regulatory T cells, macrophages, neutrophils, DCs, and natural killer cells. CDH1 was highly positively correlated with EPCAM and appeared to be directly regulated by miR-383. Conclusions The identified oncogenic alterations provide theoretical support for the development of novel biomarkers to advance early-stage BC diagnosis and personalized therapy.

Abstract Hexagonal boron nitride (hBN) has recently been demonstrated to contain optically polarized and detected electron spins that can be utilized for implementing qubits and quantum sensors in nanolayered-devices. Understanding the coherent dynamics of microwave driven spins in hBN is of crucial importance for advancing these emerging new technologies. Here, we demonstrate and study the Rabi oscillation and related phenomena of a negatively charged boron vacancy (V $${}_{{{{{{{{\rm{B}}}}}}}}}^{-}$$ B − ) spin ensemble in hBN. We report on different dynamics of the V $${}_{{{{{{{{\rm{B}}}}}}}}}^{-}$$ B − spins at weak and strong magnetic fields. In the former case the defect behaves like a single electron spin system, while in the latter case it behaves like a multi-spin system exhibiting multiple-frequency dynamical oscillation as beat in the Ramsey fringes. We also carry out theoretical simulations for the spin dynamics of V $${}_{{{{{{{{\rm{B}}}}}}}}}^{-}$$ B − and reveal that the nuclear spins can be driven via the strong electron nuclear coupling existing in V $${}_{{{{{{{{\rm{B}}}}}}}}}^{-}$$ B − center, which can be modulated by the magnetic field and microwave field.

Objective: Multiple brain metastases are a severe condition for cancer patients. To date, no general consensus exists regarding the optimal treatment procedure for multiple brain metastases. Radiotherapy is the most commonly used treatment option. The role of surgical resection for multiple brain metastases is unclear. The aim of this study was to compare the outcomes of patients with multiple brain metastases treated with either surgery or stereotactic radiosurgery (SRS). Methods: The medical records of 279 consecutive adult patients with multiple brain metastases treated with either surgery (26 patients) or SRS (253 patients) were retrospectively reviewed. Propensity score matching was conducted to correct for discrepancies in the baseline characteristics, and 78 patients (26 receiving surgery and 52 receiving SRS) were chosen for comparison of outcomes, such as overall survival, local tumor control rate, and symptom improvement. Results: The tumor size in the surgery group was significantly greater than that in the SRS group after propensity score matching. However, the neurological recovery rate, incidence of leptomeningeal metastasis after surgery, 1-year local tumor control rate, and overall survival were not significantly different between groups. Conclusions: Our data demonstrate that surgery and radiosurgery have identical overall survival and local tumor control rates in patients with 2 to 4 brain metastases. Although SRS remains the primary and standard option for patients with brain metastasis, surgery offers several distinct advantages, such as establishing a diagnosis or relieving mass effects, and may additionally be beneficial in carefully selected patients with 2–4 brain metastases.

Gear transmission characteristics are the most important research contents in gear transmission, and contact characteristics are important factors that affect gear transmission performance. The establishment of tooth surface contact analysis (TCA) model of a gear pair plays a guiding role in analyzing its contact characteristics. The rotary surface equation of the variable hyperbolic circular-arc-tooth-trace (VH-CATT) cylindrical gear cutter is obtained with the large cutter forming principle, and the mathematical model of the gear tooth surface is established based on the gear meshing conditions. With the influence of installation error on gear contact performance considered, a TCA model with installation error was established. The influence of different installation errors and different design parameters on the geometric contact characteristics and sensitivity of the gear pair is analyzed. The analysis results show that the central distance error may affect the contact ratio of the VH-CATT cylindrical gear pair and that the shaft parallelism error has a great influence on its transmission characteristics, greatly changing the size and position of the gear pair contact area. The design parameters also affect the size and location of the contact area to various degrees.

Summary: Much progress has been made toward generating analogs of early embryos, such as gastruloids and embryoids, in vitro. However, methods for how to fully mimic the cell movements of gastrulation and coordinate germ-layer patterning to induce head formation are still lacking. Here, we show that a regional Nodal gradient applied to zebrafish animal pole explant can generate a structure that recapitulates the key cell movements of gastrulation. Using single-cell transcriptome and in situ hybridization analysis, we assess the dynamics of the cell fates and patterning of this structure. The mesendoderm differentiates into the anterior endoderm, prechordal plate, notochord, and tailbud-like cells along an anterior-posterior axis, and an anterior-posterior-patterned head-like structure (HLS) progressively forms during late gastrulation. Among 105 immediate Nodal targets, 14 genes contain axis-induction ability, and 5 of them induce a complete or partial head structure when overexpressed in the ventral side of zebrafish embryos.

Excitatory amino acid transporter 1 (EAAT1) is a glutamate transporter belonging to the SLC1 family of solute carriers. It plays a key role in the regulation of the extracellular glutamate concentration in the mammalian brain. The structure of EAAT1 was determined in complex with UCPH-101, apotent, non-competitive inhibitor of EAAT1. Alanine serine cysteine transporter 2 (ASCT2) is a neutral amino acid transporter, which regulates pools of amino acids such as glutamine between intracellular and extracellular compartments . ASCT2 also belongs to the SLC1 family and shares 58% sequence similarity with EAAT1. However, allosteric modulation of ASCT2 via non-competitive inhibitors is unknown. Here, we explore the UCPH-101 inhibitory mechanisms of EAAT1 and ASCT2 by using rapid kinetic experiments. Our results show that UCPH-101 slows substrate translocation rather than substrate or Na+ binding, confirming a non-competitive inhibitory mechanism, but only partially inhibits wild-type ASCT2. Guided by computational modeling using ligand docking and molecular dynamics simulations, we selected two residues involved in UCPH-101/EAAT1 interaction, which were mutated in ASCT2 (F136Y, I237M, F136Y/I237M) in the corresponding positions. We show that in the F136Y/I237M double-mutant transporter, 100% of the inhibitory effect of UCPH-101 could be restored, and the apparent affinity was increased (Ki = 4.3 μM), much closer to the EAAT1 value of 0.6 μM. Finally, we identify a novel non-competitive ASCT2 inhibitor, through virtual screening and experimental testing against the allosteric site, further supporting its localization. Together, these data indicate that the mechanism of allosteric modulation is conserved between EAAT1 and ASCT2. Due to the difference in binding site residues between ASCT2 and EAAT1, these results raise the possibility that more potent, and potentially selective ASCT2 allosteric inhibitors can be designed .

The study aimed to examine the cohesive tie effect on reading comprehension through the grammatical knowledge cognition process. The present meta-analysis examined the correlation between grammatical knowledge and reading comprehension based on empirical results published between 1998 and 2021. This study selected 86 studies with a total of 14,852 readers whose grades were grouped from primary school to university. The results showed that the overall correlation effect size between grammatical knowledge and reading comprehension was large, and the significant interaction effect of the grade group was confirmed through moderator analysis. The results suggested that the grammatical knowledge’s function of the cohesive tie has a transfer effect across different text comprehension scripts.

Laser altimetry data from the Ice, Cloud, and land Elevation Satellite-2 (ICESat-2) contain a lot of noise, which necessitates the requirement for a signal photon extraction method. In this study, we propose a density clustering method, which combines slope and elevation information from optical stereo images and adaptively adjusts the neighborhood search direction in the along-track direction. The local classification density threshold was calculated adaptively according to the uneven spatial distribution of noise and signal density, and reliable surface signal points were extracted. The performance of the algorithm was validated for strong and weak beam laser altimetry data using optical stereo images with different resolutions and positioning accuracies. The results were compared qualitatively and quantitatively with those obtained using the ATL08 algorithm. The signal extraction quality was better than that of the ATL08 algorithm for steep slope and low signal-to-noise ratio (SNR) regions. The proposed method can better balance the relationship between recall and precision, and its F1-score was higher than that of the ATL08 algorithm. The method can accurately extract continuous and reliable surface signals for both strong and weak beams among different terrains and land cover types.

Background: We aimed to investigate the association of free thyroxin (FT4), free triiodothyronine (FT3), subclinical hypothyroidism (SCH), and thyroid peroxidase antibody (TPOab) in the first trimester with gestational diabetes mellitus (GDM). Methods: We recruited 110 pregnant women with GDM and 100 pregnant women without GDM who had normal 75 g oral glucose tolerance test (OGTT) results between June 2019 and June 2021. We collected basic data from all participants and compared serum FT3 and FT4 levels, SCH, and TPOab (+) incidences in the first trimester between the two groups. We used logistic regression to identify factors that influence the development of GDM. Results: Serum FT3 levels were 4.58 ± 0.78 and 4.61 ±1.42 pmol/L in the GDM group and Control group, while FT4 levels were 9.32 ± 2.54 and 10.24 ± 2.77 pmol/L. The incidence of SCH were 25.5% and 14.0%, while TPO (+) were 20.0% and 10.0%. The GDM group’s FT4 levels were significantly lower than the control group’s, whereas the GDM group’s age, incidence of SCH, and TPOab (+) were significantly higher (p < 0.05). Logistic regression analysis demonstrated that age, SCH and TPO (+) were risk factors for GDM (p < 0.05), the regression equation: logit p = –3.484 + 0.105 (age) + 1.128 (SCH) + 1.294 (TPOab (+)). Conclusions: Our findings suggest that monitoring the changes in FT4 levels, SCH, and TPOab (+) incidence in the first trimester may be useful in predicting the occurrence and development of GDM.

Aiming at the problem of chemical-mechanics-hydro (C-M-H) action encountered by rocks in underground engineering, chemical damage variables, water damage variables, and force damage variables are introduced to define the degree of degradation of rock materials. Stone is selected as the sample for acid corrosion treatment at pH 3, 4, and 7, and a chemical damage factor is defined that coupled the pH value and duration of exposure. Then based on the spatial mobilized plane (SMP) criterion and the Lemaitre strain equivalence hypothesis, this research develops a constitutive model considering rock chemical corrosion-water-confining pressure damage. The proposed damage constitutive model employs the extremum method to ascertain the two Weibull distribution parameters (m and F0) by theoretical derivation and exhibits satisfactory conformity between the theoretical and experimental curves. The damage constitutive model can be consistent in the stress–strain characteristics of the rock triaxial compression process, which verifies the rationality and reliability of the model parameters. The model effectively represents the mechanical properties and damage characteristics of rocks when subjected to the combined influence of water chemistry and confinement. The presented model contributes to a better understanding of tangible rock-engineered structures subjected to chemical corrosion in underwater environments.

Abstract Pediatric airway management is a huge challenge for anaesthetists, and airway-related complications should be actively addressed and focused on.

Abstract Angiopoietin-like-4 (ANGPTL4), a secreted glycoprotein that is mainly known as a regulator in lipid metabolism, now, is also indicated to be involved in the regulation of cancer progression and metastasis. However, little is known about not only biological functions, but also underlying mechanism of ANGPTL4 in the progression of osteosarcoma (OS). Here, we discovered that ANGPTL4 is downregulated in OS, and is associated with branched-chain amino acid (BCAA) metabolism. The BCAAs (valine, leucine, and isoleucine) are essential amino acids that play an important role in metabolic regulation. Aberrant BCAA metabolism is also found in various cancers and is associated with tumor progression, including proliferation, invasion, and metastasis. In this study, we indicated that the negative relation between the expression of ANGPTL4 and BCAA catabolism in OS samples and cell lines. The knockdown of ANGPTL4 in OS cells resulted in the accumulation of BCAAs, which in turn activated the mTOR signaling pathway, enhancing OS cell proliferation. Thus, reduced expression of ANGPTL4 is associated with the progression of OS. Taken together, our results demonstrated that the ANGPTL4/BCAA/mTOR axis is an important pathway in OS progression and may be a potential therapeutic target to slow OS progression.

Abstract Detection of weak moving targets with a low signal‐to‐clutter ratio (SCR) in heavy‐tailed non‐Gaussian sea clutter is a challenge problem in radar signal processing. In this study, an easily implementable suboptimum detector in compound‐Gaussian (CG) clutter is proposed based on suprathreshold stochastic resonance (SSR). The structure of the locally optimum coherent detector for weak target detection in CG clutter is first analysed and the authors proved that it can be implemented using a pre‐processing system followed by the adaptive matched filter (AMF) used in Gaussian backgrounds. A suboptimum pre‐processing system is designed using the SSR system consisting of a parallel array of quantisers, which overcomes the high computation cost caused by the calculation of the data‐dependent threshold for optimum detectors. Its input–output characteristic can be adjusted by adding different quantiser noise at the input of the system, making it suitable to be used for different distributions of input clutter. The gain of the SSR pre‐processing system is introduced and the parameter determination for quantiser noise is analysed. Experiments on both simulated clutter and real sea clutter data in the Council for Scientific and Industrial Research's database and Intelligent PIXel Grimsby database have shown that the proposed detector based on SSR could achieve robust detection performance and perform better than the existing methods.