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Abstract Bladder cancer (BCa) stands out as a highly prevalent malignant tumor affecting the urinary system. The Sex determining region Y-box protein family is recognized for its crucial role in BCa progression. However, the effect of Sex determining region Y-box 7 (SOX7) on BCa progression has not been fully elucidated. Herein, RNA-sequencing, western blot (WB), immunohistochemistry (IHC), immunofluorescence (IF) and tissue microarray were utilized to assess SOX7 expression in vitro and in vivo. Additionally, SOX7 expression, prognosis, and SOX7 + cytoglobin (CYGB) score were analyzed using R software. In vitro and vivo experiments were performed with BCa cell lines to validate the effect of SOX7 knockdown and overexpression on the malignant progression of BCa. The results showed that SOX7 exhibits low expression in BCa. It functions in diverse capacities, inhibiting the proliferative, migratory, and invasive capabilities of BCa. In addition, the experimental database demonstrated that SOX7 binds to the promoter of DNA methyltransferase 3 beta (DNMT3B), leading to the transcriptional inhibition of DNMT3B. This subsequently results in a reduced methylation of CYGB promoter, ultimately inhibiting the tumor progression of BCa. SOX7 + CYGB scores were significantly linked to patient prognosis. In conclusion, SOX7 inhibits the malignant progression of BCa via the DNMT3B/CYGB axis. Additionally, the SOX7 + CYGB score is capable of predicting the prognostic outcomes of BCa patients. Therefore, SOX7 and CYGB may play an important role in the progression of bladder cancer, and they can be used as prognostic markers of bladder cancer patients.

Abstract Acute pancreatitis (AP) is a multifaceted inflammatory disorder stemming from the aberrant activation of trypsin within the pancreas. Despite the contribution of various factors to the pathogenesis of AP, such as trypsin activation, dysregulated increases in cytosolic Ca2+ levels, inflammatory cascade activation, and mitochondrial dysfunction, the precise molecular mechanisms underlying the disease are still not fully understood. Mitophagy, a cellular process that preserves mitochondrial homeostasis under stress, has emerged as a pivotal player in the context of AP. Research suggests that augmenting mitophagy can mitigate pancreatic injury by clearing away malfunctioning mitochondria. Elucidating the role of mitophagy in AP may pave the way for novel therapeutic strategies. This review article aims to synthesize the current research findings on mitophagy in AP and underscore its significance in the clinical management of the disorder.

Abstract High-power terahertz (THz) quantum cascade laser, as an emerging THz solid-state radiation source, is attracting attention for numerous applications including medicine, sensing, and communication. However, due to the sub-wavelength confinement of the waveguide structure, direct beam brightness upscaling with device area remains elusive due to several mode competition and external optical lens is normally used to enhance the THz beam brightness. Here, we propose a metallic THz photonic crystal resonator with a phase-engineered design for single mode surface emission over a broad area. The quantum cascade surface-emitting laser is capable of delivering an output peak power over 185 mW with a narrow beam divergence of 4.4° × 4.4° at 3.88 THz. A high beam brightness of 1.6 × 107 W sr−1m−2 with near-diffraction-limited M2 factors of 1.4 in both vertical and lateral directions is achieved from a large device area of 1.6 × 1.6 mm2 without using any optical lenses. The adjustable phase shift between the lattices enables a stable and high-intensity surface emission over a broad device area, which makes it an ideal light extractor for large-scale THz emitters. Our research paves the way to high brightness solid-state THz lasers and facilitates new applications in standoff THz imaging, detection, and diagnosis.

Abstract Background ATPase activity and the antioxidant function of intestinal tissue can reflect intestinal cell metabolic activity and oxidative damage, which might be related to intestinal function. However, the specific influence of intestinal ATPase activity and antioxidant function on growth performance, feed conversion efficiency, and the intestinal microbiota in sheep remains unclear. Results This study analyzed the correlation between ATPase activity and antioxidant function in the jejunum of 92 Hu sheep and their growth performance and feed conversion efficiency. Additionally, individuals with the highest (H group) and lowest (L group) jejunum MDA content and Na+ K+-ATPase activity were further screened, and the effects of jejunum ATPase activity and MDA content on the morphology and microbial community of sheep intestines were analyzed. There was a significant correlation between jejunum ATPase and SOD activity and the initial weight of Hu sheep (P < 0.01). The H-MDA group exhibited significantly higher average daily gain (ADG) from 0 to 80 days old and higher body weight (BW) after 80 days. ATPase and SOD activities, and MDA levels correlated significantly and positively with heart weight. The jejunum crypt depth and circular muscle thickness in the H-ATP group were significantly higher than in the L-ATP group, and the villus length, crypt depth, and longitudinal muscle thickness in the H-MDA group were significantly higher than in the L-MDA group (P < 0.01). High ATPase activity and MDA content significantly reduced the jejunum microbial diversity, as indicated by the Chao1 index and observed species, and affected the relative abundance of specific taxa. Among species, the relative abundance of Olsenella umbonata was significantly higher in the H-MDA group than in the L-MDA group (P < 0.05), while Methanobrevibacter ruminantium abundance was significantly lower than in the L-MDA group (P < 0.05). In vitro culture experiments confirmed that MDA promoted the proliferation of Olsenella umbonata. Thus, ATPase and SOD activities in the jejunum tissues of Hu sheep are predominantly influenced by congenital factors, and lambs with higher birth weights exhibit lower Na+ K+-ATPase, Ca2+ Mg2+-ATPase, and SOD activities. Conclusions The ATPase activity and antioxidant performance of intestinal tissue are closely related to growth performance, heart development, and intestinal tissue morphology. High ATPase activity and MDA content reduced the microbial diversity of intestinal tissue and affect the relative abundance of specific taxa, representing a potential interaction between the host and its intestinal microbiota.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a major thread to the global swine industry, lack of effective control strategies. This study explores the regulatory role of a small non-coding RNA, miR-191-5p, in PRRSV infection. We observed that miR-191-5p significantly inhibits PRRSV in porcine alveolar macrophages (PAMs), contrasting with negligible effects in MARC-145 and HEK293-CD163 cells, suggesting a cell-specific antiviral effect. Further investigation unveiled that miR-191-5p directly targets the porcine epidermal growth factor receptor (EGFR), whose overexpression or EGF-induced activation suppresses type I interferon (IFN-I) signaling, promoting PRRSV replication. In contrast, siRNA-or miR-191-5p-induced EGFR downregulation or EGFR inhibitor boosts IFN-I signaling, reducing viral replication. Notably, this miRNA alleviates the suppressive effect of EGF on IFN-I signaling, underscoring its regulatory function. Further investigation revealed interconnections among miR-191-5p, EGFR and signal transducer and activator of transcription 3 (STAT3). Modulation of STAT3 activity influenced IFN-I signaling and PRRSV replication, with STAT3 knockdown countering EGFR activation-induced virus replication. Combination inhibition of STAT3 and miR-191-5p suggests that STAT3 acts downstream in EGFR’s antiviral response. Furthermore, miR-191-5p’s broad efficacy in restricting various PRRSV strains in PAMs was identified. Collectively, these findings elucidate a novel mechanism of miR-191-5p in activating host IFN-I signaling to inhibit PRRSV replication, highlighting its potential in therapeutic applications against PRRSV.

Abstract Topological lasers (TLs) have attracted widespread attention due to their mode robustness against perturbations or defects. Among them, electrically pumped TLs have gained extensive research interest due to their advantages of compact size and easy integration. Nevertheless, limited studies on electrically pumped TLs have been reported in the terahertz (THz) and telecom wavelength ranges with relatively low output powers, causing a wide gap between practical applications. Here, we introduce a surface metallic Dirac-vortex cavity (SMDC) design to solve the difficulty of increasing power for electrically pumped TLs in the THz spectral range. Due to the strong coupling between the SMDC and the active region, robust 2D topological defect lasing modes are obtained. More importantly, enough gain and large radiative efficiency provided by the SMDC bring in the increase of the output power to a maximum peak power of 150 mW which demonstrates the practical application potential of electrically pumped TLs.

Abstract The chemokine CXCL8, also known as the neutrophil chemotactic factor, plays a crucial role in mediating inflammatory responses and managing cellular immune reactions during viral infections. Porcine reproductive and respiratory syndrome virus (PRRSV) primarily infects pulmonary alveolar macrophages (PAMs), leading to acute pulmonary infections. In this study, we explored a novel long non-coding RNA (lncRNA), termed lnc-CAST, situated within the Cxcl8 gene locus. This lncRNA was found to be highly expressed in porcine macrophages. We observed that both lnc-CAST and CXCL8 were significantly upregulated in PAMs following PRRSV infection, and after treatments with lipopolysaccharide (LPS) or lipoteichoic acid (LTA). Furthermore, we noticed a concurrent upregulation of lnc-CAST and CXCL8 expression in lungs of PRRSV-infected pigs. We then determined that lnc-CAST positively influenced CXCL8 expression in PAMs. Overexpression of lnc-CAST led to an increase in CXCL8 production, which in turn enhanced the migration of epithelial cells and the recruitment of neutrophils. Conversely, inhibiting lnc-CAST expression resulted in reduced CXCL8 production in PAMs, leading to decreased migration levels of epithelial cells and neutrophils. From a mechanistic perspective, we found that lnc-CAST, localized in the nucleus, facilitated the enrichment of histone H3K27ac in CXCL8 promoter region, thereby stimulating CXCL8 transcription in a cis-regulatory manner. In conclusion, our study underscores the pivotal critical role of lnc-CAST in regulating CXCL8 production, offering valuable insights into chemokine regulation and lung damage during PRRSV infection.

Abstract The unique physical tumor microenvironment (TME) and aberrant immune metabolic status are two obstacles that must be overcome in cancer immunotherapy to improve clinical outcomes. Here, an in situ mechano‐immunometabolic therapy involving the injection of a biomimetic hydrogel is presented with sequential release of the anti‐fibrotic agent pirfenidone, which softens the stiff extracellular matrix, and small interfering RNA IDO1, which disrupts kynurenine‐mediated immunosuppressive metabolic pathways, together with the multi‐kinase inhibitor sorafenib, which induces immunogenic cell death. This combination synergistically augmented tumor immunogenicity and induced anti‐tumor immunity. In mouse models of clear cell renal cell carcinoma, a single‐dose peritumoral injection of a biomimetic hydrogel facilitated the perioperative TME toward a more immunostimulatory landscape, which prevented tumor relapse post‐surgery and prolonged mouse survival. Additionally, the systemic anti‐tumor surveillance effect induced by local treatment decreased lung metastasis by inhibiting epithelial‐mesenchymal transition conversion. The versatile localized mechano‐immunometabolic therapy can serve as a universal strategy for conferring efficient tumoricidal immunity in “cold” tumor postoperative interventions.

The modular multilevel matrix converter (M3C) is a potential frequency converter for low-frequency AC transmission. However, capacitor voltage control of high-voltage and large-capacity M3C is more difficult, especially for voltage balancing between branches. To solve this problem, this paper defines sequence circulating components and theoretically analyzes the influence mechanism of different sequence circulating components on branch capacitor voltage. A fully decoupled branch energy balancing control method based on four groups of sequence circulating components is proposed. This method can control capacitor voltages of nine branches in horizontal, vertical and diagonal directions. Considering influences of both circulating current and voltage, a cross decoupled control is designed to improve control precision. Simulation results are taken from a low-frequency transmission system based on PSCAD/EMTDC, and effectiveness and precision of the proposed branch energy balancing control method are verified in the case of nonuniform parameters and an unbalanced power system.

Abstract Background Glypican‐3 (GPC3) is highly expressed in testicular yolk sac tumor (TYST). GPC3 has been evaluated as a cancer vaccine for some types of tumors, but little is known on the effects of GPC3 peptide‐based therapy on TYST. Here, we evaluated the antitumor effect of GPC3144‐152 on TYST and its potential mechanisms. Methods GPC3144‐152‐specific CD8+ T cells were induced by vaccine immunization and examined by ELISPOT. The CD8+ T cells were purified for testing their cytotoxicity in vitro against TYST cells by CCK‐8 and TUNEL assays and in vivo against tumor growth. The influence of GPC3144‐152 loading and/or cGAS silencing on the tumor growth, apoptosis and cGAS/STING signaling was tested by immunohistochemistry, immunofluorescence, flow cytometry, and Western blot. Results Vaccination with GPC3144‐152 induced tumor‐specific CD8+ T cells that secreted high levels of IFN‐γ and granzyme B, and had potent cytotoxicity against TYST in a dose‐dependent manner. Adoptive transfer of CD8+ T cells and treatment with GPC3144‐152 significantly inhibited the growth of TYST tumors, but less effective for cGAS‐silenced TYST tumors in vivo. Treatment with GPC3144‐152 enhanced the infiltration of CD8+ T cells into the tumor environment and their cytotoxicity against TYST tumors in vivo by up‐regulating granzyme B and IFN‐β expression, but down‐regulating GPC3 expression in the tumors. Co‐culture of CD8+ T cells with TYST in the presence of exogenous GPC3144‐152 enhanced peptide‐specific CD8+ T‐cell cytotoxicity in vitro, accompanied by enhancing cGAS, γH2AX, TBK1, and IRF3 phosphorylation in TYST cells, but less effective in cGAS‐silenced TYST cells. Conclusions These data indicated that GPC3 peptide‐specific CD8+ T cells had potent antitumor activity against TYST tumor, particularly for combined treatment with the peptide, which was partially dependent on the intratumoral cGAS/STNG signaling. GPC3 peptide vaccine may be valuable for the combination treatment of TYST.

BackgroundEarly research indicates that cancer patients are more vulnerable to adverse outcomes and mortality when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nonetheless, the specific attributes of SARS-CoV-2 in lung Adenocarcinoma (LUAD) have not been extensively and methodically examined.MethodsWe acquired 322 SARS-CoV-2 infection-related genes (CRGs) from the Human Protein Atlas database. Using an integrative machine learning approach with 10 algorithms, we developed a SARS-CoV-2 score (Cov-2S) signature across The Cancer Genome Atlas and datasets GSE72094, GSE68465, and GSE31210. Comprehensive multi-omics analysis, including assessments of genetic mutations and copy number variations, was conducted to deepen our understanding of the prognosis signature. We also analyzed the response of different Cov-2S subgroups to immunotherapy and identified targeted drugs for these subgroups, advancing personalized medicine strategies. The expression of Cov-2S genes was confirmed through qRT-PCR, with GGH emerging as a critical gene for further functional studies to elucidate its role in LUAD.ResultsOut of 34 differentially expressed CRGs identified, 16 correlated with overall survival. We utilized 10 machine learning algorithms, creating 101 combinations, and selected the RFS as the optimal algorithm for constructing a Cov-2S based on the average C-index across four cohorts. This was achieved after integrating several essential clinicopathological features and 58 established signatures. We observed significant differences in biological functions and immune cell statuses within the tumor microenvironments of high and low Cov-2S groups. Notably, patients with a lower Cov-2S showed enhanced sensitivity to immunotherapy. We also identified five potential drugs targeting Cov-2S. In vitro experiments revealed a significant upregulation of GGH in LUAD, and its knockdown markedly inhibited tumor cell proliferation, migration, and invasion.ConclusionOur research has pioneered the development of a consensus Cov-2S signature by employing an innovative approach with 10 machine learning algorithms for LUAD. Cov-2S reliably forecasts the prognosis, mirrors the tumor’s local immune condition, and supports clinical decision-making in tumor therapies.

Lactic acid bacteria (LAB) belong to a significant group of probiotic bacteria that provide hosts with considerable health benefits. Our previous study showed that pigs with abundant LAB had more robust immune responses in a vaccination experiment. In this study, 52 isolate strains were isolated from the pigs with superior immune responses. Out of these, 14 strains with higher antibacterial efficacy were chosen. We then assessed the probiotic features of the 14 LAB strains, including such as autoaggregation, coaggregation, acid resistance, bile salt resistance, and adhesion capability, as well as safety aspects such as antibiotic resistance, hemolytic activity, and the presence or absence of virulence factors. We also compared these properties with those of an opportunistic pathogen EB1 and two commercial probiotics (cLA and cLP). The results showed that most LAB isolates exhibited higher abilities of aggregation, acid and bile salt resistance, adhesion, and antibacterial activity than the two commercial probiotics. Out of the 14 strains, only LS1 and LS9 carried virulence genes and none had hemolytic activity. We selected three LAB strains (LA6, LR6 and LJ1) with superior probiotic properties and LS9 with a virulence gene for testing their safety in vivo. Strains EB1, cLA and cLP were also included as control bacteria. The results demonstrated that mice treated LAB did not exhibit any adverse effects on weight gain, organ index, blood immune cells, and ileum morphology, except for those treated with LS9 and EB1. Moreover, the antimicrobial effect of LR6 and LA6 strains was examined in vivo. The results indicated that these strains could mitigate the inflammatory response, reduce bacterial translocation, and alleviate liver, spleen, and ileum injury caused by Salmonella typhimurium infection. In addition, the LR6 treatment group showed better outcomes than the LA6 treatment group; treatment with LR6 substantially reduced the mortality rate in mice. The study results provide evidence of the probiotic properties of the LAB isolates, in particular LR6, and suggest that oral administration of LR6 could have valuable health-promoting benefits.

Abstract Ischemic stroke is an acute serious cerebrovascular disease with high mortality and disability. Ferroptosis is an important regulated cell death (RCD) in ischemic stroke. 15‐Hydroxyprostaglandin dehydrogenase (15‐PGDH), a degrading enzyme of prostaglandin E2 (PGE2), is shown to regulate RCD such as autophagy and apoptosis. The study aimed to determine whether 15‐PGDH regulates ferroptosis and ischemic stroke, and further the exact mechanism. We demonstrated that overexpression of 15‐PGDH in the brain tissues or primary cultured neurons significantly aggravated cerebral injury and neural ferroptosis in ischemic stroke. While inhibition of 15‐PGDH significantly protected against cerebral injury and neural ferroptosis, which benefits arise from the activation of the PGE2/PGE2 receptor 4 (EP4) axis. While the impact of 15‐PGDH was abolished with glutathione peroxidase 4 (GPX4) deficiency. Then, 15‐PGDH inhibitor was found to promote the activation of cAMP‐response element‐binding protein (CREB) and nuclear factor kappa‐B (NF‐κB) via the PGE2/EP4 axis, subsequently transcriptionally upregulate the expression of GPX4. In summary, our study indicates that inhibition of 15‐PGDH promotes the activation PGE2/EP4 axis, subsequently transcriptionally upregulates the expression of GPX4 via CREB and NF‐κB, and then protects neurons from ferroptosis and alleviates the ischemic stroke. Therefore, 15‐PGDH may be a potential therapeutic target for ischemic stroke.

ObjectiveImproving the detection capability and efficiency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA specimens is very important for the prevention and control of the outbreak of Coronavirus disease 2019 (COVID-19). In this study, we evaluated the detection capability and efficiency of two outbreaks of COVID-19 before and after the process re-engineering in April and July 2022.MethodsThis retrospective cross-sectional study involved 359,845 SARS-CoV-2 RNA specimens 2 weeks before and 2 weeks after the two outbreaks of COVID-19 in April and July. The number, transportation time and detection time of specimens, and the number of reports of more than 24 h were analyzed by SPSS software.ResultsWhile 16.84% of people chose nasopharyngeal swabs (NPS) specimens, 83.16% chose oropharyngeal swabs (OPS) specimens to detect SARS-CoV-2 RNA. There were significant upward trends in the percentage of 10 sample pooling (P-10) from April before process re-engineering to July after process re-engineering (p

To realize the efficient transient simulation of a grid-connected power generation system based on multiple inverters, this paper proposes a hybrid simulation method integrating the models of electromagnetic transient and dynamic phasors. Based on a demonstration of the concepts and properties of dynamic phasors, the models of single-phase and three-phase inverters described by dynamic phasors are established first. Considering the numerical compatibility problem between dynamic phasors and instantaneous values, an interface scheme between dynamic phasors and instantaneous values is designed, and the efficiency and precision differences of various transformation methods are compared in detail. Finally, by utilizing MATLAB/Simulink, a hybrid simulation platform of a multi-inverter grid-connected system is built, and the efficiency and accuracy of the hybrid simulation are validated via comparison with the full electromagnetic transient simulation.

BackgroundDisulfidptosis is a newly identified variant of cell death characterized by disulfide accumulation, which is independent of ATP depletion. Accordingly, the latent influence of disulfidptosis on the prognosis of lung adenocarcinoma (LUAD) patients and the progression of tumors remains poorly understood.MethodsWe conducted a multifaceted analysis of the transcriptional and genetic modifications in disulfidptosis regulators (DRs) specific to LUAD, followed by an evaluation of their expression configurations to define DR clusters. Harnessing the differentially expressed genes (DEGs) identified from these clusters, we formulated an optimal predictive model by amalgamating 10 distinct machine learning algorithms across 101 unique combinations to compute the disulfidptosis score (DS). Patients were subsequently stratified into high and low DS cohorts based on median DS values. We then performed an exhaustive comparison between these cohorts, focusing on somatic mutations, clinical attributes, tumor microenvironment, and treatment responsiveness. Finally, we empirically validated the biological implications of a critical gene, KYNU, through assays in LUAD cell lines.ResultsWe identified two DR clusters and there were great differences in overall survival (OS) and tumor microenvironment. We selected the "Least Absolute Shrinkage and Selection Operator (LASSO) + Random Survival Forest (RFS)" algorithm to develop a DS based on the average C-index across different cohorts. Our model effectively stratified LUAD patients into high- and low-DS subgroups, with this latter demonstrating superior OS, a reduced mutational landscape, enhanced immune status, and increased sensitivity to immunotherapy. Notably, the predictive accuracy of DS outperformed the published LUAD signature and clinical features. Finally, we validated the DS expression using clinical samples and found that inhibiting KYNU suppressed LUAD cells proliferation, invasiveness, and migration in vitro.ConclusionsThe DR-based scoring system that we developed enabled accurate prognostic stratification of LUAD patients and provides important insights into the molecular mechanisms and treatment strategies for LUAD.

Introduction: Hepatic hereditary haemorrhagic telangiectasia (HHHT) is a rare autosomal dominant genetic disease. Some patients may develop cardiac failure, portal hypertension, and biliary ischaemia. To date, there is no standard surgical treatment for HHHT. The present authors propose a move from open to laparoscopic surgery; however, laparoscopic surgery has not been reported previously as a surgical treatment for HHHT. Report: Two women were admitted with histories of exertional dyspnoea and upper abdominal pain, respectively. Combined with recurrent epistaxis and their positive family history, a diagnosis of clinical HHHT was made based on Curacao criteria after comprehensive evaluation of imaging features. Next generation sequencing (NGS) results also confirmed typical gene mutations responsible for HHT. Both patients underwent laparoscopic double hepatic artery banding and or ligation successfully and were discharged four to six days after operation without severe complications. The symptoms of cardiac insufficiency including exertional dyspnoea and shortness of breath of the first patient improved six months after the operation. The second patient, with epigastric pain, remained pain free without medication three months after the operation. Discussion: Laparoscopic surgery for HHHT is technically challenging. Clinical data and follow up information showed that laparoscopic double hepatic artery banding and or ligation was a technically feasible surgical approach for HHHT patients with simple hepatic artery dilation.

Stroke-induced immunosuppression is a process that leads to peripheral suppression of the immune system after a stroke and belongs to the central nervous system injury-induced immunosuppressive syndrome. Stroke-induced immunosuppression leads to increased susceptibility to post-stroke infections, such as urinary tract infections and stroke-associated pneumonia, worsening prognosis. Molecular chaperones are a large class of proteins that are able to maintain proteostasis by directing the folding of nascent polypeptide chains, refolding misfolded proteins, and targeting misfolded proteins for degradation. Various molecular chaperones have been shown to play roles in stroke-induced immunosuppression by modulating the activity of other molecular chaperones, cochaperones, and their associated pathways. This review summarizes the role of molecular chaperones in stroke-induced immunosuppression and discusses new approaches to restore host immune defense after stroke.

Abstract Most of the current excellent models in speaker verification are ResNet-based deep models and attention-based models. These models have a general weakness, which is the large number of parameters and high hardware requirements. On the other hand, many deep structures only generate embedding features from the features extracted by the last frame-level layer, which causes shallow features and channel-related features to be ignored. To solve these problems, this paper proposed a shallow speaker verification model based on Lambda-vector, its main structure is composed of three Lambda-SE modules. The module extracts long-distance dependencies between frame-level features and channel-related interaction information to enhance representation of features. Meanwhile, so that adequately mine the information in deep and shallow features, the model introduces multi-layer feature aggregation to fuse the features of different frame-level layers together. It can increase the detailed information in the deep features and improve the model's ability to represent complex information. The experimental results on the public datasets Voxceleb1 and Voxceleb2 show that the model has more stable training speed, fewer model parameters, and better identification performances than baseline models.

The photonic crystal surface-emitting laser (PCSEL) has attracted much attention due to the advantages of a small far-field divergence angle and high output power. Here, we report a high-power terahertz (THz) photonic crystal laser with high beam quality through the optimization of the absorption boundary condition and the introduction of the symmetrically distributed electrodes. Single-mode surface emission at 3.4 THz with the maximum peak output power of 50 mW is demonstrated. Meanwhile, a high symmetric far-field pattern with C6 symmetry and a small divergence angle is achieved. In this device, the integration of the stable single-mode operation, high beam quality and high output power is realized, which may have great significance for practical applications.

With the increasing amount of astronomical observation data, it is an inevitable trend to use artificial intelligence methods for automatic analysis and identification of light curves for full samples. However, data sets covering all known classes of variable stars that meet all research needs are not yet available. There is still a lack of standard training data sets specifically designed for any type of light-curve classification, but existing light-curve training sets or data sets cannot be directly merged into a large collection. Based on the open data sets of the All-Sky Automated Survey for SuperNovae, Gaia, and Zwicky Transient Facility, we construct a compatible light-curve data set named LEAVES for automated recognition of variable stars, which can be used for training and testing new classification algorithms. The data set contains a total of 977,953 variable and 134,592 nonvariable light curves, in which the supported variables are divided into six superclasses and nine subclasses. We validate the compatibility of the data set through experiments and employ it to train a hierarchical random forest classifier, which achieves a weighted average F1-score of 0.95 for seven-class classification and 0.93 for 10-class classification. Experimental results prove that the classifier is more compatible than the classifier established based on a single band and a single survey, and has wider applicability while ensuring classification accuracy, which means it can be directly applied to different data types with only a relatively small loss in performance compared to a dedicated model.

Abstract Colorectal cancer (CRC) is among the most widely spread cancers globally. Aberrant alternative polyadenylation (APA) plays a role in cancer onset and its progression. Consequently, this study focused on highlighting the role of APA events and signals in the prognosis of patients with CRC. The APA events, RNA sequencing (RNA-seq), somatic mutations, copy number variants (CNVs), and clinical information of the CRC cohort were obtained from The Cancer Genome Atlas (TCGA) database and UCSC (University of California-Santa Cruz) Xena database. The whole set was sorted into two sets: a training set and a test set in a ratio of 7:3. 197 prognosis-related APA events were collected by performing univariate Cox regression signature in patients with CRC. Subsequently, a signature for APA events was established by least absolute shrinkage and selection operator (LASSO) and multivariate Cox analysis. The risk scores were measured for individual patients on the basis of the signature and patients were sorted into two groups; the high-risk group and the low-risk group as per their median risk scores. Kaplan–Meier curves, principal component analysis (PCA), and time-dependent receiver operator characteristic (ROC) curves revealed that the signature was able to predict patient prognosis effectively and further validation was provided in the test set and the whole set. The high-risk and low-risk groups displayed various distributions of mutations and CNVs. Tumor mutation burden (TMB) alone and in combination with the signature predicted the prognosis of CRC patients, but the gene frequencies of TMBs and CNVs did not change in the low- and high-risk groups. Moreover, immunotherapy and chemotherapy treatments showed different responses to PD-1 inhibitors and multiple chemotherapeutic agents in the low and high-risk groups based on the tumor immune dysfunction and exclusion (TIDE) and genomics of drugs sensitivity in cancer (GDSC) databases. This study may help in understanding the potential roles of APA in CRC, and the signature for prognosis-related APA events can work as a potential predictor for survival and treatment in patients with CRC.

Abstract Aldehyde dehydrogenases (ALDHs) play an essential role in regulating malignant tumor progression; however, their role in cholangiocarcinoma (CCA) has not been elucidated. We analyzed the expression of ALDHs in 8 paired tumor and peritumor perihilar cholangiocarcinoma (pCCA) tissues and found that ALDH3B1 and ALDH3B2 were upregulated in tumor tissues. Further survival analysis in intrahepatic cholangiocarcinoma (iCCA, n = 27), pCCA (n = 87) and distal cholangiocarcinoma (dCCA, n = 80) cohorts have revealed that ALDH3B2 was a prognostic factor of CCA and was an independent prognostic factor of iCCA and pCCA. ALDH3B2 expression was associated with serum CEA in iCCA and dCCA, associated with tumor T stage, M stage, neural invasion and serum CA19-9 in pCCA. In two cholangiocarcinoma cell lines, overexpression of ALDH3B2 promoted cell proliferation and clone formation by promoting the G1/S phase transition. Knockdown of ALDH3B2 inhibited cell migration, invasion, and EMT in vitro, and restrained tumor metastasis in vivo. Patients with high expression of ALDH3B2 also have high expression of ITGB1 in iCCA, pCCA, and dCCA at both mRNA and protein levels. Knockdown of ALDH3B2 downregulated the expression of ITGB1 and inhibited the phosphorylation level of c-Jun, p38, and ERK. Meanwhile, knockdown of ITGB1 inhibited the promoting effect of ALDH3B2 overexpression on cell proliferation, migration, and invasion. ITGB1 is also a prognostic factor of iCCA, pCCA, and dCCA and double-positive expression of ITGB1 and ALDH3B2 exhibits better performance in predicting patient prognosis. In conclusion, ALDH3B2 promotes tumor proliferation and metastasis in CCA by regulating the expression of ITGB1 and upregulating its downstream signaling pathway. The double-positive expression of ITGB1 and ALDH3B2 serves as a better prognostic biomarker of CCA.

Clear cell renal cell carcinoma (ccRCC) is a lethal urological malignancy. DNA methylation is involved in the regulation of ccRCC occurrence and progression. This study aimed to establish a prognostic model based on DNA methylation to predict the overall survival (OS) of patients with ccRCC. To create this model, we used the transcriptome and DNA methylation data of patients with ccRCC from The Cancer Genome Atlas (TCGA) database. We then used the MethylMix R package to identify methylation-driven genes, and LASSO regression and multivariate Cox regression analyses established the prognostic risk model, from which we derived risk scores. We incorporated these risk scores and clinical parameters to develop a prognostic nomogram to predict 3-, 5-, and 7-year overall survival, and its predictive power was validated using the ArrayExpress cohort. These analyses identified six methylation-driven genes (SAA1, FUT6, SPATA18, SHROOM3, AJAP1, and NPEPL1) that produced risk scores, which were sorted into high- and low-risk patient groups. These two groups differed in nomogram-predicted prognosis, the extent of immune cell infiltration, tumor mutational burden, and expected response to additional therapies. In conclusion, we established a nomogram based on six DNA methylation-driven genes with excellent accuracy for prognostic prediction in ccRCC patients. This nomogram model might provide novel insights into the epigenetic mechanism and individualized treatment of ccRCC.

Background: Knowledge of metformin-induced hepatotoxicity is based on case reports. The aim of this study was to investigate the clinical features of metformin-induced hepatotoxicity.Methods: We collected relevant literature on metformin-induced hepatotoxicity published from January 1994 to February 2022 by searching Chinese and English databases.Results: Thirty patients (19 males and 11 females) from 29 articles were included, with a median age of 61 years (range 29–83). The median time to onset of liver injury was 4 weeks (range 0.3–648) after metformin administration. Clinical symptoms occurred in 28 patients, including gastrointestinal reactions (56.7%), jaundice (50.0%), fatigue (36.7%), anorexia (23.3%), pruritus (13.3%), dark urine (13.3%), and clay-colored stools (10.0%). Serum alanine transaminase, aspartate transaminase, γ-glutamyl transferase, total bilirubin and alkaline phosphatase were elevated to varying degrees. Liver imaging in 26 patients showed hepatic steatosis (6 cases, 23.1%) and gallbladder wall thickening (11.5%). Liver biopsies from 13 patients showed portal phlebitis (61.5%), cholestatic hepatitis (38.5%), and parenchymal inflammation (38.5%). After metformin discontinuation, liver function returned to normal levels at a median of 6 weeks (range 2–16).Conclusions: Metformin-induced hepatotoxicity is a rare adverse reaction. Physicians and patients should be alert to metformin-induced hepatotoxicity.

AbstractWith the development of high-pressure and high-temperature condensate gas wells, the wellbore blockage problems have become increasingly serious. Hence, selecting appropriate treatment technology plays a crucial role in solving the wellbore blockage problems. This study presents a comprehensive literature review on understanding the blockage type, mechanism, and treatment of the high-temperature and high-pressure condensate gas wells. The causes, endangerments, mechanisms, influences, and preventive technologies of the 4 wellbore blockage types are presented. The significant aspects of the treatment technology, such as the principle, type, advantage and disadvantage, adaptability, limitation, and future research direction of the treatment technologies, are thoroughly discussed. The breakthrough solid autogenetic heat treatment technology has been selected to remove hydrate blockage. The present review highlights the current state in the industry, future position, and strategies for the researchers to follow. Finally, the advantages and disadvantages and future research directions of specific treatment technology are presented on the removing effect, cost, and environmental aspects.

Abstract Background Cholangiocarcinoma is a highly malignant cancer with very dismal prognosis. Perihilar cholangiocarcinoma(pCCA) accounts for more than 50% of all cholangiocarcinoma and is well-characterized for its low rate of radical resection. Effects of radiotherapy and chemotherapy of pCCA are very limited. Methods Here we screened potential biomarkers of pCCA with transcriptome sequencing and evaluated the prognostic significance of HMGA1 in a large cohort pCCA consisting of 106 patients. With bioinformatics and in vitro/vivo experiments, we showed that HMGA1 induced tumor cell stemness and epithelial-mesenchymal-transition (EMT), and thus facilitated proliferation, migration and invasion by promoting TRIP13 transcription. Moreover, TRIP13 was also an unfavorable prognostic biomarker of pCCA, and double high expression of HMGA1/TRIP13 could predict prognosis more sensitively. TRIP13 promoted pCCA progression by suppressing FBXW7 transcription and stabilizing c-Myc. c-Myc in turn induced the transcription and expression of both HMGA1 and TRIP13, indicating that HMGA-TRIP13 axis facilitated pCCA stemness and EMT in a positive feedback pathway. Conclusions HMGA1 and TRIP13 were unfavorable prognostic biomarkers of pCCA. HMGA1 enhanced pCCA proliferation, migration, invasion, stemness and EMT, by inducing TRIP13 expression, suppressing FBXW7 expression and stabilizing c-Myc. Moreover, c-Myc can induce the transcription of HMGA1 and TRIP13, suggesting that HMGA-TRIP13 axis promoted EMT and stemness in a positive feedback pathway dependent on c-Myc.

Abstract Background Long noncoding RNA (lncRNA) is highly associated with inflammatory response and virus-induced interferon production. By far the majority of studies have focused on the immune-related lncRNAs of mice and humans, but the function of lncRNAs in porcine immune cells are poorly understood. Porcine reproductive and respiratory syndrome virus (PRRSV) impairs local immune responses in the lungs of nursery and growing pigs, whereas the virus triggers the inflammatory responses. Porcine alveolar macrophage (PAM) is the primary target cell of PRRSV, thus PRRSV is used as an in vitro model of inflammation. Here, we profiled lncRNA and mRNA repertories from PRRSV-infected PAMs to explore the underlying mechanism of porcine lncRNAs in regulating host immune responses. Results In this study, a total of 350 annotated lncRNAs and 1792 novel lncRNAs in PAMs were identified through RNA-seq analysis. Among them 86 differentially expressed (DE) lncRNAs and 406 DE protein-coding mRNAs were identified upon PRRSV incubation. GO category and KEGG pathway enrichment analyses revealed that these DE lncRNAs and mRNAs were mainly involved in inflammation- and pathogen infection-induced pathways. The results of dynamic correlated expression networks between lncRNAs and their predicted target genes uncovered that numerous lncRNAs, such as XLOC-022175, XLOC-019295, and XLOC-017089, were correlated with innate immune genes. Further analysis validated that these three lncRNAs were positively correlated with their predicted target genes including CXCL2, IFI6, and CD163. This study suggests that porcine lncRNAs affect immune responses against PRRSV infection through regulating their target genes in PAMs. Conclusion This study provides both transcriptomic and epigenetic status of porcine macrophages. In response to PRRSV infection, comprehensive DE lncRNAs and mRNAs were profiled from PAMs. Co-expression analysis demonstrated that lncRNAs are emerging as the important modulators of immune gene activities through their critical influence upon PRRSV infection in porcine macrophages.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane protein enriched on the surface of some cells, including melanoma, glioblastoma, and macrophages. GPNMB has been reported to have multifaceted roles, such as facilitating cell–cell adhesion and migration, stimulating kinase signaling, and regulating inflammation. Porcine reproductive and respiratory syndrome virus (PRRSV) is the leading cause of severe economic loss in the swine industry worldwide. In this study, the role of GPNMB was investigated in porcine alveolar macrophages during PRRSV infection. We observed that GPNMB expression was markedly reduced in PRRSV-infected cells. The inhibition of GPNMB by specific small interfering RNA led to an enhancement in virus yields, and GPNMB overexpression decreased PRRSV replication. Further studies revealed that the overexpression of GPNMB could induce the accumulation of autophagosome through inhibiting autophagosome-lysosome fusion. Using a specific inhibitor, we confirmed that the inhibition of autophagosome-lysosome fusion significantly inhibited viral replication. Taken together, our data demonstrate that GPNMB inhibits PRRSV replication by inhibiting the autophagosome-lysosome fusion and provides a novel therapeutic target for virus infection.

Abstract Background The Mnk2 kinase, encoded by MKNK2 gene, plays critical roles in MAPK signaling and was involved in oncogenesis. Human MKNK2 pre-mRNA can be alternatively spliced into two splicing isoforms, the MKNK2a and MKNK2b, thus yielding Mnk2a and Mnk2b proteins with different domains. The involvement of Mnk2 alternative splicing in colon cancer has been implicated based on RNA-sequencing data from TCGA database. This study aimed at investigating the upstream modulators and clinical relevance of Mnk2 alternative splicing in colon adenocarcinoma (CAC). Methods PCR, western blotting and immunohistochemistry (IHC) were performed to assess the expression of Mnk2 and upstream proteins in CAC. The function of Mnk2 and its regulators were demonstrated in different CAC cell lines as well as in xenograft models. Two independent cohorts of CAC patients were used to reveal the clinical significance of MKNK2 alternative splicing. Results Comparing with adjacent nontumorous tissue, CAC specimen showed a decreased MKNK2a level and an increased MKNK2b level, which were correlated with KRAS mutation and tumor size. The SRSF1 (serine/arginine-rich splicing factor 1) was further confirmed to be the major splicing factor targeting MKNK2 in CAC cells. Higher expression of SRPK1/2 or decreased activity of PP1α were responsible for enhancing SRSF1 phosphorylation and nucleus translocation, subsequently resulted in a switch of MKNK2 alternative splicing. Conclusions Our data showed that phosphorylation and subcellular localization of SRSF1 were balanced by SRPK1/2 and PP1α in CAC cells. High nucleus SRSF1 promoted MKNK2 splicing into MKNK2b instead of MNK2a, consequently enhanced tumor proliferation.

Background and PurposeStroke is a serious fatal and disabling disease. Stroke-associated pneumonia (SAP) is the most common complication of stroke, which may further aggravate the stroke. The prevention and early prediction of SAP is a key clinical strategy. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is involved in pneumonia, while its relationship with SAP has yet to be determined. Therefore, we investigated the predictive value of 15-PGDH for SAP and visualized their relationship.MethodsStroke patients were recruited and divided into SAP group and Non-SAP group. Baseline demographic and clinical data were obtained from the medical record system, blood samples were collected to detect relevant variables and 15-PGDH levels. Patient characteristics were compared with a t-test. Binary logistic regression analysis was performed to determine the predictive value of 15-PGDH for SAP. Restricted cubic splines (RCS) were performed to visualize the relationship between 15-PGDH and SAP risk. Finally, the SAP patient characteristics between the severe group and mild group were compared.Results50 patients were enrolled and divided into SAP group (n = 26) and Non-SAP group (n = 24). 15-PGDH in the SAP group was lower than that in the Non-SAP group (0.258 ± 0.275 vs. 0.784 ± 0.615, p = 0.025). Binary logistic regression analysis revealed that the lower 15-PGDH, the higher the risk of SAP (OR = 0.04, 95%CI, 0.010–0.157, p < 0.001). The RCS model showed the L-shaped relationship between 15-PGDH and SAP.ConclusionsIn stroke patients, serum 15-PGDH is a valuable biomarker for predicting SAP. There is an L-shaped relationship between the level of 15-PGDH and the risk of SAP.

Background: Ferroptosis is a potential target for cancer therapy, and lncRNAs can also affect ferroptosis by regulating related genes. The pathogenesis of clear cell renal cell carcinoma (ccRCC) regarding the regulation of ferroptosis by lncRNAs is still unknown.Methods: We constructed a risk model based on data in ccRCC patients obtained from the TCGA database and validated the diagnostic and prognostic value of the model. In addition, immune function and immune checkpoint variability analysis validated the association of ferroptosis with ccRCC tumor immunity.Results: The characteristics of ferroptosis-related lncRNAs (FRLs) were significantly correlated with the prognosis of ccRCC patients. The prognostic characteristics of FRLs were independent prognostic factors in ccRCC patients. Gene function in the high-risk group was associated with oxygen metabolic processes and immune pathways. Immune checkpoint variability analysis showed that HAVCR2, NRP1, and HHLA2 were upregulated in the low-risk group, while CD44, TNFRSF18, TNFSF14, TNFRSF8, CD276, and TNFRSF25 were upregulated in the high-risk group.Conclusions: The prognostic characteristics of FRLs can effectively predict the prognosis of ccRCC patients and provide a new direction for clinical treatment.

BackgroundThis study aimed to investigate risk factors and prognostic factors in patients with clear cell renal cell carcinoma (ccRCC) with bone metastasis (BM) and establish nomograms to provide a quantitative prediction of the risk of BM and survival probability.MethodsThe clinicopathological characteristics of patients with ccRCC between January 2010 and December 2015 were obtained from the Surveillance, Epidemiology and End Results (SEER) database. Independent factors for BM in ccRCC patients were identified using univariate and multivariate logistic regression analyses. Prognostic factors for predicting cancer-specific death were evaluated using univariate and multivariate analyses based on a competing risk regression model. We then constructed a diagnostic nomogram and a prognostic nomogram. The two nomograms were evaluated using calibration curves, receiver operating characteristic curves, and decision curve analysis.ResultsOur study included 34,659 patients diagnosed with ccRCC in the SEER database, with 1,415 patients who presented with bone metastasis. Risk factors for BM in patients with ccRCC included age, stage T, stage N, brain metastasis, liver metastasis, lung metastasis, tumor size, and laterality. Independent prognostic factors for patients with ccRCC patients with BM were Fuhrman grade, tumor size, T stage, N stage, brain metastases, lung metastasis, and surgery. For the diagnostic nomogram, the area under the curve values in the training and testing cohorts were 0.863 (95% CI, 0.851–0.875) and 0.859 (95% CI, 0.839–0.878), respectively. In the prognostic cohort, the area under the curve values for 1-, 2-, and 3-year cancer-specific survival rates in the training cohort were 0.747, 0.774, and 0.780, respectively, and 0.671, 0.706, and 0.696, respectively, in the testing cohort. Through calibration curves and decision curve analyses, the nomograms displayed excellent performance.ConclusionsSeveral factors related to the development and prognosis of BM in patients with ccRCC were identified. The nomograms constructed in this study are expected to become effective and precise tools for clinicians to improve cancer management.

Ferroptosis is a new form of regulatory cell death named by Dixon in 2012, which is characterized by the accumulation of lipid peroxides and iron ions. Molecular chaperones are a class of evolutionarily conserved proteins in the cytoplasm. They recognize and bind incompletely folded or assembled proteins to help them fold, transport or prevent their aggregation, but they themselves do not participate in the formation of final products. As the largest number of molecular chaperones, heat shock proteins can be divided into five families: HSP110 (HSPH), HSP90 (HSPC), HSP70 (HSPA), HSP40 (DNAJ) and small heat shock proteins (HSPB). Different heat shock proteins play different roles in promoting or inhibiting ferroptosis in different diseases. It is known that ferroptosis is participated in tumors, nervous system diseases, renal injury and ischemia-reperfusion injury. However, there are few reviews about the relationship of heat shock proteins and ferroptosis. In this study, we systematically summarize the roles of heat shock proteins in the occurrence of ferroptosis, and predict the possible mechanisms of different families of heat shock proteins in the development of ferroptosis.

IntroductionUrinary stones cause hydronephrosis, which leads to kidney function impairment. The serum creatinine level is frequently used as a marker of kidney function. However, in some patients with hydronephrosis, it does not reflect the kidney function changes in the early stages of kidney stone disease. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel indicator of the kidney function. Previous NGAL-related research has focused on its role in acute kidney injury. This study aimed to determine the usefulness of NGAL as an early marker of the kidney function in patients with urinary stones and hydronephrosis.MethodsEighty-five patients with urinary stones who were admitted to the Shanghai Tenth People's Hospital (USP group) and 65 healthy volunteers (NC group) were recruited. Blood and urine samples collected from the study participants were evaluated using an enzyme-linked immunosorbent assay to determine the NGAL concentration. Data on the height, weight, age, medical history, and blood and urine findings were collected. Computed tomography data were collected from the USP group.ResultsCompared to in the NC group, NGAL levels were significantly elevated in the USP group (P < 0.001). However, no significant differences in the NGAL levels were observed among the USP group members with different degrees of hydronephrosis. Furthermore, no significant between-group differences in the creatinine level or the estimated glomerular filtration rate were observed. The areas under the receiver operating characteristic curves for the serum and urinary NGAL levels with hydronephrosis were 92.03 and 99.54%, respectively. The areas under the receiver operating characteristic curves for the serum and urinary NGAL levels with kidney stones were 85.05 and 91.89%, respectively.ConclusionNGAL is a sensitive indicator of hydronephrosis secondary to urinary stones.

Flexible zinc batteries have great potential in wearable electronic devices due to their high safety, low cost, and environmental friendliness. In the past few years, a great deal of work on flexible zinc batteries has been reported, with exciting results. Therefore, many solutions have been proposed in electrode design and electrolyte preparation to ensure the desired flexibility without sacrificing the capacity. This paper reviews the recent progress of flexible zinc batteries. We discuss the differences between various anode materials, cathode materials, and electrolytes, introduce the differences of electrode preparation methods of active materials on flexible substrates and their influence on the performance of the battery. Finally, the challenges and future research trends of flexible zinc batteries in capacity and mechanical properties are pointed out.

Although many studies have explored the relationship between the built environment and metro ridership, the literature offers limited evidence on the nonlinear effect of origin and destination built environments on station-to-station ridership. Using data from Chongqing, this study uses the gradient boosting decision trees (GBDT) model to explore the nonlinear impact of origin and destination built environments on metro ridership. The research results show that the built environment at the origin has a greater impact on metro ridership than the built environment at the destination. All the independent variables examined have complex nonlinear effects and threshold effects on metro ridership. The distance to the city center, the number of companies, and the building volume rate have a greater positive effect on metro ridership, both at the origin and at the destination. The research results provide suggestions for optimizing the built environment around metro stations.

Background: Perihilar cholangiocarcinoma (PHCC) is the most common subtype of cholangiocarcinoma(CCA). We previously investigated the expression pattern of Sprouty(SPRY) in intrahepatic cholangiocarcinoma(ICC), but the expression and clinical significance of SPRY family members in PHCC are still unknown. Methods: The expression of SPRY family members(SPRY1-4) was detected in different subtypes of CCA and corresponding adjacent tissues. SPRY4 expression in 142 cases of PHCC was detected by immunohistochemistry, and its clinical significance was evaluated using univariate and multivariate analyses. The functions of SPRY4 in the FGFR-induced proliferation and migration of PHCC cells were investigated through in vitro and in vivo experiments. We further investigated the effects and mechanisms of SPRY4 on FGFR-induced ERK phosphorylation and cell cycle distribution in the presence of FGFR and ERK inhibitors. Findings: SPRY4 was the only SPRY family member associated with PHCC prognosis, and it was identified as an independent factor predicting favorable prognosis. In PHCC, SPRY4 expression was extensively associated with FGFR2, and its expression can be induced by ectopic FGFR2 activation. Through in vitro and in vivo experiments, we demonstrated that SPRY4 suppressed FGFR-induced proliferation and migration by inhibiting ERK phosphorylation. Moreover, SPRY4 knockdown was shown to decrease the percentage of cells in the G1 phase and promote the percentage of cells in the S and G2/M phases by increasing cyclin D1 expression, which also required FGFR-induced ERK phosphorylation. Interpretation: High expression of SPRY4 was an independent biomarker of favorable prognosis in PHCC. SPRY4 expression can be induced by ectopic FGFR2 activation in PHCC. SPRY4 arrested the cell cycle at G1 phase and suppressed FGFR-induced proliferation and migration by inhibiting ERK phosphorylation, indicating that SPRY4 may be a potential therapeutic target in PHCC. Keywords: Sprouty 4, Perihilar cholangiocarcinoma, Prognosis, Proliferation, Cell cycle

Objective: To introduce TURP-E, a modification to the classical TURP mixed with enucleation skills, and to compare the intraoperative and postoperative outcomes in the treatment of benign prostatic hyperplasia (BPH) with standard TURP.

Ferroptosis, an iron-dependent form of selective cell death, is involved in the development of many cancers. However, ferroptosis related genes (FRGs) in prostate cancer (PCa) are not been well studied. In this study, we collected the mRNA expression profiles and clinical information of PCa patients from TCGA and MSKCC databases. The univariate, LASSO, and multivariate Cox regression analyses were performed to construct a prognostic signature. Seven FRGs, AKR1C3, ALOXE3, ATP5MC3, CARS1, MT1G, PTGS2, and TFRC, were included to establish a risk model, which was validated in the MSKCC dataset. The results showed that the high-risk group was apparently correlated with copy number alteration load, tumor burden mutation, immune cell infiltration, mRNAsi, immunotherapy, and bicalutamide response. Moreover, we found that TFRC overexpression induced the proliferation and invasion of PCa cell lines in vitro. These results demonstrate that this risk model can accurately predict prognosis, suggesting that FRGs are promising prognostic biomarkers and potential drug targets in PCa patients.

Background: Cholangiocarcinoma (CCA), consisting of intrahepatic (IHCCA), perihilar (PHCCA), and distal (DCCA) CCA, is a type of highly aggressive malignancy with a very dismal prognosis. Potential biomarkers and drug targets of CCA are urgently needed. As a new member of the Annexin (ANXA) family, the role of ANXA10 in the progression and prognosis of CCA is unknown. Methods: Potential PHCCA biomarkers were screened by transcriptome sequencing of 5 pairs of PHCCA and adjacent tissues. The clinical significance of ANXA10 was evaluated by analyzing its correlation with clinicopathological variables, and the prognostic value of ANXA10 was evaluated with univariate and multivariate analyses. The function of ANXA10 in the epithelial-mesenchymal transition (EMT), proliferation, invasion and metastasis was detected with in vitro and in vivo experiments. Moreover, we screened the key molecule in ANXA10-induced CCA progression by mRNA sequencing and evaluated the correlation between PLA2G4A and ANXA10. The effect of PLA2G4A downstream signaling, including Cyclooxygenase 2, Prostaglandin E2(PGE2) and Signal transducer and activator of transcription 3(STAT3), on EMT and metastasis was further detected with in vitro and in vivo experiments. Findings: ANXA10 expression was upregulated in PHCCA and DCCA but not in IHCCA. High ANXA10 expression was significantly associated with poor tumor differentiation and prognosis. ANXA10 promoted the proliferation, migration and invasion of the PHCCA cells. PLA2G4A expression was regulated by ANXA10 and high PLA2G4A predicted poor prognosis in PHCCA and DCCA. ANXA10 facilitated EMT and promoted metastasis by upregulating PLA2G4A expression, thus increasing PGE2 levels and activating STAT3. Interpretation: ANXA10 was an independent prognostic biomarker of PHCCA and DCCA but not IHCCA. ANXA10 promoted the progression of PHCCA and facilitated metastasis by promoting the EMT process via the PLA2G4A/PGE2/STAT3 pathway. ANXA10, PLA2G4A and their downstream molecules, such as COX2 and PGE2, may be promising drug targets of PHCCA and DCCA. Keywords: Annexin 10, Perihilar cholangiocarcinoma, Distal cholangiocarcinoma, Prognosis, Metastasis, Epithelial-mesenchymal transition

Summary: Development of spermatogonia and spermatocytes are the critical steps of spermatogenesis, impacting on male fertility. Investigation of the related regulators benefits the understanding of male reproduction. The proteasome system has been reported to regulate spermatogenesis, but the mechanisms and key contributing factors in vivo are poorly explored. Here we found that ablation of REGγ, a proteasome activator, resulted in male subfertility. Analysis of the mouse testes after birth showed there was a decreased number of PLZF+ spermatogonia and spermatocytes. Molecular analysis found that REGγ loss significantly increased the abundance of p53 protein in the testis, and directly repressed PLZF transcription in cell lines. Of note, allelic p53 haplodeficiency partially rescued the defects in spermatogenesis observed in REGγ-deficient mice. In summary, our results identify REGγ-p53-PLZF to be a critical pathway that regulates spermatogenesis and establishes a new molecular link between the proteasome system and male reproduction. : In this article, Lei Li and colleagues show that ablation of REGγ, a proteasome activator, resulted in male subfertility, partially because of a decreased number of PLZF+ spermatogonia and spermatocytes. Mechanistically, REGγ loss significantly increased the abundance of p53 protein, and transcriptionally represses PLZF expression. Allelic p53 haplodeficiency partially rescued the defects in spermatogenesis observed in REGγ-deficient mice. Keywords: REGγ, PLZF, p53, spermatogonial stem cells, mouse reproduction

Background: Perihilar cholangiocarcinoma (PHCC) is the most common type of cholangiocarcinoma with the worst prognosis. Radical resection of PHCC is difficult; thus, few effective biomarkers or useful molecular profiles for PHCC have been reported in recent years. Therefore, in this study, we aimed to assess biomarkers for PHCC. Methods: We screened potential biomarkers for PHCC using exome and transcriptome sequencing with PHCC tissues and paired normal tissues. Transcription factor 7 (TCF7) expression was evaluated using quantitative reverse transcription polymerase chain reaction, western blotting, and immunohistochemistry. The correlations between TCF7 and clinicopathological factors were analyzed with Chi-square test, and the prognostic significance of TCF7 was evaluated with univariate and multivariate analyses. The functions of TCF7 and its main effectors in PHCC cells were investigated in vitro and in vivo. Findings: TCF7 expression was upregulated in PHCC and was an unfavorable prognostic biomarker. c-Myc was a main effector of TCF7 in PHCC cells and modulated TCF7-induced proliferation, invasion, and migration. FOS-like antigen 1 (FOSL1) was identified as a downstream target of TCF7 and was required in TCF7-induced PHCC proliferation. Triple-positive expression of TCF7, c-Myc, and FOSL1 predicted a much worse prognosis in patients with PHCC than TCF7 expression alone. Interpretation: Postoperative detection of TCF7, c-Myc, and FOSL1 may be useful for stratifying patients with a high risk of unfavorable prognosis, and suppressing TCF7 or its downstream effectors may be a promising strategy for the treatment of PHCC. Keywords: Transcription factor 7, Perihilar cholangiocarcinoma, C-Myc, FOS-like antigen 1, Prognosis, Progression

Abstract Background Previous study demonstrated that extracellular ATP could promote cell migration and invasion in multiple human cancers. Till now, the pro-invasive mechanisms of ATP and P2RX6, a preferred receptor for ATP, are still poorly studied in RCC. Methods Bioinformatics analysis was performed to identify the differentially expressed genes during RCC different stages. Tissue microarray, IHC staining and survival analysis was respectively used to evaluate potential clinical function. In vitro and in vivo assays were performed to explore the P2RX6 biological effects in RCC progression. Results We found that ATP might increase RCC cells migration and invasion through P2RX6. Mechanism dissection revealed that ATP-P2RX6 might modulate the Ca2+-mediated p-ERK1/2/MMP9 signaling to increase the RCC cells migration and invasion. Furthermore, METTL14 implicated m6A modification in RCC and down-regulated P2RX6 protein translation. In addition, human clinical survey also indicated the positive correlation of this newly identified signaling in RCC progression and prognosis. Conclusions Our findings revealed that the newly identified ATP-P2RX6-Ca2+-p-ERK1/2-MMP9 signaling facilitates RCC cell invasion and metastasis. Targeting this novel signaling pathway with small molecules might help us to develop a new approach to better suppress RCC progression.

Abstract Background It is an established fact that excess of glucocorticoids could cause the harmful effects, such as suppression on the male reproduction. Although glucocorticoids pharmacologically inhibit the Leydig cell function, their roles in Leydig cell development are unclear. Therefore, the present study was designed to investigate effects of synthetic glucocorticoid dexamethasone (DEX) on rat stem Leydig cell proliferation and differentiation. Methods Male Sprague-Dawley rats received a single intraperitoneal injection of 75 mg/kg EDS to eliminate Leydig cells and an in vitro culture system of the seminiferous tubules was established from Leydig cell-depleted testis. Using basal medium and Leydig cell differentiation-inducing medium (LIM) in the culture system, we examined the effects of DEX (0–100 nM) on the proliferation and differentiation of the stem Leydig cells in vitro, respectively. Results Results showed that LIM is a good agent to induce stem Leydig cell differentiation into Leydig cells that produce testosterone in vitro. DEX inhibited the differentiation of stem Leydig cells by reducing the expression levels of Cyp17a1 and Scarb1 and that NR3C1 antagonist RU38486 reversed the DEX-mediated effects. However, DEX are not involved with the proliferation of stem Leydig cells. Conclusions DEX suppressed the differentiation of rat Leydig cells in vitro and glucocorticoid-induced effects acted through NR3C1. This suppression partially targets on Cyp17a1 and Scarb1 gene expression.

Over the past decades, imaging and spectroscopy techniques have been developed rapidly with widespread applications in non-destructive agro-food quality determination. Seeds are one of the most fundamental elements of agriculture and forestry. Seed viability is of great significance in seed quality characteristics reflecting potential seed germination, and there is a great need for a quick and effective method to determine the germination condition and viability of seeds prior to cultivate, sale and plant. Some researches based on spectra and/or image processing and analysis have been explored in terms of the external and internal quality of a variety of seeds. Many attempts have been made in image segmentation and spectra correction methods to predict seed quality using various traditional and novel methods. This review focuses on the comparative introduction, development and applications of emerging techniques in the analysis of seed viability, in particular, near infrared spectroscopy, hyperspectral and multispectral imaging, Raman spectroscopy, infrared thermography, and soft X-ray imaging methods. The basic theories, principle components, relative chemometric processing, analytical methods and prediction accuracies are reported and compared. Additionally, on the foundation of the observed applications, the technical challenges and future outlook for these emerging techniques are also discussed. Keywords: Seed viability, NIR, Hyperspectral imaging, Raman spectroscopy, Infrared thermography, Soft X-ray imaging

Paraoxonase-1 (PON1), an esterase with specifically paraoxonase activity, has been proven to be involved in inflammation and infection. Porcine reproductive and respiratory syndrome virus (PRRSV) is still a major concern in pigs and causes severe economic losses to the swine industry worldwide. In this study, the role of PON1 was investigated in porcine alveolar macrophages (PAMs) during PRRSV infection. The results showed that PRRSV replication downregulated PON1, and the knockdown of PON1 significantly decreased PRRSV replication. Similarly, PON1 overexpression could enhance PRRSV replication. Interestingly, we observed that PON1 interacted with PRRSV nonstructural protein 9 (Nsp9), the RNA-dependent RNA polymerase, and the knockdown of PON1 lowered the RNA binding ability of Nsp9, suggesting that PON1 can facilitate Nsp9 function in viral replication. In addition, the knockdown of PON1 expression led to the amplification of type I interferon (IFN) genes and vice versa. In summary, our data demonstrate that PON1 facilitates PRRSV replication by interacting with Nsp9 and inhibiting the type I IFN signaling pathway. Hence, PON1 may be an additional component of the anti-PRRSV defenses.