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Abstract Background The rapid advancements in deep neural network models have significantly enhanced the ability to extract features from microbial sequence data, which is critical for addressing biological challenges. However, the scarcity and complexity of labeled microbial data pose substantial difficulties for supervised learning approaches. To address these issues, we propose DNASimCLR, an unsupervised framework designed for efficient gene sequence data feature extraction. Results DNASimCLR leverages convolutional neural networks and the SimCLR framework, based on contrastive learning, to extract intricate features from diverse microbial gene sequences. Pre-training was conducted on two classic large scale unlabelled datasets encompassing metagenomes and viral gene sequences. Subsequent classification tasks were performed by fine-tuning the pretrained model using the previously acquired model. Our experiments demonstrate that DNASimCLR is at least comparable to state-of-the-art techniques for gene sequence classification. For convolutional neural network-based approaches, DNASimCLR surpasses the latest existing methods, clearly establishing its superiority over the state-of-the-art CNN-based feature extraction techniques. Furthermore, the model exhibits superior performance across diverse tasks in analyzing biological sequence data, showcasing its robust adaptability. Conclusions DNASimCLR represents a robust and database-agnostic solution for gene sequence classification. Its versatility allows it to perform well in scenarios involving novel or previously unseen gene sequences, making it a valuable tool for diverse applications in genomics.

Abstract Background To evaluate the comprehensive effect of translucency, thickness, cement shades, and background color on the masking ability of resin-matrix ceramic veneer restorations. Methods Resin-matrix ceramic specimens with 2 translucencies (LT, HT) and 3 thicknesses (0.5, 1.0, and 1.5 mm) were made of Upcera Hyramic (A2 shade). Cement specimens were made of Variolink N in 4 shades (yellow, white, transparent, and bleach XL). Five background specimens were made of IPS Natural Die Material in 5 shades (ND1, ND2, ND3, ND4, and ND5). Color coordinates of 120 subgroups (n = 5) of combined specimens composed of different ceramic, cement, and background specimens were obtained using a spectroradiometer. Color difference (ΔE00) compared with a 4-mm thick specimen of LT and HT ceramics was calculated and four-way ANOVA was used for statistical analysis (α = 0.05). Results Translucency, thickness, cement shade, background color, and their interaction had significant effects on ΔE00 (p

Abstract The combination of cisplatin and pemetrexed remains the gold standard chemotherapy for malignant pleural mesothelioma (MPM), although resistance and poor response pose a significant challenge. Cytidine deaminase (CDA) is a key enzyme in the nucleotide salvage pathway and is involved in the adaptive stress response to chemotherapy. The cytidine analog capecitabine and its metabolite 5′-deoxy-5-fluorocytidine (5’-DFCR) are converted via CDA to 5-fluorouracil, which affects DNA and RNA metabolism. This study investigated a schedule-dependent treatment strategy, proposing that initial chemotherapy induces CDA expression, sensitizing cells to subsequent capecitabine treatment. Basal CDA protein expression was low in different mesothelioma cell lines but increased in the corresponding xenografts. Standard chemotherapy increased CDA protein levels in MPM cells in vitro and in vivo in a schedule-dependent manner. This was associated with epithelial-to-mesenchymal transition and with HIF-1alpha expression at the transcriptional level. In addition, pretreatment with cisplatin and pemetrexed in combination sensitized MPM xenografts to capecitabine. Analysis of a tissue microarray (TMA) consisting of samples from 98 human MPM patients revealed that most human MPM samples had negative CDA expression. While survival curves based on CDA expression in matched samples clearly separated, significance was not reached due to the limited sample size. In non-matched samples, CDA expression before but not after neoadjuvant therapy was significantly associated with worse overall survival. In conclusion, chemotherapy increases CDA expression in xenografts, which is consistent with our in vitro results in MPM and lung cancer. A subset of matched patient samples showed increased CDA expression after therapy, suggesting that a schedule-dependent treatment strategy based on chemotherapy and capecitabine may benefit a selected MPM patient population.

Abstract. Background:. We previously reported that activation of the cell cycle in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enhances their remuscularization capacity after human cardiac muscle patch transplantation in infarcted mouse hearts. Herein, we sought to identify the effect of magnesium lithospermate B (MLB) on hiPSC-CMs during myocardial repair using a myocardial infarction (MI) mouse model. Methods:. In C57BL/6 mice, MI was surgically induced by ligating the left anterior descending coronary artery. The mice were randomly divided into five groups (n = 10 per group); a MI group (treated with phosphate-buffered saline only), a hiPSC-CMs group, a MLB group, a hiPSC-CMs + MLB group, and a Sham operation group. Cardiac function and MLB therapeutic efficacy were evaluated by echocardiography and histochemical staining 4 weeks after surgery. To identify the associated mechanism, nuclear factor (NF)-κB p65 and intercellular cell adhesion molecule-1 (ICAM1) signals, cell adhesion ability, generation of reactive oxygen species, and rates of apoptosis were detected in human umbilical vein endothelial cells (HUVECs) and hiPSC-CMs. Results:. After 4 weeks of transplantation, the number of cells that engrafted in the hiPSC-CMs + MLB group was about five times higher than those in the hiPSC-CMs group. Additionally, MLB treatment significantly reduced tohoku hospital pediatrics-1 (THP-1) cell adhesion, ICAM1 expression, NF-κB nuclear translocation, reactive oxygen species production, NF-κB p65 phosphorylation, and cell apoptosis in HUVECs cultured under hypoxia. Similarly, treatment with MLB significantly inhibited the apoptosis of hiPSC-CMs via enhancing signal transducer and activator of transcription 3 (STAT3) phosphorylation and B-cell lymphoma-2 (BCL2) expression, promoting STAT3 nuclear translocation, and downregulating BCL2-Associated X, dual specificity phosphatase 2 (DUSP2), and cleaved-caspase-3 expression under hypoxia. Furthermore, MLB significantly suppressed the production of malondialdehyde and lactate dehydrogenase and the reduction in glutathione content induced by hypoxia in both HUVECs and hiPSC-CMs in vitro. Conclusions:. MLB significantly enhanced the potential of hiPSC-CMs in repairing injured myocardium by improving endothelial cell function via the NF-κB/ICAM1 pathway and inhibiting hiPSC-CMs apoptosis via the DUSP2/STAT3 pathway.

Abstract Introduction To assess the safety and efficacy of repeated intravitreal injections of RC28-E, a novel bispecific antibody that simultaneously binds vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients with neovascular age-related macular degeneration (AMD). This was a prospective, multicenter, open-label clinical trial; 37 patients with choroidal neovascularization secondary to AMD and best-corrected visual acuity (BCVA) letter scores between 73 and 34 were enrolled. Methods Treatment regimens consisted of a 3-month loading phase and a pro re nata (PRN) maintenance phase. This study included three treatment groups: the 0.5, 1.0, and 2.0 mg RC28-E groups, with escalating doses ranging from 0.5 to 2.0 mg. Patients were evaluated monthly for 48 weeks. Safety was assessed based on ocular and systemic adverse events (AEs), pharmacokinetic characteristics, and the presence of anti-RC28-E antibodies. Efficacy was assessed using the mean change in BCVA and central subfield thickness (CST) from baseline to week 48. Results Most AEs were mild or moderate. The most common AE was a minor injection-related subconjunctival hemorrhage (16.2%). The AEs did not increase with dose or repeated injections. At week 48, mean improvements in BCVA from baseline in the 0.5, 1.0, and 2.0 mg groups were 6.1 ± 8.3, 9.9 ± 10.7, and 7.6 ± 9.38 letters, respectively; mean reductions in CST in the three groups were 112.1 ± 160.5, 175.1 ± 212.4, and 128.7 ± 145.8 μm, respectively. The serum RC28-E concentrations in 95% of the patients were below the quantification limit of the assay. No significant change from baseline was observed in the mean plasma concentrations of VEGF or FGF over the 48 weeks of treatment. Pre-treatment antibodies to RC28-E were detected in 1 of the 37 patients. Antibodies to RC28-E were detected in two patients after dosing with RC28-E for 48 weeks. Conclusion RC28-E was well tolerated and exhibited an overall favorable safety profile with evidence of improvements in BCVA and anatomical parameters.

BackgroundLynch syndrome (LS) is an autosomal dominant inherited disorder caused by mutations in mismatch repair genes. Genetic counseling is crucial for the prevention and treatment of LS, as individuals with these mutations have an increased lifetime risk of developing multiple cancers. MutS Homolog 2 (MSH2) is a protein-coding gene that plays a key role in LS. A significant number of LS cases are linked to harmful heterozygous mutations in the MSH2 gene.Case PresentationThe proband was a 50-year-old endometrial dedifferentiated carcinoma patient with a dMMR/MSI-H tumor negative for MSH2/MSH6 expression by immunohistochemistry. Genetic counseling and tumor gene testing were conducted using next-generation sequencing (NGS) technology, which revealed a previously unknown germline MSH2 gene nonsense mutation NM_000251.2:exon2.354T>A (p.Y118*), leading to a diagnosis of LS. Further analysis of this variant in five family members of the patient confirmed its presence in all individuals, with one family member being diagnosed with colorectal cancer (CRC) at the age of 43. The proband received postoperative chemoradiotherapy and achieved a disease-free survival of 2 years, with ongoing follow-up.ConclusionThis study provides evidence that the MSH2 nonsense mutation c.354T>A is a highly likely pathogenic mutation and is responsible for typical LS-associated endometrial carcinoma. It emphasizes the importance of genetic counseling for proband family members to facilitate early diagnosis of LS-related carcinoma.

Summary: Background: In order to address the low compliance and dissatisfied specificity of low-dose computed tomography (LDCT), efficient and non-invasive approaches are needed to complement its limitations for lung cancer screening and management. The ASCEND-LUNG study is a prospective two-stage case–control study designed to evaluate the performance of a liquid biopsy-based comprehensive lung cancer screening and post-screening pulmonary nodules management system. Methods: We aimed to develop a comprehensive lung cancer system called Peking University Lung Cancer Screening and Management System (PKU-LCSMS) which comprises a lung cancer screening model to identify specific populations requiring LDCT and an artificial intelligence-aided (AI-aided) pulmonary nodules diagnostic model to classify pulmonary nodules following LDCT. A dataset of 465 participants (216 cancer, 47 benign, 202 non-cancer control) were used for the two models’ development phase. For the lung cancer screening model development, cancer participants were randomly split at a ratio of 1:1 into the train and validation cohorts, and then non-cancer controls were age-matched to the cancer cases in a 1:1 ratio. Similarly, for the AI-aided pulmonary nodules model, cancer and benign participants were also randomly divided at a ratio of 2:1 into the train and validation cohorts. Subsequently, during the model validation phase, sensitivity and specificity were validated using an independent validation cohort consisting of 291 participants (140 cancer, 25 benign, 126 non-cancer control). Prospectively collected blood samples were analyzed for multi-omics including cell-free DNA (cfDNA) methylation, mutation, and serum protein. Computerized tomography (CT) images data was also obtained. Paired tissue samples were additionally analyzed for DNA methylation, DNA mutation, and messenger RNA (mRNA) expression to further explore the potential biological mechanisms. This study is registered with ClinicalTrials.gov, NCT04817046. Findings: Baseline blood samples were evaluated for the whole screening and diagnostic process. The cfDNA methylation-based lung cancer screening model exhibited the highest area under the curve (AUC) of 0.910 (95% CI, 0.869–0.950), followed by the protein model (0.891 [95% CI, 0.845–0.938]) and lastly the mutation model (0.577 [95% CI, 0.482–0.672]). Further, the final screening model, which incorporated cfDNA methylation and protein features, achieved an AUC of 0.963 (95% CI, 0.942–0.984). In the independent validation cohort, the multi-omics screening model showed a sensitivity of 99.2% (95% CI, 0.957–1.000) at a specificity of 56.3% (95% CI, 0.472–0.652). For the AI-aided pulmonary nodules diagnostic model, which incorporated cfDNA methylation and CT images features, it yielded a sensitivity of 81.1% (95% CI, 0.732–0.875), a specificity of 76.0% (95% CI, 0.549–0.906) in the independent validation cohort. Furthermore, four differentially methylated regions (DMRs) were shared in the lung cancer screening model and the AI-aided pulmonary nodules diagnostic model. Interpretation: We developed and validated a liquid biopsy-based comprehensive lung cancer screening and management system called PKU-LCSMS which combined a blood multi-omics based lung cancer screening model incorporating cfDNA methylation and protein features and an AI-aided pulmonary nodules diagnostic model integrating CT images and cfDNA methylation features in sequence to streamline the entire process of lung cancer screening and post-screening pulmonary nodules management. It might provide a promising applicable solution for lung cancer screening and management. Funding: This work was supported by Science, Science, Technology & Innovation Project of Xiongan New Area, Beijing Natural Science Foundation, CAMS Innovation Fund for Medical Sciences (CIFMS), Clinical Medicine Plus X-Young Scholars Project of Peking University, the Fundamental Research Funds for the Central Universities, Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, Peking University People's Hospital Research and Development Funds, National Key Research and Development Program of China, and the fundamental research funds for the central universities.

Abstract Centrosymmetric-oxide/polydimethylsiloxane elastomers emit ultra-strong non-pre-irradiation mechanoluminescence under stress and are considered one of the most ideal mechanoluminescence materials. However, previous centrosymmetric-oxide/polydimethylsiloxane elastomers show severe mechanoluminescence degradation under stretching, which limits their use in applications. Here we show an elastomer based on centrosymmetric fluoride CaF2:Tb3+ and polydimethylsiloxane, with mechanoluminescence that can self-recover after each stretching. Experimentation indicates that the self-recoverable mechanoluminescence of the CaF2:Tb3+/polydimethylsiloxane elastomer occurs essentially due to contact electrification arising from contact-separation interactions between the centrosymmetric phosphors and the polydimethylsiloxane. Accordingly, a contact-separation cycle model of the phosphor–polydimethylsiloxane couple is established, and first-principles calculations are performed to model state energies in the contact-separation cycle. The results reveal that the fluoride–polydimethylsiloxane couple helps to induce contact electrification and maintain the contact-separation cycle at the interface, resulting in the self-recoverable mechanoluminescence of the CaF2:Tb3+/polydimethylsiloxane elastomer. Therefore, it would be a good strategy to develop self-recoverable mechanoluminescence elastomers based on centrosymmetric fluoride phosphors and polydimethylsiloxane.

BackgroundDespite extensive literature on therapeutic strategies for cervical cancer, a bibliometric analysis specifically focused on immunotherapy for advanced, recurrent, or metastatic (A/R/M) cervical malignancies remains unexplored. This study aims to address this gap by presenting a comprehensive overview that includes general characteristics, research focal points, the trajectory of evolution, and current emerging trends in this under-researched area.MethodsA systematic search was conducted using the Web of Science Core Collection (WOSCC) to identify articles related to A/R/M cervical cancer published between 2000 and 2022. Citespace and VOS viewer were the primary tools used to identify research focal points, intriguing future patterns, and to evaluate contributions and co-occurrences among authors, institutions, countries, and journals.ResultsA total of 1,001 original articles were identified, involving 6,387 authors from 66 countries and 1,474 institutions, and published across 366 academic journals. The United States contributed most significantly. The most productive researcher was Van der Burg SH from Leiden University Medical Center. The International Journal of Cancer and Cancer Research were identified as the most productive and influential journals, respectively. Analysis of co-citation clusters highlighted 25 clusters, primarily focusing on potential predictive biomarkers, dendritic cell-based tumor vaccines, therapeutic HPV vaccinations, peptide-based cancer vaccines, tumor immune microenvironments, and adoptive cell transfer (ACT). The latest significant trends in A/R/M cervical cancer immunotherapy research included ACT, CAR-T, and immune checkpoint inhibitors (ICIs), as revealed by keyword and reference burst detection.ConclusionThis pioneering study provides a detailed landscape of immunotherapy research in A/R/M cervical cancer. It underscores the importance of global collaboration, enriches our understanding of the immunology of A/R/M cervical cancer, expands on potential beneficiaries of immunotherapy, and explores clinical applications of various therapies, including therapeutic vaccines, adoptive cell transfer, and ICIs, particularly in combination with established treatments such as chemotherapy, radiotherapy, and targeted therapy.

Introduction: Malignant pleural mesothelioma (MPM) is a rare and universally lethal malignancy with limited treatment options. Immunotherapy with immune checkpoint inhibitors (ICIs) has recently been approved for unresectable MPM, but response to ICIs is heterogeneous, and reliable biomarkers for prospective selection of appropriate subpopulations likely to benefit from ICIs remain elusive. Methods: We performed multiscale integrative analyses of published primary tumor data set from The Cancer Genome Atlas (TCGA) and the French cohort E-MTAB-1719 to unravel the tumor immune microenvironment of MPM deficient in BAP1, one of the most frequently mutated tumor suppressor genes (TSGs) in the disease. The molecular profiling results were validated in independent cohorts of patients with MPM using immunohistochemistry and multiplex immunohistochemistry. Results: We revealed that BAP1 deficiency enriches immune-associated pathways in MPM, leading to increased mRNA signatures of interferon alfa/gamma response, activating dendritic cells, immune checkpoint receptors, and T-cell inflammation. This finding was confirmed in independent patient cohorts, where MPM tumors with low BAP1 levels are associated with an inflammatory tumor immune microenvironment characterized by increased exhausted precursor T-cells and macrophages but decreased myeloid-derived suppressor cells (MDSCs). In addition, BAP1low MPM cells are in close proximity to T cells and therefore can potentially be targeted with ICIs. Finally, we revealed that BAP1-proficient MPM is associated with a hyperactive mitogen-activated protein kinase (MAPK) pathway and may benefit from treatment with MEK inhibitors (MEKis). Conclusion: Our results suggest that BAP1 plays an immunomodulatory role in MPM and that BAP1-deficient MPM may benefit from immunotherapy, which merits further clinical investigation.

Abstract Existing studies about wind pressure on agricultural greenhouse buildings concentrate on the mean wind pressure while ignoring the systematic research on fluctuating wind pressure characteristics and the influence of roof shape on the wind pressure characteristics, which are closely associated with the wind-induced damage mechanism. In this study, two typical agricultural greenhouse buildings on tropical islands are selected as prototypes to conduct pressure measurement experiments in the wind tunnel. Based on the wind pressure time series for the two greenhouses, the mean and fluctuating wind pressure distribution pattern and the localized high-pressure generation mechanism are analyzed. Then, the shape coefficient of the two greenhouses is compared in depth to the standards from four countries. Besides, wind pressure non-Gaussian determination criteria for agricultural greenhouse buildings considering the roof shape and wind directions are proposed. Lastly, the differences in wind pressure spectra on the roofs and walls of the two greenhouses are summarized. The results indicate the roof shape has a significant influence on the wind pressure characteristics. Compared with the pitched roof, the vaulted roof will increase the suction effect on the windward front zone and the middle area, mitigate the suction impact on the leeward roof, and weaken the wind pressure non-Gaussian characteristics. The experimental shape coefficient of the pitched-roof greenhouse is basically consistent with the standard from the U.S., while that of the vaulted-roof greenhouse has some deviation from the existing standards. The results provide a theoretical basis for the wind-resistant design of agricultural greenhouse buildings on tropical islands.

The pathogeny of polycystic ovary syndrome (PCOS) is intricate, with endocrine disruptors (EDCs) being acknowledged as significant environmental factors. Research has shown a link between exposure to per- and polyfluoroalkyl substances (PFAS) and the development and progression of PCOS, although the precise mechanism is not fully understood. This study utilized toxicogenomics and comparative toxicogenomics databases to analyze data and investigate how PFAS mixtures may contribute to the development of PCOS. The results indicated that 74 genes are associated with both PFAS exposure and PCOS progression. Enrichment analysis suggested that cell cycle regulation and steroid hormone synthesis may be crucial pathways through which PFAS mixtures participate in the development of PCOS, involving important genes such as CCNB1 and SRD5A1. Furthermore, the study identified transcription factors (TFs) and miRNAs that may be involved in the onset and progression of PCOS, constructing regulatory networks encompassing TFs-mRNA interactions and miRNA-mRNA relationships to elucidate their regulatory roles in gene expression. By utilizing data mining techniques based on toxicogenomic databases, this study provides relatively comprehensive insights into the association between exposure factors and diseases compared to traditional toxicology studies. These findings offer new perspectives for further in vivo or in vitro investigations and contribute to understanding the pathogenesis of PCOS, thereby providing valuable references for identifying clinical treatment targets.

Ganoderma lucidum polysaccharides (G. PS) have been recognized for their immune-modulating properties. In this study, we investigated the impact of G. PS in a sepsis mouse model, exploring its effects on survival, inflammatory cytokines, Treg cell differentiation, bacterial load, organ dysfunction, and related pathways. We also probed the role of macrophages through chlorphosphon-liposome pretreatment. Using the cecal ligation and puncture (CLP) model, we categorized mice into normal, PBS, and G. PS injection groups. G. PS significantly enhanced septic mouse survival, regulated inflammatory cytokines (TNF-α, IL-17A, IL-6, IL-10), and promoted CD4+Foxp3+ Treg cell differentiation in spleens. Additionally, G. PS reduced bacterial load, mitigated organ damage, and suppressed the NF-κB pathway. In vitro, G. PS facilitated CD4+ T cell differentiation into Treg cells via the p-STAT5 pathway. Chlorphosphon-liposome pretreatment heightened septic mortality, bacterial load, biochemical markers, and organ damage, emphasizing macrophages' involvement. G. PS demonstrated significant protective effects in septic mice by modulating inflammatory responses, enhancing Treg cell differentiation, diminishing bacterial load, and inhibiting inflammatory pathways. These findings illuminate the therapeutic potential of G. PS in sepsis treatment.

ABSTRACTAmphenmulin is a novel pleuromutilin derivative with great anti-mycoplasma potential. The present study evaluated the action characteristics of amphenmulin against Mycoplasma gallisepticum using pharmacokinetic/pharmacodynamic (PK/PD) modeling approaches. Following intravenous administration, amphenmulin exhibited an elimination half-life of 2.13 h and an apparent volume of distribution of 3.64 L/kg in healthy broiler chickens, demonstrating PK profiles of extensive distribution and rapid elimination. The minimum inhibitory concentration (MIC) of amphenmulin against M. gallisepticum was determined to be 0.0039 µg/mL using the broth microdilution method, and the analysis of the static time–kill curves through the sigmoid Emax model showed a highly correlated relationship (R ≥ 0.9649) between the kill rate and drug concentrations (1–64 MIC). A one-compartment open model with first-order elimination was implemented to simulate the in vivo anti-mycoplasma effect of amphenmulin, and it was found that bactericidal levels were reached with continuous administration for 3 days at doses exceeding 0.8 µg/mL. Furthermore, the area under the concentration–time curve divided by MIC (AUC/MIC) correlated well with the anti-mycoplasma effect of amphenmulin within 24 h after each administration, with a target value of 904.05 h for predicting a reduction of M. gallisepticum by 1 Log10CFU/mL. These investigations broadened the antibacterial spectrum of amphenmulin and revealed its characteristics of action against M. gallisepticum, providing a theoretical basis for further clinical development.IMPORTANCEMycoplasma has long been recognized as a significant pathogen causing global livestock production losses and public health concerns, and the use of antimicrobial agents is currently one of the mainstream strategies for its prevention and control. Amphenmulin is a promising candidate pleuromutilin derivative that was designed, synthesized, and screened by our laboratory in previous studies. Moreover, this study further confirms the excellent antibacterial activity of amphenmulin against Mycoplasma gallisepticum and reveals its action characteristics and model targets on M. gallisepticum by establishing an in vitro pharmacokinetic/pharmacodynamic synchronization model. These findings can further broaden the pharmacological theoretical basis of amphenmulin and serve as data support for its clinical development, which is of great significance for the discovery of new antimicrobial drugs and the control of bacterial diseases in humans and animals.

Abstract Cancer exerts a multitude of effects on metabolism, including the reprogramming of cellular metabolic pathways and alterations in metabolites that facilitate inappropriate proliferation of cancer cells and adaptation to the tumor microenvironment. There is a growing body of evidence suggesting that aberrant metabolites play pivotal roles in tumorigenesis and metastasis, and have the potential to serve as biomarkers for personalized cancer therapy. Importantly, high-throughput metabolomics detection techniques and machine learning approaches offer tremendous potential for clinical oncology by enabling the identification of cancer-specific metabolites. Emerging research indicates that circulating metabolites have great promise as noninvasive biomarkers for cancer detection. Therefore, this review summarizes reported abnormal cancer-related metabolites in the last decade and highlights the application of metabolomics in liquid biopsy, including detection specimens, technologies, methods, and challenges. The review provides insights into cancer metabolites as a promising tool for clinical applications.

Bilirubin-induced liver injury is a severe health issue with inadequate treatment. This study examined whether saffron's Crocin and Crocetin could reduce bile stasis-induced liver injury. This study also investigated how these compounds may affect bile acid metabolism by inhibiting ERK phosphorylation. Network pharmacology analysis and in vitro and in vivo experiments showed that Crocin and Crocetin could affect the ERK signaling pathway, reducing bile acid production and bile stasis-induced liver injury. The study found that Crocin and Crocetin reduced CYP7A1 synthesis by inhibiting ERK signaling pathway phosphorylation and promoting PPARα binding to the promoter. Crocin and Crocetin also increased Mrp3 and Mrp4, which reduced bile acid formation and mitigated bile stasis-induced liver injury. These findings offer new insights into developing novel bile stasis-induced liver injury treatments.

Immune checkpoint blockade (ICB) therapies, that is, using monoclonal antibodies to reinvigorate tumor-reactive, antigen-specific T cells from the inhibitory effects of CTLA-4, PD-1 and PD-L1 immune checkpoints, have revolutionized the therapeutic landscape of modern oncology. However, only a subset of patients can benefit from the ICB therapy. Biomarkers associated with ICB response, resistance and prognosis have been subjected to intensive research in the past decade. Early studies focused on the analysis of tumor specimens and their residing microenvironment. However, biopsies can be challenging to obtain in clinical practice, and do not reflect the dynamic changes of immunological parameters during the ICB therapy. Recent studies have investigated profiles of antigen-specific T cells derived from the peripheral compartment using multi-omics approaches. By tracking the clonotype and diversity of tumor-reactive T cell receptor repertoire, these studies collectively establish that de novo priming of antigen-specific T cells in peripheral blood occurs throughout the course of ICB, whereas preexisting T cells prior to ICB are exhausted to various degrees. Here, we review what is known about ICB-induced T cell phenotypic and functional changes in cancer patients both within the tumor microenvironment and in the peripheral compartment. A better understanding of parameters influencing the response to ICBs will provide rationales for developing novel diagnostics and combinatorial therapeutic strategies to maximize the clinical efficacies of ICB therapies.

Environmental copper (Cu) contamination is a complex worldwide public health problem. However, information on the effects of Cu pollution on human reproduction is limited. Although our previous studies have indicated that Cu exposure disrupts ovarian folliculogenesis, the underlying mechanism needs to be further explored. In this study, human luteinized ovarian granulosa cells and a rat animal model were used to investigate whether Cu exposure affects ovarian follicle development by inducing apoptosis and to elucidate the possible mechanisms. The results showed that Cu exposure from weaning to sexual maturity significantly decreased the proportion of preantral follicles but increased the proportion of atretic follicles (P

Background: Ganoderma lucidum (G. lucidum) is a popular traditional remedy medicine used in Asia to promote health and longevity, which has also been highlighted for anti-cancer effects. This study investigated the molecular pharmacological mechanism of G. lucidum triterpenes in influencing intestinal flora imbalance in non-hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) based on 16S rRNA sequencing technology and network pharmacology analysis.Methods: 16S rRNA sequencing data of fecal samples from normal controls and HCC patients were obtained from the SRA database. G. lucidum triterpenes and HCC-related targets were screened by BATMAN-TCM, ETCM, and GeneCards databases. The TCGA-LIHC dataset was downloaded through the TCGA database to analyze the differential expression of key genes. NHBV-related HCC-related transcriptome RNA sequencing dataset was downloaded via the GEO database.Results: Abundance of intestinal flora in the HBV-related HCC and NHBV-related samples was higher than that of control samples. The intestinal flora of NHBV samples was mainly enriched in apoptosis and p53 pathways. Totally, 465 G. lucidum triterpenes-related targets were intersected with 4186 HCC-related targets, yielding 176 intersected targets. Among them, apoptosis and p53 pathway factors were located at the core of the protein-protein interactions network. Ganosporelactone B, the active component of G. lucidum triterpenes, had the lowest binding free energy to CASP3. CASP3 expression were upregulated in HCC tissue samples, and had higher predictive value in NHBV-related HCC patients.Conclusion: Therefore, Ganosporelactone B, the active ingredient of G. lucidum triterpenes, improves the imbalance of intestinal flora and ultimately curtails development of NHBV-related HCC.

ObjectivesNeoadjuvant chemoimmunotherapy is the optimal choice in the treatment of NSCLC; however, the optimal number of therapeutic cycles remains unclear. The primary aim of this study was to determine the optimal number of neoadjuvant therapeutic cycles in NSCLC.MethodsThis study was a real-world clinical analysis that included patients who received neoadjuvant chemoimmunotherapy followed by surgery from January 2020 to August 2022. Patients were divided into two groups based on the number of therapeutic cycles: 2-cycle group and 3-4-cycles group. The primary endpoint was the major pathological response (MPR) rate.ResultsA total of 251 patients were included: 150 in the 2-cycle group and 101 in the 3-4-cycles group. Baseline characteristics were well-balanced between the groups. The MPR in the 2-cycle group was 57.3% and not significantly different from that of 57.4% in the 3-4-cycles group (p=0.529). Thirty-two patients (31.7%) in the 3-4-cycles group underwent surgery > 42 days after the final cycle of neoadjuvant therapy, significantly more than the 24 patients (16.0%) in the 2-cycle group (p=0.003). The incidence of adverse events related to neoadjuvant therapy was higher in the 3-4-cycles vs 2-cycle groups (72.3% versus 58.0%, respectively; p=0.021), while the 2-cycle group had a higher rate of postoperative morbidities (28.0% versus 12.9%, respectively; p=0.004). Additionally, for patients with ≤ 44.2% regression in diameter on computed tomography after two cycles of treatment, the MPR rate was higher in the 3-4-cycles vs 2-cycle group (47.3% versus 29.9%, respectively; p=0.048). For cases with programmed death-ligand 1 expression, regarding tumor proportion score ≤ 10%, 3-4 cycles of neoadjuvant treatment increased the MPR rate compared with 2 cycles (37.5% versus 9.5%, respectively; p=0.041).ConclusionOur data support the positive role of chemoimmunotherapy in the neoadjuvant treatment of NSCLC. Extending to 3–4 cycles instead of 2 cycles of neoadjuvant chemoimmunotherapy may improve the safety of surgery and result in a lower incidence of postoperative morbidities; however, the MPR rate may not increase significantly. CT re-evaluation during treatment and PD-L1 expression at initial diagnosis are potential indicators to guide the choice of the number of therapeutic cycles.

Tilmicosin is a semi-synthetic macrolide for veterinary use with strong antibacterial effect on respiratory bacteria. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) integration of tilmicosin against Pasteurella multocida (P. multocida) was evaluated by establishing a piglet tissue cage infection model. Concentration of tilmicosin and bacterial numbers of P. multocida in the tissue-cage fluid were monitered. After the population of P. multocida was equal to or greater than 107 CFU/mL in a tissue cage, piglets received an oral administration of tilmicosin at a dose of 30, 40, 50, and 60 mg/kg b.w., once daily for 3 days, respectively. Bacteria were counted every 24 h after drug administration and at 48 and 72 h after the last administration. A sigmoidal Emax model was used to fit the relationship between PK/PD parameters and the antibacterial effect. AUC24h/MIC was the best PK/PD index that correlated with effectiveness of tilmicosin against P. multocida. The magnitude of AUC24h/MIC required for continuous 1/3-log, 1/2-log, and 3/4-log reductions were 19.65 h, 23.86 h, and 35.77 h, respectively, during each 24 h treatment period. In this study, when the dosage was >50 mg/kg, the AUC24h/MIC was still >35.77 h in the period of 24–48 h after the last administration due to the slow elimination, that is, tilmicosin exhibited a potent antibacterial effect against P. multocida after three successive daily administrations. The data provide meaningful guidance to optimize regimens of tilmicosin to treat respiratory tract infections caused by P. multocida.

Cancer morbidity and mortality are growing rapidly worldwide and it is urgent to develop a convenient and effective method that can identify cancer patients at an early stage and predict treatment outcomes. As a minimally invasive and reproducible tool, liquid biopsy (LB) offers the opportunity to detect, analyze and monitor cancer in any body fluids including blood, complementing the limitations of tissue biopsy. In liquid biopsy, circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are the two most common biomarkers, displaying great potential in the clinical application of pan-cancer. In this review, we expound the samples, targets, and newest techniques in liquid biopsy and summarize current clinical applications in several specific cancers. Besides, we put forward a bright prospect for further exploring the emerging application of liquid biopsy in the field of pan-cancer precision medicine.

Abstract Background The impact of neoadjuvant chemoimmunotherapy on pulmonary resection and related outcomes had been poorly reported in previous studies. The present study aims to clarify the efficacy and safety of neoadjuvant chemoimmunotherapy, and intraoperative difficulty in the following surgery, in comparison with chemotherapy alone in non‐small cell lung cancer (NSCLC). Methods Patients with newly diagnosed clinical stages IB–IIIB(T3‐4N2) NSCLC, received neoadjuvant chemotherapy + PD‐1 inhibitors (PD‐1 + Chemo group) or chemotherapy alone (Chemo group) followed by surgery between December 2018 and December 2020 were included. The clinicopathological characteristics were retrospectively reviewed and analyzed. Results There were 69 NSCLC patients in the PD‐1 + Chemo group and 121 in the Chemo group. The major pathological response (MPR) rate in the PD‐1 + Chemo group was 49.3%, higher than that of 19.0% in the Chemo group (p 0.05). Conclusions Neoadjuvant chemoimmunotherapy for NSCLC is safe and feasible, with higher MPR rates, as well as favorable DFS than chemotherapy alone. Surgical complexity might be increased in certain patients, with comparable perioperative morbidity and mortality.

BackgroundArsenic is recognized as a kind of developmental toxicant, which can pass through the placenta barrier and induce health defects in offspring. However, the effects of environmental levels of arsenic exposure during gestation on the reproductive system of adult male offspring remain unclear.ObjectiveTo investigate the impact of environmental levels of arsenic exposure during gestation on testosterone synthesis and sperm quality in F1 adult male rats.MethodsForty sexually mature Wistar female rats were randomly divided into four groups according to body weight, namely control group, low-dose sodium arsenite (NaAsO2) group, middle-dose NaAsO2 group, and high-dose NaAsO2 group. They were mated with sexually mature Wistar male rats in a ratio of 2:1, and the day with presence of a vaginal plug or spermatozoa in the vaginal smear was designated as gestational day 0 (GD0). Pregnant rats were provided drinking water containing 0, 1, 5,, or 25 mg·L−1 NaAsO2 until delivery. At postnatal day 70, the F1 male rats were euthanized. Anogenital distance was measured, testis and epididymis were weighed, and associated organ coefficients were calculated. Epididymal sperm quality was evaluated. The histological changes of testis were observed. The levels of testosterone and estradiol in serum were determined with ELISA kit. The testicular mRNA relative expression levels of key steroidogenic enzymes were determined by quantitative real-time PCR. The protein relative expression levels of key steroidogenic enzymes were determined by Western blotting.ResultsCompared with the control group, the testicular coefficients and epididymis coefficients were increased in the low- and middle-dose groups (P

Low-molecular-weight adhesives (LMWAs) possess many unique features compared to polymer adhesives but fabrication of LMWAs with adhesion strengths higher exceeding those of polymeric materials is a significant challenge. Here, the authors propose an ionic liquid based thin coating adhesive with high adhesion strength.

Abstract Introduction Esophageal squamous cell carcinoma (ESCC) represents a major malignancy with poor clinical outcomes. Long noncoding RNAs (lncRNAs) are known to regulate the development and progression of multiple cancers. However, how lncRNAs are involved in ESCC is currently undefined. Methods LIPH-4 levels in ESCC tissue specimens and cells were assessed by qRT-PCR. The biological function of LIPH-4 was examined in cell and animal studies, applying CCK-8, EdU, colony formation and flow cytometry assays as well as xenograft model experiments. The underlying mechanisms of action of LIPH-4 were explored through bioinformatics, luciferase reporter assay, RNA-immunoprecipitation assay and immunoblot. Results We identified a novel lncRNA, LIPH-4, which showed elevated amounts in ESCC tissues and positive correlations with increased tumor size and poor prognosis in ESCC patients. Functional studies showed that LIPH-4 promoted the growth, mediated cell cycle progression and inhibited apoptosis in ESCC cells in vitro, and promoted tumor growth in mice. In terms of mechanism, LIPH-4 could bind to miR-216b and act as a competing endogenous RNA (ceRNA) to induce the expression of miR-216’s target gene IGF2BP2. LIPH-4 played an oncogenic role in ESCC through the miR-216b/IGF2BP2 axis. Conclusions This study suggested that LIPH-4 functions as a novel oncogenic lncRNA by acting as a ceRNA for miR-216b to regulate IGF2BP2, indicating LIPH-4 likely constitutes a prognostic biomarker and therapeutic target in ESCC.

Abstract Long noncoding RNAs (lncRNAs) represent an important group of endogenous RNAs with limit protein-encoding capability, with a length of more than 200 nucleotides. Emerging evidence have demonstrated that lncRNAs are greatly involved in multiple cancers by playing critical roles in tumor initiation and progression. Long intergenic non-protein coding RNA 460 (LINC00460), a novel cancer-related lncRNA, exhibits abnormal expression and oncogenic function in multiple cancers, and positively correlates with poor clinical characteristics of cancer patients. LINC00460 has also been shown to be a promising biomarker for diagnosis as well as prognostic evaluation in cancer patients. In this review, we briefly summarized recent knowledge on the expression, functional roles, molecular mechanisms, and diagnostic and prognostic values of LINC00460 in human malignancies.

Pod shattering causes severe yield loss in rapeseed (Brassica napus L.) under modern agricultural practice. Identification of highly shatter-resistant germplasm is desirable for the development of rapeseed cultivars for mechanical harvesting. In the present study, an elite line OR88 with strong shatter resistance and a lignified-layer bridge (LLB) structure was identified. The LLB structure was unique to OR88 and co-segregated with high pod-shatter resistance. The LLB structure is differentiated at stage 12 of gynoecium development without any gynoecium defects. Genetic analysis showed that LLB is controlled by a single recessive gene. By BSA-Seq and map-based cloning, the resistance gene location was delimited to a 0.688 Mb region on chromosome C09. Transcriptome analysis suggested BnTCP8.C09 as the gene responsible for LLB. The expression of BnTCP.C09 was strongly downregulated in OR88, suppressing cell proliferation in the pod valve margin. KASP markers linked to the candidate gene were developed. This pod shatter-resistant line could be used in rapeseed breeding programs by direct transfer of the gene with the assistance of the DNA markers.

The quantity of recharge of groundwater lateral flow from mountainous areas to plain areas is a long-term controversial and unresolved problem, which is always estimated to be too small or too large in arid inland basins in northwest China. Based on previous studies, this paper uses the technical methods of geological and hydrogeological investigation, geophysical exploration, drilling, pumping test, groundwater dynamic observation, hydrochemical test, basin groundwater level measurement and comprehensive study to identify the geological structure contact relationship, stratigraphic lithology contact relationship at the southern mountain-basin transition zone of the middle reaches of the Heihe River Basin, and the Cretaceous weathering crust aquifer structure and hydrogeological parameters at the Liyuan estuary. Through the analysis of the surface water and groundwater transformation relationships of different watershed levels in the mountainous areas, the recharge zones of groundwater lateral flow from the mountainous areas to the plain areas are divided into the large and medium-sized river valley recharge sections and shallow mountain recharge sections composed of small and micro rivers and gully groups. The exploration data of the river valley recharge sections are abundant, and the Darcy section flow method is used to calculate the recharge quantity. In view of the fact that the recharge section of the shallow mountain belt extremely lacks the exploration data, the runoff of the Liyuan estuary section is used as a reference. The estimation method of recharge of the groundwater lateral flow from the mountainous areas in the shallow mountain belt to the plain area is constructed with three variables of lithology, catchment area and precipitation. The results show that the quantity of recharge of groundwater lateral flow from the southern mountainous area to the plain area in the shallow mountain zone of the middle reaches of the Heihe River Basin is 0.40 × 108 m3/a, and that of bedrock in the valley sections is 0.07 × 108 m3/a. The quantity of recharge of groundwater of the Quaternary sediments in the valley sections is 0.30 × 108 m3/a. The sum of the three recharges is 0.77 × 108 m3/a, accounting for 3.0 % of the basin groundwater resources. This method provides an example for the estimation of the recharge of groundwater lateral flow from the mountainous areas to the plain areas in the northwest inland arid basins.

Increasing evidence has shown that gut microbes play an important role in the reproductive endocrine system and the development of polycystic ovary syndrome (PCOS). However, whether environmental factors are involved in these gut microbiota alterations has seldom been studied. In this study, we aimed to explore the crucial role of an imbalanced gut microbiota on abnormal ovarian follicle development induced by Cu. A 1:1 matched case-control study with 181 PCOS patients and 181 controls was conducted using a propensity score matching protocol. Information regarding dietary Cu intake was obtained from a face-to-face dietary intake interview. Alterations in the gut microbiota were detected by high-throughput 16 S rDNA sequencing. The results showed that dietary Cu intake was positively correlated with the risk of PCOS, and the risk threshold was approximately 1.992 mg/d. Compared with those with dietary Cu intakes lower than 1.992 mg/d, those who had a higher dietary Cu intake had a 1.813-fold increased risk of PCOS (OR=1.813, 95% CI: 1.150–2.857). PCOS patients had a lower relative abundance of Bacteroides than controls (P = 0.003), and Bacteroides played a partial mediating role between dietary Cu exposure and PCOS (Pindirect effect=0.026, 95% CI: 0.002–0.072). In addition, an animal model of Cu exposure through the diet showed that Cu can induce gut microbiota disorder; increase serum levels of LPS, MDA, and IL-6; and alter host ovarian steroidogenesis to affect ovarian follicle development. Staphylococcus played a partial mediating role between Cu exposure and CYP17A1 (Pg_Staphylococcus=0.083, 95% CI: 0.001–0.228). Overall, this study shows that long-term exposure to high dietary Cu levels can affect the composition of the gut microbiota, cause inflammation and oxidative stress, and then interfere with hormone signaling, ultimately affecting ovarian follicle development.

Qaidam cattle (CDM) are indigenous breed inhabiting Northwest China. In the present study, we newly sequenced 20 Qaidam cattle to investigate the copy number variants (CNVs) based on the ARS-UMD1.2 reference genome. We generated the CNV region (CNVR) datasets to explore the genomic CNV diversity and population stratification. The other four cattle breeds (Xizang cattle, XZ; Kazakh cattle, HSK; Mongolian cattle, MG; and Yanbian cattle, YB) from the regions of North China embracing 43 genomic sequences were collected and are distinguished from each of the other diverse populations by deletions and duplications. We also observed that the number of duplications was significantly more than deletions in the genome, which may be less harmful to gene formation and function. At the same time, only 1.15% of CNVRs overlapped with the exon region. Population differential CNVRs and functional annotations between the Qaidam cattle population and other cattle breeds revealed the functional genes related to immunity (MUC6), growth (ADAMTSL3), and adaptability (EBF2). Our analysis has provided numerous genomic characteristics of some Chinese cattle breeds, which are valuable as customized biological molecular markers in cattle breeding and production.

PurposeNeoadjuvant chemoimmunotherapy (nCIT) is becoming a new therapeutic frontier for resectable esophageal squamous cell carcinoma (ESCC); however, crucial details and technical know-how regarding surgical techniques and the perioperative challenges following nCIT remain poorly understood. The study investigated and compared the advantages and disadvantages of esophagectomy following nCIT with neoadjuvant chemotherapy (nCT) and chemoradiotherapy (nCRT).MethodsWe retrospectively analyzed data of patients initially diagnosed with resectable ESCC at clinical stage T2-4N+ and received neoadjuvant therapy followed by esophagectomy at the Hunan Cancer Hospital between October 2014 and February 2021. Patients were divided into three groups according to neoadjuvant treatment: (i) nCIT; (ii) nCT; and (iii) nCRT.ResultsThere were 34 patients in the nCIT group, 97 in the nCT group, and 31 in the nCRT group. Compared with nCT, nCIT followed by esophagectomy achieved higher pathological complete response (pCR; 29.0% versus 4.1%, p

Temperature is an inherent property of groundwater.Groundwater temperature field and dynamic characteristics are objective manifestations of groundwater flow system.Based on multi-point, long series and high precision groundwater temperature monitoring data, the characteristics of shallow groundwater temperature distribution and dynamic type of water temperature in Jiuquan East Basin are studied, in order to reveal the relationship between the characteristics of shallow groundwater temperature field and groundwater flow system under the influence of human activities such as groundwater exploitation in northwest inland basin.The results show that the shallow groundwater temperature ranges from 9.33℃ to 20.77℃, and the average water temperature is 13.54℃.From the recharge area to the discharge area, the shallow groundwater temperature increases gradually along the direction of groundwater runoff, and the average groundwater temperature in January is higher than that in July.The comparison of different groundwater flow systems with similar circulation depth shows that the shallow groundwater temperature is negatively correlated with groundwater dynamic conditions.The average groundwater temperature of the water flow system with large surface water recharge and strong hydrodynamic conditions is lower, and that of the water flow system with small recharge and weak hydrodynamic conditions is higher.The temperature dynamics of shallow groundwater are affected by human activities such as natural groundwater circulation and groundwater exploitation.From groundwater recharge area to oasis area in the middle reaches and drainage area in the lower reaches, the temperature dynamic of shallow groundwater can be divided into four basic types, which are river recharge type, water temperature stability type, groundwater exploitation related type and sinusoidal fluctuation type respectively.

Abstract Background Oncogenic KRAS mutations are prevalent in human cancers, but effective treatment of KRAS-mutant malignancies remains a major challenge in the clinic. Increasing evidence suggests that aberrant metabolism plays a central role in KRAS-driven oncogenic transformation. The aim of this study is to identify selective metabolic dependency induced by mutant KRAS and to exploit it for the treatment of the disease. Method We performed an integrated analysis of RNAi- and CRISPR-based functional genomic datasets (n = 5) to identify novel genes selectively required for KRAS-mutant cancer. We further screened a customized library of chemical inhibitors for candidates that are synthetic lethal with NOP56 depletion. Functional studies were carried out by genetic knockdown using siRNAs and shRNAs, knockout using CRISPR/Cas9, and/or pharmacological inhibition, followed by cell viability and apoptotic assays. Protein expression was determined by Western blot. Metabolic ROS was measured by flow cytometry-based quantification. Results We demonstrated that nucleolar protein 5A (NOP56), a core component of small nucleolar ribonucleoprotein complexes (snoRNPs) with an essential role in ribosome biogenesis, confers a metabolic dependency by regulating ROS homeostasis in KRAS-mutant lung cancer cells and that NOP56 depletion causes synthetic lethal susceptibility to inhibition of mTOR. Mechanistically, cancer cells with reduced NOP56 are subjected to higher levels of ROS and rely on mTOR signaling to balance oxidative stress and survive. We also discovered that IRE1α-mediated unfolded protein response (UPR) regulates this process by activating mTOR through p38 MAPK. Consequently, co-targeting of NOP56 and mTOR profoundly enhances KRAS-mutant tumor cell death in vitro and in vivo. Conclusions Our findings reveal a previously unrecognized mechanism in which NOP56 and mTOR cooperate to play a homeostatic role in the response to oxidative stress and suggest a new rationale for the treatment of KRAS-mutant cancers.

Spatial distribution and orientation of pods on the main raceme (stem) and branches could affect rapeseed yield. However, genomic regions underlying the pod orientation were not described in Brassica species. Here, we determined the extent of genetic variation in pod orientation, described as the angles of pedicel on raceme (APR) and angles of the pod on pedicel (APP) among 136 rapeseed accessions grown across three environments of the upper, middle and lower Yangtze River in China. The APR ranged from 59° to 109°, while the APP varied from 142° to 178°. Statistical analysis showed that phenotypic variation was due to genotypic (G) and environmental (E) effects. Using the genome-wide association analysis (GWAS) approach, two QTLs for APR (qBnAPR.A02 and qBnAPR.C02) and two for APP (qBnAPP.A05 and qBnAPP.C05), having minor to moderate allelic effects (4.30% to 19.47%) were identified. RNA-seq analysis revealed 606 differentially expressed genes (DEGs) in two rapeseed accessions representing the extreme phenotypes for pod orientation and different alleles at the QTLs of APR. Three DEGs (BnLAZY4.A02, BnSAUR32.A02, and BnSAUR32.C02) were identified as the most likely candidates responsible for variation in pod orientation (APR). This study elucidates the genomic regions and putative candidate genes underlying pod orientation in B. napus.

The Nsa cytoplasmic male sterility (CMS) system confers stable male sterility and offers great potential for production of hybrid seeds in oilseed rape. However, genes responsible for male sterility in Nsa CMS have not been identified. By mitochondrial genome sequencing of Nsa CMS and its maintainer line, we identified in an Nsa CMS line several chimeric genes encoding hypothetical proteins harboring transmembrane domains. One novel chimeric gene orf346 showed high identity with cox1 at the 5′ terminal region and was co-transcribed with nad3 and rps12 genes. Transgenic plants of orf346 fused with or without mitochondrial targeting peptide conferred complete male sterility in Arabidopsis. ORF346 was mitochondrion-localized. Expression of orf346 in Escherichia coli inhibited bacterial growth, with excessive accumulation of reactive oxygen species and decreased ATP content. These results reveal a link between the newly identified mitochondrial gene orf346 and the abortion of Nsa CMS. Inadequate energy supply and excessive accumulation of reactive oxygen species may account for pollen abortion in Nsa CMS plants.

BackgroundHuman wellbeing has been linked with lifestyle factors such as physical activity, diet balance, sleep quality, depression, and anxiety. However, few studies illustrate the relationship between such lifestyle factors and HPV infection. In this study, we investigated the association between lifestyle factors, age, disease status and HPV infection.Participants and methodsParticipants were recruited through a digital eHealth platform in Shenzhen, Mainland China. Both lifestyle factors and cervicovaginal mucus (CVM) samples to test for HPV outcomes were collected from each participant as a cross-sectional study. In addition, the eHealth platform recorded age and current or history diseases, which were adjusted to apply for both univariable and multivariable logistic regression. Furthermore, lifestyle factors were categorized as different levels to conduct stratification analysis.ResultsWe recruited 149 HPV positive and 346 HPV negative participants through HPV detection. Physical activity and diet balance were significantly associated with HPV infection in lifestyle factors (P values < 0.001) after adjusting for age and current or history diseases. However, stratified analysis showed three factors were insignificant for HPV infection – namely, sleep quality, depression, and anxiety. Most HPV infections involved a sole HPV serotype (83%), and diet balance was the most significant difference between sole and multiple HPV infections.ConclusionsAmong lifestyle factors, physical inactivity or diet imbalance can significantly increase HPV infection risk. In particular, diet balance might be related to the number of HPV serotypes. Our results suggest that exercising and regulating diet may reduce the risk of HPV infection.

Ponazuril is a triazine anticoccidial drug which is the main metabolite of toltrazuril in animals, it has excellent activity against many protozoa, including Cystoisospora suis, and has broad application prospects in the control of swine coccidiosis. To evaluate the pharmacokinetic and excretion characteristics of ponazuril, 12 healthy piglets aged 10–14 days were divided into 2 groups for pharmacokinetic studies, which were given 20 mg/kg body weight ponazuril orally and intravenously, respectively. And 6 other piglets were housed individually in metabolic cages and given the same oral dose of ponazuril. After administration, the concentration of ponazuril in plasma, fecal, and urine samples collected was determined using high-performance liquid chromatography (HPLC). The plasma concentration profiles of ponazuril obtained after intravenous and oral administration were analyzed simultaneously by the nonlinear mixed-effects (NLME) model. Following the results, the pharmacokinetics of ponazuril exhibited a Michaelis-Menten elimination with Michaelis-Menten constant Km and maximum metabolic rate Vm of 10.8 μg/mL and 0.083 mg/kg/h. The apparent volume of distribution was calculated to be 735 mL/kg, and the final estimated oral bioavailability was 81%. Besides, cumulatively 86.42 ± 2.96% of ponazuril was recovered from feces and 0.31% ± 0.08% from urine during 0–1,020 h after oral administration. These findings indicated a good oral absorption of ponazuril in piglets with nonlinear disposition and slow excretion largely via feces, implying sustained drug concentration in vivo and long-lasting anticoccidial effects.

Abstract Background The long noncoding RNA gastric cancer associated transcript 3 (GACAT3) has been demonstrated to be implicated in the carcinogenesis and progression of many malignancies. However, GACAT3’s levels and role in esophageal squamous cell carcinoma (ESCC) has not been elucidated. Methods GACAT3 amounts were investigated in ESCC tissues and cell lines by qPCR. Its biological functions were examined by CCK-8 assay, colony formation assay, flow cytometry, wound healing assay, transwell assay, and xenograft model establishment. The relationship between GACAT3 and miR-149 was assessed by dual-luciferase reporter assay. Results GACAT3 amounts were elevated in ESCC tissue and cell specimens. Functional studies showed that GACAT3 silencing reduced the proliferation, migration and invasion of cultured ESCC cells, and decreased tumor growth in mice. Furthermore, GACAT could directly interact with miR-149. In addition, colony formation and invasion assays verified that GACAT3 promotes ESCC tumor progression through miR-149. Moreover, GACAT3 acted as a competing endogenous RNA (ceRNA) to modulate FOXM1 expression. Conclusions These findings indicate that GACAT3 functions as an oncogene by acting as a ceRNA for miR-149 to modulate FOXM1 expression in ESCC, suggesting that GACAT3 might constitute a therapeutic target in ESCC.

Background About 60% of the annual precipitation in the Loess Plateau occurs during the summer fallow season, and does not align with the wheat growing season. In addition, the nitrogen use efficiency is low in this area because nutrient availability is affected by drought. As a result, rainwater storage during the summer fallow season is very important to increasing nitrogen use efficiency, and to the stable production of dryland wheat in the Loess Plateau. Methods A 3-year field experiment in the eastern part of the Loess Plateau was conducted with two tillage methods (no tillage (NT) and deep ploughing (DP)) and five N rates (0, 120, 150, 180, and 210 kg N ha−1) to study the effect of tillage on soil water utilization, plant nitrogen utilization, and wheat yield. Result Compared to NT, DP showed a larger increase in soil water storage (SWSf) and precipitation storage efficiency (PSEf) during the two dry summer fallow seasons than in the normal summer fallow season. DP substantially increased the pre-anthesis soil water consumption (SWCpre) and N translocation. The average yield under DP was 12.46% and 14.92–18.29% higher than under NT in the normal and dry seasons, respectively. A 1 mm increase in SWCpre could increase grain yield by 25.28 kg ha−1, water use efficiency (WUE) by 0.069 kg ha−1 mm−1, and nitrogen utilization efficiency (NUtE) by 0.029 kg kg−1. DP could reduce the N rate by 11.49–53.34% in the normal seasons and 40.97–65.07% in the dry seasons compared to the same highest point of yield, WUE, and NUtE under NT. Conclusion Deep ploughing in the summer fallow season, paired with optimized N application, could help increase wheat yield and nitrogen efficiency in dryland.

A simple strategy to rapidly detect glucose was developed by utilizing core (Fe3O4)–shell (Pt) magnetic nanoparticles (Fe3O4@Pt NPs) as a nanoenzyme and a paper-based colorimetric sensor. In the presence of H2O2, Fe3O4@Pt NPs catalyze the redox reaction of 3,3′,5,5′-tetramethylbenzidine (TMB) and generate a colour change from colourless to blue. On this basis, a colorimetric glucose sensing method assisted by glucose oxidase (GOx) was developed. Under the optimal conditions, the detection limits of the proposed assay for H2O2 and glucose were 0.36 µM and 1.27 µM, respectively. Furthermore, the fabricated colorimetric method was successfully applied to analyze glucose concentrations by using a paper device as a measuring platform without a spectrometer. In addition, this method exhibited satisfactory recovery for glucose detection in human serum samples and urine samples, which satisfied the requirements for normal detection of real samples. This study provides a good candidate for health monitoring of glucose and also expands the applications of nanoenzymes and paper-based colorimetric assays in point-of-care testing.

Arsenic contamination is a worldwide public health problem, and the effect of arsenic on male reproduction has been extensively studied; however, data on the biotoxicity of arsenic in terms of female reproduction are more scarce. In this study, a human-cell-animal translational strategy was applied to explore the effect of arsenic exposure on ovarian steroidogenesis and its potential mechanism. We conducted a 1:1 propensity score matched case–control study involving 127 diminished ovarian reserve (DOR) cases and 127 healthy controls. The ovarian follicular fluid levels of 21 metal elements, including arsenic, were measured. The results showed that there were significant differences in follicular fluid metal profiles between DOR patients and controls and that arsenic, molybdenum, and strontium played important roles in DOR progression [OR (95 % CI): 2.203 (1.385, 3.503), 2.308 (1.490, 3.575) and 2.922 (1.864, 4.580), respectively]. In the primary ovarian granulosa cell culture model, we found that treatment with 8 μM arsenic for 24 and 48 h induced a decrease in human granulosa cell viability. The estradiol (E2) level was significantly decreased after arsenic exposure (P

C10H11N5O2, orthorhombic, Pca21 (no. 29), a = 22.6173(13) Å, b = 4.8730(3) Å, c = 9.9921(5) Å, V = 1101.27(11) Å3, Z = 4, Rgt (F) = 0.0440, wRref (F 2) = 0.0999, T = 200(2) K.

BackgroundNeoadjuvant chemoimmunotherapy becomes more widespread in the treatment of NSCLC, but few studies have reported the details of surgical techniques and perioperative challenges following neoadjuvant chemoimmunotherapy until now. The primary aim of our study was to address the feasibility and safety of pulmonary resection after neoadjuvant chemoimmunotherapy via different surgical approaches, video-assisted thoracoscopic surgery (VATS) and open thoracotomy.MethodsPatients with an initial diagnosis of clinical stage IB-IIIB(T3-4N2) NSCLC, who received neoadjuvant chemoimmunotherapy and surgery between January 2019 and August 2021 were included. Patients were retrospectively divided into two groups (VATS, and thoracotomy), and differences in perioperative, oncological, and survival outcomes were compared.ResultsIn total, there were 131 NSCLC patients included. Surgery was delayed beyond 42 days in 21 patients (16.0%), and radical resection (R0) was achieved in 125 cases (95.4%). Lobectomy was the principal method of pulmonary resection (102 cases, 77.9%) and pneumonectomy was performed in 11 cases (8.4%). Postoperative complications within 30 days occurred in 28 patients (21.4%), and no 90-day mortality was recorded. There were 53 patients (38.5%) treated with VATS, and 78 (59.5%) with open thoracotomy. VATS could achieve similar definitive resection rates, postoperative recovery courses, comparable morbidities, and equivalent RFS rates(p>0.05), with the advantages of reduced operative time (160.1 ± 40.4 vs 177.7 ± 57.7 min, p=0.042), less intraoperative blood loss (149.8 ± 57.9 vs 321.2 ± 72.3 ml, p=0.021), and fewer intensive care unit(ICU) stays after surgery (3.8% vs 20.5%, p=0.006) compared with open thoracotomy. However, the mean number of total lymph nodes resected was lower in the VATS group (19.5 ± 7.9 vs 23.0 ± 8.1, p=0.013). More patients in the thoracotomy group received bronchial sleeve resection/bronchoplasty (53.8% vs 32.1%, p=0.014) and vascular sleeve resection/angioplasty (23.1% vs 3.8%, p=0.003). After propensity score matching (PSM) analysis, VATS still had the advantage of fewer ICU stays after surgery (2.3% vs. 20.5%, p=0.007).ConclusionsOur results have confirmed that pulmonary resection following neoadjuvant PD-1 inhibitors plus chemotherapy is safe and feasible. VATS could achieve similar safety, definitive surgical resection, postoperative recovery, and equivalent oncological efficacy as open thoracotomy, with the advantage of fewer ICU stays after surgery.

Abstract Background Pemetrexed (MTA) plus cisplatin combination therapy is considered the standard of care for patients with advanced non-small-cell lung cancer (NSCLC). However, in advanced NSCLC, the 5-year survival rate is below 10%, mainly due to resistance to therapy. We have previously shown that the fraction of mesenchymal-like, chemotherapy-resistant paraclone cells increased after MTA and cisplatin combination therapy in the NSCLC cell line A549. Cytidine deaminase (CDA) and thymidine phosphorylase (TYMP) are key enzymes of the pyrimidine salvage pathway. 5′-deoxy-5-fluorocytidine (5′-DFCR) is a cytidine analogue (metabolite of capecitabine), which is converted by CDA and subsequently by TYMP into 5-fluorouracil, a chemotherapeutic agent frequently used to treat solid tumors. The aim of this study was to identify and exploit chemotherapy-induced metabolic adaptations to target resistant cancer cells. Methods Cell viability and colony formation assays were used to quantify the efficacy of MTA and cisplatin treatment in combination with schedule-dependent addition of 5′-DFCR on growth and survival of A549 paraclone cells and NSCLC cell lines. CDA and TYMP protein expression were monitored by Western blot. Finally, flow cytometry was used to analyze the EMT phenotype, DNA damage response activation and cell cycle distribution over time after treatment. CDA expression was measured by immunohistochemistry in tumor tissues of patients before and after neoadjuvant chemotherapy. Results We performed a small-scale screen of mitochondrial metabolism inhibitors, which revealed that 5′-DFCR selectively targets chemotherapy-resistant A549 paraclone cells characterized by high CDA and TYMP expression. In the cell line A549, CDA and TYMP expression was further increased by chemotherapy in a time-dependent manner, which was also observed in the KRAS-addicted NSCLC cell lines H358 and H411. The addition of 5′-DFCR on the second day after MTA and cisplatin combination therapy was the most efficient treatment to eradicate chemotherapy-resistant NSCLC cells. Moreover, recovery from treatment-induced DNA damage was delayed and accompanied by senescence induction and acquisition of a hybrid-EMT phenotype. In a subset of patient tumors, CDA expression was also increased after treatment with neoadjuvant chemotherapy. Conclusions Chemotherapy increases CDA and TYMP expression thereby rendering resistant lung cancer cells susceptible to subsequent 5′-DFCR treatment.

Human papillomavirus (HPV) is a common virus, and about 5% of all cancers worldwide is caused by persistent high-risk HPV infections. Here, we reported a comprehensive analysis of the molecular features for HPV-related cancer types using TCGA (The Cancer Genome Atlas) data with HPV status. We found that the HPV-positive cancer patients had a unique oncogenic process, tumor microenvironment, and drug response compared with HPV-negative patients. In addition, HPV improved overall survival for the four cancer types, namely, cervical squamous cell carcinoma (CESC), head and neck squamous cell carcinoma (HNSC), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC). The stronger activity of cell-cycle pathways and lower driver gene mutation rates were observed in HPV-positive patients, which implied the different carcinogenic processes between HPV-positive and HPV-negative groups. The increased activities of immune cells and differences in metabolic pathways helped explain the heterogeneity of prognosis between the two groups. Furthermore, we constructed HPV prediction models for different cancers by the virus infection score (VIS) which was linearly correlated with HPV load and found that VIS was associated with drug response. Altogether, our study reveals that HPV-positive cancer patients have unique molecular characteristics which help the development of precision medicine in HPV-positive cancers.

Abstract Long non-coding RNAs (lncRNAs) represent an important class of RNAs comprising more than 200 nucleotides, which are produced by RNA polymerase II. Although lacking an open reading framework and protein-encoding activity, lncRNAs can mediate endogenous gene expression by serving as chromatin remodeler, transcriptional or post-transcriptional modulator, and splicing regulator during gene modification. In recent years, increasing evidence shows the significance of lncRNAs in many malignancies, with vital roles in tumorigenesis and cancer progression. Moreover, lncRNAs were also considered potential diagnostic and prognostic markers in cancer. The lncRNA small nuclear RNA host gene 16 (SNHG16), found on chromosome 17q25.1, represents a novel tumor-associated lncRNA. SNHG16 was recently found to exhibit dysregulated expression in a variety of malignancies. There are growing evidence of SNHG16’s involvement in characteristics of cancer, including proliferation, apoptosis, together with its involvement in chemoresistance. In addition, SNHG16 has been described as a promising diagnostic and prognostic biomarker in cancer patients. The current review briefly summarizes recently reported findings about SNHG16 and discuss its expression, roles, mechanisms, and diagnostic and prognostic values in human cancers.

Sinapis arvensis, belonging to the genus Sinapis of the family Brassicaceae, has good agronomic characters that make it a valuable genetic resource for crop improvement and is a cytoplasmic source of heterologous cytoplasmic male sterility (CMS). In addition, S. arvensis has played an important role in the evolution of the six major cultivated Brassica species involved in the triangle of U. Using next-generation sequencing, we assembled and revealed the gene composition of S. arvensis cytoplasmic genome. The chloroplast genome comprises 153,590 bp, with 112 individual genes, including 4 rRNA, 29 tRNA, and 79 protein-coding genes. The mitochondrial genome comprises 240,024 bp, with 54 genes, including 18 tRNA, three rRNA and 33 protein-coding genes. Genome structure and evolutionary analysis indicated that the sequences of the S. arvensis organellar genomes were more similar to those of Brassica nigra and B. carinata than to those of other Brassicaceae species. Four mitochondrial open reading frames displaying chimeric structural features and encoding hypothetical proteins with transmembrane domains may account for the infertility of Nsa CMS previously derived from somatic cell hybridization between B. napus and S. arvensis. These results will not only contribute to utilize the germplasm resource of S. arvensis, and comprehend the evolution of organelle genomes within the Brassicaceae family, but also help to identify genes conditioning the alloplasmic male sterility of Nsa CMS in B. napus.