Development and validation of a novel nomogram for predicting overall survival patients with neuroblastoma.

PURPOSE: The aim of this study was to develop a nomogram specially for predicting overall survival (OS) for Chinese patients with neuroblastoma (NB). METHODS: Patients with pathologically confirmed NB who were newly diagnosed and received treatments at our hospital from October 2013 to October 2021 were retrospectively reviewed. The nomogram for OS were built based on Cox regression analysis. The validation of the prognostic model was evaluated by concordance index (C-index), calibration curves, and decision curve analyses (DCAs). RESULTS: A total of 254 patients with NB were included in this study. They were randomly divided into a training cohort (n = 178) and a validation cohort (n = 76) at a ratio of 7:3. Multivariate analyses revealed that prognostic variables significantly related to the OS were age at diagnosis, bone metastasis, hepatic metastasis, INSS stage, MYCN status and DNA ploidy. The nomogram was constructed based on above 6 factors. The C-index values of the nomogram for predicting 3-year and 5-year OS were 0.926 and 0.964, respectively. The calibration curves of the nomogram showed good consistency between nomogram prediction and actual survival. The DCAs showed great clinical usefulness of the nomograms. Furthermore, patients with low-risk identified by our nomogram had much higher OS than those with high-risk (p < 0.001). CONCLUSION: The nomogram we constructed exhibited good predictive performance and could be used to assist clinicians in their decision-making process.

APLN promotes the proliferation, migration, and glycolysis of cervical cancer through the PI3K/AKT/mTOR pathway.

Apelin (APLN) is an endogenous ligand of the G protein-coupled receptor APJ (APLNR). APLN has been implicated in the development of multiple tumours. Herein, we determined the effect of APLN on the biological behaviour and underlying mechanisms of cervical cancer. The expression and survival curves of APLN were determined using Gene Expression Profiling Interactive Analysis. The cellular functions of APLN were detected using CCK-8, clone formation, EdU, Transwell assays, flow cytometry, and seahorse metabolic analysis. The underlying mechanisms were elucidated using gene set enrichment analysis and Western blotting. APLN was upregulated in the samples of patients with cervical cancer and is associated with poor prognosis. APLN knockdown decreased the proliferation, migration, and glycolysis of cervical cancer cells. The opposite results were observed when APLN was overexpressed. Mechanistically, we determined that APLN was critical for activating the PI3K/AKT/mTOR pathway via APLNR. APLN receptor inhibitor ML221 reversed the effect of APLN overexpression on cervical cancer cells. Treatment with LY294002, the PI3K inhibitor, drastically reversed the oncological behaviour of APLN-overexpressing C-33A cells. APLN promoted the proliferation, migration, and glycolysis of cervical cancer cells via the PI3K/AKT/mTOR pathway.

Iron efflux by IetA enhances ß-lactam aztreonam resistance and is linked to oxidative stress through cellular respiration in Riemerella anatipestifer.

BACKGROUND: Riemerella anatipestifer encodes an iron acquisition system, but whether it encodes the iron efflux pump and its role in antibiotic resistance are largely unknown. OBJECTIVES: To screen and identify an iron efflux gene in R. anatipestifer and determine whether and how the iron efflux gene is involved in antibiotic resistance. METHODS: In this study, gene knockout, streptonigrin susceptibility assay and inductively coupled plasma mass spectrometry were used to screen for the iron efflux gene ietA. The MIC measurements, scanning electron microscopy and reactive oxygen species (ROS) detection were used to verify the role of IetA in aztreonam resistance and its mechanism. Mortality and colonization assay were used to investigate the role of IetA in virulence. RESULTS: The deletion mutant ΔietA showed heightened susceptibility to streptonigrin, and prominent intracellular iron accumulation was observed in ΔfurΔietA under excess iron conditions. Additionally, ΔietA exhibited increased sensitivity to H2O2-produced oxidative stress. Under aerobic conditions with abundant iron, ΔietA displayed increased susceptibility to the ß-lactam antibiotic aztreonam due to heightened ROS production. However, the killing efficacy of aztreonam was diminished in both WT and ΔietA under anaerobic or iron restriction conditions. Further experiments demonstrated that the efficiency of aztreonam against ΔietA was dependent on respiratory complexes Ⅰ and Ⅱ. Finally, in a duckling model, ΔietA had reduced virulence compared with the WT. CONCLUSION: Iron efflux is critical to alleviate oxidative stress damage and ß-lactam aztreonam killing in R. anatipestifer, which is linked by cellular respiration.

Landscape of m6A RNA methylation regulators in liver cancer and its therapeutic implications.

Liver cancer remains as the third leading cause of cancer-related death globally as of 2020. Despite the significant progress made in the field of liver cancer treatment, there is still a lack of effective therapies in patients with advanced cancer and the molecular mechanisms underlying liver cancer progression remain largely elusive. N6-methyladenosine (m6A) modification, as the most prevalent and abundant internal RNA modification in eukaryotic RNAs, plays an essential role in regulating RNA metabolism including RNA splicing, stability, translation, degradation. To date, there is mounting evidence showing that m6A dysregulation is closely associated with the onset and development of many tumors including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and hepatoblastoma (HB). In this review, we summarize the last research progress regarding the functions of m6A-related regulators in liver cancer and its underlying mechanisms. Additionally, we also discuss the therapeutic applications of m6A-based inhibitors in liver cancer treatment.

A Histopathologic Image Analysis for the Classification of Endocervical Adenocarcinoma Silva Patterns Depend on Weakly Supervised Deep Learning.

Twenty-five percent of cervical cancers are classified as endocervical adenocarcinomas (EACs), which comprise a highly heterogeneous group of tumors. A histopathologic risk stratification system known as the Silva pattern system was developed based on morphology. However, accurately classifying such patterns can be challenging. The study objective was to develop a deep learning pipeline (Silva3-AI) that automatically analyzes whole slide image-based histopathologic images and identifies Silva patterns with high accuracy. Initially, a total of 202 patients with EACs and histopathologic slides were obtained from Qilu Hospital of Shandong University for developing and internally testing the Silva3-AI model. Subsequently, an additional 161 patients and slides were collected from seven other medical centers for independent testing. The Silva3-AI model was developed using a vision transformer and recurrent neural network architecture, utilizing multi-magnification patches, and its performance was evaluated based on a class-specific area under the receiver-operating characteristic curve. Silva3-AI achieved a class-specific area under the receiver-operating characteristic curve of 0.947 for Silva A, 0.908 for Silva B, and 0.947 for Silva C on the independent test set. Notably, the performance of Silva3-AI was consistent with that of professional pathologists with 10 years' diagnostic experience. Furthermore, the visualization of prediction heatmaps facilitated the identification of tumor microenvironment heterogeneity, which is known to contribute to variations in Silva patterns.

Analysis of Changes in KPS Scores and Imaging Signs in Deep Brain Gliomas by DWI Combined with Intraoperative Ultrasound Resection.

Objective: This study investigates the efficacy of DWI combined with intraoperative ultrasound for deep brain glioma treatment, analyzing changes in Karnofsky performance status (KPS) scores and imaging signs. Objectives include elucidating the approach's advantages, addressing knowledge gaps, and contributing insights into its effectiveness for enhancing deep brain glioma management. Methods: In this retrospective study, we analyzed a total of 346 patients with deep brain glioma who underwent surgical treatment at our hospital from July 2015 to January 2022. After applying inclusion and exclusion criteria, 310 patients were selected and categorized into a control group (n = 150) and an observation group (n = 160) based on different auxiliary techniques of surgical treatment. The degree of resection and Karnofsky performance status (KPS) scores were assessed at 1 day preoperatively, 1 week, and 1 month postoperatively for both groups. Additionally, we conducted a comprehensive analysis of DWI and ultrasound imaging signs among patients with different grades of deep brain glioma. The study duration covered the specified period, and statistical analyses were performed to evaluate the outcomes. Results: In our study, the observation group demonstrated significantly improved resection degrees, with a total resection rate of 82.50% compared to the control group's 65.33%. Preoperative Karnofsky performance status scores showed no significant difference between groups (P > .05), but postoperative scores at 1 week and 1 month were significantly higher in the observation group (P < .05). Intraoperative ultrasound and DWI revealed distinct imaging signs differentiating low-grade and high-grade patients. These results highlight the efficacy of DWI combined with intraoperative ultrasound resection in enhancing resection outcomes and influencing postoperative Karnofsky performance status. Conclusions: DWI combined with intraoperative ultrasonic resection in deep brain glioma has a significant effect, with specific imaging signs, which can effectively improve the total resection rate and KPS score, and is worthy of clinical promotion. DWI combined with intraoperative ultrasound has important clinical significance in the resection of deep brain gliomas. The better resection results and improved postoperative Karnofsky performance-status score that we observed suggest a possible benefit in patient outcomes, which could influence treatment strategies. The precise imaging signs identified by this method provide valuable guidance for targeted and effective tumor resection.

Characterizing the cumulative health risks of 19 kinds of pesticides in Chinese food from the cancer and non-cancer perspective.

Food safety is an important issue of most concern for health, while pesticides are one of the main threats to food safety. In view of the potential health hazard of pesticides in food, the cancer and non-cancer risks were assessed for 19 kinds of pesticides in Chinese food in this study. Furthermore, the health risks of different types of pesticides were compared to uncover the most polluted pesticide types in this study. Results show that methyl parathion, dichlorvos and 2,4-D residues in some food groups exceed the Chinese food standards. The cumulative disease burden of six carcinogenic pesticides for people older than 40 years ranges from 1.03 × 10-6 to 2.27 × 10-6, which exceeds the WHO recommended limit of 10-6. The non-cancer risks of 13 kinds of pesticides are all lower than 1 and will not pose appreciable health risk to the consumers. Livestock and poultry (contribution rate = 38.93%) and Milk and dairy products (contribution rate = 22.38%) are the dominate risk exposure sources for carcinogenic pesticides while staple foods (contribution rate = 31.62%) and vegetables (contribution rate = 21.5%) are the main risk exposure sources for non-carcinogenic pesticides. Comparing the risks of different pesticide types, insecticide is the most harmful category in this study, followed by herbicide and acaricide. This study characterized the health risks of pesticides in Chinese food and provided a scientific basis for pesticide management.

The Challenging Path to Diagnosing Extraintestinal Amoebiasis: A Case Report of an HIV-Infected Patient.

Background: Amoebiasis, an infectious disease caused by the parasitic protozoan E. histolytica, is easily misdiagnosed due to its declining incidence and atypical symptoms. Case Presentation: A 31-year-old male presented to the hospital with dyspnea and inability to lie flat. Imaging studies indicated a large amount of pleural effusion on the right side and multiple huge cysts in the liver. The patient underwent liver tumor resection surgery at another hospital due to suspected malignancy, but no evidence of relevant malignant tumors was found in the pathological examination. Subsequently, we performed metagenomic next-generation sequencing on the liver drainage fluid and obtained liver pathology slides from the hospital where the surgery was performed at that time. Both of them confirmed the diagnosis of amoebic infection. Empirical treatment with metronidazole was initiated before the diagnosis was confirmed, along with symptomatic treatments such as thoracic drainage and liver drainage. Eventually, the patient's condition improved and he was discharged smoothly. Conclusion: In order to avoid misdiagnosis of amoebiasis, thoroughly inquiring about the patient's medical history, shifting perspectives and continuing investigating are necessary when one diagnostic approach proves ineffective. Besides, interdisciplinary collaboration and persistent efforts are crucial for accurate diagnosis.

NS5 hijacks TRAF3 to inhibit type I interferon signaling during duck Tembusu virus infection.

The tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) is a key signaling molecule in the retinoic acid-inducible gene I (RIG-I) signaling pathway and plays an important role in host innate immune regulation. The function of TRAF3 has been extensively studied in mammals, however, the role of TRAF3 in ducks remains unclear. In order to reveal the function of duck TRAF3 (duTRAF3) in the innate immune response induced by virus infection, the TRAF3 homologue of mallard (Anas platyrhynchos) has been cloned and the function of duTRAF3 is investigated in this study. We sequenced duTRAF3 and found that the open reading frame (ORF) region of duTRAF3 is 1704 bp long and encodes 567 amino acids (aa), which has a similar functional domain to the mammalian gene. Analysis of tissue distribution of duTRAF3 in 7-day-old ducks showed that the expression of duTRAF3 was highest in harderian gland, followed by heart and lung. Subsequently, duck Tembusu virus (DTMUV) has been shown to enhance duTRAF3 expression, and overexpression of duTRAF3 inhibits DTMUV replication in a dose-dependent manner. In addition, duTRAF3 activates the transcriptional activity of IFN-α and its downstream interferon-stimulating genes (ISGs) induced after DTMUV infection. In this process, DTMUV non-structural (NS) protein 5 resists this innate immune process by interacting with TRAF3 and inhibiting TRAF3 expression. These data support the conclusion that duTRAF3 is an antiviral protein that plays a key role in the defense against DTMUV invasion. These results lay a theoretical foundation for developing new anti-DTMUV strategies.

Identification of lymph node metastasis in pre-operation cervical cancer patients by weakly supervised deep learning from histopathological whole-slide biopsy images.

BACKGROUND: Lymph node metastasis (LNM) significantly impacts the prognosis of individuals diagnosed with cervical cancer, as it is closely linked to disease recurrence and mortality, thereby impacting therapeutic schedule choices for patients. However, accurately predicting LNM prior to treatment remains challenging. Consequently, this study seeks to utilize digital pathological features extracted from histopathological slides of primary cervical cancer patients to preoperatively predict the presence of LNM. METHODS: A deep learning (DL) model was trained using the Vision transformer (ViT) and recurrent neural network (RNN) frameworks to predict LNM. This prediction was based on the analysis of 554 histopathological whole-slide images (WSIs) obtained from Qilu Hospital of Shandong University. To validate the model's performance, an external test was conducted using 336 WSIs from four other hospitals. Additionally, the efficiency of the DL model was evaluated using 190 cervical biopsies WSIs in a prospective set. RESULTS: In the internal test set, our DL model achieved an area under the curve (AUC) of 0.919, with sensitivity and specificity values of 0.923 and 0.905, respectively, and an accuracy (ACC) of 0.909. The performance of the DL model remained strong in the external test set. In the prospective cohort, the AUC was 0.91, and the ACC was 0.895. Additionally, the DL model exhibited higher accuracy compared to imaging examination in the evaluation of LNM. By utilizing the transformer visualization method, we generated a heatmap that illustrates the local pathological features in primary lesions relevant to LNM. CONCLUSION: DL-based image analysis has demonstrated efficiency in predicting LNM in early operable cervical cancer through the utilization of biopsies WSI. This approach has the potential to enhance therapeutic decision-making for patients diagnosed with cervical cancer.

Secretory pathways and multiple functions of nonstructural protein 1 in flavivirus infection.

The genus Flavivirus contains a wide variety of viruses that cause severe disease in humans, including dengue virus, yellow fever virus, Zika virus, West Nile virus, Japanese encephalitis virus and tick-borne encephalitis virus. Nonstructural protein 1 (NS1) is a glycoprotein that encodes a 352-amino-acid polypeptide and has a molecular weight of 46-55 kDa depending on its glycosylation status. NS1 is highly conserved among multiple flaviviruses and occurs in distinct forms, including a dimeric form within the endoplasmic reticulum, a cell-associated form on the plasma membrane, or a secreted hexameric form (sNS1) trafficked to the extracellular matrix. Intracellular dimeric NS1 interacts with other NSs to participate in viral replication and virion maturation, while extracellular sNS1 plays a critical role in immune evasion, flavivirus pathogenesis and interactions with natural vectors. In this review, we provide an overview of recent research progress on flavivirus NS1, including research on the structural details, the secretory pathways in mammalian and mosquito cells and the multiple functions in viral replication, immune evasion, pathogenesis and interaction with natural hosts, drawing together the previous data to determine the properties of this protein.

Duck plague virus tegument protein vp22 plays a key role in the secondary envelopment and cell-to-cell spread.

Duck plague virus (DPV) is one of the major infectious and fatal diseases of geese, ducks, and other wild waterfowl. The DPV UL49 gene product VP22 is one of the most abundant tegument proteins. However, the role of the DPV VP22 is enigmatic to be clarified. In this study, we found deletion of the UL49 gene resulted in reduced viral growth curve and smaller plaque size in duck embryo fibroblast (DEF) cells, confirming that DPV VP22 is required for efficient viral growth in vitro. In addition, deletion of the UL49 gene inhibited the secondary envelopment of the virus, the release of viral particles, and the spread of viruses between cells. Our study signified the importance of VP22 for DPV secondary envelopment, release, cell-to-cell spread, and accumulation of viral RNA. These findings provide a basis for further study of the function of VP22 in DPV or other herpesviruses.

Petroleum pollution changes microbial diversity and network complexity of soil profile in an oil refinery.

Introduction: Petroleum pollution resulting from spills and leakages in oil refinery areas has been a significant environmental concern for decades. Despite this, the effects of petroleum pollutants on soil microbial communities and their potential for pollutant biodegradation still required further investigation. Methods: In this study, we collected 75 soil samples from 0 to 5 m depths of 15 soil profiles in an abandoned refinery to analyze the effect of petroleum pollution on soil microbial diversity, community structure, and network co-occurrence patterns. Results: Our results suggested soil microbial a-diversity decreased under high C10-C40 levels, coupled with significant changes in the community structure of soil profiles. However, soil microbial network complexity increased with petroleum pollution levels, suggesting more complex microbial potential interactions. A module specific for methane and methyl oxidation was also found under high C10-C40 levels of the soil profile, indicating stronger methanotrophic and methylotrophic metabolic activities at the heavily polluted soil profile. Discussion: The increased network complexity observed may be due to more metabolic pathways and processes, as well as increased microbial interactions during these processes. These findings highlight the importance of considering both microbial diversity and network complexity in assessing the effects of petroleum pollution on soil ecosystems.

Functional Characterization of FeoAB in Iron Acquisition and Pathogenicity in Riemerella anatipestifer.

The bacterium Riemerella anatipestifer requires iron for growth, but the mechanism of iron uptake is not fully understood. In this study, we disrupted the Feo system and characterized its function in iron import in R. anatipestifer ATCC 11845. Compared to the parent strain, the growth of the ΔfeoA, ΔfeoB, and ΔfeoAB strains was affected under Fe3+-limited conditions, since the absence of the feo system led to less intracellular iron than in the parent strain. In parallel, the ΔfeoAB strain was shown to be less sensitive to streptonigrin, an antibiotic that requires free iron to function. The sensitivity of the ΔfeoAB strain to hydrogen peroxide was also observed to be diminished compared with that of the parent strain, which could be related to the reduced intracellular iron content in the ΔfeoAB strain. Further research revealed that feoA and feoB were directly regulated by iron through the Fur regulator and that the transcript levels of feoA and feoB were significantly increased in medium supplemented with 1 mM MnCl2, 400 µM ZnSO4, and 200 µM CuCl2. Finally, it was shown that the ΔfeoAB strain of R. anatipestifer ATCC 11845 was significantly impaired in its ability to colonize the blood, liver, and brain of ducklings. Taken together, these results demonstrated that FeoAB supports ferrous iron acquisition in R. anatipestifer and plays an important role in R. anatipestifer colonization. IMPORTANCE In Gram-negative bacteria, the Feo system is an important ferrous iron transport system. R. anatipestifer encodes an Feo system, but its function unknown. As iron uptake may be required for oxidative stress protection and virulence, understanding the contribution of iron transporters to these processes is crucial. This study showed that the ΔfeoAB strain is debilitated in its ability to import iron and that its intracellular iron content was constitutively low, which enhanced the resistance of the deficient strain to H2O2. We were surprised to find that, in addition to responding to iron, the Feo system may play an important role in sensing manganese, zinc, and copper stress. The reduced colonization ability of the ΔfeoAB strain also sheds light on the role of iron transporters in host-pathogen interactions. This study is important for understanding the cross talk between iron and other metal transport pathways, as well as the pathogenic mechanism in R. anatipestifer.

N-Linked Glycosylation and Expression of Duck Plague Virus pUL10 Promoted by pUL49.5.

Duck plague virus (DPV) is a member of the alphaherpesvirus subfamily, and its genome encodes a conserved envelope protein, protein UL10 (pUL10). pUL10 plays complex roles in viral fusion, assembly, cell-to-cell spread, and immune evasion, which are closely related to its protein characteristics and partners. Few studies have been conducted on DPV pUL10. In this study, we identified the characteristics of pUL10, such as the type of glycosylation modification and subcellular localization. The characteristic differences in pUL10 in transfection and infection suggest that there are other viral proteins that participate in pUL10 modification and localization. Therefore, pUL49.5, the interaction partner of pUL10, was explored. We found that pUL10 interacts with pUL49.5 during transfection and infection. Their interaction entailed multiple interaction sites, including noncovalent forces in the pUL49.5 N-terminal domains and C-terminal domains and a covalent disulfide bond between two conserved cysteines. pUL49.5 promoted pUL10 expression and mature N-linked glycosylation modification. Moreover, deletion of UL49.5 in DPV caused the molecular mass of pUL10 to decrease by approximately3 to 10 kDa, which suggested that pUL49.5 was the main factor affecting the N-linked glycosylation of DPV pUL10 during infection. This study provides a basis for future exploration of the effect of pUL10 glycosylation on virus proliferation. IMPORTANCE Duck plague is a disease with high morbidity and mortality rates, and it causes great losses for the duck breeding industry. Duck plague virus (DPV) is the causative agent of duck plague, and DPV UL10 protein (pUL10) is a homolog of glycoprotein M (gM), which is conserved in herpesviruses. pUL10 plays complex roles in viral fusion, assembly, cell-to-cell spread, and immune evasion, which are closely related to its protein characteristics and partners. In this study, we systematically explored whether pUL49.5 (a partner of pUL10) plays roles in the localization, modification, and expression of pUL10.

[Determination of 26 bisphenols in dust by ultra performance liquid chromatography-tandem mass spectrometry].

Bisphenol A (BPA) is one of the most widely produced compounds in the world and was listed as a substance of very high concern by the European Chemicals Agency in 2016. Because of its toxicity, many countries and regions, including China, have banned BPA addition in feeding-bottles. And the European Union (EU) has banned BPA use in other food contact materials and thermal paper. Restrictions on BPA have contributed to the widespread use of alternatives. As the toxicity of BPA alternatives continues to be revealed, the alternatives of BPA alternatives are being developing. As the most extensive alternative for BPA, bisphenol S (BPS) was proven to have estrogen-disrupting effects and developmental toxicity of the neuroendocrine system. Therefore, BPS alternatives are used in thermal paper. In this study, alternatives to both BPA and BPS are collectively referred to as bisphenols (BPs). As a pooling matrix of many indoor chemicals, dust is an important pathway for human exposure to BPs. BPA and its alternatives are routinely detected in dust. As BPS alternatives have been detected in recycled paper and sludge, it is also very important to detected in dust. However, common analytical methods for BPs have low sensitivity and contain few BPS alternatives. Therefore, a high-throughput, high-accuracy, and high-sensitivity method must be established for the determination of BPs in dust; this will lay the foundation for subsequent studies on the environmental behavior and exposure risk of BPs. In this study, an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous determination of 26 variations of BPs in dust. UPLC-MS/MS parameters of the variations were optimized to compare the separation effect and response intensity in different columns and mobile phases. The influence of the extraction solvent and solid phase extraction (SPE) on the extraction efficiency and purification effect of target compounds were optimized by using the isotopic internal standard method, and the 26 variations of BPs in dust was quantitatively analyzed. Finally, the dust samples were extracted by using 3 mL of acetonitrile and 3 mL of a 50% methanol aqueous solution in an ultrasound bath. The combined extract was further purified by using an Oasis HLB cartridge (60 mg/3 mL). The cartridge was then washed with a 40% methanol aqueous solution (0.5 mL) and eluted with methanol (2 mL). The target compounds were separated on a CORTECS® UPLC® C18 column (100 mm×2.1 mm, 1.6 µm), with methanol and 1 mmol/L ammonium fluoride solution as mobile phases and a flow rate of 0.3 mL/min. Electrospray ionization (ESI) was applied in the positive, negative, and multiple reaction monitoring (MRM) modes for the mass scan. Under optimized conditions, the linear ranges of the 26 targets behaved well linearly in their respective ranges with correlation coefficients (r2)>0.999. The limits of detection (LODs) and limits of quantification (LOQs) were assessed using signal-to-noise (S/N) ratios of 3 and 10, respectively. The LODs and LOQs of the method were 0.01-0.75 µg/kg and 0.02-2.50 µg/kg, respectively. The accuracy of the method was evaluated by conducting a recovery test at three spiked levels: LOQ, two times the LOQ, and 10 times the LOQ, with the average recoveries ranging from 83.7% to 114.9%. The precision of the method was evaluated by using the relative standard deviation (RSD). The intra-day RSDs and inter-day RSDs were 0.86%-9.79% (n=6) and 5.16%-19.5% (n=6), respectively. The established method was used to determine 11 dust samples. Fifteen BPs were detected at a detection rate of 9.1%-100.0%. The detection rate for BPA, BPS, bisphenol F (BPF), 4-hydroxy-4'-isopropoxydiphenylsulfone (BPSIP), and diphenyl sulfone (DPS) was 100.0%. BPSIP, 4-allyloxy-4'-hydroxydiphenyl sulfone (BPS-MAE), and bis-(3-allyl-4-hydroxyphenyl) sulfone (TGSA) were first detected in Chinese dust, whereas 4-benzyloxy-4'-hydroxydiphenyl sulfone (BPS-MPE), 4-hydroxybenzoic acid benzyl (PHBB), and DPS were first detected in dust samples worldwide. This method is simple, rapid, and sensitive, and is suitable for the qualitative screening and quantitative analysis of the 26 BPs in dust samples.

Development and validation of a deep learning survival model for cervical adenocarcinoma patients.

BACKGROUND: The aim was to develop a personalized survival prediction deep learning model for cervical adenocarcinoma patients and process personalized survival prediction. METHODS: A total of 2501 cervical adenocarcinoma patients from the surveillance, epidemiology and end results database and 220 patients from Qilu hospital were enrolled in this study. We created our deep learning (DL) model to manipulate the data and evaluated its performance against four other competitive models. We tried to demonstrate a new grouping system oriented by survival outcomes and process personalized survival prediction by using our DL model. RESULTS: The DL model reached 0.878 c-index and 0.09 Brier score in the test set, which was better than the other four models. In the external test set, our model achieved a 0.80 c-index and 0.13 Brier score. Thus, we developed prognosis-oriented risk grouping for patients according to risk scores computed by our DL model. Notable differences among groupings were observed. In addition, a personalized survival prediction system based on our risk-scoring grouping was developed. CONCLUSIONS: We developed a deep neural network model for cervical adenocarcinoma patients. The performance of this model proved to be superior to other models. The results of external validation supported the possibility that the model can be used in clinical work. Finally, our survival grouping and personalized prediction system provided more accurate prognostic information for patients than traditional FIGO stages.

BX795, a kinase inhibitor, inhibit duck plague virus infection via targeting US3 kinase.

Duck plague virus (DPV) is a typical DNA virus of waterfowl, it causes huge economic losses to the duck industry due to the higher mortality and lower egg production. The disease is one of the frequent epidemics and outbreaks on duck farms because present vaccines could not provide complete immunity and there are no specific antiviral drugs available. Therefore, the development of antiviral drugs is urgently needed. In this study, we evaluated the antiviral activity of BX795, a specific kinase inhibitor of 3-phosphoinositide-dependent kinase 1 (PDK1), protein kinase B (AKT) and Tank binding kinase 1 (TBK1), against DPV in different duck cells. Our study demonstrated that BX795 reveals prominent antiviral activity in a dose-dependent manner in different types of duck cells. Time-addition and antiviral duration analysis uncovered that BX795 inhibits viral infection therapeutically and its antiviral activity lasts longer than 96 h. Further studies have shown that BX795 prevents cell-to-cell spread of the DPV rather than affects other stage of viral life cycle. Mechanistically, BX795 can inhibit DPV US3 kinase activity, reduce the phosphorylation of US3 substrates, and prevent the interaction between US3 and UL47. Taking together, our study demonstrated BX795, which disrupts the viral kinase activity, is a candidate antiviral agent for DPV.

Manganese Efflux Achieved by MetA and MetB Affects Oxidative Stress Resistance and Iron Homeostasis in Riemerella anatipestifer.

In bacteria, manganese homeostasis is controlled by import, regulation, and efflux. Here, we identified 2 Mn exporters, MetA and MetB (manganese efflux transporters A and B), in Riemerella anatipestifer CH-1, encoding a putative cation diffusion facilitator (CDF) protein and putative resistance-nodulation-division (RND) efflux pump, respectively. Compared with the wild type (WT), ΔmetA, ΔmetB, and ΔmetAΔmetB exhibited sensitivity to manganese, since they accumulated more intracellular Mn2+ than the WT under excess manganese conditions, while the amount of iron in the mutants was decreased. Moreover, ΔmetA, ΔmetB, and ΔmetAΔmetB were more sensitive to the oxidant NaOCl than the WT. Further study showed that supplementation with iron sources could alleviate manganese toxicity and that excess manganese inhibited bacterial cell division. RNA-Seq showed that manganese stress resulted in the perturbation of iron metabolism genes, further demonstrating that manganese efflux is critical for iron homeostasis. metA transcription was upregulated under excess manganese but was not activated by MetR, a DtxR family protein, although MetR was also involved in manganese detoxification, while metB transcription was downregulated under iron depletion conditions and in fur mutants. Finally, homologues of MetA and MetB were found to be mainly distributed in members of Flavobacteriaceae. Specifically, MetB represents a novel manganese exporter in Gram-negative bacteria. IMPORTANCE Manganese is required for the function of many proteins in bacteria, but in excess, manganese can mediate toxicity. Therefore, the intracellular levels of manganese must be tightly controlled. Manganese efflux transporters have been characterized in some other bacteria; however, their homologues could not be found in the genome of Riemerella anatipestifer through sequence comparison. This indicated that other types of manganese efflux transporters likely exist. In this study, we characterized 2 transporters, MetA and MetB, that mediate manganese efflux in R. anatipestifer in response to manganese overload. MetA encodes a putative cation diffusion facilitator (CDF) protein, which has been characterized as a manganese transporter in other bacteria, while this is the first observation of a putative resistance-nodulation-division (RND) transporter contributing to manganese export in Gram-negative bacteria. In addition, the mechanism of manganese toxicity was studied by observing morphological changes and by transcriptome sequencing. Taken together, these results are important for expanding our understanding of manganese transporters and revealing the mechanism of manganese toxicity.