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Fructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeogenesis and an important tumor suppressor in human malignancies. Here, we aimed to investigate the expression profile of FBP1 in ovarian cancer, the molecular mechanisms that regulate FBP1 expression and to examine how the FBP1 regulatory axis contributes to tumorigenesis and progression in ovarian cancer. We showed that FBP1 expression was significantly decreased in ovarian cancer tissues compared with normal ovarian tissues, and low-FBP1 expression predicted poor prognosis in patients with ovarian cancer. The enhanced expression of FBP1 in ovarian cancer cell lines suppressed proliferation and 2-D/3-D invasion, reduced aerobic glycolysis, and sensitized cancer cells to cisplatin-induced apoptosis. Moreover, DNA methylation and C-MYC binding at the promoter inhibited FBP1 expression. Furthermore, through physical interactions with signal transducer and activator of transcription 3 (STAT3), FBP1 suppressed nuclear translocation of STAT3 and exerted its non-metabolic enzymatic activity to induce the dysfunction of STAT3. Thus, our study suggests that FBP1 may be a valuable prognostic predictor for ovarian cancer. C-MYC-dependent downregulation of FBP1 acted as a tumor suppressor via modulating STAT3, and the C-MYC/FBP1/STAT3 axis could be a therapeutic target.

The worldwide pandemic of coronavirus disease 2019 (COVID-19) presents us with a serious public health crisis. To combat the virus and slow its spread, wider testing is essential. There is a need for more sensitive, specific, and convenient detection methods of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Advanced detection can greatly improve the ability and accuracy of the clinical diagnosis of COVID-19, which is conducive to the early suitable treatment and supports precise prophylaxis. In this article, we combine and present the latest laboratory diagnostic technologies and methods for SARS-CoV-2 to identify the technical characteristics, considerations, biosafety requirements, common problems with testing and interpretation of results, and coping strategies of commonly used testing methods. We highlight the gaps in current diagnostic capacity and propose potential solutions to provide cutting-edge technical support to achieve a more precise diagnosis, treatment, and prevention of COVID-19 and to overcome the difficulties with the normalization of epidemic prevention and control.

Nowadays, tumor has been the serious threat to human health and life. To further explore the mechanism of tumor genesis and development is necessarily for developing the effective treatment strategy. Extracellular vesicles are the vesicles secreted by almost all types of cells, and they play an important part in intercellular communication by transporting their cargoes. Immune cells are the vital components of the human defense system, which defense against infection and tumor through cytotoxicity, immune surveillance, and clearance. However, via release tumor-derived extracellular vesicles, tumor could induce immune cells dysfunction to facilitate its proliferation and metastasis. Studies have shown that tumor-derived extracellular vesicles play dual role on immune cells by their specific cargoes. Here, we reviewed the effects of tumor-derived extracellular vesicles on immune cells in recent years and also summarized their research progress in the tumor immunotherapy and diagnosis.

It is of great significance to establish an assessment model for organ failures in the early stage of admission in acute pancreatitis (AP). And the clinical notes are underutilized. To predict organ failures for AP patients using early clinical notes in hospital, early text features obtained from the pretrained Chinese Bidirectional Encoder Representations from Transformers model and attention-based LSTM were combined with early structured features (laboratory tests, vital signs, and demographic characteristics) to predict organ failures (respiratory, cardiovascular, and renal) in 12,748 AP inpatients in West China Hospital, Sichuan University, from 2008 to 2018. The text plus structured features fusion model was used to predict organ failures, compared to the baseline model with only structured features. The performance of the model with text features added is superior to the model that only includes structured features.

Summary Mechanoreceptors are essential components of the somatosensory system that convert received mechanical signals into electrical signals that can be sent to the brain. These receptors provide the ability to sense a variety of stimuli from the external environment, including touch, vibration, and heat. Mechanoreceptors do not convert signals monotonically; in addition, several fundamental characteristics are embedded in mechanoreceptors, including thresholds and adaptation properties. In this study, we proposed and experimentally demonstrated a van der Waals stacking field-effect transistor (VS-FET), which was inspired by an FET with a floating gate structure, to realize the important characteristics of mechanoreceptors. The VS-FET can not only demonstrate the fundamental biological functions but also produce other unique properties such as fatigue and accommodation. We also integrated an artificial touch receptor with an array of the proposed VS-FET to demonstrate the feasibility of these devices experimentally in artificial humanoid systems.

Cancer stem‐like cells (CSCs) induce drug resistance and recurrence of tumors when they experience DNA replication stress. However, the mechanisms underlying DNA replication stress in CSCs and its compensation remain unclear. Here, we demonstrate that upregulated c‐Myc expression induces stronger DNA replication stress in patient‐derived breast CSCs than in differentiated cancer cells. Our results suggest critical roles for mini‐chromosome maintenance protein 10 (MCM10), a firing (activating) factor of DNA replication origins, to compensate for DNA replication stress in CSCs. MCM10 expression is upregulated in CSCs and is maintained by c‐Myc. c‐Myc‐dependent collisions between RNA transcription and DNA replication machinery may occur in nuclei, thereby causing DNA replication stress. MCM10 may activate dormant replication origins close to these collisions to ensure the progression of replication. Moreover, patient‐derived breast CSCs were found to be dependent on MCM10 for their maintenance, even after enrichment for CSCs that were resistant to paclitaxel, the standard chemotherapeutic agent. Further, MCM10 depletion decreased the growth of cancer cells, but not of normal cells. Therefore, MCM10 may robustly compensate for DNA replication stress and facilitate genome duplication in cancer cells in the S‐phase, which is more pronounced in CSCs. Overall, we provide a preclinical rationale to target the c‐Myc‐MCM10 axis for preventing drug resistance and recurrence of tumors., We provide evidence that upregulated c‐Myc expression induces stronger DNA replication stress in patient‐derived breast cancer stem‐like cells than in differentiated cancer cells. Our results suggest critical roles for mini‐chromosome maintenance protein 10 (MCM10), which is a firing (activating) factor of the DNA replication origins, to compensate for the DNA replication stress.

It is currently uncertain to what extent genetic transformations of strategic crops (targeting diverse traits) have improved their N use efficiency (NUE), and what the key factors affecting their NUE are. Based on data collected from 130 publications, the effect sizes of genetic transformations and the key factors influencing NUE for three major cereal crops (rice, maize, and wheat), were investigated using a meta-analysis approach. Genetic transformations increased yield, shoot biomass, N uptake efficiency (NUpE), and partial factor productivity of N (PFPN) in the crops, but decreased shoot NUE (SNUE) and grain NUE (GNUE). Transporter genes improved yield and NUE parameters more efficiently, than did the other gene types. The effect sizes for some NUE parameters varied according to crop species and experimental conditions but did not differ between the overexpression and ectopic expression methods. Most effect sizes did not correlate with gene overexpression levels. These results indicate a promising potential of genetic transformations approaches for improving certain NUE parameters.

Previous research focused on the qualitative discussion of the correlation between surgical time and mortality in acute pancreatitis (AP). Recommendations for surgical timing of necrotizing pancreatitis are delayed as far as possible, without recommendations for individuals. The aim of this article is to predict timing of surgical intervention in necrotizing pancreatitis with recurrent neural network (RNN). Time series data in AP were retrospectively extracted from a hospital in China (n = 15,813) to develop model, and the Cerner Health Facts database in the United States (n = 142,650) was used to externally validate. The developed model, time-aware Phased-Decay long short-term memory (LSTM), was used to predict timing of surgical intervention and critical clinical features in necrotizing pancreatitis based on laboratory tests, compared to other machine learning models. Area under the ROC curve (AUC) of RNN-based models was more than 0.70. The AUC of time-aware Phased-Decay LSTM (0.75) with more explanatory was similar to that (0.76) of Phased-Decay LSTM to predict surgical timing. The developed model visualized the specific surgical process and laboratory indicators changes for the patients with AP from the onset to discharge. Different clinical features had different contribution modes with time to the specific surgical event in AP. Heart function contributed the most to the prediction of surgical intervention at the onset and in the first week. Our developed model could monitor the specific surgical process from the onset of AP to discharge and extract the contribution modes of clinical features with time in necrotizing pancreatitis.

Patients with triple-negative breast cancer have a poor prognosis as only a few efficient targeted therapies are available. Cancer cells are characterized by their unregulated proliferation and require large amounts of nucleotides to replicate their DNA. One-carbon metabolism contributes to purine and pyrimidine nucleotide synthesis by supplying one carbon atom. Although mitochondrial one-carbon metabolism has recently been focused on as an important target for cancer treatment, few specific inhibitors have been reported. In this study, we aimed to examine the effects of DS18561882 (DS18), a novel, orally active, specific inhibitor of methylenetetrahydrofolate dehydrogenase (MTHFD2), a mitochondrial enzyme involved in one-carbon metabolism. Treatment with DS18 led to a marked reduction in cancer-cell proliferation; however, it did not induce cell death. Combinatorial treatment with DS18 and inhibitors of checkpoint kinase 1 (Chk1), an activator of the S phase checkpoint pathway, efficiently induced apoptotic cell death in breast cancer cells and suppressed tumorigenesis in a triple-negative breast cancer patient-derived xenograft model. Mechanistically, MTHFD2 inhibition led to cell cycle arrest and slowed nucleotide synthesis. This finding suggests that DNA replication stress occurs due to nucleotide shortage and that the S-phase checkpoint pathway is activated, leading to cell-cycle arrest. Combinatorial treatment with both inhibitors released cell-cycle arrest, but induced accumulation of DNA double-strand breaks, leading to apoptotic cell death. Collectively, a combination of MTHFD2 and Chk1 inhibitors would be a rational treatment option for patients with triple-negative breast cancer.

Background Propofol and sevoflurane are two commonly used perioperative anesthetics. Some studies have found that these anesthetic drugs affect tumorigenesis. Previous studies have mostly focused on in vitro experiments, and the specimens collected were mainly peripheral body fluids, lacking direct evidence of the impact of anesthetic drugs on human tissues. This study aimed to elucidate the effects of propofol and sevoflurane on lung cancer using next-generation sequencing through an in vivo experiment. Methods Patients were randomly assigned to a group receiving either propofol or sevoflurane during surgery. Then, the patients’ tumor and paired normal samples were collected and sequenced by next-generation sequencing. Differentially expressed genes (DEG) were analyzed by two statistical models, followed by cluster analysis, PCA, Gene Ontology, and KEGG pathway analysis. Candidate genes were confirmed by qRT–PCR. Results The demographic data of the two study groups were not statistically significant. Through single-factor model analysis, 810 DEG in the propofol group and 508 DEG in the sevoflurane group were obtained. To better reflect the differential effects between propofol and sevoflurane while reducing the false-positive DEG, we used multifactor model analysis, which resulted in 124 DEG. In PCA and cluster analysis, four groups (propofol cancer group, propofol normal group, sevoflurane cancer group, sevoflurane normal group) were separated adequately, indicating the accuracy of the analysis. We chose seven significant pathways (cellular response to interleukin-1, chemokine-mediated signaling pathway, chemokine signaling pathway, cytokine–cytokine receptor interaction, inflammatory response, immune response, and TNF signaling pathway) for downstream analysis. Based on the pathway analysis, three candidate genes (CXCR1, CXCL8, and TNFAIP3) were chosen, and their qRT–PCR results were consistent with the sequencing results. Conclusions Through RNA-seq analysis, the effects of propofol and sevoflurane during lung cancer resection were different, mainly in inflammatory-related pathways, which might be possibly by targeting CXCL8. Trial registration Trial registry number was ChiCTR1900026213.

Significance Human breast cancer develops after a long period of latency under premalignant conditions. Strategies to target the premalignant conditions have yet to materialize since the molecular mechanisms remain obscure. Here, we discovered that FRS2β, expressed in a subset of mammary epithelial cells, directly activates nuclear factor–κB (NF-κB) and drives the initiation and promotion of the stroma-rich premalignant conditions. The FRS2β-triggered activation of NF-κB takes place in the early endosomes, the organelles, which have not been believed to be a major place for NF-κB signaling. The endosome signaling should be a novel focus for targeting therapy for prevention of breast cancer. This work paves a new way to develop preventive strategies of breast tumor development., Although it is held that proinflammatory changes precede the onset of breast cancer, the underlying mechanisms remain obscure. Here, we demonstrate that FRS2β, an adaptor protein expressed in a small subset of epithelial cells, triggers the proinflammatory changes that induce stroma in premalignant mammary tissues and is responsible for the disease onset. FRS2β deficiency in mouse mammary tumor virus (MMTV)–ErbB2 mice markedly attenuated tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2β-deficient premalignant tissues. We found that colocalization of FRS2β and the NEMO subunit of the IκB kinase complex in early endosomes led to activation of nuclear factor–κB (NF-κB), a master regulator of inflammation. Moreover, inhibition of the activities of the NF-κB–induced cytokines, CXC chemokine ligand 12 and insulin-like growth factor 1, abrogated tumorigenesis. Human breast cancer tissues that express higher levels of FRS2β contain more stroma. The elucidation of the FRS2β–NF-κB axis uncovers a molecular link between the proinflammatory changes and the disease onset.

Objective: Previous studies discussing phenotypic and temporal heterogeneity of knee osteoarthritis (KOA) separately have fatal limitations that either clustering patients with similar severity or assuming all knees have a single common progression pattern, which are unreliable. This study tried to uncover more reliable information on phenotypic and temporal heterogeneity of KOA.Design: Data were from Osteoarthritis Initiative database. Six hundred and seventy-eight unilateral knees that have greater Kellgren and Lawrence (KL) grade than the contralateral knees at baseline and in all follow-up 48 months were included. Measurements of biomarkers at baseline were chosen. Subtype and Stage Inference model (SuStaIn) was applied as a subtype-progression model to identify subtypes, subtype biomarker progress sequences and stages of KOA.Results: This study identified three subtypes which account for 15, 61, and 24% of knees, respectively. Each subtype has distinct subtype biomarker progress sequence. For knees with KL grade 0/1, 2, 3, and 4, they have different distributions on stage and 26, 53, 89, and 95% of them are strongly assigned to subtypes. When assessing whether a knee has KL (grade ≥ 2), subtypes and stages from subtypes-progression model (SuStaIn) are significantly better fitting than those from subtypes-only (mixture of Gaussians) (likelihood ratio = 105.59, p = 2.2 × 10−16) or stages-only (SuStaIn where setting c = 1) (likelihood ratio = 58.04, p = 2.57 × 10−14) model. Stages in subtypes-progression model has greater β than stages-only model. Subtypes from subtypes-progression model have no statistical significance.Conclusions: For subtypes-progression model, stages contain more complete temporal information and subtypes are closer to real OA subtypes.

Sepsis is an inflammatory syndrome with life-threatening organ dysfunction resulting from a dysregulated host response to infection. Although the treatment for sepsis has improved a lot in the last 30 years, sepsis related mortality remains high. In the recent 10 years, high dose intravenous injection of vitamin C, the first line antioxidant of human, has received more and more attention in the field of critical care, its beneficial effect has been demonstrated by several small scale clinical trial and animal studies, but the effect of high dose vitamin C on sepsis in a larger trial seems warranted in further study. Here we will conduct a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial named as HDVCIS. The trial protocol has been approved by Clinical Trail Ethics Committee of Ruijin Hospital of Shanghai JiaoTong University School of Medicine. This trial has been registered in Chinese Clinical Trial Registry (ChiCTR1800017633) in August 7, 2018. Patients will be recruited from 4 medical centers in China. Its object is to testify the efficacy and safety of high dose vitamin C in the treatment of sepsis.

Objective Stage I‐II uterine papillary serous carcinoma (UPSC) has aggressive biological behavior and leads to poor prognosis. However, clinicopathologic risk factors to predict cancer‐specific survival of patients with stage I‐II UPSC were still unclear. This study was undertaken to develop a prediction model of survival in patients with early‐stage UPSC. Methods Using Surveillance, Epidemiology, and End Results (SEER) database, 964 patients were identified with International Federation of Gynecology and Obstetrics (FIGO) stage I‐II UPSC who underwent at least hysterectomy between 2004 and 2015. By considering competing risk events for survival outcomes, we used proportional subdistribution hazards regression to compare cancer‐specific death (CSD) for all patients. Based on the results of univariate and multivariate analysis, the variables were selected to construct a predictive model; and the prediction results of the model were visualized using a nomogram to predict the cancer‐specific survival and the response to adjuvant chemotherapy and radiotherapy of stage I‐II UPSC patients. Results The median age of the cohort was 67 years. One hundred and sixty five patients (17.1%) died of UPSC (CSD), while 8.6% of the patients died from other causes (non‐CSD). On multivariate analysis, age ≥ 67 (HR = 1.45, P = .021), tumor size ≥ 2 cm (HR = 1.81, P = .014) and >10 regional nodes removed (HR = 0.52, P = .002) were significantly associated with cumulative incidence of CSD. In the age ≥67 cohort, FIGO stage IB‐II was a risk factor for CSD (HR = 1.83, P = .036), and >10 lymph nodes removed was a protective factor (HR = 0.50, P = .01). Both adjuvant chemotherapy combined with radiotherapy and adjuvant chemotherapy alone decreased CSD of patients with stage I‐II UPSC older than 67 years (HR = 0.47, P = .022; HR = 0.52, P = .024, respectively). The prediction model had great risk stratification ability as the high‐risk group had higher cumulative incidence of CSD than the low‐risk group (P, Our prediction model of CSD based on proportional subdistribution hazards regression showed good performance in predicting the cancer‐specific survival of early‐stage UPSC patients and contributes to selection of adjuvant therapy for stage I‐II UPSC patients in clinical treatment strategy.

As one of the representatives of jawless vertebrates, lamprey is an important animal model for research on the evolution of adaptive immune system. Although it is widely accepted that the key characteristic of the immune response in jawed vertebrates is the functional cooperation between different immune effector cell lineages, whether immune cells of lamprey can communicate with each other is still unclear. Recently, mounting evidence has revealed the emerging role of exosomes in mediating intercellular communication. In this study, by means of ultrafiltration followed by size exclusion chromatography, exosomes are purified from conditioned growth medium of the primary supraneural myeloid body cells (SMB cells) in LPS-immunized and control Lampetra japonica (Japanese lamprey). The proteomic profiling and qualitative comparison are performed between protein components enriched in exosomes released by SMB cells under quiescent and activated conditions. Our results demonstrate that SMB cells can release exosomes with well-defined characteristics comparable to their mammalian counterparts on their size, morphology and protein markers, which supports exosomes are evolutionarily conserved between lamprey and other higher vertebrate species. In terms of comparison with exosomes released by quiescent SMB cells, activated SMB cell-derived exosomes contain more and significantly different protein components. The unique exosomal protein 'fingerprint' might reflect that exosomes from the SMB cells with different states of activation have distinguishing functional roles as well as targeting properties. Further bioinformatic analysis suggests that compared to quiescent exosomes, activated SMB cell-derived exosomes mainly participate in distinctive biological processes including activation of cellular component biogenesis and regulation of cell proliferation. Moreover, activated exosomes may function through the specific signaling pathways associated with the regulation of cell mitosis and immune response. Our results give valuable clues about the immunomodulatory functions of SMB cell-derived exosomes and provide the foundation for further investigation in the regulation mechanism of the adaptive immune response in lamprey.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) are effective in patients with non–small‐cell lung cancer (NSCLC) harboring EGFR mutations. However, due to acquired resistance to EGFR‐TKIs, even patients on third‐generation osimertinib have a poor prognosis. Resistance mechanisms are still not fully understood. Here, we demonstrate that the increased expression of MUSASHI‐2 (MSI2), an RNA‐binding protein, is a novel mechanism for resistance to EGFR‐TKIs. We found that after a long‐term exposure to gefitinib, the first‐generation EGFR‐TKI lung cancer cells harboring the EGFR‐TKI‐sensitive mutations became resistant to both gefitinib and osimertinib. Although other mutations in EGFR were not found, expression levels of Nanog, a stemness core protein, and activities of aldehyde dehydrogenase (ALDH) were increased, suggesting that cancer stem‐like properties were increased. Transcriptome analysis revealed that MSI2 was among the stemness‐related genes highly upregulated in EGFR‐TKI‐resistant cells. Knockdown of MSI2 reduced cancer stem‐like properties, including the expression levels of Nanog, a core stemness factor. We demonstrated that knockdown of MSI2 restored sensitivity to osimertinib or gefitinib in EGFR‐TKI‐resistant cells to levels similar to those of parental cells in vitro. An RNA immunoprecipitation (RIP) assay revealed that antibodies against MSI2 were bound to Nanog mRNA, suggesting that MSI2 increases Nanog expression by binding to Nanog mRNA. Moreover, overexpression of MSI2 or Nanog conferred resistance to osimertinib or gefitinib in parental cells. Finally, MSI2 knockdown greatly increased the sensitivity to osimertinib in vivo. Collectively, our findings provide proof of principle that targeting the MSI2‐Nanog axis in combination with EGFR‐TKIs would effectively prevent the emergence of acquired resistance., Osimertinib (AZD9291) is a third‐generation irreversible, oral EGFR‐TKI that is effective without serious adverse effects, however, similar to earlier generations of EGFR‐TKIs, acquired resistance to osimertinib remains a major challenge. We discovered MSI2 as a novel target to overcome resistance to EGFR‐TKIs including osimertinib. Mechanistically, we demonstrate that MSI2 confers cancer stem‐like properties in lung adenocarcinoma cells, leading to resistance to the EGFR‐TKIs.

Background: Recent evidences have shown that gut microbiome of patients with COVID-19 significantly changes and can reflect the severity of the disease. And gut microbiota richness was not restored to normal levels after 6-month recovery. However, SARS-CoV-2 primarily infects the respiratory tract, few studies investigate whether the alterations of oropharyngeal microbiome is associated with disease severity in patients with COVID-19, and whether interferences in microbiome composition, if any, eliminate with clearance of the SARS-CoV-2 virus. We employed metatranscriptomic sequencing to analyse oropharyngeal swabs collected within a week of diagnosis COVID-19 (period of disease group: PDG) and two months after clearance of the SARS-CoV-2 virus (convalescent group: CG) from 47 patients with COVID-19. Meanwhile, oropharyngeal swabs from 40 healthy subjects were analyzed as healthy control group (HCG). Results: Oropharyngeal microbial composition was significantly altered in patients with COVID-19 compared with healthy controls even two months after clearance of the SARS-CoV-2 virus. Little changes in α-diversity among HCG, PDG and CG ( P ＞0.05), but obviously changes in β-diversity among them. Notably, Prevotella increased significantly in PDG than that in HCG (Wilcoxon rank-sum test, P ＜0.001) and increased gradually along with the severity of patients with COVID-19 aggravated. There was a positive correlation between Prevotella and the elevation of Neutrophil percentage (R = 0.301, P = 0.040). Similarly, SARS-CoV-2 and Aspergillus increased remarkably in critical Patients with COVID-19. There was a negative correlation between SARS-CoV-2 viral load and platelet counts (R = −0.330, P = 0.022). Conclusions: The oropharyngeal microbiome in patients with COVID-19 present persistent dysbiosis even two months after clearance of the SARS-CoV-2 virus. Furthermore, alterations in oropharyngeal microbial composition reflected the severity of disease in patients with COVID-19. Our findings underscore that there is an urgent need to understand the specific roles of oropharyngeal microorganisms in COVID-19 disease progression and rehabilitation.

Background: Predicting the risk of progression to severe coronavirus disease 2019 (COVID-19) could facilitate personalized diagnosis and treatment options, thus optimizing the use of medical resources.Methods: In this prospective study, 206 patients with COVID-19 were enrolled from regional medical institutions between December 20, 2019, and April 10, 2020. We collated a range of data to derive and validate a predictive model for COVID-19 progression, including demographics, clinical characteristics, laboratory findings, and cytokine levels. Variation analysis, along with the least absolute shrinkage and selection operator (LASSO) and Boruta algorithms, was used for modeling. The performance of the derived models was evaluated by specificity, sensitivity, area under the receiver operating characteristic (ROC) curve (AUC), Akaike information criterion (AIC), calibration plots, decision curve analysis (DCA), and Hosmer–Lemeshow test.Results: We used the LASSO algorithm and logistic regression to develop a model that can accurately predict the risk of progression to severe COVID-19. The model incorporated alanine aminotransferase (ALT), interleukin (IL)-6, expectoration, fatigue, lymphocyte ratio (LYMR), aspartate transaminase (AST), and creatinine (CREA). The model yielded a satisfactory predictive performance with an AUC of 0.9104 and 0.8792 in the derivation and validation cohorts, respectively. The final model was then used to create a nomogram that was packaged into an open-source and predictive calculator for clinical use. The model is freely available online at https://severeconid-19predction.shinyapps.io/SHINY/.Conclusion: In this study, we developed an open-source and free predictive calculator for COVID-19 progression based on ALT, IL-6, expectoration, fatigue, LYMR, AST, and CREA. The validated model can effectively predict progression to severe COVID-19, thus providing an efficient option for early and personalized management and the allocation of appropriate medical resources.

Background: Coronavirus disease 2019 (COVID-19) pandemic is continuing to impact multiple countries worldwide and effective treatment options are still being developed. In this study, we investigate the potential of high-dose intravenous vitamin C (HDIVC) in the prevention of moderate COVID-19 disease aggravation.Methods: In this retrospective before-after case-matched clinical study, we compare the outcome and clinical courses of patients with moderate COVID-19 patients who were treated with an HDIVC protocol (intravenous injection of vitamin C, 100 mg/kg/day, 1 g/h, for 7 days from admission) during a one-month period (between March 18 and april 18, 2020, HDIVC group) with a control group treated without the HDIVC protocol during the preceding two months (January 18 to March 18, 2020). Patients in the two groups were matched in a 1:1 ratio according to age and gender.Results: The HDIVC and control groups each comprised 55 patients. For the primary outcomes, there was a significant difference in the number of patients that evolved from moderate to severe type between the two groups (HDIVC: 4/55 vs. control: 12/55, relative risk [RR] = 0.28 [0.08, 0.93], P = 0.03). Compared to the control group, there was a shorter duration of systemic inflammatory response syndrome (SIRS) (P = 0.0004) during the first week and lower SIRS occurrence (2/21 vs 10/22, P = 0.0086) on Day 7 (6–7 days after admission). In addition, HDIVC group had lower C-reactive protein levels (P = 0.005) and higher number of CD4+ T cells from Day 0 (on admission) to Day 7 (P = 0.04).” The levels of coagulation indicators, including activated partial thromboplastin time and D-dimer were also improved in the HDIVC compared to the control group on Day 7.Conclusion: HDIVC may be beneficial in limiting disease aggravation in the early stage of COVID-19 pneumonia, which may be related to its improvements on the inflammatory response, immune function and coagulation function. Further randomized controlled trials are required to augment these findings.

The SARS-CoV-2 virus, the causative agent of COVID-19, is undergoing constant mutation. Here, we utilized an integrative approach combining epidemiology, virus genome sequencing, clinical phenotyping, and experimental validation to locate mutations of clinical importance. We identified 35 recurrent variants, some of which are associated with clinical phenotypes related to severity. One variant, containing a deletion in the Nsp1-coding region (Δ500-532), was found in more than 20% of our sequenced samples and associates with higher RT-PCR cycle thresholds and lower serum IFN-β levels of infected patients. Deletion variants in this locus were found in 37 countries worldwide, and viruses isolated from clinical samples or engineered by reverse genetics with related deletions in Nsp1 also induce lower IFN-β responses in infected Calu-3 cells. Taken together, our virologic surveillance characterizes recurrent genetic diversity and identified mutations in Nsp1 of biological and clinical importance, which collectively may aid molecular diagnostics and drug design., Graphical Abstract, Bringing together epidemiological, genetic, and clinical data, Lin et al. identify viral mutations that associate with clinical phenotypes. The 500-532 locus in the Nsp1 coding region is a deletion hotspot in the SARS-CoV-2 genome, and deletion variants lead to lower IFN-I response. Prevalence of 500-532 deletion variants is accumulating worldwide.

Objective. In order to find the quantitative relationship between timing of surgical intervention and risk of death in necrotizing pancreatitis. Methods. The generalized additive model was applied to quantitate the relationship between surgical time (from the onset of acute pancreatitis to first surgical intervention) and risk of death adjusted for demographic characteristics, infection, organ failure, and important lab indicators extracted from the Electronic Medical Record of West China Hospital of Sichuan University. Results. We analyzed 1,176 inpatients who had pancreatic drainage, pancreatic debridement, or pancreatectomy experience of 15,813 acute pancreatitis retrospectively. It showed that when surgical time was either modelled alone or adjusted for infection or organ failure, an L-shaped relationship between surgical time and risk of death was presented. When surgical time was within 32.60 days, the risk of death was greater than 50%. Conclusion. There is an L-shaped relationship between timing of surgical intervention and risk of death in necrotizing pancreatitis.

Objective To explore the influence by not performing an oral glucose tolerance test (OGTT) in Han Chinese over 40 years. Design Overall, 6682 participants were included in the prospective cohort study and were followed up for 3 years. Methods Fasting plasma glucose (FPG), 2-h post-load plasma glucose (2h-PG), FPG and 2h-PG (OGTT), and HbA1c testing using World Health Organization (WHO) or American Diabetes Association (ADA) criteria were employed for strategy analysis. Results The prevalence of diabetes is 12.4% (95% CI: 11.6–13.3), while the prevalence of prediabetes is 34.1% (95% CI: 32.9–35.3) and 56.5% (95% CI: 55.2–57.8) using WHO and ADA criteria, respectively. 2h-PG determined more diabetes individuals than FPG and HbA1c. The testing cost per true positive case of OGTT is close to FPG and less than 2h-PG or HbA1c. FPG, 2h-PG and HbA1c strategies would increase costs from complications for false-positive (FP) or false-negative (FN) results compared with OGTT. Moreover, the least individuals identified as normal by OGTT at baseline developed (pre)diabetes, and the most prediabetes individuals identified by HbA1c or FPG using ADA criteria developed diabetes. Conclusions The prevalence of isolated impaired glucose tolerance and isolated 2-h post-load diabetes were high, and the majority of individuals with (pre)diabetes were undetected in Chinese Han population. Not performing an OGTT results in underdiagnosis, inadequate developing risk assessment and probable cost increases of (pre)diabetes in Han Chinese over 40 years and great consideration should be given to OGTT in detecting (pre)diabetes in this population. Further population-based prospective cohort study of longer-term effects is necessary to investigate the risk assessment and cost of (pre)diabetes.

The genotype VII Newcastle disease virus (NDV) vaccine has begun to replace the traditional genotype II NDV vaccine and is widely used in the commercial poultry of China. However, the effect of homologous and heterogeneous anti-NDV serum on the evolution of prevalent NDV is unknown. To understand the effect of genotype II and VII anti-NDV serum on the evolution of genotype VII NDV strains, ZJ1 (waterfowl origin) and CH/SD/2008/128 (ND128; chicken origin) were used for serial passage of 30 generations in DF-1 cells without anti-NDV serum or with genotype II and VII anti-NDV serum independently. The F and HN genes of the 2 viruses were amplified for the 10th, 20th, and 30th generations of each serial passage group and compared with their respective original viruses. We found that there was only one mutation at position 248 in the F gene of ZJ1 due to the serum pressure of genotype VII anti-NDV. Similarly, mutations at residue 527 of the F gene, and position 9 and 319 of the HN gene of ND128 were noted in both anti-NDV serum groups. The results show that the nonsynonymous (NS)-to-synonymous (S) ratio of the F gene of ZJ1 virus was 1.6, and for the HN gene, it was 2.5 in the anti-II serum group. In the anti-VII serum group, the NS/S ratio for the F gene was 2.1, and for the HN gene, it was 2.5. The NS/S ratio of the F gene of the ND128 virus was 0.8, and for the HN gene, it was 3 in the anti-II serum group. Furthermore, the NS/S ratio of the F gene was 0.8, and the HN gene was 2.3 in the anti-VII group. Taken together, our findings highlight that there was no significant difference in the variation of protective antigens in genotype VII NDV under the selection pressure of homologous and heterogeneous genotype NDV inactivated vaccines.

Fructose-1,6-bisphosphatase-1 (FBP1), a gluconeogenesis rate-limiting enzyme expressed in various tissues, is important in the carcinogenesis of various cancers. To evaluate the association of FBP1 expression and carcinogenesis and chemoresistance in cervical cancer, the present study analyzed 140 patients of squamous cell carcinoma of cervical cancer (CSCC) who had adjuvant concurrent chemoradiation therapy following radical surgery. By detecting FBP1 protein expression in paraffin-embedded tumor tissues through immunohistochemistry, it was observed that 50% of the cases had a low expression of FBP1, which was associated with a shorter overall survival time (P=0.011). In addition, FBP1 mRNA level was downregulated in tumor tissues, compared with cervical normal tissues. Among the tumor-associated prognostic factors, loss of FBP1 expression (chi(2)-test, P=0.025) was significantly associated with the tumor recurrence and greater tumor stage of cervical cancer patients (2-test, P

Butyric acid (BA), one of the short chain fatty acids (SCFAs), has positive actions on the metabolism, inflammation, etc. However, whether it influences the reproductive physiology and if so the detail mechanism involved has not yet been determined. In this study, the porcine granulosa cells (PGCs) were treated with gradient concentrations of BA. After 24h culture, 0.05mM BA significantly stimulated the progesterone (P4) secretion (P

Background To evaluate the predictive value of serum albumin (ALB) for persistent organ failure (POF) in acute pancreatitis (AP). Methods We selected 158 patients with AP in this retrospective study from Jan.1st, 2015 to Dec.31st, 2015. Forty-six patients were diagnosed with POF. All the values of laboratory parameters were measured upon admission to hospital. And 48 h after admission, we examined serum albumin of each patient again, called ‘ALB2’. Uni-and multi-variate logistic regression were used to evaluate the impact of ALB to predict POF. Results The median age of the whole population was 48 years and 53.8% were male. The admission-time albumin of AP patients with POF was distinctly lower than patients without POF (28.9 (25.3–33.1) g/L vs. 38.5 (34.0–40.1) g/L, p

Objective The main purpose of this study was to evaluate propofol and its combined effect with cisplatin on apoptosis of cervical cancer cells and molecular mechanisms of this phenomenon. Methods The effects of propofol and cisplatin on cell viability and apoptosis were detected by cell counting kit-8 (CCK-8) assay, colony formation assay and flow cytometry assay. Besides, protein expression of EGFR/JAK2/STAT3 pathway was determined by western blot. STAT3 was over-expressed in cervical cancer cells by STAT3 cDNA. Expression of EGFR and STAT3 protein of human tissues was evaluated by immunohistochemistry (IHC) assay. Results In this study, we found that not only propofol alone could inhibit cervical cancer cells viability but also could increase the inhibitory effect of cisplatin on cervical cancer cells growth. Meanwhile, propofol sensitized cervical cancer cells to cisplatin-induced apoptosis but not affected normal cervical cells. In genetic level, propofol could enhance the anti-tumor effect of cisplatin through EGFR/JAK2/STAT3 pathway. Further studies indicated that overexpression of EGFR and STAT3 is related to poor prognoses in cervical cancer patients, which contributed to confirm the clinical role of combined application of propofol and cisplatin. Conclusion Propofol enhances the cisplatin-induced cell apoptosis cervical cancer cells via EGFR/JAK2/STAT3 pathway and may be developed as a potential therapeutic agent to treat cervical cancer.

Free drug concentration (Cf) is instantaneous and susceptible to sampling time, which can confuse clinicians and cause them to adjust the dosage regimen. In the present work, we indicated a new parameter, the plasma protein binding (PPB) of clinical plasma samples, and discussed its application in TDM (Therapeutic Drug Monitoring). Furthermore, carbamazepine was selected as a model drug to develop a simple pretreatment method for the determination of PPB, in which Cf and Ct can be simultaneously analyzed in one plasma sample using a single device. Our results demonstrated that this proposed method exhibited some advantages, including perfect recovery (approximately 100%) and high precision (CV% < 3.0%). Furthermore, it achieved successful application in real plasma samples. Individual differences in PPB (from 10.1–68.9%) were among patients, and in additon, between the patients and healthy people (p < 0.05). Moreover, there was a weak correlation between Ct and Cf (r2 = 0.470 and p < 0.05), so the Cf of CBZ cannot be estimated from Ct. However, the primary cause of the variability of Cf is the change in PPB. As a consequence, applying PPB to guide individual dose adjustment is more accurate and more scientific than using Cf or Ct.

A low density refractory high entropy alloy of composition TiCrVNb0.5Al0.5 was prepared by vacuum arc melting. Due to the formation of a single-phase BCC structure with uniform element distribution and a gradient passive film with a high concentration of passivating elements, the TiCrVNb0.5Al0.5 high entropy alloy (HEA) exhibits low corrosion current density (10−7~10−8 A cm−2), high breakdown potential (1.8–1.9 VSCE) and excellent repassivation ability in 3.5 wt% NaCl and 1M HCl solutions. The properties were compared with HEAs, bulk metallic glasses (BMGs) and traditional alloys reported in literatures. The results show that TiCrVNb0.5Al0.5 possesses the most outstanding corrosion resistance in chloride environment.

Fatal road traffic crashes are often related to multifarious risk factors, among which driving under the influence of drugs (DUID) has been reported as a significantly contributing cause. The first worry about the side-effect of influencing driving drugs is central nervous system adverse reaction, and anti-hypersensitivity drugs are a class of drugs with such side effects meanwhile has been widely used for common allergic diseases thus posing a great challenge to road safety and demanding a rapid and efficient method to detect. In this work, a method based on magnetic graphene oxide dispersive solid phase extraction (MGO-D-SPE) combined with ion mobility spectrometry (IMS) was firstly introduced for simultaneous determination of ephedrine, pseudoephedrine, diphenhydramine, promethazine and terfenadine in saliva and urine matrices. The prepared MGO was characterized by Fourier transform infrared (FT-IR) spectroscopy and thermo gravimetric analysis (TGA). Various parameters affecting extraction efficiency as well as instrumental acquisition sensitivity were studied and optimized. Under the optimum experimental conditions, the method was fully validated and the results demonstrated that the proposed method exhibited some advantages, including a good linearity covering large concentration ranges of 51.0-3040 ng ml-1 for five anti-hypersensitivity drugs, and good accuracy was also obtained with high precision (CV% < 5.0 %). LODs and LOQs were 10.2-50.4 ng·mL-1 and 30.6-101.3 ng·mL-1, respectively. Consequently, the MGO-D-SPE-IMS methodology succeeded in building a hitherto unexplored tool for quantifying anti-hypersensitivity drugs in saliva and urine matrices of interest in DUID research field.

Objective Host immune response have a pivotal role in the course of Mycobacterium tuberculosis (Mtb) infection. IL27 plays both pro-inflammatory and anti-inflammatory activities in infectious diseases via STAT1/STAT3 mechanism. To investigate the association of single nucleotide polymorphisms (SNPs) of IL27 and STAT3 on the susceptibility of tuberculosis, we conducted a large size of case-control study in western Chinese Han population. Methods A total of seven SNPs were genotyped using multiplex ligation detection reaction method in 900 patients with tuberculosis and 1534 healthy controls. Results Variants of three SNPs (rs181206, rs17855750, rs26528) within IL27 gene, the genotype and allele frequencies of rs17855750 were significantly different (p = .013, p = .004, respectively) between the TB patients and healthy controls. Subjects carrying C allele for rs17855750 showed a decreased tuberculosis risk (OR = 0.75, 95% CI = 0.62–0.91, p = .004). Genetic model analysis revealed that dominant modal was associated with lower TB risk (OR = 0.74, 95% CI = 0.60–0.92, p = .042). Haplotype of ACG (representing rs181206, rs17855750 and rs26528) showed a reduced risk to TB (OR = 0.79, 95% CI = 0.65–0.96, p = .017). There were no significant differences between TB cases and healthy controls in the variants of four SNPs (rs1053005, rs2293152, rs744166, rs4796793) within STAT3 gene. Conclusions The polymorphisms of IL27, rs17855750, but not rs181206 and rs26528, plays a protective role on the susceptibility to TB.

The transmission and infections of multidrug-resistant bacteria can be prevented by rapid identification and antibiotic susceptibility testing (AST) for pathogenic bacteria in a clinical microbiology laboratory. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has been routinely used as a tool for the identification of pathogens; however, a simple and accurate method for a rapid determination of the antimicrobial susceptibility profile is an urgent requisite. The present study established a method based on mass spectrometry to determine the drug resistance. Acinetobacter baumannii complex isolates were tested as an example. After short-term culture, the isolates were incubated with meropenem of different concentrations to determine the growth or the inhibition of the growth by MALDI-TOF MS. The agreement of minimum inhibitory concentration (MIC) values between MALDI-TOF MS-based rapid AST and broth microdilution method in susceptible and resistant strains was 77.1% and 70.1%, respectively. The susceptibility-breakpoint concentration (2 μg/mL) achieved a 98.9% sensitivity and 100% specificity with respect to resistance detection. Similarly, 96.9% sensitivity and 100% specificity were obtained for resistance detection with meropenem concentration at 8 μg/mL. MALDI-TOF MS-based rapid AST was applied to determine the drug resistance at breakpoint concentration, although MS-MICs might shift to a low dilution. Thus, it is critical for patients to accelerate the AST result from two days to several hours.

Past research has demonstrated negative associations between exposure to stressors and quality of interpersonal relationships among children and adolescents. Nevertheless, underlying mechanisms of this association remain unclear. Chronic stress has been shown to disrupt prefrontal functioning in the brain, including inhibitory control abilities, and evidence is accumulating that inhibitory control may play an important role in secure interpersonal relationship quality, including peer problems and social competence. In this prospective longitudinal study, we examine whether changes in inhibitory control, measured at both behavioral and neural levels, mediate the association between stress and changes in secure relationship quality with parents and peers. The sample included 167 adolescents (53% males) who were first recruited at age 13 or 14 years and assessed annually three times. Adolescents’ inhibitory control was measured by their behavioral performance and brain activities, and adolescents self-reported perceived stress levels and relationship quality with mothers, fathers, and peers. Results suggest that behavioral inhibitory control mediates the association between perceived stress and adolescent’s secure relationship quality with their mothers and fathers, but not their peers. In contrast, given that stress was not significantly correlated with neural inhibitory control, we did not further test the mediation path. Our results highlight the role of inhibitory control as a process through which stressful life experiences are related to impaired secure relationship quality between adolescents and their mothers and fathers. National Institute on Drug Abuse NIDA: DA036017

We tested a novel multi-component emotion self-regulation (ER) construct that captured physiological (vagal tone), cognitive (reappraisal), and temperament (effortful control) aspects of ER as a moderator of the link between more stressors and greater negative/less positive affectivity. A socioeconomically diverse sample of 151 women with young children completed questionnaires and a laboratory visit (including cognitive and parent-child interaction tasks, and vagal tone measurement). Women with more stressors had more negative affectivity and less positive affectivity. Furthermore, for negative affectivity only, having more stressors was substantially associated with negative affectivity but only among women with the lowest ER. This pattern was evident for the composite as well as individual indicators of ER. Results were not attributable to individual differences in executive function. Findings are discussed in light of the diathesis-stress model of stress and coping.

Phosphoglucomutase (pgm) is an important enzyme in carbohydrate metabolism that is located at the branching point between glycolysis and the Leloir pathway. pgm catalyzes the reversible conversion reaction between glucose-6-phosphate (Glc-6-P) and glucose-1-phosphate (Glc-1-P). The glpgm gene was cloned in Escherichia coli, and the recombinant pgm protein from Ganoderma lucidum was purified in this study. The activity of native pgm was also detected to demonstrate that this predicted gene was functional in G. lucidum. Interestingly, silencing the glpgm gene in the fungus reduced hyphal growth. Moreover, glpgm silencing was associated with declining extracellular polysaccharide (EPS) production (approximately 20-40% of that in the WT strain) and increasing intracellular polysaccharide (IPS) production (approximately 1.7-fold that in the WT strain). Additionally, in our research, cell wall components were also shown to differ according to the glpgmi strain. Compared with WT, chitin significantly increased by 1.5-fold; however, the content of β-1,3-glucan was observably reduced to 60-70% that of the WT. Further research showed that the cell wall component changes were associated with the transcription of related genes. These findings provide references for further study on the potential physiological function of pgm in G. lucidum.

Copper ferrites are emerging transition metal oxides that have potential applications in energy storage devices. However, it still lacks in-depth designing of copper ferrites based anode architectures with enhanced electroactivity for lithium-ion batteries. Here, we report a facile synthesis technology of copper ferrites anchored on reduced graphene oxide (CuFeO2@rGO and Cu/CuFe2O4@rGO) as the high-performance electrodes. In the resulting configuration, reduced graphene offers continuous conductive channels for electron/ion transfer and high specific surface area to accommodate the volume expansion of copper ferrites. Consequently, the sheet-on-sheet CuFeO2@rGO electrode exhibits a high reversible capacity (587 mAh g−1 after 100 cycles at 200 mA g−1). In particular, Cu/CuFe2O4@rGO hybrid, which combines the advantages of nano-copper and reduced graphene, manifests a significant enhancement in lithium storage properties. It reveals superior rate capability (723 mAh g−1 at 800 mA g−1; 560 mAh g−1 at 3200 mA g−1) and robust cycling capability (1102 mAh g−1 after 250 cycles at 800 mA g−1). This unique structure design provides a strategy for the development of multivalent metal oxides in lithium storage device applications.

Two-dimensional layered K4Nb6O17 (KN) was easily formed as a secondary phase caused by the volatilization of alkali metal ions, when preparing ferroelectric K x Na1−x NbO3 based ceramics and films. In this work, it was believed that KN film is with weak ferroelectricity and has a little effect on the ferroelectric properties of K x Na1−x NbO3 based films. Moreover, temperature dependent (77–500 K) dielectric functions of KN film have been firstly extracted by fitting ellipsometric spectra with the Adachi dielectric function model and a four-phase layered model. The high-frequency dielectric constant linearly increases and optical band gap slightly decreases with increasing the temperature. We also research its photoelectrochemical properties and its application in high-efficient light-induced H2 evolution. In addition, X-ray photoelectron spectroscopy, Raman scattering, temperature dependent transmittance and infrared reflectance spectra, and first-principles calculation were conjointly performed to further reveal the intrinsic optoelectronic features and relevant mechanisms of KN.

In this work, for the first time, a high-performance ion mobility spectrometry with electrospray ionization (ESI-HPIMS) method has been employed as a rapid screening tool for the detection of acetaminophen, ibuprofen, naproxen, diclofenac sodium and indomethacin illegally added in anti-rheumatic herbal supplements and herbal remedies. Samples were dissolved and filtered through a 0.45μm microporous membrane, then the filtrate was directly injected into the high-performance ion mobility spectrometry for analysis. Using this approach, the screening of illegal additions can be accomplished in as rapid as two to three minutes with no pretreatment required. The proposed method provided a LOD of 0.06-0.33μgmL-1, as well as a good seperation of the five NSAIDs. The precision of the method was 0.1-0.4% (repeatability, n=6) and 0.9-3.3% (reproducibility, n=3). The proposed method appeared to be simple, rapid and highly specific, thus could be effective for the in-situ screening of NSAIDs in anti-rheumatic herbal supplements and herbal remedies.