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Abstract Background CDC6 is an oncogenic protein whose expression level fluctuates during the cell cycle. Although several E3 ubiquitin ligases responsible for the ubiquitin-mediated proteolysis of CDC6 have been identified, the deubiquitination pathway for CDC6 has not been investigated. Methods The proteome-wide deubiquitinase (DUB) screening was used to identify the potential regulator of CDC6. Immunofluorescence, protein half-life and deubiquitination assays were performed to determine the protein stability of CDC6. Gain- and loss-of-function experiments were implemented to analyse the impacts of OUTD6A-CDC6 axis on tumour growth and chemosensitivity in vitro. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced conditional Otud6a knockout (CKO) mouse model and tumour xenograft model were performed to analyse the role of OTUD6A-CDC6 axis in vivo. Tissue specimens were used to determine the association between OTUD6A and CDC6. Results OTUD6A interacts with, depolyubiquitinates and stabilizes CDC6 by removing K6-, K33-, and K48-linked polyubiquitination. Moreover, OTUD6A promotes cell proliferation and decreases sensitivity to chemotherapy by upregulating CDC6. CKO mice are less prone to BCa tumorigenesis induced by BBN, and knockdown of OTUD6A inhibits tumour progression in vivo. Furthermore, OTUD6A protein level has a positive correlation with CDC6 protein level, and high protein levels of OTUD6A and CDC6 are associated with poor prognosis in patients with bladder cancer. Conclusions We reveal an important yet missing piece of novel DUB governing CDC6 stability. In addition, our findings propose a model for the OTUD6A-CDC6 axis that provides novel insights into cell cycle and chemosensitivity regulation, which may become a potential biomarker and promising drug target for cancer treatment.

Detecting faulty lines in small-current, grounded systems is a crucial yet challenging task in power system protection. Existing methods often struggle with the accurate identification of faults due to the complex and dynamic nature of current and voltage signals in these systems. This gap in reliable fault detection necessitates more advanced methodologies to improve system stability and safety. Here, a novel approach, using learning spiking neural P systems combined with a normalized least mean squares (NLMS) algorithm to enhance faulty line detection in small-current, grounded systems, is proposed. The proposed method analyzes the features of current and voltage signals, as well as active and reactive power, by separately considering their transient and steady-state components. To improve fault detection accuracy, we quantified the likelihood of a fault occurrence based on feature changes and expanded the feature space to higher dimensions using an ascending dimension structure. An adaptive learning mechanism was introduced to optimize the convergence and precision of the detection model. Simulation scheduling datasets and real-world data were used to validate the effectiveness of the proposed approach, demonstrating significant improvements over traditional methods. These findings provide a robust framework for faulty-line detection in small-current, grounded systems, contributing to enhanced reliability and safety in power system operations. This approach has the potential to be widely applied in power system protection and maintenance, advancing the broader field of intelligent fault diagnosis.

In order to enhance earthquake emergency response capability, and to conveniently and quickly obtain seismic influence field, earthquake emergency thematic maps, and to rapidly assess post-earthquake reports, it is able to provide professional technical support for earthquake emergency decision-making and rescue. We develop visualization form through QT, use the Tianditu map API to call Tianditu map as the base map, and use Tianditu map geocoding API to obtain the basic geographic information, and finally overlay the seismic thematic data. After users input information such as epicenter latitude and longitude coordinates, arcpy library automatically creates a batch of earthquake thematic maps for the epicenter area, and a rapid assessment report is automatically output by using the Python-docx library. The actual application results show that the system program has only a single file after the Python script encapsulated, which is ready to be copied and used, making it easy to deploy. It has features such as mass production of thematic maps and automated output of earthquake briefings. These functions have led to a significant increase in emergency response efficiency. The level of seismic emergency information service has been significantly advanced.

ObjectiveTo observe the effectiveness and safety of Lianhua Qingwen granule in the treatment of non-influenza viral pneumonia.MethodsThis study was a multicenter, randomized, double-blind, placebo-controlled trial. Subjects who met the inclusion and exclusion criteria and were clinically diagnosed with viral pneumonia (negative for influenza virus) were randomly divided into the Lianhua Qingwen granule trial group and placebo control group. Patients in the trial group was given Lianhua Qingwen granule, 2 bags at a time, 3 times a day, and the controls were given placebo, with a treatment course of 7 days. Patients’ clinical symptoms and signs, and treatment-associated adverse events were observed. Subjects should be included in the full analysis set (FAS) as long as they were all given the medication and had an effectiveness test performed after randomization. Subjects should be included in the Per Protocol Set (PPS),a subset of the total analysis set, which should contain those with strong compliance, no protocol violations, and complete baseline values for the primary indicators.ResultsA total of 169 subjects were enrolled in 12 subcenters, including 151 (76 in the trial group and 75 in the control group) in the FAS and 140 (68 in the trial group and 72 in the control group) in the PPS. After 7 days of treatment, the clinical symptom relief rates were 82.98% (FAS) and 87.12% (PPS) in the trial group, and 75.11% (FAS) and 76.02% (PPS) in the control group, respectively. The clinical symptom relief rates in the trial group were significantly higher than those in the control group (p 0.05).SafetyThere were no significant differences in body weight, vital signs, blood routine, urine routine, stool routine, and blood biochemical indicators (CK, AST, ALT, Cr, and Bun) between the two groups before and after treatment (p > 0.05). During treatment, there were no significant differences in the incidence of adverse events and serious adverse events between the two groups (p > 0.05).ConclusionLianhua Qingwen granules improved the clinical symptoms of patients with non-influenza virus pneumonia, especially ameliorating cough and expectoration. Lianhua Qingwen granules were associated with good safety.

Context QiShenYiQi pill (QSYQ) is a traditional Chinese medicine with a myocardial protective effect.Objective To explore the effect of QSYQ on myocardial collagen metabolism in rats with autoimmune cardiomyopathy and explore the underlying mechanism from the aspect of apoptosis.Materials and methods We established an autoimmune cardiomyopathy model using Lewis rats. The rats were then randomly divided into six groups (n = 8): control, model, 3-methyladenine (15 mg/kg, intraperitoneal injection), QSYQ low-dose (135 mg/kg, gavage), QSYQ medium dose (270 mg/kg, gavage), and QSYQ high-dose (540 mg/kg, gavage) for four weeks. Van Gieson staining was applied for myocardial pathological characteristics, TUNEL fluorescence for myocardial cell apoptosis, enzyme-linked immunosorbent assay (ELISA) for serum PICP, PIIINP, and CTX-I levels, and western blot analysis for type I/III myocardial collagen, Bcl-2, Bax, and caspase-3 proteins.Results Results showed that QSYQ (135, 270, or 540 mg/kg) significantly reduced the expression of myocardial type I/III collagen, and concentrations of serum PICP, PIIINP, and CTX-I in rats. Moreover, QSYQ could alleviate myocardial fibrosis more effectively at a higher dose. QSYQ could also inhibit myocardial apoptosis via downregulating Bcl-2 expression, and upregulating Bax and caspase-3 expression levels.Discussion and conclusions The QSYQ can improve myocardial collagen metabolism by inhibiting apoptosis, which provides a potential therapeutic approach for autoimmune cardiomyopathy.

One of the most common routes of chronic hepatitis B virus (HBV) infection is mother-to-child transmission (MTCT). Approximately 6.4 million children under the age of five have chronic HBV infections worldwide. HBV DNA high level, HBeAg positivity, placental barrier failure, and immaturity of the fetal immune are the possible causes of chronic HBV infection. The passive-active immune program for children, which consists of the hepatitis B vaccine and hepatitis B immunoglobulin, and antiviral therapy for pregnant women who have a high HBV DNA load (greater than 2 × 105 IU/ml), are currently two of the most important ways to prevent the transmission of HBV from mother to child. Unfortunately, some infants still have chronic HBV infections. Some studies have also found that some supplementation during pregnancy can increase cytokine levels and then affect the level of HBsAb in infants. For example, IL-4 can mediate the beneficial effect on infants’ HBsAb levels when maternal folic acid supplementation. In addition, new research has indicated that HBV infection in the mother may also be linked to unfavorable outcomes such as gestational diabetes mellitus, intrahepatic cholestasis of pregnancy, and premature rupture of membranes. The changes in the immune environment during pregnancy and the hepatotropic nature of HBV may be the main reasons for the adverse maternal outcomes. It is interesting to note that after delivery, the women who had a chronic HBV infection may spontaneously achieve HBeAg seroconversion and HBsAg seroclearance. The maternal and fetal T-cell immunity in HBV infection is important because adaptive immune responses, especially virus-specific CD8 T-cell responses, are largely responsible for viral clearance and disease pathogenesis during HBV infection. Meanwhile, HBV humoral and T-cell responses are important for the durability of protection after fetal vaccination. This article reviews the literature on immunological characteristics of chronic HBV-infected patients during pregnancy and postpartum, blocking mother-to-child transmissions and related immune mechanisms, hoping to provide new insights for the prevention of HBV MTCT and antiviral intervention during pregnancy and postpartum.

ObjectiveTo investigate the sustained virological response and relapse in chronic hepatitis B (CHB) patients with hepatitis B e antigen (HBeAg) positive after stopping oral antiviral drugs, and to monitor the disease progression and the incidence of adverse events such as liver cirrhosis and hepatocellular carcinoma.MethodsThis is a prospective observational study. Patients who continued nucleos(t)ide analogue (NA) treatment after achieving HBeAg seroconversion for more than 3 years were enrolled. After signing the informed consent form, patients stopped NA treatment and received follow-up. During the follow-up, the antiviral treatment information of the patients was collected, and the follow-up observation was carried out every 3 months since the enrollment. We monitored the virological indexes, liver and kidney function, serology and liver imaging during follow-up. The purpose of this study was to explore the sustained virological response rate, HBV DNA recurrence rate, clinical relapse rate and the related factors after drug withdrawal.ResultsA total of 82 patients were enrolled, including 42 males (51.22%) and 40 females (48.78%), with a median age of 34.00 (31.00, 37.25) years. All enrolled patients were followed up for 1 year. At the end of the follow-up, 36.59% (30/82) of patients had sustained virological response, 63.41% (52/82) of patients had HBV DNA reactivation, 17.07% (14/82) of patients had clinical relapse, and 10.98% (9/82) of patients had HBeAg reversion. During the follow-up, there were no adverse events such as liver cirrhosis and hepatocellular carcinoma. The median level of hepatitis B surface antigen (HBsAg) in patients with sustained virological response was lower than that in patients with HBV DNA reactivation (2.92 vs.3.18 log10IU/ml, Z=-1.492/P=0.136), and the median level of baseline HBsAg in patients with HBV DNA reactivation was lower than that in patients with clinical relapse (3.01 vs.3.45 log10IU/mL, Z=-1.795/P=0.073), but the difference was not significant. There was no significant statistical difference between patients with sustained virological response and HBV DNA reactivation of the median total treatment time [69.50 (56.25, 86.00) vs.62.50 (44.00, 88.50) months, Z=-0.689/P=0.491], and the consolidation treatment time [41.50 (36.75, 54.75) vs.40.50 (36.00, 53.75) months, Z=-0.419/P=0.675].ConclusionThe sustained virological response rate of HBeAg positive CHB patients after stopping oral antiviral treatment is lower, and it is more common in patients with lower HBsAg levels. Patients still need to be closely monitored after stopping NA therapy.

ObjectiveTo explore dynamic changes of cytokines and virological markers associated with hepatitis B surface antigen (HBsAg) loss during peginterferon alpha-2a (PEG-IFN α-2a) treatment in hepatitis B e antigen (HBeAg) positive chronic hepatitis B (CHB) patients.MethodsIt was a single-center prospective cohort study. HBeAg-positive CHB patients were prospectively and consecutively enrolled. Cytokines were detected at baseline, week 12 and 24 of PEG-IFN treatment. HBsAg disappearance rate was the primary evaluation index at 48 weeks of PEG-IFN treatment.ResultsAmong 100 patients who completed the 48-week PEG-IFN α-2a treatment, 38 patients achieved serum HBeAg disappearance, 25 patients achieved HBeAg seroconversion, 9 patients achieved functional cure, 37 patients had HBsAg decline of ≥1 log IU/ml, and 8 patients produced hepatitis B surface antibody (HBsAb). Albumin (ALB), fms-like tyrosine kinase 3 ligand (FLT3-L) and interferon-alpha2 (IFN-α2) in the clinical cure group were significantly lower than those in the non-clinical-cure group at baseline. After 12 weeks of treatment, HBsAg in the clinical cure group was significantly lower than that in the non-clinical-cure group (median 1.14 vs. 3.45 log10IU/ml, Z=-4.355, P < 0.001). The decrease of HBsAg and hepatitis B virus desoxyribose nucleic acid (HBV DNA) in the clinical cure group was significantly higher than that in non-clinical-cure group (median: HBsAg 1.96 vs. 0.33 log10IU/ml, Z=-4.703, P< 0.001; HBV DNA 4.49 vs.3.13 log10IU/ml, Z=-3.053, P=0.002). The increase of IFN-α2 in the cure group was significantly higher than that in the non-clinical-cure group (497.89 vs. 344.74, Z=-2.126, P=0.034). After 24 weeks of treatment, HBsAg, HBeAg, Flt3-L, and IL-10 in the clinical cure group were significantly lower than those in the non-clinical-cure group (median: HBsAg 0.70 vs. 3.15 log10IU/ml, Z=-4.535, P< 0.001; HBeAg 1.48 vs. 13.72 S/CO, Z = 2.512, P = 0.012; Flt3-l 0.00 vs 2.24 pg/ml, Z = 3.137, P=0.002; IL-10 0.70 vs. 2.71 pg/ml, Z=-4.067, P < 0.001). HBsAg decreased significantly in the clinical cure group compared with non-clinical-cure group (median 3.27 vs. 0.45, Z=-4.463, P < 0.001).ConclusionDynamic changes of cytokines and virology markers during early PEG IFN α-2a treatment were associated with HBsAg loss in HBeAg-positive CHB patients.

ObjectiveThe ideal endpoint of antiviral therapy in chronic hepatitis B (CHB) patients is to clear hepatitis B surface antigen (HBsAg). This study aimed to evaluate whether the expression of functional molecules on plasmacytoid dendritic cells (pDCs) is associated with HBsAg loss in HBeAg-positive patients during peginterferon alpha-2a (PEG IFN α-2a) therapy.MethodsA single-center prospective cohort study was performed in HBeAg-positive CHB patients who were treated with PEG-IFN α-2a and followed up for 4 years. HBsAg clearance, HBeAg loss and undetectable HBV DNA achieved by PEG-IFN α-2a therapy was considered as functional cure. The frequencies of pDC and CD86+ pDC in peripheral blood, and the mean fluorescence intensity of CD86 (CD86MFI) on the surface of pDC were measured at starting therapy, after 12 and 24 weeks of therapy.ResultsOf 63 patients enrolled, 17 patients achieved HBsAg loss. The baseline HBV DNA load in Non-functional-cure group was significantly higher than that in Functional cure group, and the CD86+ pDC% was significantly lower in patients without functional cure. HBV DNA load (OR=0.146, P = 0.002) and CD86+ pDC% (OR=1.183, P = 0.025) were independent factors associated with functional cure confirmed by binary logistic regression analysis. In the Functional cure group, HBsAg, HBeAg, and HBV DNA loads decreased remarkably after 12 weeks and 24 weeks of treatment compared to baseline. In Non-functional-cure group, CD86+ pDC% and CD86MFI increased significantly from baseline after 12 weeks of treatment. In the Functional cure group, compared with baseline, pDC% increased significantly at 24 weeks, while CD86MFI increased significantly after 24 weeks of treatment.ConclusionThe lower the baseline HBV DNA load and the more the baseline CD86+ pDC%, the easier it is for patients to obtain functional cure.

Various diseases caused by food-borne or environmental pathogenic microorganisms have been a persistent threat to public health and global economies. It is necessary to regularly detect microorganisms in food and environment to prevent infection of pathogenic microorganisms. However, most traditional detection methods are expensive, time-consuming, and unfeasible in practice in the absence of sophisticated instruments and trained operators. Point-of-care testing (POCT) can be used to detect microorganisms rapidly on site and greatly improve the efficiency of microbial detection. Lab-on-chip (LOC) is an emerging POCT technology with great potential by integrating most of the experimental steps carried out in the laboratory into a single monolithic device. This review will primarily focus on principles and techniques of LOC for detection of microbial nucleic acid in food and environment, including sample preparation, nucleic acid amplification and sample detection.

The fuzzy reasoning numerical spiking neural P systems (FRNSN P systems) are proposed by introducing the interval-valued triangular fuzzy numbers into the numerical spiking neural P systems (NSN P systems). The NSN P systems were applied to the SAT problem and the FRNSN P systems were applied to induction motor fault diagnosis. The FRNSN P system can easily model fuzzy production rules for motor faults and perform fuzzy reasoning. To perform the inference process, a FRNSN P reasoning algorithm was designed. During inference, the interval-valued triangular fuzzy numbers were used to characterize the incomplete and uncertain motor fault information. The relative preference relationship was used to estimate the severity of various faults, so as to warn and repair the motors in time when minor faults occur. The results of the case studies showed that the FRNSN P reasoning algorithm can successfully diagnose single and multiple induction motor faults and has certain advantages over other existing methods.

Antibody-drug conjugates (ADC) are effective antibody-based therapeutics for hematopoietic and lymphoid tumors. However, there is need to identify new targets for ADCs, particularly for solid tumors and cancers with unmet needs. From a hybridoma library developed against cancer cells, we selected the mouse monoclonal antibody 33B7, which was able to bind to, and internalize, cancer cell lines. This antibody was used for identification of the target by immunoprecipitation and mass spectrometric analysis, followed by target validation. After target validation, 33B7 binding and target positivity were tested by flow cytometry and western blot analysis in several cancer cell lines. The ability of 33B7 conjugated to saporin to inhibit in vitro proliferation of PTFRN positive cell lines was investigated, as well as the 33B7 ADC in vivo effect on tumor growth in athymic mice. All flow cytometry and in vitro internalization assays were analyzed for statistical significance using a Welsh's T-test. Animal studies were analyzed using Two-Way Analysis of Variance (ANOVA) utilizing post-hoc Bonferroni analysis, and/or Mixed Effects analysis. The 33B7 cell surface target was identified as Prostaglandin F2 Receptor Negative Regulator (PTGFRN), a transmembrane protein in the Tetraspanin family. This target was confirmed by showing that PTGFRN-expressing cells bound and internalized 33B7, compared to PTGFRN negative cells. Cells able to bind 33B7 were PTGFRN-positive by Western blot analysis. In vitro treatment PTGFRN-positive cancer cell lines with the 33B7-saporin ADC inhibited their proliferation in a dose-dependent fashion. 33B7 conjugated to saporin was also able to block tumor growth in vivo in mouse xenografts when compared to a control ADC. These findings show that screening antibody libraries for internalizing antibodies in cancer cell lines is a good approach to identify new cancer targets for ADC development. These results suggest PTGFRN is a possible therapeutic target via antibody-based approach for certain cancers.

Long noncoding RNA (lncRNA) GASL1 was identified as a novel lncRNA, which plays an important role in the proliferation and apoptosis of cells. This study aimed to compare the expression of GASL1 mRNA in kidney cancer cells and normal cells and detect the biological role of GASL1 in kidney cancer cell line A498. Polymerase chain reaction (PCR) was performed to examine the expression of GASL1 mRNA in kidney cancer tissues, normal tissues, and the cell lines. GASL1 overexpression was achieved in kidney cancer cell lines A498 through transfection. MTT was used to detect the effects of GASL1 overexpression in A498 cells. GASL1 mRNA was significantly overexpressed in adjacent normal tissues compared with renal cell carcinoma. The expression of GASL1 is lower in kidney cancer cell lines than in normal kidney epithelium cell line HREpiC. Overexpression of GASL1 inhibits the proliferation of renal carcinoma cell lines. GASL1 mRNA was down-regulated in kidney cancer tissues and may play a role in kidney cancer cell proliferation.

As an important variant of membrane computing models, fuzzy reasoning spiking neural P systems (FRSN P systems) were introduced to build a link between P systems and fault diagnosis applications. An FRSN P system offers an intuitive illustration based on a strictly mathematical expression, a good fault-tolerant capacity, a good description for the relationships between protective devices and faults, and an understandable diagnosis model-building process. However, the implementation of FRSN P systems is still at a manual process, which is a time-consuming and hard labor work, especially impossible to perform on large-scale complex power systems. This manual process seriously limits the use of FRSN P systems to diagnose faults in large-scale complex power systems and has always been a challenging and ongoing task for many years. In this work we develop an automatic implementation method for automatically fulfilling the hard task, named membrane computing fault diagnosis (MCFD) method. This is a very significant attempt in the development of FRSN P systems and even of the membrane computing applications. MCFD is realized by automating input and output, and diagnosis processes consists of network topology analysis, suspicious fault component analysis, construction of FRSN P systems for suspicious fault components, and fuzzy inference. Also, the feasibility of the FRSN P system is verified on the IEEE14, IEEE 39, and IEEE 118 node systems.

A genome-wide association study had showed G-protein-coupled receptor kinase 5 (GRK5) rs10886471 was related to the risk of type 2 diabetes mellitus (T2DM) through upregulated GRK5 mRNA expression. Rs10886471 is located in the intron region of GRK5. However, the mechanism by which intronic SNP affects gene expression remains unclear, whether the effect on gene expression depends on the intronic short tandem repeat (STR) (CA)n splicing regulator or not. Here we investigated the STR (CA)n polymorphism in rs10886471 and further discussed its role in the T2DM risk of Chinese Hainan Island individuals. A total of 1164 subjects were recruited and classified into a normal fasting glucose (NFG) group, an impaired fasting glucose (IFG) group, an impaired glucose tolerance (IGT) group, and a T2DM group. STR (CA)n polymorphisms were detected through polymerase chain reaction and sequencing. Five intronic (CA)n alleles, (CA)15 to (CA)19, were identified in GRK5 rs10886471. Only the (CA)16 allele was significantly associated with increased prediabetes and T2DM risk [odds ratio (OR)>1, P