Prostaglandin F2 Receptor Negative Regulator (PTGFRN) Expression Correlates With a Metastatic-like Phenotype in Epidermoid Carcinoma, Pediatric Medulloblastoma, and Mesothelioma.

Prostaglandin F2 receptor negative regulator (PTGFRN) is a transmembrane protein associated with metastatic characteristics of certain cancer types. However, it remains poorly characterized and its direct function in cancer remains unclear. The study presented here aims to further examine whether PTGFRN expression affects a cancer cell's phenotype, as well as metastatic-like characteristics. We used stable shRNA and cDNA transfections to respectively knockdown and overexpress PTGFRN in three different cancer cell lines, two of which are representative of rare and aggressive cancers (Mesothelioma and Pediatric Medulloblastoma). We then examined the characteristics of the resulting clones and showed a decrease in proliferation, migration, colony formation, and spheroid growth capabilities in cells where PTGFRN expression had been inhibited, while cells overexpressing PTGFRN showed the opposite. In addition, we showed that PTGFRN displayed direct binding to two protein partners, Integrin ß1 and E. Cadherin, the latter of which is a novel direct binding partner to PTGFRN. Furthermore, silencing PTGFRN expression impacted the cellular process of autophagy, thereby providing another avenue by which PTGFRN potentially contributes to a cancer cell phenotype. Our findings demonstrate the potential role of PTGFRN in cancer metastasis and suggest PTGFRN as a future target for drug development in the treatment of metastatic cancers.

Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance.

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.

QiShenYiQi pill for myocardial collagen metabolism and apoptosis in rats of autoimmune cardiomyopathy.

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.

Fuzzy Reasoning Numerical Spiking Neural P Systems for Induction Motor Fault Diagnosis.

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.

Anti-progranulin/GP88 antibody AG01 inhibits triple negative breast cancer cell proliferation and migration.

BACKGROUND: Triple negative breast cancer (TNBC) is characterized by invasiveness and short survival. Identifying novel TNBC-targeted therapies, to potentiate standard of care (SOC) therapy, is an unmet need. Progranulin (PGRN/GP88) is a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC). PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level is associated with poor outcomes. Since PGRN/GP88 expression is elevated in 30% TNBC, we investigated the involvement of progranulin on TNBC. METHODS: The effect of inhibiting PGRN/GP88 expression in TNBC cells by siRNA was investigated. The effects of a neutralizing anti-human PGRN/GP88 monoclonal antibody AG01 on the proliferation and migration of two TNBC cell lines expressing PGRN/GP88 were then examined in vitro and in vivo. RESULTS: Inhibition of GP88 expression by siRNA and AG01 treatment to block PGRN/GP88 action reduced proliferation and migration in a dose-dependent fashion in MDA-MB-231 and HS578-T cells. Western blot analysis showed decreased expression of phosphorylated protein kinases p-Src, p-AKT, and p-ERK upon AG01 treatment, as well as inhibition of tumor growth and Ki67 expression in vivo. CONCLUSION: PGRN/GP88 represents a therapeutic target with companion diagnostics. Blocking PGRN/GP88 with antibody treatment may provide novel-targeted solutions in TNBC treatment which could eventually address the issue of toxicity and unresponsiveness associated with SOC.

QiShenYiQi pill improves the reparative myocardial fibrosis by regulating autophagy.

QiShenYiQi pill (QSYQ), a traditional Chinese medicine, is well known for improving the myocardial remodelling, but the dose-effect relationship of its intervention in the reparative myocardial fibrosis is still unclear. We investigated the effect of QSYQ on the reparative myocardial fibrosis in cardiac myosin-induced rats and explored its mechanism of action by regulating autophagy. The results indicated that QSYQ increased LVEF and LVFS, and decreased the LVEDD, LVESD, HMI, LVMI, myocardial inflammation histology score, and collagen volume fraction in a dose-dependent manner. In addition, QSYQ declined the number of autophagosomes, down-regulated the expression of myocardial Beclin-1 and LC3B, up-regulated the expression of myocardial p62 and increased the ratios of myocardial p-PI3K/PI3K, p-Akt/Akt and p-mTOR/mTOR. We provided evidence for that QSYQ could inhibit excessive myocardial autophagy by regulating the PI3K/Akt-mTOR pathway and can be a potential therapeutic approach in treating the cardiovascular diseases such as myocarditis and dilated cardiomyopathy.

Disease severity and clinical outcomes of community-acquired pneumonia caused by non-influenza respiratory viruses in adults: a multicentre prospective registry study from the CAP-China Network.

Although broad knowledge of influenza viral pneumonia has been established, the significance of non-influenza respiratory viruses in community-acquired pneumonia (CAP) and their impact on clinical outcomes remains unclear, especially in the non-immunocompromised adult population.Hospitalised immunocompetent patients with CAP were prospectively recruited from 34 hospitals in mainland China. Respiratory viruses were detected by molecular methods. Comparisons were conducted between influenza and non-influenza viral infection groups.In total, 915 out of 2336 adult patients with viral infection were enrolled in the analysis, with influenza virus (28.4%) the most frequently detected virus, followed by respiratory syncytial virus (3.6%), adenovirus (3.3%), human coronavirus (3.0%), parainfluenza virus (2.2%), human rhinovirus (1.8%) and human metapneumovirus (1.5%). Non-influenza viral infections accounted for 27.4% of viral pneumonia. Consolidation was more frequently observed in patients with adenovirus infection. The occurrence of complications such as sepsis (40.1% versus 39.6%; p=0.890) and hypoxaemia (40.1% versus 37.2%; p=0.449) during hospitalisation in the influenza viral infection group did not differ from that of the non-influenza viral infection group. Compared with influenza virus infection, the multivariable adjusted odds ratios of CURB-65 (confusion, urea >7 mmol·L-1, respiratory rate ≥30 breaths·min-1, blood pressure <90 mmHg (systolic) or ≤60 mmHg (diastolic), age ≥65 years) ≥3, arterial oxygen tension/inspiratory oxygen fraction <200 mmHg, and occurrence of sepsis and hypoxaemia for non-influenza respiratory virus infection were 0.87 (95% CI 0.26-2.84), 0.72 (95% CI 0.26-1.98), 1.00 (95% CI 0.63-1.58) and 1.05 (95% CI 0.66-1.65), respectively. The hazard ratio of 90-day mortality was 0.51 (95% CI 0.13-1.91).The high incidence of complications in non-influenza viral pneumonia and similar impact of non-influenza respiratory viruses relative to influenza virus on disease severity and outcomes suggest more attention should be given to CAP caused by non-influenza respiratory viruses.

An Optimization Numerical Spiking Neural Membrane System with Adaptive Multi-Mutation Operators for Brain Tumor Segmentation.

Magnetic Resonance Imaging (MRI) is an important diagnostic technique for brain tumors due to its ability to generate images without tissue damage or skull artifacts. Therefore, MRI images are widely used to achieve the segmentation of brain tumors. This paper is the first attempt to discuss the use of optimization spiking neural P systems to improve the threshold segmentation of brain tumor images. To be specific, a threshold segmentation approach based on optimization numerical spiking neural P systems with adaptive multi-mutation operators (ONSNPSamos) is proposed to segment brain tumor images. More specifically, an ONSNPSamo with a multi-mutation strategy is introduced to balance exploration and exploitation abilities. At the same time, an approach combining the ONSNPSamo and connectivity algorithms is proposed to address the brain tumor segmentation problem. Our experimental results from CEC 2017 benchmarks (basic, shifted and rotated, hybrid, and composition function optimization problems) demonstrate that the ONSNPSamo is better than or close to 12 optimization algorithms. Furthermore, case studies from BraTS 2019 show that the approach combining the ONSNPSamo and connectivity algorithms can more effectively segment brain tumor images than most algorithms involved.

Effect of PTFGRN Expression on the Proteomic Profile of A431 Cells and Determination of the PTGFRN Interactome.

Prostaglandin F2 receptor negative regulator (PTGFRN) is a transmembrane protein whose expression has been previously implicated in cancer metastasis. However, the exact molecular mechanisms by which PTGFRN influences cancer progression are still unknown. As such, our laboratory set out to investigate how PTGFRN knockdown affected the expression of other proteins. We also carried out coimmunoprecipitation experiments using a monoclonal anti-PTGFRN antibody. We employed mass spectrometry-based proteomics for both experiments to identify proteins that were associated with PTGFRN. Our data show that PTGFRN knockdown increased pathways related to innate immune responses and decreased pathways associated with the synthesis of metabolic precursors and protein processing, among others. Additionally, the coimmunoprecipitation experiments indicated that PTGFRN is associated with proteins involved in processing and metabolism, as well as VEGF signaling molecules. These results highlight the role of PTGFRN as a protein processing regulator, which may be influencing cancer progression.

Accuracy of IgM antibody testing, FQ-PCR and culture in laboratory diagnosis of acute infection by Mycoplasma pneumoniae in adults and adolescents with community-acquired pneumonia.

BACKGROUND: Diagnosis of community-acquired pneumonia (CAP) caused by Mycoplasma pneumoniae in adults and adolescents is hampered by a lack of rapid and standardized tests for detection. METHODS: CAP patients from 12 teaching hospitals were prospectively and consecutively recruited. Basic and clinical information, throat swabs and paired sera were collected. Mycoplasma pneumoniae was detected by IgG and IgM antibody tests, fluorescence quantitative polymerase chain reaction (FQ-PCR) and culture. A comparative study of the diagnostic values of three methods, including sensitivity, specificity, positive and negative predictive values and positive likelihood ratio (PLR) was conducted. A fourfold or greater increase of IgG antibody titers of paired sera was set as the diagnostic "gold standard". RESULTS: One hundred and twenty-five CAP patients (52.8% males, median age 47 years, range 14-85) were enrolled. Twenty-seven (21.6%) patients were diagnosed with acute Mycoplasma pneumoniae infections by the "gold standard". Specificity values of all three methods were around 90%. An increasing trend of sensitivity, positive predictive value and PLR was found, with the lowest in IgM testing (7.4%, 28.6% and 1.45), intermediate in FQ-PCR (40.7%, 50% and 3.63), and highest in culture (55.6%, 75% and 10.9). CONCLUSIONS: In the defined group of patients, there was a good agreement between positive rate of MP cultivation of throat swabs and acute M. pneumoniae infection (PLR of 10.9). Since the sensitivity is low in all of the evaluated methods, the logical approach would be to incorporate PCR, culture and serological tests for optimum diagnosis of acute Mycoplasma pneumoniae infections in adults and adolescents.

[Etiologic characteristics of adult patients with community-acquired pneumonia in Beijing].

OBJECTIVE: To explore the etiologic characteristics of adult patients with community-acquired pneumonia (CAP) in Beijing. METHODS: A multicenter cohort of 510 adult CAP patients were enrolled from Beijing during the period of November 2010 to May 2012. Multiplex polymerase chain reaction (PCR), real-time fluorescence quantitative PCR and legionella urinary antigen were used to detect common respiratory viruses, Mycoplasma pneumoniae and legionella respectively. Bacteria were detected by sputum culture, blood culture and Streptococcus pneumoniae urinary antigen. Statistical analyses were performed for the etiologic characteristics and seasonal distribution of detected pathogens. RESULTS: Pathogens were detected in 240/500 (47.1%) study patients. The mixed infection of different pathogens was present in 42 cases (8.2%), viruses in 164 (32.2%), Mycoplasma pneumoniae in 91 (17.8%), bacteria in 26 (5.1%) and Legionella in 3 (0.6%). Among 164 patients infected with viruses, 194 viral strains were detected. Influenza virus represented the greatest proportion with 105 (54.1%) in viral infections. Between November 2010 to October 2011, Influenza A infections increased gradually in November 2010, peaked in February 2011 and declined by March 2011 in China. Mycoplasma pneumoniae was predominant in winter and spring. CONCLUSIONS: There is a high detection rate of virus and Mycoplasma pneumoniae in adult CAP patients in Beijing. And more consideration should be given to influenza virus and Mycoplasma pneumoniae infections in winter and early spring.

A randomized trial: The safety, pharmacokinetics and preliminary pharmacodynamics of ropivacaine oil delivery depot in healthy subjects.

INTRODUCTION: Ropivacaine oil delivery depot (RODD) can slowly release ropivacaine and block nerves for a long timejavascript:;. The aim of the present work was to investigate the safety, pharmacokinetics, and preliminary pharmacodynamics of RODD in subcutaneous injection among healthy subjects. METHODS: The abdomens of 3 subjects were subcutaneously administered with a single-needle RODD containing 12~30 mg of ropivacaine. The irritation, nerve blocking range and optimum dose were investigated. Forty-one subjects were divided into RODD groups containing 150, 230, 300, 350 and 400 mg of ropivacaine and a ropivacaine hydrochloride injection (RHI) 150 mg group. Multineedle subcutaneous injection of RODD or RHI was performed in the abdomens of the subjects. The primary endpoint was a safe dose or a maximum dose of ropivacaine (400 mg). Subjects' vital signs were observed; their blood was analyzed; their cardiovascular system and nervous systems were monitored, and their dermatological reactions were observed and scored. Second, the ropivacaine concentrations in plasma were determined, pharmacokinetic parameters were calculated, and the anesthetic effects of RODD were studied, including RODD onset time, duration and intensity of nerve block. RESULTS: Single-needle injection of RODD 24 mg was optimal for 3 subjects, and the range of nerve block was 42.5±20.8 mm. Multineedle subcutaneous injection of RODD in the abdomens of subjects was safe, and all adverse events were no more severe than grade II. The incidence rate of grade II adverse events, such as pain, and abnormal ST and ST-T segment changes on electrocardiography, was approximately 1%. The incidence rate of grade I adverse events, including erythema, papules, hypertriglyceridemia, and hypotension was greater than 10%. Erythema and papules were relieved after 24 h and disappeared after 72 h. Other adverse reactions disappeared after 7 days. The curve of ropivacaine concentration-time in plasma presented a bimodal profile. The results showed that ropivacaine was slowly released from the RODD. Compared with the 150 mg RHI group, Tmax was longer in the RODD groups. In particular, Tmax in the 400 mg RODD group was longer than that in the RHI group (11.8±4.6 h vs. 0.77±0.06 h). The Cmax in the 150 mg RODD group was lower than that in the 150 mg RHI group (0.35±0.09 vs. 0.58±0.13 µg·mL-1). In particular, the Cmax increased by 48% when the dose was increased by 2.6 times in the 400 mg group. Cmax, the AUC value and the intensity of the nerve block increased with increasing doses of RODD. Among them, the 400 mg RODD group presented the strongest nerve block (the percentage of level 2 and 3, 42.9%). The corresponding median onset time was 0.42 h, and the duration median was 35.7⁓47.7 h. CONCLUSIONS: RODD has a sustained release effect. Compared with the RHI group, Tmax was delayed in the RODD groups, and the duration of nerve block was long. No abnormal reaction was found in the RODD group containing 400 mg of ropivacaine after subcutaneous injection among healthy subjects, suggesting that RODD was adequately safe. TRIAL REGISTRATION: Chictr.org: CTR2200058122; Chinadrugtrials.org: CTR20192280.

Efficacy and safety of Lianhua Qingwen granule in the treatment of non-influenza viral pneumonia: a randomized, double-blind, placebo-controlled, multicenter clinical study.

Objective: To observe the effectiveness and safety of Lianhua Qingwen granule in the treatment of non-influenza viral pneumonia. Methods: This 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. Results: A 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 < 0.001). Significant improvements in single symptoms of cough and expectoration in the trial group were observed compared with the control group (p < 0.05). There were no statistical differences in fever, sputum color change, chest pain, muscle pain, dyspnea, chills, and thirst between the two groups (p > 0.05). Safety: There 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). Conclusion: Lianhua 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.

Effects of hepatitis B virus infection and strategies for preventing mother-to-child transmission on maternal and fetal T-cell immunity.

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.

Weighted selective collapsing strategy for detecting rare and common variants in genetic association study.

BACKGROUND: Genome-wide association studies (GWAS) have been used successfully in detecting associations between common genetic variants and complex diseases. However, common SNPs detected by current GWAS only explain a small proportion of heritable variability. With the development of next-generation sequencing technologies, researchers find more and more evidence to support the role played by rare variants in heritable variability. However, rare and common variants are often studied separately. The objective of this paper is to develop a robust strategy to analyze association between complex traits and genetic regions using both common and rare variants. RESULTS: We propose a weighted selective collapsing strategy for both candidate gene studies and genome-wide association scans. The strategy considers genetic information from both common and rare variants, selectively collapses all variants in a given region by a forward selection procedure, and uses an adaptive weight to favor more likely causal rare variants. Under this strategy, two tests are proposed. One test denoted by BwSC is sensitive to the directions of genetic effects, and it separates the deleterious and protective effects into two components. Another denoted by BwSCd is robust in the directions of genetic effects, and it considers the difference of the two components. In our simulation studies, BwSC achieves a higher power when the casual variants have the same genetic effect, while BwSCd is as powerful as several existing tests when a mixed genetic effect exists. Both of the proposed tests work well with and without the existence of genetic effects from common variants. CONCLUSIONS: Two tests using a weighted selective collapsing strategy provide potentially powerful methods for association studies of sequencing data. The tests have a higher power when both common and rare variants contribute to the heritable variability and the effect of common variants is not strong enough to be detected by traditional methods. Our simulation studies have demonstrated a substantially higher power for both tests in all scenarios regardless whether the common SNPs are associated with the trait or not.

Oseltamivir compared with the Chinese traditional therapy maxingshigan-yinqiaosan in the treatment of H1N1 influenza: a randomized trial.

BACKGROUND: Observational studies from Asia suggest that maxingshigan-yinqiaosan may be effective in the treatment of acute H1N1 influenza. OBJECTIVE: To compare the efficacy and safety of oseltamivir and maxingshigan-yinqiaosan in treating uncomplicated H1N1 influenza. DESIGN: Prospective, nonblinded, randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00935194) SETTING: Eleven hospitals from 4 provinces in China. PATIENTS: 410 persons [corrected] aged 15 to 69 [corrected] years with laboratory-confirmed H1N1 influenza. INTERVENTION: Oseltamivir, 75 mg twice daily; maxingshigan-yinqiaosan decoction (composed of 12 Chinese herbal medicines, including honey-fried Herba Ephedrae), 200 mL 4 times daily; oseltamivir plus maxingshigan-yinqiaosan; or no intervention (control). Interventions and control were given for 5 days. MEASUREMENTS: Primary outcome was time to fever resolution. Secondary outcomes included symptom scores and viral shedding determined by using real-time reverse transcriptase polymerase chain reaction. RESULTS: Significant reductions in the estimated median time to fever resolution compared with the control group (26.0 hours [95% CI, 24.0 to 33.0 hours]) were seen with oseltamivir (34% [95% CI, 20% to 46%]; P < 0.001), maxingshigan-yinqiaosan (37% [CI, 23% to 49%]; P < 0.001), and oseltamivir plus maxingshigan-yinqiaosan (47% [CI, 35% to 56%]; P < 0.001). Time to fever resolution was reduced by 19% (CI, 0.3% to 34%; P = 0.05) with oseltamivir plus maxingshigan-yinqiaosan compared with oseltamivir. The interventions and control did not differ in terms of decrease in symptom scores (P = 0.38). Two patients who received maxingshigan-yinqiaosan reported nausea and vomiting. LIMITATIONS: Participants were young and had mild H1N1 influenza virus infection. Missing viral data precluded definitive conclusions about viral shedding. CONCLUSION: Oseltamivir and maxingshigan-yinqiaosan, alone and in combination, reduced time to fever resolution in patients with H1N1 influenza virus infection. These data suggest that maxingshigan-yinqiaosan may be used as an alternative treatment of H1N1 influenza virus infection. PRIMARY FUNDING SOURCE: Beijing Science and Technology Project and Beijing Nova Program.

Enzymatic Numerical Spiking Neural Membrane Systems and their Application in Designing Membrane Controllers.

Spiking neural P systems (SN P systems), inspired by biological neurons, are introduced as symbolical neural-like computing models that encode information with multisets of symbolized spikes in neurons and process information by using spike-based rewriting rules. Inspired by neuronal activities affected by enzymes, a numerical variant of SN P systems called enzymatic numerical spiking neural P systems (ENSNP systems) is proposed wherein each neuron has a set of variables with real values and a set of enzymatic activation-production spiking rules, and each synapse has an assigned weight. By using spiking rules, ENSNP systems can directly implement mathematical methods based on real numbers and continuous functions. Furthermore, ENSNP systems are used to model ENSNP membrane controllers (ENSNP-MCs) for robots implementing wall following. The trajectories, distances from the wall, and wheel speeds of robots with ENSNP-MCs for wall following are compared with those of a robot with a membrane controller for wall following. The average error values of the designed ENSNP-MCs are compared with three recently fuzzy logical controllers with optimization algorithms for wall following. The experimental results showed that the designed ENSNP-MCs can be candidates as efficient controllers to control robots implementing the task of wall following.

Pathway of Cell Death and Its Role in Virus Infection.

The global pandemic of SARS-CoV-2 in the past 2 years has aroused great attention to infectious diseases, and emerging virus outbreaks have brought huge challenges to the global health system. Viruses are specific pathogens that completely rely on host cells for their own survival and disease transmission. At present, a growing number of studies have proved that inducing the death of virus-infected cells can prevent the spread of virus and promote disease recovery. Therefore, many ways to induce the death of infected cells are considered to be beneficial to host immunity. Cell death is a basic biological phenomenon. Programmed cell death (PCD), as an important part of the host's innate immune response, provides effective protection against virus transmission. Pyroptosis, apoptosis, and necroptosis are the most commonly studied pathways of PCD. Recent studies have found that three pathways of cell death can be activated during virus infection. More and more studies have shown the existence of extensive connections between PCDs, and this complex relationship is defined as PANoptosis, an inflammatory PCD pathway regulated by the PANoptosome complex, whose characteristics cannot be explained by any of the three PCD pathways. During viral infection, PANoptosis can promote inflammatory response by inducing the production of inflammatory cytokines and cell death to exert an antiviral mechanism. This article reviews the various effects of cell death pathways during viral infection and provides new ideas for clinical antiviral therapy and related immunotherapy.

Detection of SARS-CoV-2 Antibodies in Oral Fluid Using a Magnetic Particle-Based Chemiluminescence Immunoassay - Beijing Municipality, China, 2021.

Introduction: Oral fluids (OFs) have been broadly used as non-invasive samples for evaluating protective IgG antibodies from natural infection or vaccination, especially in pediatric populations. Methods: Paired OF and serum were collected from both individuals who received a booster dose of the inactive coronavirus disease 2019 (COVID-19) vaccine as well as those who did not have a history of COVID-19 vaccination and infection (as the control group). The total human IgG antibody (HIgG) content was evaluated as a marker of OF sampling quality. An in-house adapted magnetic particle-based chemiluminescence immunoassay was used for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG antibody detection in the OF. The SARS-CoV-2 IgG antibody in the serum samples was detected using a commercial immunoassay. Results: In total, 579 paired OF and serum samples were collected. An additional 172 OF samples were collected from preschool children. The results indicated that the HIgG concentration in qualified OF samples should be higher than 0.3 µg/mL. Compared to the serum assay, the in-house OF immunoassay for detecting IgG antibodies against SARS-CoV-2 had 95.06% accuracy, 95.03% sensitivity, and 100% specificity. Conclusions: Overall, the in-house immunoassay for detecting SARS-CoV-2 IgG antibodies in OF showed high potential for application towards serological surveillance and immunization effect assessment after large-scale, inactive COVID-19 vaccination in China.

Expression of Functional Molecule on Plasmacytoid Dendritic Cells Is Associated With HBsAg Loss in HBeAg-Positive Patients During PEG-IFN α-2a Treatment.

Objective: The 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. Methods: A 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. Results: Of 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. Conclusion: The lower the baseline HBV DNA load and the more the baseline CD86+ pDC%, the easier it is for patients to obtain functional cure.