This article presents an uncertainty analysis method for systems with hybrid stochastic and fuzzy uncertainty parameters based on polynomial chaos expansion (PCE). Parameters in the system are ...described by probability boxes, interval numbers, and fuzzy sets, respectively, based on the differences in their limited stochastic knowledge. First, this method transforms the uncertain parameters into standard normal distribution and interval variables through equal probability transformation or α$$ \alpha $$‐cut operations. Second, the Legendre and Hermite polynomials are used as the PCE model's primary functions, and the expansion coefficients are calculated by the Galerkin projection method based on sparse grid numerical integration. Then, the system response bounds under the pre‐defined confidence level can be obtained using a genetic algorithm to solve the optimization problem constructed based on PCE models. Finally, the feasibility and effectiveness of the method are illustrated by taking the tank bi‐directional stabilized system and the double‐pendulum‐controlled system as examples. The numerical results show that the system response bounds obtained by the PCE model optimization algorithm are consistent with the Monte Carlo simulation. Still, the computational efficiency is much higher. The proposed method effectively combines fuzzy sets and probability boxes and dramatically simplifies the analysis process of uncertain systems. The method exhibits fine precision even in high‐dimensional uncertainty analysis problems.
Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is an epigenetic mark generally associated with transcriptional activation, yet the global functions of H2Bub1 remain poorly understood. ...Ferroptosis is a form of non‐apoptotic cell death characterized by the iron‐dependent overproduction of lipid hydroperoxides, which can be inhibited by the antioxidant activity of the solute carrier family member 11 (SLC7A11/xCT), a component of the cystine/glutamate antiporter. Whether nuclear events participate in the regulation of ferroptosis is largely unknown. Here, we show that the levels of H2Bub1 are decreased during erastin‐induced ferroptosis and that loss of H2Bub1 increases the cellular sensitivity to ferroptosis. H2Bub1 epigenetically activates the expression of SLC7A11. Additionally, we show that the tumor suppressor p53 negatively regulates H2Bub1 levels independently of p53's transcription factor activity by promoting the nuclear translocation of the deubiquitinase USP7. Moreover, our studies reveal that p53 decreases H2Bub1 occupancy on the SLC7A11 gene regulatory region and represses the expression of SLC7A11 during erastin treatment. These data not only suggest a noncanonical role of p53 in chromatin regulation but also link p53 to ferroptosis via an H2Bub1‐mediated epigenetic pathway. Overall, our work uncovers a previously unappreciated epigenetic mechanism for the regulation of ferroptosis.
Synopsis
This study uncovers a previously unknown epigenetic regulatory mechanism for the control of ferroptosis by p53‐USP7‐H2Bub1 axis.
H2Bub1 is a novel epigenetic regulator of ferroptosis.
p53 regulates H2Bub1 independent of its transcription factor activity by recruiting the H2Bub1 deubiquitinase USP7 to chromatin.
p53‐USP7 interplay reduces the occupancy of H2Bub1 on the SLC7A11 regulatory region, resulting in transcriptional repression and increased sensitivity to ferroptosis induction.
These results not only suggest a novel role of H2Bub1 in the regulation of ferroptosis but also reveal a relative direct role of p53 in the regulation of chromatin events.
p53 recruits USP7 to the regulatory region of SLC7A11 to reduce H2B monoubiquitination, resulting in transcriptional repression of SCL7A11 and ferroptosis induction. These results uncover an epigenetic regulatory mechanism for the control of ferroptosis.
Local and systemic manifestations have been reported in association with pancreatitis, anecdotally. However, a systematic collection on the prevalence of each of these symptoms in pancreatitis is ...lacking. We aimed to determine the prevalence of symptoms and diagnoses reported by a cohort of patients with pancreatitis, refer to as "extra pancreatic manifestation of pancreatitis".
Cross-sectional study approved by the IRB and administered through a REDCap survey by "Mission: Cure", a nonprofit organization.
Of the 225 respondents analyzed; 89% were adults, 69% females, 89% Caucasians with 74% residing in the USA. 42% of children and 50% of adults reported exocrine pancreatic insufficiency while 8% of children and 26% of adults reported DM. Type 3c DM was reported in all children and 45% of adult DM cases. Children were diagnosed with genetic or hereditary pancreatitis more frequently compared to adults (33.3% versus 8%; p = <0.001). Significantly more symptoms and diagnoses were reported by adults when compared to children including nighttime sweats, bloating, or cramping, greasy or oily stools, feeling cold and GERD with p values of 0.002, 0.006, 0.046, 0.002 and 0.003 respectively.
Adults with pancreatitis frequently report symptoms not known to be associated with pancreatitis. Studies investigating mechanisms for these associated symptoms should be explored.
Numerous studies have highlighted that long non-coding RNAs (lncRNAs) can bind to microRNA (miRNA) sites as competing endogenous RNAs (ceRNAs), thereby affecting and regulating the expression of ...mRNAs and target genes. These lncRNA-associated ceRNAs have been theorized to play a significant role in cancer initiation and progression. However, the roles and functions of the lncRNA-miRNA-mRNA ceRNA network in squamous cell carcinoma of the tongue (SCCT) are still unclear.
The miRNA, mRNA and lncRNA expression profiles from 138 patients with SCCT were downloaded from The Cancer Genome Atlas database. We identified the differential expression of miRNAs, mRNAs, and lncRNAs using the limma package of R software. We used the clusterProfiler package for GO and KEGG pathway annotations. The survival package was used to estimate survival analysis according to the Kaplan-Meier curve. Finally, the GDCRNATools package was used to construct the lncRNA-miRNA-mRNA ceRNA network.
In total, 1943 SCCT-specific mRNAs, 107 lncRNAs and 100 miRNAs were explored. Ten mRNAs (CSRP2, CKS2, ADGRG6, MB21D1, GMNN, RIPOR3, RAD51, PCLAF, ORC1, NAGS), 9 lncRNAs (LINC02560, HOXC13 - AS, FOXD2 - AS1, AC105277.1, AC099850.3, STARD4 - AS1, SLC16A1 - AS1, MIR503HG, MIR100HG) and 8 miRNAs (miR - 654, miR - 503, miR - 450a, miR - 379, miR - 369, miR - 190a, miR - 101, and let-7c) were found to be significantly associated with overall survival (log-rank p < 0.05). Based on the analysis of the lncRNA-miRNA-mRNA ceRNA network, one differentially expressed (DE) lncRNA, five DEmiRNAs, and three DEmRNAs were demonstrated to be related to the pathogenesis of SCCT.
In this study, we described the gene regulation by the lncRNA-miRNA-mRNA ceRNA network in the progression of SCCT. We propose a new lncRNA-associated ceRNA that could help in the diagnosis and treatment of SCCT.
Algal growth causes a drastic change in aquatic conditions over a diel cycle, which may induce sensitive feedback systems in sediments, causing P release. In this study, a microcosm experiment was ...performed using a suction sampler (Rhizon) to observe changes in soluble reactive phosphorus (SRP) and soluble Fe(II) concentrations in the top 20 mm sediment layer on a 3-h time interval, at different phases of harmful algal bloom (HAB) development. The results showed that the algal blooms prevailed up to 15 days after incubation, after which the process of bloom collapse proceeded until the 70th day. The concentrations of pore-water soluble Fe(II) and SRP increased throughout the incubation period. Compared to day 1, maximum increases of 214% in soluble Fe(II) and 387% in SRP were observed at night during the bloom and collapse periods, respectively. The diffusive fluxes of Fe and P at the sediment-water interface (SWI) generally corresponded to their changes in concentrations. Hourly fluctuation in soluble Fe(II) and SRP concentrations were observed with two distinct concentration peaks occurred at 21:00 p.m. and 06:00 a.m. (or 03:00 a.m.), respectively. These findings suggest that Fe-P coupling mechanisms are responsible for the release of P from sediments. During the collapse period, soluble Fe(II) concentrations were suppressed by the increase of labile S(-II) at night. Meanwhile, SRP concentrations were decoupled from Fe cycling with small fluctuations (<11% RSD) on an hourly timescale, and the decomposition of algae was a dominant source contributing to the release of P from sediments. These results significantly improved the understanding of processes and mechanisms behind the stimulated release of P from sediments during HABs.
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•HABs significantly increased pore-water SRP and soluble Fe(II) concentrations.•Soluble Fe(II) fluctuated on hourly scale with two peaks at 21:00 p.m. and 06:00 a.m.•SRP appeared two-peak fluctuation before 15 days and disappeared after that.•The release of SRP is controlled by Fe-P coupling mechanism during algal blooms.•The main release of SRP occurs from the degradation of algae during bloom collapse.
Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in more than 5% of hepatocytes in the absence of excessive alcohol consumption and other secondary causes of ...hepatic steatosis. In 2020, the more inclusive term metabolic (dysfunction)-associated fatty liver disease (MAFLD) - defined by broader diagnostic criteria - was proposed to replace the term NAFLD. The new terminology and revised definition better emphasize the pathogenic role of metabolic dysfunction and uses a set of definitive, inclusive criteria for diagnosis. Diagnosis of MAFLD is based on evidence of hepatic steatosis (as assessed by liver biopsy, imaging techniques or blood biomarkers and scores) in persons who are overweight or obese and have type 2 diabetes mellitus or metabolic dysregulation, regardless of the coexistence of other liver diseases or excessive alcohol consumption. The known association between NAFLD and chronic kidney disease (CKD) and our understanding that CKD can occur as a consequence of metabolic dysfunction suggests that individuals with MAFLD - who by definition have fatty liver and metabolic comorbidities - are at increased risk of CKD. In this Perspective article, we discuss the clinical associations between MAFLD and CKD, the pathophysiological mechanisms by which MAFLD may increase the risk of CKD and the potential drug treatments that may benefit both conditions.
Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is an epigenetic mark generally associated with transcriptional activation, yet the global functions of H2Bub1 remain poorly understood. ...Ferroptosis is a form of non-apoptotic cell death characterized by the iron-dependent overproduction of lipid hydroperoxides, which can be inhibited by the antioxidant activity of the solute carrier family member 11 (SLC7A11/xCT), a component of the cystine/glutamate antiporter. Whether nuclear events participate in the regulation of ferroptosis is largely unknown. Here, we show that the levels of H2Bub1 are decreased during erastin-induced ferroptosis and that loss of H2Bub1 increases the cellular sensitivity to ferroptosis. H2Bub1 epigenetically activates the expression of SLC7A11. Additionally, we show that the tumor suppressor p53 negatively regulates H2Bub1 levels independently of p53's transcription factor activity by promoting the nuclear translocation of the deubiquitinase USP7. Moreover, our studies reveal that p53 decreases H2Bub1 occupancy on the SLC7A11 gene regulatory region and represses the expression of SLC7A11 during erastin treatment. These data not only suggest a noncanonical role of p53 in chromatin regulation but also link p53 to ferroptosis via an H2Bub1-mediated epigenetic pathway. Overall, our work uncovers a previously unappreciated epigenetic mechanism for the regulation of ferroptosis.
Reports state that chlorination of drinking water and wastewater affects the proportions of antibiotic-resistant bacteria by potentially assisting in microbial selection. Studies on the effect of ...chlorination on like species of antibiotic-resistant bacteria, however, have shown to be conflicting; furthermore, few studies have inspected the regrowth or reactivation of antibiotic-resistant bacteria after chlorination in wastewater. To understand the risks of chlorination resulting from potentially selecting for antibiotic-resistant bacteria, inactivation and reactivation rates of both total heterotrophic bacteria and antibiotic-resistant bacteria (including penicillin-, ampicillin-, tetracycline-, chloramphenicol-, and rifampicin-resistant bacteria) were examined after chlorinating secondary effluent samples from a municipal wastewater treatment plant in this study.
Our experimental results indicated similar inactivation rates of both total heterotrophic bacteria and antibiotic-resistant bacteria. Microbial community composition, however, was affected by chlorination: treating samples with 10 mg Cl
2/L for 10 min resulted in chloramphenicol-resistant bacteria accounting for nearly 100% of the microbial population in contrast to 78% before chlorination. This trend shows that chlorination contributes to selection of some antibiotic-resistant strains. Reactivation of antibiotic-resistant bacteria occurred at 2.0 mg Cl
2/L for 10 min; specifically, chloramphenicol-, ampicillin-, and penicillin-resistant bacteria were the three prevalent groups present, and the reactivation of chloramphenicol-resistant bacteria exceeded 50%. Regrowth and reactivation of antibiotic-resistant bacteria in secondary effluents after chlorination with a long retention time could threaten public health security during wastewater reuse.
► Selection of antibiotic-resistant bacteria in the wastewater effluent existed during chlorination and reactivation after chlorination. ► Proportion of chloramphenicol-resistant bacteria increased in the chlorinated secondary effluent. ► Reactivation of chloramphenicol-, ampicillin-, penicillin-resistant bacteria occurred at a low dosage of chlorination. ► A higher concentration of chlorine with a shorter contact time is advantageous to help control the reactivation of inactivated antibiotic-resistant bacteria.
Respiratory syncytial virus (RSV) is leading cause of respiratory tract infections in early childhood. Gut microbiota is closely related with the pulmonary antiviral immunity. Recent evidence shows ...that gut dysbiosis is involved in the pathogenesis of RSV infection. Therefore; pharmacological and therapeutic strategies aiming to readjust the gut dysbiosis are increasingly important for the treatment of RSV infection. In this study, we evaluated the therapeutic effects of a probiotic mixture on RSV-infected mice. This probiotic mixture consisted of Lactobacillus rhamnosus GG, Escherichia coli Nissle 1917 and VSL#3 was orally administered to neonatal mice on a daily basis either for 1 week in advance or for 3 days starting from the day of RSV infection. We showed that administration of the probiotics protected against RSV-induced lung pathology by suppressing RSV infection and exerting an antiviral response via alveolar macrophage (AM)-derived IFN-β. Furthermore, administration of the probiotics reversed gut dysbiosis and significantly increased the abundance of short-chain fatty acid (SCFA)-producing bacteria in RSV-infected mice, which consequently led to elevated serum SCFA levels. Moreover, administration of the probiotics restored lung microbiota in RSV-infected mice. We demonstrated that the increased production of IFN-β in AMs was attributed to the increased acetate in circulation and the levels of Corynebacterium and Lactobacillus in lungs. In conclusion, we reveal that probiotics protect against RSV infection in neonatal mice through a microbiota-AM axis, suggesting that the probiotics may be a promising candidate to prevent and treat RSV infection, and deserve more research and development in future.
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