A statistical analysis method for probability distributions in Erdös-Rényi random networks with preferential cutting-rewiring operation.

The study of specific physiological processes from the perspective of network physiology has gained recent attention. Modeling the global information integration among the separated functionalized modules in structural and functional brain networks is a central problem. In this article, the preferentially cutting-rewiring operation (PCRO) is introduced to approximatively describe the above physiological process, which consists of the cutting procedure and the rewiring procedure with specific preferential constraints. By applying the PCRO on the classical Erdös-Rényi random network (ERRN), three types of isolated nodes are generated, based on which the common leaves (CLs) are formed between the two hubs. This makes the initially homogeneous ERRN experience drastic changes and become heterogeneous. Importantly, a statistical analysis method is proposed to theoretically analyze the statistical properties of an ERRN with a PCRO. Specifically, the probability distributions of these three types of isolated nodes are derived, based on which the probability distribution of the CLs can be obtained easily. Furthermore, the validity and universality of our statistical analysis method have been confirmed in numerical experiments. Our contributions may shed light on a new perspective in the interdisciplinary field of complexity science and biological science and would be of great and general interest to network physiology.

The Alarming Situation of Highly Pathogenic Avian Influenza Viruses in 2019-2023.

Avian influenza viruses (AIVs) have the potential to cause severe illness in wild birds, domestic poultry, and humans. The ongoing circulation of highly pathogenic avian influenza viruses (HPAIVs) has presented significant challenges to global poultry industry and public health in recent years. This study aimed to elucidate the circulation of HPAIVs during 2019 to 2023. Specifically, we assess the alarming global spread and continuous evolution of HPAIVs. Moreover, we discuss their transmission and prevention strategies to provide valuable references for future prevention and control measures against AIVs.

Associations of exposure to bisphenol-A or parabens with markers of liver injury/function among US adults in NHANES 2011-2016.

BACKGROUND: Bisphenol-A (BPA) and parabens are common endocrine-disrupting compounds (EDCs) that are used extensively in consumer products worldwide and are widely found in the environment. OBJECTIVE: The purpose of this study was to comprehensively explore the correlations between urinary BPA/parabens levels and liver injury/function markers. METHODS: In this cross-sectional study, we used National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2016. The exposure variables were urinary BPA and four urinary parabens [methylparaben (MPB), ethylparaben (EPB), propylparaben (PPB), and butylparaben (BPB)], while the outcome variables were indicators of liver function/injury [alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ ALT, albumin (ALB), total protein (TP), total bilirubin (TBIL), alkaline phosphatase (ALP), and the fibrosis-4 index (FIB-4)]. Multiple linear regression and weighted quantile sum (WQS) regression analyses were applied to explore the relationships between the individual/combined exposure variables and the liver injury/function indicators, respectively. Furthermore, stratified analysis was employed to detect the associations influenced by age and sex. RESULTS: A total of 2,179 adults were eligible for the present analysis. Multivariate linear regression analysis revealed positive associations of EPB with AST, ALT, TP, and FIB-4 scores and negative associations of BPA with TP and ALB. The effects of urinary parabens on adverse outcomes in the liver (AST and ALT) were significant in the female and middle-aged subgroups. In addition, the WQS analysis revealed that the mixture of four compounds was negatively associated with ALB. BPA had the greatest effect on the serum ALB concentration (weight = 0.688). IMPACT: Our present study provided novel evidence of significant associations between BPA or certain parabens and numerous markers of liver injury/function indicators. We found that higher urinary BPA concentrations were associated with worse liver function. Exposure to high EPB/PPB ratios was significantly associated with biomarkers of liver injury.

Programmed cell death, from liver Ischemia-Reperfusion injury perspective: An overview.

Liver ischemia-reperfusion injury (LIRI) commonly occurs in liver resection, liver transplantation, shock, and other hemorrhagic conditions, resulting in profound local and systemic effects via associated inflammatory responses and hepatic cell death. Hepatocyte death is a significant component of LIRI and its mechanism was previously thought to be limited to apoptosis and necrosis. With the discovery of novel types of programmed cell death (PCD), necroptosis, ferroptosis, pyroptosis, autophagy, NETosis, and parthanatos have been shown to be involved in LIRI. Understanding the mechanisms underlying cell death following LIRI is indispensable to mitigating the widespread effects of LIRI. Here, we review the roles of different PCD and discuss potential therapy in LIRI.

Emergence of chimeralike oscillation modes in excitable complex networks with preferentially cutting-rewiring operation.

In this paper, the preferentially cutting-rewiring operation (PCRO) consisting of the cutting procedure and the rewiring procedure is proposed and is applied on an excitable Erdös-Rényi random network (EERRN), by which the structure of the initially homogeneous network changes dramatically, and lots of common leaves (CLs) are formed between the two hubs. Subsequently, besides the single-mode oscillations that can be usually observed in homogeneous excitable systems, a new kind of multi-mode oscillations composed of synchronous and asynchronous parts can self-organize to emerge, which are similar to the coherent and incoherent clusters in traditional chimera states and are consequently named as the chimeralike oscillation modes (CLOMs). Importantly, by utilizing the dominant phase-advanced driving method, both the mechanisms for the formation and the emergence of CLOMs in EERRNs with PCRO are well explained, among which the CL is exposed to play a key role in forming the CLOMs. Furthermore, the PCRO-induced CLOM phenomena can also be observed in other paradigmatic network models or with other paradigmatic excitable dynamics, which definitely confirms that the PCRO is an universal method in inducing the CLOMs in excitable complex networks. Our contributions may shed lights on a new perspective of the emergence of CLOMs in complex systems and would have great impacts in related fields.

Analyzing the methanation thermodynamic feasibility of steel plant byproduct gases.

To improve the utilization of byproduct gases in the steel plant, the coke oven gas (COG) methanation combined with blast furnace gas (BFG) and basic oxygen furnace gas (BOFG) was proposed in viewpoint of economy and environment. The optimization mathematics model based on Gibbs free energy minimization was established to predict the thermodynamic feasibility of the proposed methanation. To solve the proposed model, the convenient method was implemented by using the Gibbs module in Aspen Plus software. Effects of operation parameters on the methanation performance were revealed to identify the optimized conditions. To reduce the solid carbon concentration, it was found that the optimized conditions of temperature, pressure and stoichiometric number were 650 °C, 30 bar and 3.0, respectively. Moreover, it was discovered that 10 mol% of BFG or BOFG could be mixed into COG to obtain the maximum methane yield. In addition, it was testified that there were the good agreements between calculated results and industrial and published data, which indicated that the proposed methanation was thermodynamically feasible. Therefore, the simple and easy method was developed to evaluate the methanation operating conditions from the aspect of thermodynamic equilibrium, which provided the basic process conditions of byproduct gases methanation to enhance the steel plant efficiency and reduce carbon emissions.

Nanoplastic propels diet-induced NAFL to NASH via ER-mitochondrial tether-controlled redox switch.

Nonalcoholic steatohepatitis (NASH) is multifactorial that lifestyle, genetic, and environmental factors contribute to its onset and progression, thereby posing a challenge for therapeutic intervention. Nanoplastic (NP) is emerged as a novel environmental metabolism disruptor but the etiopathogenesis remains largely unknown. In this study, C57BL/6 J mice were fed with normal chow diet (NCD) and high-fat diet (HFD) containing 70 nm polystyrene microspheres (NP). We found that dietary-derived NP adsorbed proteins and agglomerated during the in vivo transportation, enabling diet-induced hepatic steatosis to NASH. Mechanistically, NP promoted liver steatosis by upregulating Fatp2. Furthermore, NP stabilized the Ip3r1, and facilitated ER-mitochondria contacts (MAMs) assembly in the hepatocytes, resulting in mitochondrial Ca2+ overload and redox imbalance. The redox-sensitive Nrf2 was decreased in the liver of NP-exposed mice, which positively regulated miR26a via direct binding to its promoter region [-970 bp to -847 bp and -318 bp to -176 bp]. NP decreased miR26a simultaneously upregulated 10 genes involved in MAMs formation, lipid uptake, inflammation, and fibrosis. Moreover, miR26a inhibition elevated MAMs-tether Vdac1, which promoted the nucleus translocation of NF-κB P65 and Keap1 and functionally inactivated Nrf2, leading to a vicious cycle. Hepatocyte-specific overexpressing miR26a effectively restored ER-mitochondria miscommunication and ameliorated NASH phenotype in NP-exposed and Keap1-overexpressed mice on HFD. The hepatic MAM-tethers/Nrf2/miR26a feedback loop is an essential metabolic switch from simple steatosis to NASH and a promising therapeutic target for oxidative stress-associated liver damage and NASH.

Activation of cGAS-STING signaling pathway promotes liver fibrosis and hepatic sinusoidal microthrombosis.

Inflammation plays an essential role in the development liver fibrosis.The Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is a central cytoplasmic DNA sensor which can recognize cytoplasmic DNA, known to trigger stimulator of interferon genes (STING) and downstream proinflammatory factors. Here, we investigated the role of cGAS-STING signaling pathway in the pathogenesis of liver fibrosis.Differentially expressed genes (DEGs) in human liver tissue were identified using RNA-Seq analysis. As models of liver fibrosis, chronic Carbon tetrachloride (CCl4) exposure were applied in cGAS-knockout mice. LX-2 cells were co-cultured with human liver sinusoidal endothelial cells (LSECs) to explore the underlying mechanisms of hepatic sinusoidal microthrombosis in an inflammatory microenvironment. The endoscopic ultrasound-guided portal vein pressure gradient (EUS-PPG) method was used to analyze the associations between hepatic sinusoidal microthrombosis and PPG in patients with liver fibrosis and portal hypertension (PTH). The RNA-seq analysis results showed that DEGs were enriched in inflammation and endothelial cell activation. The upregulation of the cGAS-STING signaling exacerbated liver fibrosis and intrahepatic inflammation. It also exacerbated LSECs impairment and increased the contribution of hepatic sinusoidal microthrombosis to liver fibrosis in vivo and in vitro. Prothrombotic mediators and proinflammatory factors were associated with PPG in patients with liver fibrosis and portal hypertension. Therefore, activating cGAS-STING signaling pathway promotes liver fibrosis and hepatic sinusoidal microthrombosis, which may lead to increased portal vein pressure.

The ubiquitin-binding protein MdRAD23D1 mediates drought response by regulating degradation of the proline-rich protein MdPRP6 in apple (Malus domestica).

RAD23 (RADIATION SENSITIVE23) proteins are a group of UBL-UBA (ubiquitin-like-ubiquitin-associated) proteins that shuttle ubiquitylated proteins to the 26S proteasome for breakdown. Drought stress is a major environmental constraint that limits plant growth and production, but whether RAD23 proteins are involved in this process is unclear. Here, we demonstrated that a shuttle protein, MdRAD23D1, mediated drought response in apple plants (Malus domestica). MdRAD23D1 levels increased under drought stress, and its suppression resulted in decreased stress tolerance in apple plants. Through in vitro and in vivo assays, we demonstrated that MdRAD23D1 interacted with a proline-rich protein MdPRP6, resulting in the degradation of MdPRP6 by the 26S proteasome. And MdRAD23D1 accelerated the degradation of MdPRP6 under drought stress. Suppression of MdPRP6 resulted in enhanced drought tolerance in apple plants, mainly because the free proline accumulation is changed. And the free proline is also involved in MdRAD23D1-mediated drought response. Taken together, these findings demonstrated that MdRAD23D1 and MdPRP6 oppositely regulated drought response. MdRAD23D1 levels increased under drought, accelerating the degradation of MdPRP6. MdPRP6 negatively regulated drought response, probably by regulating proline accumulation. Thus, "MdRAD23D1-MdPRP6" conferred drought stress tolerance in apple plants.

Tumor-associated macrophages-derived exo-let-7a promotes osteosarcoma metastasis via targeting C15orf41 in osteosarcoma.

BACKGROUND: Osteosarcoma (OS) immune environment is complexed and the immune factors-related to OS progression need to be explored. Tumor-associated macrophages (TAMs) are regarded as immune suppressive and tumor-promoting cells. However, the underlying mechanisms through which TAMs function are still fragmentary. Here, we aim to explore the underlying mechanisms by which TAMs regulate OS progression. METHODS: TAMs from OS tissues were isolated by flow cytometry. Exosomes derived from TAMs were separated using ultracentrifugation and western blotting. Transmission electron microscopy (TEM), and flow cytometry were constructed to characterize TAMs-derived exosomes. Additionally, the differential MicroRNAs (miRNAs) and genes were detected through RNA sequencing, and further validated using real-time PCR (RT-PCR). OS cell metastasis ability was assessed using transwell invasion and scratch wound healing assays. MiRNAs mimic and lentiviral vectors were utilized to explore the effects on OS progression. RESULTS: Exosome secreted by TAMs accelerated the OS metastasis. Let-7a level was upregulated in TAMs derived exosomes, which downregulated C15orf41 by targeting 3'-untranslated region (UTR). Furthermore, overexpressing let-7a enhanced invasion and migration by blocking the transcription of C15orf41. In consistent, up-regulating let-7a promoted OS progression and made the prognosis to be worse, which can be reversed by C15orf41 overexpression. CONCLUSION: This study highlighted the critical role of TAMs-derived exosomes in OS progression and explored the potential value of the let-7a/C15orf41 axis as an indicator or target for OS.

The Prognostic Value of a lncRNA Risk Model Consists of 9 m6A Regulator-Related lncRNAs in Hepatocellular Carcinoma (HCC).

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. Although the RNA modification N6-methyladenine (m6A) has been reported to be involved in HCC carcinogenesis, early diagnostic markers and promising personalized therapeutic targets are still lacking. In this study, we identified that 19 m6A regulators and 34 co-expressed lncRNAs were significantly upregulated in HCC samples; based on these factors, we established a prognostic signal of HCC associated with 9 lncRNAs and 19 m6A regulators using LASSO Cox regression analysis. Kaplan-Meier survival estimate revealed correlations between the risk scores and patients' OS in the training and validation dataset. The ROC curve demonstrated that the risk score-based curve has satisfactory prediction efficiency for both training and validation datasets. Multivariate Cox's proportional hazard regression analysis indicated that the risk score was an independent risk factor within the training and validation dataset. In addition, the risk score could distinguish HCC patients from normal non-cancerous samples and HCC samples of different pathological grades. Eventually, 232 mRNAs were co-expressed with these 9 lncRNAs according to GSE101685 and GSE112790; these mRNAs were enriched in cell cycle and cell metabolic activities, drug metabolism, liver disease-related pathways, and some important cancer related pathways such as p53, MAPK, Wnt, RAS and so forth. The expression of the 9 lncRNAs was significantly higher in HCC samples than that in the neighboring non-cancerous samples. Altogether, by using the Consensus Clustering, PCA, ESTIMATE algorithm, LASSO regression model, Kaplan-Meier survival assessment, ROC curve analysis, and multivariate Cox's proportional hazard regression model analysis, we established a prognostic marker consisting of 9 m6A regulator-related lncRNAs that markers may have prognostic and diagnostic potential for HCC.

Transmissibility of tuberculosis among students and non-students: an occupational-specific mathematical modelling.

BACKGROUND: Recently, despite the steady decline in the tuberculosis (TB) epidemic globally, school TB outbreaks have been frequently reported in China. This study aimed to quantify the transmissibility of Mycobacterium tuberculosis (MTB) among students and non-students using a mathematical model to determine characteristics of TB transmission. METHODS: We constructed a dataset of reported TB cases from four regions (Jilin Province, Xiamen City, Chuxiong Prefecture, and Wuhan City) in China from 2005 to 2019. We classified the population and the reported cases under student and non-student groups, and developed two mathematical models [nonseasonal model (Model A) and seasonal model (Model B)] based on the natural history and transmission features of TB. The effective reproduction number (Reff) of TB between groups were calculated using the collected data. RESULTS: During the study period, data on 456,423 TB cases were collected from four regions: students accounted for 6.1% of cases. The goodness-of-fit analysis showed that Model A had a better fitting effect (P < 0.001). The average Reff of TB estimated from Model A was 1.68 [interquartile range (IQR): 1.20-1.96] in Chuxiong Prefecture, 1.67 (IQR: 1.40-1.93) in Xiamen City, 1.75 (IQR: 1.37-2.02) in Jilin Province, and 1.79 (IQR: 1.56-2.02) in Wuhan City. The average Reff of TB in the non-student population was 23.30 times (1.65/0.07) higher than that in the student population. CONCLUSIONS: The transmissibility of MTB remains high in the non-student population of the areas studied, which is still dominant in the spread of TB. TB transmissibility from the non-student-to-student-population had a strong influence on students. Specific interventions, such as TB screening, should be applied rigorously to control and to prevent TB transmission among students.

Evaluation of Taraxacum mongolicum flavonoids in diets for Channa argus based on growth performance, immune responses, apoptosis and antioxidant defense system under lipopolysaccharide stress.

To ascertain the effects of Taraxacum mongolicum flavonoids (TMF) on the growth performance, digestive enzyme activity, immune indices, inflammatory response and antioxidant capacity of Channa argus, 400 C. argus with an average body weight of (8.08 ± 0.21) g were selected and divided randomly into four groups. They were fed with four experimental diets supplemented with TMF of 0 (control), 25, 50 and 100 mg/kg for 56 d, and then challenged with lipopolysaccharide (LPS) for 96 h, afterwards indices were detected. The results manifested that the addition of TMF above 50 mg/kg in the dietary could significantly improve the final body weight, WGR, SGR and PER of C. argus, while decreased FCR (P < 0.05). Similarly, the 50 mg/kg group had the highest activity of digestive enzymes (protease, lipase, amylase) in intestine and hepatopancreas, which were notably higher than those in the control group (P < 0.05). Nevertheless, 100 mg/kg group could effectively inhibit the liver and gut injury caused by LPS and reduce the contents of ALT and AST, LPS and LBP in serum. In the immune (LY, AKP, ACP, IgM, C3) and antioxidant (T-AOC, SOD, CAT, GSH-PX, GR, ASA, MDA) systems, 100 mg/kg groups were the optimal group, which were remarkably higher than those of the control group (P < 0.05). Additionally, the expression of genes revealed that 100 mg/kg group could noteworthy restrain the expression of pro-inflammatory factors (tnf-α, il-1ß, il-8) and pro-apoptosis (cas-3,8,9, p53, bax, bcl-2) related genes, up-regulate the expression of anti-inflammatory (il-10, tgf-ß) factors, antioxidant-related (nrf2, gpx, gst, cat) genes and heat shock proteins (hsp70, hsp90). Simultaneously, the survival rate of C. argus in the 100 mg/kg TMF-supplemented group was the highest after LPS challenge. Our results elucidate that dietary supplementation TMF protects C. argus from LPS-induced inflammatory injury, to ameliorate digestion, immune response, antioxidant status and apoptosis, implying that TMF could be regarded as an anti-inflammatory and antioxidant agent adding to aquatic animal feed.

Feasibility and Safety of ERCP in the Treatment of Biliary Strictures after Liver Transplantation: With a Report of 37 Cases.

Background: Liver transplantation (LT) is an effective treatment option for patients with end-stage liver disease; biliary complications are important cause of death in posttransplant patients. Endoscopic retrograde cholangiopancreatography (ERCP) has an irreplaceable role in the diagnosis and treatment of patients with biliary tract disease. Methods: The clinical data of patients with biliary strictures (BS) after LT treated with ERCP admitted to the Third Xiangya Hospital of Central South University from September 2016 to October 2021 were reviewed; the changes in temperature, bilirubin, and albumin before and after treatment and postoperative complications were analyzed. Results: A total of 41 patients were included in the study, and biliary stents were successfully placed in 37 cases (90.2%), while 4 cases (9.8%) were unsuccessful due to complete BS. Patients with ERCP guided biliary stenting had a significant improvement in bilirubin index compared to the preoperative period (P < 0.05). 27 patients (73.0%) had complete relief of symptoms after 1 ERCP-guided treatment, and 10 patients (27.0%) developed BS again at different times after the first ERCP treatment, among which 8 patients developed BS again within 1 year after the first treatment and 2 patients developed BS again after 1 year after the first treatment. The incidence of endoscopy-related adverse events was 35.14%, with no serious adverse events. Conclusion: ERCP-guided biliary stenting was an effective and safety treatment for BS after LT.

Intracellular antibody targeting HBx suppresses invasion and metastasis in hepatitis B virus-related hepatocarcinogenesis via protein phosphatase 2A-B56γ-mediated dephosphorylation of protein kinase B.

OBJECTIVES: Hepatitis B virus X (HBx) is closely associated with HBV-related hepatocarcinogenesis via the inactivation of tumour suppressors. Protein phosphatase 2A (PP2A) regulatory subunit B56 gamma (B56γ), as a tumour suppressor, plays a critical role in regulating cellular phosphorylation signals via dephosphorylation of signalling proteins. However, the underlying mechanism that B56γ involved in regulating HBx-associated hepatocarcinogenesis phenotypes and mediating anti-HBx antibody-mediated tumour suppression remains unknown. MATERIALS AND METHODS: We used bioinformatics analysis, paired HCC patient specimens, HBx transgenic (HBx-Tg) mice, xenograft nude mice, HBV stable replication in the HepG2.2.15 cells, and anti-HBx antibody intervention to systematically evaluate the biological function of protein kinase B (AKT) dephosphorylation through B56γ in HBx-associated hepatocarcinogenesis. RESULTS: Bioinformatics analysis revealed that AKT, matrix metalloproteinase 2 (MMP2), and MMP9 were markedly upregulated, while cell migration and viral carcinogenesis pathways were activated in HBV-infected liver tissues and HBV-associated HCC tissues. Our results demonstrated that HBx-expression promotes AKT phosphorylation (p-AKTThr308/Ser473 ), mediating the migration and invasion phenotypes in vivo and in vitro. Importantly, in clinical samples, HBx and B56γ were downregulated in HBV-associated HCC tumour tissues compared with peritumor tissues. Moreover, intervention with site-directed mutagenesis (AKTT308A , AKTS473A ) of p-AKTThr308/Ser473 mimics dephosphorylation, genetics-based B56γ overexpression, and intracellular anti-HBx antibody inhibited cell growth, migration, and invasion in HBx-expressing HCC cells. CONCLUSIONS: Our results demonstrated that B56γ inhibited HBV/HBx-dependent hepatocarcinogenesis by regulating the dephosphorylation of p-AKTThr308/Ser473 in HCC cells. The intracellular anti-HBx antibody and the activator of B56γ may provide a multipattern chemopreventive strategy against HBV-related HCC.

Evaluation of theTherapeutic Effect of the Hybrid Operation on Patients with Aneurysms Associated with Cerebral Arteriovenous Malformations with different Redekop Classifications.

BACKGROUND: Intracranial aneurysms associated with cerebral arteriovenous malformations (AVMs) are a rare condition in the clinic, and treatment is very difficult due to their particular anatomical features. We present our experience in the treatment of intracranial aneurysms with AVMs and evaluate the effectiveness and safety of endovascular treatment combined with microsurgical resection (the hybrid operation). METHODS: This was a single-center retrospective study in our neurosurgical department from January 2015 to January 2021. We collected clinical data from 48 patients with intracranial aneurysms associated with AVMs and categorized them according to Redekop classifications according to the results of cerebral imaging examination to compare the therapeutic effects of endovascular embolization and the hybrid operation. RESULTS: Compared to nonaneurysmal AVMs, intracranial aneurysms with AVMs more often presented with intracranial hemorrhage (P<0.05). Massive hematoma and severe neurological impairment were more often found in patients with intracranial aneurysms with AVMs (P<0.05). For flow-related aneurysms, the hybrid surgery had a higher one-stage cure rate than endovascular embolization alone (P<0.05). Both treatment methods had similar effects on intranidal aneurysms (P>0.05). There were no significant differences in prognostic indicators between the two treatments. However, the recurrence rate of AVMs with proximal flow-related aneurysms was lower in patients who underwent the hybrid operation (P<0.05). CONCLUSION: The hybrid operation was safe and effective for patients with intracranial aneurysms associated with AVMs. For flow-related aneurysms, the one-stage cure rate was higher and the recurrence rate was lower with the hybrid operation than with endovascular embolization alone.

Shigellosis seasonality and transmission characteristics in different areas of China: A modelling study.

Objective: In China, the burden of shigellosis is unevenly distributed, notably across various ages and geographical areas. Shigellosis temporal trends appear to be seasonal. We should clarify seasonal warnings and regional transmission patterns. Method: This study adopted a Logistic model to assess the seasonality and a dynamics model to compare the transmission in different areas. The next-generation matrix was used to calculate the effective reproduction number (R eff) to quantify the transmissibility. Results: In China, the rate of shigellosis fell from 35.12 cases per 100,000 people in 2005 to 7.85 cases per 100,000 people in 2017, peaking in June and August. After simulation by the Logistic model, the 'peak time' is mainly concentrated from mid-June to mid-July. China's 'early warning time' is primarily focused on from April to May. We predict the 'peak time' of shigellosis is the 6.30th month and the 'early warning time' is 3.87th month in 2021. According to the dynamics model results, the water/food transfer pathway has been mostly blocked off. The transmissibility of different regions varies greatly, such as the mean R eff of Longde County (3.76) is higher than Xiamen City (3.15), higher than Chuxiong City (2.52), and higher than Yichang City (1.70). Conclusion: The 'early warning time' for shigellosis in China is from April to May every year, and it may continue to advance in the future, such as the early warning time in 2021 is in mid-March. Furthermore, we should focus on preventing and controlling the person-to-person route of shigellosis and stratified deploy prevention and control measures according to the regional transmission.

New Burst-Oscillation Mode in Paced One-Dimensional Excitable Systems.

A new type of burst-oscillation mode (BOM) is reported for the first time, by extensively investigating the response dynamics of a one-dimensional (1D) paced excitable system with unidirectional coupling. The BOM state is an alternating transition between two distinct phases, i.e., the phase with multiple short spikes and the phase with a long interval. The realizable region and the unrealizable region for the evolution of BOM are identified, which is determined by the initial pulse number in the system. It is revealed that, in the realizable region, the initial inhomogeneous BOM will eventually evolve to the homogeneously distributed spike-oscillation mode (SOM), while it can maintain in the unrealizable region. Furthermore, several dynamical features of BOM and SOM are theoretically predicted and have been verified in numerical simulations. The mechanisms of the emergence of BOM are discussed in detail. It is revealed that three key factors, i.e., the linking time, the system length, and the local dynamics, can effectively modulate the pattern of BOM. Moreover, the suitable parameter region of the external pacing (A, f) that can produce the new type of BOM, has been explicitly revealed. These results may facilitate a deeper understanding of bursts in nature and will have a useful impact in related fields.

Targeting Mitochondrial COX-2 Enhances Chemosensitivity via Drp1-Dependent Remodeling of Mitochondrial Dynamics in Hepatocellular Carcinoma.

Mitochondria are highly dynamic organelles and undergo constant fission and fusion, which are both essential for the maintenance of cell physiological functions. Dysregulation of dynamin-related protein 1 (Drp1)-dependent mitochondrial dynamics is associated with tumorigenesis and the chemotherapeutic response in hepatocellular carcinoma (HCC). The enzyme cyclooxygenase-2 (COX-2) is overexpressed in most cancer types and correlates with a poor prognosis. However, the roles played by the translocation of mitochondrial COX-2 (mito-COX-2) and the interaction between mito-COX-2 and Drp1 in chemotherapeutic responses remain to be elucidated in the context of HCC. Bioinformatics analysis, paired HCC patient specimens, xenograft nude mice, immunofluorescence, transmission electron microscopy, molecular docking, CRISPR/Cas9 gene editing, proximity ligation assay, cytoplasmic and mitochondrial fractions, mitochondrial immunoprecipitation assay, and flow cytometry analysis were performed to evaluate the underlying mechanism of how mito-COX-2 and p-Drp1Ser616 interaction regulates the chemotherapeutic response via mitochondrial dynamics in vitro and in vivo. We found that COX-2 and Drp1 were frequently upregulated and confer a poor prognosis in HCC. We also found that the proportion of mito-COX-2 and p-Drp1Ser616 was increased in HCC cell lines. In vitro, we demonstrated that the enhanced mitochondrial translocation of COX-2 promotes its interaction with p-Drp1Ser616 via PTEN-induced putative kinase 1 (PINK1)-mediated Drp1 phosphorylation activation. This increase was associated with higher colony formation, cell proliferation, and mitochondrial fission. These findings were confirmed by knocking down COX-2 in HCC cells using CRISPR/Cas9 technology. Furthermore, inhibition of Drp1 using pharmacologic inhibitors (Mdivi-1) or RNA interference (siDNM1L) decreased mito-COX-2/p-Drp1Ser616 interaction-mediated mitochondrial fission, and increased apoptosis in HCC cells treated with platinum drugs. Moreover, inhibiting mito-COX-2 acetylation with the natural phytochemical resveratrol resulted in reducing cell proliferation and mitochondrial fission, occurring through upregulation of mitochondrial deacetylase sirtuin 3 (SIRT3), which, in turn, increased the chemosensitivity of HCC to platinum drugs in vitro and in vivo. Our results suggest that targeting interventions to PINK1-mediated mito-COX-2/p-Drp1Ser616-dependent mitochondrial dynamics increases the chemosensitivity of HCC and might help us to understand how to use the SIRT3-modulated mito-COX-2/p-Drp1Ser616 signaling axis to develop an effective clinical intervention in hepatocarcinogenesis.