Arachidonic acid activates NLRP3 inflammasome in MDSCs via FATP2 to promote post-transplant tumour recurrence in steatotic liver grafts.

Background & Aims: The steatotic grafts have been applied in liver transplantation frequently owing to the high incidence of non-alcoholic fatty liver disease. However, fatty livers are vulnerable to graft injury. Myeloid-derived suppressor cell (MDSC) recruitment during liver graft injury promotes tumour recurrence. Lipid metabolism exerts the immunological influence on MDSCs in tumour progression. Here, we aimed to explore the role and mechanism of inflammasome activation in MDSCs induced by lipid metabolism during fatty liver graft injury and the subsequent effects on tumour recurrence. Methods: MDSC populations and nucleotide-binding oligomerisation domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome levels were investigated in a clinical cohort and a rat liver transplantation model. The mechanism of NLRP3 activation by specific fatty acids was explored in mouse hepatic ischaemia/reperfusion injury (IRI) with tumour recurrence model and in vitro studies. Results: MDSC populations and NLRP3 levels were increased with higher tumour recurrent rate in patients using steatotic grafts. NLRP3 was upregulated in MDSCs with lipid accumulation post mouse fatty liver IRI. Mechanistically, arachidonic acid was discovered to activate NLRP3 inflammasome in MDSCs through fatty acid transport protein 2 (FATP2), which was identified by screening lipid uptake receptors. The mitochondrial dysfunction with enhanced reactive oxygen species bridged arachidonic acid uptake and NLRP3 activation in MDSCs, which subsequently stimulated CD4+ T cells producing more IL-17 in fatty liver IRI. Blockade of FATP2 inhibited NLRP3 activation in MDSCs, IL-17 production in CD4+ T cells, and the tumour recurrence post fatty liver IRI. Conclusions: During fatty liver graft injury, arachidonic acid activated NLRP3 inflammasome in MDSCs through FATP2, which subsequently stimulated CD4+ T cells producing IL-17 to promote tumour recurrence post transplantation. Impact and implications: The high incidence of non-alcoholic fatty liver disease resulted in the frequent application of steatotic donors in liver transplantation. Our data showed that the patients who underwent liver transplantation using fatty grafts experienced higher tumour recurrence. We found that arachidonic acid activated NLRP3 inflammasome in MDSCs through FATP2 during fatty liver graft injury, which led to more IL-17 secretion of CD4+ T cells and promoted tumour recurrence post transplantation. The inflammasome activation by aberrant fatty acid metabolism in MDSCs bridged the acute-phase fatty liver graft injury and liver tumour recurrence.

Systematic Evaluation and Nursing Outlook of Clinical Characteristics of 60 Twin Pregnancies with Complete Hydatidiform Mole and a Coexistent Viable Foetus.

Objective: To analyse the clinical data of and provide a reference for the care and perinatal health care of twin pregnancy patients with complete hydatidiform mole and a coexistent foetus (CHM & CF). Methods: We searched the China National Knowledge Infrastructure (CNKI) and Wanfang and VIP databases to comprehensively collect clinical studies on the "clinical characteristics of complete hydatidiform mole and coexisting foetal twin pregnancy". Patients' data were extracted from the literature, and 60 patients were divided into Group A (live newborns not delivered, 47) and Group B (live newborns delivered, 13). The clinical characteristics of the two groups were compared to explore the pregnancy outcomes and influencing factors of persistent gestational trophoblastic disease (pGTD) in patients with CHM & CF. Results: The gestational week of diagnosis (Odd Ratio (OR)=0.203, 95% Confidence Interval (CI)=0.055-0.753) and number of complications (OR=0.328, 95% CI=0.135-0.793) were found to be independent influencing factors of pregnancy outcomes in patients with CHM & CF (p < 0.05). Ovulation induction therapy (OR=2.333, 95% CI=0.561-9.708), preeclampsia (OR=75.000, 95% CI=11.041-509.486) and the number of complications (OR=4.768, 95% CI=1.914-11.875) were the independent influencing factors of developing pGTD (p < 0.05). Conclusion: Pregnancy should not be terminated immediately after the early detection of CHM & CF, and multiple factors should be considered. Preeclampsia may indicate a poor prognosis, and ovulation induction may increase the incidence of pGTD. Targeted nursing and psychological nursing should be carried out according to the clinical symptoms of the patients.

Studies of Dopamine Oxidation Process by Atmospheric Pressure Glow Discharge Mass Spectrometry.

An atmospheric pressure glow discharge ionisation source was constructed and utilized to study the dopamine (DA) oxidation process coupling with mass spectrometry. During the DA oxidation process catalysed by polyphenol oxidase (PPO), six cationic intermediates were directly detected by the atmospheric pressure glow discharge mass spectrometry (APGD-MS). Combined with tandem mass spectrometry, the structures of the dopamine o-semiquinone radical (DASQ) and leukodopaminochrome radical (LDAC●) intermediates and structures of the isomers of dopaminochrome (DAC) and 5,6-dihydroxyindole (DHI) were further characterised with the introduction of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and deuterium oxide (D2O) to APGD-MS. Meanwhile, UV-Vis studies confirmed the important role of PPO in catalyzing the DA oxidation reaction. Based on APGD-MS studies, a possible mechanism could be proposed for DA oxidation catalysed by PPO. Furthermore, APGD-MS could provide possibilities for the effective detection and characterisation of short-lived intermediates, even in complicated systems.

Kupffer cell pyroptosis mediated by METTL3 contributes to the progression of alcoholic steatohepatitis.

Chronic alcohol consumption is a major risk factor for alcoholic steatohepatitis (ASH). Previous studies have shown that direct injury of hepatocytes is the key factor in its occurrence and development. However, our study shows that the role of Kupffer cells in ASH cannot be ignored. We isolated Kupffer cells from the livers of ASH mice and found that alcohol consumption induced Kupffer cell pyroptosis and increased the release of interleukin-1ß (IL-1ß). Furthermore, we screened the related m6A enzyme methyltransferase-like 3 (METTL3) from liver Kupffer cells, and found that silencing METTL3 alleviated inflammatory cytokine eruption by Kupffer cell pyroptosis in ASH mice. In vitro, we silenced METTL3 with lentivirus in BMDMs and RAW264.7 cells and confirmed that METTL3 could reduce pyroptosis by influencing the splicing of pri-miR-34A. Together, our results revealed a critical role of KC pyroptosis in ASH and highlighted the mechanism by which METLL3 relieves cell pyroptosis, which could be a promising therapeutic strategy for ASH.

The Landscape of Aberrant Alternative Splicing Events in Steatotic Liver Graft Post Transplantation via Transcriptome-Wide Analysis.

The application of steatotic liver graft has been increased significantly due to the severe donor shortage and prevalence of non-alcoholic fatty liver disease. However, steatotic donor livers are vulnerable to acute phase inflammatory injury, which may result in cancer recurrence. Alternative splicing events (ASEs) are critical for diverse transcriptional variants in hepatocellular carcinoma (HCC). Here, we aimed to depict the landscape of ASEs, as well as to identify the differential ASEs in steatotic liver graft and their association with tumor recurrence after transplantation. The overall portrait of intragraft transcripts and ASEs were elucidated through RNA sequencing with the liver graft biopsies from patients and rat transplant models. Various differential ASEs were identified in steatotic liver grafts. CYP2E1, ADH1A, CYP2C8, ADH1C, and HGD, as corresponding genes to the common pathways involved differential ASEs in human and rats, were significantly associated with HCC patients' survival. The differential ASEs related RNA-binding proteins (RBPs) were enriched in metabolic pathways. The altered immune cell distribution, particularly macrophages and neutrophils, were perturbated by differential ASEs. The cancer hallmarks were enriched in steatotic liver grafts and closely associated with differential ASEs. Our work identified the differential ASE network with metabolic RBPs, immune cell distribution, and cancer hallmarks in steatotic liver grafts. We verified the link between steatotic liver graft injury and tumor recurrence at post-transcriptional level, offered new evidence to explore metabolism and immune responses, and provided the potential prognostic and therapeutic markers for tumor recurrence.

Acid-sensitive ion channel 1a regulates TNF-α expression in LPS-induced acute lung injury via ERS-CHOP-C/EBPα signaling pathway.

BACKGROUND: Acute lung injury (ALI) is the local inflammatory response of the lungs involved in a variety of inflammatory cells. Macrophages are immune cells and inflammatory cells widely distributed in the body. Acid-sensitive ion channel 1a (ASIC1a) is involved in the occurrence of ALI, but the mechanism is still unclear. METHODS: Kunming mouse were stimulated by Lipopolysaccharides (LPS) to establish ALI model in vivo, and RAW264.7 cells were stimulated by LPS to establish inflammatory model in vitro. Amiloride was used as a blocker of ASIC1a to treat mice, and dexamethasone was used as a positive drug for ALI. After blockers and RNAi blocked or silenced the expression of ASIC1a, the expressions of ASIC1a, endoplasmic reticulum-related proteins GRP78, CHOP, C/EBPα and TNF-α were detected. The Ca2+ concentration was measured by a laser confocal microscope. The interaction between CHOP and C/EBPα and the effect of C/EBPα on the activity of TNF-α promoter were detected by immunoprecipitation and luciferase reporter. RESULTS: The expressions of ASIC1a and TNF-α were increased significantly in LPS group. After the blocker and RNAi blocked or silenced ASIC1a, the expressions of TNF-α, GRP78, CHOP were reduced, and the intracellular Ca2+ influx was weakened. The results of immunoprecipitation showed that CHOP and C/EBPα interacted in the macrophages. After silencing CHOP, C/EBPα expression was increased, and TNF-α expression was decreased. The results of the luciferase reporter indicated that C/EBPα directly binds to TNF-α. CONCLUSION: ASIC1a regulates the expression of TNF-α in LPS-induced acute lung injury via ERS-CHOP-C/EBPα signaling pathway.

N-phenethyl-5-phenylpicolinamide alleviates inflammation in acute lung injury by inhibiting HIF-1α/glycolysis/ASIC1a pathway.

AIMS: Acute lung injury (ALI) is triggered by an acute inflammatory response. Lipopolysaccharide (LPS) is recognized as an important participant in the pathogenesis of sepsis, which may induce ALI. N-phenethyl-5-phenylpicolinamide (N5P) is a newly synthesized HIF-1α inhibitor. The purpose of the present study was to investigate the potential protective effects of N5P on LPS-induced ALI and the underlying mechanisms. MAIN METHODS: In vivo experiment, the ALI rat model was induced by intratracheal injection of LPS, and various concentrations of N5P were injected intraperitoneally before LPS administration. In vitro experiment, RAW264.7 macrophages were administrated LPS and N5P to detect inflammatory cytokine changes. HIF-1α overexpression plasmid (HIF1α-OE) and granulocyte-macrophage colony-stimulating factor (GM-CSF), a glycolysis agonist, were used to examine the relationship between the HIF-1α/glycolysis/ASIC1a pathway. KEY FINDINGS: Pretreatment with N5P inhibited not only the histopathological changes that occurred in the lungs but also lung dysfunction in LPS-induced ALI. N5P also decreased the levels of lactic acid in lung tissue and arterial blood, and inflammatory factors IL-1ß and IL-6 levels in serum. LPS increased HIF-1α, glycolysis proteins GLUT1, HK2, ASIC1a, IL-1ß, IL-6, and these changes were reversed by N5P in primary alveolar macrophages and RAW264.7 macrophages. Overexpression of HIF-1α significantly increased glycolysis genes and ASIC1a as well as inflammatory cytokines. Excessive glycolysis levels weaken the ability of N5P to inhibit inflammation. SIGNIFICANCE: N5P may alleviate inflammation in ALI through the HIF-1α/glycolysis/ASIC1a signaling pathway. The present findings have provided pertinent information in the assessment of N5P as a potential, future therapeutic drug for ALI.

HFE promotes mitotic cell division through recruitment of cytokinetic abscission machinery in hepatocellular carcinoma.

HFE (Hemochromatosis) is a conventional iron level regulator and its loss of function due to gene mutations increases the risk of cancers including hepatocellular carcinoma (HCC). Likewise, studies focusing on HFE overexpression in cancers are all limited to linking up these events as a consequence of iron level deregulation. No study has explored any iron unrelated role of HFE in cancers. Here, we first reported HFE as an oncogene in HCC and its undescribed function on promoting abscission in cytokinesis during mitotic cell division, independent of its iron-regulating ability. Clinical analyses revealed HFE upregulation in tumors linking to large tumor size and poor prognosis. Functionally and mechanistically, HFE promoted cytokinetic abscission via facilitating ESCRT abscission machinery recruitment to the abscission site through signaling a novel HFE/ALK3/Smads/LIF/Hippo/YAP/YY1/KIF13A axis. Pharmacological blockage of HFE signaling axis impeded tumor phenotypes in vitro and in vivo. Our data on HFE-driven HCC unveiled a new mechanism utilized by cancer cells to propel rapid cell division. This study also laid the groundwork for tumor intolerable therapeutics development given the high cytokinetic dependency of cancer cells and their vulnerability to cytokinetic blockage.

Recent Advances in Acid-sensitive Ion Channels in Central Nervous System Diseases.

Acid-sensitive ion channels (ASICs) are cationic channels activated by extracellular protons and widely distributed in the nervous system of mammals. It belongs to the ENaC/DEG family and has four coding genes: ASIC1, ASIC2, ASIC3, and ASIC4, which encode eight subunit proteins: ASIC1a, ASIC1b, ASIC1b2, ASIC2a, ASIC2b, ASIC3, ASIC4, and ASIC5. Different subtypes of ASICs have different distributions in the central nervous system, and they play an important role in various physiological and pathological processes of the central nervous system, including synaptic plasticity, anxiety disorders, fear conditioning, depressionrelated behavior, epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, malignant Glioma, pain, and others. This paper reviewed the recent studies of ASICs on the central nervous system to improve the understanding of ASICs' physiological functions and pathological effects. This article also references studying the molecular mechanisms and therapeutic measures of nervous system-related diseases.

Evidence-based summary for the safety of multiple medication in elderly patients with ischemic stroke.

Background: To retrieve, analyze, and summarize the relevant evidence of home-based medications use for stroke patients, so as to provide evidence for safe home-based medication of elderly patients with ischemic stroke. Methods: We performed a search in the databases of British Medical Journal (BMJ) Best Practice, UpToDate, Joanna Briggs Institute (JBI) Evidence-based Health Care Center Library, Cochrane Library, PubMed, China National Knowledge Infrastructure (CNKI), Wanfang Knowledge Data Service Platform, and others, according to the evidence pyramid model. We retrieved all evidence on the safety of home-based multiple medications use in elderly patients with ischemic stroke, including clinical decision-making, expert consensus, guidelines, systematic reviews, and summary of evidence. The search time limit was from the establishment of the database to March 2021. The literature evaluation standard and evidence grading system of JBI Evidence-based Health Care Center were used to evaluate the quality of the literature, and to classify the extracted evidence. Results: A total of 17 articles were included in this study, comprising 2 guidelines, 11 systematic reviews, 3 evidence summaries, and 1 expert consensus. This article summarizes the 7 best evidences from 5 aspects: drug dispensing, drug identification, medication time, prescription simplification, and self-management plan. Conclusions: The evidence of home-based multiple medication use in elderly patients with ischemic stroke provides an evidence-based reference for ensuring the safety of medications for patients, and guides elderly patients with ischemic stroke and their caregivers by applying the best available evidence.

Incidence of medically attended influenza and influenza virus infections confirmed by serology in Ningbo City from 2017-2018 to 2019-2020.

OBJECTIVES: In mainland China, the disease burden of influenza is not yet fully understood. Based on population-based data, we aimed to estimate incidence rates of medically attended influenza and influenza virus infections in Ningbo City. METHODS: We used data for outpatient acute respiratory illness (OARI) from a platform covering all health and medical institutes in Yingzhou District, Ningbo City. We applied generalized additive regression models to estimate influenza-associated excess incidence rate of OARI by age. We recruited local residents aged ≥60 years in the autumn of 2019 and conducted follow-up nearly 9 months later. Every survey, the sera were collected for testing hemagglutination inhibition antibody. RESULTS: From 2017-2018 to 2019-2020, the annual average of influenza-associated incidence rate of OARI in all ages was 10.9%. The influenza-associated incidence rate of OARI was the highest in 2017-2018 (16.9%) and the lowest in 2019-2020 (4.8%). Regularly, influenza-associated incidence rates of OARI were the highest in children aged 5-14 years (range: 44.1-77.6%) and 0-4 years (range: 8.3-46.6%). The annual average of excess OARI incidence rate in all ages was the highest for influenza B/Yamagata (3.9%). The overall incidence rate of influenza infections indicated by serology in elderly people was 21% during the winter season of 2019-2020. CONCLUSIONS: We identified substantial outpatient influenza burden in all ages in Ningbo. Our cohort study limited in elderly people found that this age group had a high risk of seasonal influenza infections. Our study informs the importance of increasing influenza vaccine coverage in high-risk population including elderly people.

Evidence summary on the timing and frequency of screening for perinatal depression.

BACKGROUND: This study sought to search, evaluate, and summarize the best evidence about the time and frequency of screening for perinatal depression (PND). METHODS: The UpToDate, Scottish Intercollegiate Network, National Institute for Health and Care Excellence, National Guideline Clearinghouse, Guidelines International Network, BMJ Best Practice, Cochrane Library, Embase, Campbell Collaboration, CINAHL, Joanna Briggs Institute Library, Medline, CNKI, Wanfang, VIP, and CBM databases were searched to retrieve relevant articles. RESULTS: A total of 9 articles were included in the meta-analysis, comprising 2 guidelines, 1 expert consensus, 1 evidence summary, 3 systematic reviews, and 2 clinical decisions. A total of 11 articles of best evidence were collected. The evidence was mainly related to the two aspects of screening time and frequency. CONCLUSIONS: There is abundant evidence on the best screening time for and frequency of PND; however, some evidence was from foreign evidence-based resources. Local clinical conditions need to be considered at the time of application.

Efficient identification of raw and ripe tung oil using headspace GC-MS.

To differentiate between the raw type and ripe type of tung oil, it is important to distinguish between the types of tung oil before its application. In the present work, an efficient headspace gas chromatography-mass spectrometry (HS-GC-MS) method was developed for identifying eight samples T1-T8, including the raw tung oil and ripe tung oil. The HS-GC-MS experiments results showed that octanoic acid existed only in ripe tung oil of T2, T4, T6, T8, not in raw tung oil of T1, T3, T5, T7. Combined with structural characterization by tandem mass spectrometry, octanoic acid was screened as an effective marker for distinguishing between raw tung oil and ripe tung oil. Then, the HS-GC-MS method was applied into the putty samples of X1 (raw tung oil with lime) and X2 (ripe tung oil with lime) and successfully identified the samples X1 mixed with raw tung oil and X2 mixed with ripe tung oil. The further validations results suggested that the detection limit of our HS-GC-MS method could reach 1.05 mg/L for octanoic acid, whereas the detection limit of derivative gas chromatography-mass spectrometry (DR-GC-MS) method was 2.74 mg/L for methyl octanoate. The investigation results can also provide the useful information and technical support for the selection of restoration materials and technology in ancient buildings.

Inonotsuoxide B regulates M1 to M2 macrophage polarization through sirtuin-1/endoplasmic reticulum stress axis.

We explored the effect of tetracyclic triterpenoid inonotsuoxide B (IB) extracts of Inonotus obliquus on M1 to M2 macrophage polarization and its possible underlying mechanism. Lipopolysaccharide (LPS)-activated M1 macrophages exert pro-inflammatory effects and release inflammatory cytokines including interleukin (IL)-1ß and tumor necrosis factor (TNF)-α. The model and various groups were treated with different IB concentrations (2.5, 5, and 10 µg/mL) to observe changes in the M1 and M2 phenotypes, gene expression of NAD-dependent deacetylase sirtuin-1 (Sirt1), and endoplasmic reticulum stress (ERS). SIRT1-siRNA and thapsigargin (TG), an ERS agonist, were used to examine the relationship between SIRT1/ERS and the effect of IB on M1 to M2 RAW264.7 macrophage phenotypic changes. We found that IB had no effect on RAW264.7 cell proliferation at 10 µg/mL. Increasing concentrations of IB (2.5, 5, and 10 µg/mL) decreased the number of phenotypic M1 macrophages and, consequently, decreased the release of the inflammatory cytokines, IL-1ß and TNF-α. Furthermore, IB treatment increased the level of phenotypic M2 macrophages, which increased the release of anti-inflammatory cytokines such as arginase (Arg)-1 and found in inflammatory zone 1 (FIZZ1) in a dose-dependent manner. Further, we found that IB increased the expression of SIRT1 and inhibited that of ERS. Inhibition of Sirt1 expression by siRNA significantly increased that of ERS marker genes and IL1ß. Excessive ERS levels inhibited the IB-induced transformation of phenotypic M1 macrophage to the M2 macrophage phenotype. Therefore, IB, an extract of I. obliquus, may regulate macrophage polarization through the SIRT1/ERS signaling pathway.

The interaction of ASIC1a and ERS mediates nerve cell apoptosis induced by insulin deficiency.

Diabetes-related brain complications are the most serious complications of terminal diabetes. The increasing evidence have showed that the predisposing factor is not only hyperglycemia, but also insulin deficiency. In this study, we demonstrated that insulin deficiency was involved in the apoptosis of nerve cells, and it was related to the interaction between acid-sensitive ion channel 1a (ASIC1a) and endoplasmic reticulum stress (ERS). By silencing C/EBP homologous protein (CHOP) and ASIC1a, the pro-apoptotic effect of insulin deficiency on NS20y cells was relieved. Further research found that the binding of CHOP and C/EBPα was increased in the nucleus of cells cultured without insulin, and C/EBPα was competitively inhibited as a negative regulator of ASIC1a, which further increased the ERS and lead to neuronal apoptosis. In summary, ERS and ASIC1a play an important role in neurological damage caused by insulin deficiency. Our finding may lead to new ideas and treatment of diabetes-related brain complications.

ASIC1a regulates miR-350/SPRY2 by N6 -methyladenosine to promote liver fibrosis.

As a reversible scar repair reaction, liver fibrosis can be blocked or even reversed by proper intervention during its formation. Our work suggests that acid-sensitive ion channel 1a (ASIC1a) participates in liver fibrosis and presents a novel mechanism involving m6 A modification and miR-350/SPRY2. We demonstrated that the expression of ASIC1a was significantly increased in liver tissue of patients with liver fibrosis and animal models of liver fibrosis, as well as PDGF-BB-induced activated HSC-T6. After downregulating the expression of ASIC1a, the degree of liver fibrosis is reduced and HSC activation was inhibited, the level of m6 A modification and miR-350 expression were also reduced. The results of dual luciferase reporter assay showed that miR-350 can bind to the target gene SPRY2 and inhibit its expression. We also found that METTL3 can regulate the extent of m6 A modification of pri-miR-350 by binding to DGCR8. In addition, silencing or blocking the expression of ASIC1a can reduce the expression of PI3K/AKT and ERK signaling pathway-related proteins in activated HSCs. Taken together, we demonstrated that ASIC1a regulates the processing of miR-350 through METTL3-dependent m6 A modification, and mature miR-350 targets SPRY2 and further promotes liver fibrosis through the PI3K/KT and ERK pathways.

PI3-kinase/Akt pathway-regulated membrane transportation of acid-sensing ion channel 1a/Calcium ion influx/endoplasmic reticulum stress activation on PDGF-induced HSC Activation.

Acid-sensing ion channel 1a (ASIC1a) allows Na+ and Ca2+ flow into cells. It is expressed during inflammation, in tumour and ischaemic tissue, in the central nervous system and non-neuronal injury environments. Endoplasmic reticulum stress (ERS) is caused by the accumulation of misfolded proteins that interferes with intracellular calcium homoeostasis. Our recent reports showed ASIC1a and ERS are involved in liver fibrosis progression, particularly in hepatic stellate cell (HSC) activation. In this study, we investigated the roles of ASIC1a and ERS in activated HSC. We found that ASIC1a and ERS-related proteins were up-regulated in carbon tetrachloride (CCl4 )-induced fibrotic mouse liver tissues, and in patient liver tissues with hepatocellular carcinoma with severe liver fibrosis. The results show silencing ASIC1a reduced the expression of ERS-related biomarkers GRP78, Caspase12 and IREI-XBP1. And, ERS inhibition by 4-PBA down-regulated the high expression of ASIC1a induced by PDGF, suggesting an interactive relationship. In PDGF-induced HSCs, ASIC1a was activated and migrated to the cell membrane, leading to extracellular calcium influx and ERS, which was mediated by PI3K/AKT pathway. Our work shows PDGF-activated ASIC1a via the PI3K/AKT pathway, induced ERS and promoted liver fibrosis progression.

Neonatal phthalate ester exposure induced placental MTs, FATP1 and HFABP mRNA expression in two districts of southeast China.

Plastic production releases phthalate esters (PAEs), which can alter the expression of metallothioneins (MTs), fatty acid transport protein 1 (FATP1) and heart fatty acid binding protein (HFABP). A total of 187 mother-infant pairs were recruited, 127 from Chenghai (high exposed group) and 60 from Haojiang (low exposed group), to investigate the association between neonatal PAE exposure and mRNA expression of placental MTs, FATP1 and HFABP. Umbilical cord blood and placenta samples were collected for measuring five PAE concentrations and detecting mRNA levels of MTs, FATP1 and HFABP. Butylbenzyl phthalate (BBP), di(2-ethylhexyl) phthalate (DEHP), di-n-octyl phthalate (DNOP) were significantly higher in the high exposed group compared to the low exposed group. FATP1 and HFABP mRNA in the high exposed group were higher than that in the low exposed group while MT-1A was contrary. Both dimethyl phthalate (DMP) and DEHP were correlated with higher MT and MT-2A expression, while diethyl phthalate (DEP) was also positively correlated with MT-1A and FATP1 expression in female infants. DEHP exposure was negatively correlated with birth weight and gestational age in male infants. These results show that neonatal PAE exposure alters the mRNA expression of placental MTs and FATP1, which are related to fetal growth and development.

High-throughput state-machine replication using software transactional memory.

State-machine replication is a common way of constructing general purpose fault tolerance systems. To ensure replica consistency, requests must be executed sequentially according to some total order at all non-faulty replicas. Unfortunately, this could severely limit the system throughput. This issue has been partially addressed by identifying non-conflicting requests based on application semantics and executing these requests concurrently. However, identifying and tracking non-conflicting requests require intimate knowledge of application design and implementation, and a custom fault tolerance solution developed for one application cannot be easily adopted by other applications. Software transactional memory offers a new way of constructing concurrent programs. In this article, we present the mechanisms needed to retrofit existing concurrency control algorithms designed for software transactional memory for state-machine replication. The main benefit for using software transactional memory in state-machine replication is that general purpose concurrency control mechanisms can be designed without deep knowledge of application semantics. As such, new fault tolerance systems based on state-machine replications with excellent throughput can be easily designed and maintained. In this article, we introduce three different concurrency control mechanisms for state-machine replication using software transactional memory, namely, ordered strong strict two-phase locking, conventional timestamp-based multiversion concurrency control, and speculative timestamp-based multiversion concurrency control. Our experiments show that speculative timestamp-based multiversion concurrency control mechanism has the best performance in all types of workload, the conventional timestamp-based multiversion concurrency control offers the worst performance due to high abort rate in the presence of even moderate contention between transactions. The ordered strong strict two-phase locking mechanism offers the simplest solution with excellent performance in low contention workload, and fairly good performance in high contention workload.

Event Coverage Detection and Event Source Determination in Underwater Wireless Sensor Networks.

With the advent of the Internet of Underwater Things, smart things are deployed in the ocean space and establish underwater wireless sensor networks for the monitoring of vast and dynamic underwater environments. When events are found to have possibly occurred, accurate event coverage should be detected, and potential event sources should be determined for the enactment of prompt and proper responses. To address this challenge, a technique that detects event coverage and determines event sources is developed in this article. Specifically, the occurrence of possible events corresponds to a set of neighboring sensor nodes whose sensory data may deviate from a normal sensing range in a collective fashion. An appropriate sensor node is selected as the relay node for gathering and routing sensory data to sink node(s). When sensory data are collected at sink node(s), the event coverage is detected and represented as a weighted graph, where the vertices in this graph correspond to sensor nodes and the weight specified upon the edges reflects the extent of sensory data deviating from a normal sensing range. Event sources are determined, which correspond to the barycenters in this graph. The results of the experiments show that our technique is more energy efficient, especially when the network topology is relatively steady.