Peroxisomes account for ~35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl‐CoA oxidase 1) is the first and rate‐limiting enzyme in fatty acid β‐oxidation and a major producer ...of H2O2. ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases H2O2 production and oxidative DNA damage, which can be alleviated by ACOX1 knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome‐induced oxidative stress, in liver protection, and in suppressing HCC development.
Synopsis
This study reveals a role for SIRT5 in regulating peroxisomal H2O2 and ROS homeostasis and indicates its potential function in liver protection and hepatocellular carcinoma suppression.
SIRT5 is localized in peroxisomes where it controls H2O2 metabolism.
SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation.
SIRT5 downregulation increases ACOX1 activity and oxidative DNA damage response in HCC.
This study reveals a role for SIRT5 in regulating peroxisomal H2O2 and ROS homeostasis and indicates its potential function in liver protection and hepatocellular carcinoma suppression.
Cooperative Intersection Management: A Survey Lei Chen; Englund, Cristofer
IEEE transactions on intelligent transportation systems,
02/2016, Letnik:
17, Številka:
2
Journal Article
Recenzirano
Intersection management is one of the most challenging problems within the transport system. Traffic light-based methods have been efficient but are not able to deal with the growing mobility and ...social challenges. On the other hand, the advancements of automation and communications have enabled cooperative intersection management, where road users, infrastructure, and traffic control centers are able to communicate and coordinate the traffic safely and efficiently. Major techniques and solutions for cooperative intersections are surveyed in this paper for both signalized and nonsignalized intersections, whereas focuses are put on the latter. Cooperative methods, including time slots and space reservation, trajectory planning, and virtual traffic lights, are discussed in detail. Vehicle collision warning and avoidance methods are discussed to deal with uncertainties. Concerning vulnerable road users, pedestrian collision avoidance methods are discussed. In addition, an introduction to major projects related to cooperative intersection management is presented. A further discussion of the presented works is given with highlights of future research topics. This paper serves as a comprehensive survey of the field, aiming at stimulating new methods and accelerating the advancement of automated and cooperative intersections.
Coronavirus disease 2019 (COVID-19) causes severe community and nosocomial outbreaks. Comprehensive data for serial respiratory viral load and serum antibody responses from patients infected with ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not yet available. Nasopharyngeal and throat swabs are usually obtained for serial viral load monitoring of respiratory infections but gathering these specimens can cause discomfort for patients and put health-care workers at risk. We aimed to ascertain the serial respiratory viral load of SARS-CoV-2 in posterior oropharyngeal (deep throat) saliva samples from patients with COVID-19, and serum antibody responses.
We did a cohort study at two hospitals in Hong Kong. We included patients with laboratory-confirmed COVID-19. We obtained samples of blood, urine, posterior oropharyngeal saliva, and rectal swabs. Serial viral load was ascertained by reverse transcriptase quantitative PCR (RT-qPCR). Antibody levels against the SARS-CoV-2 internal nucleoprotein (NP) and surface spike protein receptor binding domain (RBD) were measured using EIA. Whole-genome sequencing was done to identify possible mutations arising during infection.
Between Jan 22, 2020, and Feb 12, 2020, 30 patients were screened for inclusion, of whom 23 were included (median age 62 years range 37–75). The median viral load in posterior oropharyngeal saliva or other respiratory specimens at presentation was 5·2 log10 copies per mL (IQR 4·1–7·0). Salivary viral load was highest during the first week after symptom onset and subsequently declined with time (slope −0·15, 95% CI −0·19 to −0·11; R2=0·71). In one patient, viral RNA was detected 25 days after symptom onset. Older age was correlated with higher viral load (Spearman's ρ=0·48, 95% CI 0·074–0·75; p=0·020). For 16 patients with serum samples available 14 days or longer after symptom onset, rates of seropositivity were 94% for anti-NP IgG (n=15), 88% for anti-NP IgM (n=14), 100% for anti-RBD IgG (n=16), and 94% for anti-RBD IgM (n=15). Anti-SARS-CoV-2-NP or anti-SARS-CoV-2-RBD IgG levels correlated with virus neutralisation titre (R2>0·9). No genome mutations were detected on serial samples.
Posterior oropharyngeal saliva samples are a non-invasive specimen more acceptable to patients and health-care workers. Unlike severe acute respiratory syndrome, patients with COVID-19 had the highest viral load near presentation, which could account for the fast-spreading nature of this epidemic. This finding emphasises the importance of stringent infection control and early use of potent antiviral agents, alone or in combination, for high-risk individuals. Serological assay can complement RT-qPCR for diagnosis.
Richard and Carol Yu, May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Michael Tong, Marina Lee, Government Consultancy Service, and Sanming Project of Medicine.
The demands for green production of hydrogen peroxide have triggered extensive studies in the photocatalytic synthesis, but most photocatalysts suffer from rapid charge recombination and poor 2e− ...oxygen reduction reaction (ORR) selectivity. Here, a novel composite photocatalyst of cyano‐rich graphitic carbon nitride g‐C3N4 is fabricated in a facile manner by sodium chloride‐assisted calcination on dicyandiamide. The obtained photocatalysts exhibit superior activity (7.01 mm h−1 under λ ≥ 420 nm, 16.05 mm h−1 under simulated sun conditions) for H2O2 production and 93% selectivity for 2e− ORR, much higher than that of the state‐of‐the‐art photocatalyst. The porous g‐C3N4 with Na dopants and cyano groups simultaneously optimize two limiting steps of the photocatalytic 2e− ORR: photoactivity, and selectivity. The cyano groups can adjust the band structure of g‐C3N4 to achieve high activity. They also serve as oxygen adsorption sites, in which local charge polarization facilitates O2 adsorption and protonation. With the aid of Na+, the O2 is reduced to produce more superoxide radicals as the intermediate products for H2O2 synthesis. This work provides a facile approach to simultaneously tune photocatalytic activity and 2e− ORR selectivity for boosting H2O2 production, and then paves the way for the practical application of g‐C3N4 in environmental remediation and energy supply.
Two limiting steps in photocatalytic hydrogen peroxide synthesis are simultaneously optimized using porous g‐C3N4 with Na dopants and cyano groups. The CN adjusts the band structure, and serves as oxygen adsorption and reduction sites, with the aid of Na+, to generate superoxide radicals as intermediates for H2O2 production, achieving a high H2O2 generation rate (7.01 mm h−1) and selectivity (93%).
Background
Emerging studies have shown that HOTAIR acts as an oncogene in gastric cancer (GC). However, its role in the extracellular matrix and in tumor immune infiltration remains unknown.
Methods
...HOTAIR and COL5A1 levels were analyzed by bioinformatics analysis and validated by qRT-PCR, western blotting and immunohistochemistry assays. The regulatory relationships between components of the HOTAIR/miR-1277-5p/COL5A1 axis and the role of this axis in GC were predicted by bioinformatics analysis, and validated by in vitro and in vivo experiments. The correlation between COL5A1 and GC immune infiltration was assessed by bioinformatics analysis and a COL5A1-based predictive nomogram was established using the Stomach Adenocarcinoma dataset from The Cancer Genome Atlas.
Results
We found that HOTAIR and COL5A1 were overexpressed in GC compared to normal controls, which predicted poor prognosis. The regulatory relationship of the HOTAIR/miR-1277-5p/COL5A1 axis in GC was demonstrated, and HOTAIR and COL5A1 were found to promote GC growth while miR-1277-5p exerted the reverse effects. In addition, COL5A1 was negatively associated with tumor purity but positively associated with immune infiltration, which suggested that COL5A1-mediated GC growth may be partially mediated by the regulation of immune infiltration. Additionally, the established COL5A1-based nomogram showed that COL5A1 can serve as a prognostic biomarker in GC.
Conclusions
HOTAIR regulates GC growth by sponging miR-1277-5p and upregulating COL5A1, and COL5A1-mediated GC cell proliferation may be mediated by effects on the tumor microenvironment, which provides novel targets for GC treatment.
As one of the most induced genes in activated macrophages, immune-responsive gene 1 (IRG1) encodes a mitochondrial metabolic enzyme catalysing the production of itaconic acid (ITA). Although ITA has ...an anti-inflammatory property, the underlying mechanisms are not fully understood. Here we show that ITA is a potent inhibitor of the TET-family DNA dioxygenases. ITA binds to the same site on TET2 as the co-substrate α-ketoglutarate, inhibiting TET2 catalytic activity. Lipopolysaccharide treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals that TET2 is a major target of ITA in suppressing lipopolysaccharide-induced genes, including those regulated by the NF-κB and STAT signalling pathways. In vivo, ITA decreases the levels of 5-hydroxymethylcytosine, reduces lipopolysaccharide-induced acute pulmonary oedema as well as lung and liver injury, and protects mice against lethal endotoxaemia, depending on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory responses.
Central to the economic theory of sticky costs is the proposition that managers consider adjustment costs when changing resource levels. We test this proposition using employment protection ...legislation (EPL) provisions in different countries as a proxy for labor adjustment costs. Using a large sample of firms in 19 OECD countries during 1990–2008, we find that the degree of cost stickiness at the firm level varies with the strictness of the country-level EPL provisions. This finding supports the theory that cost stickiness reflects the deliberate resource commitment decisions of managers in the presence of adjustment costs.
► We develop and test the economic theory that can explain the pervasive empirical findings of sticky costs. ► If the theory holds, higher adjustment costs should increase stickiness. ► Employment protection legislation (EPL) strictness is a reliable empirical proxy for labor adjustment costs. ► In cross-country analysis for 19 OECD countries, stricter EPL is associated with higher stickiness, supporting the theory.
The novel SARS-CoV-2 Omicron variant (B.1.1.529), first found in early November 2021, has sparked considerable global concern and it has >50 mutations, many of which are known to affect ...transmissibility or cause immune escape. In this study, we sought to investigate the virological characteristics of the Omicron variant and compared it with the Delta variant which has dominated the world since mid-2021. Omicron variant replicated more slowly than the Delta variant in transmembrane serine protease 2 (TMPRSS2)-overexpressing VeroE6 (VeroE6/TMPRSS2) cells. Notably, the Delta variant replicated well in Calu3 cell line which has robust TMPRSS2 expression, while the Omicron variant replicated poorly in this cell line. Competition assay showed that Delta variant outcompeted Omicron variant in VeroE6/TMPRSS2 and Calu3 cells. To confirm the difference in entry pathway between the Omicron and Delta variants, we assessed the antiviral effect of bafilomycin A1, chloroquine (inhibiting endocytic pathway), and camostat (inhibiting TMPRSS2 pathway). Camostat potently inhibited the Delta variant but not the Omicron variant, while bafilomycin A1 and chloroquine could inhibit both Omicron and Delta variants. Moreover, the Omicron variant also showed weaker cell-cell fusion activity when compared with Delta variant in VeroE6/TMPRSS2 cells. Collectively, our results suggest that Omicron variant infection is not enhanced by TMPRSS2 but is largely mediated via the endocytic pathway. The difference in entry pathway between Omicron and Delta variants may have an implication on the clinical manifestations or disease severity.
Sorafenib is an oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis and promotes tumor cell apoptosis It was approved by the FDA for the treatment of advanced renal ...cell carcinoma in 2006, and as a unique target drug for advanced hepatocellular carcinoma （HCC） in 2007. Sorafenib can significantly extend the median survival time of patients but only by 3-5 months. Moreover, it is associated with serious adverse side effects, and drug resistance often develops. Therefore, it is of great importance to explore the mechanisms underlying sorafenib resistance and to develop individualized therapeutic strategies for coping with these problems. Recent studies to the primary resistance, mechanisms are underying the acquired resistance to sorafenib, such as crosstalk involving PI3K/Akt and JAK-STAT pathways, the activation of hypoxia-inducible pathways, and epithelial-mesenchymal transition. Here, we briefly describe the function of sorafenib, its clinical application, and the molecular mechanisms for drug resistance, especially for HCC patients.
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