Indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2 activity and severe course of COVID-19.

COVID-19 is a pandemic with high morbidity and mortality. In an autopsy cohort of COVID-19 patients, we found extensive accumulation of the tryptophan degradation products 3-hydroxy-anthranilic acid and quinolinic acid in the lungs, heart, and brain. This was not related to the expression of the tryptophan-catabolizing indoleamine 2,3-dioxygenase (IDO)-1, but rather to that of its isoform IDO-2, which otherwise is expressed rarely. Bioavailability of tryptophan is an absolute requirement for proper cell functioning and synthesis of hormones, whereas its degradation products can cause cell death. Markers of apoptosis and severe cellular stress were associated with IDO-2 expression in large areas of lung and heart tissue, whereas affected areas in brain were more restricted. Analyses of tissue, cerebrospinal fluid, and sequential plasma samples indicate early initiation of the kynurenine/aryl-hydrocarbon receptor/IDO-2 axis as a positive feedback loop, potentially leading to severe COVID-19 pathology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

High Levels of Neutrophil Extracellular Traps Persist in the Lower Respiratory Tract of Critically Ill Patients With Coronavirus Disease 2019.

Lower respiratory tract (LRT) disease induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can deteriorate to acute respiratory distress syndrome (ARDS). Because the release of neutrophil extracellular traps (NETs) is implicated in ARDS pathogenesis, we investigated the presence of NETs and correlates of pathogenesis in blood and LRT samples of critically ill patients with COVID-19. Plasma NET levels peaked early after intensive care unit admission and were correlated with the SARS-CoV-2 RNA load in sputum and levels of neutrophil-recruiting chemokines and inflammatory markers in plasma samples. The baseline plasma NET quantity was correlated with disease severity but was not associated with soluble markers of thrombosis or with development of thrombosis. High NET levels were present in LRT samples and persisted during the course of COVID-19, consistent with the detection of NETs in bronchi and alveolar spaces in lung tissue from deceased patient with COVID-19. Thus, NETs are produced and retained in the LRT of critically ill patients with COVID-19 and could contribute to SARS-CoV-2-induced ARDS disease.

Synthesis of a molecularly imprinted polymer on mSiO2 @Fe3 O4 for the selective adsorption of atrazine.

Atrazine contamination of water is of considerable concern because of the potential hazard to human health. In this study, a magnetic molecularly imprinted polymer for atrazine was prepared by the surface-imprinting technique using Fe3 O4 as the core, mesoporous silica as the carrier, atrazine as the template, and itaconic acid as the functional monomer. The magnetic molecularly imprinted polymer was characterized by Fourier-transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction, and vibration-sample magnetometry. The binding properties of the magnetic molecularly imprinted polymer toward atrazine were investigated by adsorption isotherms, kinetics, and competitive adsorption. It was found that the adsorption equilibrium was achieved within 2 h, the maximum adsorption capacity of atrazine was 8.8 µmol/g, and the adsorption process could be well described by the Langmuir isotherm model and pseudo-second-order kinetic model. The magnetic molecularly imprinted polymer exhibited good adsorption selectivity for atrazine with respect to structural analogues, such as cyanazine, simetryne, and prometryn. The reusability of the magnetic molecularly imprinted polymer was demonstrated for at least five repeated cycles without a significant decrease in adsorption capacity. These results suggested that the magnetic molecularly imprinted polymer could be used as an efficient material for the selective adsorption and removal of atrazine from water samples.

The integrity of PRRSV nucleocapsid protein is necessary for up-regulation of optimal interleukin-10 through NF-κB and p38 MAPK pathways in porcine alveolar macrophages.

Porcine reproductive and respiratory syndrome (PRRS), a highly contagious disease, has been constantly causing huge economic losses all over the world. PRRS virus (PRRSV) infection results in immunosuppression and IL-10 up-regulation. The relationship between them is still in dispute. Previous studies demonstrated the protein of PRRSV nucleocapsid (N) protein is able to up-regulate IL-10, yet the underlying molecular mechanisms remain unknown. In this study, the expression kinetics of IL-10 up-regulation induced by PRRSV N protein were analyzed in immortalized porcine alveolar macrophages (PAMs). N protein induced IL-10 expression in a time- and dose-dependent manner. Inhibition experiments of signaling pathways suggested NF-κB and p38 MAPK pathways are both involved in N protein-induced IL-10 up-regulation. Besides, the integrity of N protein is essential for significant IL-10 up-regulation. This research is beneficial for further understanding of the interplay between PRRSV and host immune system.

High levels of acetoacetate and glucose increase expression of cytokines in bovine hepatocytes, through activation of the NF-κB signalling pathway.

Elevated levels of blood interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) increase insulin resistance and result in inflammation. It is not clear whether elevated blood level of acetoacetate (ACAC) and decreased blood level of glucose, which are the predominant characteristics of clinical biochemistry in ketotic dairy cows, increase proinflammatory cytokines and subsequent inflammation. The objective of this study was to test the hypothesis that ACAC and glucose activate the NF-κB signalling pathway to regulate cytokines expression in bovine hepatocytes. Bovine hepatocytes were cultured with ACAC (0-4.8 mm) and glucose (0-5.55 mm) with or without NF-κB inhibitor PDTC for 24 h. The secretion and mRNA levels of cytokines were determined by enzyme-linked immunosorbent assay (ELISA) and real-time fluorescence quantitative polymerase chain reaction (qRT-PCR). The NF-κB signalling pathway activation was evaluated by western blotting. Results showed that the secretion and expression of IL-1ß, IL-6 and TNF-α increased in an ACAC dose-dependent manner. Additionally, there was an increase in the secretion and mRNA expression of these three cytokines in glucose treatment group, which increased significantly when the glucose concentrations exceed 3.33 mm. Furthermore, both ACAC and glucose upregulated NF-κB p65 protein expression and IκBα phosphorylation levels. However, these effects were reduced by PDTC. These results demonstrate that elevated levels of ACAC and glucose increase the synthesis and expression of proinflammatory factors by activating NF-κB signalling pathway in hepatocytes, which may contribute to inflammation injury in ketotic dairy cows.

BHBA influences bovine hepatic lipid metabolism via AMPK signaling pathway.

ß-hydroxybutyric acid (BHBA), an important metabolite in ß-oxidation, is involved in the development of ketosis in dairy cows. It is known that AMP-activated protein kinase (AMPK) signaling pathway plays an important role in the regulation of lipid metabolism in hepatocytes. In the present study, bovine hepatocytes were treated with BHBA at variable concontrations and Compound C (Cpd C, an AMPK inhibitor) to investigate the effects of BHBA on the AMPK signaling pathway. The results showed that when the concentration of BHBA reached 1.2 mM, the AMPK signaling pathway was activated and the expression of sterol regulatory element binding protein-1c (SREBP-1c) as well as its target genes were significantly decreased. And these decreases were blocked by Cpd C. The binding activity and nucleus translocation of SREBP-1c showed a similar trend. The expression of peroxisome proliferator activated receptor-α (PPARα), carbohydrates response element binding protein (ChREBP) and their target genes were significantly increased while they were negatively suppressed by the Cpd C. The content of triglyceride (TG) had no obviously change in the BHBA and Cpd C-treated groups. These results indicate that BHBA can activate AMPK signaling pathway and regulate lipid synthesis and lipid oxidation genes of AMPK but showed no effect on TG in bovine hepatocytes.

3Cpro of foot-and-mouth disease virus antagonizes the interferon signaling pathway by blocking STAT1/STAT2 nuclear translocation.

UNLABELLED: Foot-and-mouth disease virus (FMDV) causes a highly contagious, debilitating disease in cloven-hoofed animals with devastating economic consequences. To survive in the host, FMDV has evolved to antagonize the host type I interferon (IFN) response. Previous studies have reported that the leader proteinase (L(pro)) and 3C(pro) of FMDV are involved in the inhibition of type I IFN production. However, whether the proteins of FMDV can inhibit type I IFN signaling is less well understood. In this study, we first found that 3C(pro) of FMDV functioned to interfere with the JAK-STAT signaling pathway. Expression of 3C(pro) significantly reduced the transcript levels of IFN-stimulated genes (ISGs) and IFN-stimulated response element (ISRE) promoter activity. The protein level, tyrosine phosphorylation of STAT1 and STAT2, and their heterodimerization were not affected. However, the nuclear translocation of STAT1/STAT2 was blocked by the 3C(pro) protein. Further mechanistic studies demonstrated that 3C(pro) induced proteasome- and caspase-independent protein degradation of karyopherin α1 (KPNA1), the nuclear localization signal receptor for tyrosine-phosphorylated STAT1, but not karyopherin α2, α3, or α4. Finally, we showed that the protease activity of 3C(pro) contributed to the degradation of KPNA1 and thus blocked STAT1/STAT2 nuclear translocation. Taken together, results of our experiments describe for the first time a novel mechanism by which FMDV evolves to inhibit IFN signaling and counteract host innate antiviral responses. IMPORTANCE: We show that 3C(pro) of FMDV antagonizes the JAK-STAT signaling pathway by blocking STAT1/STAT2 nuclear translocation. Furthermore, 3C(pro) induces KPNA1 degradation, which is independent of proteasome and caspase pathways. The protease activity of 3C(pro) contributes to the degradation of KPNA1 and governs the ability of 3C(pro) to inhibit the JAK-STAT signaling pathway. This study uncovers a novel mechanism evolved by FMDV to antagonize host innate immune responses.

Limit of Riemann solutions to the nonsymmetric system of Keyfitz-Kranzer type.

The limit of Riemann solutions to the nonsymmetric system of Keyfitz-Kranzer type with a scaled pressure is considered for both polytropic gas and generalized Chaplygin gas. In the former case, the delta shock wave can be obtained as the limit of shock wave and contact discontinuity when u - > u + and the parameter ϵ tends to zero. The point is, the delta shock wave is not the one of transport equations, which is obviously different from cases of some other systems such as Euler equations or relativistic Euler equations. For the generalized Chaplygin gas, unlike the polytropic or isothermal gas, there exists a certain critical value ϵ 2 depending only on the Riemann initial data, such that when ϵ drops to ϵ 2, the delta shock wave appears as u - > u +, which is actually a delta solution of the same system in one critical case. Then as ϵ becomes smaller and goes to zero at last, the delta shock wave solution is the exact one of transport equations. Furthermore, the vacuum states and contact discontinuities can be obtained as the limit of Riemann solutions when u - < u + and u - = u +, respectively.

Development of a nomogram for membranous nephropathy prediction in patients with primary Sjögren's syndrome: a 6-year retrospective study.

Objectives: Nephritis is a life-threatening complication of primary Sjögren's syndrome (pSS), with membranous nephropathy (MN) being prevalent. Renal biopsy is the gold standard for MN diagnosis, but it is invasive and cannot be repeatedly performed. This study aimed to develop a nomogram for the prediction of MN in patients with pSS. Methods: This retrospective study included patients with pSS admitted to the Rheumatology and Immunology Department of the First Affiliated Hospital of China Medical University between January 2015 and January 2021. A nomogram was developed using multivariable logistic regression analysis and evaluated using receiver operating characteristic (ROC) curve analysis. Bootstrap resampling analysis (1,000 times) was performed to evaluate the nomogram for discrimination and the calibration curve for consistency. Results: A total of 237 patients with pSS [aged 53.00 (44.00, 61.00) years] were included, with 35 pSS-MN patients. Based on clinical practice and multivariable logistic regression analysis, seven variables associated with pSS-MN were selected, including white blood cells, creatine, complement 3, rheumatoid factor, antinuclear antibodies, anti-SSA antibody, and interstitial lung disease. The area under the ROC curve was 0.860 (95% confidence interval: 0.796-0.919), indicating good predictive power. In addition, the nomogram exhibited excellent performance, as demonstrated by the calibration curve and decision curve analysis. Conclusion: This study developed a risk prediction nomogram for MN in patients with pSS, with high predictive power. It may be used to improve the management of patients with pSS.

Hyaluronidase improves the efficacy of nab-paclitaxel after prolonged angiogenesis inhibition in preclinical models for esophagogastric cancer.

BACKGROUND: Long-term anti-angiogenesis leads to pruned vasculature, densely deposited extracellular matrix (ECM), and consequently reduced chemotherapy delivery in esophagogastric cancer (EGC). To address this issue, we evaluated the efficacy of adding a hyaluronidase or a NO-donor to the regimen of chemotherapy and anti-angiogenic drugs. METHODS: A patient-derived EGC xenograft model was developed. Grafted mice were randomly assigned to four experimental groups and one control group. The experimental groups received DC101, a murine angiogenesis inhibitor, and nab-paclitaxel (NPTX), with the addition of hyaluronidase (PEGPH20), or NO-donor (nitroglycerine, NTG), or their combination, respectively. We compared tumor growth during 17 days of treatment. We performed immunohistochemistry for ECM components hyaluronan (HA) and collagen, CD31 for endothelial cells, and γH2AX for DNA damage. The positively stained areas were quantified, and vessel diameters were measured using QuPath software. RESULTS: Prolonged DC101 treatment induced deposition of HA (p<0.01) and collagen (p<0.01). HA was effectively degraded by PEGPH20 (p<0.001), but not by NTG as expected. Both PEGPH20 (p<0.05) and NTG (p<0.01) dilated vessels collapsed in response to long-term DC101 treatment. However, only PEGPH20 (rather than NTG) was found to significantly inhibit tumor growth (p<0.05) in combination with NPTX and DC101. CONCLUSIONS: These findings suggest that the mechanical barrier of HA is the major reason responsible for the resistance developed during prolonged anti-angiogenesis in EGC. Incorporating PEGPH20 into the existing treatment regimen is promising to improve outcomes for patients with EGC.

Marked IDO2 expression and activity related to autophagy and apoptosis in brain tissue of fatal tuberculous meningitis.

In about 1% of tuberculosis (TB) patients, Mycobacterium tuberculosis (M. tuberculosis) can disseminate to the meninges, causing tuberculous meningitis (TBM) with mortality rate up to 60%. Chronic granulomatous inflammation (non-necrotizing and necrotizing) in the brain is the histological hallmark of TBM. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and the generated kynurenine metabolites exert major effector functions relevant to TB granuloma functioning. Here we have assessed immunohistochemically IDO1 expression and activity and its effector function and that of its isoform, IDO2, in post-mortem brain tissue of patients that demised with neurotuberculosis. We also related these findings to brain tissue of fatal/severe COVID-19. In this study, IDO1 and IDO2 were abundantly expressed and active in tuberculoid granulomas and were associated with the presence of M. tuberculosis as well as markers of autophagy and apoptosis. Like in fatal/severe COVID-19, IDO2 was also prominent in specific brain regions, such as the inferior olivary nucleus of medulla oblongata and cerebellum, but not associated with granulomas or with M. tuberculosis. Spatially associated apoptosis was observed in TBM, whereas in fatal COVID-19 autophagy dominated. Together, our findings highlight IDO2 as a potentially relevant effector enzyme in TBM, which may relate to the symptomology of TBM.

The role of TEMRA cell-mediated immune senescence in the development and treatment of HIV disease.

Human Immunodeficiency Virus (HIV) has plagued human society for a long time since its discovery, causing a large number of patients to suffer and costing hundreds of millions of medical services every year. Scientists have found that HIV and antiretroviral therapy accelerate immune aging by inducing mitochondrial dysfunction, and that terminal effector memory T cells (TEMRA cells) are crucial in immune aging. This specific subset of effector memory T cells has terminally differentiated properties and exhibits high cytotoxicity and proinflammatory capacity. We therefore explored and described the interplay between exhaustion features, essential markers, functions, and signaling pathways from previous studies on HIV, antiretroviral therapy, immune senescence, and TEMRA cells. Their remarkable antiviral capacity is then highlighted by elucidating phenotypic changes in TEMRA cells during HIV infection, describing changes in TEMRA cells before, during, and after antiretroviral therapy and other drug treatments. Their critical role in complications and cytomegalovirus (CMV)-HIV superinfection is highlighted. These studies demonstrate that TEMRA cells play a key role in the antiviral response and immune senescence during HIV infection. Finally, we review current therapeutic strategies targeting TEMRA cells that may be clinically beneficial, highlight their potential role in HIV-1 vaccine development, and provide perspectives and predictions for related future applications.

Mechanisms and applications of probiotics in prevention and treatment of swine diseases.

Probiotics can improve animal health by regulating intestinal flora balance, improving the structure of the intestinal mucosa, and enhancing intestinal barrier function. At present, the use of probiotics has been a research hotspot in prevention and treatment of different diseases at home and abroad. This review has summarized the researchers and applications of probiotics in prevention and treatment of swine diseases, and elaborated the relevant mechanisms of probiotics, which aims to provide a reference for probiotics better applications to the prevention and treatment of swine diseases.

Novel p22 and p30 dual-proteins combination based indirect ELISA for detecting antibodies against African swine fever virus.

Introduction: African swine fever virus (ASFV) infection is one of the most complex and fatal hemorrhagic viral diseases, causing a devastating loss to the swine industry. Since no effective vaccine is available, prevention and control of ASFV heavily depends on early diagnostic detection. Methods: In this study, a novel indirect ELISA was established for detecting antibodies against ASFV using dual-proteins, p22 and p30. Recombinants p22 and p30 were expressed and purified from E.coli vector system by recombined plasmids pET-KP177R and pET-CP204L. p22 and p30 were mixed as antigens for developing the indirect ELISA. Results: Through optimizing coating concentrations of p30 and p22, coating ratio (p30: p22 = 1:3), and serum dilution (as 1:600), the established ELISA performed higher specificity, sensitivity, and repeatability against ASFV-positive serum. Furthermore, 184 clinical serum samples from suspected diseased pigs were verified the established ELISA in clinical diagnosis. The results showed that compared with two commercial ELISA kits, the established ELISA possessed higher sensitivity and almost uniform coincidence rate. Conclusion: The novel indirect ELISA based on dual-proteins p30 and p22 performed a valuable role in diagnostic detection of ASFV, providing a broad insight into serological diagnostic methods of ASFV.

Comparison of the cross-protection of PPRSV sublineage 8.7 MLV vaccines against the recombinant NADC30-like strain.

The emergence of recombinant porcine reproductive and respiratory syndrome virus (PRRSV) has caused a substantial threat to the swine industry in recent years. However, the protective efficacy of different sublineage 8.7 PRRSV modified-live virus (MLV) vaccines against emerging strains were still obscure. In this study, a broad epidemiological investigation of PRRSV showed the prevalence of NADC30-like strain increased in Shandong Province, China from 2018 to 2020. Through piglet trial for vaccination and challenge with recombinant NADC30-like SDlz1601 strain, CH-1R MLV vaccine showed better protective effect than JXA1-R and TJM-F92 MLV vaccines in terms of clinical score and pathological observation. Moreover, all three MLV vaccines could reduce virus loads in the serum of piglets. This study provides valuable insights into the prevalence of the NADC30-like strain and the protective effect of PRRS MLV vaccines against recombinant NADC30-like strains, which could help to improve the prevention and control of PRRSV infections.

Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress in post-acute sequelae of SARS-CoV-2 infection.

BACKGROUND: Post-acute sequela of SARS-CoV-2 infection (PASC) encompass fatigue, post-exertional malaise and cognitive problems. The abundant expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase-2 (IDO2) in fatal/severe COVID-19, led us to determine, in an exploratory observational study, whether IDO2 is expressed and active in PASC, and may correlate with pathophysiology. METHODS: Plasma or serum, and peripheral blood mononuclear cells (PBMC) were obtained from well-characterized PASC patients and SARS-CoV-2-infected individuals without PASC. We assessed tryptophan and its degradation products by UPLC-MS/MS. IDO2 activity, its potential consequences, and the involvement of the aryl hydrocarbon receptor (AHR) in IDO2 expression were determined in PBMC from another PASC cohort by immunohistochemistry (IHC) for IDO2, IDO1, AHR, kynurenine metabolites, autophagy, and apoptosis. These PBMC were also analyzed by metabolomics and for mitochondrial functioning by respirometry. IHC was also performed on autopsy brain material from two PASC patients. FINDINGS: IDO2 is expressed and active in PBMC from PASC patients, as well as in brain tissue, long after SARS-CoV-2 infection. This is paralleled by autophagy, and in blood cells by reduced mitochondrial functioning, reduced intracellular levels of amino acids and Krebs cycle-related compounds. IDO2 expression and activity is triggered by SARS-CoV-2-infection, but the severity of SARS-CoV-2-induced pathology appears related to the generated specific kynurenine metabolites. Ex vivo, IDO2 expression and autophagy can be halted by an AHR antagonist. INTERPRETATION: SARS-CoV-2 infection triggers long-lasting IDO2 expression, which can be halted by an AHR antagonist. The specific kynurenine catabolites may relate to SARS-CoV-2-induced symptoms and pathology. FUNDING: None.

Comparative effectiveness of membrane technologies and disinfection methods for virus elimination in water: A review.

The pandemic of the 2019 novel coronavirus disease (COVID-19) has brought viruses into the public horizon. Since viruses can pose a threat to human health in a low concentration range, seeking efficient virus removal methods has been the research hotspots in the past few years. Herein, a total of 1060 research papers were collected from the Web of Science database to identify technological trends as well as the research status. Based on the analysis results, this review elaborates on the state-of-the-art of membrane filtration and disinfection technologies for the treatment of virus-containing wastewater and drinking water. The results evince that membrane and disinfection methods achieve a broad range of virus removal efficiency (0.5-7 log reduction values (LRVs) and 0.09-8 LRVs, respectively) that is attributable to the various interactions between membranes or disinfectants and viruses having different susceptibility in viral capsid protein and nucleic acid. Moreover, this review discusses the related challenges and potential of membrane and disinfection technologies for customized virus removal in order to prevent the dissemination of the waterborne diseases.

N,N'-Bis(4-nitro-phen-yl)biphenyl-2,2'-dicarboxamide.

In the title compound, C(26)H(18)N(4)O(6), the amide units are approximately coplanar with the benzene ring bonded to the N atom [dihedral angles of 10.59 (10) and 24.00 (12)°], but twisted significantly out of the plane of the benzene ring bonded to the carbonyl C atom [dihedral angles of 57.82 (9) and 58.05 (9)°]. The dihedral angle between the two rings of the biphenyl unit is 77.66 (4)°. Intra-molecular N-H⋯O hydrogen bonds and weak C-H⋯O inter-actions occur. The crystal structure is stabilized by inter-molecular N-H⋯O hydrogen bonds and C-H⋯O contacts.

Gold-Catalyzed Synthesis of Icetexane Cores: Short Synthesis of Taxamairin B and Rosmaridiphenol.

We report the short synthesis of two natural products, rosmaridiphenol and taxamairin B, from key intermediates 5a and 5b, which were prepared from enynals 8a and 9b, respectively, by using a gold-catalyzed cyclization reaction. This approach can be widely applied in the synthesis of [6,7,6]-fused tricyclic compounds found in many icetexane diterpenoids.