Humic-like components in dissolved organic matter inhibit cadmium sequestration by sediment.

China's lakes are plagued by cadmium (Cd) pollution. Dissolved organic matter (DOM) significantly regulates Cd(II) transport properties at the sediment-water interface. Understanding the effects of different DOM components on the transportation properties of Cd(II) at the sediment-water interface is essential. In this study, typical DOM from different sources was selected to study Cd(II) mobility at the sediment-water interface. Results showed that terrestrial-derived DOM (fulvic acids, FA) and autochthonous-derived DOM (α-amylase, B1) inhibit Cd(II) sequestration by sediments (42.5% and 5.8%, respectively), while anthropogenic-derived DOM (sodium dodecyl benzene sulfonate, SDBS) increased the Cd(II) adsorption capacity by sediments by 2.8%. Fluorescence quenching coupling with parallel factor analysis (EEM-PARAFAC) was used to characterize different DOM components. The results showed that FA contains three kinds of components (C1, C3: protein-like components, C2: humic-like components); SDBS contains two kinds of components (C1, C2: protein-like components); B1 contains three kinds of components (C1, C2: protein-like components, C3: humic-like components).Three complex reaction models were used to characterize the ability of Cd(II) complex with DOM, and it was found that the humic-like component could hardly be complex with Cd(II). Accordingly, humic-like components compete for Cd(II) adsorption sites on the sediment surface and inhibit Cd(II) adsorption from sediments. Fourier transform infrared spectroscopy (FTIR) of the sediment surface before and after Cd(II) addition was analyzed and proved the competitive adsorption theory. This study provides a better understanding of the Cd(II) mobilization behavior at the sediment-water interface and indicates that the input of humic-like DOM will increase the bioavailability of Cd.

Thermodynamic Entropy-Based Fatigue Life Assessment Method for Nickel-Based Superalloy GH4169 at Elevated Temperature Considering Cyclic Viscoplasticity.

This paper develops a thermodynamic entropy-based life prediction model to estimate the low-cycle fatigue (LCF) life of the nickel-based superalloy GH4169 at elevated temperature (650 °C). The gauge section of the specimen was chosen as the thermodynamic system for modeling entropy generation within the framework of the Chaboche viscoplasticity constitutive theory. Furthermore, an explicitly numerical integration algorithm was compiled to calculate the cyclic stress-strain responses and thermodynamic entropy generation for establishing the framework for fatigue life assessment. A thermodynamic entropy-based life prediction model is proposed with a damage parameter based on entropy generation considering the influence of loading ratio. Fatigue lives for GH4169 at 650 °C under various loading conditions were estimated utilizing the proposed model, and the results showed good consistency with the experimental results. Finally, compared to the existing classical models, such as Manson-Coffin, Ostergren, Walker strain, and SWT, the thermodynamic entropy-based life prediction model provided significantly better life prediction results.

Facilely Modified Nickel-Based Hole Transporting Layers for Organic Solar Cells with 19.12% Efficiency and Enhanced Stability.

Hole transporting layers (HTLs), strategically positioned between electrode and light absorber, play a pivotal role in shaping charge extraction and transport in organic solar cells (OSCs). However, the commonly used poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) HTL, with its hygroscopic and acidic nature, undermines the operational durability of OSC devices. Herein, an environmentally friendly approach is developed utilizing nickel acetate tetrahydrate (NiAc·4H2O) and [2-(9H-carbazol-9-yl)ethyl] phosphonic acid (2PACz) as the NiAc·4H2O/2PACz HTL, aiming at overcoming the limitations posed by the conventional PEDOT:PSS one. Encouragingly, a remarkable power conversion efficiency (PCE) of 19.12% is obtained for the OSCs employing NiAc·4H2O/2PACz as the HTL, surpassing that of devices with the PEDOT:PSS HTL (17.59%), which is ranked among the highest ones of OSCs. This improvement is attributed to the appropriate work function, enhanced hole mobility, facilitated exciton dissociation efficiency, and lower recombination loss of NiAc·4H2O/2PACz-based devices. Furthermore, the NiAc·4H2O/2PACz-based OSCs exhibit superior operational stability compared to their PEDOT:PSS-based counterparts. Of significant note, the NiAc·4H2O/2PACz HTL demonstrates a broad generality, boosting the PCE of the PM6:PY-IT and PM6:Y6-based OSCs from 16.47% and 16.79% (with PEDOT:PSS-based analogs as HTLs) to 17.36% and 17.57%, respectively. These findings underscore the substantial potential of the NiAc·4H2O/2PACz HTL in advancing OSCs, offering improved performance and stability, thereby opening avenue for highly efficient and reliable solar energy harvesting technologies.

Mechanisms of cadmium release from manganese-rich sediments driven by exogenous DOM and the role of microorganisms.

Dissolved organic matter (DOM) is a crucial component of natural sediments that alters Cd sequestration. Nevertheless, how different types of DOM fuel Cd mobilization in Mn-rich sediments has not been elucidated. In the present study, four typical DOM, fluvic acid (FA), bovine serum albumin (BSA), sodium alginate (SA), and sodium dodecyl benzene sulfonate (SDBS), were used to amend Cd-contaminated sediment to study their effects on Cd/Mn biotransformation and microbial community response. The results demonstrated that different DOM drive microbial community shifts and enhance microbially mediated Mn oxide (MnO) reduction and Cd release. The amendment of terrestrial- and anthropogenic-derived DOM (FA and SDBS) mainly contributed to enriching Mn-reducing bacteria phylum Proteobacteria, and its abundance increased by 38.16-74.47 % and 56.41-73.98 %, respectively. Meanwhile, microbial-derived DOM (BSA and SA) mainly stimulated the abundances of metal(loid)-resistant bacteria phylum Firmicutes. Accompanied by microbial community structure, diversity, and co-occurrence network shifts, the DOM concentration and oxidation-reduction potential changed, resulting in enhanced Cd mobilization. Importantly, FA stimulated Cd release most remarkably, probably because of the decreased cooperative interactions between bacterial populations, stronger reduction of MnOs, and higher aromaticity and hydrophobicity of the sediment DOM after amendment. This study linked DOM types to functional microbial communities, and explored the potential roles of different DOM types in Cd biotransformation in lake sediments.

MiR-22 inhibits myocardial fibrosis in rats with myocardial infarction by targeting PTEN/Akt/mTOR signaling pathway.

This study aimed to evaluate the effects of miR-22 on myocardial fibrosis in rats with myocardial infarction (MI) and to further explore the possible underlying mechanism. A total of 80 rats were randomly divided into Sham group, miR-22 overexpression group, MI group or MI + miR-22 overexpression group. Reverse transcription-polymerase chain reaction (RT-PCR) results showed that compared with Sham group, miR-22 expression level in myocardial tissues of rats decreased significantly in MI group. Overexpression of miR-22 could remarkably relieve cardiac insufficiency in MI rats, increase EF% and FS%, and reduce collagen deposition and the mRNA expression level of fibrosis-promoting genes in myocardial tissues of MI rats. The cross-sectional area of myocardial cells in MI + miR-22 mimic group was smaller than that in MI group. According to the results of immunohistochemical staining, overexpression of miR-22 notably reduced the level of oxidative stress marker 4-HNE in myocardial tissues of MI rats. Meanwhile, myocardial cells in MI + miR-22 mimic group exhibited a prominently lower apoptosis rate than those in MI group. Furthermore, Western blotting results demonstrated that overexpression of miR-22 inhibited the activation of the phosphatase and tensin homolog deleted on chromosome ten (PTEN)/Akt/mTOR signaling pathway in myocardial tissues of MI rats. The inhibitory effects of miR-22 on myocardial fibrosis and hypertrophy after MI in rats may be related to its inhibition on the PTEN/Akt/mTOR signaling pathway. All our findings suggested that miR-22 is expected to become a targeted drug for the clinical treatment of MI.

Acute hospitalizations after proton therapy versus intensity-modulated radiotherapy for locally advanced non-small cell lung cancer in the durvalumab era.

INTRODUCTION: It was hypothesized that use of proton beam therapy (PBT) in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiation and consolidative immune checkpoint inhibition is associated with fewer unplanned hospitalizations compared with intensity-modulated radiotherapy (IMRT). METHODS: Patients with locally advanced non-small cell lung cancer treated between October 2017 and December 2021 with concurrent chemoradiation with either IMRT or PBT ± consolidative immune checkpoint inhibition were retrospectively identified. Logistic regression was used to assess the association of radiation therapy technique with 90-day hospitalization and grade 3 (G3+) lymphopenia. Competing risk regression was used to compare G3+ pneumonitis, G3+ esophagitis, and G3+ cardiac events. Kaplan-Meier method was used for progression-free survival and overall survival. Inverse probability treatment weighting was applied to adjust for differences in PBT and IMRT groups. RESULTS: Of 316 patients, 117 (37%) received PBT and 199 (63%) received IMRT. The PBT group was older (p < .001) and had higher Charlson Comorbidity Index scores (p = .02). The PBT group received a lower mean heart dose (p < .0001), left anterior descending artery V15 Gy (p = .001), mean lung dose (p = .008), and effective dose to immune circulating cells (p < .001). On inverse probability treatment weighting analysis, PBT was associated with fewer unplanned hospitalizations (adjusted odds ratio, 0.55; 95% CI, 0.38-0.81; p = .002) and less G3+ lymphopenia (adjusted odds ratio, 0.55; 95% CI, 0.37-0.81; p = .003). There was no difference in other G3+ toxicities, progression-free survival, or overall survival. CONCLUSIONS: PBT is associated with fewer unplanned hospitalizations, lower effective dose to immune circulating cells and less G3+ lymphopenia compared with IMRT. Minimizing dose to lymphocytes may be warranted, but prospective data are needed.

Pneumonitis Rates Before and After Adoption of Immunotherapy Consolidation in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiation.

PURPOSE: We hypothesized that after adoption of immune checkpoint inhibitor (ICI) consolidation for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy (cCRT), rates of symptomatic pneumonitis would increase, thereby supporting efforts to reduce lung radiation dose. METHODS AND MATERIALS: This single institution, multisite retrospective study included 783 patients with LA-NSCLC treated with definitive cCRT either before introduction of ICI consolidation (pre-ICI era cohort [January 2011-September 2017]; N = 448) or afterward (ICI era cohort [October 2017-December 2021]; N = 335). Primary endpoint was grade ≥2 pneumonitis (G2P) and secondary endpoint was grade ≥3 pneumonitis (G3P), per Common Terminology Criteria for Adverse Events v5.0. Pneumonitis was compared between pre-ICI era and ICI era cohorts using the cumulative incidence function and Gray's test. Inverse probability of treatment weighting (IPTW)-adjusted Fine-Gray models were generated. Logistic models were developed to predict the 1-year probability of G2P as a function of lung dosimetry. RESULTS: G2P was higher in the ICI era than in the pre-ICI era (1-year cumulative incidence 31.4% vs 20.1%; P < .001; IPTW-adjusted multivariable subdistribution hazard ratio, 2.03; 95% confidence interval, 1.53-2.70; P < .001). There was no significant interaction between ICI era treatment and either lung volume receiving ≥20 Gy (V20) or mean lung dose in Fine-Gray regression for G2P; however, the predicted probability of G2P was higher in the ICI era at clinically relevant values of lung V20 (≥24%) and mean lung dose (≥14 Gy). Cut-point analysis revealed a lung V20 threshold of 28% in the ICI era (1-year G2P rate 46.0% above vs 19.8% below; P < .001). Among patients receiving ICI consolidation, lung V5 was not associated with G2P. G3P was not higher in the ICI era (1-year cumulative incidence 7.5% vs 6.0%; P = .39; IPTW-adjusted multivariable subdistribution hazard ratio, 1.12; 95% confidence interval, 0.63-2.01; P = .70). CONCLUSIONS: In patients with LA-NSCLC treated with cCRT, the adoption of ICI consolidation was associated with an increase in G2P but not G3P. With ICI consolidation, stricter lung dose constraints may be warranted.

Patterns of Failure, Low-Volume Relapse, and Subsequent Ablative Management in Locally Advanced Non-Small Cell Lung Cancer Treated With Definitive Chemoradiation and Consolidation Immune Checkpoint Inhibitors.

PURPOSE: The objective of this study was to describe the patterns of failure, frequency of low-volume relapse (LVR), and candidacy for ablative therapy at time of disease progression (PD) after chemoradiation and consolidative immunotherapy (CRT + ICI) in patients with stage III non-small cell lung cancer. METHODS AND MATERIALS: We identified 229 consecutive patients with stage III non-small cell lung cancer treated with CRT + ICI between October 2017 and December 2021 at a single institution. PD was classified as isolated locoregional failure (LRF), isolated distant failure (DF), or synchronous LRF + DF. Any LRF was subclassified as in-field failure, marginal failure, or out-of-field failure. LVR was defined as 3 or fewer sites of PD in any number of organs. Ablative candidates were defined as having 5 or fewer sites of PD radiographically amenable to high-dose radiation or surgery. Time-to-event data were calculated using cumulative incidence analysis and Kaplan-Meier methods. Multivariable Cox modeling was used to examine the correlations between characteristics of relapse and postprogression survival. RESULTS: Of the 229 patients, 119 (52%) had PD. Of these 119 patients, 20 (21%) had isolated LRF, 28 (24%) had synchronous LRF + DF, and 71 (60%) had isolated DF. Of the 48 patients with any LRF, 28 (58%) had in-field failure, 10 (21%) marginal failure, and 10 (21%) out-of-field failure. The cumulative incidence of LRF and DF was 13% (95% CI, 9.2%-18%) and 32% (95% CI, 26%-38%) at 1 year and 19% (95% CI, 14%-24%) and 39% (95% CI, 33%-46%) at 2 years, respectively. Overall, 64 patients (54%) were considered to have LVR. At time of PD, 60 patients (50%) were eligible for ablative therapy. Patients with LVR had longer median survival versus with high-volume relapse (37.4 vs 15.2 months, P < .001). On multivariable analysis, LVR (hazard ratio, 0.32; 95% CI, 0.18-0.56; P < .001) was associated with improved postprogression survival. CONCLUSIONS: After CRT + ICI, approximately half of patients experience LVR at time of PD and are candidates for ablative therapies. Prospective trials are needed to validate the optimal treatment strategy for LVR.

Cardiac radiation dose is associated with inferior survival but not cardiac events in patients with locally advanced non-small cell lung cancer in the era of immune checkpoint inhibitor consolidation.

PURPOSE: We assessed the association of cardiac radiation dose with cardiac events and survival post-chemoradiation therapy (CRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) after adoption of modern radiation therapy (RT) techniques, stricter cardiac dose constraints, and immune checkpoint inhibitor (ICI) consolidation. METHODS AND MATERIALS: This single-institution, multi-site retrospective study included 335 patients with LA-NSCLC treated with definitive, concurrent CRT between October 2017 and December 2021. All patients were evaluated for ICI consolidation. Planning dose constraints included heart mean dose < 20 Gy (<10 Gy if feasible) and heart volume receiving ≥ 50 Gy (V50Gy) < 25 %. Twenty-one dosimetric parameters for three different cardiac structures (heart, left anterior descending coronary artery [LAD], and left ventricle) were extracted. Primary endpoint was any major adverse cardiac event (MACE) post-CRT, defined as acute coronary syndrome, heart failure, coronary revascularization, or cardiac-related death. Secondary endpoints were: grade ≥ 3 cardiac events (per CTCAE v5.0), overall survival (OS), lung cancer-specific mortality (LCSM), and other-cause mortality (OCM). RESULTS: Median age was 68 years, 139 (41 %) had baseline coronary heart disease, and 225 (67 %) received ICI consolidation. Proton therapy was used in 117 (35 %) and intensity-modulated RT in 199 (59 %). Median LAD V15Gy was 1.4 % (IQR 0-22) and median heart mean dose was 8.7 Gy (IQR 4.6-14.4). Median follow-up was 3.3 years. Two-year cumulative incidence of MACE was 9.5 % for all patients and 14.3 % for those with baseline coronary heart disease. Two-year cumulative incidence of grade ≥ 3 cardiac events was 20.4 %. No cardiac dosimetric parameter was associated with an increased risk of MACE or grade ≥ 3 cardiac events. On multivariable analysis, cardiac dose (LAD V15Gy and heart mean dose) was associated with worse OS, driven by an association with LCSM but not OCM. CONCLUSIONS: With modern RT techniques, stricter cardiac dose constraints, and ICI consolidation, cardiac dose was associated with LCSM but not OCM or cardiac events in patients with LA-NSCLC.

The effective radiation dose to immune cells predicts lymphopenia and inferior cancer control in locally advanced NSCLC.

PURPOSE: To explore the association of the effective dose to immune cells (EDIC) with disease control, lymphopenia, and toxicity in patients with non-small cell lung cancer (NSCLC) and identify methods to reduce EDIC. METHODS: We abstracted data from all patients with locally advanced NSCLC treated with chemoradiation with or without consolidative immunotherapy over a ten-year period. Associations between EDIC and progression-free survival (PFS) and overall survival (OS) were modeled with Cox proportional hazards and Kaplan-Meier method. Logistic regression was used to model predictors of lymphopenia and higher EDIC. Analyses were performed with EDIC as a continuous and categorical variable. Lymphopenia was graded per CTCAE v5.0. RESULTS: Overall, 786 patients were included (228 of which received consolidative immunotherapy); median EDIC was 4.7 Gy. Patients with EDIC < 4.7 Gy had a longer median PFS (15.3 vs. 9.0 months; p < 0.001) and OS (34.2 vs. 22.4 months; p < 0.001). On multivariable modeling, EDIC correlated with inferior PFS (HR 1.08, 95 % CI 1.01-1.14, p = 0.014) and OS (HR 1.10, 95 % CI 1.04-1.18, p = 0.002). EDIC was predictive of grade 4 lymphopenia (OR 1.16, 95 % CI 1.02-1.33, p = 0.026). EDIC ≥ 4.7 Gy was associated with increased grade 2 + pneumonitis (6-month incidence: 26 % vs 20 %, p = 0.04) and unplanned hospitalizations (90-day incidence: 40 % vs 30 %, p = 0.002). Compared to protons, photon therapy was associated with EDIC ≥ 4.7 Gy (OR 5.26, 95 % CI 3.71-7.69, p < 0.001) in multivariable modeling. CONCLUSIONS: EDIC is associated with inferior disease outcomes, treatment-related toxicity, and the development of severe lymphopenia. Proton therapy is associated with lower EDIC. Further investigations to limit radiation dose to the immune system appear warranted.

Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling.

Ulcerative colitis (UC) is an inflammatory bowel disease and associated with metabolic imbalance. Luteolin (LUT) reportedly exhibits anti-inflammatory activity. However, its regulatory effects on metabolites remain indistinct. Here, the effects of LUT on immune response and oxidative stress in UC were determined. Serum metabolomics profiles of UC rats treated with LUT were obtained utilizing liquid chromatography-mass spectrometry. The results revealed that LUT treatment alleviated colon tissue injury, colon shortening, weight loss, and inflammatory response in UC rats. Additionally, the levels of superoxide dismutase and total antioxidant capacity were elevated, but malondialdehyde content was reduced in serum of UC rats, while these changes were abrogated by LUT. Metabolomics analysis unveiled that l-malic acid, creatinine, l-glutamine, and l-lactic acid levels were remarkably decreased, while dimethyl sulfone, 5-methylcytosine, cysteine-S-sulfate, and jasmonic acid levels were notably increased after LUT treatment. Furthermore, differential metabolites primarily participated in d-glutamine and d-glutamate metabolism, glutathione metabolism, and citrate cycle pathways. In summary, these results demonstrated that LUT improved immune response, alleviated oxidative stress, and altered metabolites in UC rats. This study lays the root for further exploring the mechanism of LUT in the treatment of UC.

Manganese oxides mediated dissolve organic matter compositional changes in lake sediment and cadmium binding characteristics.

In sediment environments, manganese (Mn) minerals have high dissolved organic matter (DOM) affinities, and could regulate the changes of DOM constituents and reactivity by fractionation. However, the effects of DOM fractionation by Mn minerals on the contaminant behaviors remain unclear. Herein, the transformations of mineral phases, DOM properties, and Cd(II) binding characteristics to sediment DOM before and after adsorption by four Mn oxides (δ-MnO2, ß-MnO2, γ-MnOOH, and Mn3O4) were investigated using multi-spectroscopic tools. Results showed a subtle structural variation of Mn oxides in response to DOM reduction, and no phase transformations were observed. Two-dimensional correlation spectroscopy based on synchronous fluorescence spectra and Fourier transform infrared spectroscopy indicated that tryptophan-like substances and the amide (II) N-H groups could preferentially interact with Cd(II) for the original DOM. Nevertheless, preferential bonding of Cd(II) to tyrosine-like substances and phenolic OH groups was exhibited after fractionations by Mn oxides. Furthermore, the binding stability and capacity of each DOM fraction to Cd(II) were decreased after fractionation based on the modified Stern-Volmer equation. These differences may be attributed to DOM molecules with high aromaticity, hydrophobicity, molecular weight, and amounts of O/N-containing group were preferentially removed by Mn oxides. Overall, the environmental hazard of Cd will be more severe after DOM fractionation on Mn minerals. This study facilitates a better understanding of the Cd geochemical cycle in lake sediments under the DOM-mineral interactions, and recommends being careful with outbreaks of aquatic Cd pollution when sediments are rich in dissolved protein-like components and Mn minerals.

Biological and Immunological Characterization of a Functional L-HN Derivative of Botulinum Neurotoxin Serotype F.

Botulinum neurotoxins (BoNTs) can cause nerve paralysis syndrome in mammals and other vertebrates. BoNTs are the most toxic biotoxins known and are classified as Class A biological warfare agents. BoNTs are mainly divided into seven serotypes A-G and new neurotoxins BoNT/H and BoNT/X, which have similar functions. BoNT proteins are 150 kDa polypeptide consisting of two chains and three domains: the light chain (L, catalytic domain, 50 kDa) and the heavy chain (H, 100 kDa), which can be divided into an N-terminal membrane translocation domain (HN, 50 kDa) and a C-terminal receptor binding domain (Hc, 50 kDa). In current study, we explored the immunoprotective efficacy of each functional molecule of BoNT/F and the biological characteristics of the light chain-heavy N-terminal domain (FL-HN). The two structure forms of FL-HN (i.e., FL-HN-SC: single chain FL-HN and FL-HN-DC: di-chain FL-HN) were developed and identified. FL-HN-SC could cleave the vesicle associated membrane protein 2 (VAMP2) substrate protein in vitro as FL-HN-DC or FL. While only FL-HN-DC had neurotoxicity and could enter neuro-2a cells to cleave VAMP2. Our results showed that the FL-HN-SC had a better immune protection effect than the Hc of BoNT/F (FHc), which indicated that L-HN-SC, as an antigen, provided the strongest protective effects against BoNT/F among all the tested functional molecules. Further in-depth research on the different molecular forms of FL-HN suggested that there were some important antibody epitopes at the L-HN junction of BoNT/F. Thus, FL-HN-SC could be used as a subunit vaccine to replace the FHc subunit vaccine and/or toxoid vaccine, and to develop antibody immune molecules targeting L and HN domains rather than the FHc domain. FL-HN-DC could be used as a new functional molecule to evaluate and explore the structure and activity of toxin molecules. Further exploration of the biological activity and molecular mechanism of the functional FL-HN or BoNT/F is warranted.

Epstein-Barr virus envelope glycoprotein 110 inhibits NF-κB activation by interacting with NF-κB subunit p65.

Epstein-Barr virus (EBV) is a member of the lymphotropic virus family and is highly correlated with some human malignant tumors. It has been reported that envelope glycoprotein 110 (gp110) plays an essential role in viral fusion, DNA replication, and nucleocapsid assembly of EBV. However, it has not been established whether gp110 is involved in regulating the host's innate immunity. In this study, we found that gp110 inhibits tumor necrosis factor α-mediated NF- κB promoter activity and the downstream production of NF- κB-regulated cytokines under physiological conditions. Using dual-luciferase reporter assays, we showed that gp110 might impede the NF-κB promoter activation downstream of NF-κB transactivational subunit p65. Subsequently, we used coimmunoprecipitation assays to demonstrate that gp110 interacts with p65 during EBV lytic infection, and that the C-terminal cytoplasmic region of gp110 is the key interaction domain with p65. Furthermore, we determined that gp110 can bind to the N-terminal Rel homologous and C-terminal domains of p65. Alternatively, gp110 might not disturb the association of p65 with nontransactivational subunit p50, but we showed it restrains activational phosphorylation (at Ser536) and nuclear translocation of p65, which we also found to be executed by the C-terminal cytoplasmic region of gp110. Altogether, these data suggest that the surface protein gp110 may be a vital component for EBV to antagonize the host's innate immune response, which is also helpful for revealing the infectivity and pathogenesis of EBV.

Sex differences in global disability-adjusted life years due to ischemic stroke: findings from global burden of diseases study 2019.

To investigate the sex differences in disability-adjusted life years (DALYs) due to ischemic stroke (IS) by year, location and age. We extracted sex-specific data on DALYs number, age-standardized DALYs rate (ASDR) and all-age DALYs rate of IS by year, location and age from the Global Burden of Diseases study 2019. The estimated annual percentage changes (EAPC) were calculated to evaluate the temporal trend of ASDR. For both sexes, although the ASDR of IS slightly decreased from 1990 to 2019, there has been an 60.3% increase in DALYs number worldwide. Sex difference in DALYs number (men minus women) decreased from - 2.83 million in 1990 to 0.14 million in 2019, while the men to women's ASDR ratio slightly increased from 1.10 in 1990 to 1.21 in 2019. The sex differences in IS DALYs showed remarkable regional variation. The largest sex differences in DALYs number and ASDR were in China and Vietnam. Middle-aged men had a higher IS DALYs than their age-matched counterparts. High systolic blood pressure accounted for the highest DALYs number in 2019, but the top three attributable risk factors that had the greatest sex differences were tobacco, dietary risk, and alcohol use. Sex differences in IS DALYs varied by year, location and age, mostly attributed to the disproportion of cardiovascular risk factors between sexes. Considering the population growth and aging, it is necessary to monitor the sex difference in IS DALYs in different populations and thus provide evidence for local administration to improve current preventive and management strategies of IS.

The Molecular Mechanism of Herpes Simplex Virus 1 UL31 in Antagonizing the Activity of IFN-ß.

Virus infection triggers intricate signal cascade reactions to activate the host innate immunity, which leads to the production of type I interferon (IFN-I). Herpes simplex virus 1 (HSV-1), a human-restricted pathogen, is capable of encoding over 80 viral proteins, and several of them are involved in immune evasion to resist the host antiviral response through the IFN-I signaling pathway. Here, we determined that HSV-1 UL31, which is associated with nuclear matrix and is essential for the formation of viral nuclear egress complex, could inhibit retinoic acid-inducible gene I (RIG-I)-like receptor pathway-mediated interferon beta (IFN-ß)-luciferase (Luc) and (PRDIII-I)4-Luc (an expression plasmid of IFN-ß positive regulatory elements III and I) promoter activation, as well as the mRNA transcription of IFN-ß and downstream interferon-stimulated genes (ISGs), such as ISG15, ISG54, ISG56, etc., to promote viral infection. UL31 was shown to restrain IFN-ß activation at the interferon regulatory factor 3 (IRF3)/IRF7 level. Mechanically, UL31 was demonstrated to interact with TANK binding kinase 1 (TBK1), inducible IκB kinase (IKKi), and IRF3 to impede the formation of the IKKi-IRF3 complex but not the formation of the IRF7-related complex. UL31 could constrain the dimerization and nuclear translocation of IRF3. Although UL31 was associated with the CREB binding protein (CBP)/p300 coactivators, it could not efficiently hamper the formation of the CBP/p300-IRF3 complex. In addition, UL31 could facilitate the degradation of IKKi and IRF3 by mediating their K48-linked polyubiquitination. Taken together, these results illustrated that UL31 was able to suppress IFN-ß activity by inhibiting the activation of IKKi and IRF3, which may contribute to the knowledge of a new immune evasion mechanism during HSV-1 infection. IMPORTANCE The innate immune system is the first line of host defense against the invasion of pathogens. Among its mechanisms, IFN-I is an essential cytokine in the antiviral response, which can help the host eliminate a virus. HSV-1 is a double-stranded DNA virus that can cause herpes and establish a lifelong latent infection, due to its possession of multiple mechanisms to escape host innate immunity. In this study, we illustrate for the first time that the HSV-1-encoded UL31 protein has a negative regulatory effect on IFN-ß production by blocking the dimerization and nuclear translocation of IRF3, as well as promoting the K48-linked polyubiquitination and degradation of both IKKi and IRF3. This study may be helpful for fully understanding the pathogenesis of HSV-1.

Traditional Chinese medicine for precancerous lesions of gastric cancer: A review.

Gastric cancer (GC) is the fifth most common type of cancer and the third leading cause of death due to cancer worldwide. The gastric mucosa often undergoes many years of precancerous lesions of gastric cancer (PLGC) stages before progressing to gastric malignancy. Unfortunately, there are no effective Western drugs for patients with PLGC. In recent years, traditional Chinese medicine (TCM) has been proven effective in treating PLGC. Classical TCM formulas and chemical components isolated from some Chinese herbal medicines have been administered to treat PLGC, and the main advantage is their comprehensive intervention with multiple approaches and multiple targets. In this review, we focus on recent studies using TCM treatment for PLGC, including clinical observations and experimental research, with a focus on targets and mechanisms of drugs. This review provides some ideas and a theoretical basis for applying TCM to treat PLGC and prevent GC.

Subcellular Localization of Epstein-Barr Virus BLLF2 and Its Underlying Mechanisms.

Epstein-Barr virus (EBV), the pathogen of several human malignancies, encodes many proteins required to be transported into the nucleus for viral DNA reproduction and nucleocapsids assembly in the lytic replication cycle. Here, fluorescence microscope, mutation analysis, interspecies heterokaryon assays, co-immunoprecipitation assay, RNA interference, and Western blot were performed to explore the nuclear import mechanism of EBV encoded BLLF2 protein. BLLF2 was shown to be a nucleocytoplasmic shuttling protein neither by a chromosomal region maintenance 1 (CRM1)- nor by a transporter associated with antigen processing (TAP)-dependent pathway. Yet, BLLF2's two functional nuclear localization signals (NLSs), NLS1 (16KRQALETVPHPQNRGR31) and NLS2 (44RRPRPPVAKRRRFPR58), were identified, whereas the predicted NES was nonfunctional. Finally, BLLF2 was proven to transport into the nucleus via a Ran-dependent and importin ß1-dependent pathway. This mechanism may contribute to a more extensive insight into the assembly and synthesis of EBV virions in the nucleus, thus affording a new direction for the treatment of viruses.

Association Between the Concentration and Rangeability of Cystatin C and Mortality of COVID-19 Patients With or Without Type 2 Diabetes Mellitus: A Retrospective Analysis.

Background: We investigated if the concentration and "rangeability" of cystatin C (CysC) influenced the prognosis of coronavirus disease 2019 (COVID-19) in patients suffering from, or not suffering from, type 2 diabetes mellitus (T2DM). Methods: A total of 675 T2DM patients and 572 non-T2DM patients were divided into "low" and "high" CysC groups and low and high CysC-rangeability groups according to serum CysC level and range of change of CysC level, respectively. Demographic characteristics, clinical data, and laboratory results of the four groups were analyzed. Results: COVID-19 patients with a high level and rangeability of CysC had more organ damage and a higher risk of death compared with those with a low level or low rangeability of CysC. Patients with a higher level and rangeability of CysC had more blood lymphocytes and higher levels of C-reactive protein, alanine aminotransferase, and aspartate aminotransferase. After adjustment for possible confounders, multivariate analysis revealed that CysC >0.93 mg/dL was significantly associated with the risk of heart failure (OR = 2.231, 95% CI: 1.125-5.312) and all-cause death (2.694, 1.161-6.252). CysC rangeability >0 was significantly associated with all-cause death (OR = 4.217, 95% CI: 1.953-9.106). These associations were stronger in patients suffering from T2DM than in those not suffering from T2DM. Conclusions: The level and rangeability of CysC may influence the prognosis of COVID-19. Special care and appropriate intervention should be undertaken in COVID-19 patients with an increased CysC level during hospitalization and follow-up, especially for those with T2DM.

Luteolin alleviates ulcerative colitis through SHP-1/STAT3 pathway.

BACKGROUND: Previous studies have demonstrated that Luteolin has a positive effect on epithelial barrier integrity by promoting the function of tight protein, however, little is known about the underline mechanism of Luteolin. In this study, we constructed Caco-2 cell monolayer to explore the effects and the regulation mechanism of Luteolin in intestinal epithelial barrier integrity. METHODS: Caco-2 cells were co-treated with TNF-α, Interferon-γ (IFN-γ) and Luteolin for 24 h. Overexpression or knockdown of SHP-1 was applied to study the effects of protein phosphoserine phosphatase-1 (SHP-1) on epithelial barrier integrity. Cell viability was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Barrier function was detected by trans-epithelial electrical resistance (TEER) and FITC-dextran assay. The expression levels of SHP-1, phosphorylation signal transducer and activator of transcription 3 (p-STAT3), STAT3 and tight junction proteins were measured by qRT-PCR or western blot. In vivo model of ulcerative colitis was established to detect the function of Luteolin in ulcerative colitis. RESULTS: We clarified that Luteolin protected intestinal epithelial barrier function of Caco-2 monolayers by increasing the resistance values and tight junction (TJ) protein expression. The expression of OCLN, CLDN1, and ZO1 was increased by Luteolin, while the expression of CLDN2 was decreased. Furthermore, Luteolin significantly alleviated the symptom of ulcerative colitis in DSS-induced mice. The in vitro cell model proved that overexpression of SHP-1 promotes the epithelial barrier function and knockdown of SHP-1 or STAT3 activation destroyed the protective effects of Luteolin on the expression of TJ proteins. CONCLUSION: We found that the treatment of Luteolin promoted epithelial barrier function and Luteolin might preserve intestinal epithelial barrier function through suppression of STAT3 signaling pathway by SHP-1.