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Mycoplasma gallisepticum (MG) is the main pathogen of chronic respiratory disease (CRD), an infectious disease in chickens with high morbidity. Exosomal miRNAs are emerging as important regulators in host immune response to microbial invasion. Previously, we found that gga-miR-193a was significantly up-regulated in exosomes from MG-infected primary chicken type II pneumocytes (CP-IIs). Therefore, the purpose of this study was to investigate the role of exosomal gga-miR-193a in MG infection. Exosomes were isolated and identified via ultracentrifugation, transmission electron microscopy, and nanoparticle-tracking analysis. Real-time quantitative PCR and Western blot were used to detect the gene expression. Enzyme-linked immunosorbent assay was used to examine the levels of the inflammatory cytokines. CCK-8 and flow cytometry assays were applied to analyze the cell functions. The results showed that MG infection induced high expression of gga-miR-193a in exosomes from CP-IIs. Moreover, exosomes secreted by MG-infected CP-IIs could selectively transport gga-miR-193a into DF-1 cells. Exosomal gga-miR-193a internalized by DF-1 cells inhibited cell proliferation, promoted apoptosis, and increased interleukin-1β and tumor necrosis factor-α secretions by targeting the RAS/ERK signaling pathway. These results suggest that MG induced the secretion of gga-miR-193a by exosomes to damage the life activities of normal cells, which partially interpreted the mechanism of MG establishing systemic chronic infection in the body.

Flue-cured tobacco (Nicotiana tabacum L.) is a major cash crop in Yunnan, China, and the yield, chemical components, and their proportions decide the quality of tobacco leaves. To understand the effects of environmental factors (soil and climatic factors) on the yield and quality of flue-cured tobacco and determine the main regulating factors, we selected three flue-cured tobacco cultivars [K326, Yunyan87 (Yun87), and Honghuadajinyuan (Hongda)] grown in the Honghe Tobacco Zone. Indices related to yield and economic traits, chemical component properties, soil physical and chemical properties, and climatic factors at different planting sites, were evaluated. We used variance analysis, correlation analysis, and redundancy analysis (RDA) in this study. The results showed that the yield and chemical component properties of flue-cured tobacco, except for the number of left leaves and plant total sugar (PTS) content, were significantly correlated with climatic factors. Particularly, the yield increased in drier and sunnier weather. In terms of the carbon supply capacity, PTS, petroleum ether (PPE), and starch contents (PS) were higher under high-altitude and high-latitude climatic conditions, whereas for the nitrogen supply capacity, plant nitrogen (PTN) and nicotine (PN) contents improved under low-altitude and low-latitude climatic conditions. PTS, reducing sugar (PRS), potassium (PTK), chlorine (PCL), and PPE contents were negatively related to soil clay content, soil pH, and soil organic matter, whereas PRS and PTK contents were positively correlated with alkali-hydrolyzed nitrogen (AN). According to RDA, the soil clay, AN, available phosphorus (AP), and soil chlorine content (SCL) strongly affected the quality of flue-cured tobacco. The quality of the K326 and Yun87 cultivars was mostly influenced by moisture, whereas the quality of the Hongda cultivar was mostly affected by temperature. In conclusion, compared with soil properties, climatic factors more significantly affect the yield and quality of Honghe flue-cured tobacco leaves.

In the early stage of virus infection, the pattern recognition receptor (PRR) signaling pathway of the host cell is activated to induce interferon production, activating interferon-stimulated genes (ISGs) that encode antiviral proteins that exert antiviral effects. Viperin is one of the innate antiviral proteins that exert broad-spectrum antiviral effects by various mechanisms. Porcine epidemic diarrhea virus (PEDV) is a coronavirus that causes huge losses to the pig industry. Research on early antiviral responses in the gastrointestinal tract is essential for developing strategies to prevent the spread of PEDV. In this study, we investigated the mechanisms of viperin in PEDV-infected IPEJ-C2 cells. Increased expression of interferon and viperin and decreased replication of PEDV with a clear reduction in the viral load were observed in PEDV-infected IPEC-J2 cells. Amino acids 1–50 of porcine viperin contain an endoplasmic reticulum signal sequence that allows viperin to be anchored to the endoplasmic reticulum and are necessary for its function in inhibiting PEDV proliferation. The interaction of the viperin S-adenosylmethionine domain with the N protein of PEDV was confirmed via confocal laser scanning microscopy and co-immunoprecipitation. This interaction might interfere with viral replication or assembly to reduce virus proliferation. Our results highlight a potential mechanism whereby viperin is able to inhibit PEDV replication and play an antiviral role in innate immunity.

Cells recognize virus nucleic acid by pattern recognition receptors (PRRs), virus involve in the activation of signaling cascade of variable adaptor proteins, TANK-binding kinase1(TBK1)/ inhibitor of nuclear factor kappa-B kinase subunit epsilon(IKKi) complex, IκB kinase(IKKs) to trigger activation of transcription factor, interferon regulatory factor 3/7(IRF3/7), ultimately, leading to the production of type I interferon and exert anti-viral effects. In this study, E3 ubiquitin ligase ankyrin repeat and SOCS box-containing 8(ASB8) interacted with TBK1/IKKi and phosphorylation modification of ASB8 at site of Ser17 to further strengthen its ubiquitination activity were verified. Conversely, phosphorylated ASB8 accelerate K48-linked ubiquitination and degradation of TBK1/IKKi, which further reduces phosphorylation level of IRF3 and inhibits production of IFN-β. At the same time, a new bridge molecule Leucine-rich repeat containing protein 10B(LRRC10B) upregulated after viral infection are involved in the formation and interaction with ASB8-TBK1/IKKi complex was reported. Our study reveals a new mechanism of ubiquitin ligase ASB8 modulating antiviral innate immunity by altering stability of TBK1/IKKi kinase complex.

The lateral hypothalamus (LH) is physiologically critical in brain functions. The LH also plays an important role in drug addiction. However, neural circuits underlying LH involvement of drug addiction remain obscure. In the present study,our results showed that in male mice, during context-induced expression of morphine withdrawal memory, LH glutamatergic neurons played an important role; dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) projecting from the core of nucleus accumbens (NAcC) to the LH were an important upstream circuit to activate LH glutamatergic neurons; D1-MSNs projecting from the NAcC to the LH activated LH glutamatergic neurons through inhibiting LH local gamma-aminobutyric acid (GABA) neurons. These results suggest that disinhibited LH glutamatergic neurons by neural circuits from the NAcC importantly contribute to context-induced the expression of morphine withdrawal memory.

Environmental estrogen contamination poses severe threat to wildlife and human. Biodegradation is an efficient strategy to remove the wide-spread natural estrogen, while strains suitable for hostile environments and fit for practical application are rare. In this work, Microbacterium hominis SJTG1 was isolated and identified with high degrading efficiency for 17β-estradiol (E2) and great environment fitness. It could degrade nearly 100% of 10 mg/L E2 in minimal medium in 6 days, and remove 93% of 1 mg/L E2 and 74% of 10 mg/L E2 in the simulated E2-polluted solid soil in 10 days. It maintained stable E2-degrading efficiency in various harsh conditions like non-neutral pH, high salinity, stress of heavy metals and surfactants. Genome mining and comparative genome analysis revealed that there are multiple genes potentially associated with steroid degradation in strain SJTG1. One 3β/17β-hydroxysteroid dehydrogenase HSD-G129 induced by E2 catalyzed the 3β/17β-dehydrogenation of E2 and other steroids efficiently. The transcription of hsd-G129 gene was negatively regulated by the adjacent LysR-type transcriptional regulator LysR-G128, through specific binding to the conserved site. E2 can release this binding and initiate the degradation process. This work provides an efficient and adaptive E2-degrading strain and promotes the biodegrading mechanism study and actual remediation application.

Bioremediation is considered as a cost-effective, efficient and free-of-secondary-pollution technology for petroleum pollution remediation. Due to the limitation of soil environmental conditions and the nature of petroleum pollutants, the insufficient number and the low growth rate of indigenous petroleum-degrading microorganisms in soil lead to long remediation cycle and poor remediation efficiency. Bioaugmentation can effectively improve the biodegradation efficiency. By supplying functional microbes or microbial consortia, immobilized microbes, surfactants and growth substrates, the remediation effect of indigenous microorganisms on petroleum pollutants in soil can be boosted. This article summarizes the reported petroleum-degrading microbes and the main factors influencing microbial remediation of petroleum contaminated soil. Moreover, this article discusses a variety of effective strategies to enhance the bioremediation efficiency, as well as future directions of bioaugmentation strategies.

Frailty has been related with the risk of postoperative complication in patients with colorectal cancer (CRC). However, the association between frailty and long-term survival in patients with CRC has not been comprehensively evaluated. We performed a meta-analysis to systematically evaluate the relationship between frailty and long-term survival of these patients.Relevant cohort studies with follow-up duration ≥ 1 year were identified from Medline, Embase, and Web of Science. A random-effect model after incorporation of the between-study heterogeneity was selected to pool the results.Ten cohort studies with 35,546 patients were included, and 4100 (11.5%) of them had frailty. Pooled results showed that patients with frailty had worse overall survival compared to those without frailty at baseline (relative risk [RR]: 2.21, 95% confidence interval [CI] 1.43-3.41, P 0.001; IFrailty at admission is associated with worse survival of patients with colorectal cancer.

The landscape of both recreational and medicinal cannabis use has changed dramatically over the past decade; however, research examining the risks and benefits of cannabis and cannabinoid use has lagged significantly behind the increased media promotion and their use by the general public and cancer patients. The National Cancer Institute (NCI) has supported cannabis-related research projects and funding opportunity announcements. In addition, NCI organized a virtual symposium on December 15-18, 2020, to discuss recent research findings on the use of cannabis and cannabinoids in relationship to cancer risk, prevention, and care. Specifically, the symposium sought to highlight the state of the science regarding cannabis, including the chemical constituents of cannabis (eg, cannabinoids), and cancer research involving cannabis, including cancer epidemiology, use in cancer patients, cancer biology and prevention, and preclinical and clinical cancer symptom and treatment side effect management with cannabis and cannabinoids as therapeutics. The symposium identified promising areas of future study, current barriers to conducting the research, and strategies to overcome those barriers. The series of papers in this special edition provide a summary of the symposium sessions as well as a synopsis of opportunities and challenges related to conducting research in this area.

Background: Pseudomonas citronellolis SJTE-3 can efficiently degrade 17β-estradiol (E2) and other estrogenic chemicals. However, the enzyme responsible for E2 metabolism within strain SJTE-3 has remained unidentified. Objective: Here, a novel 3-oxoacyl-(acyl-carrier protein) (ACP) reductase, HSD-X1 (WP_ 009617962.1), was identified in SJTE-3 and its enzymatic characteristics for the transformation of E2 were investigated. Methods: Multiple sequence alignment and homology modelling were used to predict the protein structure of HSD-X1. The concentrations of different steroids in the culture of recombinant strains expressing HSD-X1 were determined by high performance liquid chromatography. Additionally, the transcription of hsd-x1 gene was investigated using reverse transcription and quantitative PCR analysis. Heterologous expression and affinity purification were used to obtain recombinant HSD- X1. Results: The transcription of hsd-x1 gene in P. citronellolis SJTE-3 was induced by E2. Multiple sequence alignment (MSA) indicated that HSD-X1 contained the two consensus regions and conserved residues of short-chain dehydrogenase/reductases (SDRs) and 17β-hydroxysteroid dehydrogenases (17β-HSDs). Over-expression of hsd-x1 gene allowed the recombinant strain to degrade E2. Recombinant HSD-X1 was purified with a yield of 22.15 mg/L and used NAD+ as its cofactor to catalyze the oxidization of E2 into estrone (E1) while exhibiting a Km value of 0.025 ± 0.044 mM and a Vmax value of 4.92 ± 0.31 mM/min/mg. HSD-X1 could tolerate a wide range of temperature and pH, while the presence of divalent ions exerted little influence on its activity. Further, the transformation efficiency of E2 into E1 was over 98.03% across 15 min. Conclusion: Protein HSD-X1 efficiently catalyzed the oxidization of E2 and participated in estrogen degradation by P. citronellolis SJTE-3.

Background: Infection analysisamongst malignant cancer patients remains elusive. The objective of this study is to investigate the characteristics of both infection and anti-infection treatments in patients group with malignant cancer. Methods: We retrospectively studied the clinical data of 148 patients with malignant cancer and 171 benign patients enrolled in the pharmacist consultation from April 2015 to April 2017. Statistical analysis was performed by chi-square test to compare the classification of primary disease, sites of infection, composition of pathogenic bacteria, and the effectiveness of drug treatment. P value

Addiction memory is subjected to time-dependent shifts toward neocortex in remote period to promote long-term addiction memory storage, which plays an important role in drug relapse. However, how the activity and neuroplasticity of the anterior cingulate cortex (ACC) change after contextual morphine withdrawal conditioning and what factors determine this change remain to be determined. In this paper, using immunohistochemical and single-cell microinjection techniques, combining behavioral assay, we found that (1) contextual withdrawal conditioning increases the expression of c-Fos, but not Arc, in the ACC in morphine withdrawal mice; (2) at the first day after conditioning, conditioned context has no influence on the expression of c-Fos and Arc in the ACC in morphine withdrawal mice; (3) at the 14th day after conditioning, conditioned context increases the expression of both c-Fos and Arc in the ACC in morphine withdrawal mice; (4) the inhibition of dendritic spines of the ACC or projection neurons from the CA3 of the hippocampus to the ACC attenuates the conditioned context-induced increase of Arc expression in the ACC and abolishes the retrieval of withdrawal memory at the 14th day after conditioning. These results suggest that the ACC may exhibit a change in neuroplasticity at the 14th day after conditioning, and the dendritic spines of the ACC and the projection neurons from the CA3 of the hippocampus to the ACC are key determinants for conditioned context induced-increase in Arc expression in the ACC and the retrieval of withdrawal memory at the 14th day after conditioning.

Background This study aims to analyze the trends of premature mortality caused from four major non-communicable diseases (NCDs), namely cardiovascular disease (CVD), cancer, chronic respiratory diseases, and diabetes in Nanjing between 2007 and 2018 and project the ability to achieve the “Healthy China 2030” reduction target. Methods Mortality data of four major NCDs for the period 2007–2018 were extracted from the Death Information Registration and Management System of Chinese Center for Disease Control and Prevention. Population data for Nanjing were provided by the Nanjing Bureau of Public Security. The premature mortality was calculated using the life table method. Joinpoint regression model was used to estimate the average annual percent changes (AAPC) in mortality trends. Results From 2007 to 2018, the premature mortality from four major NCDs combined in Nanjing decreased from 15.5 to 9.5%, with the AAPC value at − 4.3% (95% CI [− 5.2% to − 3.4%]). Overall, it can potentially achieve the target, with a relative reduction 28.6%. The premature mortality from cancer, CVD, chronic respiratory diseases and diabetes all decreased, with AAPC values at − 4.2, − 5.0%, − 5.9% and − 1.6% respectively. A relative reduction of 40.6 and 41.2% in females and in rural areas, but only 21.0 and 12.8% in males and in urban areas were projected. Conclusion An integrated approach should be taken focusing on the modifiable risk factors across different sectors and disciplines in Nanjing. The prevention and treatment of cancers, diabetes, male and rural areas NCDs should be enhanced.

The process through which early memories are transferred to the cerebral cortex to form long-term memories is referred to as memory consolidation, and the basolateral amygdala (BLA) is an important brain region involved in this process. Although functional connections between the BLA and multiple brain regions are critical for the consolidation of withdrawal memory, whether the projection from the BLA to the anterior cingulate cortex (ACC) is involved in the formation or consolidation of withdrawal memory remains unclear. In this paper, we used a chemical genetic method to specifically label the BLA-ACC projection in a combined morphine withdrawal and conditioned place aversion (CPA) animal model. We found that (1) the inhibition of the BLA-ACC projection during conditioning had no effects on the formation of early withdrawal memory; (2) the inhibition of the BLA-ACC projection had no effects on the retrieval of either early or long-term withdrawal memory; and (3) the persistent inhibition of the BLA-ACC projection after early withdrawal memory formation could inhibit the formation of long-term withdrawal memory and decrease Arc protein expression in the ACC. These results suggested that the persistent activation of the BLA-ACC projection after the formation of early withdrawal memory facilitates the formation of long-term withdrawal memory by increasing the plasticity of ACC neurons.

Objective We investigated the correlations between cyclin-dependent kinase 4/6 (CDK4/6) levels and human papillomavirus (HPV) infection state in head and neck squamous cell cancer (HNSCC). The aim was to explore the potential value of CDK4/6 inhibitors in the treatment of HNSCC. Methods Multiomic sequencing data for HNSCC were obtained from The Cancer Genome Atlas (TCGA), and the mRNA levels and copy number variations (CNVs) of CDK4 and CDK6 were strictly analyzed. Overall survival (OS) curves were produced using the Kaplan-Meier method, and survival differences between groups were assessed by the log-rank test. Next, gene set enrichment analysis (GSEA) was applied to interrogate CDK4/6-associated molecular pathways in HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC. Last, lymphoid cell infiltrates in each type of HNSCC were explored, and the correlations between CDK4/6 expression and lymphoid infiltrates were explored by Tumor Immune Estimation Resource (TIMER) analysis. Results Overexpression of either CDK6 or CDK4 was not a relevant factor for OS in HPV- HNSCC (CDK6: top 40%vs. bottom 40%, P=0.885; CDK4: top 40% vs. bottom 40%, P=0.267). In HPV+ HNSCC, CDK6 but not CDK4 was a relevant factor for OS (CDK6: top 40% vs. bottom 40%, P=0.002; CDK4: top 40% vs. bottom 40%, P=0.452). GSEA found that overexpressed CDK6 in HPV+ HNSCC inhibited pathways involved in the tumor immune response, suggesting its roles in antitumor immunity. TIMER analysis results revealed that CDK6 but not CDK4 accumulation was negatively correlated with the number of tumor-infiltrating lymphocytes specific for HPV+ HNSCC, which led to tumor response suppression. Conclusions CDK6, but not CDK4, is a poor prognostic marker specific in HPV+ HNSCC patients. Overexpressed CDK6 might stimulate tumor progression by suppressing lymphocytes infiltration independent of its kinase activity. Only abrogating its kinase activity using current CDK4/6 inhibitors was not enough to block its tumor promotion function.

Synthetic estrogens are the most hazardous and persistent environmental estrogenic contaminants, with few reports on their biodegradation. Pseudomonas citronellolis SJTE-3 degraded natural steroids efficiently and metabolized 17α-ethynylestradiol (EE2) with the addition of different easily used energy sources (glucose, peptone, ethanol, yeast extract, fulvic acid and ammonia). Over 92% of EE2 (1 mg/L) and 55% of EE2 (10 mg/L) in culture were removed in seven days with the addition of 0.1% ethanol, and the EE2-biotransforming efficiency increased with the increasing ethanol concentrations. Two novel intermediate metabolites of EE2 (C22H22O and C18H34O2) were identified with high-performance liquid chromatography (HPLC) and GC-Orbitrap/MS. Comparative analysis and genome mining revealed strain SJTE-3 contained a unique genetic basis for EE2 metabolism, and the putative EE2-degrading genes exhibited dispersed distribution. The EE2 metabolism of strain SJTE-3 was inducible and the transcription of eight genes were significantly induced by EE2. Three genes (sdr3, yjcH and cyp2) encoding a short-chain dehydrogenase, a membrane transporter and a cytochrome P450 hydroxylase, respectively, were vital for EE2 metabolism in strain SJTE-3; their over-expression accelerated EE2 metabolic processes and advanced the generation of intermediate metabolites. This work could promote the study of bacterial EE2 metabolism mechanisms and facilitate efficient bioremediation for EE2 pollution.

There is growing evidence that estrogen receptors (ER) are expressed in lung cancer cells, and are able to interact with the epidermal growth factor receptor (EGFR) signaling pathway. However, data on the association between cytoplasmic ER expression and the response to EGFR-tyrosine kinase inhibitors (TKI) treatment are limited. The aim of the present study was to investigate the associations between ERα/ERβ expression and EGFR mutational status and response to TKI treatment in metastatic lung adenocarcinoma. A retrospective study of 126 consecutive patients with lung adenocarcinoma who were diagnosed with stage IV disease and had received EGFR-TKI treatment was conducted. ER expression was detected by immunohistochemistry. EGFR and GTPase KRas (KRAS) mutational statuses were evaluated by denaturing high performance liquid chromatography and PCR-restriction fragment length polymorphism, respectively. In the overall cohort of 126 lung adenocarcinoma samples analyzed, ERα expression in the nucleus of tumor cells was identified in 17 (18.9%) patients, whereas ERβ expression was identified in the nucleus (22/126, 17.5%) and cytoplasm (17/126, 13.5%). The nuclear expression of ERβ was positively associated with the degree of tumor differentiation (P=0.010). EGFR-sensitizing mutations were significantly associated with improved objective response rates (ORR), disease control rates (DCR), median progression-free survival (mPFS) and median overall survival (mOS) (P

BACKGROUND: Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase). METHODS: We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay. RESULTS: Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P

Background Agonistic 4-1BB monoclonal antibodies were preclinically validated as promising cancer immunotherapies, both as monotherapy and as potentiators of the activity of PD-(L)1–blocking agents. However, toxicity and a narrow therapeutic window have hampered their clinical development. DuoBody-PD­-L1×4-1BB, a first-in-class, bispecific, next-generation checkpoint immunotherapy, was designed to overcome these limitations by activating T cells through conditional 4-1BB costimulation, while simultaneously blocking the PD-L1 axis. We present preliminary data from the ongoing, first-in-human, open-label, phase I/IIa trial of DuoBody-PD-L1×4-1BB in advanced solid tumors (NCT03917381). Methods During dose escalation, patients with metastatic or unresectable solid tumors not eligible for standard therapy received flat-dose DuoBody-PD-L1×4-1BB (25–1200 mg) intravenously every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary endpoints included pharmacokinetic parameters and antitumor activity (RECIST 1.1). Pharmacodynamic biomarkers and antitumor activity (iRECIST) were assessed as exploratory endpoints. Results As of June 22, 2020, 61 patients were enrolled (median age: 59 years). The most common cancer types were colorectal (19.7%), ovarian (14.8%), pancreatic (9.8%), and NSCLC (9.8%). Patients had previously received a median (range) of 3 (1–11) treatments; 44.2% had prior anti-PD-(L)1 immunotherapy. Patients received a median (range) of 4 (1–15) treatment cycles; Cmax was observed shortly after the end of infusion (mean T½: 2.3–10.3 days). Maximum tolerated dose was not reached; 6 patients experienced DLTs. The most common (=10%) treatment-related AEs (all grades; grades 3–4) were transaminase elevation (24.6%; 9.8%), hypothyroidism (16.4%; 1.6%), and fatigue (13.1%; 1.6%). Treatment-related grade-3 transaminase elevations decreased upon corticosteroid administration; no treatment-related bilirubin increases or grade-4 transaminase elevations occurred. Disease control, including stable disease at first assessment and partial responses in triple-negative breast cancer, ovarian cancer, and immune checkpoint inhibitor (ICI)–pretreated NSCLC, occurred in 40/61 patients (65.6%). Pharmacologic activity, as measured by modulation of adaptive immunity mediators, was observed across a broad range of dose levels. Peripheral proliferating (Ki67+) CD8+ effector memory T cells and serum interferon-gamma levels showed maximum induction relative to baseline (p=0.01) 8 days following treatment. Conclusions DuoBody-PD-L1×4-1BB demonstrated biologic activity and a manageable safety profile. Encouraging early clinical activity across different dose levels was observed in a heavily pretreated population with advanced solid tumors, including those resistant to prior immunotherapy or typically less sensitive to ICIs. Expansion cohorts of patients for whom DuoBody-PD-L1×4-1BB treatment could be relevant and biologically sound have started enrollment. Updated data will be presented. Acknowledgements The authors thank Manish Gupta, Lei Pang, and Thomas Breuer at Genmab A/S; Alice Bexon, Alexander Muik, and Friederike Gieseke at BioNTech SE; and Zuzana Jirakova (formerly at BioNTech SE) for their valuable contributions. This trial was funded by Genmab A/S and BioNTech SE. Trial Registration ClinicalTrials. gov; trial number: NCT03917381 Ethics Approval This trial is undertaken following full approval of the final protocol, amendments, informed consent form, applicable recruiting materials, and subject compensation programs by the Independent Ethics Committee/Institutional Review Board. Consent Written informed consent, in accordance with principles that originated in the Declaration of Helsinki 2013, current ICH guidelines including ICH-GCP E6(R2), applicable regulatory requirements, and sponsor policy, was provided by the patients.

Non-pitch coal-based activated carbon (NPAC), using a novel non-pitch binder, was used to inexpensively prepare oxidized activated carbon (NPAC-O0) by oxidation modification of oxygen-depleted. Using a fixed bed reactor and BET, FTIR and XPS techniques, this research investigated the denitrification rate, the changes in acidic/basic surface functional groups, and the mechanism of NOx removal. The results demonstrated that in the preparation of catalyst NPAC-O0, oxygen reacted with microcrystalline edges, defect parts and specific chemical functional groups adsorbed on the surface of NPAC to build and ream pores, such that the total pore volume increased by 30.26%. Additionally, the basic functional group content decreased by 36.42%, which was ascribed to a reduction in the pyridine-like and pyrrolic moieties, whereas the acidic functional group content increased by 128.7%, which was a result of the introduction of C O and O C O groups. The removal of NOx by oxidized activated carbon (NPAC-O0) involves both adsorption and catalytic conversion, where the acidic groups absorbed NH3 and the polar/basic functional groups absorbed O2 and NO enhancing the activated carbon activity. The NH3 adsorption is the critical step in the NH3 NO O2 reaction. In the mechanism, the increased acidic C O groups promote chemical absorption of NH3 and assist in H-abstraction of NH3 to formation NH2, which then reacts with adsorbed NO2 or NO to generate N2 and H2O in the presence of oxygen. At 30 °C, the denitrification rate of NPAC-O0 remained at 79.46% after a 140 min reaction.

Briquetting and pyrolysis technology is of crucial importance in the development and efficient multi-level use of low-rank pulverized lignite. The main aim is to study the influence of pyrolysis and entering temperature (350 °C–800 °C), heating rate (5 °C min −1 ∼ 30 °C min −1 ), residence time (0–140 min), and particle size (0.45 mm–30 mm) on the characteristics of pyrolytic products of binder cold-briquetted lignite (BCBL). Characterization of gas pyrolyzates, semi-char, and tar are characterized by Gas chromatography (GC), FTIR spectroscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, and gas chromatography–mass spectroscopy (GC–MS). The results indicate that the residence time and pyrolysis temperature have little effect on the pyrolysis products, whereas, heating rate, the fast heating from high entering temperature and particle size show a crucial effect relatively. With increasing pyrolysis temperature, the effects on carbon, oxygen, hydrogen, nitrogen, and sulfur contents are studied. H 2 and CH 4 start evolving at 375–400 °C and their rates increase gradually. Various functional groups are partially removed during pyrolysis and the crystallinity of semi-char increases. As the pryolysis temperature increasing, the concentrations of C C/C H increase, whereas, that of C O, COO- and C O decrease, which was consistent with the results of FTIR spectra. The results reported in this work provide a theoretical and technical basis on comprehensive utilization of the low-rank pulverized coal.

Mycoplasma gallisepticum (MG) can cause chronic respiratory disease (CRD) in chickens. While several studies have reported the inflammatory functions of microRNAs during MG infection, the mechanism by which exosomal miRNAs regulate MG‐induced inflammation remains to be elucidated. The expression of exosome‐microRNA derived from MG‐infected chicken type II pneumocytes (CP‐II) was screened, and the target genes and function of differentially expressed miRNAs (DEGs) were predicted. To verify the role of exosomal gga‐miR‐451, Western blot, ELISA and RT‐qPCR were used in this study. The results showed that a total of 722 miRNAs were identified from the two exosomal small RNA (sRNA) libraries, and 30 miRNAs (9 up‐regulated and 21 down‐regulated) were significantly differentially expressed. The target miRNAs were significantly enriched in the treatment group, such as cell cycle, Toll‐like receptor signalling pathway and MAPK signalling pathway. The results have also confirmed that gga‐miR‐451‐absent exosomes derived from MG‐infected CP‐II cells increased inflammatory cytokine production in chicken fibroblast cells (DF‐1), and wild‐type CP‐II cell–derived exosomes displayed protective effects. Collectively, our work suggests that exosomes from MG‐infected CP‐II cells alter the dynamics of the DF‐1 cells, and may contribute to pathology of the MG infection via exosomal gga‐miR‐451 targeting YWHAZ involving in inflammation.

MicroRNAs (miRNAs) have been determined to be important regulators for pathogenic microorganism infection. However, it is largely unclear how miRNAs are triggered during pathogen infection. We previously reported that the up-regulation of gga-miR-451 negatively regulates the Mycoplasma gallisepticum (MG)-induced production of inflammatory cytokines via targeting tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein zeta (YWHAZ). The aim of this study was to investigate the mechanism regulating gga-miR-451 in MG infection in chickens. Analysis of gga-miR-451 precursor, pri-miR-451, and pre-miR-451 indicated that the regulation occurred transcriptionally. We also identified the transcriptional regulatory region of gga-miR-451 that contained consensus-binding motif for aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (Arnt) complex, which is known as the transcription factor that regulates gene expression. Luciferase reporter assays combined with chromatin immunoprecipitation (ChIP) demonstrated that AhR:Arnt bound directly to the promoter elements of gga-miR-451, which were responsible for gga-miR-451 transcription in the context of MG infection. Furthermore, upregulation of AhR:Arnt significantly induced gga-miR-451 and inhibited YWHAZ expression, suggesting that AhR:Arnt may play an anti-inflammatory role in MG infection. This discovery suggests that induced gga-miR-451 expression is modulated by AhR:Arnt in response to MG infection.

Mycoplasma gallisepticum (MG), a pathogen that infects chickens and some other birds, triggers chronic respiratory disease (CRD) in chickens, which is characterized by inflammation. The investigation of microbial pathogenesis would contribute to the deep understanding of infection control. Since microribonucleic acids (miRNAs) play a key role in this process, gga-mir-146c, an upregulated miRNA upon MG infection, was selected according to our previous RNA-sequencing data. In this paper, we predicted and validated that MMP16 is one of gga-miR-146c target genes. Results show that MMP16 is the target of gga-miR-146c and gga-miR-146c can downregulate MMP16 expression within limits. gga-miR-146c upregulation significantly increased the expression of TLR6, NF-&kappa, B p65, MyD88, and TNF-&alpha, whereas the gga-miR-146c inhibitor led to an opposite result. gga-miR-146c upregulation effectively decreased apoptosis and stimulated DF-1 cells proliferation upon MG infection. On the contrary, gga-miR-146c inhibitor promoted apoptosis and repressed the proliferation. Collectively, our results suggest that gga-miR-146c upregulation upon MG infection represses MMP16 expression, activating TLR6/MyD88/NF-&kappa, B pathway, promoting cell proliferation by inhibiting cell apoptosis, and, finally, enhancing cell cycle progression to defend against host MG infection.

Caprine arthritis-encephalitis (CAE) is a chronic progressive infectious disease caused by caprine arthritis-encephalitis virus (CAEV) that seriously threatens the goat industry. Chronic infection and life-long multi-tissue inflammation are the typical features of the disease. Innate antiviral immunity is essential for the host defense system that rapidly recognizes and eliminates invading viruses. Interferon β (IFN-β) is important for innate immunity and regulates immunity against a broad spectrum of viruses. To investigate the details of the IFN-β response to CAEV infection, the effects of six viral proteins and the molecular mechanisms by which they affect IFN-β production were analyzed. Overexpression of DU and Vif promote virus proliferation and inhibit the production of IFN-β. qRT-PCR and luciferase reporter assays showed that overexpression of Vif inhibits the expression of luciferase under the control of the ISRE, NF-κB or IFN-β promoter but does not affect the expression of IFN-β activated by IRF3, indicating that Vif negatively regulates IFN-β production by affecting upstream signal transduction of IRF3. Amino acids 149-164 of Vif were found to be necessary for the inhibitory effect of IFN-β production. Our results indicate that CAEV evades surveillance and clearance by intracellular innate immunity by downregulating IFN-β production.

CD trim process is incline to run on strip tool because of the low cost and high throughput benefit. However, CD stability is the key challenge. In this article, PR descum process for CD trim was studied on the chamber with substrate temperature

Mycoplasma gallisepticum (MG) mainly infects chickens to initiate chronic respiratory disease (CRD). microRNAs (miRNAs) play vital roles according to previously reported studies. Our previous study showed that gga-miR-16-5p, in MG-infected lungs of chicken embryo, was upregulated by Illumina sequencing. The study aimed to reveal what role gga-miR-16-5p plays in CRD progression. gga-miR-16-5p was upregulated in MG-infected fibroblast cells (DF-1). Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) was demonstrated as the target gene of gga-miR-16-5p. Furthermore, PIK3R1 expression was lower in MG-infected groups than it in noninfected controls measured by qPCR. Additionally, overexpressed gga-miR-16-5p could downregulate PIK3R1 and phosphorylated serine/threonine kinase (p-Akt) to express protein, whereas there is an opposite effect on inhibition. Overexpressed gga-miR-16-5p resulted in decreased activity of tumor necrosis factor alpha (TNF-&alpha, ) and the nuclear factor-kappaB (NF-&kappa, B) by qPCR. Furthermore, overexpressed gga-miR-16-5p restricted cell multiplication, cycle progression, and increased apoptosis of MG-infected DF-1 cells, whereas inhibited gga-miR-16-5p led to the opposite effect. Collectively, upregulated gga-miR-16-5p could decrease multiplication, cycle progression, and increase apoptosis of MG-infected DF-1 cells, at least partly through directly targeting PIK3R1 and inhibiting PI3K/Akt/NF-&kappa, B pathway to exert an anti-inflammatory effect. Our results will provide more experimental evidence to bring pathogenesis of MG infection to light.

Background: Conditioned context-induced retrieval of drug withdrawal memory contributes to drug relapse. The basolateral amygdala (BLA) plays an important role in conditioned context-induced retrieval of morphine withdrawal memory. However, the upstream pathways of the activation of the BLA by conditioned context remains to be studied. Methods: Using the conditioned place aversion model, chemical-genetic method, trans-neuronal virus tracing technique and immunohistochemical method, we studied the upstream neural circuits of the activation of the BLA during conditioned context-induced retrieval of morphine withdrawal memory. Findings: The present results show that the dorsal CA1 of the hippocampus is an upstream brain region of the activation of the BLA during conditioned context-induced withdrawal memory retrieval; the indirect connection from dorsal CA1 of the hippocampus to the BLA is enhanced in mice with conditioned place aversion; the postrhinal cortex (POR) is a brain region that connects the dorsal CA1 of the hippocampus and the activation of the BLA in conditioned context-induced retrieval of morphine withdrawal memory. Interpretation: These results suggest that a series circuit from CA1 of dorsal hippocampus to basolateral amygdala via postrhinal cortex participates in conditioned context-induced retrieval of morphine withdrawal memory. Funding Statement: This study was supported by the National Program of Basic Research sponsored by the Ministry of Science and Technology of China (2009CB52201 and 2013CB835100) and Project of Foundation of National Natural Science of China (31121061, 91332204, 81371466 and 31070932). Declaration of Interests: All authors declare no conflicts of interest. Ethics Approval Statement: All experimental procedures conformed to Fudan University as well as international guidelines on the ethical use of animals. All efforts were made to minimize animal suffering and reduce the number of animals used.

Modified activated coke was prepared by introducing CeOx and MnOx on non-pitch coal-based activated coke (NPAC) using a novel non-pitch binder. Employing a fixed bed reactor and N2 adsorption–desorption, X-ray diffraction, and X-ray photoelectron spectroscopy techniques, we investigated the changes of surface functional groups, pore structure characteristics, denitrification activity and adsorption behavior. It was also found that the presence of Ce3+ and Ce4+ species, promoting NO oxidation adsorption, significantly increased the starting denitrification activity and the catalysis of Mn species, helping NH3 adsorption, showed a gradual increase in activity after a time delay. For co-impregnation modification of MnOx and CeOx, the manganese species and cerium species incorporated activated coke to formed cerium manganese carbide. With the increase in impregnation amount, the graphite crystalline structure was destroyed, causing the degree of graphitization to be reduced and the peak of Mn 2p3/2 to be shifted to a lower binding energy. The addition of CeOx played an important role in changing the existing state of the manganese oxide and adding MnOx contributed to the oxidation of Ce3+ to Ce4+. On MnOx–CeOx-7.40 adsorbed NH3 can react with adsorbed NOx species (adsorbed NO3 and NO2) following a Langmuir–Hinshelwood mechanism. The denitrification rate of MnOx–CeOx-7.40 at 140 °C was as high as 75.36%.