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Changes in the metabolic profile within the intestine of lenok (Brachymystax lenok) when challenged to acute and lethal heat stress (HS) are studied using no-target HPLC-MS/MS metabonomic analysis. Of 51 differentially expressed metabolites identified in response to HS, 34 occurred in the positive ion mode and 17 in negative ion mode (VIP > 1, P < 0.05). Changes in metabolites (i.e. alpha-D-glucose, stachyose and L-lactate) related to carbohydrate and glycolysis are identified in HS-treated lenok. Fatty acid β-oxidation in HS-treated lenok was inhibited by accumulation of acetyl carnitine, palmitoylcarnitine, carnitine, and erucic acid. Many amino acids (L-tryptophan, D-proline, L-leucine, L-phenylalanine, L-aspartate, L-tyrosine, L-methionine, L-histidine and L-glutamine) decreased to support energy demands in HS-treated lenok. Oxidative damage in HS-treated lenok was indicated by decreased glycerophospholipid metabolites (i.e. glycerophosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphoethanolamine, 1-palmitoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine, and 1, 2-dioleoyl-sn-glycero-3-phosphatidylcholine), and increased oxylipin production (12-HETE and 9R, 10S-EpOME). Oxidative stress increased formation of eicosanoids and dicarboxylic acids, overwhelming the mitochondrial β-oxidation pathway, while minor oxidative pathways (omega-oxidation and peroxisomal beta-oxidation) were likely to be activated in HS-treated lenok.

BACKGROUND Although endoscopy is the gold standard to assess disease activity and infliximab efficacy in inflammatory bowel disease (IBD), the invasive, costly, and time-consuming procedure limits its routine applications. We aimed to investigate the clinical value of serum oncostatin M (OSM) as a surrogate biomarker. METHODS Fifty healthy controls, 34 non-IBD patients, and 189 IBD patients who were pre-infliximab treatment (n = 122) or in infliximab maintenance (n = 67) were enrolled. A chemiluminescence immunoassay (CLIA) was constructed to quantify serum OSM concentrations. Receiver operator characteristic (ROC) curve analysis was used to evaluate the performance of blood biomarkers for IBD management. RESULTS The methodology of CLIA exhibited great analytical performance with a wide linear range of 31.25-25000 pg/mL, a low detection limit of 23.2 pg/mL, acceptable precision, and applicable accuracy. Patients with IBD (121.5 [43.3-249.4] pg/mL, p

The main defense response to Soybean mosaic virus (SMV) infection in soybean [Glycine max (L.) Merr.] is thought to be blockage of intercellular virus transport by callose deposition on plasmodesmata. But the specific regulatory mechanism remains largely unknown. In this study, we found that hydrogen peroxide (H2O2) signal downstream of NO was associated with the regulation of callose accumulation. Abundant H2O2 was produced on the cell membrane and cell wall in the incompatible combination of soybean cultivar Jidou 7 and SMV strain N3, whereas no obvious H2O2 was observed in the compatible combination of Jidou 7 and strain SC-8. When H2O2 production was inhibited, callose accumulation induced by SMV infection decreased to a level insufficient to restrict virus transport in the incompatible combination. The H2O2-associated transcriptome dynamics of soybean during SMV infection was investigated. Transcriptome and functional analysis using virus-induced gene silencing showed that GmSEOB and GmPAP27, two genes regulated by H2O2, functioned in resistance by positively regulating the accumulation of callose in response to SMV infection. These results lay a foundation for further research on the signal transduction and molecular regulation of callose deposition during soybean resistance to SMV infection.

Qian Ye, Junying Guo, Yansong Chen, Zhaolei Cui, Yan Chen Department of Laboratory Medicine, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou City, Fujian Province, 350014, People’s Republic of ChinaCorrespondence: Zhaolei Cui; Yan ChenDepartment of Laboratory Medicine, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, No. 420 Fuma Road, Jin’an District, Fuzhou City, Fujian Province, 350014, People’s Republic of ChinaEmail cuileidizi@163.com; chenyan220422@fjmu.edu.cnObjective: The aim of this study was to evaluate the effectiveness of Epstein–Barr virus (EBV) VCA-IgA antibody, EBV DNA and HSP90α alone or in combinations for the diagnosis and prognostic prediction of nasopharyngeal carcinoma (NPC).Methods: A total of 113 treatment-naïve patients with NPC and 40 healthy controls were enrolled. Plasma HSP90α and serum EBV VCA IgA antibody were detected using ELISA, and plasma EBV DNA was quantified using qPCR assay. The effectiveness of plasma HSP90α level, serum EBV VCA IgA antibody and plasma EBV DNA was examined in the diagnosis and prognosis prediction of NPC.Results: Higher plasma HSP90α, serum EBV VCA IgA antibody and plasma viral load of EBV DNA were detected in NPC patients than in healthy controls (P < 0.001). The plasma HSP90α levels, serum EBV VCA IgA antibody titers and plasma viral load of EBV DNA were significantly greater in NPC patients with stages III and IV than in those with stages I and II (P < 0.001), and significantly lower plasma HSP90α levels, serum EBV VCA IgA antibody titers and plasma viral load of EBV DNA were found in the good prognosis group than in the poor prognosis group post-treatment (P < 0.05). The area under representative operating curves (AUCs) of plasma HSP90α, serum EBV VCA IgA antibody and plasma EBV DNA alone and in combination were 0.884, 0.841, 0.934 and 0.954 for the diagnosis of NPC, respectively. Univariate and multivariate Cox proportional hazards regression analyses identified HSP90α as an independent prognostic factor for NPC.Conclusion: The combination of plasma HSP90α, serum EBV VCA IgA antibody and plasma EBV DNA shows high diagnostic performance for NPC, and plasma HSP90α may be a potential marker for diagnosis and prognosis prediction of NPC.Keywords: nasopharyngeal carcinoma, EBV VCA-IgA antibody, EBV DNA, HSP90α, diagnostic performance, prognosis prediction

Yan Chen, 1, 2 Jiafei Cheng, 1 Yiling Zhang, 1 Jiande DZ Chen, 1, 3 Florin M Seralu 1 1Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Division of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 3Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USACorrespondence: Florin M SeraluDivision of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USATel/Fax +1 4105023147Email fselaru1@jhmi.eduJiande DZ ChenDivision of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USATel +1 7346475749Email Jiandedzchen@gmail.comPurpose: The aim of the study was to investigate the effects of electroacupuncture (EA) at ST36 on rectal hypersensitivity and compliance in DSS-treated post-inflammation rats. In addition, we explored the involvement of mast cells-triggered NGF/TrkA/TRPV1 peripheral afferent pathway.Methods: Rats were provided water with 5% dextran sulphate sodium (DSS) for 7 days. Two weeks after the DSS treatment they were subjected to initial and repetitive EA. Different sets of parameters were compared in the initial test and then EA with the selected parameters were performed for 2 weeks. Rectal compliance was assessed by colorectal distension while visceral sensitivity was evaluated by abdominal withdraw reflexes (AWR) and electromyogram (EMG). Masson’s trichrome staining was performed to stain collagen and toluidine blue staining was applied to assess the degranulation of mast cells. Nerve growth factor (NGF), tryptase, TrkA and TRPV1 were measured by Western blot or immunofluorescence staining.Results: EA at 100 Hz was more effective in improving rectal compliance and visceral hypersensitivity. Daily EA improved visceral hypersensitivity but not rectal compliance. Five weeks after DSS treatment, fibrosis was noted in both sham-EA and EA groups. The expression and activation of mast cells were significantly reduced after the 2-week EA treatment with a concurrent decrease in the expression of colonic NGF/TrkA and TRPV1 in both colon and dorsal root ganglions.Conclusion: EA at ST36 with a special set of parameters has no effect on reduced rectal compliance but relieves visceral hypersensitivity via the mast cells-triggered NGF/TrkA/TRPV1 peripheral afferent pathway in DSS-treated post-inflammation rats.Keywords: electroacupuncture, inflammation remission, ulcerative colitis, visceral hypersensitivity, mast cellsErratum for this paper has been published

Objectives The aim of this study was to investigate the genomic epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in China to identify predominant lineages and their associations with clinical data and antimicrobial resistance profiles. Methods We performed a national prevalence study of patients with S. aureus infections in 22 tertiary hospitals in China from 2015 to 2017. Clinical data from patients and the antimicrobial phenotypes were collected for each isolate. Genome sequencing was performed on a proportion of isolates and a phylogenetic analysis was undertaken. Genotypic and phenotypic β-lactam susceptibilities were compared. Results A total of 1900 patients with S. aureus infections were included, of which 40% involved MRSA. Community-associated MRSA (CA-MRSA) infections were 24% of the total isolates. Genomic data showed that more than three-quarters of the MRSA were from three dominant lineages CC239 (25%, 116/471), CC5 (21%, 96/471) and CC59 (33%, 154/471) with CC59 accounting for more than half of the CA-MRSA isolates. Penicillin susceptibility genomic features were observed in 53% (251/470) of MRSA, including almost all of the CC59 (152/154) lineage, and 96% (242/251) of these isolates demonstrated in vitro susceptibility to penicillin or amoxicillin combined with clavulanic acid. Phylogenetic analysis indicated that the CC59 lineage can be divided into six lineages with all Asian CC59 isolates likely arising from an ancestral Mainland China lineage. Conclusions This study showed a high prevalence of CA-MRSA in China, largely due to the widespread presence of CC59. As almost all isolates in this lineage possess genetic variants leading to increased β-lactam susceptibility, we suggest that to improve antibiotic stewardship combinations of penicillins and β-lactamase inhibitors should be included in the antibiotic susceptibility testing panels used to inform treatment decisions and research undertaken on this combination therapy.

For the treatment of lake water with algae, the coagulation–ultrafiltration–ozone–biologically activated carbon (CUF–O3–BAC) integrated process was first used to treat East Taihu Lake water in China, aiming at evaluating the removal efficiencies of algae, permanganate index (CODMn), UV254, NH3-N and disinfection by-products (DBPs) precursors. In addition, the long-term performance of the membrane operation under the fluxes of 60, 70, 80 and 90 L/(m2·h) was also investigated, and kinetic models were established. The experimental results showed that the integrated process had positive impaction of algae, CODMn, UV254 and NH3-N removal, and the removal rates were 95.89 ± 1.52, 76.18 ± 4.38, 72.06 ± 4.72 and 81.31 ± 6.71%, respectively. The CUF process was prone to increase the formation potentials of DBPs. Although ozone could reduce the formation risks of chlorinated trihalomethanes (THMs) to a certain extent, it is ineffective to reduce those of brominated THMs and haloacetic acids (HAA5). However, the CUF–O3–BAC process was an effective technology for the removal of THMs and HAA5 precursors in drinking water treatment. Finally, it was found that the relationship between transmembrane pressure (TMP) and time conformed to the first-order and second-order kinetic models, and the linear fitting coefficients were all above 90%. HIGHLIGHTS The treatment of lake water with algae by ultrafiltration–ozone–biologically activated carbon.; Study on the removal of disinfection by-products precursors.; The kinetic models of transmembrane pressure and running time were established.

Introduction Alzheimer’s disease (AD) is a progressive brain disorder, and one of the most common causes of dementia and amnesia. Due to the complex pathogenesis of AD, the underlying mechanisms remain unclear. Although scientists have made increasing efforts to develop drugs for AD, no effective therapeutic agents have been found. Objectives Natural products and their constituents have shown promise for treating neurodegenerative diseases, including AD. Thus, in-depth study of medical plants, and the main active ingredients thereof against AD, is necessary to devise therapeutic agents. Methods In this study, N2a/APP cells and SAMP8 mice were employed as in vitro and in vivo models of AD. Multiple molecular biological methods were used to investigate the potential therapeutic actions of oxyphylla A, and the underlying mechanisms. Results Results showed that oxyphylla A, a novel compound extracted from Alpinia oxyphylla, could reduce the expression levels of amyloid precursor protein (APP) and amyloid beta (Aβ) proteins, and attenuate cognitive decline in SAMP8 mice. Further investigation of the underlying mechanisms showed that oxyphylla A exerted an antioxidative effect through the Akt-GSK3β and Nrf2-Keap1-HO-1 pathways. Conclusions. Taken together, our results suggest a new horizon for the discovery of therapeutic agents for AD.

Background Recombinant protein subunit vaccination is considered to be a safe, fast and reliable technique when combating emerging and re-emerging diseases such as coronavirus disease 2019 (COVID-19). Typically, such subunit vaccines require the addition of adjuvants to attain adequate immunogenicity. AS01, which contains adjuvants MPL and saponin QS21, is a liposome-based vaccine adjuvant system that is one of the leading candidates. However, the adjuvant effect of AS01 in COVID-19 vaccines is not well described yet. Methods In this study, we utilized a mixture of AS01 as the adjuvant for an S1 protein-based COVID-19 vaccine. Results The adjuvanted vaccine induced robust immunoglobulin G (IgG) binding antibody and virus-neutralizing antibody responses. Importantly, two doses induced similar levels of IgG binding antibody and neutralizing antibody responses compared with three doses and the antibody responses weakened only slightly over time up to six weeks after immunization. Conclusion These results suggested that two doses may be enough for a clinical vaccine strategy design using MPL & QS21 adjuvanted recombinant protein, especially in consideration of the limited production capacity of COVID-19 vaccine in a public health emergency.

Aims The ubiquilin‐like protein ubiquilin 2 (UBQLN2) is associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD). The biological function of UBQLN2 has previously been shown to be related to stress granules (SGs). In this study, we aimed to clarify the regulatory relationship between UBQLN2 and SGs. Methods In this study, we transfected UBQLN2‐WT or UBQLN2‐P497H plasmids into cell lines (HEK293T, HeLa), and observed the process of SG dynamics by immunofluorescence. Meanwhile, immunoblot analyses the protein changes of stress granules related components. Results We observed that ubiquilin 2 colocalizes with the SG component proteins G3BP1, TIA‐1, ATXN2, and PABPC1. In cells expressing WT UBQLN2 or P497H mutants, in the early stages of SG formation under oxidative stress, the percentage of cells with SGs and the number of SGs per cell decreased to varying degrees. Between WT and mutant, there was no significant difference in eIF2α activity after stress treatment. Interestingly, the UBQLN2 P497H mutant downregulates the level of TIA‐1. In addition, the overexpression of the UBQLN2 P497H mutant inhibited the phosphorylation of 4E‐BP1 and affected the nucleoplasmic distribution of TDP‐43. Conclusions Ubiquilin 2 colocalizes with the SG component proteins G3BP1, TIA‐1, ATXN2, and PABPC1. It participates in regulating SG dynamics. And UBQLN2 mutation affects the assembly of stress granules by regulating TIA‐1. In addition, the overexpression of the UBQLN2 P497H mutant inhibited the phosphorylation of 4E‐BP1 and affected the nuclear and cytoplasmic distribution of TDP‐43. These provide new insights into the role of UBQLN2 in oxidative stress and the pathogenesis of ALS., Stresses activate eIF2‐Á kinases that phosphorylate eIF2‐Á, deplete the ternary complex, and promote the assembly of a noncanonical Pre‐initation complex£¨PIC£©; these interfaces recruit RNA‐BPs such as TIA‐1, increasing the local concentration of these proteins to promote LLPS and assembly of SG seeds. However, UBQLN2 P497H could repress the level of TIA‐1, thereby inhibiting stress granule assembly.

Allergic disease is one of the most common chronic diseases, which can affect both children and adults, be often caused by allergen-induced unfavorable immune responses, and initiate various symptoms in different organs, including up-/low-airways and skin, such as asthma, atopic dermatitis, and rhinosinusitis. With increasing prevalence of allergic disease worldwide and their impact on the quality of life, new biological therapeutic approaches for these disorders become hot areas of intensive research. Multiple factors are involved and play important role in the pathogenesis of allergic disease, which can promote or trigger T helper 2 (Th2)-type immune responses, leading to production of the type 2 cytokines and immunoglobulin E (IgE)，the two critical events in the allergic diseases. Using monoclonal antibodies to target these molecules, therefore, might provide possible benefits for the patients suffered from these diseases. Apart of those having approved biologics for allergic diseases, some potential targets such as epithelial-derived alarmins thymic stromal lymphopoietin (TSLP) and interleukin 33 (IL-33) have been also described and proposed to develop monoclonal antibodies against either these cytokines, their receptors, or both. These new and potential targets have substantially enriched the therapeutic opportunities in the field of allergic diseases. The present review aims to briefly outline the role of monoclonal antibodies targeting the cytokines and immunoglobulin involved in the development of allergic diseases, and to discuss the clinical effects of these antibodies.

Aquaporin 4 (AQP4), usually expressed at astrocytes end-feet, is a main component of the lymph-lymphatic system and promotes paravascular cerebrospinal fluid-interstitial fluid exchange. Moreover, angiotensin II type 1 (AT1) receptor affects amyloid β (Aβ) levels. This study aimed to detect the effect of AT1 receptor deficiency on the blood-brain barrier (BBB) of traumatic brain injury (TBI) mice and the effect on Aβ level and glial lymphatic circulation. TBI model was built using AT1 receptor knockout mice (AT1-KO) and C57BL/6 mice (wild type, WT). BBB integrity was detected by Evans blue extravasation. The expression of the astrocytic water channel AQP4 and astrocyte activation were evaluated with immunofluorescence. The expressions of amyloid precursor protein (APP), junction protein zonula occludens protein-1 (ZO-1) and occludin in mice brain were detected by Western blot (WB). Aβ levels were assayed by enzyme-linked immunosorbent assay (ELISA). AT1 receptor deficiency defended BBB integrity and rescued occludin and ZO-1 decrease in mice brain induced by TBI. AT1-KO mice had less increase of APP expression and Aβ 1–42, Aβ 1–40 levels compared to WT mice under TBI. Moreover, AT1 receptor deficiency was found to significantly inhibit AQP4 depolarization after TBI. T1 receptor deficiency attenuated TBI-induced impairments of BBB by rescuing tight junction proteins and inhibited AQP4 polarization, thus improving the function of glymphatic system to enhance interstitial Aβ clearance in TBI mice brain.

Aims Our previous study demonstrated that Ca2+ influx through the Orai1 store-operated Ca2+ channel in macrophages contributes to foam cell formation and atherosclerosis via the calcineurin–ASK1 pathway, not the classical calcineurin–nuclear factor of activated T-cell (NFAT) pathway. Moreover, up-regulation of NFATc3 in macrophages inhibits foam cell formation, suggesting that macrophage NFATc3 is a negative regulator of atherogenesis. Hence, this study investigated the precise role of macrophage NFATc3 in atherogenesis. Methods and results Macrophage-specific NFATc3 knockout mice were generated to determine the effect of NFATc3 on atherosclerosis in a mouse model of adeno-associated virus-mutant PCSK9-induced atherosclerosis. NFATc3 expression was decreased in macrophages within human and mouse atherosclerotic lesions. Moreover, NFATc3 levels in peripheral blood mononuclear cells from atherosclerotic patients were negatively associated with plaque instability. Furthermore, macrophage-specific ablation of NFATc3 in mice led to the atherosclerotic plaque formation, whereas macrophage-specific NFATc3 transgenic mice exhibited the opposite phenotype. NFATc3 deficiency in macrophages promoted foam cell formation by potentiating SR-A- and CD36-meditated lipid uptake. NFATc3 directly targeted and transcriptionally up-regulated miR-204 levels. Mature miR-204-5p suppressed SR-A expression via canonical regulation. Unexpectedly, miR-204-3p localized in the nucleus and inhibited CD36 transcription. Restoration of miR-204 abolished the proatherogenic phenotype observed in the macrophage-specific NFATc3 knockout mice, and blockade of miR-204 function reversed the beneficial effects of NFATc3 in macrophages. Conclusion Macrophage NFATc3 up-regulates miR-204 to reduce SR-A and CD36 levels, thereby preventing foam cell formation and atherosclerosis, indicating that the NFATc3/miR-204 axis may be a potential therapeutic target against atherosclerosis.

BACKGROUND Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been adopted as the standard of care for non-small cell lung cancer (NSCLC) patients harboring EGFR sensitizing mutations. Besides the two common mutations exon 19 deletion and L858R, which together comprise approximately 85% of EGFR mutations in NSCLC, rare EGFR mutations also exist, including point mutations, deletions, and insertions spanning EGFR exons 18-25. However, the responsiveness of uncommon EGFR mutations to EGFR TKIs remains elusive and attracts increasing interest. CASE SUMMARY Herein, we report a 55-year-old male patient with stage IV NSCLC harboring a rare EGFR L833F-L861Q compound mutation in cis. The patient achieved a partial response to first-line treatment with afatinib and a progression-free survival of 10 mo. After afatinib failure, the patient received multiple line treatments with chemotherapy. Upon disease progression, the heavily pretreated patient was treated with osimertinib and bevacizumab, and both lung lesion and brain metastases were stable for more than 3 mo. He had an overall survival of 25 mo. CONCLUSION Our case revealed that both afatinib and the osimertinib + bevacizumab combination demonstrated clinical efficacy in NSCLC harboring an EGFR L833F-L861Q compound mutation. The results provide more therapeutic options for patients with rare compound mutations.

B cells are essential for Ab production during humoral immune responses. From decades of B cell research, there is now a detailed understanding of B cell subsets, development, functions, and most importantly, signaling pathways. The complicated pathways in B cells and their interactions with each other are stage-dependent, varying with surface marker expression during B cell development. With the increasing understanding of B cell development and signaling pathways, the mechanisms underlying B cell related diseases are being unraveled as well, making it possible to provide more precise and effective treatments. In this review, we describe several essential and recently discovered signaling pathways in B cell development and take a look at newly developed therapeutic strategies targeted at B cell signaling.

Background Coxsackie virus group A type 16 (CoxA16) is the main pathogen and usually an alternative to or joins in prevalence with enterovirus 71 (EV71) causing hand, foot and mouth disease (HFMD). The objective of this study was to estimate the seroprevalence of CoxA16 antibody among people of various age groups by a systematic review and meta-analysis. Methods The literature of seroprevalence of CoxA16 antibody among people has been systematically searched through databases from the date of their establishment to Jan. 2021. Estimates of seroprevalence of CoxA16 antibody by gender and age groups have been summarized by using fixed- and random- effect models. All analyses have been conducted in STATA version 12.0 software. Results A total of 14 publications with 9 in English and 5 in Chinese containing 9562 samples were finally included in the meta-analysis. The seroprevalence of CoxA16 antibody reported in different studies range from 24.85 to 76.92 %. Meta-analysis has revealed that the seroprevalence of CoxA16 antibody was 56.3 % (95 %CI: 47.7 %~64.9 %) in the overall population and 55.1 % (95 %CI: 44.1 %~66.1 %) in the Chinese population. Subgroup analysis by gender has revealed that the seroprevalence of CoxA16 antibody was 56.1 % (95 %CI: 45.2 %~67.1 %) in males and 60.0 % (95 %CI: 50.0 %~69.9 %) in females. Subgroup analysis by age groups has revealed that the seroprevalence of CoxA16 antibody was 49.1 % (95 %CI: 36.2 %~62.0 %) in the 0 ~ 5 age group and 63.9 % (95 %CI: 53.1 %~74.7 %) in the over 5 age group. Begg’s funnel plots have suggested that there were no publication bias in all groups. Sensitive analysis has suggested that the result of the meta-analysis was stable. Conclusions The seroprevalence of CoxA16 antibody was closely related to age. Children under 5 years old were the main susceptible groups for CoxA16 and also the key groups for the prevention and control of HFMD.

The recurrence rate of lymphoma is very high, and tumor stem cells may be an important mechanism. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) can inhibit antitumor immunity and promote cancer progression, but its role and mechanism in lymphoma are still unclear. Here we collected lymphoma tissue and peripheral blood from patients with diffuse large B-cell lymphoma (DLBCL). Results showed that CTLA-4 expression and CD44+ cell in the high-risk group were significantly higher than that in the low-risk group. Correlation analysis showed that CTLA-4 expression positively correlated with CD44+ cell in lymphoma tissue and regulatory T (Treg) cells in lymphocytes. In vitro experiment showed that CTLA-4 increased the ratio of lymphoma stem cells, and proliferation and invasion of lymphoma cells through TGF-β pathway. Moreover, CTLA-4 enhanced the proliferation of Treg cells induced by lymphoma cells. Animal experiments showed that CTLA-4 can promote transplanted lymphoma growth. Immunohistochemistry results showed that both Ki-67 and CD44+ cells increased significantly in the CTLA-4 group. TGF-β neutralization can significantly block these effects of CTLA-4. In conclusion, CTLA-4 promoted DLBCL progression through lymphoma stem cell enrichment and immunosuppression.

Shifts in the realized niches of exotic species may play an important role in their invasion. Galinsoga quadriradiata has invaded China widely and occupied many climate zones that are different from its native range. We addressed the climatic niche shift of G. quadriradiata and evaluated how this could contribute to its invasion in China. We used the Maxent model to predict the potential distribution of G. quadriradiata using its native and invaded range occurrences and climatic variables. Principal component analysis was conducted to measure climatic niche shifts of G. quadriradiata during its invasion in China. The models revealed only 32.7% niche overlap between the native and invasive populations. The niche similarity of the two populations was significantly low (Schoener’s D = 0.093, P < 0.005), suggesting the occurrence of a niche shift. The envelop and center of the realized climatic niche in China has shifted to lower temperature and less precipitation compared to that in its native range. The majority of invaded areas in southern China are in the stabilizing zone, whereas the colonization and adaptation zones are predicted to be at the leading edge of G. quadriradiata invasion in northern China. This suggests that the regional distribution of G. quadriradiata may be in a quasi-equilibrium state, and that the species continues to invade environmentally suitable areas. Alterations in G. quadriradiata’s niche would help to explain why this species is so invasive in China.

A new genus and species, Multistria orthotropagen. et sp. nov., and a new species, Dachibangus huisp. nov., of Mimarachnidae are described from the mid-Cretaceous Burmese amber. These new taxa display unique wing color patterns and extend the Mesozoic diversity of Mimarachnidae. The evolution of wing venation, phylogenetic placement of Mimarachnidae, and anti-predation defenses of this family in Burmese amber forest are briefly discussed.

Invariant natural killer T cells (iNKTs) bridge the innate immunity with the adaptive immunity and their interaction with B cells has been extensively studied. Here, we give a complete overview of these two cells, from their mechanism of interaction to clinical prospects and existing problems. In our introduction, we describe the relationship between iNKTs and B cells and explore the current research hotspots and future directions. We begin with how B cells interact and benefit from the innate and adaptive help of iNKTs. Next, we describe the multiple roles of these cells in infections, autoimmunity, and cancers. Lastly, we look into the potential immunotherapies that can be based on iNKTs and the possible treatments for infectious, autoimmune, and other diseases.

Several microRNAs (miRNAs) and circular RNAs (circRNAs) were reported to be involved in the Docetaxel (DTX) chemoresistance of cancer treatment, but the underlying mechanisms remain to be explored. In this study, we established cellular and animal models respectively to study the effect and underlying molecular mechanisms of the dysregulation of circRNA_0006404 and circRNA_0000735 in tumor response to DTX treatment. Quantitative real-time PCR was performed to measure the expression of circRNA_0006404, miR-346, circRNA_0000735, miR-526b, Dickkopf-related protein 3 (DKK3), and Dickkopf-related protein 4 (DKK4) mRNA. The expression of circRNA_0006404 and circRNA_0000735 was remarkably suppressed and activated in DTX-treated SKOV3-R cell lines, respectively. As revealed by luciferase assays, circRNA_0006404 and circRNA_0000735 was found to be respectively targeted by miR-346 and miR-526b, while DKK3 and DKK4 were respectively targeted by miR-346 and miR-526b. Moreover, the expression of DKK3 and DKK4, which were targets of miR-346 and miR-526b, respectively, was significantly altered along with the expression of p-GP. Furthermore, circ_0006404 shRNA and circRNA_0000735 shRNA showed remarkable efficiency in stimulating the expression of circRNA_0006404, miR-346, DKK3, circRNA_0000735, miR-526b, DKK4, and p-GP in cellular and animal models. Accordingly, the cell apoptosis and proliferation were apparently changed by circ_0006404 shRNA and circRNA_0000735 shRNA in both cellular and animal models. In summary, our study found the involvement of the circRNA_0006404/miR-346/DKK3/p-GP and circRNA_0000735/miR-546b/DKK4/p-GP axis in the tumor response to DTX. Both the up-regulation of circRNA_0006404 and down-regulation of circRNA_0000735 could inhibit the expression of p-GP in vivo and ex vivo, leading to the suppressed tumor response to DTX treatment.

Sweet cherry is one of the most popular fresh fruits in the world. Previously, we isolated a soilborne dark septate endophyte (DSE) strain, S16, which promoted the growth of Gisela 5 sweet cherry rootstock. However, little is known about the molecular mechanism of the effect of S16 on the growth of sweet cherry. In this study, the physiological parameters and transcript profiles of sweet cherry roots were analyzed under S16 treatment compared with a control to elucidate the molecular mechanisms of the effect of this strain on sweet cherry growth. After inoculation with S16, sweet cherry seedlings exhibited more vigorous growth. Moreover, we identified 4249 differentially expressed genes (DEGs) between S16-treated plants and the control. Many of the DEGs are involved in pathways related to plant growth, such as cellular metabolic and plant hormone pathways. Additionally, some genes involved in nitrate regulation were also enriched; and these genes may be involved in the regulation of nitrate uptake in plants. Physiological index detection demonstrated that S16 could improve the nitrate assimilation of sweet cherry via NO3− transporters. This RNA-seq dataset provides comprehensive insight into the transcriptomic landscape to reveal the molecular mechanisms whereby the DSE influences the growth of sweet cherry.

Two new species of the small and rarely collected family Megalyridae are described from China: Carminator daliensis Chen & Liuhe, sp. nov. from Yunnan and Ettchellsia hainanensis Chen & Liuhe, sp. nov. from Hainan. A key to megalyrid species of China is provided. The biogeographical implication of the new taxa is discussed.

International audience; Many insects metamorphose from antagonistic larvae into mutualistic adult pollinators, with reciprocal adaptation leading to specialized insect-plant associations. It remains unknown how such interactions are established at molecular level. Here we assemble high-quality genomes of a fig species, Ficus pumila var. pumila, and its specific pollinating wasp, Wiebesia pumilae. We combine multi-omics with validation experiments to reveal molecular mechanisms underlying this specialized interaction. In the plant, we identify the specific compound attracting pollinators and validate the function of several key genes regulating its biosynthesis. In the pollinator, we find a highly reduced number of odorant-binding protein genes and an odorant-binding protein mainly binding the attractant. During antagonistic interaction, we find similar chemical profiles and turnovers throughout the development of galled ovules and seeds, and a significant contraction of detoxification-related gene families in the pollinator. Our study identifies some key genes bridging coevolved mutualists, establishing expectations for more diffuse insect-pollinator systems.

Fish as an important food source, with the increase of consumption rate, the resulting allergic phenomenon increased year by year. Food allergen in aquatic products was an important allergy-inducing factor, which had a great impact on the body’s tissue, inflammatory factors, immunoglobulin and intestinal flora. The research objective of this study was to evaluate the allergenic risk of turbot parvalbumin (PV) and provided effective biological reference markers for the safety assessment of aquatic products. Results showed PV has high purity, high binding capacity with IgE and IgG, influenced release of inflammatory factors in DCs (IL-6/10/12p70), induced allergic response in mice. PV increased the levels of PV-specific IgE, total IgE, IgG1, monocyte chemotactic protein 1(MCP-1), histamine, tryptase significantly. PV obviously mutagenic effect on spleen, intestinal tissue. Sequencing of microbial diversity showed that microorganism Ruminiclostridium and Alistipes in PV group changed significantly, which proved that the structure of intestinal microorganism has changed. In summary, Turbot parvalbumin triggered fish allergic responses by induced imbalance of inflammatory factors and microbial composition of IL-6/10/12p70, IgE/IgG and Ruminiclostridium, Alistipes. These results indicated that PV had high-risk allergy inducing ability, and the changes of the above indicators provided biological reference markers for risk assessment of the safety of aquatic products intake.

Purpose PR loss in ER+/HER2- breast cancer indicates worse prognosis and insensitivity to anti-estrogen therapy, while the mechanisms of PR loss in ER+/HER2- breast cancer remain unrevealed. Methods In this study, ER+/PR+/HER2- and ER+/PR-/HER2- breast cancer cases from TCGA were used. 1387 pathways were analyzed and used as variables for classifying the two groups with LASSO regression. Results ER+/PR+/HER2- and ER+/PR-/HER2- breast cancer groups can be classified by a combination of 13 pathways using their activity score. Among the 13 pathways, those involving growth factors and ion-channel transporters were most significant in the distinction, followed by pathways involving immune modulation and cell metabolism. Two growth factor pathways, EGF and IGF-1, were deferentially regulated in ER+/PR+/HER2- and ER+/PR-/HER2- groups. Conclusions In conclusion, this study indicated in ER+/HER2- breast cancers the various status of PR expression can be an indication of molecular variation, particularly for the growth factor pathway activation.

Qing Song,1– 3 Yi-Yang Zhao,1– 3 Yu-Qin Zeng,1– 3 Cong Liu,1– 3 Wei Cheng,1– 3 Min-Hua Deng,4 Xin Li,5 Li-Bing Ma,6 Yan Chen,1– 3 Shan Cai,1– 3 Ping Chen1– 3 1Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 4Department of Respiratory, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, People’s Republic of China; 5Division 4 of Occupational Disease, Hunan Occupational Disease Prevention and Treatment Hospital, Changsha, Hunan, 410000, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541000, People’s Republic of ChinaCorrespondence: Ping ChenDepartment of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, Hunan, 410011, People’s Republic of ChinaTel +86 731 8529 5248Fax +86 731 8529 5848Email pingchen0731@csu.edu.cnBackground: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 separated pulmonary function from combined assessment. We aimed to analyze the characteristics of airflow limitation and future exacerbations in different GOLD groups of chronic obstructive pulmonary disease (COPD) patients.Methods: For this prospective observational study, stable COPD outpatients were enrolled and divided into Groups A, B, C and D based on GOLD 2017, and followed-up for 18 months. Data on demographics, pulmonary function, COPD assessment test (CAT), Clinical COPD Questionnaire (CCQ), modified Medical Research Council (mMRC), exacerbations, mortality and treatments were collected. A post-bronchodilator ratio of forced expiratory volume in one second to forced vital capacity < 0.70 confirms the presence of airflow limitation.Results: A total of 993 subjects were classified into Groups A (n = 170, 17.1%), B (n = 360, 36.3%), C (n = 122, 12.3%), and D (n = 341, 34.3%). There were significant differences in mMRC, CAT, CCQ, exacerbations and hospitalizations rates among the different groups (P < 0.001). Groups B and D had more severe airflow limitation than Groups A and C (P < 0.05). In the same groups with different severity of airflow limitation, the differences were mainly observed in body mass index, CAT, CCQ and treatment with long-acting muscarinic antagonist (LAMA) and LAMA + long-acting β 2-agonist + inhaled corticosteroid (P < 0.05). After 18 months of follow-up, the exacerbations and hospitalizations rates were significantly different among different groups (P < 0.05). However, in the same groups with different airflow limitation severity, the mortality rates and number of exacerbations, hospitalizations and frequent exacerbators showed no differences.Conclusion: In the GOLD groups, different severity of airflow limitation had no impact on future exacerbations and mortality rate. It implies that pulmonary function is not a good indicator for predicting exacerbation.Keywords: chronic obstructive pulmonary disease, Global Initiative for Chronic Obstructive Lung Disease, pulmonary function, exacerbation

Ubiquitin-specific peptidase 18 (USP18) plays an important role in the development of CD11b + dendritic cells (DCs) and Th17 cells, however, its role in the differentiation of other T cell subsets, especially in regulatory T (Treg) cells, is unknown. In our study, we used Usp18 KO mice to study the loss of USP18 on the impact of Treg cell differentiation and function. We found that USP18 deficiency upregulates the differentiation of Treg cells, which may lead to disrupted homeostasis of peripheral T cells, and downregulates INF-γ, IL-2, IL-17A producing CD4 + T cells and INF-γ producing CD8 + T cells. Mechanistically, we also found that the upregulation of Tregs is due to elevated expression of CD25 in Usp18 KO mice. Finally, we found that the suppressive function of Usp18 KO Tregs is downregulated. Altogether, our study was the first to identify the role of USP18 in Tregs differentiation and its suppressive function, which may provide a new reference for the treatment of Treg function in many autoimmune diseases, and USP18 can be used as a new therapeutic target for precise medical treatment.

AIMS This study aims to evaluate the effects of dexmedetomidine on organ function, inflammation response, and oxidative stress in elderly patients following iatrogenic lower limb ischaemia-reperfusion (IR) during unilateral total knee arthroplasty. METHODS Following unilateral total knee arthroplasty, 54 elderly patients were randomized to receive either intraoperative intravenous injection of dexmedetomidine (n = 27) or equivalent volume of 0.9% saline (n = 27). Blood samples were harvested at 5 minutes before lower limb tourniquet release (baseline); and 1, 6 and 24 hours after tourniquet release. Surrogate markers of cardiac, pulmonary, hepatic and renal function, oxidative stress, inflammatory response, along with parasympathetic and sympathetic activity were recorded and analysed. RESULTS The levels of blood xanthine oxidase, creatine kinase, lactic acid and respiratory index increased in patients following tourniquet-induced lower limb IR injury. Dexmedetomidine administration decreased the respiratory index (P = .014, P = .01, and P = .043) and the norepinephrine level (P

Ying Cao,1,&ast; Yibei Dai,1,&ast; Lingyu Zhang,1 Danhua Wang,1 Wen Hu,2 Qiao Yu,3 Xuchu Wang,1 Pan Yu,1 Weiwei Liu,1 Ying Ping,1 Tao Sun,1 Yiwen Sang,1 Zhenping Liu,4 Yan Chen,3 Zhihua Tao1 1Department of Laboratory Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, People’s Republic of China; 2National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, People’s Republic of China; 3Center for Inflammatory Bowel Diseases, Department of Gastroenterology, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, People’s Republic of China; 4Department of Laboratory Medicine, the First People’s Hospital of Yuhang District, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Chen; Zhihua Tao Tel +86 571 8778 3752Fax +86 571 8689 8730Email chenyan72_72@zju.edu.cn; zrtzh@zju.edu.cnBackground: Fecal biomarkers have emerged as one of the most useful tools for clinical management of inflammatory bowel disease (IBD). Oncostatin M (OSM), like fecal calprotectin (FC), is highly expressed in the inflamed intestinal mucosa which may have potential usefulness. We aimed to evaluate the additional utility of these two fecal biomarkers for IBD diagnosis, activity, and prediction of infliximab response over FC alone.Methods: In group 1, 236 IBD patients (145 Crohn’s disease, 91 ulcerative colitis), 50 disease controls, and 32 healthy controls were recruited for IBD diagnosis and activity. In group 2, baseline stool samples were collected from 62 patients to predict infliximab response at week 28 and 52. The performance of fecal biomarkers for IBD management was assessed by the area under the receiver operating characteristic curve (AUC).Results: Fecal OSM and FC levels were increased in IBD patients and were positively correlated with clinical and endoscopic activity. Their combination showed a better ability for disease diagnosis (AUC = 0.93) and slightly improved the capability to identify mucosal healing (AUC = 0.923). Baseline OSM and FC levels were elevated in non-responders at week 28 and 52. The AUCs of OSM, FC, and their combination to predict therapeutic response were 0.763, 0.834, and 0.859 at week 28, 0.638, 0.661, and 0.704 at week 52, respectively. Combined use of fecal and blood biomarkers improved predictive accuracy with an AUC of 0.919 at week 28 and 0.887 at week 52.Conclusion: In addition to FC, OSM is a novel fecal biomarker, and their combination is more beneficial for disease diagnosis and prediction of infliximab response but not for disease activity in IBD patients. Further larger-scale studies are required to confirm our findings.Keywords: inflammatory bowel disease, fecal biomarkers, oncostatin M, calprotectin, diagnosis, activity, infliximab response

Chemokines are important regulators of the immune system, inducing specific cellular responses by binding to receptors on immune cells. In SLE patients, decreased expression of CCL2 on mesenchymal stem cells (MSC) prevents inhibition of B-cell proliferation, causing the characteristic autoimmune phenotype. Nevertheless, the intrinsic role of CCL2 on B-cell autoimmunity is unknown. In this study using Ccl2 KO mice, we found that CCL2 deficiency enhanced BCR signaling by upregulating the phosphorylation of the MST1-mTORC1-STAT1 axis, which led to reduced marginal zone (MZ) B cells and increased germinal center (GC) B cells. The abnormal differentiation of MZ and GC B cells were rescued by in vivo inhibition of mTORC1. Additionally, the inhibition of MST1-mTORC1-STAT1 with specific inhibitors in vitro also rescued the BCR signaling upon antigenic stimulation. The deficiency of CCL2 also enhanced the early activation of B cells including B-cell spreading, clustering and signalosome recruitment by upregulating the DOCK8-WASP-actin axis. Our study has revealed the intrinsic role and underlying molecular mechanism of CCL2 in BCR signaling, B-cell differentiation, and humoral response.

Summary Safflower (Carthamus tinctorius L.), a member of the Asteraceae, is a popular crop due to its high linoleic acid (LA) and flavonoid (such as hydroxysafflor yellow A) contents. Here, we report the first high‐quality genome assembly (contig N50 of 21.23 Mb) for the 12 pseudochromosomes of safflower using single‐molecule real‐time sequencing, Hi‐C mapping technologies and a genetic linkage map. Phyloge nomic analysis showed that safflower diverged from artichoke (Cynara cardunculus) and sunflower (Helianthus annuus) approximately 30.7 and 60.5 million years ago, respectively. Comparative genomic analyses revealed that uniquely expanded gene families in safflower were enriched for those predicted to be involved in lipid metabolism and transport and abscisic acid signalling. Notably, the fatty acid desaturase 2 (FAD2) and chalcone synthase (CHS) families, which function in the LA and flavonoid biosynthesis pathways, respectively, were expanded via tandem duplications in safflower. CarFAD2‐12 was specifically expressed in seeds and was vital for high‐LA content in seeds, while tandemly duplicated CarFAD2 genes were up‐regulated in ovaries compared to CarFAD2‐12, which indicates regulatory divergence of FAD2 in seeds and ovaries. CarCHS1, CarCHS4 and tandem‐duplicated CarCHS5˜CarCHS6, which were up‐regulated compared to other CarCHS members at early stages, contribute to the accumulation of major flavonoids in flowers. In addition, our data reveal multiple alternative splicing events in gene families related to fatty acid and flavonoid biosynthesis. Together, these results provide a high‐quality reference genome and evolutionary insights into the molecular basis of fatty acid and flavonoid biosynthesis in safflower.

This study was to investigate the effects of oxidative stress in cigarette smoke (CS)-induced cell apoptosis in mice with emphysema. Thirty-two mice were divided into four groups: the control group, the CS group, the CS + Pifithrin-α group, and the CS + NAC group. Pathological changes and apoptosis in lung tissue of mice were detected. The activity of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (T-AOC) were measured using spectrophotometer. The proteins expression of p53, Bcl-2, Bax, and caspase-3 were determined by western blot. The results showed that cell apoptosis, lung structural damage, and the activity of MDA, as well as the expression of apoptosis-related proteins Bax, total caspase-3, and cleaved caspase-3 were increased in CS-treated mice. The activity of SOD, CAT, and T-AOC, as well as the expression of anti-apoptosis protein Bcl-2 were decreased in CS-treated mice when compared with the control group. However, Pifithrin-α (p53 inhibitor) and N-Acetylcysteine (NAC) could reduce cell apoptosis, lung structural damage and oxidative stress, accelerate the expression of Bcl-2, while suppressing the expression of Bax, total caspase-3 and cleaved caspase-3. More importantly, the treatment with NAC even inhibited the expression of p53. In conclusions, oxidative stress linking the p53 is involved in cell apoptosis in CS-treated emphysema mice.

Goal: Idiopathic generalized epilepsy (IGE) represents generalized spike-wave discharges (GSWD) and distributed changes in thalamocortical circuit. The purpose of this study is to investigate how the ongoing alpha oscillation acts upon the local temporal dynamics and spatial hyperconnectivity in epilepsy. Methods: We evaluated the spatiotemporal regulation of alpha oscillations in epileptic state based on simultaneous EEG-fMRI recordings in 45 IGE patients. The alpha-BOLD temporal consistency, as well as the effect of alpha power windows on dynamic functional connectivity strength (dFCS) was analyzed. Then, stable synchronization networks during GSWD were constructed, and the spatial covariation with alpha-based network integration was investigated. Results: Increased temporal covariation was demonstrated between alpha power and BOLD fluctuations in thalamus and distributed cortical regions in IGE. High alpha power had inhibition effect on dFCS in healthy controls, while in epilepsy, high alpha windows arose along with the enhancement of dFCS in thalamus, caudate and some default mode network (DMN) regions. Moreover, synchronization networks in GSWD-before, GSWD-onset and GSWD-after stages were constructed, and the connectivity strength in prominent hub nodes (precuneus, thalamus) was associated with the spatially disturbed alpha-based network integration. Conclusion: The results indicated spatiotemporal regulation of alpha in epilepsy by means of the increased power and decreased coherence communication. It provided links between alpha rhythm and the altered temporal dynamics, as well as the hyperconnectivity in thalamus-default mode circuit. Significance: The combination between neural oscillations and epileptic representations may be of clinical importance in terms of seizure prediction and non-invasive interventions.

BACKGROUND Spontaneous renal rupture is a rare disease in the clinic. The causes of spontaneous renal rupture include extrarenal factors, intrarenal factors, and idiopathic factors. Reports on infection secondary to spontaneous renal rupture and the complications of spontaneous renal rupture are scarce. Furthermore, there are few patients with spontaneous renal rupture who present only with fever. CASE SUMMARY We present the case of a 52-year-old female patient who was admitted to our hospital. She presented only with fever, and the cause of the disease was unclear. She underwent a contrast-enhanced computed tomography (CT) scan, which showed that the left renal capsule had a crescent-shaped, low-density shadow; the perirenal fat was blurred, and exudation was visible with no sign of calculi, malignancies, instrumentation, or trauma. Under ultrasound guidance, a pigtail catheter was inserted into the hematoma, and fluid was drained and used for the bacterial test, which proved the presence of Klebsiella pneumoniae. Two months later, abdominal CT showed that the hematoma was absorbed, so the drainage tube was removed. The abdominal CT was normal after 4 mo. CONCLUSION Spontaneous renal rupture due to intrarenal factors causes a higher proportion of shock and is more likely to cause anemia.

Biliary atresia (BA) is an immune-related disorder and signal transducer and activator of transcription 3 (STAT3) is a key signalling molecule in inflammation. The present study was designed to clarify the function of STAT3 in BA. STAT3 expression was examined in patients and a mouse BA model in which STAT3 levels were further altered with a specific inhibitor or activator. Neutrophil accumulation and the levels of the neutrophil chemoattractants (C–X–C motif) ligand 1 (CXCL1) and IL-8 were determined. The effects of STAT3 inhibition on IL-8 expression were examined in human biliary epithelial cell (BEC) cultures. Functional changes in liver STAT3+ neutrophils in the mouse model were analysed with 10× single cell RNA-seq methods. Results showed STAT3 and p-STAT3 expression was reduced in BA liver tissue compared with control samples. Administration of a STAT3 inhibitor increased jaundice and mortality and reduced body weight in BA mice. In contrast, the STAT3 activator ameliorated BA symptoms. Extensive neutrophil accumulation together with CXCL1 up-regulation, both of which were suppressed by an anti-CXCL1 antibody, were observed in the STAT3 inhibitor-treated group. Recombinant IL-8 administration increased disease severity in BA mice, and the STAT3 activator had the reverse effect. Inhibiting STAT3 increased apoptosis of human BECs together with up-regulated IL-8 expression. RNA-seq analysis revealed reduced the numbers of STAT3 expressing neutrophil in BA which was accompanied by marked enhanced interferon-related antiviral activities. In conclusion, STAT3 reduction, enhanced IL-8 and CXCL1 expression and promoted the accumulation of interferon-responsive neutrophils resulting in BEC damage in BA.

Actin cytoskeleton dynamic rearrangement is required for tumor cell metastasis and is a key characteristic of Helicobacter pylori (H. pylori)-infected host cells. Actin cytoskeleton modulation is coordinated by multiple actin-binding proteins (ABP). Through Kyoto encyclopedia of gene and genomes database, GEPIA website, and real-time PCR data, we found that H. pylori infection significantly induced L-plastin, a key ABP, in gastric cancer cells. We further explored the regulation and function of L-plastin in H. pylori–associated gastric cancer and found that, mechanistically, H. pylori infection induced gastric cancer cells to express L-plastin via cagA-activated ERK signaling pathway to mediate SP1 binding to L-plastin promoter. Moreover, this increased L-plastin promoted gastric cancer cell proliferation and migration in vitro and facilitated the growth and metastasis of gastric cancer in vivo. Finally, we detected the expression pattern of L-plastin in gastric cancer tissues, and found that L-plastin was increased in gastric cancer tissues and that this increase of L-plastin positively correlated with cagA+ H. pylori infection status. Overall, our results elucidate a novel mechanism of L-plastin expression induced by H. pylori, and a new function of L-plastin–facilitated growth and metastasis of gastric cancer, and thereby implicating L-plastin as a potential therapeutic target against gastric cancer. Implications: Our results elucidate a novel mechanism of L-plastin expression induced by H. pylori in gastric cancer, and a new function of L-plastin–facilitated gastric cancer growth and metastasis, implicating L-plastin as a potential therapeutic target against gastric cancer.

Peripheral nerve injury could lead to chronic neuropathic pain. Understanding transcriptional changes induced by nerve injury could provide fundamental insights into the complex pathogenesis of neuropathic pain. Gene expression profiles of dorsal root ganglia (DRG) in neuropathic pain condition have been studied. However, little is known about transcriptomic changes in individual DRG neurons after peripheral nerve injury. Here we performed single-cell RNA sequencing on dissociated mouse DRG cells after spared nerve injury (SNI). In addition to DRG neuron types that are found under physiological conditions, we identified three SNI-induced neuronal clusters (SNIICs) characterized by the expression of Atf3/Gfra3/Gal (SNIIC1), Atf3/Mrgprd (SNIIC2) and Atf3/S100b/Gal (SNIIC3). These SNIICs originated from Cldn9(+)/Gal(+), Mrgprd(+) and Trappc3l(+) DRG neurons, respectively. Interestingly, SNIIC2 switched to SNIIC1 by increasing Gal and reducing Mrgprd expression 2 days after nerve injury. Inferring the gene regulatory networks after nerve injury, we revealed that activated transcription factors Atf3 and Egr1 in SNIICs could enhance Gal expression while activated Cpeb1 in SNIIC2 might suppress Mrgprd expression within 2 days after SNI. Furthermore, we mined the transcriptomic changes in the development of neuropathic pain to identify potential analgesic targets. We revealed that cardiotrophin-like cytokine factor 1, which activates astrocytes in the dorsal horn of spinal cord, was upregulated in SNIIC1 neurons and contributed to SNI-induced mechanical allodynia. Therefore, our results provide a new landscape to understand the dynamic course of neuron type changes and their underlying molecular mechanisms during the development of neuropathic pain.

The genus Bidens (Asteraceae) encompasses over 240 different species. One of them is Bidens pilosa L. that is an easy‐to‐grow perennial, and broadly distributed in tropical and subtropical regions of the world. This plant has been regarded as an edible plant by the Food and Agriculture Organization of the United Nations since 1975, and has been traditionally used as a food and medicine in America, Africa, and Asia. B. pilosa has been claimed to possess active compounds with more than 40 distinct bioactivities. Although considerable progress has been made in studying the phytochemistry and biology of B. pilosa and its compounds over recent years, a critical review of its dietary functions for metabolic syndrome is unavailable. The present review summarizes the nutrition, benefits, phytochemistry, and safety of B. pilosa with respect to metabolic syndrome. As well as highlighting studies of the use of B. pilosa for metabolic syndrome, scientific evidence regarding the antimetabolic action, mechanism, and application of this species and its active phytochemicals are discussed. This review consolidates information for further study into the medicinal benefits of the compounds in this plant.

The Scoliidae occur predominantly in tropical and subtropical regions and are ectoparasitoids of Scarabaeoidea larvae (especially of Melolonthinae) which are immobilised, parasitised by the female wasp in their terrestrial larval gallery and buried deeper in a special cell by the female wasp. Herein, we provided, for the first time, illustrated keys to 11 genera and 52 species of Scoliidae from China, based on specimens in the Naturalis Biodiversity Center (RMNH, Leiden) and additional specimens from the Chinese Academy of Insect Science (Beijing), Zhejiang University (ZJUH, Hangzhou) and Sun Yat-sen University (SYSU, Guangzhou) and it is a first attempt to make keys available for all the Scoliidae species in China.

Transcription-induced chimeric RNAs are an emerging area of research into molecular signatures for disease biomarker and therapeutic target development. Despite their importance, little is known for chimeric RNAs-relevant roles and the underlying mechanisms for cancer pathogenesis and progression. Here we describe a unique ASTN2-PAPPA(antisense) chimeric RNA (A-P-as chiRNA) that could be the first reported chimeric RNA derived from the splicing of exons and intron antisense of two neighboring genes, respectively. Aberrant A-P-as chiRNA level in ESCC tissues was associated with tumor progression and patients' outcome. In vitro and in vivo studies demonstrated that A-P-as chiRNA aggravated ESCC metastasis and enhanced stemness through modulating OCT4. Mechanistic studies demonstrated that ERK5-mediated non-canonical PAF1 activity was required for A-P-as chiRNA-induced cancer malignancy. The study defined an undocumented function of chimeric RNAs in aggravating cancer stemness and metastasis.

Chronic hepatitis B virus (HBV) infection is one of the major global health problems. Although the small protein of hepatitis B virus surface antigen (HBsAg), SHBs, is the most abundant HBV viral protein, its pathogenic role and molecular mechanism in malignant progression of HBV-related hepatocellular carcinoma (HCC) remain largely unknown. Here we reported that SHBs expression induced epithelial-mesenchymal transition (EMT) process in HCC cells and significantly increased their migratory and invasive ability as well as metastatic potential. Mechanistically, SHBs expression in HCC cells induced endoplasmic reticulum (ER) stress that activated the activating transcription factor 4 (ATF4) to increase the expression and secretion of fibroblast growth factor 19 (FGF19). The autocrine released FGF19 in turn activated JAK2/STAT3 signaling for induction of EMT process in HCC. Notably, SHBs was positively correlated with the expression of mesenchymal markers, the phosphorylation status of JAK2 and STAT3 as well as FGF19 levels in human HCC samples. HCC patients with SHBs positive had a more advanced clinical stage and worse prognosis. These results suggest an important role of SHBs in the metastasis and progression of HCC and may highlight a potential target for preventive and therapeutic intervention of HBV-related HCC and its malignant progression.

Background Chemically strategies to generate hepatic cells from human pluripotent stem cells (hPSCs) for the potential clinical application have been improved. However, producing high quality and large quantities of hepatic cells remain challenging, especially in terms of step-wise efficacy and cost-effective production requires more improvements. Methods Here, we systematically evaluated chemical compounds for hepatoblast (HB) expansion and maturation to establish a robust, cost-effective, and reproducible methodology for self-renewal HBs and functional hepatocyte-like cell (HLC) production. Results The established chemical cocktail could enable HBs to proliferate nearly 3000 folds within 3 weeks with preserved bipotency. Moreover, those expanded HBs could be further efficiently differentiated into homogenous HLCs which displayed typical morphologic features and functionality as mature hepatocytes including hepatocyte identity marker expression and key functional activities such as cytochrome P450 metabolism activities and urea secretion. Importantly, the transplanted HBs in the injured liver of immune-defect mice differentiated as hepatocytes, engraft, and repopulate in the injured loci of the recipient liver. Conclusion Together, this chemical compound-based HLC generation method presents an efficient and cost-effective platform for the large-scale production of functional human hepatic cells for cell-based therapy and drug discovery application.

Zhiguo Zhong,1 Yuyun Li,2,3 Yan Chen,2,3 Wen Chen,2 Siyan Li,4 Xiaohua Lv,2 Shiying Luo2 1Traditional Chinese Medicine Department, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524023, People’s Republic of China; 2Department of Pharmacology, School of Pharmacy, Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, 524023, People’s Republic of China; 3Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, 523808, People’s Republic of China; 4School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of ChinaCorrespondence: Shiying LuoDepartment of Pharmacology, School of Pharmacy, Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Biomedical Research Institute, Guangdong Medical University, No. 2 East Wenming Road, Xiashan District, Zhanjiang, 524023, Guangdong, People’s Republic of ChinaTel +86 13763058766Fax +86 7592388588Email luosy76@gdmu.edu.cnBackground: Erzhi Pill (EZP), a traditional Chinese medicine (TCM) prescription, has been widely applied to improve bone metabolism and treat osteoporosis (OP) in China. However, its effective constituents and mechanisms remain unclear.Methods: By combining network pharmacology and zebrafish experiments, an integrative method was employed to address this problem. Firstly, the disease targets of OP were collected from two public gene databases. Secondly, the active compounds and drug targets of EZP were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). Thirdly, a drug-target-disease interaction network was constructed, and the key active components were identified by analyzing the topological characteristics of the network. Finally, these predicted results were tested by zebrafish experiments and compared with those from the literature. Specifically, quercetin as an important representative active component of EZP was applied to wild type and transgenic zebrafish larvae to assess its effects on skull mineralization and osteoplastic differentiation.Results: Our study identified 72 active compounds, 220 targets and 166 signaling pathways probably involved in the prevention and treatment of OP by EZP, wherein quercetin, apigenin, daidzein, luteolin, ursolic acid and kaempferol could be the key compounds, while PI3K-Akt signaling pathway, TNF signaling pathway and IL-17 signaling pathway could be the key signaling pathways. The experiments indicated that quercetin attenuated both the decrease of skull mineralization and the inhibition of skull osteoplastic differentiation in zebrafish larvae trigged by dexamethasone.Conclusion: Our study not only investigated potentially effective constituents and mechanisms of EZP in the prevention and treatment of OP, but also provided a reference for the in-depth research, development and application of TCM.Keywords: Erzhi Pill, osteoporosis, network pharmacology, mechanisms, zebrafish, quercetin

Introduction Endothelial dysfunction appears in many smoking-related diseases, it is also an important pathophysiological feature. Endothelial progenitor cells (EPCs) are precursors of endothelial cells and have a crucial effect on the repair and maintenance of endothelial integrity. Sca-1 is not only common in bone marrow-derived hematopoietic stem cells (HSCs), but it is also expressed in nonhematopoietic organs by tissue-resident stem and progenitor cells. The aim of this study is to investigate the impact of cigarette smoke extract (CSE) on the function of bone marrow-derived EPCs and the expression level of Sca-1 in EPCs, and also whether the methylation of Sca-1 is involved in EPC dysfunction. Methods We measured EPC capacities including adhesion, secretion and proliferation, the concentration of endothelial nitric oxide synthase (eNOS) and apoptosis-inducing factor (AIF) in cell culture supernatant, and also Sca-1 expression and promoter methylation in EPCs induced by CSE. Decitabine (Dec) was applied to test whether it could alter the impact caused by CSE. Results The adhesion, proliferation and secretion ability of EPCs can be induced to be decreased by CSE in vitro, accompanied by decreased concentrations of AIF and eNOS in cell culture supernatant and decreased Sca-1 expression in EPCs. In addition, Dec could partly attenuate the impact described above. There were no significant differences in the quantitative analysis of Sca-1 promoter methylation among different groups. Conclusions The decreased Sca-1 expression was related to EPC dysfunction induced by CSE. EPC dysfunction resulting from CSE may be related to methylation mechanism, but not the methylation of Sca-1 promoter.