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Myeloid-derived suppressor cells (MDSCs) are heterogeneous myeloid cell populations with immunosuppressive capacity, which contribute to immune regulation and tolerance induction. We previously reported impaired MDSC function in patients with primary Sjögren’s syndrome (pSS) and mice with experimental SS (ESS). However, the molecular mechanisms underlying MDSCs dysfunction remain largely unclear. In this study, we first found that aryl hydrocarbon receptor (AhR) was highly expressed by human and murine polymorphonuclear MDSCs (PMN-MDSCs). Indole-3-propionic acid (IPA), a natural AhR ligand produced from dietary tryptophan, significantly promoted PMN-MDSC differentiation and their suppressive function on CD4+ T cells. In contrast, feeding tryptophan-free diet resulted in decreased PMN-MDSC response, a phenotype that could be reversed by IPA supplementation. The functional importance of PMN-MDSCs was demonstrated in ESS mice by cell-depletion approach. Notably, AhR expression was reduced in PMN-MDSCs during ESS development, while AhR antagonism resulted in exacerbated ESS pathology and dysregulated T effector cells, which could be phenocopied by tryptophan-free diet. Interferon regulatory factor 4 (IRF4), a repressive transcription factor, was upregulated in PMN-MDSCs during ESS progression. Chromatin immunoprecipitation analysis revealed the binding capacity of IRF4 to the promoter region of AhR, while IRF4 deficiency markedly enhanced AhR-mediated PMN-MDSC responses. Furthermore, dietary supplementation of IPA markedly ameliorated salivary glandular pathology in ESS mice with restored MDSC immunosuppressive function. Together, our results identify a novel function of AhR in modulating PMN-MDSC response and demonstrate the therapeutic potential of targeting AhR for the treatment of pSS.

Chinese goldthread (Coptis chinensis Franch.) is an important medicinal plant worldwide. However, its clinical safety is negatively impacted by high cadmium (Cd) and chromium (Cr) levels. Understanding the accumulation pattern and detoxification mechanism of heavy metals, such as Cd and Cr, is important for regulating their transportation and reducing their accumulation in plants. Free amino acids (FAAs), metallothioneins, and chemical forms of heavy metals are closely associated with heavy metal accumulation and detoxification mechanisms. In the present study, we evaluated the uptake of Cd and Cr in Chinese goldthread and characterized the changes in FAA levels, CcMT2, a metallothionein gene, expression under Cd and Cr stress, and Cr chemical forms in various tissues of Chinese goldthread. The majority of Cd and Cr was retained in the roots; this might be the tolerance strategy utilized by Chinese goldthread to protect the aboveground photosynthetic tissues. A chemical continuous extraction method was utilized to analyze the chemical forms of Cr, and the results suggested that Cr was primarily fixed by oxalate in all tissues, and after Cr treatment, Cr tended to combine with phosphate to form an insoluble complex that reduced the toxicity and bioavailability of Cr in Chinese goldthread. The accumulation of Cd and Cr was significantly positively correlated with valine, histidine, threonine, tyrosine, and serine levels and significantly negatively correlated with glutamic acid and alanine levels. The variation in proline levels under Cd stress was different than that under Cr stress. FAAs might affect the accumulation of and resistance to Cd and Cr through various detoxification strategies, such as chelation with heavy metals ions and conversion into the required products. Furthermore, CcMT2 was isolated for the first time and found to be dominantly expressed in leaves. CcMT2 was induced under Cd and Cr stress in all plant tissues, indicating its role in the accumulation of and tolerance to Cd and Cr.

Many real-world systems involving higher-order interactions can be modeled by hypergraphs, where vertices represent the systemic units and hyperedges describe the interactions among them. In this paper, we focus on the problem of hyperlink prediction which aims at inferring missing hyperlinks based on observed hyperlinks. We propose three similarity indices for hyperlink prediction based on local random walks and Jensen-Shannon divergence. Numerical experiments show that the proposed indices outperform the state-of-the-art methods on a broad range of datasets., IoP Latex, 15 pages, 1 figures

A great many circular RNAs (circRNAs) are considered key modulators of human malignancies. However, the function of circRNA lysophosphatidic acid receptor 3 (LPAR3) in the radioresistance of prostate cancer (PCa) cells is still uncertain. circLPAR3, microRNA (miR)-329-3p, and JPT1 expression in PCa tissues and cells were detected by real-time quantitative PCR or western blot. Cell proliferation was detected by CCK-8 (cell proliferation assay) and colony formation assay, apoptosis was by flow cytometry, and migration and invasion ability were by Transwell assay. Cell glycolysis was analyzed by glucose uptake, lactate production, and ATP metabolism. Under different doses of radiation, the radiosensitivity of PCa cells was detected by colony formation assay. The relationship between circLPAR3, miR-513b-5p, and JPT1 was confirmed by dual luciferase reporter gene detection and RIP assay. The data presented that circLPAR3 and JPT1 expression was elevated in PCa, while miR-513b-5p expression was reduced. Repression of circLPAR3 depressed cell advancement, and restrained glycolysis, but enhanced the radiosensitivity of PCa cells. CircLPAR3’s target miRNA was miR-513b-5p which targeted JPT1. Elevated JPT1 reversed the repressive effects of circLPAR3 knockdown or miR-513b-5p overexpression on PCa advancement, glycolysis, and radiosensitivity. In summary, the knockdown of circLPAR3 reduces glycolysis, but promotes PCa radiosensitivity via the miR-513b-5p/JPT1 axis, discovering a novel mechanism in PCa progression.

The CuPt-A type ordered CdZnTe phases have first been characterized comprehensively in CdZnTe single crystals. The possible crystal structure and formation mechanism of such ordered phase have been proposed based on the TEM results.

Cancer progression can be regulated by noncoding circular RNAs. A recent study has indicated that circ_0044556 facilitated the progression of colorectal cancer. This research was performed to explore the regulatory mechanism of circ_0044556 in CRC. Circ_0044556, miR-665 and Diaphanous Homolog 1 levels were detected by the quantitative real-time polymerase chain reaction. Cell proliferation analysis was performed by cell counting kit-8 assay and Edu assay. Cell cycle progression was assessed using flow cytometry. The protein examination was conducted using western blot. Transwell assay was used to analyze cell migration and invasion. Dual-luciferase reporter assay was performed to validate the interaction between targets. In vivo research was implemented by xenograft tumor assay. Circ_0044556 was upregulated in colorectal cancer samples and cells. Silencing circ_0044556 inhibited cell proliferation, cell cycle progression, migration, invasion, and epithelial-mesenchymal transition in CRC cells. Circ_0044556 could directly target miR-665 and the function of circ_0044556 was associated with the regulation of miR-665. In addition, Diaphanous Homolog 1 was a target gene for miR-665 and the anti-tumor role of miR-665 in colorectal cancer was dependent on the downregulation of Diaphanous Homolog 1. Diaphanous Homolog 1 level was regulated by circ_0044556 via sponging miR-665 in CRC cells. In vivo assay suggested that circ_0044556 promoted CRC tumor growth by regulating the miR-665 and Diaphanous Homolog 1 levels. Our findings manifested that circ_0044556 functioned as an oncogenic circRNA in colorectal cancer by mediating the miR-665/Diaphanous Homolog 1 axis, elucidating the molecular mechanism of circ_0044556 in CRC progression.

Objectives The genus Reynoutria belonging to the family Polygonaceae is widely distributed in the north temperate zone and used in folk medicine. It is administered as a sedative, tonic and digestive, also as a treatment for canities and alopecia. Herein, we reported a review on traditional uses, phytochemistry and pharmacology reported from 1985 up to early 2022. All the information and studies concerning Reynoutria plants were summarized from the library and digital databases (e.g. ScienceDirect, SciFinder, Medline PubMed, Google Scholar, and CNKI). Key findings A total of 185 articles on the genus Reynoutria have been collected. The phytochemical investigations of Reynoutria species revealed the presence of more than 277 chemical components, including stilbenoids, quinones, flavonoids, phenylpropanoids, phospholipids, lactones, phenolics and phenolic acids. Moreover, the compounds isolated from the genus Reynoutria possess a wide spectrum of pharmacology such as anti-atherosclerosis, anti-inflammatory, antioxidative, anticancer, neuroprotective, anti-virus and heart protection. Summary In this paper, the traditional uses, phytochemistry and pharmacology of genus Reynoutria were reviewed. As a source of traditional folk medicine, the Reynoutria genus have high medicinal value and they are widely used in medicine. Therefore, we hope our review can help genus Reynoutria get better development and utilization.

Oxidative stress and inflammation were considered to be the major mechanisms in liver damage caused by clofibrate (CF). In order to obtain lipid-lowering drugs with less liver damage, the structure of clofibrate was optimized by O-desmethyl anetholtrithione and got the target compound clofibrate-O-desmethyl anetholtrithione (CF-ATT). CF-ATT significantly reduced the levels of plasma triglycerides (TG), total cholesterol (TC) in hyperlipidemia mice induced by Triton WR-1339. In addition, CF-ATT has a significantly protective effect on the liver compared with CF. The liver weight and liver coefficient were reduced. The hepatic function indexes were also decreased, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Histopathological examination of the liver revealed that inflammatory cell infiltration, nuclear degeneration, cytoplasmic loosening and hepatocyte necrosis were ameliorated by administration with CF-ATT. The hepatoprotective mechanism showed that CF-ATT significantly up-regulated Nrf2 and HO-1 protein expression and down-regulated p-NF-κB P65 expression in the liver. CF-ATT has obviously antioxidant and anti-inflammatory activity. These findings suggested that CF-ATT has significant hypolipidemia activity and exact hepatoprotective effect possibly through the Nrf2/NF-κB-mediated signal pathway.

Recent studies have demonstrated a central role for plasma cells in the development of autoimmune diseases, such as systemic lupus erythematosus (SLE). Currently, both the phenotypic features and functional regulation of autoreactive plasma cells during SLE pathogenesis remain largely unclear. In this study, we first found that a major subset of IL-17 receptor-expressing plasma cells potently produced anti-dsDNA IgG upon IL-17A (IL-17) stimulation in SLE patients and lupus mice. Using a humanized lupus mouse model, we showed that the transfer of Th17 cell-depleted PBMCs from lupus patients resulted in a significantly reduced plasma cell response and attenuated renal damage in recipient mice compared to the transfer of total SLE PBMCs. Moreover, long-term BrdU incorporation in lupus mice detected highly enriched long-lived BrdU(+) subsets among IL-17 receptor-expressing plasma cells. Lupus mice deficient in IL-17 or IL-17 receptor C (IL-17RC) exhibited a diminished plasma cell response and reduced autoantibody production with attenuated renal damage, while the adoptive transfer of Th17 cells triggered the plasma cell response and renal damage in IL-17-deficient lupus mice. In reconstituted chimeric mice, IL-17RC deficiency resulted in severely impaired plasma cell generation but showed no obvious effect on germinal center B cells. Further mechanistic studies revealed that IL-17 significantly promoted plasma cell survival via p38-mediated Bcl-xL transcript stabilization. Together, our findings identified a novel function of IL-17 in enhancing plasma cell survival for autoantibody production in lupus pathogenesis, which may provide new therapeutic strategies for the treatment of SLE.

To quantitatively analyze and study the water stability of crushed gravel asphalt mixture by using surface energy theory, the surface energy parameters of crushed gravel samples at 20℃ are tested by using the gas sorption method, and the surface energy parameters of four anti-stripping agent asphalts with different dosages (0%, 0.2%, 0.4%, 0.6%) at 20℃ are tested by using the Wilhelmy plate method. Then, the binding energy of crushed gravel and anti-stripping agent asphalts with different dosages and the surface energy evaluation index of water stability are calculated. On this basis, quantitative analysis and sequencing of water stability of crushed gravel asphalt mixture were carried out. The microscopic mechanism of the anti-stripping agent's improvement on adhesion between crushed gravel and asphalt was analyzed from the angle of surface energy. Marshall test (immersion Marshall test, vacuum saturation Marshall test, freeze-thaw splitting test) with anti-stripping agent contents of 0%, 0.2%, 0.4%, and 0.6% was conducted through strict control of crushed gravel material, gradation, and oil-stone ratio. Results show that (1) the surface energy parameters of crushed gravel are dominated by polar alkali component; (2) the addition of anti-stripping agent will reduce the surface energy of asphalt, thus increasing the wettability of asphalt to aggregate; (3) the improvement of the adhesion between crushed gravel and asphalt by adding anti-stripping agent is mainly reflected in two aspects: reducing the cohesive energy of asphalt itself to increase its wettability to aggregate and increasing the surface energy acid component of asphalt to increase its adhesion binding energy to aggregate; and (4) the order of microscopic surface energy evaluation index of water stability of crushed gravel asphalt mixture is the same as that of macroscopic performance test index, thus demonstrating the accuracy of the surface energy system for quantitative analysis of the water stability of the crushed gravel asphalt mixture.

The hot-injection method was used for the synthesis of ternary metal chalcogenide nanocrystals (NCs) CuInS2 (CIS); this was achieved by using the metal precursors (copper iodide and indium acetate) and four different types of sulfur precursor solutions. It was discovered that CIS NCs synthesized with different sulfur precursor solutions exhibited the chalcopyrite structure with similar particle sizes of ~4.2 nm. As a comparison, CIS NCs synthesized using ODE-S precursor displayed an enhanced luminescence intensity and a long PL decay lifetime, which could be considered as an evidence of improved interior crystallinity.

Background. Fatigue is a common symptom in adults that may cause physical and psychological problems and reduce quality of life. Aromatherapy could possibly provide relief for those suffering from fatigue. Here, we evaluated the effect of aromatherapy on fatigue in adults. Methods. We searched the PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature, SinoMed, Wanfang, and Chinese Scientific Journal Database databases for randomized controlled trials of aromatherapy treatment for fatigue in adults from their inception to June 2021. Two reviewers searched independently, extracted the characteristics of the studies, and assessed the risk of bias using the Cochrane risk-of-bias tool and Stata v. 14.0. Results. Nineteen studies were included in this systematic review. Aromatherapy had a significant effect on fatigue (standardized mean difference −0.64, 95% confidence interval−1.14, −0.15, I2 94.4%, P < 0.001 ). Subgroup analysis according to aromatic type, substance, frequency, treatment duration, intervention, outcomes measurement, and population type showed that aromatherapy had a significantly greater effect in the intervention group, compared to the control group. Funnel plots and Egger’s test indicated no significant publication bias. Conclusion. Our results suggest that aromatherapy ameliorates fatigue in adults who suffer from chronic diseases. A rigorous intervention program and larger randomized controlled trials are needed.

Amphioxus (e.g., Branchiostoma belcheri, Bb) has recently emerged as a new model for studying the origin and evolution of vertebrate immunity. Mammalian lymphocyte-specific tyrosine kinase (Lck) plays crucial roles in T cell activation, differentiation and homeostasis, and is reported to phosphorylate both the ITIM and ITSM of PD-1 to induce the recruitment of phosphatases and thus the inhibitory function of PD-1. Here, we identified and cloned the amphioxus homolog of human Lck. By generating and using an antibody against BbLck, we found that BbLck is expressed in the amphioxus gut and gill. Through overexpression of BbLck in Jurkat T cells, we found that upon TCR stimulation, BbLck was subjected to tyrosine phosphorylation and could partially rescue Lck-dependent tyrosine phosphorylation in Lck-knockdown T cells. Mass spectrometric analysis of BbLck immunoprecipitates from immunostimulants-treated amphioxus, revealed a BbLck-associated membrane-bound receptor LRR (BbLcLRR). By overexpressing BbLcLRR in Jurkat T cells, we demonstrated that BbLcLRR was tyrosine phosphorylated upon TCR stimulation, which was inhibited by Lck knockdown and was rescued by overexpression of BbLck. By mutating single tyrosine to phenylalanine (Y-F), we identified three tyrosine residues (Y539, Y655, and Y690) (3Y) of BbLcLRR as the major Lck phosphorylation sites. Reporter gene assays showed that overexpression of BbLcLRR but not the BbLcLRR-3YF mutant inhibited TCR-induced NF-κB activation. In Lck-knockdown T cells, the decline of TCR-induced IL-2 production was reversed by overexpression of BbLck, and this reversion was inhibited by co-expression of BbLcLRR but not the BbLcLRR-3YF mutant. Sequence analysis showed that the three tyrosine-containing sequences were conserved with the tyrosine-based inhibition motifs (ITIMs) or ITIM-like motifs. And TCR stimulation induced the association of BbLcLRR with tyrosine phosphatases SHIP1 and to a lesser extent with SHP1/2. Moreover, overexpression of wild-type BbLcLRR but not its 3YF mutant inhibited TCR-induced tyrosine phosphorylation of multiple signaling proteins probably via recruiting SHIP1. Thus, we identified a novel immunoreceptor BbLcLRR, which is phosphorylated by Lck and then exerts a phosphorylation-dependent inhibitory role in TCR-mediated T-cell activation, implying a mechanism for the maintenance of self-tolerance and homeostasis of amphioxus immune system and the evolutionary conservatism of Lck-regulated inhibitory receptor pathway.

BACKGROUND The aim of this study was to assess the incidence, clinicopathologic characteristics, prognostic factors, and treatment outcomes in lung large cell neuroendocrine carcinoma (LCNEC). MATERIAL AND METHODS Patients diagnosed with lung LCNEC between 2000 and 2013 were identified using the Surveillance, Epidemiology, and End-Results database. Kaplan-Meier methods and univariate and multivariate analyses were used for statistical analysis. RESULTS A total of 2097 patients were identified. The total age-adjusted incidence rate of lung LCNEC was 0.3/100 000, with a rise in incidence over the study period. The 5-year lung cancer-specific survival (LCSS) and overall survival (OS) were 20.7% and 16.7%, respectively. Multivariate analysis indicated that age ³65 years, male sex, advanced tumor stage, advanced nodal stage, not undergoing surgery. and not undergoing chemotherapy were independent adverse indicators for survival outcomes. After stratification by tumor stage, undergoing surgery was associated with more favorable LCSS and OS compared with those without surgery, regardless of tumor stage. CONCLUSIONS LCNEC is a rare lung cancer subtype with a dismal prognosis. Primary surgical treatment has significant survival benefits, even for stage IV patients. The optimal treatment strategies for lung LCNEC require further investigation.

Objectives This study aims to determine a role of interleukin‐17A (IL‐17) in salivary gland (SG) dysfunction and therapeutic effects of targeting IL‐17 in SG for treating autoimmune sialadenitis in primary Sjögren’s syndrome (pSS). Methods Salivary IL‐17 levels and IL‐17‐secreting cells in labial glands of pSS patients were examined. Kinetic changes of IL‐17‐producing cells in SG from mice with experimental Sjögren’s syndrome (ESS) were analysed. To determine a role of IL‐17 in salivary secretion, IL‐17‐deficient mice and constructed chimeric mice with IL‐17 receptor C (IL‐17RC) deficiency in non‐hematopoietic and hematopoietic cells were examined for saliva flow rates during ESS development. Both human and murine primary SG epithelial cells were treated with IL‐17 for measuring cholinergic activation‐induced calcium movement. Moreover, SG functions were assessed in ESS mice with salivary retrograde cannulation of IL‐17 neutralisation antibodies. Results Increased salivary IL‐17 levels were negatively correlated with saliva flow rates in pSS patients. Both IL‐17‐deficient mice and chimeric mice with non‐hematopoietic cell‐restricted IL‐17RC deficiency exhibited no obvious salivary reduction while chimeric mice with hematopoietic cell‐restricted IL‐17RC deficiency showed significantly decreased saliva secretion during ESS development. In SG epithelial cells, IL‐17 inhibited acetylcholine‐induced calcium movement and downregulated the expression of transient receptor potential canonical 1 via promoting Nfkbiz mRNA stabilisation. Moreover, local IL‐17 neutralisation in SG markedly attenuated hyposalivation and ameliorated tissue inflammation in ESS mice. Conclusion These findings identify a novel function of IL‐17 in driving salivary dysfunction during pSS development and may provide a new therapeutic strategy for targeting SG dysfunction in pSS patients., In this study, we found that increased salivary IL‐17 levels were negatively correlated with saliva flow rates in patients with primary Sjögren’s syndrome (pSS). We further identified a novel function of IL‐17 in driving salivary dysfunction by impairing transient receptor potential canonical 1‐mediated calcium movement during pSS pathogenesis. This pre‐clinical study demonstrated that neutralization of IL‐17 in salivary glands attenuated hyposalivation and ameliorated tissue inflammation in mice with experimental SS, suggesting a therapeutic potential of local targeting IL‐17 for treating xerostomia and autoimmune sialadenitis in pSS patients.

Background. Coronavirus disease 2019 (COVID-19) causes psychological distress and can have a negative impact on the general mental health and rehabilitation in affected patients under currently implemented isolation guidelines. Auricular point pressure (APP) as well-established technique in traditional Chinese medicine may help to relieve sleep disturbance and anxiety in COVID-19 patients. Methods. During the early phase of the epidemic/pandemic, patients were enrolled in this study (02/2020 until 03/2020 n = 84). They were strictly isolated on specific wards at the Hubei Provincial Hospital of Integrated Chinese and Western Medicine in Hubei. The retrospective cohort study design included two groups. Group A patients were treated with an auricular point pressure (APP) in addition to standard intensive care medicine while Group B participants (No-APP) received routine nursing measures alone. Treatment outcome was measured using the St. Mary’s Hospital Sleep Questionnaire (SMH) Score and the 7-Item Generalized Anxiety Disorder Scale (GAD-7). Both scores were measured in each patient at baseline and on the discharge day. Results. The SMH score and sleep status changed in APP patients at the end of the treatment period when compared with No-APP patients ( P < 0.01 ). APP-treated patients demonstrated lower GAD-7 scores than No-APP controls ( P < 0.01 ). Further, no significant differences in safety or adverse events between the APP and No-APP groups were observed. Conclusion. The results from our snapshot study during the early phase of the SARS-CoV-2 epidemic/pandemic suggest that auricular point pressure could be a simple and effective tool to relieve insomnia and situational anxiety in hospitalized patients suffering from COVID-19 and kept under disconcerting conditions of isolation.