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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.

Listening to long video/audio recordings from video conferencing and online courses for acquiring information is extremely inefficient. Even after ASR systems transcribe recordings into long-form spoken language documents, reading ASR transcripts only partly speeds up seeking information. It has been observed that a range of NLP applications, such as keyphrase extraction, topic segmentation, and summarization, significantly improve users' efficiency in grasping important information. The meeting scenario is among the most valuable scenarios for deploying these spoken language processing (SLP) capabilities. However, the lack of large-scale public meeting datasets annotated for these SLP tasks severely hinders their advancement. To prompt SLP advancement, we establish a large-scale general Meeting Understanding and Generation Benchmark (MUG) to benchmark the performance of a wide range of SLP tasks, including topic segmentation, topic-level and session-level extractive summarization and topic title generation, keyphrase extraction, and action item detection. To facilitate the MUG benchmark, we construct and release a large-scale meeting dataset for comprehensive long-form SLP development, the AliMeeting4MUG Corpus, which consists of 654 recorded Mandarin meeting sessions with diverse topic coverage, with manual annotations for SLP tasks on manual transcripts of meeting recordings. To the best of our knowledge, the AliMeeting4MUG Corpus is so far the largest meeting corpus in scale and facilitates most SLP tasks. In this paper, we provide a detailed introduction of this corpus, SLP tasks and evaluation methods, baseline systems and their performance., Comment: Paper accepted to the 2023 IEEE International Conference on Acoustics, Speech, and Signal Processing (ICASSP 2023), Rhodes, Greece

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.

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.

International audience; A series of arene-bridged dithorium complexes was synthesized via the reduction by potassium graphite of a Th(IV) precursor in the presence of arenes. All these compounds adopt an inverse-sandwich structure, with the arene bridging two thorium centers in a μ-η6,η6-mode. Structural and spectroscopic data support the assignment of two Th(IV) ions and an arene tetraanion, which is an aromatic structure according to Hückel’s rule. Arene exchange reactions revealed that the stability of the corresponding compounds follows the series naphthalene ≪ toluene < benzene ≈ biphenyl. Reactivity studies showed that they function as four-electron reductants capable to reduce anthracene, cyclooctatetraene, alkynes, and azobenzene, while a mononuclear thorium anthracene complex could reduce benzene. Density functional theory calculations unveiled that the bonding interactions consist of δ bonds between thorium 6d and 5f orbitals and arene π* orbitals, showing a significant covalent character, able to stabilize highly reduced arene ligands.

The well-defined mammalian slp76-signalosome is crucial for T-cell immune response, yet whether slp76-signalosome exists in invertebrates and how it evolved remain unknown. Here we investigated slp76-signalosome from an evolutionary perspective in amphioxus Branchiostoma belcheri (bb). We proved slp76-signalosome components bbslp76, bbGADS and bbItk are present in amphioxus and bbslp76 interacts with bbGADS and bbItk, but differences exist between the interaction manners within slp76-signalosome components of amphioxus and human (h). Specifically, bbslp76 has a unique WW-domain that blocked its association with hItk and decreased TCR-induced tyrosine-phosphorylation and NFAT-activation. Deletion of WW-domain shifted the constitutive association between bbslp76 and hPLCγ1 to a TCR-enhanced association. Among slp76-signalosome, the interaction between slp76 and PLCγ1 is the most conserved and the binding between Itk and slp76 evolved from constitutive to stimulation-regulated. Sequence alignment and 3D structural analysis of slp76-signalosome molecules from keystone species indicated slp76 evolved into a more unfolded and flexible adaptor due to lack of WW-domain and several low-complexity-regions (LCRs) while GADS turned into a larger protein by a LCR gain, thus preparing more space for nucleating the coevolving slp76-signalosome. Altogether, through deletion of WW-domain and manipulation of LCRs, slp76-signalosome evolves from a rigid and stimulation-insensitive to a more flexible and stimulation-responding complex.

Copper indium sulfide quantum dots (CuInS2 QDs) were incorporated into a nanocrystalline TiO2 film by using spin coating-assisted successive ionic layer adsorption and reaction process to fabricate CuInS2 QD-sensitized TiO2 photoelectrodes for the solid-state quantum dot-sensitized solar cell (QDSSC) applications. The result shows that the photovoltaic performance of solar cell is extremely dependent on the number of cycles, which has an appreciable impact on the coverage ratio of CuInS2 on the surface of TiO2 and the density of surface defect states. In the following high-temperature annealing process, it is found that annealing TiO2/CuInS2 photoelectrode at a suitable temperature would be beneficial for decreasing the charge recombination and accelerating the charge transport. After annealing at 400 °C, a significantly enhanced photovoltaic properties of solid-state CuInS2 QDSSCs are obtained, achieving the power conversion efficiency (PCE) of 3.13%, along with an open-circuit voltage (VOC) of 0.68 V, a short-circuit photocurrent density (JSC) of 11.33 mA cm−2, and a fill factor (FF) of 0.41. The enhancement in the performance of solar cells is mainly ascribed to the suppression of charge recombination and the promotion of the electron transfer after annealing.

Purpose Monitoring of key markers for lung cancer detection and tracking of acquired drug resistance is critical for the management of the disease. We aim to ascertain the value of monitoring both total cell free DNA concentrations and mutant EGFR DNA content within diverse groups of individuals most vulnerable to the disease. Methods We proposed longitudinal monitoring of circulating DNA using digital PCR. Circulating DNA present in peripheral blood can be obtained non-invasively and provide timely disease status update. 25 heavy smokers and 50 patients undergoing TKI therapy were recruited. Peripheral blood specimens were taken at different time points and their circulating DNA were analyzed and quantified. Results Significant higher concentrations of total cell free DNA were detected when compared with healthy high-risk individuals. Levels were stable throughout the treatment cycles, which makes it potentially a useful tool for patient stratification. Concurrent mutant T790M DNA detection of lung cancer patients at baseline achieved 82 % concordance with matched tissue analysis. Samples initially negative for the T790M gene mutation that became positive during treatment were corroborated with a repeat biopsy. The results showed its usefulness for serial monitoring. Conclusion Monitoring of circulating DNA addresses the need for disease detection and shows the ability to capture the dynamic changes of the disease. Electronic supplementary material The online version of this article (doi:10.1186/s40064-016-2141-5) contains supplementary material, which is available to authorized users.

Many studies have demonstrated that microRNA-21 (miR-21) acts as an oncogene in the tumourigenesis of a variety of tumours and may be involved in the chemotherapeutic drug resistance of tumour cells. In this study, we utilized the leukaemia cell line K562 as an in vitro cell model to investigate whether miR-21 is involved in X-ray irradiation resistance.Retroviral transduction and antisense oligonucleotide transfection were used to overexpress or knock down miR-21 expression, respectively. An MTT assay was used to measure cell viability, and western blotting was performed to detect the expression of the miR-21 target gene, PTEN (phosphatase and tensin homologue), and its downstream signalling components, phosphatidylinositol 3-kinase (PI3K), and AKT.The overexpression of miR-21 decreased the protein expression levels of PTEN, increased the phosphorylation level of AKT, and enhanced the X-ray irradiation resistance in K562 cells. In contrast, the knockdown of miR-21 increased the PTEN protein expression, reduced the phosphorylation levels of the AKT, and increased the sensitivity of K562 cells to X-ray irradiation. The overexpression of PTEN or the knockdown of AKT also increased the sensitivity of K562 cells to X-ray irradiation.By regulating the expression of its target gene PTEN, which subsequently affects the PI3K/AKT signalling pathway, miR-21 exerts its regulatory role on the radiation sensitivity of K562 cells. These results may help to provide the basis for microRNA-based targeted therapies to overcome radiation resistance in tumour cells.