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Rheumatoid arthritis (RA) is a chronic and progressive autoimmune disease.

For the purpose of heavy metals’ spatial-temporal trends and source allocation in arable soil with the rapid urbanization in Western China, samples were collected in two stages (2008 and 2017) in Chengdu city which was chosen for the case study. Positive Matrix Factorization (PMF) receptor models and Multivariate statistical analysis were used to understand the heavy metals’ spatial-temporal variability. The results showed that Cd, Cr, and As in arable soil were presented with an increasing trend during the 10-year period. Semi-variation analysis showed that the block basis ratios of the five heavy metals (Pb, As, Cr, Hg, and Cd) showed an increasing trend, which suggests that the spatial distribution of heavy metals in arable soil is more influenced by human disturbances. The source analysis shows that the enrichment of As is closely related to agricultural activities in both phases (2008 and 2017). Further source analysis showed that source of As did not change, but the contribution increased significantly. The main sources of Hg pollution changed from agricultural activities to medical equipment manufacturing, Cd changed from soil parent material sources to chemical industry waste emissions, and the sources of Pb and Cr expanded from single transportation sources to multiple sources such as road traffic and human construction. In this study, the examining of the temporal and spatial patterns of heavy metal contamination in farmland of typical rapidly developing cities in China can also provide a basis for the conservation and management of arable soil in similar areas in the context of rapid urbanization in China.

Recent studies have shown that circRNAs can act as oncogenic factors or tumor suppressors by sponging microRNAs (miRNAs). The upregulation of circ_0023984 was reported in esophageal squamous cell carcinoma (ESCC). However, its functional role in ESCC remain unclear. In the present study, circ_0023984 expression in ESCC cells and tissues were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB). Subcellular fraction experiment was performed to determine relative nuclear-cytoplasmic localization. The loss-of-function effects of circ_0023984 in ESCC cell lines were investigated by shRNA-mediated knockdown. Functional assays including cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EDU) incorporation, colony formation and Transwell migration assays were conducted to assess the malignant phenotype. The interaction between the two molecules was analyzed by RNA pull-down, luciferase reporter assay and RNA immunoprecipitation (RIP). The subcutaneous tumor model in nude mice was used to assess the role of circ-0023984 in tumorigenesis. We found that ESCC patients with high circ_0023984 expression was associated with a poor prognosis. The knockdown of circ_0023984 suppressed cell growth, invasion, and migration in ESCC cells. Circ_0023984 interacted with miR-134-5p and inhibited its activity, which promoted the expression of CST4 (Cystatin-S). Circ_0023984 also regulated tumorigenesis in a CST4-dependent manner. Together, our study indicates that the oncogenic role of Circ_0023984 is mediated by miR-134-5p/CST4 Axis in ESCC, which could serve as potential targets for future therapeutic strategies.

Indigo and indirubin, the active molecules of traditional Chinese medicine indigo naturalis, exert therapeutic activity for ulcerative colitis (UC). Indigo and indirubin are isomers and have distinctive profiles in anti-inflammation, immune regulation, intestinal microbiota regulation, oxidative stress regulation, and intestinal mucosal repair for UC treatment. Thus, exploring its combined administration’s integrated advantages for UC is critical. This study is aimed at clarifying the effect and mechanisms of the combined administration of indigo and indirubin on colitis mouse models. The results showed that all the treatment groups could improve the disease symptoms, and the combined administration showed the best effect. Additionally, compared with indigo and indirubin alone, the combination group could significantly reinforce intestinal barrier function by increasing the expression of E-cadherin, occludin, ZO-1, and MUC2 and improving intestinal permeability. The treatment groups significantly improved the expression of cytokines, including TNF-α, IFN-γ, IL-12, IL-23, and IL-17A, and indirubin presented the most potent anti-inflammatory effect. Furthermore, all the treatment groups reduced the infiltration of the immune cells in intestinal lamina propria and the production of ROS/RNS. Notably, indigo exhibited a more substantial capacity to regulate natural killer (NK) cells, ILC3, neutrophils, and dendritic cells, followed by the combination group and indirubin alone. Finally, all the treatment groups modulated intestinal microbiota composition, increased the proportion of beneficial microbiota, and decreased the proportion of microbiota. Our results indicated that indigo and indirubin synergistically reinforced the intestinal barrier function, which may be associated with integrating the indirubin anti-inflammatory and intestinal microbiota regulating strength and indigo immune and ROS/RNS regulation advantage.

Fever in children is one of the most common symptoms of pediatric diseases and the most common complaint in pediatric clinics, especially in the emergency department. Diseases such as pneumonia, sepsis, and meningitis are leading causes of death in children, and the early manifestations of these diseases are accompanied by fever symptoms. Accurate diagnosis and real-time monitoring of the status of febrile children, rapid and effective identification of the cause, and treatment can have a positive impact on relieving their symptoms and improving their quality of life. In recent years, wearable diagnostic sensors have attracted special attention for their high flexibility, real-time monitoring, and sensitivity. Temperature sensors and heart rate sensors have provided new advances in detecting children's body temperature and heart rate. Furthermore, some novel formulations have also received wide attention for addressing bottlenecks in medication administration for febrile children, such as difficulty in swallowing and inaccurate dosing. In this context, the present review provides recent advances of novel wearable medical sensor devices for diagnosing fever. Moreover, the application progress of innovative dosage forms of classical antipyretic drugs for children is presented. Finally, challenges and prospects of wearable sensor-based diagnostics and novel agent-based treatment of fever in children are discussed in brief.

The biological functions of circular RNAs in liver tumorigenesis have been well demonstrated by a number of studies. Nevertheless, to the best of our knowledge, the role and mechanism of action of hsa_circ_0008537 (circ_0008537) in liver cancer pathogenesis remain undetermined. In the present study, circ_0008537 expression was associated with the GLI3 gene and was markedly increased in liver cancer tissue specimens and cells. High expression levels of circ_0008537 exhibited a poor prognosis. In addition, circ_0008537 overexpression resulted in an increased proliferation, migration and invasion of liver cancer cells, whereas circ_0008537 knockdown exhibited opposite effects. circ_0008537 acted as a sponge of microRNA‑153‑3p (miR‑153‑3p), and a negative correlation was observed between circ_0008537 and miR‑153‑3p expression in liver cancer. Transfection with miR‑153‑3p further abolished the effects of circ_0008537 on the malignant behavior of liver cancer cells. Furthermore, circ_0008537 indirectly affected the expression levels of pro‑survival protein myeloid cell leukemia 1 (MCL1) and snail family zinc finger 1 (Snail1) via miR‑153‑3p in liver cancer cells. In conclusion, the data indicated that circ_0008537 facilitated liver carcinogenesis by indirectly regulating miR‑153‑3p and leading to the release of MCL1 and Snail1.

Inflammatory bowel disease (IBD) is a global health problem in which gut microbiota dysbiosis plays an important pathogenic role. However, the current drugs for IBD treatment are far from optimal. Previous researches indicated that parthenolide (PTL) had not only anti-cancer properties but also strong anti-inflammatory activities. Rationale: To investigate the protective effect of PTL on colon inflammation and demonstrate the underlying gut microbiota-dependent mechanism. Methods: Colon inflammation severity in mouse model was measured by body weight change, mortality, colon length, disease activity index (DAI) score, H&E staining and colonoscopy evaluation. Gut microbiota alteration and short-chain fatty acids (SCFAs) production were analyzed through 16S rRNA sequencing and targeted metabolomics. Luminex cytokine microarray and Enzyme-linked immunosorbent assay (ELISA) were conducted to measure the colon cytokines profile. The frequency of immune cells in lamina propria (LP) and spleen were phenotyped by flow cytometry. Results: The PTL-treated mice showed significantly relieved colon inflammation, as evidenced by a reduction in body weight loss, survival rate, shortening of colon length, DAI score, histology score and colonoscopy score. Notably, when the gut microbiota was depleted using antibiotic cocktails, the protective effect of PTL on colon inflammation disappeared. PTL treatment downregulated the level of proinflammatory cytokines, including IL-1β, TNF-α, IL-6, and IL-17A and upregulated the immunosuppressive cytokine IL-10 in colon tissue. 16S rRNA sequencing indicated that PTL-treated mice exhibited much more abundant gut microbial diversity and flora composition. Targeted metabolomics analysis manifested the increased SCFAs production in PTL-treated mice. Additionally, PTL administration selectively upregulated the frequency of colonic regulatory T (Treg) cells as well as downregulated the ratio of colonic T helper type 17 (Th17) cells, improving the Treg/Th17 balance to maintain intestinal homeostasis. Gut microbiota depletion and fecal microbiota transplantation (FMT) was performed to confirm this gut microbiota-dependent mechanism. Conclusions: PTL ameliorated colon inflammation in a gut microbiota-dependent manner. The underlying protective mechanism was associated with the improved Treg/Th17 balance in intestinal mucosa mediated through the increased microbiota-derived SCFAs production. Collectively, our results demonstrated the role of PTL as a potential gut microbiota modulator to prevent and treat IBD.

Well-balanced interactions between gut microbiota and the immune system are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). Toll-like receptor 4 (TLR4) functions as a sensor mediating the crosstalk between the intestinal commensal microbiome and host immunity, but the influence of TLR4 on the shaping of intestinal microbiota and immune responses during colon inflammation remains poorly characterized. We investigated whether the different susceptibilities to colitis between wild-type (WT) and TLR4We performed antibiotic depletion of the microbiota, cohousing experiments, and faecal microbiota transplantation (FMT) in WT and TLR4TLR4Our results demonstrate a novel protective role of TLR4 against intestinal inflammation, wherein it can modulate A. muciniphila-associated immune responses. These findings provide a new perspective on host-commensal symbiosis, which may be beneficial for developing potential therapeutic strategies. Video abstract.

Psoriasis, an incurable autoimmune skin disease, is one of the most common immune-mediated disorders. Presently, numerous clinical research studies are underway, and treatment options are available. However, these treatments focus on improving symptoms of the disease and fail to achieve a radical cure; they also have certain toxic side effects. In recent years, natural products have increasingly gained attention because of their high efficiency and low toxicity. Despite their obvious therapeutic effects, natural products’ biological activity was limited by their instability, poor solubility, and low bioavailability. Novel drug delivery systems, including liposomes, lipospheres, nanostructured lipid carriers, niosomes, nanoemulsions, nanospheres, microneedles, ethosomes, nanocrystals, and foams could potentially overcome the limitations of poor water solubility and permeability in traditional drug delivery systems. Thus, to achieve a therapeutic effect, the drug can reach the epidermis and dermis in psoriatic lesions to interact with the immune cells and cytokines.

Background The endoglycosidase heparanase which degrades heparan sulfate proteoglycans, exerts a pro-inflammatory mediator in various inflammatory disorders. However, the function and underlying mechanism of heparanase in acute pancreatitis remain poorly understood. Here, we investigated the interplay between heparanase and the gut microbiota in the development of acute pancreatitis. Methods Acute pancreatitis was induced in wild-type and heparanase-transgenic mice by administration of caerulein. The differences in gut microbiota were analyzed by 16S ribosomal RNA sequencing. Antibiotic cocktail experiment, fecal microbiota transplantation, and cohousing experiments were used to assess the role of gut microbiota. Results As compared with wild-type mice, acute pancreatitis was exacerbated in heparanase-transgenic mice. Moreover, the gut microbiota differed between heparanase-transgenic and wild-type mice. Heparanase exacerbated acute pancreatitis in a gut microbiota-dependent manner. Specially, the commensal Parabacteroides contributed most to distinguish the differences between wild-type and heparanase-transgenic mice. Administration of Parabacteroides alleviated acute pancreatitis in wild-type and heparanase-transgenic mice. In addition, Parabacteroides produced acetate to alleviate heparanase-exacerbated acute pancreatitis through reducing neutrophil infiltration. Conclusions The gut–pancreas axis played an important role in the development of acute pancreatitis and the acetate produced by Parabacteroides may be beneficial for acute pancreatitis treatment.

Trimethylamine N-oxide (TMAO), as a gut-derived metabolite, has been found to be associated with enhanced risk for atherosclerosis and cardiovascular disease. We presented a method for targeted profiling of TMAO and betaine in serum and food samples based on a combination of one-step sample pretreatment and proton nuclear magnetic resonance spectroscopy. The key step included a processing of sample preparation using a selective solid-phase extraction column for retention of basic metabolites. Proton signals at δ 3.29 and δ 3.28 were employed to quantify TMAO and betaine, respectively. The developed method was examined with acceptable linear relationship, precision, stability, repeatability, and accuracy. It was successfully applied to detect serum levels of TMAO and betaine in TMAO-fed mice and high-fructose-fed rats and also used to determine the contents of TMAO and betaine in several kinds of food, such as fish, pork, milk, and egg yolk.

This paper proposes a one-shot voice conversion (VC) solution. In many one-shot voice conversion solutions (e.g., Auto-encoder-based VC methods), performances have dramatically been improved due to instance normalization and adaptive instance normalization. However, one-shot voice conversion fluency is still lacking, and the similarity is not good enough. This paper introduces the weight adaptive instance normalization strategy to improve the naturalness and similarity of one-shot voice conversion. Experimental results prove that under the VCTK data set, the MOS score of our proposed model, weight adaptive instance normalization voice conversion (WINVC), reaches 3.97 with five scales, and the SMOS reaches 3.31 with four scales. Besides, WINVC can achieve a MOS score of 3.44 and a SMOS score of 3.11 respectively for one-shot voice conversion under a small data set of 80 speakers with 5 pieces of utterances per person.

Hepatic stellate cells activation is the key process of liver fibrosis, revealing the molecular mechanism of which is helpful to provide an effective target for inhibiting liver fibrosis. Rab31, a small GTPase, regulates the specificity of intracellular vesicular transport system, and is crucial for signal transduction. However, whether Rab31 is involved in hepatic stellate cells activation is unknown.Analysis of the differences in gene expression between human healthy and fibrotic liver tissues by sequencing revealed that Rab31 was significantly upregulated in fibrotic tissues. Immunohistochemistry and immunofluorescence analysis confirmed that Rab31 positively correlated with hepatic fibrosis. Next, mouse primary hepatic stellate cells were prepared, and their continuous activation was accompanied by Rab31 expression increased. Interestingly, knockdown of Rab31 by lentivirus can significantly restrict those cell activation. Subsequently, the vary of signal transduction after Rab31 knockdown was detected, its presented that the TGF-β/Smads signaling was obviously affected. Following experiments identified that Rab31 knockdown significantly inhibited the TGF-β activation and led to the failure of hepatic stellate cells activation. Importantly, we revealed that Rab31 knockdown could inhibit TGF-β receptor II complex endocytosis, a prerequisite for the activation of TGF-β signaling. Finally, in a mouse CClOur study demonstrated that Rab31 could promote hepatic stellate cells activation by accelerating TGF-β Receptor II complex endocytosis, suggesting that interfering with Rab31 could be an effectively strategy to inhibit hepatic fibrosis progression.

Background: Recent evidence suggests that antidepressant and anti-anxiety treatments may also have a place in resolving inflammation through the gut-brain axis. Lithium carbonate (LC) is one of the most commonly used drugs for bipolar disorder. However, little is known about the effects of LC on gut inflammation. In this study, we explore the protective effect of LC on colitis, and clarify its underlying mechanism of intestinal microbial dependence. Methods: Colitis mice were established by oral administration of 2.5% dextran sulfate sodium (DSS). Colon inflammation severity in mouse model was measured by body weight change, mortality, colon length, disease activity index (DAI) score and H&E staining. Gut microbiota alteration were analyzed through high-throughput 16S rRNA gene sequencing. Enzyme-linked immunosorbent assay (ELISA) were conducted to measure the colon cytokines profile. The frequency of immune cells in lamina propria (LP) were phenotyped by flow cytometry. Findings: LC treatment significantly alleviated colon inflammation in DSS-induced colitis models. It is worth noting that when antibiotics (ABX) are used to deplete the intestinal microbiota, the protective effect of LC on colon inflammation is not significant. LC treatment downregulated the levels of pro-inflammatory cytokines IL-1β, TNF-α, IL-6 and IL-17A in colon tissue, and upregulated the levels of immunosuppressive cytokine IL-10. The 16S rRNA sequencing results showed that LC administration significantly increased gut microbial diversity and altered flora composition, especially accumulated the abundance of potential probiotics Akkermansia muciniphila (A. muciniphila). Moreover, LC treatment selectively activated the anti-inflammatory responses of colonic regulatory T (Treg) cells and maintained intestinal homeostasis. Fecal microbiota transplantation (FMT), and Akkermansia muciniphila (A. muciniphila) single bacteria gavage experiments confirmed this intestinal flora-dependent mechanism. Interpretation: Accordingly, our results demonstrate the role of LC as a potential regulator of intestinal flora in the prevention and treatment of gut inflammation. Therefore, LC treatment or targeting specific microbiota, such as A. muciniphila, provides a new strategy for the treatment of ulcerative colitis or IBD. Funding Statement: This work was supported by the National Natural Science Foundation of China (Grant NO.82030020). Declaration of Interests: None declared. Ethics Approval Statement: All animal experimental protocols were performed following the guidelines of the National Institutes of Health guide for the care and use of Laboratory Animals, approved by the Third Military Medical University Institutional Animal Care and Use Committee.

Background Recent evidence suggests that neuropsychiatric stabilizers have a place in resolving gastrointestinal disorders. Lithium carbonate (LC) is one of the most commonly used drugs for bipolar disorder clinically. Here, we estimate the therapeutic function of LC against colitis and investigate the mechanism of intestinal flora and metabolism modulation. Methods A colitis model was constructed by continuously administering 2.5% dextran sodium sulfate (DSS) solution daily for 7 days. Analysis of gut microbiota was carried out by 16 S rRNA gene high-throughput sequencing. Spectrum antibiotic cocktail (ABX) and faecal microbiota transplantation (FMT) were employed to evaluate the protective effect of intestinal flora. Colonic Treg cells and related immune responses were detected by flow cytometry. Results LC treatment significantly alleviated colon inflammation by regulating gut microbial diversity and altering flora composition. Notably, LC treatment upregulated short-chain fatty acid (SCFA)-producing bacteria, especially Akkermansia muciniphila (A. muciniphila), and transformed metabolite SCFA profiles. LC activated anti-inflammatory Treg cell responses in colonic LP in a G-protein coupled receptor 43 (GPR43)-dependent mechanism. ABX, FMT and single bacteria gavage experiments were conducted to confirm the above mechanism. Conclusions As an intestinal microbiome and metabolite modulator, LC alleviates colon inflammation in a GPR43-dependent manner through activating Treg cell responses. Therefore, the therapeutic strategy of the microbiome-metabolite-immune axis, as observed in the A. muciniphila-SCFA-Treg cell axis in our study, might provide a new direction for the treatment of IBD.

Heparin is the earliest and most widely used anticoagulant and antithrombotic drug that is still used in a variety of clinical indications. Since it was discovered in 1916, after more than a century of repeated exploration, heparin has not been replaced by other drugs, but a great progress has been made in its basic research and clinical application. Besides anticoagulant and antithrombotic effects, heparin also has antitumor, anti-inflammatory, antiviral, and other pharmacological activities. It is widely used clinically in cardiovascular and cerebrovascular diseases, lung diseases, kidney diseases, cancer, etc., as the first anticoagulant medicine in COVID-19 exerts anticoagulant, anti-inflammatory and antiviral effects. At the same time, however, it also leads to a lot of adverse reactions, such as bleeding, thrombocytopenia, elevated transaminase, allergic reactions, and others. This article comprehensively reviews the modern research progress of heparin compounds; discusses the structure, preparation, and adverse reactions of heparin; emphasizes the pharmacological activity and clinical application of heparin; reveals the possible mechanism of the therapeutic effect of heparin in related clinical applications; provides evidence support for the clinical application of heparin; and hints on the significance of exploring the wider application fields of heparin.

Liver X receptors (LXR) α and β serve important roles in cholesterol homeostasis, anti-inflammatory processes and the activation of hepatic stellate cells (HSCs). However, the development of therapies for liver fibrosis based on LXR agonists have been hampered due to side-effects such as liver steatosis. In this study, we demonstrated that HSCs expressed high levels of LXRβ, but not LXRα, and that overexpression of LXRβ suppressed fibrosis and HSC activation in a carbon tetrachloride (CCl4)-induced fibrosis mouse model, without resulting in liver steatosis. Furthermore, Hedgehog (Hh)-regulated proteins, markedly increased in the CCl4-affected liver and mainly expressed in activated HSCs, were repressed under conditions of LXRβ overexpression. In addition, LXRβ knockout led to activation of Hh signaling and triggering of HSC activation, while overexpression of LXRβ led to the inhibition of the Hh pathway and suppression of HSC activation. These results suggest that LXRβ suppresses the activation mechanism of HSCs by inhibiting Hh signaling. In conclusion, LXRβ, by restoring the differentiation of HSCs, may be a promising therapeutic target for liver fibrosis without the adverse side-effects of LXRα activation.

Optically pumped atomic magnetometers based on spin exchange relaxation free regime have recently become a powerful tool in the field of magnetoencephalography measurements. For this application of magnetometers, simultaneous multilocation magnetic field measurements are desired. To fulfill the requirement, we develop a multi-channel sensor module based on a single large vapor cell. The probe beam passes through the vapor cell twice by reflection and then records the two-dimensional spatial magnetic field distribution with two 2 × 2 photodiode matrixes. Comparing with the previous multi-channel tangential magnetic field measuring sensors, our magnetometer is sensitive to the normal magnetic field by operating in the longitudinal parametric modulation mode. Measuring the normal component is considered more suitable for magnetoencephalography, because the normal component provides more information. The sensitivities of the channels are approximately 10 fT/Hz1/2 in the normal direction. The auditory evoked magnetic fields of the four adjacent locations perpendicular to the scalp are detected simultaneously. Our magnetometer can measure the normal and tangential magnetic fields simultaneously. The dual-axis vector measurement of magnetic field is very important for magnetoencephalography.

Optically pumped atomic magnetometers operating in the spin exchange relaxation free (SERF) regime play increasingly important roles in magnetoencephalography measurements. In this application, a multichannel arrangement is necessary. A method to construct the multichannel system is to arrange multiple individual sensor modules, where each sensor module is designed in the one-beam configuration with the necessary magnetic modulation. However, such an arrangement restricts the spatial resolution, affects the uniformity of the sensor characteristics, and increases the system complexity. To address these issues, we developed a compact multichannel pump-probe configuration magnetometer based on a single vapor cell. Each channel of the multichannel system shares the same vapor cell. As a result, the influence of different cells is eliminated. Further, a two-beam configuration with an independent pump and probe beam is introduced. Compared with the one-beam configuration, the two-beam magnetometer achieves a higher sensitivity and does not require extra magnetic modulation. And then the magnetic field crosstalk between adjacent channels can be avoided. A sensitivity of 10 fT/Hz1/2 at 2 Hz is achieved for all channels. Using the compact multichannel magnetometer, an auditory evoked response is clearly observed. If more channels are required, the arrangement based on the single vapor cell configuration can be easily expanded by applying the photodiode with more than four quadrants.

This paper represents a series of online monitoring data from a 500kV bushing on a converter station's transformer. An online monitoring system with a novel tgd measuring method has been successfully used for bushing tgd supervision. Long term data acquisition is evaluated for the insulation integrity of the bushing. It shows that bushing tgδ depends on its temperature/voltage intersect influence during operation. The largest bushing tgd occurred at the highest voltage and the lower temperatures. A further study of the temperature/voltage intersect influence on bushings need to be scheduled.