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BackgroundRenal transplantation is a very effective treatment for renal failure patients following kidney transplant. However, the clinical benefit is restricted by the high incidence of organ rejection. Therefore, there exists a wealth of literature regarding the mechanism of renal transplant rejection, including a large library of expression data. In recent years, research has shown the immune microenvironment to play an important role in renal transplant rejection. Nephrology web analysis tools currently exist to address chronic nephropathy, renal tumors and children’s kidneys, but no such tool exists that analyses the impact of immune microenvironment in renal transplantation rejection.MethodsTo fill this gap, we have developed a web page analysis tool called Comprehensive Analysis of Renal Allograft Rerejction in Immune Microenvironment (CARARIME).ResultsCARARIME analyzes the gene expression and immune microenvironment of published renal transplant rejection cohorts, including differential analysis (gene expression and immune cells), prognosis analysis (logistics regression, Univariable Cox Regression and Kaplan Meier), correlation analysis, enrichment analysis (GSEA and ssGSEA), and ROC analysis.ConclusionsUsing this tool, researchers can easily analyze the immune microenvironment in the context of renal transplant rejection by clicking on the available options, helping to further the development of approaches to renal transplant rejection in the immune microenvironment field. CARARIME can be found in http://www.cararime.com.

Abstract Graph representation learning has attracted increasing attention in a variety of applications that involve learning on non‐Euclidean data. Recently, generative adversarial networks(GAN) have been increasingly applied to the field of graph representation learning, and large progress has been made. However, most GAN‐based graph representation learning methods use adversarial learning strategies directly on the update of the vector representation instead of the deep embedding mechanism. Compared with deep models, these methods are less capable of learning nonlinear features. To address this problem and take full advantage of the essential advantages of GAN, we propose to use adversarial idea on the reconstruction mechanism of deep autoencoders. Specifically, the generator and the discriminator are the two basic components of the GAN structure. We use the deep autoencoder as the discriminator, which can capture the highly nonlinear structure of the graph. In addition, the generator another generative model is introduced into the adversarial learning system as a competitor. A series of empirical results proved the effectiveness of the new approach.

Cannabidiol, a non-psychoactive component extracted from the plant cannabis sativa, has gained growing focus in recent years since its extensive pharmacology effects have been founded. The purpose of this study intends to reveal the hot spots and frontiers of cannabidiol research using bibliometrics and data visualization methods. A total of 3,555 publications with 106,793 citations from 2004 to 2021 related to cannabidiol were retrieved in the Web of Science database, and the co-authorships, research categories, keyword burst, and reference citations in the cannabidiol field were analyzed and visualized by VOSviewer and Citespace software. Great importance has been attached to the pharmacology or pharmacy values of cannabidiol, especially in the treatment of neuropsychiatric disorders, such as epilepsy, anxiety, and schizophrenia. The mechanisms or targets of the cannabidiol have attracted the extreme interest of the researchers, a variety of receptors including cannabinoids type 1, cannabinoids type 2, 5-hydroxytriptamine1A, and G protein-coupled receptor 55 were involved in the pharmacology effects of cannabidiol. Moreover, the latest developed topic has focused on the positive effects of cannabidiol on substance use disorders. In conclusion, this study reveals the development and transformation of knowledge structures and research hotspots in the cannabidiol field from a bibliometrics perspective, exploring the possible directions of future research.

Background and Aim: Postoperative radiotherapy with concomitant temozolomide (TMZ) followed by ≤ six cycles of adjuvant TMZ chemotherapy (Stupp regimen) is the standard treatment for newly diagnosed glioblastoma (GBM); however, its effectiveness is limited. Anlotinib inhibits both tumor angiogenesis and tumor cell proliferation by targeting multiple kinases, and showing promising results in preclinical GBM models. We designed a Phase II trial to assess the efficacy and safety of the Stupp regimen plus anlotinib. Methods/Design: This is a multicenter, double-blind, randomized, placebo-controlled trial with an expected 150 patients randomly assigned 1:1 ratio to receive TMZ-based radiochemotherapy with anlotinib (Stupp regimen + anlotinib) or placebo (Stupp regimen + placebo). Postoperative patient recruitment will begin in July 2021, the analysis of primary outcome measures will be completed in July 2023, and the study will finish in July 2024. Major eligibility criteria include histologically confirmed newly diagnosed GBM and an Eastern Cooperative Oncology Group performance score ≤2. Other criteria for inclusion include age ≥18 years and lack of significant comorbidity. In this study, the primary endpoint will be the median progression-free survival (PFS). Secondary endpoints include 1-year overall survival rate, PFS at 6 months, overall response rate, duration of response, disease control rate, quality of life, and toxicity. The protocol has received approval from Sun Yat-sen University Cancer Center Ethics Committee (Approval No. B2021-073-01; approved on April 19, 2021). Discussion: Updated treatment modalities are required for newly diagnosed GBM. Our proposed treatment modality of the Stupp regimen combined with anlotinib therapy are waiting conclusion. Trial Registration: This study was registered with ClinicalTrials.gov under identifier NCT04959500 on July 13, 2021.

The next generation (6G) wireless systems aim to cater to the Internet of Everything (IoE) and revolutionize customer services and applications to a fully intelligent and autonomous system. To achieve this, the digital twin edge network (DITEN) is proposed to combine mobile/multi-access edge computing (MEC) and digital twin (DT), thereby improving the network performance such as throughput and security, and reducing the cost of communication, computation, and caching. In DITENs, the network status can be continuously monitored, and based on the obtained network states, the networking schemes, such as routing and resource management, can be studied in the established DITENs from a centralized perspective. In this survey, we present a comprehensive overview of DITEN for 6G. First, we present the fundamental aspects of DITEN, including concept, framework, and potential. Second, a comprehensive design of DITEN is devised, including the DT modeling/updating, DT deployment, key issues, and enabling technologies. Then, the typical applications of DITEN towards 6G are provided, including the Internet of Things (IoT), vehicular network, space-air-ground integrated network (SAGIN), healthcare, wireless systems, and other applications, along with the design of DITEN in each application, such as DT modeling, DT association, incentive mechanisms, and so on. Finally, challenges and open issues are discussed.

Inappropriate tillage practices and nitrogen (N) management have become seriously limitations for maize (Zea mays L.) yield and N use efficiency (NUE) in the North China Plain (NCP). In the current study, we examined the effects of strip deep rotary tillage (ST) combined with controlled-release (CR) urea on maize yield and NUE, and determined the physiological factors involved in yield formation and N accumulation during a 2-year field experiment. Compared with conventional rotary tillage (RT) and no-tillage (NT), ST increased the soil water content and soil mineral N content (Nmin) in the 20–40 cm soil layer due to reduction by 10.5 and 13.7% in the soil bulk density in the 0–40 cm soil layer, respectively. Compared with the values obtained by common urea (CU) fertilization, CR increased the Nmin in the 0–40 cm soil layers by 12.4 and 10.3% at the silking and maturity stages, respectively. As a result, root length and total N accumulation were enhanced under ST and CR urea, which promoted greater leaf area and dry matter (particularly at post-silking), eventually increasing the 1 000-kernel weight of maize. Thus, ST increased the maize yield by 8.3 and 11.0% compared with RT and NT, respectively, whereas CR urea increased maize yield by 8.9% above the values obtained under CU. Because of greater grain yield and N accumulation, ST combined with CR urea improved the NUE substantially. These results show that ST coupled with CR urea is an effective practice to further increase maize yield and NUE by improving soil properties and N supply, so it should be considered for sustainable maize production in the NCP (and other similar areas worldwide).

Background: Nasopharyngeal carcinoma (NPC) is a rare malignant tumor developing from epithelial linings of nasopharynx, and 10–50 out of 100,000 NPC cases were recorded globally particularly in the Asian countries. Methodology: The cytotoxicity of geraniin against the NPC C666-1 cells were analyzed using MTT assay. The influences of geraniin on the C666-1 cell viability with the presence of ROS and apoptosis inhibitors were also studied. The expressions of PI3K, Akt, mTOR, and autophagic markers LC3, ATG7, P62/SQSTM1 expressions in the C666-1 cells were studied by western blotting analysis. The ROS production was assayed using DCFH-DA staining. The immunofluorescence assay was performed to detect the NF-κB and β-catenin expressions in the C666-1 cells. Results: The cell viability of C666-1 cells were appreciably prevented by the geraniin. The geraniin treatment also inhibited the C666-1 cell growth with the presence of apoptotic inhibitor Z-VAD-FMK. The geraniin-treatment effectively improved the ROS production and inhibited the NF-κB and β-catenin expressions in the C666-1 cells. Geraniin appreciably modulated the PI3K/Akt/mTOR signaling axis and improved the autophagy-mediated cell death via improving the autophagic markers LC3 and ATG7 expressions in the C666-1 cells. Conclusion: In conclusion, our results proved that geraniin inhibits C666-1 cell growth and initiated autophagy-mediated cell death via modulating PI3K/Akt/mTOR cascade and improving LC3 and ATG7 expressions in the C666-1. Geraniin and it could be a hopeful and efficient candidate to treat the human NPC in the future.

Abstract Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory coronavirus 2 is currently spreading throughout the world with a high rate of infection and mortality and poses a huge threat to global public health. COVID-19 primarily manifests as hypoxic respiratory failure and acute respiratory distress syndrome, which can lead to multiple organ failure. Despite advances in the supportive care approaches, there is still a lack of clinically effective therapies, and there is an urgent need to develop novel strategies to fight this disease. Currently, stem cell therapy and stem cell-derived organoid models have received extensive attention as a new treatment and research method for COVID-19. Here, we discuss how stem cells play a role in the battle against COVID-19 and present a systematic review and prospective of the study on stem cell treatment and organoid models of COVID-19, which provides a reference for the effective control of the COVID-19 pandemic worldwide.

Abstract Background UPK2 exhibits excellent specificity for urothelial carcinoma (UC). UPK2 evaluation can be useful in making the correct diagnosis of UC. However, UPK2 detection by immunohistochemistry (IHC) has relatively low sensitivity. This paper aimed to compare the diagnostic sensitivity of RNAscope and IHC for evaluation of the UPK2 status in UC. Methods Tissue blocks from 127 conventional bladder UCs, 45 variant bladder UCs, 24 upper tract UCs and 23 metastatic UCs were selected for this study. IHC and RNAscope were used to detect the UPK2 status in UCs. Then, comparisons of the two methods were undertaken. Results There was no significant difference between RNAscope and IHC for the evaluation of the UPK2 positivity rate in UC (68.0% vs. 62.6%, P = 0.141). Correlation analysis revealed a moderate positive correlation for detection of UPK2: RNAscope vs. IHC (P < 0.001, R = 0.441). Our results showed a trend toward a higher positive UPK2 rate detected by RNAscope (53.3%) than by IHC (35.6%) in variant bladder UCs. Disappointingly, the P value did not indicate a significant difference (P = 0.057). Conclusions RNAscope for UPK2 appeared to perform similarly to IHC, with a marginally higher positive rate, suggesting it could be used as an alternative or adjunct to UPK2 IHC.

Graph representation learning has been extensively studied in recent years. It has been proven effective in network analysis and mining tasks such as node classification and link prediction. Learning method based on neural network has become mainstream solution because it can efficiently preserve nonlinear characteristics of graph. However, more efficient ways to encode complex graph structures are still being explored. In this paper, for undirected graphs, we present a novel Motif-Aware Generative Adversarial Network (MotifGAN) model to learn graph representation based on a re-weighted graph, which unifies both the Motif higher order structure and the original lower order structure. Firstly, we obtain the motif adjacency matrix by motif mining, which encodes the Motif higher order structure. Then we couple the motif adjacency matrix with the adjacency matrix of the original graph to get a reweighted matrix named motif connectivity matrix. The motif connectivity distribution implicit in the motif connectivity matrix is the target structure information we need to preserve. How to preserve a wealth of structural information is a challenge. Inspired by related applications of GAN, we formulate a GAN model to generate embedding representations that satisfy the target structure conditions. The GAN model usually consists of two components: generator and discriminator. Our generator tries to approximate the motif connectivity distribution, while the discriminator detects whether the connectivity of two vertexes is from ground truth or generated by the generator. In adversarial training, both parts can alternately and iteratively boost their performance. Experimental results on public datasets show that MotifGAN has made substantial progress in various applications, including link prediction, node classification and visualization.

Abstract Background The homeostasis of mesenchymal stem cells (MSCs) is modulated by both their own intracellular molecules and extracellular milieu signals. Hematopoiesis in the bone marrow is maintained by niche cells, including MSCs, and it is indispensable for life. The role of MSCs in maintaining hematopoietic homeostasis has been fully elucidated. However, little is known about the mechanism by which hematopoietic cells reciprocally regulate niche cells. The present study aimed to explore the close relationship between MSCs and hematopoietic cells, which may be exploited for the development of new therapeutic strategies for related diseases. Methods In this study, we isolated cells from the offspring of Tie2Cre + and Ptenflox/flox mice. After cell isolation and culture, we investigated the effect of hematopoietic cells on MSCs using various methods, including flow cytometry, adipogenic and osteogenic differentiation analyses, quantitative PCR, western bloting, and microCT analysis. Results Our results showed that when the phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene was half-deleted in hematopoietic cells, hematopoiesis and osteogenesis were normal in young mice; the frequency of erythroid progenitor cells in the bone marrow gradually decreased and osteogenesis in the femoral epiphysis weakened as the mice grew. The heterozygous loss of Pten in hematopoietic cells leads to the attenuation of osteogenic differentiation and enhanced adipogenic differentiation of MSCs in vitro. Co-culture with normal hematopoietic cells rescued the abnormal differentiation of MSCs, and in contrast, MSCs co-cultured with heterozygous null Pten hematopoietic cells showed abnormal differentiation activity. Co-culture with erythroid progenitor cells also revealed them to play an important role in MSC differentiation. Conclusion Our data suggest that hematopoietic cells function as niche cells of MSCs to balance the differentiation activity of MSCs and may ultimately affect bone development.

Abstract Most tumors with activating MAPK (mitogen-activated protein kinase) pathway alterations respond poorly to MEK inhibitors alone. Here, we evaluated combination therapy with MEK inhibitor selumetinib and MDM2 inhibitor KRT-232 in TP53 wild-type and MAPK altered colon and thyroid cancer models. In vitro, we showed synergy between selumetinib and KRT-232 on cell proliferation and colony formation assays. Immunoblotting confirmed p53 upregulation and MEK pathway inhibition. The combination was tested in vivo in seven patient-derived xenograft (PDX) models (five colorectal carcinoma and two papillary thyroid carcinoma models) with different KRAS, BRAF, and NRAS mutations. Combination therapy significantly prolonged event-free survival compared with monotherapy in six of seven models tested. Reverse-phase protein arrays and immunohistochemistry, respectively, demonstrated upregulation of the p53 pathway and in two models cleaved caspase 3 with combination therapy. In summary, combined inhibition of MEK and MDM2 upregulated p53 expression, inhibited MAPK signaling and demonstrated greater antitumor efficacy than single drug therapy in both in vitro and in vivo settings. These findings support further clinical testing of the MEK/MDM2 inhibitor combination in tumors of epithelial origin with MAPK pathway alterations.

Abstract The discovery of new edible flowers that are nontoxic, innocuous flowers having human health benefits, surveys of their phytochemicals and utilization are of great scientific and commercial interest. Dendrobium officinale and Dendrobium devonianum are precious Traditional Chinese Medicine. During the massive commercial cultivation, a lot of flowers were produced and certified as edible flowers, and the phytochemical profiles and bioactivities warrant evaluate. The present study aimed to investigate the phytochemicals and antioxidative activities in flowers of D. officinale (DOF) and D. devonianum (DDF). In total, 474 metabolites were identified using a widely targeted metabonomics method, 16 amino acids and 6 flavonoids were measured using high‐performance liquid chromatography (HPLC), and 8 fatty acids were detected using gas chromatography–mass spectrometry (GC‐MS). Both flowers contained various amino acids, including 7 essential amino acids, diverse flavonoids, especially quercetin, kaempferol and their derivatives, and high levels of methyl linoleate and methyl linolenate. The relative levels of quercetin, kaempferol and their glycosides were higher in DDF than in DOF, whereas the relative levels of several flavonoids C‐glycosides were high in DOF. Ethanol extracts of both DOF and DDF showed antioxidative capacities including the scavenging of 1,1‐diphenyl‐2‐picrylhydrazyl and hydroxyl radicals. Both edible flowers contained flavonoids, amino acids, and fatty acids and have antioxidative activities, which should be explored for use in functional foods and pharmaceuticals.

Abstract Pharmacometrics is an emerging science that interprets drug, disease, and trial information in a mathematical fashion to inform and facilitate efficient drug development and/or regulatory decisions. Pharmacometrics study is increasingly adopted in the regulatory review of new antimicrobial agents. We summarized the 31 antimicrobial agents approved by the US Food and Drug Administration (FDA) and the 26 antimicrobial agents approved by European Medicines Agency (EMA) from January 2001 to May 2019. We also reviewed recent examples of utilizing pharmacometrics to support antimicrobial agent’s registration in China, including modeling and simulation methods, effects of internal/external factors on pharmacokinetic (PK) parameters, safety and efficacy evaluation in terms of exposure‐response analysis, refinement of the wording of product labeling and package leaflet, and possible postmarketing clinical trial. Ongoing communication among regulator, academia, and industry regarding pharmacometrics is encouraged to streamline and facilitate the development of new antimicrobial agents. The industry can maximize its benefit in drug development through continued pharmacometrics education/training.

Abstract Depression is one of the most common psychiatric disorders. Recently, studies demonstrate that antidepressants generating BDNF not only maintain synaptic signal transmission but also repress neuroinflammatory cytokines such as IL-6 and IL-1β. Therefore, promoting BDNF expression provides a strategy for the treatment of depression. Our recent research has indicated that programmed cell death 4 (Pdcd4) is a new target for antidepressant treatment by facilitating BDNF. Herein, we modified Pdcd4 specific small interfering RNA (siPdcd4) with the rabies virus glycoprotein peptide (RVG/siPdcd4) which enables it cross the blood-brain barrier (BBB). We found that RVG/siPdcd4 complex was selectively delivered to neurons and microglia and silenced the expression of Pdcd4, thereby up-regulating the level of BDNF and down-regulating IL-6 and IL-1β expression. More importantly, RVG/siPdcd4 injection attenuated synaptic plasticity impairment and protected mice from CRS-induced depressive behavior. These findings suggest that RVG/siPdcd4 complex is a potential therapeutic medicine for depression.

White layer is commonly formed on the machined surface of nickel-based Inconel 718 superalloy, which probably induces the generation of cracks, leading to the fatigue life reduction of the workpieces. Nevertheless, the microstructure of the white layer is still not revealed clearly. The core issues, which this paper aims to reveal, are the transition of γ, γ′, γ'' and δ phases and dynamic recrystallization mechanism within the white layer formed during turning Inconel 718. Therefore, the dry orthogonal cutting tests with worn tools were conducted to make the white layer first. After that, the morphology and microstructure of the white layer are studied with the aid of scanning electron microscope (SEM), energy dispersive spectrometer (EDS), X-ray diffraction (XRD), and electron backscatter diffraction (EBSD). The results indicate that the thickness of the white layer is uneven and varies within three microns. Meanwhile, the amount of γ′ phase decreases, and δ phase is crushed and refined within the white layer. The lattice mismatch between γ and γ'' phases decreases and the white layer is more homogeneous than the original material. Furthermore, the grains were refined to submicron, and continuous dynamic recrystallization (CDRX) occurs in the white layer. The CDRX results in a recrystallized structure with significantly reduced defect density in the white layer formed during the turning of Inconel 718.

In Xinjiang, precision hole-sowing technology is used for cotton cultivation. A disc-type seed disperser has problems with missing seeds and multi-seeding; therefore, an interdigital (multiple pairs of coplanar electrodes crossed) capacitance sensor is designed to determine the seed pick-up status by gathering electrical capacity information. Firstly, a theoretical derivation is performed for calculating the capacitance of the sensor, and it is concluded that the interdigital spacing, interdigital width, and interdigital logarithm all affect the output capacitance. Then, by analyzing the working process of the dibble, the assemblage position of the sensor and the dimensional constraints were determined. In order to explore the impact of various structural parameters on the sensor’s performance (signal strength and capacitance variation), a Maxwell simulation platform was established, and orthogonal tests were created to optimize the structural parameters. In addition, the STM32 microcontroller is utilized as the core, and it is linked with the PCAP01-AD chip to form a tiny capacitance-detecting circuit. Finally, the capacitance threshold division test determined the capacitance threshold at different seed states. The test results demonstrate that the interdigital capacitive sensor can accurately determine the precision dibble’s seeding status, with detection accuracies of 96.9% for normal seeding, 99.67% for miss-seeding, and 93.77% for multiple seeds. These results can be used as a research reference for capacitive seeding status-detection technology.

Lignin, as a structurally complex biomaterial, offers a valuable resource for the production of aromatic chemicals; however, its selective conversion into desired products remains a challenging task. In this study, we prepared three types of Pd-based nano-catalysts and explored their application in the depolymerization of alkali lignin, under both H2-free (hydrogen transfer) conditions and H2 atmosphere conditions. The materials were well characterized with TEM, XRD, and XPS and others, and the electronic interactions among Pd, Ni, and P were analyzed. The results of lignin depolymerization experiments revealed that the ternary Pd-Ni-P catalyst exhibited remarkable performance and guaiacols could be produced under H2 atmosphere conditions in 14.2 wt.% yield with a selectivity of 89%. In contrast, Pd-Ni and Pd-P catalysts resulted in a dispersed product distribution. Considering the incorporation of P and the Pd-Ni synergistic effect in the Pd-Ni-P catalyst, a possible water-involved transformation route of lignin depolymerization was proposed. This work indicates that metal phosphides could be promising catalysts for the conversion of lignin and lignin-derived feedstocks into value-added chemicals.

The hydrogen supply system is one of the important components of a hydrogen fuel cell engine, and its performance has an important impact on the economy and power of the engine system. In this paper, a hydrogen supply system based on cyclic mode is designed for a hydrogen fuel cell stack with a full load power of 150 kW, and the corresponding hydrogen fuel cell engine simulation model is built and validated. The control strategy of the fuel cell hydrogen supply system is developed, and its effect is verified through bench tests. The results show that the developed control strategy can keep the volume fraction of nitrogen below 6%, the hydrogen excess ratio does not exceed 1.5 under medium and high operating conditions, the anode pressure is relatively stable, and the stack can operate efficiently and reliably.

Inappropriate spatial distribution of canopy and roots limits further improvements to the grain yield of maize with increased planting density. We explored an integrated management practice called strip deep rotary with staggered planting (SRS) which includes comprehensive technology for both canopy layers and topsoil. Here, field experiments were conducted under two maize cropping systems (spring maize and summer maize) to evaluate the effect of SRS on the spatial distribution of the canopy and roots for maize under high planting density (90,000 plants ha−1) and to determine the physiological factors involved in yield formation. Compared with conventional management practices (no-tillage with single planting, NTS), SRS decreased the LAI of the middle to top layers while improving the light distribution of the middle and lower layers by 72.99% and 84.78%, respectively. Meanwhile, SRS increased the root dry weight density and root sap bleeding by 51.26% and 21.77%, respectively, due to the reduction in soil bulk density by an average of 5.08% in the 0–40 cm soil layer. SRS improved the SPAD in the ear and lower leaves and maximized the LAD, which was conducive to dry matter accumulation (DMA), increasing it by 14.02–24.16% compared to that of NTS. As a result, SRS increased maize grain yield by 6.71–25.44%. These results suggest that strip deep rotary combined with staggered planting noticeably optimized the distribution of light in the canopy and reduced the soil bulk density to promote root vitality and growth, to maintain canopy longevity, and to promote the accumulation of dry matter, which eventually increased the grain yield of the maize under high planting density conditions. Therefore, SRS can be considered a better choice for the sustainable high yield of maize under high-density planting conditions in the NCP and similar areas throughout the world.

This work implements an intelligent forest monitoring system using the Internet of things (IoT) with the wireless network communication technology of a low-power wide-area network (LPWAN), a long range (LoRa), and a narrow-band Internet of things (NB-IoT). A solar micro-weather station with LoRa-based sensors and communications was built to monitor the forest status and information such as the light intensity, air pressure, ultraviolet intensity, CO2, etc. Moreover, a multi-hop algorithm for the LoRa-based sensors and communications is proposed to solve the problem of long-distance communication without 3G/4G. For the forest without electricity, we installed solar panels to supply electricity for the sensors and other equipment. In order to avoid the problem of insufficient solar panels due to insufficient sunlight in the forest, we also connected each solar panel to a battery to store electricity. The experimental results show the implementation of the proposed method and its performance.

Abstract Background 46, XY disorders of sex development (46, XY DSD) are congenital disorders with 46, XY chromosomal karyotype but inconsistent gonadal/phenotypic sex. One of the biggest concerns for parents and clinicians is the gender assignment. However, there is no standard uniform of care nor consensus at present. We sought to evaluate the current treatment's rationality and provide a reference basis for the gender reassignment in 46, XY DSD patients with a specific diagnosis. Methods We conducted a cross-sectional survey of gender role with the Pre-school Activities Inventory (PSAI), the Children's Sex Role Inventory (CSRI) in 46, XY DSD patients and set up control groups comparison. Psychiatrist assessed gender dysphoria in patients ≥ 8-year-old with the criteria of diagnostic and statistical manual of mental disorders, 5th edition (DSM-5). Results A total of 112 responders of 136 patients participated in this study (82.4%, aged 2–17.8 years, median age: 4-year-old). The follow-up period was from 6 months to 10 years (median: 2 years). Twenty-five females were reassigned to the male gender after a specific diagnosis (16/25 (64%) in 5 alfa-reductase-2 deficiency (5α-RD2), 5/25 (20%) in partial androgen insensitivity syndrome (PAIS), 4/25 (16%) in NR5A1gene mutation). Male gender assignment increased from 55.3 (n = 62) to 77.7% (n = 87). The median PSAI score was similar to the control males in 5α-RD2, PAIS, and NR5A1 gene mutation groups (p > 0.05); while identical to the control females in complete androgen insensitivity syndrome (CAIS) and CYP17A1 gene mutation groups (p > 0.05). PSAI score of children raised as male was higher than those of CAIS and CYP17A1 groups raised as female (p 0.05). None of the patients over 8-year-old (n = 44) had gender dysphoria. Conclusion The reassigned gender in 46, XY DSD patients is consistent with their gender role during early childhood. None of them had gender dysphoria. The molecular diagnosis, gonadal function, and the gender reassignment are congruent within our Chinese cohort. Long-term follow-up and more evaluation are still required.

A shutdown of the Atlantic Meridional Overturning Circulation could lead to a disproportionate increase in the occurrence of extremely cold weather in the U.S. via enhanced north-south heat exchange in the atmosphere, suggest simulations with and without a vigorous overturning circulation.

Abstract Background Urinary bladder lymphangioma is a rare and benign lesion that is often causes symptoms related to irritation and urinary tract obstruction. Because a lymphangioma may resemble a true neoplasm of the urinary bladder clinically, the lesion must be removed for accurate histologic diagnosis and to rule out malignancy. Case presentation We present a case of a 40-year-old female who was evaluated for painless gross hematuria. Clinical and diagnostic work up revealed a sharply defined mass involving the wall and bulging into the cavity on the dome of the bladder. Partial cystectomy was performed and histologic findings were compatible with cavernous lymphangioma. The symptom of hematuria relieved after the procedure and the patient was in good status without evidence of recurrence by cystoscopy at follow-up 6 months later. Conclusions Lymphangioma of the urinary bladder is treated with surgical excision and seems to have no recurrence once completely resected, but long-time follow-up may be needed.

Concomitant traumatic brain injury accelerates bone healing, but the mechanism is unclear. Here, the authors show that injured neurons, mainly those in the hippocampus, release osteogenic miRNA-enriched small extracellular vesicles, which targete osteoprogenitors to stimulate bone formation.

The prediction of PM2.5 is important for environmental forecasting and air pollution control. In this study, four machine learning methods, ground-based LiDAR data and meteorological data were used to predict the ground-level PM2.5 concentrations in Beijing. Among the four methods, the random forest (RF) method was the most effective in predicting ground-level PM2.5 concentrations. Compared with BP neural network, support vector machine (SVM), and various linear fitting methods, the accuracy of the RF method was superior by 10%. The method can describe the spatial and temporal variation in PM2.5 concentrations under different meteorological conditions, with low root mean square error (RMSE) and mean square deviation (MD), and the consistency index (IA) reached 99.69%. Under different weather conditions, the hourly variation in PM2.5 concentrations has a good descriptive ability. In this paper, we analyzed the weights of input variables in the RF method, constructed a pollution case to correspond to the relationship between input variables and PM2.5, and analyzed the sources of pollutants via HYSPLIT backward trajectory. This method can study the interaction between PM2.5 and air pollution variables, and provide new ideas for preventing and forecasting air pollution.

Abstract Absent in melanoma 2 (AIM2) is a novel member of interferon (IFN)‐inducible PYHIN proteins. In innate immune cells, AIM2 servers as a cytoplasmic double‐stranded DNA sensor, playing a crucial role in the initiation of the innate immune response as a component of the inflammasome. AIM2 expression is increased in patients with systemic lupus erythematosus (SLE), psoriasis, and primary Sjogren's syndrome, indicating that AIM2 might be involved in the pathogenesis of autoimmune diseases. Meanwhile, AIM2 also plays an antitumorigenesis role in an inflammasome independent‐manner. In melanoma, AIM2 is initially identified as a tumor suppressor factor. However, AIM2 is also found to contribute to lung tumorigenesis via the inflammasome‐dependent release of interleukin 1β and regulation of mitochondrial dynamics. Additionally, AIM2 reciprocally dampening the cGAS‐STING pathway causes immunosuppression of macrophages and evasion of antitumor immunity during antibody treatment. To summarize the complicated effect and role of AIM2 in autoimmune diseases and cancers, herein, we provide an overview of the emerging research progress on the function and regulatory pathway of AIM2 in innate and adaptive immune cells, as well as tumor cells, and discuss its pathogenic role in autoimmune diseases, such as SLE, psoriasis, primary Sjogren's syndrome, and cancers, such as melanomas, non‐small‐cell lung cancer, colon cancer, hepatocellular carcinoma, renal carcinoma, and so on, hopefully providing potential therapeutic and diagnostic strategies for clinical use.

Abstract Absent in melanoma 2 (AIM2) has been reported to be a component of inflammasomes in innate immune cells. Surprisingly, AIM2 is expressed by B cells, and higher AIM2 expression is observed in the B cells from lupus patients. To date, the inflammasome-independent function of AIM2 in B cells remains unclear. Here, we report increased expression of AIM2 in human tonsil memory and germinal center (GC) B cells and in memory B cells and plasma cells from the circulation and skin lesions of lupus patients. Conditional knockout of AIM2 in B cells reduces the CD19+ B-cell frequency in lymph nodes and spleens, and dampens KLH-induced IgG1-antibody production. In a pristane-induced mouse model of lupus, AIM2 deficiency in B cells attenuates lupus symptoms and reduces the frequency of GC B cells, T follicular helper (Tfh) cells, plasmablast cells, and plasma cells. Furthermore, the loss of AIM2 in human B cells leads to the increased expression of Blimp-1 and reduces the expression of Bcl-6. However, the silencing of Blimp-1 and Bcl-6 has no significant effect on AIM2 expression, indicating that AIM2 might be the upstream regulator for Blimp-1 and Bcl-6. In addition, IL-10 is found to upregulate AIM2 expression via DNA demethylation. Together, our findings reveal that AIM2 is highly expressed in the B cells of lupus patients and promotes B-cell differentiation by modulating the Bcl-6–Blimp-1 axis, providing a novel target for SLE treatment.

Abstract Background Soft tissue perineurioma of the kidney is rare, with only a few reported cases. We report two additional cases with histologic, immunohistochemical and genetic analyses. Case presentation Both tumors were from adults (1 female aged 49 years and 1 male aged 42 years) and grossly had maximum diameters of 6.5 and 10 cm, respectively. The tumors were overall well circumscribed but unencapsulated, with focally entrapped benign native renal tubules in one case; both tumors seemed to arise in the capsular areas. The tumors had histologic and immunohistochemical profiles consistent with soft tissue perineurioma. Fluorescence in situ hybridization analyses demonstrated that the tumors were negative for amplification of MDM2 and rearrangements of ESWR1, FUS, and KMT2A. Targeted next-generation sequencing revealed a low tumor mutation burden and likely pathogenic mutations (CYP2B6 and FLT1 mutations for 1 each). Follow-up data were available for both patients; neither had tumor recurrence or metastasis. Conclusions In conclusion, renal perineurioma is rare, usually arises in the capsular areas, and is cured by resection. Low-grade dedifferentiated liposarcoma and low-grade fibromyxoid sarcoma as well as other spindle cell lesions should be considered in the differential diagnosis.

In this paper, we first give an alternative proof for a result of Mao in [Linear Algebra Appl., 589 (2020) 96–102], then we present some results involving multiple positive definite matrices and multiple sector matrices.

ALK rearrangements have rarely been reported in S100- and CD34-co-expressing soft tissue neoplasms with lipofibromatosis-like neural tumor (LPFNT) pattern or stromal and perivascular hyalinization, mimicking NTRK-rearranged spindle cell tumors. Here, we reported ALK fusions involving related partner genes in two adult soft tissue tumors with S100 and CD34 co-expression, and conducted a literature review of mesenchymal tumors harboring ALK or other kinase fusions. Case 1 was a 25-year-old female who underwent excision of a soft tissue mass in the anterior thigh region. Morphologically, the tumor was composed of spindle cells adjacent to epithelioid cells embedded in myxedematous and hyalinized stroma, with infiltrative boundary. Spindle cells mixed with inflammatory infiltration resembling inflammatory myofibroblastic tumor (IMT) were seen sporadically. However, brisk mitosis and focal necrosis was also observed, indicating an intermediate-grade sarcoma. In case 2, the left side of the neck of a 34-year-old man was affected. The tumor was composed of monomorphic spindle cells arranged in fascicular growth or patternless pattern, with stromal and perivascular hyalinization. Sparse inflammatory cell infiltration was also observed. Both tumors showed CD34, S100, and ALK-D5F3 immunoreactivity. Next generation sequencing (NGS) test identified a PLEKHH2::ALK fusion in case 1, which was confirmed by RT-PCR and Sanger sequencing, whereas the RT-PCR (ARMS method) test detected an EML4::ALK fusion in case 2. In conclusion, this study expands the morphological and genetic landscape of tumors with S100 and CD34 co-expression harboring kinase fusions, and suggests that kinase fusion–positive mesenchymal neoplasms are becoming an enlarging entity with a variety of morphological patterns.

Summary: The clinical correlation between adiponectin (APN) signal and hypertrophic scar (HS) remains unclear. Here, we found significantly reduced expression of APN receptors (AdipoR1/2) in HS tissues and derived fibroblasts (HFs), suggesting that HS formation may be associated with APN/AdipoR1/2 decline. RNA sequencing and RT-PCR validation revealed that APN significantly elevated the expression of SIRT1. Both in vitro and in vivo experiments confirmed that SIRT1 plays important role in APN inhibiting the fibrotic phenotype transformation and proliferation of scar fibroblasts and improving skin fibrosis. Mechanistically, SIRT1 inhibited the acetylation of C/EBPβ K39, histone H3K27, and H3K9, resulting in impaired transcription activity of C/EBPβ and compact chromatin conformation, thus preventing C/EBPβ from activating the transcription of YAP. Moreover, we found that YAP was critical for the transcriptional regulation of CTGF, CCND1, and CCNE1 by TEAD4. In conclusion, our study revealed the role of APN in antagonizing HS fibrosis by regulating the SIRT1/C/EBPβ/YAP pathway.

Metanephric stromal tumor (MST) is a rare, benign pediatric renal neoplasm of uncertain histogenesis that belongs to the metanephric family of tumors. MST involving adult patients is very uncommon, which could cause significant diagnostic confusions. Recent molecular studies have revealed recurrent BRAF mutations in MST in pediatric patients which may serve as powerful diagnostic tools for distinguishing MST from other renal stromal tumors. We present a BRAF-mutated MST in an adult patient with a brief review of the pertinent literature. To our knowledge, our case represents to date the sixth report of adult MST and the first adult MST proven to harbor BRAF mutation. This is a 41-year-old man who was incidentally identified to have a left renal mass by ultrasonography. He had a 5-year history of hypertension which could be controlled with oral antihypertensive drug. Partial nephrectomy was performed which demonstrated a 2.6-cm, oval, circumscribed mass with a fibrotic and firm texture. Microscopic examination showed a hypocellular, spindle cell neoplasm with entrapped nephrons, within a predominantly fibrous and focally myxoid stroma. Foci of hyalinized stroma surrounding entrapped native renal tubules or blood vessels to form concentric collarettes-like structures, and small-sized arterioles showing angiodysplasia, were observed. Immunostains showed the tumor cells to be diffusely positive for CD34. Fluorescence in-situ hybridization analysis was negative for rearrangements involving both the EWSR1 and FUS loci. Targeted next-generation sequencing disclosed a pathogenic mutation of BRAF exon15: c.1799T>A (p.V600E). The patient’s hypertension normalized without oral antihypertensive drugs 2 months postoperatively and he was in good status 12 months after the surgery. Our case highlights the diagnostic dilemma of MST occurring in adults and points to the usefulness of molecular detection of BRAF mutation for arriving at accurate diagnosis.

Tea tree [Camellia sinensis var. sinensis or assamica (L.) O. Kuntze], an important crop worldwide, is usually pruned to heights of 70 to 80 cm, forming pruned tea tree (PTT) plantations. Currently, PTTs are transformed into unpruned tea tree (UPTT) plantations in Yunnan, China. This has improved the quality of tea products, but the underlying reasons have not been evaluated scientifically. Here, 12 samples of sun-dried green teas were manufactured using fresh leaves from an UPTT and the corresponding PTT. Using sensory evaluation, it was found that the change reduced the bitterness and astringency, while increasing sweetness and umami. Using high performance liquid chromatography detection showed that the contents of free amino acids (theanine, histidine, isoleucine and phenylalanine) and catechin gallate increased significantly (P < 0.05), whereas the content of alanine decreased significantly (P < 0.05). A liquid chromatography–mass spectrometry-based metabolomics analysis showed that the transformation to UPTT significantly decreased the relative levels of the majority of flavonols and tannins (P < 0.05), as well as γ-aminobutyric acid, caffeine and catechin (epigallocatechin, catechin, epigallocatechin gallate, gallocatechin gallate), while it significantly increased the relative contents of catechins (gallocatechin, epicatechin, epicatechin gallate and catechin gallate), phenolic acids and some amino acids (serine, oxidized glutathione, histidine, aspartic acid, glutamine, lysine, tryptophan, tyramine, pipecolic acid, and theanine) (P < 0.05). In summary, after transforming to UPTT, levels of amino acids, such as theanine increased significantly (P < 0.05), which enhanced the umami and sweetness of tea infusions, while the flavonoids (such as kaempferol, myricetin and glycosylated quercetin), and caffeine contents decreased significantly (P < 0.05), resulting in a reduction in the bitterness and astringency of tea infusions and an increase in tea quality.

Single nucleotide polymorphism (SNP) possesses a promising application in forensic individual identification due to its wide distribution in the human genome and the ability to carry out the genotyping of degraded biological samples by designing short amplicons. Some commonly used individual identification SNPs are less polymorphic in East Asian populations. In order to improve the individual identification efficiencies in East Asian populations, SNP genetic markers with relatively higher polymorphisms were selected from the 1,000 Genome Project phase III database in East Asian populations. A total of 111 individual identification SNPs (II-SNPs) with the observed heterozygosity values greater than 0.4 were screened in East Asian populations, and then, the forensic efficiencies of these selected SNPs were also evaluated in Chinese Inner Mongolia Manchu group. The observed heterozygosity and power of discrimination values at 111 II-SNPs in the Inner Mongolia Manchu group ranged from 0.4011 to 0.7005, and 0.5620 to 0.8025, respectively, and the average value of polymorphism information content was greater than 0.3978. The cumulative match probability and combined probability of exclusion values at II-SNPs were 7.447E-51 and 1-4.17E-12 in the Inner Mongolia Manchu group, respectively. The accumulative efficiency results indicated that the set of II-SNPs could be used as a potential tool for forensic individual identification and parentage testing in the Manchu group. The sequencing depths ranged from 781× to 12374×. And the mean allele count ratio and noise level were 0.8672 and 0.0041, respectively. The sequencing results indicated that the SNP genetic marker detection based on the massively parallel sequencing technology for SNP genetic markers had high sequencing performance and could meet the sequencing requirements of II-SNPs in the studied group.

In recent years, the convolutional neural network (CNN) technique has emerged as an efficient new method for designing porous structure, but a CNN model generally contains a large number of parameters, each of which could influence the predictive ability of the CNN model. Furthermore, there is no consensus on the setting of each parameter in the CNN model. Therefore, the present study aimed to investigate the sensitivity of the parameters in the CNN model for the prediction of the mechanical property of porous structures. 10,500 samples of porous structure were randomly generated, and their effective compressive moduli obtained from finite element analysis were used as the ground truths to construct and train a CNN model. 8,000 of the samples were used to train the CNN model, 2000 samples were used for the cross-validation of the CNN model and the remaining 500 new structures, which did not participate in the CNN training process, were used to test the predictive power of the CNN model. The sensitivity of the number of convolutional layers, the number of convolution kernels, the number of pooling layers, the number of fully connected layers and the optimizer in the CNN model were then investigated. The results showed that the optimizer has the largest influence on the training speed, while the fully connected layer has the least impact on the training speed. Additionally, the pooling layer has the largest impact on the predictive ability while the optimizer has the least impact on the predictive ability. In conclusion, the parameters of the CNN model play an important role in the performance of the CNN model and the parameter sensitivity analysis can help optimize the CNN model to increase the computational efficiency.

Astragalus membranaceus, as an important medicinal plant, are an excellent source of flavonoids. Flavonoid compounds in A. membranaceus have been widely used in medicine and supplement, but known of the molecular mechanism of flavonoid biosynthesis is still very few. Here, we analyzed the association between flavonoid content and gene expression pattern during six different fruit developmental stages. Sixteen gene expression trends were significantly identified, involving 8,218 genes. The gene expression trend in profile 0 was positively correlated with flavonoid content, while the gene expression trend in profile 79 was negatively correlated with flavonoid content at six developmental stages. The expression level of genes involved in the general phenylpropane pathway was higher than that of genes involved in the flavonoid biosynthesis pathway. A total of 37 genes involved in flavonoid synthesis were identified in A. membranaceus. The expression pattern of flavonoid-related genes was highly correlated with flavonoid content. Our study deepened the understanding of the flavonoid synthesis mechanism and provided useful resources for future studies on the high flavonoid molecular breeding of A. membranaceus.

As the aging population poses serious challenges to families and societies, the issue of dementia has also received increasing attention. Dementia detection often requires a series of complex tests and lengthy questionnaires, which are time-consuming. In order to solve this problem, this article aims at the diagnosis method of questionnaire survey, hoping to establish a diagnosis model to help doctors make a diagnosis through machine learning method, and use feature selection method to select important questions to reduce the number of questions in the questionnaire, so as to reduce medical and time costs. In this article, Clinical Dementia Rating (CDR) is used as the data source, and various methods are used for modeling and feature selection, so as to combine similar attributes in the data set, reduce the categories, and finally use the confusion matrix to judge the effect. The experimental results show that the model established by the bagging method has the best effect, and the accuracy rate can reach 80% of the true diagnosis rate; in terms of feature selection, the principal component analysis (PCA) has the best effect compared with other methods.

Adjusting the sowing date to optimize temperature conditions is a helpful strategy for mitigating the adverse impact of high temperature on summer maize growth in the North China Plain (NCP). However, the physiological processes of variation in summer maize yield with sowing date-associated changes in temperature conditions around flowering remain to be poorly understood. In this study, field experiments with two maize varieties and three sowing dates (early sowing date, SD1, 21 May; conventional sowing date, SD2, 10 June; delay sowing date, SD3, 30 June) were conducted at Xinxiang of Henan Province in 2019 and 2020. Early sowing markedly decreased the daily mean temperature (Tmean), maximum temperature (Tmax), and minimum temperature (Tmin) during pre-silking, while delay sowing markedly decreased those temperatures during post-silking. Under these temperature conditions, both varieties under SD1 at 12-leaf stage (V12) and silking stage (R1) while under SD3 at R1 and milking stage (R3) possessed significantly lower malondialdehyde (MDA) content in leaf due to higher activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) compared to SD2. Therefore, SD1 at V12 and R1 stages and SD3 at R1 and R3 stages for both varieties showed significantly higher photosynthetic capacity, including higher SPAD, Fv/Fm, Pn, Tr, and Gs, which promoted greater pre-silking dry matter (DM) accumulation for SD1 to increase the kernel number, and promoted greater post-silking DM accumulation for SD3 to increase the kernel weight, eventually increased the grain yield of SD1 and SD3 compared to SD2. Results of regression analysis demonstrated that Tmean, Tmax, and Tmin values from V12 to R1 stages lower than 26.6, 32.5, and 20.3°C are necessary for improving the kernel number, while Tmean, Tmax, Tmin, and accumulated temperature (AT) values from R1 to R3 stages lower than 23.2, 28.9, 17.3, and 288.6°C are necessary for improving the kernel weight. Overall, optimal temperature conditions around flowering can be obtained by early (21 May) or delay (30 June) sowing to improve the kernel number or kernel weight due to improved photosynthetic capacity, eventually increasing the grain yield of summer maize in the NCP.

Grain filling is a critical process for achieving a high grain yield in maize (Zea mays L.), which can be improved by optimal combination with genotype and nitrogen (N) fertilization. However, the physiological processes of variation in grain filling in hybrids and the underlying mechanisms of carbon (C) and N translocation, particularly under various N fertilizations, remain poorly understood. The field experiment was conducted at Gongzhuling Farm in Jilin, China. In this study, two maize hybrids, i.e., Xianyu 335 (XY335) and Zhengdan958 (ZD958) were grown with N inputs of 0, 150, and 300 kg N ha–1 (N0, N150, and N300) in 2015 and 2016. Results showed that the N application significantly optimized grain-filling parameters for both maize hybrids. In particular, there was an increase in the maximum filling rate (Gmax) and the mean grain-filling rate (Gmean) in XY335 by 8.1 and 7.1% compared to ZD958 under the N300 kg ha–1 (N300) condition, respectively. Simultaneously, N300 increased the small and big vascular bundles area of phloem, and the number of small vascular bundles in peduncle and cob at the milking stage for XY335. XY335 had higher root bleeding sap (10.4%) and matter transport efficiency (8.4%) of maize under N300 conditions, which greatly enhanced the 13C assimilates and higher C and N in grains to facilitate grain filling compared to ZD958. As a result, the grain yield and the sink capacity for XY335 significantly increased by 6.9 and 6.4% compared to ZD958 under N300 conditions. These findings might provide physiological information on appropriate agronomy practices in enhancing the grain-filling rate and grain yield for maize under different N applications, namely the optimization variety and N condition noticeably increased grain filling rate after silking by improving ear vascular structure, matter transport efficiency, and enhancing C and N assimilation translocation to grain, eventually a distinct improvement in the grain sink and the grain yield.

Adult-onset Still’s disease (AOSD) is a rare disease affecting multiple systems and organs with unknown etiology, and the clinical symptoms are usually described as spiking fever, arthritis, evanescent salmon-pink eruptions, lymphadenopathy, splenomegaly, and other manifestations. The laboratory indicators are not specific, often presenting as increased leukocyte counts and neutrophil percentage, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), hyperferritinemia, and increased inflammatory factors. ANA, ENA, and RF are negative. According to those unspecific clinical presentations and laboratory findings, infection, tumor, connective tissue disease, and other diseases must be ruled out before diagnosis. The diagnosis of AOSD is a great challenge for clinicians. The mechanism of AOSD pathogenesis is complicated and still being studied. There is a new opinion that atypical persistent skin eruptions (APSEs) with specific histological manifestations are unique for AOSD, and APSEs might be on a spectrum with classical evanescent eruptions. Studies on APSEs showed that IL-1β and IFN-γ are strongly correlated with the pathogenesis of necrosis keratinocytes in APSEs. IL-1β is strongly involved in inflammatory disease when it is abnormal, and plays an important role in the pathogenesis of neutrophil dermatosis. In the early stage of AOSD, skin lesions appear to be evanescent urticaria-like eruptions accompanied by fever, and only neutrophils infiltrate around the blood vessels in the dermis pathologically. As the course of the disease progresses, IL-1β is gradually released. Through the stimulation of other inflammatory factors and the influence of unknown factors, IL-1β gradually infiltrates into the stratum corneum and finally accumulates around the necrotic keratinocytes of the stratum corneum. However, the detailed mechanism is still unknown. IFN-γ could play a pro-inflammatory or regulatory role in some disorders. IL-1β can enhance the expression of IFN-γ, and IFN-γ can cause keratinocyte apoptosis by activating the autocrine of caspase. Also, several pieces of evidence indicate that adaptive immunity is also involved in the pathogenesis of AOSD. Increased α-soluble receptors of IL-2 may suggest T-cell activation and proliferation in AOSD patients. Increased IL-4- and IFN-γ-producing T cells were found in active AOSD and related to disease severity. Frequencies of Treg cells in AOSD were significantly lower and were inversely correlated with disease severity. According to these, more and more researchers have reached a consensus that AOSD is a disease at the crossroads of innate immunity and autoimmunity. In this review, we will provide a comprehensive insight into AOSD, describing research progress and the immunological mechanism contribution to the disease. In the meantime, different treatment options and the efficacy and safety of various biologic agents are also discussed. A further understanding of AOSD requires closer cooperation among doctors from different departments, and this review will provide a new idea for diagnosis and therapeutic options.

The present study was to investigate the molecular mechanisms underlying macrophage inflammatory response to polysaccharides from Peucedanum praeruptorum Dunn (PPDs) and elucidate the receptors and signaling pathways associated with PPDs-mediated macrophage activation. MTT and Griess method were performed to investigate the effects of PPDs on cell viability and NO production. Neutral red and FITC-dextran were used to determine the pinocytic and phagocytic activity. RT-qPCR and ELISA were employed to analyze the mRNA expression of inflammatory factors and production of cytokines and chemokines. RNA-seq and bioinformatics analysis were conducted to determine the underlying molecules, regulators and pathways, which were further validated by pathway inhibition and neutralization assays. The results indicated that PPDs significantly enhanced pinocytic and phagocytic activity, promoted the expression and secretion of inflammatory factors and chemokines, and boosted the expression of accessory and costimulatory molecules. RNA-Seq analysis identified 1343 DEGs, 405 GO terms and 91 KEGG pathways. IL6 and TNF were identified as hubs of connectivity in PPDs-mediated macrophage activation. “Cytokine-cytokine receptor interaction”, “TNF signaling pathway”, “NF-kappa B signaling pathway”, “JAK-STAT signaling pathway” and “MAPK signaling pathway” were the most significant pathways. The pathway inhibition assay revealed that MAPK and NF-κB pathways were essential to macrophage activation by PPDs. TLR2 and TLR4 were uncovered to be the functional receptors and involved in recognition of PPDs. These results indicated that PPDs modulated macrophage inflammatory response mainly through TLR2/TLR4-dependent MAPK and NF-κB pathways.

Abstract Blood–brain barrier (BBB) impairment is an early prevalent feature of multiple sclerosis (MS), and remains vital for MS progression. Microglial activation precedes BBB disruption and cellular infiltrates in the brain of MS patients. However, little is known about the function of microglia in BBB impairment. Here, microglia acts as an important modulator of BBB integrity in inflammatory demyelination. Microglial depletion profoundly ameliorates BBB impairment in experimental autoimmune encephalomyelitis (EAE). Specifically, miR‐126a‐5p in microglia is positively correlated with BBB integrity in four types of MS plaques. Mechanistically, microglial deletion of miR‐126a‐5p exacerbates BBB leakage and EAE severity. The protective effect of miR‐126a‐5p is mimicked and restored by specific inhibition of MMP9 in microglia. Importantly, Auranofin, an FDA‐approved drug, is identified to protect BBB integrity and mitigate EAE progression via a microglial miR‐126a‐5p dependent mechanism. Taken together, microglia can be manipulated to protect BBB integrity and ameliorate inflammatory demyelination. Targeting microglia to regulate BBB permeability merits consideration in therapeutic interventions in MS.

The aryl hydrocarbon receptor was previously known as an environmental receptor that modulates the cellular response to external environmental changes. In essence, the aryl hydrocarbon receptor is a cytoplasmic receptor and transcription factor that is activated by binding to the corresponding ligands, and they transmit relevant information by binding to DNA, thereby activating the transcription of various genes. Therefore, we can understand the development of certain diseases and discover new therapeutic targets by studying the regulation and function of AhR. Several autoimmune diseases, including systemic lupus erythematosus (SLE), have been connected to AhR in previous studies. SLE is a classic autoimmune disease characterized by multi-organ damage and disruption of immune tolerance. We discuss here the homeostatic regulation of AhR and its ligands among various types of immune cells, pathophysiological roles, in addition to the roles of various related cytokines and signaling pathways in the occurrence and development of SLE.

The mud crab, Scylla paramamosain, has abundant nutrients in its edible parts, ovary, hepatopancreas, and muscle during the ovarian maturation stage. The ovary of S. paramamosain can re-mature after spawning during the secondary ovarian maturation period. We aimed to analyze the characteristics of the first vitellogenesis period (FVP)1 and second vitellogenesis period (SVP)2 of S. paramamosain during ovarian maturation to understand the differences in vitellogenesis patterns between the first and second ovarian maturation periods. Accordingly, the gonadosomatic index (GSI) and hepatopancreatic index (HSI), the external and histological characteristics of the ovary and hepatopancreas, the Sp-Vg (vitellogenin, Vg) expression levels in the hepatopancreas and ovary, and the dynamics of the biochemical components in the ovary, hepatopancreas, and muscle were determined. Based on the results, the GSI was significantly positively correlated with HSI during the FVP and significantly negatively correlated with HSI from stage Ⅳ to stage Ⅴ of the SVP. A significant difference was found between the FVP and SVP in the hepatopancreas. Notably, the hepatopancreas displayed a gradual degeneration trend during the SVP. The expression level of Sp-Vg was significantly higher in the hepatopancreas than that in the ovary during the FVP and SVP. Seventeen amino acids were detected in the hepatopancreas, ovary, and muscle during the FVP and SVP, with glutamate as the predominant amino acid. During the FVP and SVP, the C16:0 and C18:1n9c were the dominant fatty acids in the hepatopancreas and ovary, the MUFA gradually increased in the ovary and hepatopancreas, and a significant difference was found in the dynamic trend of the HUFA and SFA contents from stage Ⅳ to stage Ⅴ between the FVP and SVP. These findings indicate that the ovary can re-mature after spawning in S. paramamosain and can maintain the status of the first ovarian maturation; however, the hepatopancreas gradually degenerate during the SVP.

The research on the mechanism of hydrothermal transfer and transformation and bare soil evaporation is of great significance for water balance and surface energy transformation in surface-groundwater systems. In this paper, based on long-term observations of in situ lysimeter test and numerical simulation, two cases for lysimeter with initial groundwater depths of 80 cm (shallow groundwater depth) and 290 cm (deep groundwater depth) are used to examine the dynamic process of hydrothermal transformation in the variable saturation zone with its effect on bare soil evaporation in the “wind-blown sand area” of the Ordos Basin in China. The results indicate that soil water movement in the variable saturation zone is driven by the head gradient and temperature gradient, showing different movement modes under different groundwater depths. For the situation of shallow groundwater depth, the capillary height can reach the surface, soil water transports upwards with little temperature effects driven by capillary force under the effects of head gradient under the evaporation conditions, and there is no zero flux plane in the soil. When the groundwater depth is less than the capillary height, groundwater directly contributes to soil evaporation driven by capillary force. For the situation of deep groundwater depth, head and temperature are the key factors in the soil water movement, and there is an isolated zero flux plane located at 18 cm below the ground surface, which prevents the upward soil water movement and leads to a decrease in evaporation. When the groundwater depth is greater than 1.6 times the capillary height, groundwater no longer directly involves in soil evaporation, but indirectly affects the water conversion in the unsaturated zone. Therefore, during the simulation period, the cumulative bare soil evaporation of the shallow groundwater depth was about 4 times that of the deep groundwater depth.

Abstract Background Dermatofibrosarcoma protuberans (DFSP) is a superficial fibroblastic tumor characterized by high rate of local recurrence and low metastatic potential. Fibrosarcomatous transformation can rarely arise in DFSP either de novo or as recurrent, which represents a form of tumor progression and carries an increased risk of metastasis over classic DFSP. Cytogenetically, DFSP is characterized by a recurrent unbalanced chromosome translocation t (17;22)(q22;q13), leading to the formation of COL1A1-PDGFB fusion transcript that is present in more than 90% of cases. Alternative fusions involving the PDGFD with partners of COL6A3 or EMILIN2 have recently been documented in less than 2% of cases. Herein, we report a DFSP with fibrosarcomtous morphology harboring a novel TNC-PDGFD fusion. Case presentation A 54-year-old female presented with a slowly growing mass in the right thigh. Excision demonstrated a 2-cm ovoid, well-circumscribed, gray-white, mass. Microscopic examination revealed a partially encapsulated subcutaneous nodule without dermal connection. The neoplasm was composed of cellular and fairly uniform spindle cells with brisk mitoses, arranged in elongated fascicles and herringbone patterns, with focal collagenized stroma. The neoplastic cells were positive for CD34 and smooth muscle actin. Fluorescence in-situ hybridization analyses showed negative for COL1A1-PDGFB fusion as well as NTRK1/2/3 rearrangements. A subsequent RNA sequencing detected an in-frame fusion between exon 15 of TNC and exon 6 of PDGFD. This fusion was further confirmed by nested reverse transcription polymerase chain reaction amplification followed by Sanger sequencing. A diagnosis of fibrosarcomatous DFSP was rendered and the patient was in good status at a follow-up of 12 months after the operation. Conclusions We report a fibrosarcomatous DFSP with novel TNC-PDGFD fusion, which adds to the pathologic and genetic spectrum of PDGFD-rearranged DFSP.

Abstract Methyltransferase-like 7B (METTL7B) is a member of the methyltransferase-like protein family that plays an important role in the development and progression of tumors. However, its prognostic value and the correlation of METTL7B expression and tumor immunity in some cancers remain unclear. By analyzing online data, we found that METTL7B is abnormally overexpressed in multiple human tumors and plays an important role in the overall survival (OS) of patients with 8 cancer types and disease-free survival (DFS) of patients with 5 cancer types. Remarkably, METTL7B expression was positively correlated with the OS and DFS of patients with lower-grade glioma (LGG). In addition, a positive correlation between METTL7B expression and immune cell infiltration in LGG was observed. Moreover, we identified a strong correlation between METTL7B expression and immune checkpoint gene expression in kidney chromophobe (KICH), LGG and pheochromocytoma and paraganglioma (PCPG). Furthermore, METTL7B was involved in the extracellular matrix (ECM) and immune-related pathways in LGGs. Finally, in vitro experiments showed that knockdown of METTL7B inhibited the growth, migration, invasion and the epithelial–mesenchymal transition (EMT) of LGG cells. METTL7B expression potentially represents a novel prognostic biomarker due to its significant association with immune cell infiltration in LGG.

Abstract Although chimeric antigen receptor (CAR)-engineered T cells have shown great success in the treatment of B cell malignancies, this strategy has limited efficacy in patients with solid tumors. In mouse CAR-T cells, IL-7 and CCL19 expression have been demonstrated to improve T cell infiltration and CAR-T cell survival in mouse tumors. Therefore, in the current study, we engineered human CAR-T cells to secrete human IL-7 and CCL19 (7 × 19) and found that these 7 × 19 CAR-T cells showed enhanced capacities of expansion and migration in vitro. Furthermore, 7 × 19 CAR-T cells showed superior tumor suppression ability compared to conventional CAR-T cells in xenografts of hepatocellular carcinoma (HCC) cell lines, primary HCC tissue samples and pancreatic carcinoma (PC) cell lines. We then initiated a phase 1 clinical trial in advanced HCC/PC/ovarian carcinoma (OC) patients with glypican-3 (GPC3) or mesothelin (MSLN) expression. In a patient with advanced HCC, anti-GPC3-7 × 19 CAR-T treatment resulted in complete tumor disappearance 30 days post intratumor injection. In a patient with advanced PC, anti-MSLN-7 × 19 CAR-T treatment resulted in almost complete tumor disappearance 240 days post-intravenous infusion. Our results demonstrated that the incorporation of 7 × 19 into CAR-T cells significantly enhanced the antitumor activity against human solid tumor. Trial registration: NCT03198546. Registered 26 June 2017, https://clinicaltrials.gov/ct2/show/NCT03198546?term=NCT03198546&draw=2&rank=1

Adsorption is a fundamentally important process but challenging to quantify, especially at the nanoscale. Here, the authors map the adsorption affinity and cooperativity of various ligands on single gold nanoparticles and discover adsorption crossover behaviors between different facets, leading to a strategy to control particle shape.