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Abstract Background Radiation-induced skin injury is a significant adverse reaction to radiotherapy. However, there is a lack of effective prevention and treatment methods for this complication. Ferulic acid (FA) has been identified as an effective anti-radiation agent. Conventional administrations of FA limit the reaching of it on skin. We aimed to develop a novel FA hydrogel to facilitate the use of FA in radiation-induced skin injury. Methods We cross-linked carbomer 940, a commonly used adjuvant, with FA at concentrations of 5%, 10%, and 15%. Sweep source optical coherence tomography system, a novel skin structure evaluation method, was applied to investigate the influence of FA on radiation-induced skin injury. Calcein-AM/PI staining, CCK8 assay, hemolysis test and scratch test were performed to investigate the biocompatibility of FA hydrogel. The reducibility of DPPH and ABTS radicals by FA hydrogel was also performed. HE staining, Masson staining, laser Doppler blood flow monitor, and OCT imaging system are used to evaluate the degree of skin tissue damage. Potential differentially expressed genes were screened via transcriptome analysis. Results Good biocompatibility and in vitro antioxidant ability of the FA hydrogels were observed. 10% FA hydrogel presented a better mechanical stability than 5% and 15% FA hydrogel. All three concentrations of FA remarkably promoted the recovery of radiation-induced skin injury by reducing inflammation, oxidative conidiation, skin blood flow, and accelerating skin tissue reconstruction, collagen deposition. FA hydrogel greatly inhibiting the levels of NLRP3, caspase-1, IL-18, pro-IL-1β and IL-1β in vivo and vitro levels through restraining the activation of NLRP3 inflammasome. Transcriptome analysis indicated that FA might regulate wound healing via targeting immune response, inflammatory response, cell migration, angiogenesis, hypoxia response, and cell matrix adhesion. Conclusions These findings suggest that the novel FA hydrogel is a promising therapeutic method for the prevention and treatment of radiation-induced skin injury patients. Graphical Abstract

Introduction:: Accurate identification of pulmonary arterial hypertension (PAH) in primary care and rural areas can be a challenging task. However, recent advancements in computer vision offer the potential for automated systems to detect PAH from echocardiography. Objectives:: Our aim was to develop a precise and efficient diagnostic model for PAH tailored to the unique requirements of intelligent diagnosis, especially in challenging locales like high-altitude regions. Methods:: We proposed the Chamber Attention Network (CAN) for PAH identification from echocardiographic images, trained on a dataset comprising 13,912 individual subjects. A convolutional neural network (CNN) for view classification was used to select the clinically relevant apical four chamber (A4C) and parasternal long axis (PLAX) views for PAH diagnosis. To assess the importance of different heart chambers in PAH diagnosis, we developed a novel Chamber Attention Module. Results:: The experimental results demonstrated that: 1) The substantial correspondence between our obtained chamber attention vector and clinical expertise suggested that our model was highly interpretable, potentially uncovering diagnostic insights overlooked by the clinical community. 2) The proposed CAN model exhibited superior image-level accuracy and faster convergence on the internal validation dataset compared to the other four models. Furthermore, our CAN model outperformed the others on the external test dataset, with image-level accuracies of 82.53% and 83.32% for A4C and PLAX, respectively. 3) Implementation of the voting strategy notably enhanced the positive predictive value (PPV) and negative predictive value (NPV) of individual-level classification results, enhancing the reliability of our classification outcomes. Conclusions:: These findings indicate that CAN is a feasible technique for AI-assisted PAH diagnosis, providing new insights into cardiac structural changes observed in echocardiography.

Abstract Background Inflammatory bowel disease (IBD), a chronic inflammatory condition, is caused by several factors involving aberrant immune responses. Genetic factors are crucial in IBD occurrence. Mendelian randomization (MR) can offer a new perspective in understanding IBD’s genetic background. Methods Single nucleotide polymorphisms (SNPs) were considered instrumental variables (IVs). We analyzed the relationship between 731 immunophenotypes, 1,400 metabolite phenotypes, and IBD. The total effect was decomposed into indirect and direct effects, and the ratio of the indirect effect to the total effect was calculated. Results We identified the causal effects of HLA-DR-expressing CD14 + monocytes on IBD through MR analysis. The phenotype “HLA-DR expression on CD14 + monocytes” showed the strongest association among the selected 48 immune phenotypes. Chiro-inositol metabolites mediated the effect of CD14 + monocytes expressing HLA-DR on IBD. An increase in Chiro-inositol metabolites was associated with a reduced risk of IBD occurrence, accounting for 4.97%. Conclusion Our findings revealed a new pathway by which HLA-DR-expressing CD14 + monocytes indirectly reduced the risk of IBD occurrence by increasing the levels of Chiro-inositol metabolites. The results provided a new perspective on the immunoregulatory mechanisms underlying IBD, laying a theoretical foundation for developing new therapeutic targets in the future.

Abstract Keratinocyte proliferation and differentiation in epidermis are well-controlled and essential for reacting to stimuli such as ultraviolet light. Imbalance between proliferation and differentiation is a characteristic feature of major human skin diseases such as psoriasis and squamous cell carcinoma. However, the effect of keratinocyte metabolism on proliferation and differentiation remains largely elusive. We show here that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) promotes differentiation while inhibits proliferation of keratinocyte and suppresses psoriasis development. FBP1 is identified among the most upregulated genes induced by UVB using transcriptome sequencing and is elevated especially in upper epidermis. Fbp1 heterozygous mice exhibit aberrant epidermis phenotypes with local hyperplasia and dedifferentiation. Loss of FBP1 promotes proliferation and inhibits differentiation of keratinocytes in vitro. Mechanistically, FBP1 loss facilitates glycolysis-mediated acetyl-CoA production, which increases histone H3 acetylation at lysine 9, resulting in enhanced transcription of proliferation genes. We further find that the expression of FBP1 is dramatically reduced in human psoriatic lesions and in skin of mouse imiquimod psoriasis model. Fbp1 deficiency in mice facilitates psoriasis-like skin lesions development through glycolysis and acetyl-CoA production. Collectively, our findings reveal a previously unrecognized role of FBP1 in epidermal homeostasis and provide evidence for FBP1 as a metabolic psoriasis suppressor.

Various biological effects of ionizing radiation, especially continuous exposure to low-dose radiation (LDR), have attracted considerable attention. Impaired bone structure caused by LDR has been reported, but little is known about the mechanism involved in the disruption of bone metabolism. In this study, given that LDR was found to (at a cumulative dose of 0.10 Gy) disturb the serum Mg2+ level and Notch1 signal in the mouse femur tissues, the effects of LDR on osteogenesis and the underlying molecular mechanisms were investigated based on an in vitro culture system for bone marrow stromal cells (BMSCs). Our data showed that cumulative LDR suppressed the osteogenic potential in BMSCs as a result of upregulation of Notch1 signaling. Further analyses indicated that the upregulation of NICD1 (Notch1 intracellular domain), the key intracellular domain for Notch1 signaling, under LDR was a consequence of enhanced protein stabilization caused by SUMOylation (small ubiquitin-like modification). Specifically, the downregulation of SENP1 (sentrin/SUMO-specific protease 1) expression induced by LDR enhanced the SUMOylation of NICD1, causing the accumulation of Notch1 signaling, which eventually inhibited the osteogenic potential of BMSCs. In conclusion, this work expounded on the mechanisms underlying the impacts of LDR on bone metabolism and shed light on the research on bone regeneration under radiation.

Vine pair-copula constructions exist for a mix of continuous and ordinal variables. In some steps, this can involve estimating a bivariate copula for a pair of mixed continuous-ordinal variables. To assess the adequacy of copula fits for such a pair, diagnostic and visualization methods based on normal score plots and conditional Q–Q plots are proposed. The former uses a latent continuous variable for the ordinal variable. The methods are applied to data generated from some existing probability models for a mixed continuous-ordinal variable pair, and for such models, Kullback-Leibler divergence is used to assess whether simple parametric copula families can provide adequate fits. The effectiveness of the proposed visualization and diagnostic methods is illustrated on a dataset.

Abstract Transcription is crucial for the expression of genetic information and its efficient and accurate termination is required for all living organisms. Rho-dependent termination could rapidly terminate unwanted premature RNAs and play important roles in bacterial adaptation to changing environments. Although Rho has been discovered for about five decades, the regulation mechanisms of Rho-dependent termination are still not fully elucidated. Here we report that Rof is a conserved antiterminator and determine the cryogenic electron microscopy structure of Rho-Rof antitermination complex. Rof binds to the open-ring Rho hexamer and inhibits the initiation of Rho-dependent termination. Rof’s N-terminal α-helix undergoes conformational changes upon binding with Rho, and is key in facilitating Rof-Rho interactions. Rof binds to Rho’s primary binding site (PBS) and excludes Rho from binding with PBS ligand RNA at the initiation step. Further in vivo analyses in Salmonella Typhimurium show that Rof is required for virulence gene expression and host cell invasion, unveiling a physiological function of Rof and transcription termination in bacterial pathogenesis.

Fatigue exerts a profound impact on human health. Jiuzhuan Huangjing Pills (JHP), comprising two functional foods, exhibits homology of medicine and food. In this study, we found that JHP improved fatigue in both in vivo and in vitro models by protecting against structural damage and functional disorders of mitochondria through the reduction of oxidative stress, thereby preventing cell death and enhancing energy metabolism. By investigating metabolomes in serum, skeletal muscle (SM), and SM mitochondria, JHP primarily mitigated oxidative stress by modulating the abundances of organic acids and lipids at multiple levels. Furthermore, we identified the anti-fatigue ingredients derived from JHP and conducted experimental verification to confirm that their pharmacodynamic effects were similar to those of JHP. Our findings suggested that JHP can serve as a candidate dietary supplement to improve fatigue by maintaining mitochondrial homeostasis through its antioxidant properties to enhance overall energy production in the body.

In this paper, a winding loss calculation method used in the field of converter transformers is introduced into the realm of high-frequency transformers for the first time. In addition, the impact of winding structure on the calculation accuracy of the method is considered for the first time. Comparing the calculation results of this method with those of the formula method, based on the results of finite element simulation. The feasibility of using this method to calculate the winding loss of a high-frequency transformer is verified. First, the winding loss of rectangular wire commonly used in small-capacity high-frequency transformers is analyzed. Based on the finite element simulation results, the accuracy of the hybrid method is compared with the formula calculation method to demonstrate the feasibility of the hybrid method. Then, using the same method, the accuracy of the hybrid method in calculating the winding loss of the circular wire, which is also used in small-capacity high-frequency transformers, is compared with the formula method. The maximum number of continuous winding layers has been modified, and the outcomes for various layers are being computed. Finally, the cross-transposition winding structure is also calculated, demonstrating that the hybrid method is not only applicable to wires of various shapes but also compatible with different winding structures. The results show that the hybrid method has good calculation accuracy and applicability. It can provide more precise calculation results for the winding loss of high-frequency transformers with various winding shapes.

BackgroundHigh altitude de-acclimatization (HADA) is gradually becoming a public health concern as millions of individuals of different occupations migrate to high-altitude areas for work due to economic growth in plateau areas. HADA affects people who return to lower elevations after exposure to high altitudes. It causes significant physiological and functional changes that can negatively impact health and even endanger life. However, uncertainties persist about the detailed mechanisms underlying HADA.MethodsWe established a population cohort of individuals with HADA and assessed variations in metabolite composition. Plasm samples of four groups, including subjects staying at plain (P) and high altitude (H) as well as subjects suffering from HADA syndrome with almost no reaction (r3) and mild-to-moderate reaction (R3) after returning to plain from high altitude, were collected and analyzed by Liquid Chromatography-Mass Spectrometry metabolomic. Multivariate statistical analyses were used to explore significant differences and potential clinical prospect of metabolites.ResultAlthough significantly different on current HADAS diagnostic symptom score, there were no differences in 17 usual clinical indices between r3 and R3. Further multivariate analyses showed isolated clustering distribution of the metabolites among the four groups, suggesting significant differences in their metabolic characteristics. Through K-means clustering analysis, we identified 235 metabolites that exhibited patterns of abundance change consistent with phenotype of HADA syndrome. Pathway enrichment analysis indicated a high influence of polyunsaturated fatty acids under high-altitude conditions. We compared the metabolites between R3 and r3 and found 107 metabolites with differential abundance involved in lipid metabolism and oxidation, suggesting their potential role in the regulation of oxidative stress homeostasis. Among them, four metabolites might play a key role in the occurrence of HADA, including 11-beta-hydroxyandrosterone-3-glucuronide, 5-methoxyindoleacetate, 9,10-epoxyoctadecenoic acid, and PysoPC (20:5).ConclusionWe observed the dynamic variation in the metabolic process of HADA. Levels of four metabolites, which might be provoking HADA mediated through lipid metabolism and oxidation, were expected to be explore prospective indices for HADA. Additionally, metabolomics was more efficient in identifying environmental risk factors than clinical examination when dramatic metabolic disturbances underlying the difference in symptoms were detected, providing new insights into the molecular mechanisms of HADAS.

Hepatotoxicity induced by bioactive constituents in traditional Chinese medicines or herbs, such as bavachin (BV) in Fructus Psoraleae, has a prolonged latency to overt drug-induced liver injury in the clinic. Several studies have described BV-induced liver damage and underlying toxicity mechanisms, but little attention has been paid to the deciphering of organisms or cellular responses to BV at no-observed-adverse-effect level, and the underlying molecular mechanisms and specific indicators are also lacking during the asymptomatic phase, making it much harder for early recognition of hepatotoxicity. Here, we treated mice with BV for 7 days and did not detect any abnormalities in biochemical tests, but found subtle steatosis in BV-treated hepatocytes. We then profiled the gene expression of hepatocytes and non-parenchymal cells at single-cell resolution and discovered three types of hepatocyte subsets in the BV-treated liver. Among these, the hepa3 subtype suffered from a vast alteration in lipid metabolism, which was characterized by enhanced expression of apolipoproteins, carboxylesterases, and stearoyl-CoA desaturase 1 (Scd1). In particular, increased Scd1 promoted monounsaturated fatty acids (MUFAs) synthesis and was considered to be related to BV-induced steatosis and polyunsaturated fatty acids (PUFAs) generation, which participates in the initiation of ferroptosis. Additionally, we demonstrated that multiple intrinsic transcription factors, including Srebf1 and Hnf4a, and extrinsic signals from niche cells may regulate the above-mentioned molecular events in BV-treated hepatocytes. Collectively, our study deciphered the features of hepatocytes in response to BV insult, decoded the underlying molecular mechanisms, and suggested that Scd1 could be a hub molecule for the prediction of hepatotoxicity at an early stage.

Rheumatoid arthritis (RA) is a self-immune inflammatory disease characterized by joint damage. A series of cytokines are involved in the development of RA. Oncostatin M (OSM) is a pleiotropic cytokine that primarily activates the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, and other physiological processes such as cell proliferation, inflammatory response, immune response, and hematopoiesis through its receptor complex. In this review, we first describe the characteristics of OSM and its receptor, and the biological functions of OSM signaling. Subsequently, we discuss the possible roles of OSM in the development of RA from clinical and basic research perspectives. Finally, we summarize the progress of clinical studies targeting OSM for the treatment of RA. This review provides researchers with a systematic understanding of the role of OSM signaling in RA, which can guide the development of drugs targeting OSM for the treatment of RA.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, of which the leading cause of death is cardiovascular disease (CVD). The levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) in RA decrease especially under hyperinflammatory conditions. It is conflictive with the increased risk of CVD in RA, which is called “lipid paradox”. The systemic inflammation may explain this apparent contradiction. The increased systemic proinflammatory cytokines in RA mainly include interleukin-6(IL-6)、interleukin-1(IL-1)and tumor necrosis factor alpha(TNF-α). The inflammation of RA cause changes in the subcomponents and structure of HDL particles, leading to a weakened anti-atherosclerosis function and promoting LDL oxidation and plaque formation. Dysfunctional HDL can further worsen the abnormalities of LDL metabolism, increasing the risk of cardiovascular disease. However, the specific mechanisms underlying lipid changes in RA and increased CVD risk remain unclear. Therefore, this article comprehensively integrates the latest existing literature to describe the unique lipid profile of RA, explore the mechanisms of lipid changes, and investigate the impact of lipid changes on cardiovascular disease.

Fructus psoraleae (FP) is a commonly used herb with potential reproductive toxicity. Bavachin (BV), one of essential active ingredients of FP, was found to exhibit estrogenic activity, but its effect on female reproductive system remains unknown. In this study, the impact of BV on the female zebrafish reproductive system and underlying molecular mechanism were determined in vivo and ex vivo. The results showed that BV could accumulate in zebrafish ovary, leading to obvious follicular atresia and increase in gonadal index and vitellogenin content. Endoplasmic reticulum (ER) swelling and hypertrophy were observed in the BV-treated zebrafish ovary, accompanied by an increase in the expressions of ER stress and unfolded protein response (UPR) related genes, namely atf6, ire-1α and xbp1s. In the ex vivo study, BV was found to decrease the survival rate and maturation rate of oocytes, while increasing the expression of Ca2+. Additionally, BV led to an elevation in the level of estrogen receptor ESR1 and the expressions of genes involved in ER stress and UPR, including atf6, ire-1α, xbp1s, chop and perk. Moreover, molecular docking revealed that BV could directly bind to immunoglobulin heavy chain binding protein (BiP) and estrogen receptor 1 (ESR1). Besides, the alterations induced by BV could be partially reversed by fulvestrant (FULV) and 4-phenylbutyric acid (4-PBA), respectively. Thus, long-termed BV-containing medicine treatment could generate reproductive toxicity in female zebrafish by causing follicular atresia through BiP- and ESR-mediated ER stress and UPR, providing a potential target for the prevention of reproductive toxicity caused by BV.

In order to promote energy conservation and facilitate the utilization of solid wastes, red mud, coal metakaolin, and alkaline activators were used as main raw materials to prepare red mud-coal metakaolin based geopolymer (RCG). The effects of glass fiber, basalt fiber, polypropylene fiber, and polyvinyl alcohol fiber on the compressive strength, peak strain, elastic modulus, compressive toughness, energy absorption, flexural strength, and microstructure of RCG were investigated. The toughening mechanism of four kinds of fiber on RCG was expounded, and the results indicate that incorporation of fibers can enhance the mechanical properties of RCG and improve its toughness and ductility. Among them, basalt fibers and polyvinyl alcohol fibers have similar effects on strength enhancement, but polyvinyl alcohol fibers can effectively change the brittle failure modes of RCG and enhance the compression toughness and energy absorption capacity of RCG. Through microscopic morphology analyses, polyvinyl alcohol fiber has high moisture regain, and the bonding effect with the matrix was found to outperform other fibers, so the physical and mechanical properties of RCG are improved better.

Carbon nanotubes (CNTs) and graphene nanoplatelets (GNPs) are extremely ideal nanofillers for applications in damping polymer. This work explores the damping behavior of polymer nanocomposite beams made of epoxy resin reinforced with CNTs and GNPs experimentally. Beam specimens for the vibration tests together with dynamic mechanical analysis (DMA) are fabricated with different weight ratios of CNTs and GNPs, upon which DMA and free vibration tests are conducted. Scanning electron microscope images are also obtained to check the dispersion of nanofillers in microscale. It is found that the first-order loss factor of composite beam specimens shows a rise of 41.1% at 0.4 wt% CNT content compared with that of pure epoxy, while the first-order loss factor of composite beam specimens with 0.025 wt% GNP content increases up by 128.9%. The maximum value of the first-order loss factor of nanocomposite beams with GNP reinforcement is 62.2% higher than that with CNTs.

Epoxiconazole is a triazole compound. However, the effects of epoxiconazole on crop productivity and quality were rarely reported. In this study, we investigated the effects of epoxiconazole application on yield formation, grain quality attributes, and 2-acetyl-1-pyrroline (2-AP) content in fragrant rice. A three-year field experiment was carried out with a fragrant rice variety, Meixiangzhan 2. At the heading stage, 0, 0.02, 0.04, 0.08, 0.16 and 0.32 g/L epoxiconazole solutions were foliar applied to fragrant rice plants, respectively. The results showed that epoxiconazole application significantly increased grain yield, seed-setting rate and 1000-grain weight. Chlorophyll content and net photosynthetic rate of fragrant rice during the grain-filling stage significantly increased due to epoxiconazole application. Foliar application of epoxiconazole at 0.08 g/L increased grain protein content and decreased both chalky rice rate and chalkiness area ratio of fragrant rice. Epoxiconazole also substantially increased grain 2-AP content by inducing the regulation in contents of related synthetic precursors, including proline, pyrroline-5- carboxylic acid, Δ1-pyrroline and methylglyoxal. Overall, foliar application of epoxiconazole could be used for the improvement in grain yield, grain quality and 2-AP content in fragrant rice production when applied concentration at 0.08–0.32 g/L. Our findings provided the new roles of epoxiconazole in crop production.

ObjectiveThis study aimed to investigate a new noninvasive traction method on the treatment of severe cervical kyphotic deformity.MethodsThe clinical data of patients with severe cervical kyphosis (Cobb > 40°) treated in Peking University Third Hospital from March 2004 to March 2020 were retrospectively summarized. 46 cases were enrolled, comprising 27 males and 19 females. Fifteen patients underwent skull traction, and 31 patients underwent suspensory traction. Among them, seven used combined traction after one week of suspensory traction. Bedside lateral radiographs were taken every two or three days during traction. The cervical kyphosis angle was measured on lateral radiographs in and extended position at each point in time. The correction rate and evaluated Japanese Orthopedic Association (JOA) scoring for the function of the spinal cord were also measured. The data before and after the operation were compared with paired sample t-test or Wilcoxon signed-rank test.ResultsNo neurological deterioration occurred during the skull traction and the cervical suspensory traction. There were 12 patients with normal neurological function, and the JOA score of the other 34 patients improved from 11.5 ± 2.8 to 15.4 ± 1.8 at the end of follow up (P

Abstract The deformation and failure forms of inclined coal seam roadway under the joint action of dip angle and various geological conditions are complex, and there is a lack of targeted support measures, which brings great problems to the stability control of roadway surrounding rock. In order to safely and economically mine inclined coal seams, taking the engineering geology of Shitanjing No. 2 mining area as the background, and the physical similarity model of right-angle trapezoidal roadway in inclined coal seam, in which the non-contact digital image correlation (DIC) technology and the stress sensor is employed to provide full-field displacement and stress measurements. The deformation control technology of the roadway surrounding rock was proposed, verified by numerical simulation and applied to engineering practice. The research results show that the stress and deformation failure of surrounding rock in low sidewall of roadway are greater than those in high sidewall, showing asymmetric characteristics, and the maximum stress concentration coefficients of roadway sidewall, roof and floor are 4.1, 3.4 and 2.8, respectively. A concept of roadway "cyclic failure" mechanism is proposed that is, the cyclic interaction of the two sidewalls, the sharp angles and roof aggravated the failure of roadway, resulting in the overall instability of roadway. The roadway sidewall is serious rib spalling, the roof is asymmetric "Beret" type caving arch failure, and the floor is slightly bulging. On this basis, the principle of roadway deformation control is revealed and asymmetric support design is adopted, and the deformation of roadway is controlled, which support scheme is effective.

Citrus Huanglongbing (HLB), known as the most economically devastating disease in citrus industry, is mainly caused by phloem-restricted Gram-negative bacterium “Candidatus Liberibacter asiaticus” (CLas). To date, CLas is still unculturable in vitro, which has been dramatically delaying the research on its pathogenesis, and only few Sec-dependent effectors (SDEs) have been identified to elucidate the pathogenesis of CLas. Here, we confirmed that a CLas-secreted Sec-dependent polypeptide, namely SECP8 (CLIBASIA_05330), localized in nucleus, cytoplasm and cytoplasmic membrane, and showed remarkably higher transcript abundance in citrus than in psyllids. Potato virus X (PVX)-mediated transient expression assays indicated that mSECP8 (the mature form of SECP8) suppressed pro-apoptotic mouse protein BAX and Phytophthora infestans elicitin INF1-triggered hypersensitive response (HR) associated phenotypes, including cell death, H2O2 accumulation and callose deposition. Intriguingly, mSECP8 also inhibited SDE1 (CLIBASIA_05315)-induced water-soaked and dwarfing symptoms in Nicotiana benthamiana. In addition, mSECP8 can promote the susceptibility of transgenic Wanjincheng orange (Citrus sinensis) to CLas invasion and further HLB symptom development, and it contributes to the proliferation of Xanthomonas citri subsp. citri (Xcc). Moreover, the expression of ten immunity-related genes were significantly down-regulated in mSECP8 transgenic citrus than those in wide-type (WT) plants. Overall, we propose that mSECP8 may serve as a novel broad-spectrum suppressor of plant immunity, and provide the first evidence counteractive effect among CLas effectors. This study will enrich and provide new evidences for elucidating the pathogenic mechanisms of CLas in citrus host.

Pinelliae rhizoma (PR), one kind of commonly-used Chinese herbs, is generally prescribed to treat various respiratory diseases, including acute lung injury (ALI). However, the accurate bioactive ingredients of PR and the underlying pharmacological mechanism have both not been fully elucidated. Therefore, this study aimed to identify the bioactive ingredients that could alleviate lipopolysaccharide (LPS)-induced ALI and explore the possible mechanism involved. Our results confirmed that LPS infection indeed caused acute inflammatory damage in mice lung, accompanying with the enhancement of IL-1β contents and the activation of the NLRP3 inflammasome in lung tissue and macrophagocyte, all of which were remarkably ameliorated by PR treatment. Next, mechanistically, LPS was found to trigger endoplasmic reticulum (ER) stress and downstream cellular calcium ions (Ca2+) release via activating Bip/ATF4/CHOP signaling pathway. Like PR, 4-PBA (a specific inhibitor of ER stress) not only obviously reversed Bip/ATF4/CHOP-mediated ER stress, but also significantly attenuated LPS-induced activation of the NLRP3 inflammasome. Furthermore, the bioactive ingredients of PR, which generated the anti-inflammatory effects, were screened by metabolomics and network pharmacology. In vitro experiments showed that chrysin, dihydrocapsaicin, and 7,8-dihydroxyflavone (7,8-DHF) notably suppressed LPS-induced ER stress and following NLRP3 inflammasome activation. In conclusion, our findings suggested that PR alleviated LPS-induced ALI by inhibiting ER stress-mediated NLRP3 inflammasome activation, which is mainly relevant with these three bioactive ingredients. This study provided a theoretical basis for the clinical application of PR to treat ALI, and these bioactive ingredients of PR would be promising therapeutic drugs for the treatment of ALI.

Mechanical hill wet-seeded rice machine is beneficial for establishing and growing uniform rows of seedlings. However, there is limited knowledge regarding the effects of the establishment of furrows on growth, lodging and yield, and their relationships with root traits. In this study, field experiments were conducted during 2012 and 2013 using two super rice varieties (hybrid rice Peizataifeng and inbred rice Yuxiangyouzhan) under three furrow establishment treatments (T1, both water and seed furrows were established by the machine; T2, only seed furrows were established by the machine; and T3, neither water nor seed furrows were established by the machine). Lodging index, lodging-related traits, grain yield, above-ground dry weight and root traits were measured. The results showed that the lodging index was significantly affected by the treatments with furrows (T1 and T2). The strongest lodging resistance was detected in the mechanical hill wet-seeded rice with furrow treatment (T1) in both 2012 and 2013. Lodging resistance was strongly related to the breaking resistance. No significant difference was found in grain yield or dry weight of the mechanical hill wet-seeded rice. Therefore, the mechanical hill wet-seeded rice with furrow treatment increased rice lodging resistance, which was related to root traits.

Abstract Background One striking feature of the large KRAB domain-containing zinc finger protein (KZFP) family is its rapid evolution, leading to hundreds of member genes with various origination time in a certain mammalian genome. However, a comprehensive genome-wide and across-taxa analysis of the structural and expressional features of KZFPs with different origination time is lacking. This type of analysis will provide valuable clues about the functional characteristics of this special family. Results In this study, we found several conserved paradoxical phenomena about this issue. 1) Ordinary young domains/proteins tend to be disordered, but most of KRAB domains are completely structured in 64 representative species across the superclass of Sarcopterygii and most of KZFPs are also highly structured, indicating their rigid and unique structural and functional characteristics; as exceptions, old-zinc-finger-containing KZFPs have relatively disordered KRAB domains and linker regions, contributing to diverse interacting partners and functions. 2) In general, young or highly structured proteins tend to be spatiotemporal specific and have low abundance. However, by integrated analysis of 29 RNA-seq datasets, including 725 samples across early embryonic development, embryonic stem cell differentiation, embryonic and adult organs, tissues in 7 mammals, we found that KZFPs tend to express ubiquitously with medium abundance regardless of evolutionary age and structural disorder degree, indicating the wide functional requirements of KZFPs in various states. 3) Clustering and correlation analysis reveal that there are differential expression patterns across different spatiotemporal states, suggesting the specific-high-expression KZFPs may play important roles in the corresponding states. In particular, part of young-zinc-finger-containing KZFPs are highly expressed in early embryonic development and ESCs differentiation into endoderm or mesoderm. Co-expression analysis revealed that young-zinc-finger-containing KZFPs are significantly enriched in five co-expression modules. Among them, one module, including 13 young-zinc-finger-containing KZFPs, showed an ‘early-high and late-low’ expression pattern. Further functional analysis revealed that they may function in early embryonic development and ESC differentiation via participating in cell cycle related processes. Conclusions This study shows the conserved and special structural, expressional features of KZFPs, providing new clues about their functional characteristics and potential causes of their rapid evolution.

Time difference of arrival method is commonly used in the location of partial discharges. In this method, the main problem are as follows: (1) time delay error is inevitable. (2) location algorithm is sensitive to time delay error. To solve the problems above, an ultra-high frequency localization method for transformer partial discharge based on time reversal and improved whale optimization algorithm is proposed in this article. The method is consisted of three parts, that including time delay extraction, time reversal imaging and optimal solution. Firstly, the time delay is extracted by energy accumulation method. And then the approximate position of partial discharge source is determined by time reversal imaging. Combined with the time reversal imaging, the strategy of initial population selection and weight setting in the whale optimization algorithm is improved. Finally, the improved whale optimization algorithm is used to solve the optimal solution. The results are demonstrated through simulation and experiment. Compared with other localization algorithms, it is shown that the improved whale optimization algorithm has a better control performance in stability and accuracy.

The occurrence and development of rheumatoid arthritis (RA) is regulated by numerous cytokines. Interleukin 27 (IL-27) is a soluble cytokine that exerts biological effects by regulating the Janus tyrosine kinase (JAK)/signal transducer and activator of the transcription (STAT) signaling pathway via the IL-27 receptor. IL-27 is known for its pleiotropic roles in modulating inflammatory responses. Previous studies found that IL-27 levels are elevated in RA blood, synovial fluid, and rheumatoid nodules. Cellular and animal experiments indicated that IL-27 exerts multiple regulatory functions in RA patients via different mechanisms. IL-27 inhibits ectopic-like structure (ELS) formation and CD4+ T helper type 2 (Th2) cell, CD4+ T helper type 17 (Th17) cell, and osteoclast differentiation in RA, contributing to alleviating RA. However, IL-27 promotes Th1 cell differentiation, which may exacerbate RA synovitis. Moreover, IL-27 also acts on RA synovial fibroblasts (RA-FLSs) and regulatory T cells (Tregs), but some of its functions are unclear. There is currently insufficient evidence to determine whether IL-27 promotes or relieves RA. Targeting IL-27 signaling in RA treatment should be deliberate based on current knowledge.

Immune checkpoint inhibitors (ICIs), which can enhance antitumor immunity and inhibit cancer growth, have revolutionized the treatment of multiple cancers and dramatically decreased mortality. However, treatment with ICIs is directly associated with immune-related adverse events (irAEs) because of inflammation in off-target organs and autoimmunity resulting from non-specific immune activation. These irAEs can cause rheumatic diseases and manifestations such as inflammatory arthritis, polymyalgia rheumatica, myositis, vasculitis, Sicca and Sjogen's syndrome, and systemic lupus erythematosus. Early diagnosis and treatment of these adverse events will improve outcomes and quality of life for cancer patients. The treatment of rheumatic diseases induced by ICIs requires multidisciplinary cooperation among physicians. Furthermore, the underlying mechanisms are not fully understood and it is difficult to predict and evaluate these side effects precisely. In this review, we summarize available studies and findings about rheumatic irAEs, focusing mainly on the clinical manifestations, epidemiology, possible mechanisms, and guiding principles for treating these irAEs.

The morbidity and mortality of autoimmune diseases (Ads) have been increasing worldwide, and the identification of novel therapeutic strategies for prevention and treatment is urgently needed. Sirtuin 1 (SIRT1), a member of the class III family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in the progression of several diseases. SIRT1 also regulates inflammation, oxidative stress, mitochondrial function, immune responses, cellular differentiation, proliferation and metabolism, and its altered functions are likely involved in Ads. Several inhibitors and activators have been shown to affect the development of Ads. SIRT1 may represent a novel therapeutic target in these diseases, and small molecules or natural products that modulate the functions of SIRT1 are potential therapeutic agents. In the present review, we summarize current studies of the biological functions of SIRT1 and its role in the pathogenesis and treatment of Ads.

Background: Wutou Decoction (WTD), as a classic prescription, has been generally used to treat rheumatoid arthritis (RA) for two thousand years in China. However, the potential protective effects of WTD on rheumatoid arthritis and its possible mechanism have rarely been reported.Purpose: The aim of this study was to explore the possible mechanism of WTD against RA and a promising alternative candidate for RA therapy.Methods: A model of collagen-induced arthritis (CIA) was constructed in rats to assess the therapeutic effects of WTD. Histopathological staining, immunofluorescence, and western blotting of synovial sections were conducted to detect the antiangiogenic effects of WTD. Then, cell viability assays, flow cytometry, scratch healing assays, and invasion assays were conducted to explore the effects of WTD on MH7A human fibroblast-like synoviocyte (FLS) cell proliferation, apoptosis, migration, and invasion in vitro. The ability of WTD to induce blood vessel formation after MH7A cell and human umbilical vein endothelial cell line (HUVEC) coculture with WTD intervention was detected by a tube formation assay. The mechanisms of WTD were screened by network pharmacology and confirmed by in vivo and in vitro experiments.Results: WTD ameliorated the symptoms and synovial pannus hyperplasia of CIA rats. Treatment with WTD inhibited MH7A cell proliferation, migration, and invasion and promoted MH7A apoptosis. WTD could inhibit MH7A cell expression of proangiogenic factors, including VEGF and ANGI, to induce HUVEC tube formation. Furthermore, the PI3K-AKT-mTOR-HIF-1α pathway was enriched as a potential target of WTD for the treatment of RA through network pharmacology enrichment analysis. Finally, it was confirmed in vitro and in vivo that WTD inhibits angiogenesis in RA by interrupting the PI3K-AKT-mTOR-HIF-1α pathway.Conclusion: WTD can inhibit synovial hyperplasia and angiogenesis, presumably by inhibiting the migration and invasion of MH7A cells and blocking the production of proangiogenic effectors in MH7A cells. The possible underlying mechanism by which WTD ameliorates angiogenesis in RA is the PI3K-AKT-mTOR-HIF-1α pathway.

Immunotherapy, which takes advantage of the immune system to eliminate cancer cells, has been widely studied and applied in oncology. Immune checkpoint inhibitors (ICIs) prevent the immune system from being turned off before cancer cells are eliminated. They have proven to be among the most promising and effective immunotherapies, with significant survival benefits and durable responses in diverse tumor types. However, an increasing number of retrospective studies have found that some patients treated with ICIs experience unusual responses, including accelerated proliferation of tumor cells and rapid progression of the disease, with poor outcomes. Such unexpected adverse events are termed hyperprogressive disease (HPD), and their occurrence suggests that ICIs are detrimental to a subset of cancer patients. HPD is common, with an incidence ranging between 4 and 29% in several cancer types. However, the mechanisms of HPD remain poorly understood, and no clinical predictive factors of HPD have been identified. In this review, we summarize current findings, including retrospective studies and case reports, and focus on several key issues including the defining characteristics, predictive biomarkers, potential mechanisms of HPD, and strategies for avoiding HPD after ICI treatment.

The COVID-19 outbreak has brought great challenges to healthcare resources around the world. Patients with COVID-19 exhibit a broad spectrum of clinical characteristics. In this study, the Factor Analysis of Mixed Data (FAMD)-based cluster analysis was applied to demographic information, laboratory indicators at the time of admission, and symptoms presented before admission. Three COVID-19 clusters with distinct clinical features were identified by FAMD-based cluster analysis. The FAMD-based cluster analysis results indicated that the symptoms of COVID-19 were roughly consistent with the laboratory findings of COVID-19 patients. Furthermore, symptoms for mild patients were atypical. Different hospital stay durations and survival differences among the three clusters were also found, and the more severe the clinical characteristics were, the worse the prognosis. Our aims were to describe COVID-19 clusters with different clinical characteristics, and a classifier model according to the results of FAMD-based cluster analysis was constructed to help provide better individualized treatments for numerous COVID-19 patients in the future.

Autoimmune diseases are a worldwide health problem with growing rates of morbidity, and are characterized by breakdown and dysregulation of the immune system. Although their etiology and pathogenesis remain unclear, the application of dietary supplements is gradually increasing in patients with autoimmune diseases, mainly due to their positive effects, relatively safety, and low cost. Quercetin is a natural flavonoid that is widely present in fruits, herbs, and vegetables. It has been shown to have a wide range of beneficial effects and biological activities, including anti-inflammation, anti-oxidation, and neuroprotection. In several recent studies quercetin has reportedly attenuated rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and systemic lupus erythematosus in humans or animal models. This review summarizes the evidence for the pharmacological application of quercetin for autoimmune diseases, which supports the view that quercetin may be useful for their prevention and treatment.

Objective: Fetus-in-fetu (FIF) is an extremely rare disease, and most prior publications are single case reports. Here, we describe the clinical characteristics, imaging manifestations, and the treatment and related complications of FIF from a large tertiary pediatric referral center.Materials: After institutional review board approval, patients with a diagnosis of FIF between January 2010 and November 2019 were further selected and reexamined. We analyzed the general clinical characteristics, imaging manifestations, treatment, and prognosis of the patients.Results: A total of seven (four male and three female) patients with FIF were included in the study. All patients were diagnosed with FIF during the antenatal ultrasound examination along with an abnormal increase in alpha fetoprotein, and it was confirmed by subsequent pathological examination. The median gestation period when FIF was first diagnosed was 25 (range: 22–32) weeks. Ultrasound, computed tomography, and magnetic resonance imaging were the main pre-operative diagnostic techniques used. All patients underwent FIF resection within 1 month after birth: four patients had open surgery and three had laparoscopic surgeries (one case was converted to open surgery); only one patient developed ascites after surgery. All patients are growing up healthy and without tumor recurrence at the last follow-up. The level of alpha fetoprotein decreased to normal within 1 year (range 3-10 months) after surgery performed.Conclusion: As the size of the FIF increases, it can be found and diagnosed in antenatal ultrasound examination. Surgery is an important curative treatment for FIF and generally results in excellent long-term quality of life.

Accumulated reactive oxygen species (ROS) directly contribute to biomacromolecule damage and influence various inflammatory responses. Reactive oxygen species act as mediator between innate and adaptive immune cells, thereby influencing the antigen-presenting process that results in T cell activation. Evidence from patients with chronic granulomatous disease and mouse models support the function of ROS in preventing abnormal autoimmunity; for example, by supporting maintenance of macrophage efferocytosis and T helper 1/T helper 2 and T helper 17/ regulatory T cell balance. The failure of many anti-oxidation treatments indicates that ROS cannot be considered entirely harmful. Indeed, enhancement of ROS may sometimes be required. In a mouse model of rheumatoid arthritis (RA), absence of NOX2-derived ROS led to higher prevalence and more severe symptoms. In patients with RA, naïve CD4+ T cells exhibit inhibited glycolysis and enhanced pentose phosphate pathway (PPP) activity, leading to ROS exhaustion. In this “reductive” state, CD4+ T cell immune homeostasis is disrupted, triggering joint destruction, together with oxidative stress in the synovium.

Abstract High‐affinity antibodies are produced during multiple processes in germinal centres (GCs), where follicular helper T (Tfh) cells interact closely with B cells to support B‐cell survival, differentiation and proliferation. Recent studies have revealed that a specialised subset of regulatory T cells, follicular regulatory T (Tfr) cells, especially fine‐tune Tfh cells and GC B cells, ultimately regulating GC reactions. Alterations in frequencies or function of Tfr cells may result in multiple autoantibody‐mediated or autoantibody‐associated diseases. This review discusses recent insights into the physiology and pathology of Tfr cells, with a special emphasis on their potential roles in human diseases. Discrepancies are common among studies, reflecting the limited understanding of Tfr cells. Further exploration of the mechanisms of Tfr cells in these diseases and thus targeting Tfr cells may help reinstate immune homeostasis and provide novel immunotherapy.

Abstract Background How genome complexity affects organismal phenotypic complexity is a fundamental question in evolutionary developmental biology. Previous studies proposed various contributing factors of genome complexity and tried to find the connection between genomic complexity and organism complexity. However, a general model to answer this question is lacking. Here, we introduce a ‘two-level’ model for the realization of genome complexity at phenotypic level. Results Five representative species across Protostomia and Deuterostomia were involved in this study. The intrinsic gene properties contributing to genome complexity were classified into two generalized groups: the complexity and age degree of both protein-coding and noncoding genes. We found that young genes tend to be simpler; however, the mid-age genes, rather than the oldest genes, show the highest proportion of high complexity. Complex genes tend to be utilized preferentially in each stage of embryonic development, with maximum representation during the late stage of organogenesis. This trend is mainly attributed to mid-age complex genes. In contrast, young genes tend to be expressed in specific spatiotemporal states. An obvious correlation between the time point of the change in over- and under-representation and the order of gene age was observed, which supports the funnel-like model of the conservation pattern of development. In addition, we found some probable causes for the seemingly contradictory ‘funnel-like’ or ‘hourglass’ model. Conclusions These results indicate that complex and young genes contribute to organismal complexity at two different levels: Complex genes contribute to the complexity of individual proteomes in certain states, whereas young genes contribute to the diversity of proteomes in different spatiotemporal states. This conclusion is valid across the five species investigated, indicating it is a conserved model across Protostomia and Deuterostomia. The results in this study also support ‘funnel-like model’ from a new viewpoint and explain why there are different evo–devo relation models.

Background: Plenty of evidence has suggested that autophagy plays a crucial role in the biological processes of cancers. This study aimed to screen autophagy-related genes (ARGs) and establish a novel a scoring system for colorectal cancer (CRC). Methods: Autophagy-related genes sequencing data and the corresponding clinical data of CRC in The Cancer Genome Atlas were used as training data set. The GSE39582 data set from the Gene Expression Omnibus was used as validation set. An autophagy-related signature was developed in training set using univariate Cox analysis followed by stepwise multivariate Cox analysis and assessed in the validation set. Then we analyzed the function and pathways of ARGs using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Finally, a prognostic nomogram combining the autophagy-related risk score and clinicopathological characteristics was developed according to multivariate Cox analysis. Results: After univariate and multivariate analysis, 3 ARGs were used to construct autophagy-related signature. The KEGG pathway analyses showed several significantly enriched oncological signatures, such as p53 signaling pathway, apoptosis, human cytomegalovirus infection, platinum drug resistance, necroptosis, and ErbB signaling pathway. Patients were divided into high- and low-risk groups, and patients with high risk had significantly shorter overall survival (OS) than low-risk patients in both training set and validation set. Furthermore, the nomogram for predicting 3- and 5-year OS was established based on autophagy-based risk score and clinicopathologic factors. The area under the curve and calibration curves indicated that the nomogram showed well accuracy of prediction. Conclusions: Our proposed autophagy-based signature has important prognostic value and may provide a promising tool for the development of personalized therapy.

The objective of this systematic review was to conduct a meta-analysis of the efficacy and safety of total glucosides of paeony (TGP) for the treatment of ankylosing spondylitis (AS). TGP is commonly applied as a complementary medicine, especially in combination with disease-modifying antirheumatic drugs (DMARDs) and/or non-steroidal anti-inflammatory drugs (NSAIDs) to treat AS in China. Nevertheless, the efficacy and safety of TGP combination treatment still needs more validation. A systematic literature search was conducted using PubMed, EMBASE, Web of Science, the Cochrane library, ClinicalTrials, the Chinese Biomedical Literature database (CBM), the China National Knowledge Internet (CNKI), the Wan Fang Medical Database and the VIP Database for available randomized controlled trials (RCTs) investigating the efficacy and safety of TGP on AS up to November 2018. Review Manager 5.3 software and Stata 12.0 software were used to analyze all included studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol. The pooled results of 23 RCTs exhibited better symptoms improvement (SI) (95% CI 1.16 to 1.36), lower erythrocyte sedimentation rate (ESR) (95% CI −5.89 to −1.32), lower levels of C-reactive protein (CRP) (95% CI −5.01 to −1.49), morning stiffness (MS) time (95% CI −3.46 to −1.86), finger to floor distance (FFD) (95% CI −4.80 to −0.86), peripheral joint pain index (PJPI) (95% CI −3.48 to −0.69), and higher level of thoracic expansion (TE) (95% CI 0.18–0.40) in TGP group. While Schober's test (Schober) showed no significant difference between the two groups. Adverse events (AEs) were significantly decreased (95% CI 0.48–0.79) with the usage of TGP. It is worthwhile to apply TGP as an auxiliary medicine on AS for better efficacy and less side effects, especially when considering the impact of traditional treatment on the liver. Still, further clinical trials with larger sample and better methodological quality are warranted to ascertain the potential benefits of TGP on AS.

In recent years, Chinese prefabricated buildings have re-heated and showed rapid growth. This paper analyzes the performance of the existing assembled wall panels in the Chinese market by comparing the performance of different materials and optimizing the selection of the envelope structure of the assembled substation. Studies have shown that the use of prefabricated building systems can achieve the goal of shortening the construction period, reducing manual labor, no waste during construction, and no wet work on site.

The problem of UAVs’ formation control in the process of motion is investigated in this paper. A formation control method based on artificial potential field of UAVs is proposed, established on the collision avoidance, aggregation and speed matching rules of UAVs. First establish the UAVs’ kinetic model in accordance to the motion rules, then design the formation control algorithm based on artificial potential field function, which is used to control the formation during the movement of UAVs. Finally, the results of simulation experiment show that the proposed formation control method in this paper is effective and has the advantages of easy realization, good real-time performance and excellent robustness.

Abstract Background Pancreatic intraepithelial neoplasias (PanINs) are precursors of malignant pancreatic cancer, an ideal stage for early cancer detection. We applied quantitative proteomics to identify aberrantly elevated proteins in pancreatic juice samples derived from patients with PanIN3. Results Twenty proteins were found elevated in all three PanIN juices by at least two-fold. Among these proteins, anterior gradient-2 (AGR2) was found to be 2-10 fold elevated in PanIN3 juice samples analyzed by quantitative proteomics. An ELISA assay was developed to evaluate AGR2 levels in 51 pancreatic juice samples and 23 serum samples from patients with pancreatic cancer, pre-malignant lesions (including PanIN3, PanIN2, Intraductal Papillary Mucinous Neoplasms (IPMNs)) and benign disease controls (including chronic pancreatitis). AGR2 levels in the pancreatic juice samples were found significantly elevated in patients with pre-malignant conditions (PanINs and IPMNs) as well as pancreatic cancer compared to control samples (p ≤ 0.03). By ROC analysis, the AGR2 ELISA achieved 67% sensitivity at 90% specificity in predicting PanIN3 juice samples from the benign disease controls. Conclusions These results suggest that elevation of AGR2 levels in pancreatic juice occurs in early pancreatic cancer progression and could be further investigated as a potential candidate juice biomarker for early detection of pancreatic cancer.