Multiple Signaling Pathways Are Involved in the Interleukine-4 Regulated Expression of DC-SIGN in THP-1 Cell Line

Dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) is an important pattern recognition receptor on dendritic cells (DCs), and its expression shows significant cytological and histological specificity, being interleukine-4 (IL-4) dependent. The signaling pathways through which IL-4 regulates expression of DC-SIGN are still unclear. We used phorbol 12-myristate 13-acetate- (PMA-) differentiated THP-1 cells as the in vitro model of monocyte/macrophage cells to study the signaling pathways involved in IL-4-regulated expression of DC-SIGN. We found that a high expression of DC-SIGN could be induced by IL-4 at the levels of mRNA and cell surface protein. Upregulated expression of DC-SIGN was almost completely blocked by the specific inhibitor of ERK pathway, and partly reduced by the specific inhibitors of JAK-STAT and NF-κB pathways. The activation of the three signaling pathways was directly confirmed by testing the phosphorylation of protein kinase within the cytoplasm and nucleus over time. The analysis of cis-acting elements of DC-SIGN promoter showed that the activity of DC-SIGN promoter without Ets-1 transcription factors binding site almost completely disappeared. Our results demonstrated that multiple signaling pathways are involved in IL-4 induced high expression of DC-SIGN on THP-1 cells, in which ERK pathway is the main signaling pathway and mediated by the Ets-1 transcription factors binding site

Inundation resilience analysis of metro-network from a complex system perspective using the grid hydrodynamic model and FBWM approach : a case study of Wuhan

The upward trend of metro flooding disasters inevitably brings new challenges to urban underground flood management. It is essential to evaluate the resilience of metro systems so that efficient flood disaster plans for preparation, emergency response, and timely mitigation may be developed. Traditional response solutions merged multiple sources of data and knowledge to support decision-making. An obvious drawback is that original data sources for evaluations are often stationary, inaccurate, and subjective, owing to the complexity and uncertainty of the metro station’s actual physical environment. Meanwhile, the flood propagation path inside the whole metro station network was prone to be neglected. This paper presents a comprehensive approach to analyzing the resilience of metro networks to solve these problems. Firstly, we designed a simplified weighted and directed metro network module containing six characteristics by a topological approach while considering the slope direction between sites. Subsequently, to estimate the devastating effects and details of the flood hazard on the metro system, a 100-year rainfall–flood scenario simulation was conducted using high-precision DEM and a grid hydrodynamic model to identify the initially above-ground inundated stations (nodes). We developed a dynamic node breakdown algorithm to calculate the inundation sequence of the nodes in the weighted and directed network of the metro. Finally, we analyzed the resilience of the metro network in terms of toughness strength and organization recovery capacity, respectively. The fuzzy best–worst method (FBWM) was developed to obtain the weight of each assessment metric and determine the toughness strength of each node and the entire network. The results were as follows. (1) A simplified three-dimensional metro network based on a complex system perspective was established through a topological approach to explore the resilience of urban subways. (2) A grid hydrodynamic model was developed to accurately and efficiently identify the initially flooded nodes, and a dynamic breakdown algorithm realistically performed the flooding process of the subway network. (3) The node toughness strength was obtained automatically by a nonlinear FBWM method under the constraint of the minimum error to sustain the resilience assessment of the metro network. The research has considerable implications for managing underground flooding and enhancing the resilience of the metro network

The Farnesyltransferase β-Subunit Ram1 Regulates Sporisorium scitamineum Mating, Pathogenicity and Cell Wall Integrity

The basidiomycetous fungus Sporisorium scitamineum causes a serious sugarcane smut disease in major sugarcane growing areas. Sexual mating is essential for infection to the host; however, its underlying molecular mechanism has not been fully studied. In this study, we identified a conserved farnesyltransferase (FTase) β subunit Ram1 in S. scitamineum. The ram1Δ mutant displayed significantly reduced mating/filamentation, thus of weak pathogenicity to the host cane. The ram1Δ mutant sporidia showed more tolerant toward cell wall stressor Congo red compared to that of the wild-type. Transcriptional profiling showed that Congo red treatment resulted in notable up-regulation of the core genes involving in cell wall integrity pathway in ram1Δ sporidia compared with that of WT, indicating that Ram1 may be involved in cell wall integrity regulation. In yeast the heterodimeric FTase is responsible for post-translational modification of Ras (small G protein) and a-factor (pheromone). We also identified and characterized two conserved Ras proteins, Ras1 and Ras2, respectively, and a MAT-1 pheromone precursor Mfa1. The ras1Δ, ras2Δ and mfa1Δ mutants all displayed reduced mating/filamentation similar as the ram1Δ mutant. However, both ras1Δ and ras2Δ mutants were hypersensitive to Congo red while the mfa1Δ mutant was the same as wild-type. Overall our study displayed that RAM1 plays an essential role in S. scitamineum mating/filamentation, pathogenicity, and cell wall stability

Deficient O-GlcNAc Glycosylation Impairs Regulatory T Cell Differentiation and Notch Signaling in Autoimmune Hepatitis

Post-translational modifications such as glycosylation play an important role in the functions of homeostatic proteins, and are critical driving factors of several diseases; however, the role of glycosylation in autoimmune hepatitis is poorly understood. Here, we established an O-GlcNAc glycosylation-deficient rat model by knocking out the Eogt gene by TALEN-mediated gene targeting. O-GlcNAc glycosylation deficiency overtly aggravated liver injury in concanavalin-A induced autoimmune hepatitis, and delayed self-recovery of the liver. Furthermore, flow cytometry analysis revealed increased CD4+ T cell infiltration in the liver of rats with O-GlcNAc glycosylation deficiency, and normal differentiation of regulatory T cells (Tregs) in the liver to inhibit T cell infiltration could not be activated. Moreover, in vitro experiments showed that O-GlcNAc glycosylation deficiency impaired Treg differentiation to inhibit the Notch signaling pathway in CD4+ T cells. These finding indicate that O-GlcNAc glycosylation plays a critical role in the activation of Notch signaling, which could promote Treg differentiation in the liver to inhibit T cell infiltration and control disease development in autoimmune hepatitis. Therefore, this study reveals a regulatory role for glycosylation in the pathogenesis of autoimmune hepatitis, and highlights glycosylation as a potential treatment target

Neovascularization-directed bionic eye drops for noninvasive renovation of age-related macular degeneration

The current treatment of wet age-related macular degeneration (wAMD) relies on monthly intravitreal or intravenously injection of vascular endothelial growth factor (VEGF) inhibitor or photodynamic (PDT) agents to inhibit choroidal neovascularization. However, traumatic local therapy and exogenous long-distance fundus drug delivery often lead to secondary eye damage, low treatment efficiency, and immunogenic inflammation. Herein, inspired by the natural neovascular targeting ability of endogenous low-density lipoproteins (LDL), a noninvasive bionic nano-eye-drop with enhanced ocular penetrability and lesion recognizability is developed for enabling the PDT treatment of wAMD. Verteporfin (VP) as a laser-induced PDT agent is protected inside the hydrophobic core of reconstituted LDL (rLDL) vectors. 5-carboxyfluorescein (FAM) conjugated ste-penetratin (PEN, a transmembrane peptide) is anchored on the surface of the rLDL carrier, which enabled the nanoparticles (PEN-rLDL-VP) to cross the blood-retina barrier to realizing visual therapy. Following instillation, PEN-rLDL-VP can effectively deliver VP into neovascular that overexpress LDL receptors, which can respond to laser-induced PDT. Only with a single dose of the eye-drop and laser-induced PDT, the VEGF and proinflammatory intercellular adhesion molecule-1 (ICAM-1) proteins are significantly down-regulated in vivo, which implicates the neovascular inhibition and inflammation alleviation. This study presents an attractive non-invasive strategy for the PDT of wAMD

Transcriptome analysis of Sporisorium scitamineum reveals critical environmental signals for fungal sexual mating and filamentous growth

BACKGROUND: Sporisorium scitamineum causes the sugarcane smut disease, one of the most serious constraints to global sugarcane production. S. scitamineum possesses a sexual mating system composed of two mating-type loci, a and b locus. We previously identified and deleted the b locus in S. scitamineum, and found that the resultant SsΔMAT-1b mutant was defective in mating and pathogenicity. RESULTS: To further understand the function of b-mating locus, we carried out transcriptome analysis by comparing the transcripts of the mutant strain SsΔMAT-1b, from which the SsbE1 and SsbW1 homeodomain transcription factors have previously been deleted, with those from the wild-type MAT-1 strain. Also the transcripts from SsΔMAT-1b X MAT-2 were compared with those from wild-type MAT-1 X MAT-2 mating. A total of 209 genes were up-regulated (p < 0.05) in the SsΔMAT-1b mutant, compared to the wild-type MAT-1 strain, while 148 genes down-regulated (p < 0.05). In the mixture, 120 genes were up-regulated (p < 0.05) in SsΔMAT-1b X MAT-2, which failed to mate, compared to the wild-type MAT-1 X MAT-2 mating, and 271 genes down-regulated (p < 0.05). By comparing the up- and down-regulated genes in these two sets, it was found that 15 up-regulated and 37 down-regulated genes were common in non-mating haploid and mating mixture, which indeed could be genes regulated by b-locus. Furthermore, GO and KEGG enrichment analysis suggested that carbon metabolism pathway and stress response mediated by Hog1 MAPK signaling pathway were altered in the non-mating sets. CONCLUSIONS: Experimental validation results indicate that the bE/bW heterodimeric transcriptional factor, encoded by the b-locus, could regulate S. scitamineum sexual mating and/or filamentous growth via modulating glucose metabolism and Hog1-mediating oxidative response. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-016-2691-5) contains supplementary material, which is available to authorized users

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

A Novel Classification Framework for Hyperspectral Image Data by Improved Multilayer Perceptron Combined with Residual Network

Convolutional neural networks (CNNs) have attracted extensive attention in the field of modern remote sensing image processing and show outstanding performance in hyperspectral image (HSI) classification. Nevertheless, some hyperspectral images have fixed position priors and parameter sharing between different positions, so the common convolution layer may ignore some important fine and useful information and cannot guarantee to effectively capture the optimal image features. This paper proposes an improved multilayer perceptron (IMLP) and IMLP combined with ResNet (IMLP-ResNet) two models for HSI classification. Combined with the characteristics of hyperspectral data, we design IMLP based on three improvements. Specifically, a depthwise over-parameterized convolutional layer is introduced to increase learnable parameters of the model in IMLP, which speeds up the convergence of the model without increasing the computational complexity. Secondly, a Focal Loss function is used to suppress the useless ones in the classification task and enhance the critical spectral–spatial features, which allow the IMLP network to learn more useful hyperspectral image information. Furthermore, to enhance the convergence speed of the network, cosine annealing is introduced to further improve the training performance of IMLP. Furthermore, the IMLP module is combined with a residual network (IMLP-ResNet) to construct a symmetric structure, which extracts more advanced semantic information from hyperspectral images. The proposed IMLP and IMLP-ResNet are tested on the two public HSI datasets (i.e., Indian Pines and Pavia University) and a real hyperspectral dataset (Xuzhou). Experimental results demonstrate the superiority of the proposed IMLP-ResNet method over several state-of-the-art methods with the highest OA, which outperforms CNN by 8.19%, 6.28%, 5.59% and outperforms ResNet by 3.52%, 3.54%, 2.67% on Indian Pines, Pavia University and Xuzhou datasets, respectively, and demonstrates that the well-designed MLPs can also obtain remarkable classification performance of HSI

Effects of Music Therapy Assisted Anagliptin on Glycolipid Metabolism in Patients with Type 2 Diabetes

Background Music therapy, as an emerging treatment, has a gradually evolving role in the rehabilitation of chronic diseases and is gaining increasing attention. But there are few studies on the effects of music therapy on diabetes rehabilitation. Objective To observe the effects of music assisted anagliptin on glycolipid metabolism in patients with type 2 diabetes. Methods Sixty five type 2 diabetic patients with poor glycemic control on oral agents who visited the outpatient clinic of Department of Endocrinology, Boai Hospital, China Rehabilitation Research Center, from October 2019 to February 2021 were selected. Patients were divided into group A (n=35) and group B (n=30) by random numbers, and patients in both groups maintained their original diet and exercise habits. Group A was treated with anagliptin tablets in combination with the original treatment (drug type, dose unchanged) , while group B was given music adjuvant therapy on the basis of group A. Patients in both groups were treated continuously for 12 weeks. Fasting plasma glucose (FPG) , glycated hemoglobin (HbA1c) , low-density lipoprotein cholesterol (LDL-C) , total cholesterol (TC) , triacylglycerol (TG) , high-density lipoprotein cholesterol (HDL-C) , uric acid (UA) , 2 h postprandial plasma glucose (2 hPG) , hypersensitivity C-reactive protein (hs-CRP) , free fatty acids (FFA) , insulin resistance index (HOMA-IR) , &#x03B2; Cell function secretion index (HOMA-&#x03B2;) before and 12 weeks after treatment were compared between the two groups. The patients were observed for the occurrence of adverse reactions during the treatment. Results One patient was eliminated from the trial because of adverse drug reactions during the course of the trial in both groups, and 34 and 29 patients finally completed the trial in groups A and B, respectively. Patients in group B had lower 2 hPG than those in group A after 12 weeks of treatment (P&lt;0.05) . FPG, HbA1c, and 2 hPG were lower in both groups after 12 weeks of treatment whereas HOMA-&#x03B2; were higher after treatment (P&lt;0.05) ; LDL-C and TC of group B patients after 12 weeks of treatment were lower (P&lt;0.05) . No hypoglycemic events occurred in either group. Conclusion Music-assisted alagliptin can reduce postprandial blood glucose and improve lipid profile of type 2 diabetes patients more than that without music-assisted alagliptin. It also needs to be emphasized that the effects of music therapy must be based on diet control, proper exercise, and rational medication

Fabrication of carboxymethyl chitosan-strontium chondroitin sulfate composites for potential bone regeneration

Large bone defects have been a major healthcare concern. These defects are difficult to heal because of the chronic inflammatory environment surrounding the injury area. Osteoconductive composites with anti-inflammatory effects could provide a substrate to support cell growth and guide bone defect repair. Here, we synthesized a biofunctional composite that combined carboxymethyl-chitosan (CMCS) and strontium chondroitin sulfate (SrCS), for potential use in bone regeneration. We hypothesized that the as-prepared CMCS-SrCS composites could stimulate osteogenic activity and suppress inflammatory responses. The resultant composites displayed uniformly porous structures and good swelling capacity. The effect of the composites on MC3T3-E1 cells was investigated in vitro and the live cells showed favorable viability. Moreover, the RT-PCR results indicated that the CMCS-SrCS composites could suppress inflammatory responses and promote the osteogenic differentiation of MC3T3-E1 cells. These results suggested the CMCS-SrCS composites should have osteoconductive characteristics. Thus, we believe that the developed CMCS-SrCS composites should be a promising skeletal candidate for regenerative engineering applications