To monitor the health of the fiber network and its ambient environment in densely populated access/metro network areas, in this Letter, an endogenous distributed acoustic sensing (DAS) has been proposed and achieved in a coherent digital subcarrier multiplexing (DSCM) system. Rather than specially allocating a sensing probe in general integrated communication and sensing schemes, the fractional Fourier transformed (FrFT) training sequence (TS) designated for time/frequency synchronization in DSCM coherent communications has been repurposed for sensing. While achieving excellent synchronization performance of communication, the FrFT-based TS can also be concurrently utilized to perform distributed vibration sensing. Experimental results demonstrate that the FrFT-based timing/frequency synchronization sequence is repurposed to achieve a DAS sensitivity of 70â p ε/Hz at a spatial resolution of 5â m, along with 100-Gb/s 16 quadrature amplitude modulation (QAM) DSCM transmission, without a loss of spectral efficiency.
The growth of omic data presents evolving challenges in data manipulation, analysis, and integration. Addressing these challenges, Bioconductor 1 provides an extensive community-driven biological data analysis platform. Meanwhile, tidy R programming 2 offers a revolutionary standard for data organisation and manipulation. Here, we present the tidyomics software ecosystem, bridging Bioconductor to the tidy R paradigm. This ecosystem aims to streamline omic analysis, ease learning, and encourage cross-disciplinary collaborations. We demonstrate the effectiveness of tidyomics by analysing 7.5 million peripheral blood mononuclear cells from the Human Cell Atlas 3 , spanning six data frameworks and ten analysis tools.
The anomalies of cadmium (Cd) in karst region pose a severe threat to plant growth and development. In this study, the responses of Rhododendron decorum to Cd stress were investigated at physiological, molecular, and endophytic microbial levels, and the potential correlation among these responses was assessed. The Cd stress impeded R. decorum growth and led to an increase in malondialdehyde (MDA) and hydrogen peroxide (H2O2) levels, as well as enhanced superoxide dismutase (SOD) and catalase (CAT) activities. Meanwhile, Cd stress increased the Cd (up to 80 times compared to the control), sodium (Na), aluminum (Al), and zinc (Zn) contents, while decreased the magnesium (Mg) and manganese (Mn) contents in R. decorum leaves. Transcriptome suggested that Cd significantly regulated the pathways including "protein repair", "hormone-mediated signaling pathway", and "ATP-binding cassette (ABC) transporters". Additionally, q-PCR analysis showed that Cd stress significantly up-regulated the expressions of ABCB19-like and pleiotropic drug resistance, while down-regulated the expressions of indole-3-acetic acid-amido synthetase and cytokinin dehydrogenase. The Cd stress influenced the composition of endophytic microbial communities in R. decorum leaves and enhanced the interspecific bacterial associations. Furthermore, the bacterial genera Achromobacter, Aureimonas and fungal genus Vishniacozyma exhibited a high degree of connectivity with other nodes in networks constructed by the metal element contents, differentially expressed genes (DEGs), and microbial communities, respectively. These findings provide a comprehensive insight into the response of R. decorum to Cd-induced stress, which might facilitate the breeding of the Cd-tolerant R. decorum.
Broussonetia papyrifera is widely found in cadmium (Cd) contaminated areas, with an inherent enhanced flavonoids metabolism and inhibited lignin biosynthesis, colonized by lots of symbiotic fungi, such as arbuscular mycorrhizal fungi (AMF). However, the physiological and molecular mechanisms by which Rhizophagus irregularis, an AM fungus, regulates flavonoids and lignin in B. papyrifera under Cd stress remain unclear. Here, a pot experiment of B. papyrifera inoculated and non-inoculated with R. irregularis under Cd stress was carried out. We determined flavonoids and lignin concentrations in B. papyrifera roots by LC-MS and GC-MS, respectively, and measured the transcriptional levels of flavonoids- or lignin-related genes in B. papyrifera roots, aiming to ascertain the key components of flavonoids or lignin, and key genes regulated by R. irregularis in response to Cd stress. Without R. irregularis, the concentrations of eriodictyol, quercetin and myricetin were significantly increased under Cd stress. The concentrations of eriodictyol and genistein were significantly increased by R. irregularis, while the concentration of rutin was significantly decreased. Total lignin and lignin monomer had no alteration under Cd stress or with R. irregularis inoculation. As for flavonoids- or lignin-related genes, 26 genes were co-regulated by Cd stress and R. irregularis. Among these genes, BpC4H2, BpCHS8 and BpCHI5 were strongly positively associated with eriodictyol, indicating that these three genes participate in eriodictyol biosynthesis and were involved in R. irregularis assisting B. papyrifera to cope with Cd stress. This lays a foundation for further research revealing molecular mechanisms by which R. irregularis regulates flavonoids synthesis to enhance tolerance of B. papyrifera to Cd stress.
The metapopulation network model is a mathematical framework used to study the spatial spread of epidemics with individuals' mobility. In this paper, we develop a time-varying network model in which the activity of a population is correlated with its attractiveness in mobility. By studying the spreading dynamics of the SIR (susceptible-infectious-recovered)-type disease in different correlated networks based on the proposed model, we theoretically derive the mobility threshold and numerically observe that increasing the correction between activity and attractiveness results in a reduced mobility threshold but suppresses the fraction of infected subpopulations. It also introduces greater heterogeneity in the spatial distribution of infected individuals. Additionally, we investigate the impact of nonpharmaceutical interventions on the spread of epidemics in different correlation networks. Our results show that the simultaneous implementation of self-isolation and self-protection is more effective in negatively correlated networks than that in positively correlated or non-correlated networks. Both self-isolation and self-protection strategies enhance the mobility threshold and, thus, slow down the spread of the epidemic. However, the effectiveness of each strategy in reducing the fraction of infected subpopulations varies in different correlated networks. Self-protection is more effective in positively correlated networks, whereas self-isolation is more effective in negatively correlated networks. Our study will provide insights into epidemic prevention and control in large-scale time-varying metapopulation networks.
Epidemics , Humans , Communicable Diseases/epidemiology , Communicable Diseases/transmission , Time Factors , Population Dynamics
BACKGROUND: For the first time, we investigated the oncological role of plexin domain-containing 1 (PLXDC1), also known as tumor endothelial marker 7 (TEM7), in hepatocellular carcinoma (HCC). AIM: To investigate the oncological profile of PLXDC1 in HCC. METHODS: Based on The Cancer Genome Atlas database, we analyzed the expression of PLXDC1 in HCC. Using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting, we validated our results. The prognostic value of PLXDC1 in HCC was analyzed by assessing its correlation with clinicopathological features, such as patient survival, methylation level, tumor immune microenvironment features, and immune cell surface checkpoint expression. Finally, to assess the immune evasion potential of PLXDC1 in HCC, we used the tumor immune dysfunction and exclusion (TIDE) website and immunohistochemical staining assays. RESULTS: Based on immunohistochemistry, qRT-PCR, and Western blot assays, overexpression of PLXDC1 in HCC was associated with poor prognosis. Univariate and multivariate Cox analyses indicated that PLXDC1 might be an independent prognostic factor. In HCC patients with high methylation levels, the prognosis was worse than in patients with low methylation levels. Pathway enrichment analysis of HCC tissues indicated that genes upregulated in the high-PLXDC1 subgroup were enriched in mesenchymal and immune activation signaling, and TIDE assessment showed that the risk of immune evasion was significantly higher in the high-PLXDC1 subgroup compared to the low-PLXDC1 subgroup. The high-risk group had a significantly lower immune evasion rate as well as a poor prognosis, and PLXDC1-related risk scores were also associated with a poor prognosis. CONCLUSION: As a result of this study analyzing PLXDC1 from multiple biological perspectives, it was revealed that it is a biomarker of poor prognosis for HCC patients, and that it plays a role in determining immune evasion status.
The consensus guidelines of the Geriatric Society of Chinese Medical Association (GSCMA) on the management of atrial fibrillation (AF) in the elderly was first published in 2011 and updated in 2016, with endorsement by Chinese Society of Geriatric Health Medicine (CSGHM). Since then, many important studies regarding the screening and treatment in the elderly population have been reported, necessitating this updated expert consensus guidelines. The writing committee members comprehensively reviewed updated evidence pertaining to elderly patients with AF, and formulated this 2024 update. The highlighted issues focused on the following: screening for AF, geriatric comprehensive assessment, use of the Atrial fibrillation Better Care (ABC) pathway for the elderly patients, and special clinical settings related to elderly patients with AF. New recommendations addressing smart technology facilitated AF screening, ABC pathway based management and optimal anticoagulation were developed, with a focus on the elderly.
Arbuscular mycorrhizal (AM) fungi can establish a mutualistic relationship with the roots of most terrestrial plants to increase plant nutrient uptake. The effects of potassium uptake and transport by AM symbiosis are much less reported compared to other nutrients. In this research, a heterologous yeast system was used to verify that the LbHAK has capacity for potassium uptake. The split-roots system implemented using seedlings of Lycium barbarum confirmed that R. irregularis locally induced LbHAK expression, which means that LbHAK is only expressed in mycorrhizal roots. Furthermore, the impacts of overexpression of LbHAK on the growth, nutrients and water uptake, and transport of mycorrhizal tobacco (inoculation with Rhizophagus irregularis) at 0.2 mM and 2 mM K conditions were assessed. The mycorrhizal tobacco growth and potassium accumulation were significantly enhanced through LbHAK overexpression in tobacco. In addition, overexpression of LbHAK substantially enhanced phosphorus content, while stimulating the expression of NtPT4, Rir-AQP1, and Rir-AQP2 in mycorrhizal tobacco. Moreover, LbHAK overexpression greatly promoted AM colonization. LbHAK has a potential role in facilitating potassium absorption through the mycorrhizal pathway, and overexpression of LbHAK in tobacco may promote the transport of potassium, phosphorus, and water from AM fungi to tobacco. These data imply the important roles played by the LbHAK in AM-fungi-induced potassium uptake in L. barbarum and in improving plant nutrients and AM colonization.
Cisplatin is widely employed in tumor chemotherapy, but nephrotoxicity is an unavoidable side effect of cisplatin. Several studies have demonstrated that mesenchymal stromal cells (MSCs) ameliorate cisplatin-induced kidney injury, but the underlying mechanisms are unknown. In this study, the cisplatin-induced kidney injury mouse model was established by subjecting a single intraperitoneal injection with cisplatin. One hour before cisplatin injection, the mice received human bone marrow MSCs (hBM-MSCs) with or without siRNA-transfection, recombinant human tumor necrosis factor (TNF)-α-stimulated gene/protein 6 (rhTSG-6), or PBS through tail vein. In addition, cisplatin-stimulated HK-2 cells were treated with hBM-MSCs or rhTSG-6. hBM-MSCs treatment remarkably ameliorated cisplatin-induced acute and chronic kidney injury, as evidenced by significant reductions in serum creatinine (Scr), blood urea nitrogen (BUN), tubular injury, collagen deposition, α-smooth muscle actin accumulation, as well as inflammatory responses, and by remarkable increased anti-inflammatory factor expression and Treg cells infiltration in renal tissues. Furthermore, we found that only a few hBM-MSCs engrafted into damaged kidney and that the level of human TSG-6 in serum of mice increased significantly following hBM-MSCs administration. Moreover, hBM-MSCs significantly increased the viability of damaged HK-2 cells and decreased the levels of inflammatory cytokines in the culture supernatant. However, knockdown of TSG-6 gene in hBM-MSCs significantly attenuated their beneficial effects in vivo and in vitro. On the contrary, treated with rhTSG-6 achieved similar beneficial effects of hBM-MSCs. Our results indicate that systemic administration of hBM-MSCs alleviate cisplatin-induced acute and chronic kidney injury in part by paracrine TSG-6 secretion.
BACKGROUND: The increasing volume and intricacy of sequencing data, along with other clinical and diagnostic data, like drug responses and measurable residual disease, creates challenges for efficient clinical comprehension and interpretation. Using paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) as a use case, we present an artificial intelligence (AI)-assisted clinical framework clinALL that integrates genomic and clinical data into a user-friendly interface to support routine diagnostics and reveal translational insights for hematologic neoplasia. METHODS: We performed targeted RNA sequencing in 1365 cases with haematological neoplasms, primarily paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) from the AIEOP-BFM ALL study. We carried out fluorescence in situ hybridization (FISH), karyotyping and arrayCGH as part of the routine diagnostics. The analysis results of these assays as well as additional clinical information were integrated into an interactive web interface using Bokeh, where the main graph is based on Uniform Manifold Approximation and Projection (UMAP) analysis of the gene expression data. At the backend of the clinALL, we built both shallow machine learning models and a deep neural network using Scikit-learn and PyTorch respectively. FINDINGS: By applying clinALL, 78% of undetermined patients under the current diagnostic protocol were stratified, and ambiguous cases were investigated. Translational insights were discovered, including IKZF1plus status dependent subpopulations of BCR::ABL1 positive patients, and a subpopulation within ETV6::RUNX1 positive patients that has a high relapse frequency. Our best machine learning models, LDA and PASNET-like neural network models, achieve F1 scores above 97% in predicting patients' subgroups. INTERPRETATION: An AI-assisted clinical framework that integrates both genomic and clinical data can take full advantage of the available data, improve point-of-care decision-making and reveal clinically relevant insights promptly. Such a lightweight and easily transferable framework works for both whole transcriptome data as well as the cost-effective targeted RNA-seq, enabling efficient and equitable delivery of personalized medicine in small clinics in developing countries. FUNDING: German Ministry of Education and Research (BMBF), German Research Foundation (DFG) and Foundation for Polish Science.
Lead (Pb) is a hazardous heavy metal that accumulates in many environments. Phytoremediation of Pb polluted soil is an environmentally friendly method, and a better understanding of mycorrhizal symbiosis under Pb stress can promote its efficiency and application. This study aims to evaluate the impact of two ectomycorrhizal fungi (Suillus grevillei and Suillus luteus) on the performance of Pinus tabulaeformis under Pb stress, and the biomineralization of metallic Pb in vitro. A pot experiment using substrate with 0 and 1,000 mg/kg Pb2+ was conducted to evaluate the growth, photosynthetic pigments, oxidative damage, and Pb accumulation of P. tabulaeformis with or without ectomycorrhizal fungi. In vitro co-cultivation of ectomycorrhizal fungi and Pb shots was used to evaluate Pb biomineralization. The results showed that colonization by the two ectomycorrhizal fungi promoted plant growth, increased the content of photosynthetic pigments, reduced oxidative damage, and caused massive accumulation of Pb in plant roots. The structural characteristics of the Pb secondary minerals formed in the presence of fungi demonstrated significant differences from the minerals formed in the control plates and these minerals were identified as pyromorphite (Pb5(PO4)3Cl). Ectomycorrhizal fungi promoted the performance of P. tabulaeformis under Pb stress and suggested a potential role of mycorrhizal symbiosis in Pb phytoremediation. This observation also represents the first discovery of such Pb biomineralization induced by ectomycorrhizal fungi. Ectomycorrhizal fungi induced Pb biomineralization is also relevant to the phytostabilization and new approaches in the bioremediation of polluted environments.
Chronic wounds, resulting from persistent inflammation, can trigger a cascade of detrimental effects including exacerbating inflammatory cytokines, compromised blood circulation at the wound site, elevation of white blood cell count, increased reactive oxygen species, and the potential risk of bacterial infection. The interleukin-17 (IL-17) signaling pathway, which plays a crucial role in regulating immune responses, has been identified as a promising target for treating inflammatory skin diseases. This review aims to delve deeper into the potential pathological role and molecular mechanisms of the IL-17 family and its pathways in wound repair. The intricate interactions between IL-17 and other cytokines will be discussed in detail, along with the activation of various signaling pathways, to provide a comprehensive understanding of IL-17's involvement in chronic wound inflammation and repair.
Interleukin-17 , Wound Healing , Humans , Interleukin-17/metabolism , Animals , Signal Transduction , Inflammation/pathology
Type 2 diabetes mellitus (T2DM) significantly impairs the functionality and number of endothelial progenitor cells (EPCs) and resident endothelial cells, critical for vascular repair and regeneration, exacerbating the risk of vascular complications. GLP-1 receptor agonists, like dulaglutide, have emerged as promising therapeutic agents due to their multifaceted effects, including the enhancement of EPC activity and protection of endothelial cells. This study investigates dulaglutide's effects on peripheral blood levels of CD34+ and CD133+ cells in a mouse model of lower limb ischemia and its protective mechanisms against high-glucose-induced damage in endothelial cells. Results demonstrated that dulaglutide significantly improves blood flow, reduces tissue damage and inflammation in ischemic limbs, and enhances glycemic control. Furthermore, dulaglutide alleviated high-glucose-induced endothelial cell damage, evident from improved tube formation, reduced reactive oxygen species accumulation, and restored endothelial junction integrity. Mechanistically, dulaglutide mitigated mitochondrial fission in endothelial cells under high-glucose conditions, partly through maintaining SIRT1 expression, which is crucial for mitochondrial dynamics. This study reveals the potential of dulaglutide as a therapeutic option for vascular complications in T2DM patients, highlighting its role in improving endothelial function and mitochondrial integrity.
Diabetes Mellitus, Experimental , Endothelial Progenitor Cells , Glucagon-Like Peptides , Glucose , Immunoglobulin Fc Fragments , Mitochondrial Dynamics , Recombinant Fusion Proteins , Sirtuin 1 , Animals , Immunoglobulin Fc Fragments/pharmacology , Glucagon-Like Peptides/analogs & derivatives , Glucagon-Like Peptides/pharmacology , Glucagon-Like Peptides/therapeutic use , Sirtuin 1/metabolism , Mitochondrial Dynamics/drug effects , Endothelial Progenitor Cells/drug effects , Endothelial Progenitor Cells/metabolism , Recombinant Fusion Proteins/pharmacology , Male , Mice , Glucose/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/pathology , Mice, Inbred C57BL , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Hypoglycemic Agents/pharmacology , Humans , Ischemia/metabolism , Ischemia/drug therapy , Ischemia/pathology
Objective: Prior research underscores the significance of paraspinal muscles in maintaining spinal stability. This study aims to investigate the predictive value of paraspinal muscle parameters for the occurrence of new vertebral compression fractures (NVCF) following percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP) in patients with osteoporotic vertebral compression fractures (OVCF). Methods: Retrospectively collected data from October 2019 to February 2021 (internal validation, n = 235) and March 2021 to November 2021 (external validation, n = 105) for patients with OVCF treated with PVP/PKP at our institution. They were randomly divided into training (188 cases) and validation groups (47 cases) at an 8:2 ratio. Lasso regression and multivariable logistic regression identified independent risk factors in the training set, and a Nomogram model was developed. Accuracy was assessed using receiver operating characteristic curves (ROC), calibration was evaluated with calibration curves and the Hosmer-Lemeshow test, and clinical utility was analyzed using decision curve analysis (DCA) and clinical impact curve (CIC). Results: Surgical approach, spinal computed tomography (CT) values, and multifidus skeletal muscle index (SMI) are independent predictors of postoperative NVCF in OVCF patients. A Nomogram model, based on the identified predictors, was developed and uploaded online. Internal validation results showed area under the curve (AUC) values of 0.801, 0.664, and 0.832 for the training set, validation set, and external validation, respectively. Hosmer-Lemeshow goodness-of-fit tests (χ2 = 7.311-14.474, p = 0.070-0.504) and calibration curves indicated good consistency between observed and predicted values. DCA and CIC demonstrated clinical net benefit within risk thresholds of 0.06-0.84, 0.12-0.23, and 0.01-0.27. At specificity 1.00-0.80, the partial AUC (0.106) exceeded that at sensitivity 1.00-0.80 (0.062). Conclusion: Compared to the spinal CT value, the multifidus SMI has certain potential in predicting the occurrence of NVCF. Additionally, the Nomogram model of this study has a greater negative predictive value.
Sect. tuberculata plant belongs to the Camellia genus and is named for the "tuberculiform protuberance on the surface of the ovary and fruit". It is a species of great ornamental value and potential medicinal value. However, little has been reported on the metabolites of C. tuberculata seeds. Therefore, this study was conducted to investigate the metabolites of C. tuberculata seeds based on UPLC/ESI-Q TRAP-MS/MS with extensively targeted metabolomics. A total of 1611 metabolites were identified, including 107 alkaloids, 276 amino acids and derivatives, 283 flavonoids, 86 lignans and coumarins, 181 lipids, 68 nucleotides and derivatives, 101 organic acids, 190 phenolic acids, 10 quinones, 4 steroids, 17 tannins, 111 terpenoids, and 177 other metabolites. We compared the different metabolites in seeds between HKH, ZM, ZY, and LY. The 1311 identified different metabolites were classified into three categories. Sixty-three overlapping significant different metabolites were found, of which lignans and coumarins accounted for the largest proportion. The differentially accumulated metabolites were enriched in different metabolic pathways between HKH vs. LY, HKH vs. ZM, HKH vs. ZY, LY vs. ZY, ZM vs. LY and ZM vs. ZY, with the most abundant metabolic pathways being 4, 2, 4, 7, 7 and 5, respectively (p < 0.05). Moreover, among the top 20 metabolites in each subgroup comparison in terms of difference multiplicity 7, 8 and 13. ZM and ZY had the highest phenolic acid content. Ninety-six disease-resistant metabolites and 48 major traditional Chinese medicine agents were identified based on seven diseases. The results of this study will not only lead to a more comprehensive and in-depth understanding of the metabolic properties of C. tuberculata seeds, but also provide a scientific basis for the excavation and further development of its medicinal value.
Camellia , Hydroxybenzoates , Lignans , Camellia/chemistry , Antioxidants/chemistry , Tandem Mass Spectrometry , Flavonoids/analysis , Seeds/chemistry , Metabolomics/methods , Plant Extracts/chemistry , Lignans/analysis , Coumarins/analysis
Because the mechanotransduction by stromal stiffness stimulates the rupture and repair of the nuclear envelope in pancreatic progenitor cells, accumulated genomic aberrations are under selection in the tumor microenvironment. Analysis of cell growth, micronuclei, and γH2AX foci links to mechanotransduction pressure in vivo during serial orthotopic passages of mouse KrasLSL-G12D/+;Trp53flox/flox;Pdx1-Cre (KPC) cancer cells in the tumor and in migrating through the size-restricted 3-µm micropores. To search for pancreatic cancer cell of origin, analysis of single-cell data sets revealed that the extracellular matrix shapes an alternate route of acinar-ductal transdifferentiation of acinar cells into a central hub of elegantly restrained topoisomerase II α (TOP2A)-overexpressing cancer cells that spread out as unique cancer clusters with copy number amplifications in MYC-PTK2 (protein tyrosine kinase 2) locus and PIK3CA. High-PTK2 expression is associated with 171 differentially methylated CpG loci, 319 differentially expressed genes, and poor overall survival in patients with The Cancer Genome Atlas-PAAD. Abolished RGD-integrin signaling by disintegrin KG blocked the PTK2 phosphorylation, increased cancer apoptosis, decreased VAV1 expression, and prolonged overall survival in the KPC mice. Decreases of α-smooth muscle actin deposition in the CD248 knockout KPC mice remodel the tissue stroma and down-regulated TOP2A expression in the epithelium. In summary, stromal stiffness induces the onset of cells of origin of cancer by ectopic TOP2A expression, and the genomic amplification of MYC-PTK2 locus via alternative transdifferentiation of pancreatic progenitor cells is the vulnerability useful for disintegrin KG treatment against cells-of-origin cancer.
OBJECTIVE: Psoriasis is a common, chronic inflammatory disease with unclear etiology. Keratinocytes in psoriasis are susceptible to exogenous triggers that induce inflammatory cell death. This study investigated whether GSDME-mediated pyroptosis in keratinocytes contributes to the pathogenesis of psoriasis. METHODS: Skin samples from patients with psoriasis and healthy controls were collected to evaluate the expression of GSDME, cleaved-caspase-3, and inflammatory factors. We then analyzed the data series, GSE41662, to further compare the expression of GSDME between lesional and non-lesional skin samples in those with psoriasis. In vivo, caspase-3 inhibitor and GSDME deficiency mice (Gsdme-/-) were applied to block caspase-3/GSDME activation in the imiquimod-induced psoriasis model. Skin inflammation, disease severity, and pyroptosis-related proteins were analyzed. In vitro, tumor necrosis factor-α (TNF-α)-induced caspase-3/GSDME-mediated pyroptosis in the HACAT cell line was explored. RESULTS: Our analysis of the GSE41662 data series found that GSDME were upregulated in psoriasis lesions, compared to normal skin. High levels of inflammatory cytokines such as IL-1ß, IL-6, and TNF-α were also found in psoriasis lesions. In mice of Gsdme-/- and caspase-3 inhibitor groups, the severity of skin inflammation was attenuated, and GSDME and C-caspase-3 levels decreased after imiquimod treatment. Similarly, IL-1ß, IL-6, and TNF-α were decreased in Gsdme-/- and caspase-3 inhibitor groups. In vitro, TNF-α induced HACAT cell pyroptosis through caspase-3/GSDME pathway activation, which was suppressed by blocking caspase-3 or silencing GSDME. CONCLUSION: Our study provides a novel explanation that TNF-α/caspase-3/GSDME-mediated keratinocyte pyroptosis is highly responsible for the initiation and acceleration of skin inflammation and progression of psoriasis.
The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1ß release in THP-1 cells, with an IC50 value of 0.29 µM, approximately 27-fold more potent than that of IAL (IC50: 7.86 µM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.
Drug Design , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Sesquiterpenes , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Humans , Inflammasomes/metabolism , Inflammasomes/antagonists & inhibitors , Animals , Sesquiterpenes/pharmacology , Sesquiterpenes/chemical synthesis , Sesquiterpenes/chemistry , Mice , Structure-Activity Relationship , Interleukin-1beta/metabolism , THP-1 Cells , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/metabolism , Mice, Inbred C57BL
This study aims to investigate effects of arbuscular mycorrhizal fungi (AMF) inoculation on nitrogen (N) uptake and assimilation in Populus cathayana under drought stress (DS). Herein, we measured photosynthetic performance, antioxidant enzyme system, N level and N assimilation enzymes, proteins content and distribution, transcripts of genes associated with N uptake or transport in P. cathayana with AMF (AM) or without AMF (NM) under soil water limitation and adequate irrigation. Compared with NM-DS P. cathayana, the growth, gas exchange properties, antioxidant enzyme activities, total N content and the proportion of water-soluble and membrane-bound proteins in AM-DS P. cathayana were increased. Meanwhile, nitrate reductase (NR) activity, NO3- and NO2- concentrations in AM-DS P. cathayana were reduced, while NH4+ concentration, glutamine synthetase (GS) and glutamate synthetase (GOGAT) activities were elevated, indicating that AM symbiosis reduces NO3- assimilation while promoting NH4+ assimilation. Furthermore, the transcriptional levels of NH4+ transporter genes (PcAMT1-4 and PcAMT2-1) and NO3- transporter genes (PcNRT2-1 and PcNRT3-1) in AM-DS P. cathayana roots were significantly down-regulated, as well as NH4+ transporter genes (PcAMT1-6 and PcAMT4-3) in leaves. In AM P. cathayana roots, DS significantly up-regulated the transcriptional levels of RiCPSI and RiURE, the key N transport regulatory genes in AMF compared with adequate irrigation. These results indicated that AM N transport pathway play an essential role on N uptake and utilization in AM P. cathayana to cope with DS. Therefore, this research offers a novel perspective on how AM symbiosis enhances plant resilience to drought at aspect of N acquisition and assimilation.
Droughts , Mycorrhizae , Nitrogen , Populus , Symbiosis , Populus/microbiology , Populus/metabolism , Populus/genetics , Populus/physiology , Mycorrhizae/physiology , Mycorrhizae/metabolism , Nitrogen/metabolism , Symbiosis/physiology , Gene Expression Regulation, Plant , Plant Proteins/metabolism , Plant Proteins/genetics , Plant Roots/microbiology , Plant Roots/metabolism , Photosynthesis/physiology , Drought Resistance
Purpose: To develop an individualized predictive model for postoperative recurrent lumbar disc herniation (PRLDH) in patients undergoing percutaneous endoscopic transforaminal discectomy (PETD) by considering postoperative activity factors. Patients and Methods: Retrospectively collected data from 612 LDH patients who underwent PETD in our institution from January 2017 to June 2023. They were divided into a training group (429 cases) and a validation group (183 cases). Lasso regression (Model 1) and random forest (Model 2) were applied for variable selection in the training group. The two models were compared in terms of discrimination (the area under curve, AUC), calibration (calibration curve), and clinical utility (decision curve analysis, DCA). Akaike information criterion (AIC) was used for model comparison, and internal validation employed 1000 times Bootstrap + 10-fold cross-validation. Finally, a Nomogram was constructed to display the results and uploaded to the web version. Results: Among 612 treated LDH patients, 66 (10.78%) developed PRLDH. Model 1, superior in AUC, calibration, DCA, and AIC over Model 2, was chosen as the predictive model. Logistic regression in the training group identified BMI, smoking, activity level score, time to first ambulation, diabetes, Modic change, and Pfirrmann grade as independent predictors of PRLDH. Model 1 exhibited a training group AUC of 0.813 (95% CI 0.753-0.872) and a validation group AUC of 0.868 (95% CI 0.773-0.962). At a Youden index of 0.50, sensitivity was 0.73, specificity was 0.77. Internal validation (1000 times Bootstrap + 10-fold cross-validation) for the training group showed accuracy of 0.889, kappa consistency of 0.112, and AUC of 0.757. The Hosmer-Lemeshow goodness-of-fit tests indicated good discriminative ability for Model 1 in both the training (χ2=2.895, P=0.941) and validation groups (χ2=8.197, P=0.414). The DCA and Nomogram are accessible at https://sofarnomogram.shinyapps.io/PRLDHNom/. Conclusion: The Nomogram predictive model, developed based on postoperative activity factors in this study, demonstrates excellent predictive capability, facilitating risk assessment for the occurrence of PRLDH after PETD.
