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An unprecedented spiro-C-glycoside adduct, heteryunine A (1), along with two uncommon alkaloids featuring a 2,3-diketopiperazine skeleton, heterpyrazines A (2) and B (3), were discovered in the roots of Heterosmilax yunnanensis. The detailed spectroscopic analysis helped to clarify the planar structures of these compounds. Compound 1, containing 7 chiral centers, features a catechin fused with a spiroketal and connects with a tryptophan derivative by a CC bond. Its complex absolute configuration was elucidated by rotating frame overhauser enhancement spectroscopy (ROESY), specific rotation, and the 13C nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) calculation. The possible biosynthetic routes for 1 were deduced. Compounds 1 and 2 showed significant antifibrotic effects and further research revealed that they inhibited the activation, migration and proliferation of hepatic stellate cells (HSCs) through suppressing the activity of Ras homolog family member A (RhoA).
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Fourteen new 2-benzylbenzofuran O-glycosides (1-13, 15) and one new key precursor, diarylacetone (14) were isolated from the roots of Heterosmilax yunnanensis Gagnep, which all have characteristic 2,3,4-O-trisubstituted benzyl. Their structures were elucidated by 1D and 2D NMR, HRESIMS, UV and IR. The isolated compounds were assessed for their cardioprotective activities and compounds 1, 3 and 6 could significantly improve cardiomyocytes viability. Moreover, the mechanistic study revealed that these three compounds could significantly decrease intracellular ROS levels and maintain mitochondrial homeostasis upon hypoxia inducement. Consequently, 1, 3 and 6 might serve as potential lead compounds to prevent myocardial ischemia.
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Benzofuranos , Glicosídeos , Raízes de Plantas , Glicosídeos/farmacologia , Glicosídeos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Raízes de Plantas/química , Benzofuranos/química , Benzofuranos/farmacologiaRESUMO
BACKGROUND: Circular RNAs (CircRNAs) have been shown to be involved in the development of chronic kidney disease (CKD). This study aimed to investigate the role of Circ1647 in renal fibrosis, which is a hallmark of CKD. METHODS: In this study, we established a unilateral ureteral obstruction (UUO) model and delivered Circ1647 RfxCas13d knockdown plasmid into renal parenchymal cells via retrograde injection through the ureter followed by electroporation. After that, the pathological changes were determined by Hematoxylin and Eosin. Meanwhile, Immunohistochemistry, qRT-PCR and Western blot were conducted to assess the degree of fibrosis. In addition, overexpressing of Circ1647 in renal tubular epithelial cells (TCMK1) was performed to investigate the underlying mechanisms of Circ1647. RESULTS: Our results displayed that electroporation-mediated knockdown of Circ1647 by RfxCas13d knockdown plasmid significantly inhibited renal fibrosis in UUO mice as evidenced by reduced expression of fibronectin and α-SMA (alpha-smooth muscle actin). Conversely, overexpression of Circ1647 in TCMK1 cells promoted the fibrosis. In terms of mechanism, Circ1647 may mediate the PI3K/AKT Signaling Pathway as demonstrated by the balance of the phosphorylation of PI3K and AKT in vivo and the aggravated phosphorylation of PI3K and AKT in vitro. These observations were corroborated by the effects of the PI3K inhibitor LY294002, which mitigated fibrosis post Circ1647 overexpression. CONCLUSION: Our study suggests that Circ1647 plays a significant role in renal fibrosis by mediating the PI3K/AKT signaling pathway. RfxCas13d-mediated inhibition of Circ1647 may serve as a therapeutic target for renal fibrosis in CKD.
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RNA Circular , Insuficiência Renal Crônica , Obstrução Ureteral , Animais , Camundongos , Fibrose , Rim/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/genética , Obstrução Ureteral/patologia , RNA Circular/genética , RNA Circular/metabolismoRESUMO
Pink noise and spectral distortions affect the demodulation accuracies of fiber Bragg gratings (FBGs). A noise reduction algorithm with Savitzky-Golay filtering on each intrinsic mode function component decomposed by CEEMDAN, followed by signal reconstruction from the filtered components, is presented herein. Simulations show that the algorithm retains FBG signal details while reducing noise, avoids measurement errors from excessive smoothing, and suppresses white and pink noises adequately. A resolution-enhanced peak detection algorithm with distortion spectrum correction is also proposed with high accuracy and simple calculation. The experimental results show that the goodness of fit of the FBG temperature-wavelength curve R2 improves from 0.9826 to 0.9999.
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This study aims to evaluate the anti-tumor and analgesic activities of Compound Kushen Injection(CKI) based on zebrafish model in vivo and investigate the anti-tumor mechanism. To be specific, zebrafish tumor xenotransplantation model was established by microinjection of murine LPC H12 cells into yolk sac. Then the high-dose CKI(H-CKI), medium-dose CKI(M-CKI), low-dose CKI(L-CKI) groups, and the model group were set. The anti-tumor activity of CKI was evaluated with the tumor area growth fold and integral absorbance(IA) growth fold 72 h after administration. The peripheral pain and central pain in zebrafish were respectively induced with acetic acid(AA) and phorbol myristate acetate(PMA). Zebralab ViewPoint system was employed to monitor behavioral trajectory of zebrafish, and movement times, movement time, movement distance, and movement velocity were used to evaluate the analgesic activity of CKI. Finally, real-time fluorescence quantitative polymerase chain reaction(RT-qPCR) was performed to detect the expression levels of apoptosis-related B lymphocyte tumor-2(Bcl-2) and phosphatidylinositol-3-kinase(PI3 K)/protein kinase B(Akt or PKB) pathway-related genes, for the verification of the anti-tumor mechanism. Compared with the model group, M-CKI and H-CKI significantly reduced the growth folds of tumor area and IA, relief the peripheral pain and central pain. The mechanism was that CKI can up-regulate the expression of cysteine aspartic acid specific protease-3(caspase-3, Casp3) and caspase-9(Casp9), down-regulate the expression of phosphoinositide 3-kinase(PI3 K) and Akt, and significantly reduce the expression of Bcl-2, hypoxia-inducible factor-1α(HIF-1α), and vascular endothelial growth factor(VEGF). In conclusion, CKI has significant inhibitory effect on tumor growth and pain, which is related to the PI3 K/Akt signaling pathway. The pathway mediates cell apoptosis, suppresses tumor growth, and alleviates tumor pain.
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Antineoplásicos , Neoplasias , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Antineoplásicos/farmacologia , Medicamentos de Ervas Chinesas , Subunidade alfa do Fator 1 Induzível por Hipóxia , Camundongos , Neoplasias/tratamento farmacológico , Dor/tratamento farmacológico , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-bcl-2 , Fator A de Crescimento do Endotélio Vascular , Peixe-ZebraRESUMO
The fiber Bragg grating (FBG) sensor calibration process is critical for optimizing performance. Real-time dynamic calibration is essential to improve the measured accuracy of the sensor. In this paper, we present a dynamic calibration method for FBG sensor temperature measurement, utilizing the online sequential extreme learning machine (OS-ELM). During the measurement process, the calibration model is continuously updated instead of retrained, which can reduce tedious calculations and improve the predictive speed. Polynomial fitting, a back propagation (BP) network, and a radial basis function (RBF) network were compared, and the results showed the dynamic method not only had a better generalization performance but also had a faster learning process. The dynamic calibration enabled the real-time measured data of the FBG sensor to input calibration models as online learning samples continuously, and could solve the insufficient coverage problem of static calibration training samples, so as to improve the long-term stability, accuracy of prediction, and generalization ability of the FBG sensor.
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To evaluate the safety of heavy metals contaminated Astragalus membranaceus,an appropriate protocol was established to study the heavy metals pollution level by health risk assessment. This study provided a detailed procedure to assess the medicinal herbs in quality control and safety evaluation,and expected to create awareness among the public on the safety of consuming of A. membranaceus or any other kinds of medicinal herbs. The heavy metals content of Cu,As,Cd,Pb and Hg in a total of 45 batches of A. membranaceus were carefully analyzed with a developed inductively coupled plasma mass spectrometry( ICP-MS). Besides,the heavy metal contamination level was further evaluated through 4 main assessment parameters,including maximum residue limit( MRL) set by International Standard Organization,estimated daily intake( EDI) set by IUPAC,target hazard quotients( THQ) and Total THQ set by USEPA and total THQs in raw herbs of A. membranaceus. In addition,the recommended MRLs of 5 main heavy metals aimed to A. membranaceus were calculated based on the regulated consumption quantity. The result showed that,under the ISO international standard of Chinese medicine-Chinese herbal medicine heavy metals,the unqualified rate was 8. 89% for A. membranaceus,which including 4 batches of A. membranaceus exceeded the MRL of As. Here,the standard THQ value of A. membranaceus was firstly proposed as 0. 02 and 0. 011 25 for adults and children,respectively,which were calculated with the recommended consumption quantity of 30 g and 9 g for adults and children. Furthermore,the values of THQ for As and total THQs in adults and children were exceeded the standard THQ in A. membranaceus,and the recommended MRLs of Pb,Cd,Hg and Cu in above medicinal materials that calculated based on health risk assessment model were higher than the regulated MRLs that set by ISO and Chinese Pharmacopeia. The research showed that the contents of heavy metals in A. membranaceus were not in the safe range and the certain non-carcinogenic risks to human body cannot be neglected. Based on above investigation result,it is easily known that the common evaluation method for raw herbs based on the comparison of MRL of heavy metals was not precise enough,and the international model of health risk assessment should be built for each medicinal herb. Above all,this study provided a more realistic research approach for safety evaluation of any other kinds of heavy metals contaminated medicinal herbs,including the establishment of heavy metals standard limit in a specified medicinal herb under recommended consumption quantity,and it is expected to create awareness among the public on the safety of consuming any other medicinal herbs.
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Astragalus propinquus/química , Contaminação de Medicamentos , Medicamentos de Ervas Chinesas/normas , Metais Pesados/análise , Medicamentos de Ervas Chinesas/análise , Humanos , Plantas Medicinais/química , Medição de RiscoRESUMO
BACKGROUND: We systematically reviewed and performed a meta-analysis of the available data regarding neoadjuvant chemo- and/or radiotherapy with special emphasis on tumor response/progression rates, toxicities, and clinical benefit, i.e. resection probabilities and survival estimates. METHODS AND FINDINGS: Trials were identified by searching PUBMED, MEDLINE, and the Cochrane Central Register of Controlled Trials from 1966 to Feb 2015. A total of 18 studies (n = 959) were analyzed. the estimated fraction of patients with complete response was 2.8% (CI 0.8-4.7%) and with partial response 28.7% (CI 18.9%-38.5%). Stable disease was averaged to 45.9% (CI 32.9%-58.9%) in all patients and tumor progression under therapy occurred by estimation in 16.9% (CI 10.2%-23.6%) of the patients. The weighted frequency of those who underwent resection was 65.3% (CI 54.2%-76.5%), and the proportion of R0 resection amounted to 57.4% (CI 48.2%-66.5%). The weighted mean of median survival amounted to 17.9 months (range: 14.7-21.2 months) for the overall cohort of patients, 25.9 months (range: 21.1-30.7 months) for those who were resected, and 11.9 months (range: 10.4-13.5 months) for unresected patients. CONCLUSIONS: The resection and R0 resection rates in the group of borderline resectable tumor patients after neoadjuvant therapy are similar to the resectable tumor patients, much higher than those in unresectable tumor patients. The survival estimates of borderline resectable tumor patients after neoadjuvant therapy were similar to resectable tumor patients. Patients with borderline resectable pancreatic cancer should be included in neoadjuvant protocols and subsequently be reevaluated for resection. How to find chemo-responsiveness before neoadjuvant chemotherapy so as to give individualized treatment is still an important issue.
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Antineoplásicos/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Radioterapia , Antineoplásicos/administração & dosagem , Quimioterapia Adjuvante , Humanos , Radioterapia AdjuvanteRESUMO
RNA interference (RNAi)-mediated gene therapy is a promising approach to cure various diseases. However, developing an effective, safe, specific RNAi delivery system remains a major challenge. In this study, a novel redox-responsive polyetherimide (PEI)-based nanovector, mPEG-SeSe-PEI, was developed and its efficacy evaluated. We prepared three mPEG-SeSe-PEI vector candidates for small interfering glyceraldehyde-3-phosphate dehydrogenase (siGADPH) and determined their physiochemical properties and transfection efficiency using flow cytometry and PEG11.6-SeSe-PEI polymer. We investigated the silencing efficacy of GADPH mRNA expression in PANC-1 cells and observed that PEG11.6-SeSe-PEI/siGADPH (N/P ratio=10) polyplexes possessed the appropriate size and zeta-potential and exhibited excellent in vitro gene silencing effects with the least cytotoxicity in PANC-1 cells. In conclusion, we present PEG11.6-SeSe-PEI as a potential therapeutic gene delivery system for small interfering RNA (siRNA).
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Técnicas de Transferência de Genes , Gliceraldeído 3-Fosfato Desidrogenase (NADP+)/genética , Polietilenoglicóis/administração & dosagem , Polímeros/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Linhagem Celular Tumoral , Inativação Gênica , Humanos , Polietilenoglicóis/química , Polímeros/química , Interferência de RNA , RNA Mensageiro/antagonistas & inibidoresRESUMO
In reality, the outbreak of emerging infectious diseases including SARS, A/H1N1 and Ebola are accompanied by the common cold and flu. The selective treatment measure for mitigating and controlling the emerging infectious diseases should be implemented due to limited medical resources. However, how to determine the threshold infected cases and when to implement the selective treatment tactics are crucial for disease control. To address this, we derive a non-smooth Filippov system induced by selective treatment measure. The dynamic behaviors of two subsystems have been discussed completely, and the existence conditions for sliding segment, sliding mode dynamics and different types of equilibria such as regular equilibrium, pseudo-equilibrium, boundary equilibrium and tangent point have been provided. Further, numerical sliding bifurcation analyses show that the proposed Filippov system has rich sliding bifurcations. Especially, the most interesting results are those for the fixed parameter set as the bifurcation parameter varies, the sliding bifurcations occur sequentially: crossing â buckling â real/virtual equilibrium â buckling â crossing. The key factors which affect the selective treatment measures and the threshold value of infected cases for emerging infectious disease have been discussed in more detail.
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The Wnt/ß-catenin signalling pathway is activated in pancreatic cancer initiation and progression. Dickkopf-related protein 3 (DKK3) is a member of the human Dickkopf family and an antagonist of Wnt ligand activity. However, the function of DKK3 in this pathway in pancreatic cancer is rarely known. We examined the expression of DKK3 in six human pancreatic cancer cell lines, 75 pancreatic cancer and 75 adjacent non-cancerous tissues. Dickkopf-related protein 3 was frequently silenced and methylation in pancreatic cancer cell lines (3/6). The expression of DKK3 was significantly lower in pancreatic cancer tissues than in adjacent normal pancreas tissues. Further, ectopic expression of DKK3 inhibits nuclear translocation of ß-catenin induced by hypoxia in pancreatic cancer Bxpc-3 cell. The forced expression of DKK3 markedly suppressed migration and the stem cell-like phenotype of pancreatic cancer Bxpc-3 cell in hypoxic conditions through reversing epithelial-mesenchymal transition (EMT). The stable expression of DKK3 sensitizes pancreatic cancer Bxpc-3 cell to gemcitabine, delays tumour growth and augments gemcitabine therapeutic effect in pancreatic cancer xenotransplantation model. Thus, we conclude from our finding that DKK3 is a tumour suppressor and improved gemcitabine therapeutic effect through inducing apoptosis and regulating ß-catenin/EMT signalling in pancreatic cancer Bxpc-3 cell.
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Desoxicitidina/análogos & derivados , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , beta Catenina/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal , Animais , Antimetabólitos Antineoplásicos/farmacologia , Western Blotting , Hipóxia Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Quimiocinas , Metilação de DNA , Desoxicitidina/farmacologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Camundongos Nus , Microscopia Confocal , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
Kushen (Radix Sophorae Flavescentis) has a long history of use for the treatment of tumors, inflammation and other diseases in traditional Chinese medicine. Compound Kushen Injection (CKI) is a mixture of natural compounds extracted from Kushen and Baituling (Rhizoma Smilacis Glabrae). The main principles of CKI are matrine (MT) and oxymatrine (OMT) that exhibit a variety of pharmacological activities, including anti-inflammatory, anti-allergic, anti-viral, anti-fibrotic and cardiovascular protective effects. Recent evidence shows that these compounds also produce anti-cancer actions, such as inhibiting cancer cell proliferation, inducing cell cycle arrest, accelerating apoptosis, restraining angiogenesis, inducing cell differentiation, inhibiting cancer metastasis and invasion, reversing multidrug resistance, and preventing or reducing chemotherapy- and/or radiotherapy-induced toxicity when combined with chemotherapeutic drugs. In this review, we summarize recent progress in studying the anti-cancer activities of MT, OMT and CKI and their potential molecular targets, which provide clues and references for further study.
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Antineoplásicos Fitogênicos/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Medicina Tradicional Chinesa/métodos , Neoplasias/tratamento farmacológico , Alcaloides/administração & dosagem , Animais , Antineoplásicos Fitogênicos/análise , Medicamentos de Ervas Chinesas/análise , Humanos , Injeções , Neoplasias/metabolismo , Neoplasias/patologia , Quinolizinas/administração & dosagem , Resultado do Tratamento , MatrinasRESUMO
Mathematical models can assist in the design strategies to control emerging infectious disease. This paper deduces a non-smooth infectious disease model induced by selection pressures. Analysis of this model reveals rich dynamics including local, global stability of equilibria and local sliding bifurcations. Model solutions ultimately stabilize at either one real equilibrium or the pseudo-equilibrium on the switching surface of the present model, depending on the threshold value determined by some related parameters. Our main results show that reducing the threshold value to a appropriate level could contribute to the efficacy on prevention and treatment of emerging infectious disease, which indicates that the selection pressures can be beneficial to prevent the emerging infectious disease under medical resource limitation.
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This paper addresses the asynchronous control problem for semi-Markov reaction-diffusion neural networks (SMRDNNs) under probabilistic event-triggered protocol (PETP) scheduling. A semi-Markov process with a deterministic switching rule is introduced to characterize the stochastic behavior of these networks, effectively mitigating the impacts of arbitrary switching. Leveraging statistical data on communication-induced delays, a novel PETP is proposed that adjusts transmission frequencies through a probabilistic delay division method. The dynamic adjustment of event trigger conditions based on real-time neural network is realized, and the responsiveness of the system is enhanced, which is of great significance for improving the performance and reliability of the communication system. Additionally, a dynamic asynchronous model is introduced that more accurately captures the variations between system modes and controller modes in the network environment. Ultimately, the efficacy and superiority of the developed strategies are validated through a simulation example.
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ABSTRACT: Male infertility has become a global concern, accounting for 20-70% of infertility. Dysfunctional spermatogenesis is the most common cause of male infertility; thus, treating abnormal spermatogenesis may improve male infertility and has attracted the attention of the medical community. Mitochondria are essential organelles that maintain cell homeostasis and normal physiological functions in various ways, such as mitochondrial oxidative phosphorylation (OXPHOS). Mitochondrial OXPHOS transmits electrons through the respiratory chain, synthesizes adenosine triphosphate (ATP), and produces reactive oxygen species (ROS). These mechanisms are vital for spermatogenesis, especially to maintain the normal function of testicular Sertoli cells and germ cells. The disruption of mitochondrial OXPHOS caused by external factors can result in inadequate cellular energy supply, oxidative stress, apoptosis, or ferroptosis, all inhibiting spermatogenesis and damaging the male reproductive system, leading to male infertility. This article summarizes the latest pathological mechanism of mitochondrial OXPHOS disorder in testicular Sertoli cells and germ cells, which disrupts spermatogenesis and results in male infertility. In addition, we also briefly outline the current treatment of spermatogenic malfunction caused by mitochondrial OXPHOS disorders. However, relevant treatments have not been fully elucidated. Therefore, targeting mitochondrial OXPHOS disorders in Sertoli cells and germ cells is a research direction worthy of attention. We believe this review will provide new and more accurate ideas for treating male infertility.
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Mathematical models have become indispensable tools for analyzing pest control strategies. However, in the realm of pest control studies, the consideration of a plant population being affected by a model that incorporates pests, natural enemies and disease in the pest population has been relatively limited. Therefore, this paper aims to formulate and investigate a hybrid impulsive eco-epidemic model that incorporates disease in the pest population. Initially, we examine the existence and stability of the pest-eradication periodic solution. Subsequently, to explore the impact of chemical and biological control methods, we propose an updated eco-epidemic model that incorporates varying frequencies of pesticide sprays and the release of both infected pests and natural enemies for pest control. We establish threshold values for the susceptible pest eradication periodic solution under different scenarios, illustrating the global attractiveness of this solution. Finally, we discuss the obtained results and suggest potential avenues for future research in this field.
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Controle Biológico de Vetores , Praguicidas , Controle Biológico de Vetores/métodos , Modelos Teóricos , Dinâmica PopulacionalRESUMO
The media's coverage has the potential to impact human behavior and aid in the control of emergent infectious diseases. We aim to quantify and evaluate the extent to which media coverage can influence infectious disease control through a mathematical model, thus proposing a switching epidemic model that considers the effect of media coverage. The threshold strategy incorporates media influence only when the number of infected cases surpasses a specific threshold; otherwise, it is disregarded. When conducting qualitative analysis of two subsystems, focusing on the existence and stability of equilibria. Using numerical methods, the codimension-2 bifurcation analysis is adopted here to investigate the various types of equilibria within the switching system that play a vital role in pest control. On the other hand, codimension-1 bifurcation analysis reveals the existence of periodic, chaotic solutions, period-doubling bifurcations, multiple attractors and other complexities within the proposed model, which could pose challenges in disease control. Additionally, the impact of key parameters on epidemic outbreaks is analyzed, such as the initial values of susceptible and infective individuals, and discuss the potential benefits of mass media coverage in preventing emerging infectious diseases. The modeling and analytical techniques developed for threshold control strategies can be applied to other disease control efforts.
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Epidemias , Modelos Biológicos , Humanos , Modelos Teóricos , Surtos de Doenças , Dinâmica não LinearRESUMO
Herein, a metal-free main-group catalysis system for thiosulfonylation of terminal alkynes with thiosulfonates has been established by using commercially available B(C6F5)3 as a catalyst. The protocol provides a highly regio- and stereoselective route for the synthesis of diverse (E)-(ß)-arylthiolvinyl sulfones under mild conditions with 100% atom-economy and exceptional functional group compatibility.
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Alcinos , Sulfonas , Estrutura Molecular , CatáliseRESUMO
Background Interleukin-6 (IL-6) plays a critical role in essential hypertension (EH) and cardiovascular disease. Evidence suggests two hotspot single nucleotide polymorphisms (SNPs) of the IL-6 gene (rs1800795, -174C > G and rs1800796, -572G > C) might be associated with the susceptibility of EH. However, no consensus has yet been established. Thus, we aimed to investigate the potential association between IL-6 gene polymorphisms and the risk of EH based on a case-control study in a Chinese population. Materials and methods A total of 479 subjects (272 healthy controls and 207 EH patients) were randomly enrolled in our study. After extracting the genomic DNA, two SNPs of the IL-6 gene (rs1800795, -174C > G and rs1800796, -572G > C) were genotyped to analyze the potential association between these genetic variants and EH risk. Multiple genetic models were performed to investigate the strength of association by calculating the odds ratio (OR) and 95% confidence interval (95% CI). The potential effect of SNPs on gene expression was evaluated using expression quantitative trait loci (eQTL) analysis. Results The genotyping findings of IL-6 rs1800795, -174C > G polymorphism showed three study participants with CG genotype and 204 with GG genotype in the EH patients. The IL-6 -174C > G polymorphism was significantly associated with EH risk (P = 0.046) and conferred a reduced risk of EH development (OR = 0.99, 95%CI = 0.97-1.00). Conversely, no substantial association between IL-6 rs1800796, -572G > C polymorphism and the risk of EH was found in all genetic models (P > 0.05). Moreover, the eQTL analysis indicated that the -174C > G polymorphism was significantly associated with gene expression of IL-6 (P = 0.006), and the G allele corresponded to a reduced IL-6 gene expression (Beta = -0.397). Compared with -174C > G, the -572G > C polymorphism was not found to be significantly associated with IL-6 gene expression (Beta = -0.120, P = 0.560). Conclusions Our findings provide evidence that the rs1800795, -174C > G polymorphism can affect the expression levels of IL-6, and the risk of EH occurrence. However, the rs1800796, -572G > C polymorphism does not regulate the IL-6 gene expression levels and the susceptibility of EH.
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Vanin1 (VNN1) may be a potential biomarker for the early screening of pancreatic cancer (PC)associated diabetes (PCAD). A previous study by the authors reported that cysteamine secreted by VNN1overexpressing PC cells induced the dysfunction of paraneoplastic insulinoma cell lines by increasing oxidative stress. In the present study, it was observed that both cysteamine and exosomes (Exos) secreted by VNN1overexpressing PC cells aggravated the dysfunction of mouse primary islets. PCderived VNN1 could be transported into islets through PC cellderived Exos (PCExos). However, ßcell dedifferentiation, and not cysteaminemediated oxidative stress, was responsible for the islet dysfunction induced by VNN1containing Exos. VNN1 inhibited the phosphorylation of AMPK and GAPDH, and prevented Sirt1 activation and FoxO1 deacetylation in islets, which may be responsible for the induction of ßcell dedifferentiation induced by VNN1overexpressing PCExos. Furthermore, it was demonstrated that VNN1overexpressing PC cells further impaired the functions of paraneoplastic islets in vivo using diabetic mice with islets transplanted under the kidney capsule. On the whole, the present study demonstrates that PC cells overexpressing VNN1 exacerbate the dysfunction of paraneoplastic islets by inducing oxidative stress and ßcell dedifferentiation.