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KEY MESSAGE: 63 L. bicolor WRKY genes were identified and their informatics was analyzed. The results suggested that the LbWRKY genes involved in the development and salt secretion of salt glands in L. bicolor. Salt stress, as a universal abiotic stress, severely inhibits the growth and development of plants. WRKY transcription factors play a vital role in plant growth and development, as well as in response to various stresses. Nevertheless, little is known of systematic genome-wide analysis of the WRKY genes in Limonium bicolor, a model recretohalophyte. In this study, 63 L. bicolor WRKY genes were identified (LbWRKY1-63), which were unevenly distributed across seven chromosomes and one scaffold. Based on the structural and phylogenetic characteristics, 63 LbWRKYs are divided into three main groups. Cis-elements in the LbWRKY promoters were related to growth and development, phytohormone responses, and stress responses. Colinearity analysis showed strong colinearity between LbWRKYs and GmWRKYs from soybean (Glycine max). Therefore, LbWRKY genes maybe have similar functions to GmWRKY genes. Expression analysis showed that 28 LbWRKY genes are highly expressed in roots, 9 in stems, 26 in leaves, and 12 in flowers and most LbWRKY genes responded to NaCl, ABA, and PEG6000. Silencing LbWRKY10 reduced salt gland density and salt secretion ability of leaves, and the salt tolerance of the species. Consistent with this, genes associated with salt gland development were markedly down-regulated in the LbWRKY10-silenced lines. Our findings suggested that the LbWRKY genes involved in the development and salt secretion of salt glands in L. bicolor. Our research provides new insights into the functions of the WRKY family in halophytes.
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Regulação da Expressão Gênica de Plantas , Família Multigênica , Filogenia , Proteínas de Plantas , Plumbaginaceae , Tolerância ao Sal , Plantas Tolerantes a Sal , Fatores de Transcrição , Plumbaginaceae/genética , Plumbaginaceae/fisiologia , Plantas Tolerantes a Sal/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Tolerância ao Sal/genética , Estresse Salino/genética , Estresse Fisiológico/genética , Plantas Geneticamente Modificadas/genética , Regiões Promotoras Genéticas/genética , Genes de PlantasRESUMO
Glucose oxidase (GOx) is often used to starvation therapy. However, only consuming glucose cannot completely block the energy metabolism of tumor cells. Lactate can support tumor cell survival in the absence of glucose. Here, we constructed a nanoplatform (Met@HMnO2-GOx/HA) that can deplete glucose while inhibiting the compensatory use of lactate by cells to enhance the effect of tumor starvation therapy. GOx can catalyze glucose into gluconic acid and H2O2, and then HMnO2 catalyzes H2O2 into O2 to compensate for the oxygen consumed by GOx, allowing the reaction to proceed sustainably. Furthermore, metformin (Met) can inhibit the conversion of lactate to pyruvate in a redox-dependent manner and reduce the utilization of lactate by tumor cells. Met@HMnO2-GOx/HA nanoparticles maximize the efficacy of tumor starvation therapy by simultaneously inhibiting cellular utilization of two carbon sources. Therefore, this platform is expected to provide new strategies for tumor treatment.
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SIGNIFICANCE STATEMENT: We hypothesized that triple therapy with inhibitors of the renin-angiotensin system (RAS), sodium-glucose transporter (SGLT)-2, and the mineralocorticoid receptor (MR) would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression in Col4a3 -deficient mice, a model of Alport syndrome. Late-onset ramipril monotherapy or dual ramipril/empagliflozin therapy attenuated CKD and prolonged overall survival by 2 weeks. Adding the nonsteroidal MR antagonist finerenone extended survival by 4 weeks. Pathomics and RNA sequencing revealed significant protective effects on the tubulointerstitium when adding finerenone to RAS/SGLT2 inhibition. Thus, triple RAS/SGLT2/MR blockade has synergistic effects and might attenuate CKD progression in patients with Alport syndrome and possibly other progressive chronic kidney disorders. BACKGROUND: Dual inhibition of the renin-angiotensin system (RAS) plus sodium-glucose transporter (SGLT)-2 or the mineralocorticoid receptor (MR) demonstrated additive renoprotective effects in large clinical trials. We hypothesized that triple therapy with RAS/SGLT2/MR inhibitors would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression. METHODS: We performed a preclinical randomized controlled trial (PCTE0000266) in Col4a3 -deficient mice with established Alport nephropathy. Treatment was initiated late (age 6 weeks) in mice with elevated serum creatinine and albuminuria and with glomerulosclerosis, interstitial fibrosis, and tubular atrophy. We block-randomized 40 male and 40 female mice to either nil (vehicle) or late-onset food admixes of ramipril monotherapy (10 mg/kg), ramipril plus empagliflozin (30 mg/kg), or ramipril plus empagliflozin plus finerenone (10 mg/kg). Primary end point was mean survival. RESULTS: Mean survival was 63.7±10.0 days (vehicle), 77.3±5.3 days (ramipril), 80.3±11.0 days (dual), and 103.1±20.3 days (triple). Sex did not affect outcome. Histopathology, pathomics, and RNA sequencing revealed that finerenone mainly suppressed the residual interstitial inflammation and fibrosis despite dual RAS/SGLT2 inhibition. CONCLUSION: Experiments in mice suggest that triple RAS/SGLT2/MR blockade may substantially improve renal outcomes in Alport syndrome and possibly other progressive CKDs because of synergistic effects on the glomerular and tubulointerstitial compartments.
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Diabetes Mellitus Tipo 2 , Nefrite Hereditária , Insuficiência Renal Crônica , Animais , Feminino , Masculino , Camundongos , Anti-Hipertensivos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fibrose , Proteínas Facilitadoras de Transporte de Glucose/farmacologia , Proteínas Facilitadoras de Transporte de Glucose/uso terapêutico , Nefrite Hereditária/tratamento farmacológico , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Ramipril/uso terapêutico , Receptores de Mineralocorticoides , Insuficiência Renal Crônica/tratamento farmacológico , Sistema Renina-Angiotensina , Sódio , Transportador 2 de Glucose-Sódio/farmacologia , Transportador 2 de Glucose-Sódio/uso terapêuticoRESUMO
Triple-negative breast cancer (TNBC) is a malignant breast cancer. There is an urgent need for effective drugs to be developed for TNBC. Tubocapsicum anomalum (T. anomalum) has been reported to have an anti-tumor effect, and six novel withanolides were isolated from it and designated as TAMEWs. However, its anti-TNBC effect is still unknown. The results of an MTT assay indicated a higher sensitivity of TNBC cells to TAMEWs compared to other cells. TAMEWs induced apoptosis via mitochondrial dysfunction. They caused increased levels of lipid ROS and Fe2+, with downregulation of GSH and cystine uptake, and it has been confirmed that TAMEWs induced ferroptosis. Additionally, the results of Western blotting indicate that TAMEWs significantly decrease the expressions of ferroptosis-related proteins. Through further investigation, it was found that the knockdown of the p53 gene resulted in a significant reversal of ferroptosis and the expressions of its associated proteins SLC7A11, ASCT2, and GPX4. In vivo, TAMEWs suppressed TNBC growth with no obvious damage. The IHC results also showed that TAMEWs induced apoptosis and ferroptosis in vivo. Our findings provide the first evidence that TAMEWs suppress TNBC growth through apoptosis and ferroptosis.
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Sistema y+ de Transporte de Aminoácidos , Apoptose , Ferroptose , Neoplasias de Mama Triplo Negativas , Proteína Supressora de Tumor p53 , Vitanolídeos , Ferroptose/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Humanos , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Vitanolídeos/farmacologia , Vitanolídeos/química , Apoptose/efeitos dos fármacos , Feminino , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Animais , Linhagem Celular Tumoral , Camundongos , Antígenos de Histocompatibilidade Menor/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To analyze the diagnostic value of computed tomography (CT) radiomics models in differentiating gastrointestinal stromal tumors (GIST) and other mesenchymal tumors. MATERIAL AND METHODS: A retrospective analysis of clinical data from 153 patients with pathologically confirmed gastrointestinal mesenchymal tumors treated in our hospital from July 2019 to March 2024 was conducted, including 107 cases of GIST, 18 cases of leiomyoma, and 28 cases of schwannoma. LASSO regression was used for feature selection. Logistic regression and Random Forest (RF) models were established based on selected features using machine learning algorithms, with the dataset divided into training (107 cases) and validation sets (46 cases) at a 7:3 ratio. The diagnostic performance of the models was evaluated using receiver operating characteristic (ROC) curves. RESULTS: In the training set, there were significant differences between GIST and non-GIST in terms of enhancement degree, age, maximum diameter, and tumor location distribution (P<0.05). A total of 180 radiomics features were extracted using A.K software. LASSO regression reduced the high-dimensional data to 13 radiomics features. Logistic regression and RF models were established based on these 13 features. The AUC for the Logistic regression model was 0.753 in the training set and 0.582 in the validation set, while the AUC for the RF model was 0.941 in the training set and 0.746 in the validation set. The RF model showed higher diagnostic performance than the Logistic regression model (P<0.05). Decision curve analysis showed that the net benefit of the RF model in differentiating GIST was superior to classifying all patients as either GIST or non-GIST and also superior to the Logistic regression model within a probability threshold range of 20%-90%. CONCLUSION: The machine learning models based on radiomics features have good diagnostic value in predicting the pathological classification of GIST and other mesenchymal tumors, with the RF model showing superior diagnostic value compared to the Logistic regression model.
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Tumores do Estroma Gastrointestinal , Tomografia Computadorizada por Raios X , Humanos , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Feminino , Tomografia Computadorizada por Raios X/métodos , Masculino , Pessoa de Meia-Idade , Diagnóstico Diferencial , Estudos Retrospectivos , Adulto , Processamento de Imagem Assistida por Computador/métodos , Idoso , Aprendizado de Máquina , RadiômicaRESUMO
BACKGROUND: Mitogen-activated protein kinases (MAPKs) are ubiquitous signal transduction components in eukaryotes. In plants, MAPKs play an essential role in growth and development, phytohormone regulation, and abiotic stress responses. The typical recretohalophyte Limonium bicolor (Bunge) Kuntze has multicellular salt glands on its stems and leaves; these glands secrete excess salt ions from its cells to mitigate salt damage. The number, type, and biological function of L. bicolor MAPK genes are unknown. RESULTS: We identified 20 candidate L. bicolor MAPK genes, which can be divided into four groups. Of these 20 genes, 17 were anchored to 7 chromosomes, while LbMAPK18, LbMAPK19, and LbMAPK20 mapped to distinct scaffolds. Structure analysis showed that the predicted protein LbMAPK19 contains the special structural motif TNY in its activation loop, whereas the other LbMAPK members harbor the conserved TEY or TDY motif. The promoters of most LbMAPK genes carry cis-acting elements related to growth and development, phytohormones, and abiotic stress. LbMAPK1, LbMAPK2, LbMAPK16, and LbMAPK20 are highly expressed in the early stages of salt gland development, whereas LbMAPK4, LbMAPK5, LbMAPK6, LbMAPK7, LbMAPK11, LbMAPK14, and LbMAPK15 are highly expressed during the late stages. These 20 LbMAPK genes all responded to salt, drought and ABA stress. We explored the function of LbMAPK2 via virus-induced gene silencing: knocking down LbMAPK2 transcript levels in L. bicolor resulted in fewer salt glands, lower salt secretion ability from leaves, and decreased salt tolerance. The expression of several genes [LbTTG1 (TRANSPARENT TESTA OF GL1), LbCPC (CAPRICE), and LbGL2 (GLABRA2)] related to salt gland development was significantly upregulated in LbMAPK2 knockdown lines, while the expression of LbEGL3 (ENHANCER OF GL3) was significantly downregulated. CONCLUSION: These findings increase our understanding of the LbMAPK gene family and will be useful for in-depth studies of the molecular mechanisms behind salt gland development and salt secretion in L. bicolor. In addition, our analysis lays the foundation for exploring the biological functions of MAPKs in an extreme halophyte.
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Plumbaginaceae , Plumbaginaceae/metabolismo , Mitógenos/metabolismo , Estresse Salino/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estresse Fisiológico/genética , Reguladores de Crescimento de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
BACKGROUND: Mandibular defects can greatly affect patients' appearance and functionality. The preferred method to address this issue is reconstructive surgery using a fibular flap. The current personalized guide plate can improve the accuracy of osteotomy and reconstruction, but there are still some problems such as complex design process and time-consuming. Therefore, we modified the conventional template to serve the dual purpose of guiding the mandible and fibula osteotomy and facilitating the placement of the pre-bent titanium. METHODS: The surgery was simulated preoperatively using Computer-Aided Design (CAD) technology. The template and truncatable reconstruction model were produced in the laboratory using 3D printing. After pre-bending the titanium plate according to the contour, the reconstruction model was truncated and the screw trajectory was transferred to form a modified osteotomy and positioning integrative template system (MOPITS). Next, the patient underwent a composite template-guided vascularized fibula flap reconstruction of the mandible. All cases were reviewed for the total operative time and accuracy of surgery. RESULTS: The procedures involved 2-4 fibular segments in 15 patients, averaging 3 fibular segments per procedure. The osteotomy error is 1.01 ± 1.02 mm, while the reconstruction angular error is 1.85 ± 1.69°. The preoperative and postoperative data were compared, and both p > 0.05. During the same operation, implant placement was performed on four patients, with an average operative time of 487.25 ± 60.84 min. The remaining malignant tumor patients had an average operative time of 397.18 ± 73.09 min. The average postoperative hospital stay was 12.95 ± 3.29 days. CONCLUSIONS: This study demonstrates the effectiveness of MOPITS in facilitating precise preoperative planning and intraoperative execution of fibula flap reconstruction. MOPITS represents a promising and reliable tool for reconstructive surgery, particularly for inexperienced surgeons navigating the challenges of mandible defect reconstruction.
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Retalhos de Tecido Biológico , Reconstrução Mandibular , Cirurgia Assistida por Computador , Humanos , Retalhos de Tecido Biológico/cirurgia , Fíbula/cirurgia , Reconstrução Mandibular/métodos , Titânio , Cirurgia Assistida por Computador/métodos , Mandíbula/cirurgia , Osteotomia/métodosRESUMO
Trametes sanguinea Lloyd total polysaccharide (TsLTP), was obtained by water extraction and ethanol precipitation from T. sanguinea. The structural characterization of TsLTP was elucidated mutually by TsL1 and TsL2, whose mass ratio is 1: 4. TsL1 is mainly composed of mannose, glucose, galactose, and fucose, and consist of T-Linked-Fucp, T-Linked-Manp, T-Linked-Galp, 1,4-Linked-Manp, 1,4-Linked-Glcp, 1,6-Linked-Manp, 1,6-Linked-Galp, 1,3,4-Linked-Glcp, 1,4,6-Linked-Glcp and 1,3,6-Linked-Glcp, with a molar ratio of 2.1: 1.7: 1.4: 1.0: 3.6: 2.0: 8.6: 1.3: 2.2: 1.2, while TsL2 mainly comprise of glucose and consist of T-Linked-Glcp, 1,3-Linked-Glcp, 1,4-Linked-Glcp and 1,4,6-Linked-Glcp, with a molar ratio of 1.0: 2.1: 7.6: 1.4. TsLTP exhibited strong inhibitory effects on the migration, invasion, and tube formation of human umbilical vein endothelial cells (iHUVECs) and chick embryo chorioallantoic membrane (CAM) angiogenesis, whereas no inhibitory activity on human TNBC cell lines. Taken together, our study suggests that TsLTP possesses a significant inhibition of tumor microvascular activity both inâ vitro and inâ vivo. The study of TsLTP with novel monosaccharide composition and tumor microvascular inhibitory activity might be a beneficial attempt for application of polysaccharide from the genus Trametes in tumor therapy.
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Neoplasias , Trametes , Animais , Embrião de Galinha , Células Endoteliais , Humanos , Polyporaceae , Polissacarídeos/química , Polissacarídeos/farmacologiaRESUMO
Salinized soil is a major environmental stress affecting plant growth and development. Excessive salt in the soil inhibits the growth of most plants and even threatens their survival. Halophytes are plants that can grow and develop normally on saline-alkali soil due to salt tolerance mechanisms that emerged during evolution. For this reason, halophytes are used as pioneer plants for improving and utilizing saline land. Tamarisk, a family of woody halophytes, is highly salt tolerant and has high economic value. Understanding the mechanisms of salt tolerance in tamarisk and identifying the key genes involved are important for improving saline land and increasing the salt tolerance of crops. Here, we review recent advances in our understanding of the salt tolerance mechanisms of tamarisk and the economic and medicinal value of this halophyte.
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Tolerância ao Sal , Tamaricaceae , Produtos Agrícolas , Plantas Tolerantes a Sal/genética , SoloRESUMO
Objective The study aims to investigate the effects of different adaptive statistical iterative reconstruction-Vï¼ ASiR-Vï¼ and convolution kernel parameters on stability of CT auto-segmentation which is based on deep learning. Method Twenty patients who have received pelvic radiotherapy were selected and different reconstruction parameters were used to establish CT images dataset. Then structures including three soft tissue organs (bladder, bowelbag, small intestine) and five bone organs (left and right femoral head, left and right femur, pelvic) were segmented automatically by deep learning neural network. Performance was evaluated by dice similarity coefficientï¼ DSCï¼ and Hausdorff distance, using filter back projection(FBP) as the reference. Results Auto-segmentation of deep learning is greatly affected by ASIR-V, but less affected by convolution kernel, especially in soft tissues. Conclusion The stability of auto-segmentation is affected by parameter selection of reconstruction algorithm. In practical application, it is necessary to find a balance between image quality and segmentation quality, or improve segmentation network to enhance the stability of auto-segmentation.
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Processamento de Imagem Assistida por Computador , Tomografia Computadorizada por Raios X , Algoritmos , Humanos , Redes Neurais de Computação , Doses de RadiaçãoRESUMO
Microtubules are polymers composed of αß-tubulin subunits that provide structure to cells and play a crucial role in in the development and function of neuronal processes and cilia, microtubule-driven extensions of the plasma membrane that have sensory (primary cilia) or motor (motile cilia) functions. To stabilize microtubules in neuronal processes and cilia, α tubulin is modified by the posttranslational addition of an acetyl group, or acetylation. We discovered that acetylated tubulin in microtubules interacts with the membrane sphingolipid, ceramide. However, the molecular mechanism and function of this interaction are not understood. Here, we show that in human induced pluripotent stem cell-derived neurons, ceramide stabilizes microtubules, which indicates a similar function in cilia. Using proximity ligation assays, we detected complex formation of ceramide with acetylated tubulin in Chlamydomonas reinhardtii flagella and cilia of human embryonic kidney (HEK293T) cells, primary cultured mouse astrocytes, and ependymal cells. Using incorporation of palmitic azide and click chemistry-mediated addition of fluorophores, we show that a portion of acetylated tubulin is S-palmitoylated. S-palmitoylated acetylated tubulin is colocalized with ceramide-rich platforms in the ciliary membrane, and it is coimmunoprecipitated with Arl13b, a GTPase that mediates transport of proteins into cilia. Inhibition of S-palmitoylation with 2-bromo palmitic acid or inhibition of ceramide biosynthesis with fumonisin B1 reduces formation of the Arl13b-acetylated tubulin complex and its transport into cilia, concurrent with impairment of ciliogenesis. Together, these data show, for the first time, that ceramide-rich platforms mediate membrane anchoring and interaction of S-palmitoylated proteins that are critical for cilium formation, stabilization, and function.
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Tubulina (Proteína)RESUMO
LFZ-4-46, that is [2-hydroxy-1-phenyl-1,5,6,10b-tetrahydropyrazolo(5,1-a) isoquinolin-3(2H)-yl](phenyl) methanone, a tetrahydroisoquinoline derivative with a pyrazolidine moiety, was synthetically prepared. The anti-cancer mechanism of the compound has not been clarified yet. In this study, the anticancer effects and potential mechanisms of LFZ-4-46 on human breast and prostate cancer cells were explored. (a) 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazoliumbromide assay was first performed to detect the effects of LFZ-4-46 on the viability of human cancer cells. (b) Comet assay was utilized to evaluate DNA damage. (c) Cell cycle, apoptosis and mitochondrial membrane potential were detected by flow cytometry. (d) The expression of relative proteins was detected by western blotting assay. LFZ-4-46 significantly inhibited the viability of cancer cells in a time- and dose-dependent manner and had no obviously inhibitory effect on the viability of mammary epithelial MCF-10A cells. Mechanistic studies demonstrated that LFZ-4-46-induced cell apoptosis and cycle arrest were mediated by DNA damage. It caused DNA damage through activating γ-H2AX and breaking DNA strands. Further studies showed that mitogen-activated protein kinasess pathway was involved in these activated several key molecular events. Finally, LFZ-4-46 showed a potent antitumor effect in vivo. These results suggest that LFZ-4-46 may be a potential lead compound for the treatment of breast and prostate cancer.
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Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Tetra-Hidroisoquinolinas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Mechanical heart valve replacement (MHVR) is an effective method for the treatment of severe heart valve disease; however, it subjects patient to lifelong warfarin therapy after MHVR with the attendant risk of bleeding and thrombosis. Whether internet-based warfarin management reduces complications and improves patient quality of life remains unknown. OBJECTIVE: This study aimed to compare the effects of internet-based warfarin management and the conventional approach in patients who received MHVR in order to provide evidence regarding alternative strategies for long-term anticoagulation. METHODS: This was a prospective, multicenter, randomized, open-label, controlled clinical trial with a 1-year follow-up. Patients who needed long-term warfarin anticoagulation after MHVR were enrolled and then randomly divided into conventional and internet-based management groups. The percentage of time in the therapeutic range (TTR) was used as the primary outcome, while bleeding, thrombosis, and other events were the secondary outcomes. RESULTS: A total of 721 patients were enrolled. The baseline characteristics did not reach statistical differences between the 2 groups, suggesting the random assignment was successful. As a result, the internet-based group showed a significantly higher TTR (mean 0.53, SD 0.24 vs mean 0.46, SD 0.21; P<.001) and fraction of time in the therapeutic range (mean 0.48, SD 0.22 vs mean 0.42, SD 0.19; P<.001) than did those in the conventional group. Furthermore, as expected, the anticoagulation complications, including the bleeding and embolic events had a lower frequency in the internet-based group than in the conventional group (6.94% vs 12.74%; P=.01). Logistic regression showed that internet-based management increased the TTR by 7% (odds ratio [OR] 1.07, 95% CI 1.05-1.09; P<.001) and reduced the bleeding and embolic risk by 6% (OR 0.94, 95% CI 0.92-0.96; P=.01). Moreover, low TTR was found to be a risk factor for bleeding and embolic events (OR 0.87, 95% CI 0.83-0.91; P=.005). CONCLUSIONS: The internet-based warfarin management is superior to the conventional method, as it can reduce the anticoagulation complications in patients who receive long-term warfarin anticoagulation after MHVR. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1800016204; http://www.chictr.org.cn/showproj.aspx?proj=27518. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2019-032949.
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Qualidade de Vida , Varfarina , Anticoagulantes/uso terapêutico , Valvas Cardíacas , Humanos , Coeficiente Internacional Normatizado , Internet , Estudos Prospectivos , Resultado do Tratamento , Varfarina/efeitos adversosRESUMO
Toxin-antitoxin (TA) systems are comprised of a toxin and its antidote antitoxin and are widely present in bacterial and in eukaryotic systems. However, no work regarding TA systems has been reported in insects. We characterized the Kid-Kis and MazF-MazE TA systems in Spodoptera frugiperda cells and Mythimna separata embryos and observed that the Kid and MazF toxins were highly toxic. In Sf9 cells transfected with Kid plasmid and MazF alone, the apoptosis rate was 24.37% and 29.47%, respectively. Whereas the toxicity of their cognate antitoxins were limited. Both apoptosis and necrosis were induced by the two toxins. Both the Kis and MazE antitoxins partly neutralized toxicity in a dose-dependent manner, with MazE accomplishing almost full neutralization at a 1:4 toxin:antitoxin ratio, the cell survival rate was 81% and 97%, respectively. Our results indicate that MazF-MazE is a good candidate module for application in insects, such as in developing new sterile insect technique (SIT).
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Toxinas Bacterianas , Proteínas de Escherichia coli , Animais , Proteínas de Bactérias , Proteínas de Ligação a DNA , Células Sf9RESUMO
OBJECTIVE: The aim of the study was to establish a predictive postoperative nomogram for acute kidney injury (AKI) after intracranial aneurysm clipping surgery, in order to early identify patients with high postoperative AKI risk. METHODS: This is a retrospective study, which included patients who underwent intracranial aneurysm clipping surgery. Multivariate logistic regression was employed to select confound factors that associated with AKI, then incorporated into the nomogram. The predictive accuracy of the model was assessed by concordance index (C-Index). RESULTS: A total of 365 patients after intracranial aneurysm clipping surgery were enrolled in the study eventually, of which 68 (18.63%) suffered postoperative AKI, and the incidence of stage 1, stage 2 and stage 3 were 92.65% (63/68), 5.88% (4/68), and 1.47% (1/68), respectively. Univariate logistic regression revealed that high density lipoprotein (HDL), prothrombin time (PT), estimated glomerular filtration rate (eGFR), size of aneurysm ≥10 mm, and aneurysm ruptured before surgery were associated with AKI after surgery, while multivariate logistic regression showed same results as the size of aneurysm ≥10 mm and aneurysm ruptured were independent AKI risk factors. In addition, the nomogram demonstrated a good accuracy in estimating intracranial aneurysm clipping associated AKI, as a C-Index and a bootstrap-corrected one of 0.772 and 0.737, respectively. Moreover, calibration plots showed consistency with the actual presence of AKI. CONCLUSION: The novel nomogram model can serve as a promising predictive tool to improve the identification of AKI among those who underwent intracranial aneurysm clipping surgery.
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Injúria Renal Aguda/etiologia , Aneurisma Intracraniano/cirurgia , Nomogramas , Complicações Pós-Operatórias , Medição de Risco/métodos , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Injúria Renal Aguda/mortalidade , Injúria Renal Aguda/fisiopatologia , Idoso , Feminino , Taxa de Filtração Glomerular , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Fatores de RiscoRESUMO
INTRODUCTION: Innovative strategy is urgently needed to precisely discover novel natural products as lead compounds for development of new drugs against orphan diseases such as triple-negative breast cancer (TNBC). Herein, we describe a targeting pharmacophore with probe-reactivity-guided strategy for the discovery of electrophilic sesquiterpene (ES), a class of bioactive natural product. OBJECTIVE: This study aimed to identify pharmacophore, based on pharmacophore with probe-reactivity-guided strategy for precisely discovering ESs from ethyl acetate extract of Eupatorium chinense L. (EEEChL) METHODOLOGY: MTT assay combined with ultra-performance liquid chromatography (UPLC) analysis was used to identify pharmacophore. UPLC-mass spectrometry (MS) was applied to carefully compare the intrinsic reactivity characteristics of two chemoselective nucleophilic probes: glutathione (GSH) and 4-bromothiophenol (BTP) reaction with ESs. ESs was isolated and identified from EEEChL by phytochemical methods. Furthermore, stoichiometric ratio and binding site of one typical ES 8ß-[4'-hydroxytigloyloxy]-5-desoxy-8-desacyleuparotin (HDDE) reaction with BTP were studied by UPLC-quadrupole time-of-flight (Q-TOF)-MS and two-dimensional nuclear magnetic resonance (NMR). RESULTS: Eleven ESs were identified from EEEChL, MTT assay illustrated that all of the 11 ESs possess fairly good anti-TNBC activity CONCLUSIONS: Electrophilic groups were confirmed as pharmacophore of bioactive compounds contained in EEEChL. An optimised halogenated aromatic probe BTP furnishes ES-BTP conjugates that are highly conspicuous via MS by virtue of a unique isotopic bromine signature, conjugates also have a considerable separation on C18 column. The new probe-reactivity-guided strategy can effectively improve the traditional bioassay-guided approaches, and significantly increase the probability of obtaining designated bioactive compounds.
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Eupatorium , Sesquiterpenos , Neoplasias de Mama Triplo Negativas , Fracionamento Químico , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , HumanosRESUMO
In this work, we present a series of hammering tests on full-scale unit-plate ballastless tracks used for long-span bridges. There is no denying that it is a new attempt to pave ballastless tracks on high-speed railway long-span bridges; the related issues deserve to be studied, and especially the vibration characteristics. Hence, the vibration characteristics and transmission rules of the ballastless track with geotextile or rubber isolation layers are explored, and the vibration reduction effect of the rubber isolation layer is analyzed. The main conclusions are as follows: the isolation layers change vibration modes and transmission characteristics of ballastless tracks; the introduction of the rubber isolation layer makes the excited vibration frequency range of the ballastless track concentrated; and the vibrations of the ballastless track with the rubber isolation layers are stable. Moreover, the rubber isolation layer has an obvious attenuation effect on vibration transmission in ballastless track structures. When the vibration is transmitted from the rail to the bridge deck, the vibration level differences of the ballastless track with rubber isolation layers are 20 dB larger than that of the ballastless track with the geotextile isolation layers. The vibration attenuation rate of the rubber isolation layer is about ten times larger than that of geotextile isolation layer.
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Oral cancer is a common and deadly malignancy.While multidisciplinary treatment(mainly surgery)has been applied in the treatment of cancer treatment,early diagnosis and complete removal of the primary lesion are essential for a better prognosis.Raman spectroscopy is an optical technique that detects inelastic scattered light generated by the interaction of light and matter.It can detect the vibrational spectra of biochemical and biomolecular structures and tissue conformations,and can provide the "molecular fingerprint" for cells,tissues,and biological fluids.With the development of related technologies and optical instruments,Raman spectroscopy has been widely applied in medical fields.This article reviews the research advances and application of Raman spectroscopy in the diagnosis of oral cancer.
Assuntos
Neoplasias Bucais , Análise Espectral Raman , HumanosRESUMO
In this study, citrate synthase gene(CIT2), and malate synthase gene(MLS1) were successfully knocked out in ß-amyrin-producing yeast cells by using CRISPR/CAS9. The promoter of phosphoglucose isomerase gene(PGI1) was replaced by that of cytochrome c oxidase subunit â ¦a(Cox9)to weaken its expression, aiming to channel more carbon flux into the NADPH-producing pathway. The fermentation results showed that CIT2 deletion had no effect on the ß-amyrin production. Compared with the control strain, the production of ß-amyrin was increased by 1.85 times after deleting MLS1, reaching into 3.3 mg·L~(-1). By replacing the promoter of PGI1, the ß-amyrin yield was 3.75 times higher than that of the control strain, reaching up to 6.7 mg·L~(-1). This study successfully knocked out the CITT2 and MLS1 genes and weakened the PGI1 gene by using CRISPR/CAS9, which directly influenced the production of ß-amyrin and provided some reference for the the metabolic engineering of triterpernoid producing strain.
Assuntos
Engenharia Metabólica , Saccharomyces cerevisiae/genética , Etanol , FermentaçãoRESUMO
Accumulating evidence indicates that neuroinflammation contributes to the pathogenesis and exacerbation of neurodegenerative disorders, such as Alzheimer's disease (AD). Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid that regulates many pathophysiological processes including inflammation. We present evidence here that the spinster homolog 2 (Spns2), a S1P transporter, promotes microglia pro-inflammatory activation in vitro and in vivo. Spns2 knockout (Spns2KO) in primary cultured microglia resulted in significantly reduced levels of pro-inflammatory cytokines induced by lipopolysaccharide (LPS) and amyloid-beta peptide 1-42 oligomers (Aß42) when compared with littermate controls. Fingolimod (FTY720), a S1P receptor 1 (S1PR1) functional antagonist and FDA approved drug for relapsing-remitting multiple sclerosis, partially blunted Aß42-induced pro-inflammatory cytokine generation, suggesting that Spns2 promotes microglia pro-inflammatory activation through S1P-signaling. Spns2KO significantly reduced Aß42-induced nuclear factor kappa B (NFκB) activity. S1P increased, while FTY720 dampened, Aß42-induced NFκB activity, suggesting that Spns2 activates microglia inflammation through, at least partially, NFκB pathway. Spns2KO mouse brains showed significantly reduced Aß42-induced microglia activation/accumulation and reduced levels of pro-inflammatory cytokines when compared with age-matched controls. More interestingly, Spns2KO ameliorated Aß42-induced working memory deficit detected by Y-Maze. In summary, these results suggest that Spns2 promotes pro-inflammatory polarization of microglia and may play a crucial role in AD pathogenesis.