Folic acid-functionalized drug delivery platform of resveratrol based on Pluronic 127/D-α-tocopheryl polyethylene glycol 1000 succinate mixed micelles

A folic acid (FA)-functionalized drug vehicle platform based on Pluronic 127 (P127)/D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles was orchestrated for an effective delivery of the model drug resveratrol in order to address the problem of poor water solubility and rapid metabolism of resveratrol and improve its targeted accumulation at tumor site. The FA-decorated mixed micelles were prepared using thin-film hydration method and optimized by central composite design approach. The micelles were also characterized in terms of size and morphology, drug entrapment efficiency and in vitro release profile. In addition, the cytotoxicity and cell uptake of the micelles were evaluated in folate receptor-overexpressing MCF-7 cell line. In vivo pharmacokinetic and biodistribution studies were also performed. The average size of the micelles was ~20 nm with a spherical shape and high encapsulation efficiency (99.67%). The results of fluorescence microscopy confirmed the targeting capability of FA-conjugated micelles in MCF-7 cells. FA-modified micelles exhibited superior pharmacokinetics in comparison with that of solution. Further, the low accumulation of resveratrol-loaded FA micelles formulation in the heart and kidney avoided toxicity of these vital organs. It could be concluded that folate-modified P127/TPGS mixed micelles might serve as a potential delivery platform for resveratrol

Feature selection and risk prediction for diabetic patients with ketoacidosis based on MIMIC-IV

BackgroundDiabetic ketoacidosis (DKA) is a frequent acute complication of diabetes mellitus (DM). It develops quickly, produces severe symptoms, and greatly affects the lives and health of individuals with DM.This article utilizes machine learning methods to examine the baseline characteristics that significantly contribute to the development of DKA. Its goal is to identify and prevent DKA in a targeted and early manner.MethodsThis study selected 2382 eligible diabetic patients from the MIMIC-IV dataset, including 1193 DM patients with ketoacidosis and 1186 DM patients without ketoacidosis. A total of 42 baseline characteristics were included in this research. The research process was as follows: Firstly, important features were selected through Pearson correlation analysis and random forest to identify the relevant physiological indicators associated with DKA. Next, logistic regression was used to individually predict DKA based on the 42 baseline characteristics, analyzing the impact of different physiological indicators on the experimental results. Finally, the prediction of ketoacidosis was performed by combining feature selection with machine learning models include logistic regression, XGBoost, decision tree, random forest, support vector machine, and k-nearest neighbors classifier.ResultsBased on the importance analysis conducted using different feature selection methods, the top five features in terms of importance were identified as mean hematocrit (haematocrit_mean), mean hemoglobin (haemoglobin_mean), mean anion gap (aniongap_mean), age, and Charlson comorbidity index (charlson_comorbidity_index). These features were found to have significant relevance in predicting DKA. In the individual prediction using logistic regression, these five features have been proven to be effective, with F1 scores of 1.000 for hematocrit mean, 0.978 for haemoglobin_mean, 0.747 for age, 0.692 for aniongap_mean and 0.666 for charlson_comorbidity_index. These F1 scores indicate the effectiveness of each feature in predicting DKA, with the highest score achieved by mean hematocrit. In the prediction of DKA using machine learning models, including logistic regression, XGBoost, decision tree, and random forest demonstrated excellent results, achieving an F1 score of 1.000. Additionally, by applying feature selection techniques, noticeable improvements were observed in the experimental performance of the support vector machine and k-nearest neighbors classifier.ConclusionThe study found that hematocrit, hemoglobin, anion gap, age, and Charlson comorbidity index are closely associated with ketoacidosis. In clinical practice, these five baseline characteristics should be given with the special attention to achieve early detection and treatment, thus reducing the incidence of the disease

Modeling and Analysis of Truck Mounted Concrete Pump Boom by Virtual Prototyping

By far there is lack of research on different working conditions between rigid and flexible dynamics of truck mounted concrete pump booms. First a 3D model has been established by using virtual prototyping technology of a 37 m long boom in Pro/Engineering software. Then the rigid body simulation model has been built. Next modal superimposition method is adopted to change the 4 rigid body booms into flexible ones. Kinematics law and dynamic characteristics of 4 common working conditions had been studied then. Next tip displacement and the first boom hydraulic cylinder force of the 4 working conditions between rigid and flexible models have been researched. Furthermore the first natural frequencies of the structure have been calculated. The results show that the frequency of the horizontal condition has the lowest of all and the roof condition has the largest of all. Besides the cylinder forces of the flexible model are larger than the corresponding rigid ones because of the flexible boom vibration. Finally an experiment has been done on a boom test rig which proved that the established simulation model is reasonable and the frequency results are correct. All of these provide design reference to mechanical manipulator as well as reducing product development cost of such mechanism

Overexpression of MYCT1 Inhibits Proliferation and Induces Apoptosis in Human Acute Myeloid Leukemia HL-60 and KG-1a Cells in vitro and in vivo

MYC target 1 (MYCT1), a direct target gene of c-Myc, is a novel candidate tumor suppressor gene first cloned from laryngeal squamous cell carcinoma. The downregulation of MYCT1 has been reported to be associated with carcinogenesis. However, the role of MYCT1 in the development and progress of acute myeloid leukemia (AML) remains unknown and requires further investigation. In this study, we first found that the expression level of MYCT1 was significantly lower in the bone marrow (BM) derived from AML patients than that from healthy individuals. The low expression of MYCT1 in AML BM may be due to the hypermethylation in its promoter. MYCT1 expression was strongly associated with French–American–British classifications of AML. The low expression level of MYCT1 was more often observed in patients of M1, M5 and M6 types. In vitro, lentiviral particles carrying the complete CDS of MYCT1 gene were used to mediate the forced overexpression of MYCT1 in two AML cell lines, HL-60 and KG-1a. MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. Finally, in BALB/c nude mice bearing xenograft tumors generated by HL-60 and KG-1a cells, we noted that the intratumoral injection of MYCT1 lentivirus repressed tumor growth and led to massive apoptosis. In summary, our results reveal that MYCT1’s promoter is hypermethylated and its expression is downregulated in the BM of AML patients. MYCT1 plays a tumor-suppressive role, and it may serve as a promising target for the genetic therapeutic strategy in treating AML

Rapid Degradation of Hfq-Free RyhB in<i>Yersinia pestis</i>by PNPase Independent of Putative Ribonucleolytic Complexes

The RNA chaperone Hfq in bacteria stabilizes sRNAs by protecting them from the attack of ribonucleases. Upon release from Hfq, sRNAs are preferably degraded by PNPase. PNPase usually forms multienzyme ribonucleolytic complexes with endoribonuclease E and/or RNA helicase RhlB to facilitate the degradation of the structured RNA. However, whether PNPase activity on Hfq-free sRNAs is associated with the assembly of RNase E or RhlB has yet to be determined. Here we examined the roles of the main endoribonucleases, exoribonucleases, and ancillary RNA-modifying enzymes in the degradation ofY. pestisRyhB in the absence of Hfq. Expectedly, the transcript levels of both RyhB1 and RyhB2 increase only after inactivating PNPase, which confirms the importance of PNPase in sRNA degradation. By contrast, the signal of RyhB becomes barely perceptible after inactivating of RNase III, which may be explained by the increase in PNPase levels resulting from the exemption ofpnpmRNA from RNase III processing. No significant changes are observed in RyhB stability after deletion of either the PNPase-binding domain of RNase E orrhlB. Therefore, PNPase acts as a major enzyme of RyhB degradation independent of PNPase-containing RNase E and RhlB assembly in the absence of Hfq.</jats:p

CDKL3 shapes immunosuppressive tumor microenvironment and initiates autophagy in esophageal cancer

BackgroundCDKL3 has been associated with the prognosis of several tumors. However, the potential role of CDKL3 in immunotherapy and the tumor microenvironment (TME) in esophageal carcinoma (ESCA) remains unclear.MethodsIn this study, Cox regression analysis was used to assess the predictive value of CDKL3 for ESCA outcomes. We systematically correlated CDKL3 with immunological features in the TME. The role of CDKL3 in predicting the efficacy of immunotherapy was also analyzed. Correlation analysis, Cox analysis and LASSO Cox regression were used to construct the CDKL3-related autophagy (CrA) risk score model. The relationship between CDKL3 expression and postoperative pathological complete response (pCR) rate in esophageal squamous cell carcinoma (ESCC) patients undergoing neoadjuvant chemoradiotherapy (nCRT) was evaluated using Immunohistochemical staining (IHC). The relationship between CDKL3 expression and autophagy induction was confirmed by immunofluorescence staining and western blot, and the effect of CDKL3 expression on macrophage polarization was verified by flow cytometry.ResultsHigh expression of CDKL3 was found in ESCA and was associated with poor prognosis in ESCA. Moreover, CDKL3 expression was negatively correlated with tumor-infiltrating immune cells (TIICs), the integrality of the cancer immunity cycles, and anti-tumor signatures, while CDKL3 expression was positively correlated with suppressive TME-related chemokines and receptors, immune hyperprogressive genes, and suppressive immune checkpoint, resulting in immunosuppressive TME formation in ESCA. An analysis of immunotherapy cohorts of the ESCA and pan-cancer showed a better response to immunotherapy in tumor patients with lower CDKL3 levels. The CrA risk score model was constructed and validated to accurately predict the prognosis of ESCA. Notably, the CrA risk score of ESCA patients was significantly positively correlated with M2 macrophages. Furthermore, knockdown CDKL3 in KYSE150 cells could inhibit autophagy induction and M2 macrophage polarization. And, radiation could downregulate CDKL3 expression and autophagy induction, while ESCC patients with high CDKL3 expression had a significantly lower response rate after nCRT than those with low CDKL3 expression.ConclusionCDKL3 may play an important role in anti-tumor immunity by regulating autophagy to promote the formation of immunosuppressive TME, thus playing a critical role in the prognosis of ESCA

Festividades sazonais e comunitárias no currículo em educação de infância

Relatório apresentado para a obtenção do grau de Mestre em Educação Pré-EscolarO presente relatório engloba o percurso formativo ao longo da prática de ensino supervisionada em contexto de Creche e Jardim de Infância, refletindo as aprendizagens realizadas e as dificuldades sentidas, assim como a emergência de questões decorrentes da prática. A problemática estudada, centrada nas valências de Creche e de Jardim de Infância, refere-se à Importância das festividades sazonais e comunitárias num currículo em Educação de Infância. A partir da abordagem do significado e importância das festividades feita por alguns autores, o presente estudo tem como objetivo geral compreender a importância atribuída pelas educadoras de infância à celebração das festividades, quais as datas que privilegiam, os motivos que justificam essas escolhas, assim como as implicações que identificam para as aprendizagens e para o desenvolvimento infantil. O estudo, qualitativo e de carácter exploratório, utiliza para a recolha de dados a técnica do inquérito por entrevista. Conclui-se que nas duas valências as profissionais integram no trabalho educativo a comemoração de determinados dias festivos, garantindo a sua importância e considerando que promovem aprendizagens em todas as áreas do desenvolvimento.The present report covers the formative path along the supervised teaching practice in the context of Nursery and Kindergarten, reflecting the learning achieved and difficulties experienced as well as the emergence of issues arising from practice. The studied problem, focusing on the valences of Nursery and Preschool, refers to the importance of seasonal and community festivities in a curriculum in Childhood Education. From the approach to the meaning and importance of the festivities by some authors, this study has the overall objective of understanding the importance given by the kindergarten teachers to the celebration of the festivities, which dates that privilege, the reasons for these choices, as well as identifying the implications for learning and child development. The study, of qualitative and exploratory nature, uses for data collection technique interview survey. It is concluded that on both valences, the kindergarten teachers integrate on the educational work the celebration of certain festive days, ensuring their importance as promoters of learning in all areas of development.info:eu-repo/semantics/publishedVersio

Transcriptome Analysis of Arabidopsis thaliana in Response to Plasmodiophora brassicae during Early Infection

Clubroot disease is a serious threat to cruciferous plants worldwide, especially to oilseed rape. However, knowledge on pathogenic molecular mechanisms and host interaction is limited. We presume that the recognition between Arabidopsis thaliana and Plasmodiophora brassicae occurs at the early stage of infection and within a relatively short period. In this study, we demonstrated changes on gene expression and pathways in A. thaliana during early infection with P. brassicae using transcriptome analysis. We identified 1,903 and 1,359 DEGs at 24 and 48 h post-inoculation (hpi), respectively. Flavonoids and the lignin synthesis pathways were enhanced, glucosinolates, terpenoids, and proanthocyanidins accumulated and many hormonal- and receptor-kinase related genes were expressed, caused by P. brassicae infection during its early phase. Therefore, the early interaction between A. thaliana and P. brassicae plays an important role in the entire infection process. The results provide a new contribution to a better understanding of the interaction between host plants and P. brassicae, as well as the development of future measures for the prevention of clubroot

RNA interference of Aspergillus flavus in response to Aspergillus flavus partitivirus 1 infection

RNA interference (RNAi) is one of the important defense responses against viral infection, but its mechanism and impact remain unclear in mycovirus infections. In our study, reverse genetics and virus-derived small RNA sequencing were used to show the antiviral responses of RNAi components in Aspergillus flavus infected with Aspergillus flavus partitivirus 1 (AfPV1). qRT-PCR revealed that AfPV1 infection induced the expression of the RNAi components in A. flavus compared with noninfected A. flavus. Knock mutants of each RNAi component were generated, but the mutants did not exhibit any obvious phenotypic changes compared with the A. flavus parental strain. However, after AfPV1 inoculation, production of AfPV1 was significantly less than in the parental strain. Furthermore, sporulation was greater in each AfPV1-infected mutant compared with the AfPV1-infected parental A. flavus. We also investigated the sensitivity of virus-free and AfPV1-infected RNAi mutants and the parental strain to cell wall stress, osmotic stress, genotoxic stress, and oxidative stress. The mutants of DCLs and AGOs infected by AfPV1 displayed more changes than RDRP mutants in response to the first three stresses. Small RNA sequencing analysis suggested that AfPV1 infection reduced the number of unique reads of sRNA in A. flavus, although there were many vsiRNA derived from the AfPV1 genome. GO term and KEGG pathway analyses revealed that the functions of sRNA affected by AfPV1 infection were closely related to vacuole production. These results provide a better understanding of the functional role of RNAi in the impact of AfPV1 on the hypovirulence of A. flavus