Dehydrogenative annulation under oxidizing reagent‐free conditions is an ideal strategy to construct cyclic structures. Reported herein is an unprecedented synthesis of pyrrolidine and ...tetrahydropyridine derivatives through electrochemical dehydrogenative annulation of N‐allyl amides with 1,3‐dicarbonyl compounds. The electrolytic method employs an organic redox catalyst, which obviates the need for oxidizing reagents and transition‐metal catalysts. In these reactions, the N‐allyl amides serve as a four‐atom donor to react with dimethyl malonate to give pyrrolidines by a (4+1) annulation, or with β‐ketoesters to afford tetrahydropyridine derivatives by a (4+2) annulation.
Powered by electricity: Unprecedented dehydrogenative annulation reactions of N‐allyl amides with 1,3‐dicarbonyl compounds have been developed for the efficient and modular synthesis of pyrrolidine and tetrahydropyridine derivatives. These electricity‐powered reactions employ a phenothiazine‐based organic redox catalyst, allowing the reactions to proceed under transition‐metal‐ and oxidizing‐reagent‐free conditions.
Gemcitabine-cisplatin (GP) chemotherapy is the standard first-line systemic treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In this international, double-blind, phase 3 trial ...(ClinicalTrials.gov identifier: NCT03581786), 289 patients with RM-NPC and no previous chemotherapy for recurrent or metastatic disease were randomized (1/1) to receive either toripalimab, a monoclonal antibody against human programmed death-1 (PD-1), or placebo in combination with GP every 3 weeks for up to six cycles, followed by monotherapy with toripalimab or placebo. The primary endpoint was progression-free survival (PFS) as assessed by a blinded independent review committee according to RECIST v.1.1. At the prespecified interim PFS analysis, a significant improvement in PFS was detected in the toripalimab arm compared to the placebo arm: median PFS of 11.7 versus 8.0 months, hazard ratio (HR) = 0.52 (95% confidence interval (CI): 0.36-0.74), P = 0.0003. An improvement in PFS was observed across key subgroups, including PD-L1 expression. As of 18 February 2021, a 40% reduction in risk of death was observed in the toripalimab arm compared to the placebo arm (HR = 0.603 (95% CI: 0.364-0.997)). The incidence of grade ≥3 adverse events (AEs) (89.0 versus 89.5%), AEs leading to discontinuation of toripalimab/placebo (7.5 versus 4.9%) and fatal AEs (2.7 versus 2.8%) was similar between the two arms; however, immune-related AEs (39.7 versus 18.9%) and grade ≥3 infusion reactions (7.5 versus 0.7%) were more frequent in the toripalimab arm. In conclusion, the addition of toripalimab to GP chemotherapy as a first-line treatment for patients with RM-NPC provided superior PFS compared to GP alone, and with a manageable safety profile.
Inspired by the highly parallel processing power and low energy consumption of the biological nervous system, the development of a neuromorphic computing paradigm to mimic brain‐like behaviors with ...electronic components based artificial synapses may play key roles to eliminate the von Neumann bottleneck. Random resistive access memory (RRAM) is suitable for artificial synapse due to its tunable bidirectional switching behavior. In this work, a biological spiking synapse is developed with solution processed Au@Ag core–shell nanoparticle (NP)‐based RRAM. The device shows highly controllable bistable resistive switching behavior due to the favorable Ag ions migration and filament formation in the composite film, and the good charge trapping and transport property of Au@Ag NPs. Moreover, comprehensive synaptic functions of biosynapse including paired‐pulse depression, paired‐pulse facilitation, post‐tetanic potentiation, spike‐time‐dependent plasticity, and the transformation from short‐term plasticity to long‐term plasticity are emulated. This work demonstrates that the solution processed bimetal core–shell nanoparticle‐based biological spiking synapse provides great potential for the further creation of a neuromorphic computing system.
A biological spiking synapse constructed from solution processed bimetal core–shell nanoparticle based composites is reported. The device can emulate important synaptic behaviors including spike‐rate‐dependent plasticity, spike‐time‐dependent plasticity, and transformation from short‐term plasticity to long‐term plasticity. This work demonstrates that the polymer–metal nanoparticles composites based artificial synapse have great potential for the realization of next‐generation neuromorphic computing system.
Scope
Little is known about the effect of blood vitamin D status on the gut mycobiota (i.e., fungi), a crucial component of the gut microbial ecosystem. The study aims to explore the association ...between 25‐hydroxyvitamin D 25(OH)D and gut mycobiota and to investigate the link between the identified mycobial features and blood glycemic traits.
Methods and results
The study examines the association between serum 25(OH)D levels and the gut mycobiota in the Westlake Precision Birth Cohort, which includes pregnant women with gestational diabetes mellitus (GDM). The study develops a genetic risk score (GRS) for 25(OH)D to validate the observational results. In both the prospective and cross‐sectional analyses, the vitamin D is associated with gut mycobiota diversity. Specifically, the abundance of Saccharomyces is significantly lower in the vitamin D‐sufficient group than in the vitamin D‐deficient group. The GRS of 25(OH)D is inversely associated with the abundance of Saccharomyces. Moreover, the Saccharomyces is positively associated with blood glucose levels.
Conclusion
Blood vitamin D status is associated with the diversity and composition of gut mycobiota in women with GDM, which may provide new insights into the mechanistic understanding of the relationship between vitamin D levels and metabolic health.
There is limited research conducted on the relationship between vitamin D and gut mycobiota. This study reveals that individuals with sufficient serum vitamin D exhibit a decreased abundance of fecal Saccharomyces. The results obtain from the vitamin D genetic risk score analysessupport this relationship. The study also identifies the abundance of Saccharomyces is positively associated with fasting glucose.
Background Renal impairment is common in patients with coronary artery disease and, if severe, late gadolinium enhancement (LGE) imaging for myocardial infarction (MI) evaluation cannot be performed. ...Purpose To develop a fully automatic framework for chronic MI delineation via deep learning on non-contrast material-enhanced cardiac cine MRI. Materials and Methods In this retrospective single-center study, a deep learning model was developed to extract motion features from the left ventricle and delineate MI regions on nonenhanced cardiac cine MRI collected between October 2015 and March 2017. Patients with chronic MI, as well as healthy control patients, had both nonenhanced cardiac cine (25 phases per cardiac cycle) and LGE MRI examinations. Eighty percent of MRI examinations were used for the training data set and 20% for the independent testing data set. Chronic MI regions on LGE MRI were defined as ground truth. Diagnostic performance was assessed by analysis of the area under the receiver operating characteristic curve (AUC). MI area and MI area percentage from nonenhanced cardiac cine and LGE MRI were compared by using the Pearson correlation, paired
test, and Bland-Altman analysis. Results Study participants included 212 patients with chronic MI (men, 171; age, 57.2 years ± 12.5) and 87 healthy control patients (men, 42; age, 43.3 years ± 15.5). Using the full cardiac cine MRI, the per-segment sensitivity and specificity for detecting chronic MI in the independent test set was 89.8% and 99.1%, respectively, with an AUC of 0.94. There were no differences between nonenhanced cardiac cine and LGE MRI analyses in number of MI segments (114 vs 127, respectively;
= .38), per-patient MI area (6.2 cm
± 2.8 vs 5.5 cm
± 2.3, respectively;
= .27; correlation coefficient,
= 0.88), and MI area percentage (21.5% ± 17.3 vs 18.5% ± 15.4;
= .17; correlation coefficient,
= 0.89). Conclusion The proposed deep learning framework on nonenhanced cardiac cine MRI enables the confirmation (presence), detection (position), and delineation (transmurality and size) of chronic myocardial infarction. However, future larger-scale multicenter studies are required for a full validation. Published under a CC BY 4.0 license.
See also the editorial by Leiner in this issue.
The accurate prediction of fatigue performance is of great engineering significance for the safe and reliable service of components. However, due to the complexity of influencing factors on fatigue ...behavior and the incomplete understanding of the fatigue failure mechanism, it is difficult to correlate well the influence of various factors on fatigue performance. Machine learning could be used to deal with the association or influence of complex factors due to its good nonlinear approximation and multi-variable learning ability. In this paper, the gradient boosting regression tree model, the long short-term memory model and the polynomial regression model with ridge regularization in machine learning are used to predict the fatigue strength of a nickel-based superalloy GH4169 under different temperatures, stress ratios and fatigue life in the literature. By dividing different training and testing sets, the influence of the composition of data in the training set on the predictive ability of the machine learning method is investigated. The results indicate that the machine learning method shows great potential in the fatigue strength prediction through learning and training limited data, which could provide a new means for the prediction of fatigue performance incorporating complex influencing factors. However, the predicted results are closely related to the data in the training set. More abundant data in the training set is necessary to achieve a better predictive capability of the machine learning model. For example, it is hard to give good predictions for the anomalous data if the anomalous data are absent in the training set.
Epicardial adipose tissue (EAT) contributes to the pathophysiological process of coronary artery disease (CAD). The expression profiles of long non-coding RNAs (lncRNA) in EAT of patients with CAD ...have not been well characterized. We conducted high-throughput RNA sequencing to analyze the expression profiles of lncRNA in EAT of patients with CAD compared to patients without CAD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were executed to investigate the principal functions of the significantly dysregulated mRNAs. We confirmed a dysregulated intergenic lncRNA (lincRNA) (LINC00968) by real-time quantitative PCR (RT-qPCR). Subsequently, we constructed a ceRNA network associated with LINC00968, which included 49 mRNAs. Compared with the control group, lncRNAs and genes of EAT in CAD were characterized as metabolic active and pro-inflammatory profiles. The sequencing analysis detected 2539 known and 1719 novel lncRNAs. Then, we depicted both lncRNA and gene signatures of EAT in CAD, featuring dysregulation of genes involved in metabolism, nuclear receptor transcriptional activity, antigen presentation, chemokine signaling, and inflammation. Finally, we identified a ceRNA network as candidate modulator in EAT and its potential role in CAD. We showed the expression profiles of specific EAT lncRNA and mRNA in CAD, and a selected non-coding associated ceRNA regulatory network, which taken together, may contribute to a better understanding of CAD mechanism and provide potential therapeutic targets.Trial registration Chinese Clinical Trial Registry, No. ChiCTR1900024782.
This study aims to research on the mechanical and frost resistance properties of pressed concrete blocks mixed with the polymeric aluminum chloride (PAC) waste residue. Experimental studies on the ...activity index of volcanic ash, mechanical property, frost resistance and microstructure of pressed concrete blocks mixed with PAC waste residue were carried out. The results show that the activity index of volcanic ash of PAC waste residue reaches 74.96% at a particle size of 0.075 mm or less and a curing age of 28 days. Based on results of mechanical property tests, the optimum dosage of PAC waste residue is 15%, at which time the compressive and bending strength only decreases by 14.57% and 15.84%. Based on results of frost resistance tests, the optimum dosage of PAC waste residue for pressed concrete blocks is 10%. After 50 freeze-thaw cycles, when the dosage of PAC waste residue is 10%, the strength loss rate is only 3.04%. XRD and SEM tests show that PAC waste residue participates in chemical reactions. With a small amount of PAC waste residue, the structure of the specimen remains dense and therefore the strength decreases less.
Protein glycosylation is an extensively studied field, with the most studied forms being oxygen or nitrogen-linked N-acetylglucosamine (O-GlcNAc or N-GlcNAc) glycosylation. Particular residues on ...proteins are targeted by O-GlcNAcylation, which is among the most intricate post-translational modifications. Significantly contributing to an organism's proteome, it influences numerous factors affecting protein stability, function, and subcellular localization. It also modifies the cellular function of target proteins that have crucial responsibilities in controlling pathways related to the central nervous system, cardiovascular homeostasis, and other organ functions. Under conditions of acute stress, changes in the levels of O-GlcNAcylation of these proteins may have a defensive function. Nevertheless, deviant O-GlcNAcylation nullifies this safeguard and stimulates the advancement of several ailments, the prognosis of which relies on the cellular milieu. Hence, this review provides a concise overview of the function and comprehension of O-GlcNAcylation in ischemia diseases, aiming to facilitate the discovery of new therapeutic targets for efficient treatment, particularly in patients with diabetes.
Mesoporous silica nanoparticles (MSNs) are recognized as a prime example of nanotechnology applied in the biomedical field, due to their easily tunable structure and composition, diverse surface ...functionalization properties, and excellent biocompatibility. Over the past two decades, researchers have developed a wide variety of MSNs-based nanoplatforms through careful design and controlled preparation techniques, demonstrating their adaptability to various biomedical application scenarios. With the continuous breakthroughs of MSNs in the fields of biosensing, disease diagnosis and treatment, tissue engineering, etc., MSNs are gradually moving from basic research to clinical trials. In this review, we provide a detailed summary of MSNs in the biomedical field, beginning with a comprehensive overview of their development history. We then discuss the types of MSNs-based nanostructured architectures, as well as the classification of MSNs-based nanocomposites according to the elements existed in various inorganic functional components. Subsequently, we summarize the primary purposes of surface-functionalized modifications of MSNs. In the following, we discuss the biomedical applications of MSNs, and highlight the MSNs-based targeted therapeutic modalities currently developed. Given the importance of clinical translation, we also summarize the progress of MSNs in clinical trials. Finally, we take a perspective on the future direction and remaining challenges of MSNs in the biomedical field.
PDF
