Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.

Diagnosis of cardiac abnormalities based on phonocardiogram using a novel fuzzy matching feature extraction method.

BACKGROUND: The diagnosis of cardiac abnormalities based on heart sound signal is a research hotspot in recent years. The early diagnosis of cardiac abnormalities has a crucial significance for the treatment of heart diseases. METHODS: For the sake of achieving more practical clinical applications of automatic recognition of cardiac abnormalities, here we proposed a novel fuzzy matching feature extraction method. First of all, a group of Gaussian wavelets are selected and then optimized based on a template signal. Convolutional features of test signal and the template signal are then computed. Matching degree and matching energy features between template signal and test signal in time domain and frequency domain are then extracted. To test performance of proposed feature extraction method, machine learning algorithms such as K-nearest neighbor, support vector machine, random forest and multilayer perceptron with grid search parameter optimization are constructed to recognize heart disease using the extracted features based on phonocardiogram signals. RESULTS: As a result, we found that the best classification accuracy of random forest reaches 96.5% under tenfold cross validation using the features extracted by the proposed method. Further, Mel-Frequency Cepstral Coefficients of phonocardiogram signals combing with features extracted by our algorithm are evaluated. Accuracy, sensitivity and specificity of integrated features reaches 99.0%, 99.4% and 99.7% respectively when using support vector machine, which achieves the best performance among all reported algorithms based on the same dataset. On several common features, we used independent sample t-tests. The results revealed that there are significant differences (p < 0.05) between 5 categories. CONCLUSION: It can be concluded that our proposed fuzzy matching feature extraction method is a practical approach to extract powerful and interpretable features from one-dimensional signals for heart sound diagnostics and other pattern recognition task.

Digital signal extraction approach for cardiotocography image.

BACKGROUND AND OBJECTIVE: Cardiotocography, commonly called CTG, has become an indispensable auxiliary examination in obstetrics. Generally, CTG is provided in the form of a report, so the fetal heart rate and uterine contraction signals have to be extracted from the CTG images. However, most studies focused on reading data for a single curve, and the influence of complex backgrounds was usually not considered. METHODS: An efficient signal extraction method was proposed for the binary CTG images with complex backgrounds. Firstly, the images' background grids and symbol noise were removed by templates. Then a morphological method was used to fill breakpoints of curves. Moreover, the projection map was utilized to localize the area and the starting and ending positions of curves. Subsequently, data of the curves were extracted by column scanning. Finally, the amplitude of the extracted signal was calibrated. RESULTS: This study had tested 552 CTG images simulated using the CTU-UHB database. The correlation coefficient between the extracted and original signals was 0.9991 ± 0.0030 for fetal heart rate and 0.9904 ± 0.0208 for uterine contraction, and the mean absolute error of fetal heart rate and uterine contraction were 2.4658 ± 1.8446 and 1.8025 ± 0.6155, and the root mean square error of fetal heart rate and uterine contraction were 4.2930 ± 2.9771 and 2.5214 ± 0.9640, respectively. After being validated using 293 clinical authentic CTG images, the extracted signals were remarkably similar to the original counterparts, and no significant differences were observed. CONCLUSIONS: The proposed method could effectively extract the fetal heart rate and uterine contraction signals from the binary CTG images with complex backgrounds.

N6-methyladenosine regulates maternal RNA maintenance in oocytes and timely RNA decay during mouse maternal-to-zygotic transition.

N6-methyladenosine (m6A) and its regulatory components play critical roles in various developmental processes in mammals. However, the landscape and function of m6A in early embryos remain unclear owing to limited materials. Here we developed a method of ultralow-input m6A RNA immunoprecipitation followed by sequencing to reveal the transcriptome-wide m6A landscape in mouse oocytes and early embryos and found unique enrichment and dynamics of m6A RNA modifications on maternal and zygotic RNAs, including the transcripts of transposable elements MTA and MERVL. Notably, we found that the maternal protein KIAA1429, a component of the m6A methyltransferase complex, was essential for m6A deposition on maternal mRNAs that undergo decay after zygotic genome activation and MTA transcripts to maintain their stability in oocytes. Interestingly, m6A methyltransferases, especially METTL3, deposited m6A on mRNAs transcribed during zygotic genome activation and ensured their decay after the two-cell stage, including Zscan4 and MERVL. Together, our findings uncover the essential functions of m6A in specific contexts during the maternal-to-zygotic transition, namely ensuring the stability of mRNAs in oocytes and the decay of two-cell-specific transcripts after fertilization.

Chemical modification of ovatodiolide revealed a promising amino-prodrug with improved pharmacokinetic profile.

Stepwise modification of ovatodiolide revealed a prodrug, NMP-diepoxyovatodiolide, which can provide sustained release of an active compound, substantial metabolic stability and a unique accumulation profile in the liver. Besides, NMP-diepoxyovatodiolide demonstrated therapeutic benefits in an acute autoimmune hepatitis mouse model and a broad safety window. Therefore, NMP-diepoxyovatodiolide is a very promising candidate for further development of liver-related drugs.

Rapid Construction of the Scaffold of Quorumolide A Enabled by a Tandem ROM/RCM Strategy and a Tandem Oxidative Cyclization Strategy.

A synthetically challenging framework in the plant-derived cembranoid quorumolide A was established in a seven-step sequence featuring a ring-opening/-closing metathesis cascade reaction to construct the fused butenolide ring and the 14-membered macroring in a single step. The utilization of a tandem oxidative cyclization strategy is the key to build the tetrahydro-2H-pyran moiety.

Ovatodiolides: Scalable Protection-Free Syntheses, Configuration Determination, and Biological Evaluation against Hepatic Cancer Stem Cells.

A concise, scalable, six-step (longest linear sequence) synthetic route to ovatodiolide scaffolds was developed for the first time. This protecting-group-free route features tandem ring-opening metathesis/ring-closing metathesis reactions to install the macrocycle-fused butenolide ring and a tandem allylboration/lactonization to build the α-methylene-γ-lactone. Our syntheses have enabled the determination of the hitherto unknown stereochemical configurations of this family of natural products. Preliminary tests of structure-activity relationships were conducted with four natural ovatodiolides and three analogues. Further assays indicated that the synthetic natural product isoovatodiolide can significantly decrease the population of hepatic cancer stem cells and reduce the tumorsphere-forming capability of HepG2 cells.