An efficiency-oriented innovation analysis will enhance the understanding of the operational quality related to the transformation process of limited innovation investments for improving innovation outputs. The purpose of this study was to measure the static-dynamic efficiency of agricultural science, technology, and innovation (ASTI) and identify the efficiency determinants across the Group of Twenty (G20) countries. First, the static comprehensive efficiency of ASTI was measured employing the Data Envelopment Analysis (DEA)-BCC model, and some of the binding constraints to higher efficiency were investigated. Then, we applied the DEA-Malmquist index model to calculate the efficiency change of ASTI in certain periods and decomposed the sources of efficiency change. Finally, the G20 countries were classified into four-level clusters based on the rankings of efficiency measurement and capability evaluation of ASTI to locate the type of ASTI level and identify the type change in both the efficiency and capability. The empirical results indicate the following. (1) The efficiency range of the G20 developing countries was relatively larger than the G20 developed countries. The G20 developed countries showed a fluctuating downward trend, while the G20 developing countries showed an upward trend from the perspective of efficient proportion. The R&D expenditure redundancy and the agricultural journal papers deficiency were the main binding constraints to the higher efficiency of ASTI. (2) The total factor productivity change (TFPC) of ASTI showed an alternating trend of “decline–growth–continuous decline–growth recovery”, where the G20 developed countries experienced “growth–decline–growth” and the G20 developing countries underwent a fluctuating upward trend. The TFPC of ASTI in most G20 countries was primarily due to technological change. (3) The G20 developed countries usually had advantages in capacity, while the G20 developing countries performed better in efficiency.
Small molecule inhibitor of the bromodomain and extraterminal domain (BET) family proteins is a promising option for cancer treatment. However, current BET inhibitors are limited by their potency or oral bioavailability. Here we report the discovery and characterization of NHWD-870, a BET inhibitor that is more potent than three major clinical stage BET inhibitors BMS-986158, OTX-015, and GSK-525762. NHWD-870 causes tumor shrinkage or significantly suppresses tumor growth in nine xenograft or syngeneic models. In addition to its ability to downregulate c-MYC and directly inhibit tumor cell proliferation, NHWD-870 blocks the proliferation of tumor associated macrophages (TAMs) through multiple mechanisms, partly by reducing the expression and secretion of macrophage colony-stimulating factor CSF1 by tumor cells. NHWD-870 inhibits CSF1 expression through suppressing BRD4 and its target HIF1α. Taken together, these results reveal a mechanism by which BRD4 inhibition suppresses tumor growth, and support further development of NHWD-870 to treat solid tumors.
Flame retardants (FRs) have raised public concerns because of their environmental persistence and negative impacts on human health. Recent evidence has revealed that many FRs exhibit reproductive toxicities and transgenerational impacts, whereas the toxic effects of FRs on germ cells remain barely explored. Here we investigated the multigenerational effects of three flame retardants (TBBPA, TCEP and TCPP) on germ cell development in Caenorhabditis elegans, and examined the germ cell mutagenicity of these FRs by using whole genome sequencing. Parental exposure to three FRs markedly increased germ cell apoptosis, and impeded oogenesis in F1-F6 offspring. In addition, the double-increased mutation frequencies observed in progeny genomes uncover the mutagenic actions of FRs on germ cells. Analysis of mutation spectra revealed that these FRs predominantly induced point mutations at A:T base pairs, whereas both small and large indels were almost unaffected. These results revealed the long-term effects of FRs on development and genomic stability of germ cells, which may pose risks to environmental organisms and human reproductive health. Taken together, our findings suggest that germ cell mutagenicity should be carefully examined for the environmental risk assessment of FRs and other emerging pollutants.
Abstract The clinical incidence of sjogren's syndrome combined with gastroesophageal reflux disease is high. Existing observational studies have shown inconsistent results in the association between gastroesophageal reflux disease (GERD) and Sjogren's syndrome (SS).We observed that the symptoms of SS patients also improved after receiving GERD-related treatment. Therefore, we aimed to investigate the relationship between GERD and SS through a bidirectional two-sample Mendelian randomization (MR) study. Independent SNPs associated with GERD and SS were selected from a genome-wide association study (GWAS) as instrumental variables to conduct a bidirectional two-sample Mendelian analysis of GERD and SS. Genetic data were obtained from two databases for the following two outcomes: Gastroesophageal reflux (IEU Open GWAS) [sample size = 602,604 (patients = 129,080; nonpatients = 473,524)] and SS (FinnGen) [sample size = 392,423 (patients = 2,495; nonpatients = 389,928)]. Statistical methods for the MR analysis included the inverse-variance weighting method, weighted median, simple mode and weighted mode, as well as heterogeneity and sensitivity analyses using the Cochran Q statistic, MR‒Egger regression, outlier detection methods (MR-PRESSO). In addition, Steiger Test was conducted to test the direction of causality. MR analysis showed a positive correlation between GERD and SS risk [odds ratio (OR) = 1.3279 (95% confidence interval 1.0312–1.7099, P = 0.0280)]. However, in contrast, no significant causal effect of SS on GERD was observed [OR = 1.0024 (95% CI 0.9651–1.0412; P = 0.8995)]. This bidirectional two-sample Mendelian randomization study confirmed a causal relationship between SS and GERD, and suggested that GERD is a risk factor for SS, while SS does not affect GERD.
Sargassum vachellianum is an ecologically important brown alga. It is China-specific and mainly inhabits in rocky intertidal zones in southeast coastal waters of China. In this study, we sequenced its circular complete chloroplast genome (cpDNA) and compared it with cpDNAs from S. vachellianum, S. horneri and S. thunbergii. The complete S. vachellianum cpDNA was 124,582 bp in length and consisted of a pair of inverted repeats (IRs) of 5435 bp, a large single copy (LSC) region of 73,721 bp and a small single copy (SSC) region of 39,991 bp. Totally 160 genes were predicted, including 132 protein-coding genes, four ribosomal RNA genes and 24 tRNA genes, and the coding sequences contributed 77.48% of the whole genome. In addition, 25 SSR loci and 28 highly variable regions were identified from the S. vachellianum cpDNA, which might be used as candidates for developing DNA barcode markers of Sargassum species. The phylogenetic tree based on datasets of all the plastid-encoded proteins demonstrated that species of S. subgenus Bactrophycus were firstly combined and then clustered with S. vachellianum, which belongs to S. subgen. Sargassum. The results indicate that the chloroplast genomes are good resources for developing new DNA markers for taxonomy, and also as tools for evolutionary research of closely related species in future studies.
Abstract The stromal microenvironment has been shown to affect the infiltration of esophageal carcinoma (ESCA), which is linked to prognosis. However, the complicated mechanism of how infiltration is influenced by the stromal microenvironment is not well-defined. In this study, a stromal activation classifier was established with ridge cox regression to calculate stroma scores for training (n = 182) and validation cohorts (n = 227) based on the stroma-related 32 hub genes identified by sequential bioinformatics algorithms. Patients with high stromal activation were associated with high T stage and poor prognosis in both esophagus adenocarcinoma and esophagus squamous cell carcinoma. Besides, comprehensive multi-omics analysis was used to outline stromal characterizations of 2 distinct stromal groups. Patients with activated tumor stoma showed high stromal cell infiltration (fibroblasts, endothelial cells, and monocyte macrophages), epithelial-mesenchymal transition, tumor angiogenesis and M2 macrophage polarization (CD163 and CD206). Tumor mutation burden of differential stromal groups was also depicted. In addition, a total of 6 stromal activation markers in ESCA were defined and involved in the function of carcinoma-associated fibroblasts that were crucial in the differentiation of distinct stromal characterizations. Based on these studies, a practical classifier for the stromal microenvironment was successfully proposed to predict the prognosis of ESCA patients.
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