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The gut microbiota modulate host biology in numerous ways, but little is known about the molecular mediators of these interactions. Previously, we found a widely distributed family of nonribosomal peptide synthetase gene clusters in gut bacteria. Here, by expressing a subset of these clusters in Escherichia coli or Bacillus subtilis, we show that they encode pyrazinones and dihydropyrazinones. At least one of the 47 clusters is present in 88% of the National Institutes of Health Human Microbiome Project (NIH HMP) stool samples, and they are transcribed under conditions of host colonization. We present evidence that the active form of these molecules is the initially released peptide aldehyde, which bears potent protease inhibitory activity and selectively targets a subset of cathepsins in human cell proteomes. Our findings show that an approach combining bioinformatics, synthetic biology, and heterologous gene cluster expression can rapidly expand our knowledge of the metabolic potential of the microbiota while avoiding the challenges of cultivating fastidious commensals.

Background: To identify genotypes associated with neovascular age‐related macular degeneration (nAMD) and investigate the associations between genotype variations and anti‐vascular endothelial growth factor (VEGF) treatment response. Methods: This observational, retrospective, case series study enrolled patients diagnosed with nAMD who received anti‐VEGF treatment in National Taiwan University Hospital with at least one‐year follow‐up between 2012 and 2020. A genome‐wide association study (GWAS) was conducted on enrolled patients and controls. Correlations between the genotypes identified from GWAS and the treatment response of functional/anatomical biomarkers, including visual acuity (VA), presence of intraretinal or subretinal fluid (SRF), serous or fibrovascular pigmented epithelium detachment (PED), and disruption of the ellipsoid zone (EZ), were analysed. Results: In total, 182 patients with nAMD and 1748 controls were enrolled. GWAS revealed 16 single nucleotide polymorphisms (SNPs) as risk loci for nAMD, including seven loci in CFH and ARMS2/HTRA1 and nine novel loci, including rs117517872 and rs79835234(COPB2‐DT), rs7525578(RAP1A), rs2123738(LOC105376755), rs1374879(CNTN3), rs3812692(SAR1A), rs117501587(PRKCA), rs9965945(CNDP1), and rs189769231(MATK). Our study revealed rs800292(CFH), rs11200638(HTRA1), and rs2123738(LOC105376755) correlated with poor treatment response in VA (P = 0.005), SRF (P = 0.044), and fibrovascular PED (P = 0.007), respectively. Rs9965945(CNDP1) was correlated with poor response in disruption of EZ (P = 0.046) and serous PED (P = 0.049). Conclusions: Among the 16 SNPs found in the GWAS, four loci—CFH, ARMS2/HTRA1, and two novel loci—were correlated with the susceptibility of nAMD and anatomical/functional responses after anti‐VEGF treatment. [ABSTRACT FROM AUTHOR]

Live streaming technologies transform the information processing of customers by changing the way they interact with and acquire information. However, this emerging technological artefact may induce both positive and negative consequences for customer decision making. It is yet unknown what constitutes the dimensions of the juxtaposed IT affordances and how they affect customer behaviours in this new social phenomenon. This paper contributes to IS research by uncovering the specific bright and dark sides of IT affordances in live streaming e-commerce and by explaining the cognitive mechanisms underpinning customer purchase and brand citizenship behaviours. We employed a sequential mixed-methods design to embrace and contextualise the theory of affordance, vicarious learning, and cognitive load to rigorously develop a theoretical framework of the juxtaposed IT affordance in live streaming e-commerce. The results indicate that positive affordances (e.g., interactivity, visibility, and entertainment) have stronger effects on both economic and non-economic value. However, the potential dark side (e.g., broadcasting and source diversity) has more negative effects on purchase intention than brand citizenship behaviour, underscoring the importance of involving customers in co-creating brand-related value in live streaming e-commerce. Our findings contribute considerably to the emerging literature on live streaming e-commerce and provide actionable recommendations for practitioners. [ABSTRACT FROM AUTHOR]

As an important part of die steels, hot-work die steels are mainly used to manufacture molds made of solid metal or high-temperature liquid metal from heating to recrystallization temperature. In view of the requirements for mechanical properties and service life for hot-work die steel, it is conducive to improve the thermal fatigue resistance, wear resistance, and oxidation resistance of hot work die steel. In this review, the main failure modes of hot-work die steel were analyzed. Four traditional methods of strengthening and toughening die steel were summarized, including optimizing alloying elements, electroslag remelting, increasing the forging ratio, and heat treatment process enhancement. A new nano-strengthening method was introduced that aimed to refine the microstructure of hot-work abrasive steel and improve its service performance by adding nanoparticles into molten steel to achieve uniform dispersion. This review provides an overview to improve the service performance and service life of hot work die steel. [ABSTRACT FROM AUTHOR]

Introduction: KEYNOTE-394 showed pembrolizumab significantly improved overall survival, progression-free survival, and objective response rate with manageable safety versus placebo for patients from Asia with previously treated advanced hepatocellular carcinoma. We present results on health-related quality of life (HRQoL). Methods: HRQoL was evaluated using the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EuroQol-5D-3L (EQ-5D-3L) questionnaires. Key HRQoL endpoints were least squares mean (LSM) score changes from baseline to week 12 and time to deterioration (TTD) for EORTC QLQ-C30 global health status (GHS)/QoL. p values were one-sided and nominal without adjustment for multiplicity. Results: The HRQoL population included patients randomly assigned to pembrolizumab (n = 298) and placebo (n = 152). From baseline to week 12, a greater decline in EORTC QLQ-C30 GHS/QoL score was observed with placebo (LSM, −8.4; 95% CI: −11.7 to −5.1) versus pembrolizumab (−4.0; 95% CI: −6.4 to −1.6; difference vs. placebo: 4.4; 95% CI: 0.5–8.4; nominal p = 0.0142). Similarly, a greater decline in the EQ-5D-3L visual analog scale score was observed with placebo (−6.9; 95% CI: −9.4 to −4.5) versus pembrolizumab (−2.7; 95% CI: −4.5 to −1.0; difference vs. placebo: 4.2; 95% CI: 1.2–7.2; nominal p = 0.0030). TTD in EORTC QLQ-C30 GHS/QoL score was similar between arms (hazard ratio, 0.85; 95% CI: 0.58–1.25; nominal p = 0.1993). Conclusion: Patients receiving placebo showed a greater decline in HRQoL than those receiving pembrolizumab. Combined with efficacy and safety data from KEYNOTE-394 and the global KEYNOTE-240 and KEYNOTE-224 trials, our data support the clinically meaningful benefit and manageable tolerability of pembrolizumab as second-line therapy for patients with advanced hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Tryptanthrin, an alkaloid applied in traditional Chinese medicine, exhibits a variety of pharmacological activities. This study aimed to investigate the anti‐tumor activity of the tryptanthrin derivative (8‐cyanoindolo[2,1‐b]quinazoline‐6,12‐dione [CIQ]) in breast cancer cells. In both MDA‐MB‐231 and MCF‐7 breast cancer cells, CIQ inhibited cell viability and promoted caspase‐dependent apoptosis. At the concentration‐ and time‐dependent ways, CIQ increased the levels of p‐ERK, p‐JNK, and p‐p38 in breast cancer cells. We found that exposure to the JNK inhibitor or the ERK inhibitor partially reversed CIQ's viability. We also observed that CIQ increased reactive oxygen species (ROS) generation, and upregulated the phosphorylation and expression of H2AX. However, the pretreatment of the antioxidants did not protect the cells against CIQ's effects on cell viability and apoptosis, which suggested that ROS does not play a major role in the mechanism of action of CIQ. In addition, CIQ inhibited the invasion of MDA‐MB‐231 cells and decreased the expression of the prometastatic factors (MMP‐2 and Snail). These findings demonstrated that the possibility of this compound to show promise in playing an important role against breast cancer. [ABSTRACT FROM AUTHOR]

Ferroptosis, which comprises iron-dependent cell death, is crucial in cancer and non-cancer treatments. Exosomes, the extracellular vesicles, may deliver biomolecules to regulate disease progression. The interplay between ferroptosis and exosomes may modulate cancer development but is rarely investigated in natural product treatments and their modulating miRNAs. This review focuses on the ferroptosis-modulating effects of natural products and miRNAs concerning their participation in ferroptosis and exosome biogenesis (secretion and assembly)-related targets in cancer and non-cancer cells. Natural products and miRNAs with ferroptosis-modulating effects were retrieved and organized. Next, a literature search established the connection of a panel of ferroptosis-modulating genes to these ferroptosis-associated natural products. Moreover, ferroptosis-associated miRNAs were inputted into the miRNA database (miRDB) to bioinformatically search the potential targets for the modulation of ferroptosis and exosome biogenesis. Finally, the literature search provided a connection between ferroptosis-modulating miRNAs and natural products. Consequently, the connections from ferroptosis–miRNA–exosome biogenesis to natural product-based anticancer treatments are well-organized. This review sheds light on the research directions for integrating miRNAs and exosome biogenesis into the ferroptosis-modulating therapeutic effects of natural products on cancer and non-cancer diseases. [ABSTRACT FROM AUTHOR]

Patients with type 1 diabetes mellitus are associated with impairment in vitamin A metabolism. This study evaluated whether treatment with retinoic acid, the biologically active metabolite of vitamin A, can ameliorate diabetes. All-trans retinoic acid (atRA) was used to treat streptozotocin (STZ)-induced diabetic mice which revealed atRA administration ameliorated blood glucose levels of diabetic mice. This hyperglycemic amelioration was accompanied by an increase in the amount of β cells co-expressed Pdx1 and insulin and by restoration of the vascular laminin expression. The atRA-induced production of vascular endothelial growth factor-A from the pancreatic islets was possibly the key factor that mediated the restoration of islet vascularity and recovery of β-cell mass. Furthermore, the combination of islet transplantation and atRA administration significantly rescued hyperglycemia in diabetic mice. These findings suggest that vitamin A derivatives can potentially be used as a supplementary treatment to improve diabetes management and glycemic control.