Impact of the digital economy on technical regulations and standardization in the context of the belt and road initiative

With the rapid development of the digital economy, countries along the “Belt and Road” are becoming more and more closely economically connected. This paper explores the impact of the digital economy on technical norms and standardization, and how this impact further shapes economic cooperation among countries along the “Belt and Road”. Through in-depth analysis of the digital economy, we find that the digital economy is profoundly changing the way we live and work, and redefining the meaning of technical regulation and standardization. Facing the challenges and opportunities of digital economy, we need to actively respond to them by strengthening infrastructure construction, enhancing talent training, and strengthening international cooperation, so as to promote the healthy development of digital economy and economic cooperation among countries along the “Belt and Roa

Thyroid function and polycystic ovary syndrome: a Mendelian randomization study

BackgroundMultiple evidence suggests that thyroid function is associated with polycystic ovary syndrome (PCOS), but whether thyroid function is causally related to PCOS is unclear. To investigate whether the association reflect causality, a Mendelian randomization (MR) analysis was conducted.MethodsSingle nucleotide polymorphisms (SNPs) involved in this study were acquired from The ThyroidOmics Consortium and the IEU Open Genome-wide association study (GWAS) database, respectively. In forward MR analysis, we included normal free thyroxine (FT4, n=49,269), normal thyroid-stimulating hormone (TSH, n=54,288), hypothyroidism (n=53,423) and hyperthyroidism (n=51,823) as exposure. The outcome was defined as PCOS in a sample size of 16,380,318 individuals. The exposure in the reverse MR analyses was chosen as PCOS, while the outcome consisted of the four phenotypes of thyroid function. The inverse-variance weighted (IVW) method was performed as the major analysis, supplemented by sensitivity analyses.ResultsThe occurrence of PCOS was associated with increased risk of hyperthyroidism (IVW, OR=1.08, 95%CI=1.02-1.13, P=0.004). No evidence suggested that other phenotypes of thyroid function were related to PCOS.ConclusionsOur findings demonstrate a cause-and-effect connection between PCOS and hyperthyroidism. The study established foundation for further investigation for interaction between thyroid function and PCOS

Causal role of immune cells in Hashimoto’s thyroiditis: Mendelian randomization study

ObjectivesHashimoto’s thyroiditis (HT) is a common autoimmune disease whose etiology involves a complex interplay between genetics and environment. Previous studies have demonstrated an association between immune cells and HT. However, the casual relationship was not clear. We aimed to explore the causal associations between signatures of immune cells and HT.MethodsIn this study, bidirectional two-sample Mendelian randomization (MR) analysis was conducted to investigate the potential causal relationship between 731 immune cell signatures and HT by using genome-wide association study (GWAS) data. Heterogeneity and horizontal pleiotropy were detected through extensive sensitivity analyses.ResultsThe increased levels of six immune phenotypes were observed to be causally associated with increased risk of HT P < 0.01, which were CD3 on CM CD8br, CD3 on CD39+ secreting Treg, HLA DR on CD33dim HLA DR+ CD11b−, CD3 on CD4 Treg, CD62L− plasmacytoid DC %DC, and CD3 on CD45RA+ CD4+. In addition, the levels of FSC-A on HLA DR+ T cell and CD62L on monocyte were associated with disease risk of HT P < 0.01. In addition, HT also had causal effects on CD3 on CM CD8br, CCR2 on monocyte, CD25 on CD39+ resting Treg, and CCR2 on CD62L+ myeloid DC P < 0.05.ConclusionsIn this study, we demonstrated the genetic connection between immune cell traits and HT, thereby providing guidance and direction for future treatment and clinical research

Increased expression of long-isoform thymic stromal lymphopoietin is associated with rheumatoid arthritis and fosters inflammatory responses

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine that is involved in the pathogenesis of inflammatory diseases and asthma, but the expression and biological implications of the existence of two isoforms, long TSLP (lTSLP) and short TSLP (sTSLP), in RA have yet to be elucidated. Here we report that lTSLP is the predominant TSLP isoform in RA and active RA, whereas sTSLP is the major TSLP isoform in inactive RA and healthy controls. lTSLP expression is associated with disease activity, including 28-joint Disease Activity Score (DAS28) and erythrocyte sedimentation rate (ESR), as well as proinflammatory cytokine expression, irrespective of other laboratory parameters. Importantly, lTSLP alone or combined with LPS promotes the expression of proinflammatory cytokines IL-1β, IL-6, and IL-8 in PBMCs of RA, but restrains anti-inflammatory cytokine IL-10 expression in PBMCs of RA. Furthermore, we found that STAT5 signaling is involved in lTSLP-induced inflammatory accumulation in PBMCs of RA. Therefore, these results highlight the clinical significance of lTSLP in RA pathology and inflammatory response in acute-phase disease, which may provide a therapeutic target for RA

Design, synthesis and biological evaluation of novel tetrahydrothieno [2,3-c]pyridine substitued benzoyl thiourea derivatives as PAK1 inhibitors in triple negative breast cancer

The overexpression of P21-activated kinase 1 (PAK1) is associated with poor prognosis in several cancers, which has emerged as a promising drug targets. Based on high-throughput virtual screening strategy, tetrahydrothieno [2,3-c]pyridine scaffold was identified as an initial lead for targeting PAK1. Herein we reported our structure-based optimisation strategy to discover a potent PAK1 inhibitor (7j) which displayed potent PAK1 inhibition and antiproliferatory activity in MDA-MB-231 cells. 7j induced obviously G2/M cell cycle arrest via PAK1-cdc25c-cdc2 pathway, and also inhibited MAPK-ERK and MAPK-JNK cascade to induce MDA-MB-231 cell death. Together, these results provided a novel chemical scaffold as PAK1 inhibitor for breast cancer treatment

Discovery of novel ATAD2 bromodomain inhibitors that trigger apoptosis and autophagy in breast cells by structure-based virtual screening

ATAD2 has been reported to play an important role in the processes of numerous cancers and validated to be a potential therapeutic target. This work is to discover potent ATAD2 inhibitors and elucidate the underlying mechanisms in breast cancer. A novel ATAD2 bromodomain inhibitor (AM879) was discovered by combining structure-based virtual screening with biochemical analyses. AM879 presents potent inhibitory activity towards ATAD2 bromodomain (IC50 = 3565 nM), presenting no inhibitory activity against BRD2-4. Moreover, AM879 inhibited MDA-MB-231 cells proliferation with IC50 value of 2.43 µM, suppressed the expression of c-Myc, and induced significant apoptosis. Additionally, AM978 could induce autophagy via PI3K-AKT-mTOR signalling in MDA-MB-231 cells. This study demonstrates the development of potent ATAD2 inhibitors with novel scaffolds for breast cancer therapy

The pathogenic mutations of APOA5 in Chinese patients with hyperlipidemic acute pancreatitis

Abstract Background and aims To study the role of gene mutations in the development of severe hypertriglyceridemia (HTG) in patients with hyperlipidemic acute pancreatitis (HLAP), especially different apolipoprotein A5 (APOA5) mutations. Methods Whole-exome sequencing was performed on 163 patients with HLAP and 30 patients with biliary acute pancreatitis (BAP). The pathogenicity of mutations was then assessed by combining clinical information, predictions of bioinformatics programs, information from multiple gene databases, and residue location and conservation. The pathogenic mutations of APOA5 were visualized using the software. Results 1. Compared with BAP patients, pathogenic mutations of APOA5 were frequent in HLAP patients; among them, the heterozygous mutation of p.G185C was the most common. 2. All six pathogenic mutations of APOA5 identified in this study (p.S35N, p.D167V, p.G185C, p.K188I, p.R223C, and p.H182fs) were positively correlated with severe HTG; they were all in the important domains of apolipoprotein A-V (apoA-V). Residue 223 is strictly conserved in multiple mammals and is located in the lipoprotein lipase (LPL)-binding domain (Pro215–Phe261). When Arg 223 is mutated to Cys 223, the positive charge of this residue is reduced, which is potentially destructive to the binding function of apoA-V to LPL. 3. Four new APOA5 mutations were identified, namely c.563A > T, c.667C > T, c.788G > A, and c.544_545 insGGTGC. Conclusions The pathogenic mutations of APOA5 were specific to the patients with HLAP and severe HTG in China, and identifying such mutations had clinical significance in elucidating the etiology and subsequent treatment. Graphical Abstrac