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Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare autosomal recessive disease defined by the presence of two of the three conditions: mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. Loss-of-function mutations of the autoimmune regulator (AIRE) gene have been linked to APS-1. Here we report mutational analysis and functional characterization of an AIRE mutation in a consanguineous Chinese family with APS-1. All exons of the AIRE gene and adjacent exon-intron sequences were amplified by PCR and subsequently sequenced. We identified a homozygous missense AIRE mutation c.463G>A (p.Gly155Ser) in two siblings with different clinical features of APS-1. In silico splice-site prediction and minigene analysis were carried out to study the potential pathological consequence. Minigene splicing analysis and subsequent cDNA sequencing revealed that the AIRE mutation potentially compromised the recognition of the splice donor of intron 3, causing alternative pre-mRNA splicing by intron 3 retention. Furthermore, the aberrant AIRE transcript was identified in a heterozygous carrier of the c.463G>A mutation. The aberrant intron 3-retaining transcript generated a truncated protein (p.G155fsX203) containing the first 154 AIRE amino acids and followed by 48 aberrant amino acids. Therefore, our study represents the first functional characterization of the alternatively spliced AIRE mutation that may explain the pathogenetic role in APS-1.

Abstract Background Shuanglong formula (SLF), a Chinese medicine composed of panax ginseng and salvia miltiorrhiza exhibited significant effect in the treatment of myocardial infarction (MI) in clinical. Because of the complex nature and lack of stringent quality control, it's difficult to explain the action mechanism of SLF. Method In this study, we present a "system to system" (S2S) mode. Based on this mode, SLF was simplified successively through bioactivity-guided screening to achieve an optimized minimal phytochemical composition (new formula NSLF6) while maintaining its curative effect for MI. Results Pharmacological test combining with the study of systems biology show that NSLF6 has activity for treatment MI through synergistic therapeutic efficacies between total ginsenosides and total salvianolic acids via promoting cardiac cell regeneration and myocardial angiogenesis, antagonistic myocardial cell oxidative damage. Conclusions The present S2S mode may be an effective way for the discovery of new composite drugs from traditional medicines.

BackgroundGlucagon-like peptide-1 (GLP-1) has been reported to have beneficial impacts on improving human's metabolism and ameliorating insulin resistance. While insulin is another important and conventional drug in diabetes treatment, but it has an adverse effect on weight gain.PurposeTo make sure whether GLP-1 and insulin play different roles in human adipose-derived stem cells (hADSCs).MethodsWe examined the in vitro roles and molecular mechanisms of liraglutide, a GLP-1 analogue, and human insulin on hADSCs isolated from subcutaneous adipose tissue. Different concentrations (0, 0.1, 1, 10, 100nM) of liraglutide and insulin were added to proliferation and differentiation medium of hADSCs, respectively.ResultsLiraglutide inhibits while insulin promotes the proliferation and differentiation at the concentration of 100nM. Moreover, the levels of GSK-3 increase during differentiation and liraglutide could down-regulate it when compared with insulin. We also find that the activation of phosphorylated GSK-3α and GSK-3β is involved in the differentiation roles. And classical and non-classical Wnt pathways all play roles in the differentiation, which are characterized with the up/down-regulation of the expression of adipogenesis genes such as PPAR-γ and CEBP-α.ConclusionLiraglutide and insulin have contrary effects on the proliferation and adipogenesis via Wnt pathway in primary cultured ADSCs. Those effects could partly explain the different roles of GLP-1 and insulin on weight gain and insulin resistance.

One new 2-arylbenzo[b]furan named iteafuranal F (1) as well as two known analogues (2–3) were isolated from the 95% EtOH extract of aerial parts of Itea omeiensis. Their chemical structures were constructed based on extensive analyses of UV, IR, 1D/2D NMR and HRMS spectra. Antioxidant assays revealed significant superoxide anion radical scavenging capacity of 1 with IC50 value of 0.66 mg/mL, which was comparable to the efficiency of positive control of luteolin. In addition, the preliminary MS fragmentation patterns in negative ion mode were established to distinguish 2-arylbenzo[b]furans with C-10 in different oxidation states: the characteristic loss of CO molecule [M-H-28]- was observed for 3-formyl-2-arylbenzo[b]furans, and the loss of CH2O fragment [M-H-30]- for 3-hydroxymethyl-2-arylbenzo[b]furans, and the loss of CO2 fragment [M-H-44]- for 2-arylbenzo[b]furan-3-carboxylic acids. [ABSTRACT FROM AUTHOR]

In the traditional instructional method used in international trade, teachers provide knowledge to learners by lecturing using slides and setting assignments; however, these methods merely deliver international trade knowledge rather than facilitating student development of relevant skills. To solve these problems, we proposed a simulation-based learning system for international trade, combining international trade-process simulation and business letter writing. We investigated learner opinions toward the system and the quality of business letters by using quantitative and qualitative analyses. Regarding the results, learners perceived that the proposed system improved their knowledge of international trade and business English.

Comprehensive Summary: Tumor stroma composing diverse extracellular matrixes (ECM) and stromal cells shapes a condensed physical barrier, which severely hampers the efficient accessibility of nanomedicine to tumor cells, especially these deep‐seated in the core of tumor. Such barrier significantly compromises the antitumor effects of drug‐loaded nanomedicine, revealing the remarkable importance of disrupting stromal barrier for improved tumor therapy with deep penetration ability. To achieve this goal, various nanoparticle‐based strategies have been developed, including direct depleting ECM components via delivering anti‐fibrotic agents or targeting stromal cells to suppress ECM expression, dynamic regulation of nanoparticles' physicochemical properties (i.e., size, surface charge, and morphology), mechanical force‐driven deep penetration, natural/biomimetic self‐driven nanomedicine, and transcytosis‐inducing nanomedicine. All these nanostrategies were systemically summarized in this review, and the design principles for obtaining admirable nanomedicine were included. With the rapid development of nanotechnology, elaborate design of multifunctional nanomedicine provides new opportunities for overcoming the critical stromal barriers to maximize the therapeutic index of various therapies, such as chemotherapy, photodynamic therapy, and immunotherapy. Key Scientists: In 2006, Chan et al. demonstrated that the size and shape of nanoparticles were important for biomedical applications, such as intracellular delivery rate and tissue penetration. In addition, the degradation of the structural collagen was confirmed to increase the diffusion of nanoparticles and macromolecules by Davies et al. in 2010. These findings reveal the importance of chemophysical properties of nanoparticles in determining their diffusion and the critical roles of stromal barrier in hindering nanoparticles penetration. On the basis of this, photoswitchable nanoparticles were developed by Kohane et al. for triggered tissue penetration and efficient drug delivery. In 2015, Nie et al. reported the targeted depletion of cancer‐associated fibroblasts by peptide assembly for enhanced antitumor drug delivery. In 2019, Shen et al. proposed the transcytosis strategy to promote the tumor penetration of nanoparticles. Very recently, Luo et al. reported the specific reversing of the biological function of cancer‐associated fibroblasts to suppress the generation of stromal matrix, greatly increasing the drug perfusion in tumor tissue. All these strategies fueled the design and construction of function‐specific nanoparticles for tumor therapy. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Tumor stroma composing diverse extracellular matrixes (ECM) and stromal cells shapes a condensed physical barrier, which severely hampers the efficient accessibility of nanomedicine to tumor cells, especially these deep‐seated in the core of tumor. Such barrier significantly compromises the antitumor effects of drug‐loaded nanomedicine, revealing the remarkable importance of disrupting stromal barrier for improved tumor therapy with deep penetration ability. To achieve this goal, various nanoparticle‐based strategies have been developed, including direct depleting ECM components via delivering anti‐fibrotic agents or targeting stromal cells to suppress ECM expression, dynamic regulation of nanoparticles' physicochemical properties (i.e., size, surface charge, and morphology), mechanical force‐driven deep penetration, natural/biomimetic self‐driven nanomedicine, and transcytosis‐inducing nanomedicine. All these nanostrategies were systemically summarized in this review, and the design principles for obtaining admirable nanomedicine were included. With the rapid development of nanotechnology, elaborate design of multifunctional nanomedicine provides new opportunities for overcoming the critical stromal barriers to maximize the therapeutic index of various therapies, such as chemotherapy, photodynamic therapy, and immunotherapy. Key Scientists: In 2006, Chan et al. demonstrated that the size and shape of nanoparticles were important for biomedical applications, such as intracellular delivery rate and tissue penetration. In addition, the degradation of the structural collagen was confirmed to increase the diffusion of nanoparticles and macromolecules by Davies et al. in 2010. These findings reveal the importance of chemophysical properties of nanoparticles in determining their diffusion and the critical roles of stromal barrier in hindering nanoparticles penetration. On the basis of this, photoswitchable nanoparticles were developed by Kohane et al. for triggered tissue penetration and efficient drug delivery. In 2015, Nie et al. reported the targeted depletion of cancer‐associated fibroblasts by peptide assembly for enhanced antitumor drug delivery. In 2019, Shen et al. proposed the transcytosis strategy to promote the tumor penetration of nanoparticles. Very recently, Luo et al. reported the specific reversing of the biological function of cancer‐associated fibroblasts to suppress the generation of stromal matrix, greatly increasing the drug perfusion in tumor tissue. All these strategies fueled the design and construction of function‐specific nanoparticles for tumor therapy. [ABSTRACT FROM AUTHOR]