Pharmacokinetics, distribution, metabolism, and excretion of body-protective compound 157, a potential drug for treating various wounds, in rats and dogs

Body-protective compound (BPC) 157 demonstrates protective effects against damage to various organs and tissues. For future clinical applications, we had previously established a solid-phase synthesis process for BPC157, verified its biological activity in different wound models, and completed preclinical safety evaluations. This study aimed to investigate the pharmacokinetics, excretion, metabolism, and distribution profiles of BPC157. After a single intravenous (IV) administration, single intramuscular (IM) administrations at three doses in successive increments along with repeated IM administrations, the elimination half-life (t1/2) of prototype BPC157 was less than 30 min, and BPC157 showed linear pharmacokinetic characteristics in rats and beagle dogs at all doses. The mean absolute bioavailability of BPC157 following IM injection was approximately 14%–19% in rats and 45%–51% in beagle dogs. Using [3H]-labeled BPC157 and radioactivity examination, we proved that the main excretory pathways of BPC157 involved urine and bile. [3H]BPC157 was rapidly metabolized into a variety of small peptide fragments in vivo, thus forming single amino acids that entered normal amino acid metabolism and excretion pathways. In conclusion, this study provides the first analysis of the pharmacokinetics of BPC157, which will be helpful for its translation in the clinic

Strong Inter-valley Electron-Phonon Coupling in Magic-Angle Twisted Bilayer Graphene

The unusual properties of superconductivity in magic-angle twisted bilayer graphene (MATBG) have sparked enormous research interest. However, despite the dedication of intensive experimental efforts and the proposal of several possible pairing mechanisms, the origin of its superconductivity remains elusive. Here, using angle-resolved photoemission spectroscopy with micrometer spatial resolution, we discover replicas of the flat bands in superconducting MATBG unaligned with its hexagonal boron nitride (hBN) substrate, which are absent in non-superconducting MATBG aligned with the hBN substrate. Crucially, the replicas are evenly spaced in energy, separated by 150 +- 15 meV, signalling the strong coupling of electrons in MATBG to a bosonic mode of this energy. By comparing our observations to simulations, the formation of replicas is attributed to the presence of strong inter-valley electron-phonon coupling to a K-point phonon mode. In total, the observation of these replica flat bands and the corresponding phonon mode in MATBG could provide important information for understanding the origin and the unusual properties of its superconducting phase.Comment: 17 pages, 4 figure

Subjective Social Class and the Retention Intentions of Teachers from the Publicly Funded Normal Students Program in China: The Dual Mediating Effect of Organizational and Professional Identity

A stable teaching force is an important guarantee for the sustainable development of education. Teacher turnover is one of the reasons for the teacher shortage in rural areas. Although studies have examined the influencing factors of teachers’ turnover intention, little is known about the effect of subjective social status on teachers’ turnover intention, especially for publicly funded normal students program (PFNSP) teachers who play a vital role in improving the quality of education in less developed regions of central and western China. A questionnaire survey was conducted, which returned a total of 16,731 responses (8141 public recruited teachers and 1498 teachers from PFNSP). The study explores the influence of subjective social class on PFNSP teachers’ retention intention and the mediating role of organizational and professional identity on this impact. Except for organizational identity, the subjective social class, professional identity, and retention intentions of PFNSP teachers were significantly lower than those of publicly recruited teachers. There was a significant association between subjective social class and retention intentions of PFNSP teachers. In addition, organizational identity and professional identity had a significant positive relationship to PFNSP teachers’ retention intention, and played partial mediating roles in the relationship between subjective social class and retention intentions

Subjective Social Class and the Retention Intentions of Teachers from the Publicly Funded Normal Students Program in China: The Dual Mediating Effect of Organizational and Professional Identity

A stable teaching force is an important guarantee for the sustainable development of education. Teacher turnover is one of the reasons for the teacher shortage in rural areas. Although studies have examined the influencing factors of teachers’ turnover intention, little is known about the effect of subjective social status on teachers’ turnover intention, especially for publicly funded normal students program (PFNSP) teachers who play a vital role in improving the quality of education in less developed regions of central and western China. A questionnaire survey was conducted, which returned a total of 16,731 responses (8141 public recruited teachers and 1498 teachers from PFNSP). The study explores the influence of subjective social class on PFNSP teachers’ retention intention and the mediating role of organizational and professional identity on this impact. Except for organizational identity, the subjective social class, professional identity, and retention intentions of PFNSP teachers were significantly lower than those of publicly recruited teachers. There was a significant association between subjective social class and retention intentions of PFNSP teachers. In addition, organizational identity and professional identity had a significant positive relationship to PFNSP teachers’ retention intention, and played partial mediating roles in the relationship between subjective social class and retention intentions

Parenting Stress and Parenting Efficacy of Parents Having Children with Disabilities in China: The Role of Social Support

Raising children with disabilities is challenging for parents, who experience high parenting stress. The study aimed to understand the status quo of parenting efficacy of parents having children with disabilities and to analyze the association between parent efficacy, parenting stress, and social support in China. We surveyed 373 parents having children with disabilities enrolled in special education schools or rehabilitation institutions from 14 provinces in China. The online questionnaire including Parental Stress Index-Short Form, the Child Adjustment and Parent Efficacy Scale-Developmental Disability (CAPES-DD), and Social Support Scale was applied in the study. The results suggested that parenting efficacy of parents having children with disabilities in China was at the medium level. Parenting stress, social support, and parenting efficacy were significantly related with each other, and social support played a mediating role between parenting stress and parenting efficacy. The findings indicated that reducing parenting stress and improving social support might improve parenting efficacy. We also discussed the implications of providing intervention strategies or social support to improve parenting efficacy for parents with disabled children in China

Genome-Wide Investigation of Genes Regulated by ERα in Breast Cancer Cells

Estrogen receptor alpha (ERα), which has been detected in over 70% of breast cancer cases, is a driving factor for breast cancer growth. For investigating the underlying genes and networks regulated by ERα in breast cancer, RNA-seq was performed between ERα transgenic MDA-MB-231 cells and wild type MDA-MB-231 cells. A total of 267 differentially expressed genes (DEGs) were identified. Then bioinformatics analyses were performed to illustrate the mechanism of ERα. Besides, by comparison of RNA-seq data obtained from MDA-MB-231 cells and microarray dataset obtained from estrogen (E2) stimulated MCF-7 cells, an overlap of 126 DEGs was screened. The expression level of ERα was negatively associated with metastasis and EMT in breast cancer. We further verified that ERα might inhibit metastasis by regulating of VCL and TNFRSF12A, and suppress EMT by the regulating of JUNB and ID3. And the relationship between ERα and these genes were validated by RT-PCR and correlation analysis based on TCGA database. By PPI network analysis, we identified TOP5 hub genes, FOS, SP1, CDKN1A, CALCR and JUNB, which were involved in cell proliferation and invasion. Taken together, the whole-genome insights carried in this work can help fully understanding biological roles of ERα in breast cancer

Hypoxia-Induced Mesenchymal Stem Cells Exhibit Stronger Tenogenic Differentiation Capacities and Promote Patellar Tendon Repair in Rabbits

Tendon injury is a common but tough medical problem. Unsatisfactory clinical results have been reported in tendon repair using mesenchymal stem cell (MSC) therapy, creating a need for a better strategy to induce MSCs to tenogenic differentiation. This study was designed to examine the effect of hypoxia on the tenogenic differentiation of different MSCs and their tenogenic differentiation capacities under hypoxia condition in vitro and to investigate the in vivo inductility of hypoxia in tenogenesis. Adipose tissue-derived MSCs (AMSCs) and bone marrow-derived MSCs (BMSCs) were isolated and characterized. The expression of hypoxia-induced factor-1 alpha (Hif-1α) was examined to confirm the establishment of hypoxia condition. qRT-PCR, western blot, and immunofluorescence staining were used to evaluate the expression of tendon-associated marker Col-1a1, Col-3a1, Dcn, and Tnmd in AMSCs and BMSCs under hypoxia condition, compared with Tgf-β1 induction. In vivo, a patellar tendon injury model was established. Normoxic and hypoxic BMSCs were cultured and implanted. Histological, biomechanical, and transmission electron microscopy analyses were performed to assess the improved healing effect of hypoxic BMSCs on tendon injury. Our in vitro results showed that hypoxia remarkably increased the expression of Hif-1α and that hypoxia not only promoted a significant increase in tenogenic markers in both AMSCs and BMSCs compared with the normoxia group but also showed higher inductility compared with Tgf-β1. In addition, hypoxic BMSCs exhibited higher potential of tenogenic differentiation than hypoxic AMSCs. Our in vivo results demonstrated that hypoxic BMSCs possessed better histological and biomechanical properties than normoxic BMSCs, as evidenced by histological scores, patellar tendon biomechanical parameters, and the range and average of collagen fibril diameters. These findings suggested that hypoxia may be a practical and reliable strategy to induce tenogenic differentiation of BMSCs for tendon repair and could enhance the effectiveness of MSCs therapy in treating tendon injury

A Single Codon Optimization Enhances Recombinant Human TNF-α Vaccine Expression in Escherichia coli

As a proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α) plays a pivotal role in various autoimmune diseases such as rheumatoid arthritis (RA). Thus, TNF-α has been defined as a therapeutic target for RA. Although some TNF-α antagonists including neutralizing monoclonal antibodies and soluble receptors have been approved to be successful in attenuating symptoms in patients suffering from RA, the long-term use of these passive immunization reagents could cause some problems like a variable degree of immunogenicity. In the present study, in order to wake up active immune responses of RA patients, we developed a recombinant TNF-α therapeutic vaccine (named mrTNF-PADRE) by coupling a 12-amino acid universal Pan HLA-DR Epitope (PADRE) to the protein. Codon optimization was performed to improve the secondary structure of mrTNF-PADRE mRNA to ensure its heterologous expression. As a result, a single codon synonymous mutation greatly elevated recombinant protein expression (about 30% of the total bacteria proteins) in E. coli as compared with the undetectable expression of the unoptimized gene. Although expressed as insoluble inclusion bodies (IBs), the vaccine can be effectively prepared with a purity of over 95% by IBs washing and one-step gel-infiltration chromatography. By this strategy, a stable yield of 5.2 mg purified mrTNF-PADRE per gram of cell paste could be obtained

Corona Liquid Crystalline Order Helps to Form Single Crystals When Self-Assembly Takes Place in the Crystalline/Liquid Crystalline Block Copolymers

Crystalline/ionic liquid crystalline block copolymers (BCPs) with various compositions have been successfully prepared by sequential reactions. The effect of corona liquid crystalline order on self-assembly of BCPs in selective solvent is investigated in detail. It is found that two-dimensional single crystals with well-developed shapes are formed when the liquid crystalline order is present. By contrast, ill-developed platelets with small size or one-dimensional worm-like micelles are assembled if the liquid crystalline order of the corona segments is lost. It is speculated that the preferred parallel arrangement of liquid crystalline block enables it to expose more growth front of crystals. Accordingly, epitaxial crystallization will proceed readily, leading to fabrication of the well-defined single crystals