CTLA-4 haplotype predicts HBsAg and HBcrAg levels and HBeAg seroconversion age in children with chronic HBV infection.

Background & Aim: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) attenuates cytotoxic T lymphocyte (CTL) activation. This study was performed to examine the relationships between CTLA-4 genotypes/haplotypes, hepatitis B surface antigen (HBsAg), and hepatitis B core-related antigen (HBcrAg) levels, and their potential impact on the clinical course of chronic HBV infection. Methods: We recruited 145 treatment-naïve patients with genotype B or C chronic HBV infection who were initially hepatitis B e-antigen (HBeAg)-positive and had been followed from a mean age of 7.08 years for a total of 4,787 person-years in the study cohort. We also recruited another 69 treatment-naïve adults with genotype B or C chronic HBV infection as a validation cohort. We assessed the CTLA-4 gene single nucleotide polymorphisms rs4553808 (-A1661G)/rs5742909 (-C318T) in both cohorts, and the serum HBsAg and HBcrAg levels in the study cohort. Results: CTLA-4 promoter haplotypes were associated with HBsAg and HBcrAg levels at 10 and 15 years of age in the study cohort. Patients with the CTLA-4 AA/CC haplotype showed earlier spontaneous HBeAg seroconversion (hazard ratio = 1.58; p = 0.02), and a more rapid annual decline in the serum HBsAg level than other patients (0.09 vs. 0.03 log10 IU/ml/year, p = 0.02). The CTLA-4 AA/CC haplotype was also predictive of HBeAg seroconversion in the validation cohort (p = 0.01). Conclusions: Chronic HBV-infected patients with a CTLA-4 AA/CC haplotype had lower serum HBsAg and HBcrAg levels in childhood and earlier spontaneous HBeAg seroconversion. Impact and implications: The role of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in chronic HBV-infected children has not been studied previously. In a very long-term cohort followed from childhood to adulthood, we showed that CTLA-4 haplotypes are associated with HBV biomarker levels in childhood and are correlated with the clinical course of chronic HBV infection. CTLA-4 pathway may serve as a future target for the development of therapeutic agents against HBV infection.

The impact of population aging on FDI: A panel data analysis based on 27 segments in China's manufacturing industry.

Foreign Direct Investment (FDI) is an important part of China's new "double-cycle" development pattern. Among the many factors affecting FDI, will the aging population have an impact on manufacturing, the key industry for FDI? This paper examines the direct and indirect effects of an aging population on FDI using panel data from 27 manufacturing sub-industries in China between 2005 and 2020. It is found that (1) the deepening of the population's aging negatively affects FDI inflows and this result continues to hold after a series of robustness tests. (2) Using labor quantity and labor cost as mediating variables, it is found that the population's aging indirectly affects FDI by reducing labor quantity and increasing labor cost. (3) The heterogeneity analysis study finds that the deepening of the population's aging significantly inhibits FDI in labor-intensive and capital-intensive industries among manufacturing sub-industries, and the inhibitory effect on FDI in technology-intensive industries is not significant. This study provides meso-evidence to support the findings of existing studies and provides suggestions and insights for the government to formulate relevant policies to actively cope with aging.

Two-Way FDI assists agricultural sustainable development: Based on digitalization and greening perspectives.

With the new challenges and crises facing agriculture, digitalization and green transformation have become important ways to solve the problems. This paper uses an international economics perspective to chart a new path for sustainable agricultural development. Specifically, it analyzes whether two-way international direct investment (FDI) can facilitate agricultural digital-green fusion(DGF)? Using a sample of 31 provinces (autonomous regions) from 2012 to 2021, this study finds: (1) Two-way FDI can significantly contribute to agriculture's DGF. (2) In the mechanism test, it is proved that two-way FDI can promote agriculture's DGF level by promoting green technology innovation capacity and overall regional technology innovation capacity. (3) The positive effects of two-way FDI are prominent in the eastern and central regions, coastal regions, and economically developed areas. (4) In the spatial Durbin model, the local two-way FDI growth improves agriculture's DGF level in the surrounding areas to a certain extent. The government is advised to prioritize openness, foster an environment for technological innovation, leverage spatial radiation for agricultural DGF, and advance digitally empowered agricultural modernization.

The Impact of Mindful Learning on Subjective and Psychological Well-Being in Postgraduate Students.

Mindful learning is widely known to improve learning outcomes, yet its association with students' well-being remains unexplored. This study aimed to investigate the impact of mindful learning on subjective well-being (SWB) and psychological well-being (PWB) in postgraduate students, using survey questionnaires and a randomized experimental design. In Study 1, correlation and regression analyses based on 236 postgraduate students revealed significant positive associations among mindful learning, SWB, and PWB. In Study 2, 54 students were randomly assigned to three groups: the experimental (which received Mindful Learning Coaching), active-, and blank control groups. The results from repeated-measures ANOVA showed that coaching significantly improved students' mindful learning. The participants' SWB and PWB significantly decreased in both the active- and blank control groups, whilst their SWB and PWB tended to increase in the experimental group. In conclusion, mindful learning, SWB, and PWB are significantly correlated, while the enhancement of mindful learning may be a protective factor in students' well-being.

PD-L1 expression levels in mesenchymal stromal cells predict their therapeutic values for autoimmune hepatitis.

BACKGROUND: Autoimmune hepatitis is a chronic inflammatory hepatic disorder with no effective treatment. Mesenchymal stromal cells (MSCs) have emerged as a promising treatment owing to their unique advantages. However, their heterogeneity is hampering use in clinical applications. METHODS: Wharton's jelly derived MSCs (WJ-MSCs) were isolated from 58 human donors using current good manufacturing practice conditions. Gene expression profiles of the WJ-MSCs were analyzed by transcriptome and single-cell RNA-sequencing (scRNA-seq), and subsequent functional differences were assessed. Expression levels of programmed death-ligand 1 (PD-L1) were used as an indicator to screen WJ-MSCs with varied immunomodulation activities and assessed their corresponding therapeutic effects in a mouse model of concanavalin A-induced autoimmune hepatitis. RESULTS: The 58 different donor-derived WJ-MSCs were grouped into six gene expression profile clusters. The gene in different clusters displayed obvious variations in cell proliferation, differentiation bias, trophic factor secretion, and immunoregulation. Data of scRNA-seq revealed four distinct WJ-MSCs subpopulations. Notably, the different immunosuppression capacities of WJ-MSCs were positively correlated with PD-L1 expression. WJ-MSCs with high expression of PD-L1 were therapeutically superior to WJ-MSCs with low PD-L1 expression in treating autoimmune hepatitis. CONCLUSION: PD-L1 expression levels of WJ-MSCs could be regarded as an indicator to choose optimal MSCs for treating autoimmune disease. These findings provided novel insights into the quality control of MSCs and will inform improvements in the therapeutic benefits of MSCs.

Generation of Human Endometrial Assembloids with a Luminal Epithelium using Air-Liquid Interface Culture Methods.

The endometrial lining of the uterus is essential for women's reproductive health and consists of several different types of epithelial and stromal cells. Although models such as gland-like structures (GLSs) and endometrial assembloids (EnAos) are successfully established, they lack an intact luminal epithelium, which makes it difficult to recapitulate endometrial receptivity. Here, a novel EnAo model (ALI-EnAo) is developed by combining endometrial epithelial cells (EnECs) and stromal cells (EnSCs) and using an improved matrix and air-liquid interface (ALI) culture method. ALI-EnAos exhibit intact EnSCs and glandular and luminal epithelia, which recapitulates human endometrium anatomy, cell composition, hormone-induced menstrual cycle changes, gene expression profiles, and dynamic ciliogenesis. The model suggests that EnSCs, together with the extracellular matrix and ALI culture conditions, contribute to EnAo phenotypes and characteristics reflective of the endometrial menstrual cycle. This enables to transcriptionally define endometrial cell subpopulations. It anticipates that ALI-EnAos will facilitate studies on embryo implantation, and endometrial growth, differentiation, and disease.

Dissecting peri-implantation development using cultured human embryos and embryo-like assembloids.

Studies of cultured embryos have provided insights into human peri-implantation development. However, detailed knowledge of peri-implantation lineage development as well as underlying mechanisms remains obscure. Using 3D-cultured human embryos, herein we report a complete cell atlas of the early post-implantation lineages and decipher cellular composition and gene signatures of the epiblast and hypoblast derivatives. In addition, we develop an embryo-like assembloid (E-assembloid) by assembling naive hESCs and extraembryonic cells. Using human embryos and E-assembloids, we reveal that WNT, BMP and Nodal signaling pathways synergistically, but functionally differently, orchestrate human peri-implantation lineage development. Specially, we dissect mechanisms underlying extraembryonic mesoderm and extraembryonic endoderm specifications. Finally, an improved E-assembloid is developed to recapitulate the epiblast and hypoblast development and tissue architectures in the pre-gastrulation human embryo. Our findings provide insights into human peri-implantation development, and the E-assembloid offers a useful model to disentangle cellular behaviors and signaling interactions that drive human embryogenesis.

Weighted gene co-expression network analysis and CIBERSORT screening of key genes related to m6A methylation in Hirschsprung's disease.

Hirschsprung's disease (HSCR) is a neural crest disease that results from the failure of enteric neural crest cells (ENCCs) to migrate to the corresponding intestinal segment. The RET gene, which regulates enteric neural crest cell proliferation and migration, is considered one of the main risk factors for HSCR and is commonly used to construct HSCR mouse models. The epigenetic mechanism of m6A modification is involved in HSCR. In this study, we analyzed the GEO database (GSE103070) for differentially expressed genes (DEGs) and focused on m6A-related genes. Comparing the RNA-seq data of Wide Type and RET Null, a total of 326 DEGs were identified, of which 245 genes were associated with m6A. According to the CIBERSORT analysis, the proportion of Memory B-cell in RET Null was significantly higher than that of Wide Type. Venn diagram analysis was used to identify key genes in the selected memory B-cell modules and DEGs associated with m6A. Enrichment analysis showed that seven genes were mainly involved in focal adhesion, HIV infection, actin cytoskeleton organization and regulation of binding. These findings could provide a theoretical basis for molecular mechanism studies of HSCR.

Magnetotransport and magnetic properties of Cr-modified Mn2Sb epitaxial thin films.

High-quality Mn2-xCrxSb (x = 0.01, 0.04, and 0.1) epitaxial thin films were grown on SrTiO3 (STO) (001) single-crystal substrates using molecular beam epitaxy. Magnetotransport and magnetic measurements reveal that the x = 0.01 sample undergoes a quasi-ferrimagnetic (I) [Q-FIM(I)]-to-ferrimagnetic (II) [FIM(II)] spin reorientation (SR) transition and a giant magnetoresistance (MR) associated first-order ferrimagnetic(II)-to-antiferromagnetic (AFM) phase transition upon cooling, resulting in the AFM ground state with a weak in-plane net moment. Upon increasing the doping level from x = 0.01 to 0.1, both the SR transition and the first-order magnetic transition are suppressed. For x = 0.1, the former transition is suppressed, leaving only the Q-FIM(I)-to-AFM transition within the whole temperature region. TAFM-FIM shows almost similar changes upon the application of either in-plane or out-of-plane magnetic fields. TAFM-FIM values of the x = 0.01 and 0.04 samples are much higher than those of the Mn2-xCrxSb bulk with similar doping levels, which can be understood by the clamping effect from STO substrates. For each thin-film sample, the MR effect is observed near TAFM-FIM and disappears in the high temperature Q-FIM(I) phase and low temperature AFM phase, indicating that MR is related to the spin-dependent electron scattering during the first-order magnetic phase transition. Based on the magnetotransport and magnetic data, a magnetic phase diagram is established for the Mn2-xCrxSb films in the low doping level region.

The efficacy of a mindfulness-based exercise program in older residents of a long-term care facility in Taiwan.

Older people living in long-term care facilities remain largely inactive, and therefore promoting exercise in this population is necessary. This study evaluated the efficacy of a mindfulness-based exercise program in older residents of a long-term care facility in Taiwan. A convenience sample of 72 older residents of a long-term care facility were recruited and assigned to either an experimental group or a control group. The experimental group (n = 36) participated in an 8-week mindfulness-based exercise program, and the control group (n = 36) received routine care. The generalized estimating equation showed significantly larger improvements in a fear of falling, exercise self-efficacy, dynamic balance, and muscle strength in the experimental group than in the control group from baseline to the end of the intervention and 3 months after the end of the intervention. This study provides a reference for how to improve exercise practice in older people living in long-term care facilities.

Correction: Magnetotransport and magnetic properties of Cr-modified Mn2Sb epitaxial thin films.

Correction for 'Magnetotransport and magnetic properties of Cr-modified Mn2Sb epitaxial thin films' by Ting-Wei Chen et al., Phys. Chem. Chem. Phys., 2023, 25, 5785-5794, https://doi.org/10.1039/D2CP05442F.

Engineering placenta-like organoids containing endogenous vascular cells from human-induced pluripotent stem cells.

The placenta is an essential organ that maintains the health of both the fetus and its mother. Understanding the development of human placenta has been hindered by the limitations of existing animal models and monolayer cell cultures. Models that can recapitulate the essential aspects of human placental multicellular components and vasculature are still lacking. Herein, we presented a new strategy to establish placenta-like organoids with vascular-like structures from human-induced pluripotent stem cells in a defined three-dimensional (3D) culture system. The resulting placenta-like tissue resembles first-trimester human placental development in terms of complex placental components and secretory function. The multicellular tissue was characterized by the inclusion of trophoblasts (cytotrophoblasts, syncytiotrophoblasts, extravillous trophoblasts, and other endogenous vascular cells), which were identified by immunofluorescence, flow cytometry analyses, real-time quantitative reverse transcription polymerase chain reaction and single-cell RNA-seq. Moreover, the 3D tissue was able to secrete the placenta-specific hormone human chorionic gonadotropin ß (hCG-ß) and vascular endothelial growth factor A (VEGFA). The tissue responded to the inflammatory factor tumor necrosis factor-α (TNF-α) and VEGF receptor inhibitors. This new model system can represent the major features of placental cellular components, and function, which have not been realized in 2D monolayer cultures. The developed tissue system might open new avenues for studying normal early human placental development and its disease states.

The positive significance of government-organized nationwide sports events in the post-epidemic era: The impact on citizens' psychological well-being, mindfulness level, and social avoidance distress / La importancia positiva de los eventos deportivos nacionales organizados por el gobierno en la era post-epidemia: el impacto en el bienestar psicológico, el nivel de atención plena y la angustia por evitación social de los ciudadanos

Based on the nationwide sports event "Health Walk" held in Ji'an City, we divided the subjects into sports participation group and non-sports participation group to investigate the differences between the two groups in social avoidance and distress, psychological well-being, and mindfulness level. We also examined the mediating role of mindfulness and social avoidance and distress in whether to participate in sports activities and psychological well-being. In addition, we investigated citizens' approval of the government and their city, and collected basic information about the subjects. We used a 2 (sports participation, non-sports participation) * 2 (high social avoidance and distress, low social avoidance and distress) * 2 (high mindfulness level, low mindfulness level) mixed design. We measured the subjects using Watson's Social Avoidance and Distress Scale, the short version of Ryff's Psychological Well-Being Questionnaire, the Chinese Short Version of the Five-Dimensional Mindfulness Scale, and general survey questionnaires. SPSS 27.0 and the PROCESS plug-in were used to process and analyze the data through descriptive statistics, independent sample t-tests, correlation analysis and mediation effect tests. The results showed that there were significant differences in social avoidance, distress, and mindfulness levels in whether to participate in sports activities (ps <0.001). Whether to participate in sports activities and psychological well-being were significantly correlated with mindfulness (t = 0.368, p <0.001; t = 0.250, p <0.01), and were significantly correlated with social avoidance and distress (t = -0.307, p <0.001; t = -0.443, p <0.001). Mindfulness and social avoidance fully mediated the influence of sports participation on psychological well-being (ps <0.001).(AU)

Genetically engineered mesenchymal stem cells with dopamine synthesis for Parkinson's disease in animal models.

Although striatal delivery of three critical genes for dopamine synthesis by viruses is a potential clinical approach for treating Parkinson's disease (PD), the approach makes it difficult to finely control dopamine secretion amounts and brings safety concerns. Here, we generate genetically engineered mesenchymal stem cells encoding three critical genes for dopamine synthesis (DOPA-MSCs). DOPA-MSCs retain their MSC identity and stable ability to secrete dopamine during passaging. Following transplantation, DOPA-MSCs reinstate striatal dopamine levels and correct motor function in PD rats. Importantly, after grafting into the caudate and putamen, DOPA-MSCs provide homotopic reconstruction of midbrain dopamine pathways by restoring striatal dopamine levels, and safely and long-term (up to 51 months) correct motor disorders and nonmotor deficits in acute and chronic PD rhesus monkey models of PD even with advanced PD symptoms. The long-term benefits and safety results support the idea that the development of dopamine-synthesized engineered cell transplantation is an important strategy for treating PD.

Spontaneous giant vortices and circular supercurrents in a trapped exciton-polariton condensate.

We theoretically study an exciton-polariton condensate trapped in a harmonic potential with an annular pump. With a circular pump, predictions were made for a spontaneous rotating vortex lattice packed by singly quantized vortices. If the circular pump is replaced by an annular pump, singly quantized vortices are absorbed into the central hole and form a multiply quantized vortex. For a sufficiently narrow annular width, all vortices are absorbed into the central hole, ultimately forming a giant vortex with supersonic circular supercurrents flowing around it. Vortex-antivortex pairs can be generated if a defect is present in these supersonic circular supercurrents. We further discover that the motion of the vortex-antivortex pairs depends on the position at which they were generated. We suggest that this property can be used to control whether the velocity of the circular supercurrents is above or below the sound velocity.

Tyrosine 12 of human calcitonin modulates its amyloid formation, membrane binding, and bioactivity.

Irreversible aggregation greatly limits the bioavailability and therapeutic activity of peptide-based drugs, so preventing protein or peptide aggregation is a common issue in drug formulation. Human calcitonin (hCT), a peptide hormone secreted by thyroidal parafollicular cells, can regulate blood calcium levels and maintain bone structure. Hence, it can be used as a treatment for metabolic bone diseases, such as osteoporosis and Paget's disease. However, hCT has a relatively high propensity to form amyloid fibrils that hinder its biological function and limit its pharmaceutical potential. In previous studies, we demonstrated, along with other research groups, that modifying specific residues of hCT is sufficient to prevent hCT aggregation. We proceeded to find the key residues that regulate the aggregation of hCT for a better understanding of the mechanism of hCT aggregation. In this work, we used amyloid propensity prediction software and found that Tyr12 may play a key role in regulating hCT aggregation. Thus, we propose three human calcitonin variants (Y12E, Y12P, Y12R) for hCT non-amyloidogenic substituents and examined the aggregation characteristics of variants using multiple biophysical techniques. Y12E showed the best anti-aggregation propensity and can work as inhibitor of hCT aggregation. We also found this residue is crucial for membrane binding and receptor binding. The data presented herein provides an overview of Tyr12 that should be carefully considered in peptide design.

Aromatization as an Impetus to Harness Ketones for Metallaphotoredox-Catalyzed Benzoylation/Benzylation of (Hetero)arenes.

Herein we report ketones as feedstock materials in radical cross-coupling reactions under Ni/photoredox dual catalysis. In this approach, simple condensation first converts ketones into prearomatic intermediates that then act as activated radical sources for cross-coupling with aryl halides. Our strategy enables the direct benzylation/benzoylation of (hetero)arenes under mild reaction conditions with high functional group tolerance.

Establishment of Trophoblast-Like Tissue Model from Human Pluripotent Stem Cells in Three-Dimensional Culture System.

The placenta has a lifelong impact on the health of both the mother and fetus. Despite its significance, human early placental development is poorly understood due to the limited models. The models that can reflect the key features of early human placental development, especially at early gestation, are still lacking. Here, the authors report the generation of trophoblast-like tissue model from human pluripotent stem cells (hPSCs) in three-dimensional (3D) cultures. hPSCs efficiently self-organize into blastocoel-like cavities under defined conditions, which produce different trophoblast subtypes, including cytotrophoblasts (CTBs), syncytiotrophoblasts (STBs), and invasive extravillous trophoblasts (EVTs). The 3D cultures can exhibit microvilli structure and secrete human placenta-specific hormone. Single-cell RNA sequencing analysis further identifies the presence of major cell types of trophoblast-like tissue as existing in vivo. The results reveal the feasibility to establish 3D trophoblast-like tissue model from hPSCs in vitro, which is not obtained by monolayer culture. This new model system can not only facilitate to dissect the underlying mechanisms of early human placental development, but also imply its potential for study in developmental biology and gestational disorders.

Half-skyrmions with higher topological quantum numbers in homogeneous exciton-polariton condensates.

We investigate the topological excitations of half-quantum vortices (HQVs) with higher topological quantum numbers in a homogeneous spinor exciton-polariton condensate pumped by a laser beam and an additional coherent light carrying orbital angular momentum. The spin texture and integrated topological charge can be controlled through the pump. Among these textures, the polaritonic half-skyrmions (or polaritonic merons) can be created with a suitable excitation condition. Moreover, when the pump polarization is in favor of the vortex component of the HQV, there is an inversion of circular polarization (spin flipping) from the center of the HQV towards the edge. The radial flipping position can be manipulated by the pump polarization or power. Finally, we demonstrate that the HQVs can stably exist from the linear stability analysis.

Synthetic Tryptanthrin Derivatives Induce Cell Cycle Arrest and Apoptosis via Akt and MAPKs in Human Hepatocellular Carcinoma Cells.

Trytanthrin, found in Ban-Lan-Gen, is a natural product containing an indoloquinazoline moiety and has been shown to possess anti-inflammatory and anti-viral activities. Chronic inflammation and hepatitis B are known to be associated with the progression of hepatocellular carcinoma (HCC). In this study, a series of tryptanthrin derivatives were synthesized to generate potent anti-tumor agents against HCC. This effort yielded two compounds, A1 and A6, that exhibited multi-fold higher cytotoxicity in HCC cells than the parent compound. Flow cytometric analysis demonstrated that A1 and A6 caused S-phase arrest and downregulated the expression of cyclin A1, B1, CDK2, and p-CDC2. In addition to inducing caspase-dependent apoptosis, A1 and A6 exhibited similar regulation of the phosphorylation or expression of multiple signaling targets, including Akt, NF-κB, and mitogen-activated protein kinases. The anti-tumor activities of A1 and A6 were also attributable to the generation of reactive oxygen species, accompanied by an increase in p-p53 levels. Therefore, A1 and A6 have potential clinical applications since they target diverse aspects of cancer cell growth in HCC.