Unraveling the connection between Hashimoto's Thyroiditis and non-alcoholic fatty liver disease: exploring the role of CD4+central memory T cells through integrated genetic approaches.

PURPOSE: Exploring the connection between Hashimoto's thyroiditis (HT) and non-alcoholic fatty liver disease (NAFLD) through integrated genetic approaches. METHODS: We utilized integrated genetic approaches, such as single-cell RNA sequencing (scRNA-seq) data analysis, Mendelian Randomization (MR), colocalization analysis, cell communication, and metabolic analyses, to investigate potential correlations between HT and NAFLD. RESULTS: Through the integrated analysis of scRNA-seq data from individuals with HT, NAFLD, and healthy controls, we observed an upregulation in the proportion of CD4+central memory (CD4+CM) T cells among T cells in both diseases. A total of 63 differentially expressed genes (DEGs) were identified in the CD4+CM cells after the differential analysis. By using MR, 8 DEGs (MAGI3, CSGALNACT1, CAMK4, GRIP1, TRAT1, IL7R, ERN1, and MB21D2) were identified to have a causal relationship with HT, and 4 DEGs (MAGI3, RCAN3, DOCK10, and SAMD12) had a causal relationship with NAFLD. MAGI3 was found to be causally linked to both HT and NAFLD. Therefore, MAGI3 was designated as the marker gene. Reverse MR and Steiger filtering showed no evidence of reverse causality. Colocalization analyses further indicated close links between MAGI3 and HT as well as NAFLD. Finally, based on the expression levels of MAGI3, we stratified CD4+CM cells into two subsets: MAGI3+CD4+CM cells and MAGI3-CD4+CM cells. Functional analyses revealed significant differences between the two subsets, potentially related to the progression of the two diseases. CONCLUSION: This study delves into the potential connections between HT and NAFLD through integrated genetic methods. Our research reveals an elevated proportion of CD4+CM cells within T cells in both HT and NAFLD. Through MR and colocalization analysis, we identify specific genes causally linked to HT and NAFLD, such as MAGI3. Ultimately, based on MAGI3 expression levels, we categorize CD4+CM cells into MAGI3+CD4+CM cells and MAGI3-CD4+CM cells, uncovering significant differences between them through functional analyses.

Quantitative identification of the co-exposure effects of e-waste pollutants on human oxidative stress by explainable machine learning.

Global electronic waste (e-waste) generation continues to grow. The various pollutants released during precarious e-waste disposal activities can contribute to human oxidative stress. This study encompassed 129 individuals residing near e-waste dismantling sites in China, with elevated urinary concentrations of e-waste-related pollutants including heavy metals, polycyclic aromatic hydrocarbons (PAHs), organophosphorus flame retardants (OPFRs), bisphenols (BPs), and phthalate esters (PAEs). Utilizing an explainable machine learning framework, the study quantified the co-exposure effects of these pollutants, finding that approximately 23% and 18% of the variance in oxidative DNA damage and lipid peroxidation, respectively, was attributable to these substances. Heavy metals emerged as the most critical factor in inducing oxidative stress, followed by PAHs and PAEs for oxidative DNA damage, and BPs, OPFRs, and PAEs for lipid peroxidation. The interactions between different pollutant classes were found to be weak, attributable to their disparate biological pathways. In contrast, the interactions among congeneric pollutants were strong, stemming from their shared pathways and resultant synergistic or additive effects on oxidative stress. An intelligent analysis system for e-waste pollutants was also developed, which enables more efficient processing of large-scale and dynamic datasets in evolving environments. This study offered an enticing peek into the intricacies of co-exposure effect of e-waste pollutants.

Manipulating the Dynamic Adaptivity of a Fluid Interface to Maintain the Multipotency of Mesenchymal Stromal Cells.

The native extracellular matrix is highly dynamic with continuous mutual feedback between cells being responsible for many important cell function regulators. However, establishing bidirectional interaction between complex adaptive microenvironments and cells remains elusive. Herein an adaptive biomaterial based on lysozyme monolayers self-assembled at a perfluorocarbon FC40-water interface is reported. The dynamic adaptivity of interfacially assembled protein nanosheets is modulated independently of bulk mechanical properties by covalent crosslinking. This provides a scenario to establish bidirectional interactions of cells with liquid interfaces of varying dynamic adaptivity. This is found that growth and multipotency of human mesenchymal stromal cells (hMSCs) are enhanced at the highly adaptive fluid interface. The multipotency retention of hMSCs is mediated by low cell contractility and metabolomic activity involving the continuous mutual feedback between the cells and materials. Consequently, an understanding of the cells' response to dynamic adaptivity has substantial implications for regenerative medicine and tissue engineering.

Migration deficits of the neural crest caused by CXADR triplication in a human Down syndrome stem cell model.

Down syndrome (DS) is the most common chromosomal abnormality in live-born infants and is caused by trisomy of chromosome 21. Most individuals with DS display craniofacial dysmorphology, including reduced sizes of the skull, maxilla, and mandible. However, the underlying pathogenesis remains largely unknown. Since the craniofacial skeleton is mainly formed by the neural crest, whether neural crest developmental defects are involved in the craniofacial anomalies of individuals with DS needs to be investigated. Here, we successfully derived DS-specific human induced pluripotent stem cells (hiPSCs) using a Sendai virus vector. When DS-hiPSCs were induced to differentiate into the neural crest, we found that trisomy 21 (T21) did not influence cell proliferation or apoptosis. However, the migratory ability of differentiated cells was significantly compromised, thus resulting in a substantially lower number of postmigratory cranial neural crest stem cells (NCSCs) in the DS group than in the control group. We further discovered that the migration defects could be partially attributed to the triplication of the coxsackievirus and adenovirus receptor gene (CXADR; an adhesion protein) in the DS group cells, since knockdown of CXADR substantially recovered the cell migratory ability and generation of postmigratory NCSCs in the DS group. Thus, the migratory deficits of neural crest cells may be an underlying cause of craniofacial dysmorphology in individuals with DS, which may suggest potential targets for therapeutic intervention to ameliorate craniofacial or other neural crest-related anomalies in DS.

A novel missense mutation within the domain of lysine demethylase 4D (KDM4D) gene is strongly associated with testis morphology traits in pigs.

Lysine demethylase 4D (KDM4D) encodes a histone demethylase, which can influence the androgen signaling as well as play an essential role in spermatogenesis. Recently a study has shown that the mRNA of KDM4D is the key to the successful clone of the Macaque monkeys named as "Zhongzhong" and "Huahua," which greatly increased pregnancy rates of female monkey, suggesting that the KDM4D gene may be strongly associated with reproduction. Therefore, the objective of this study was to explore possible single nucleotide polymorphisms (SNPs) within the coding region of KDM4D gene and analyze the associations with testis morphology traits of male pigs. Herein, two SNPs in exon1 of pig KDM4D gene were identified（NC_010451.4:g.1078A > G and NC_010451.4:g.1358G > C）. Among them, the g.1078A > G mutation was located at the JmjN domain which located from 15 to 55 amino acids of KDM4D. Association analyses showed that the g.1078A > G mutation was strongly associated with testis long circumference (TLC), testis short girth (TSG) and testis weight (TW) of Large White (LW) as well as Landrace (LD) (p < 0.05). The AA/AG genotype had a positive effect on testis morphology traits. Briefly, the novel missense mutation g.1078A > G could be a molecular marker for improving testis morphology traits in pig breeding.

Characterization and Therapeutic Application of Mesenchymal Stem Cells with Neuromesodermal Origin from Human Pluripotent Stem Cells.

Rationale: Mesenchymal stem cells (MSC) hold great promise in the treatment of various diseases including autoimmune diseases, inflammatory diseases, etc., due to their pleiotropic properties. However, largely incongruent data were obtained from different MSC-based clinical trials, which may be partially due to functional heterogeneity among MSC. Here, we attempt to derive homogeneous mesenchymal stem cells with neuromesodermal origin from human pluripotent stem cells (hPSC) and evaluate their functional properties. Methods: Growth factors and/or small molecules were used for the differentiation of human pluripotent stem cells (hPSC) into neuromesodermal progenitors (NMP), which were then cultured in animal component-free and serum-free induction medium for the derivation and long-term expansion of MSC. The resulted NMP-MSC were detailed characterized by analyzing their surface marker expression, proliferation, migration, multipotency, immunomodulatory activity and global gene expression profile. Moreover, the in vivo therapeutic potential of NMP-MSC was detected in a mouse model of contact hypersensitivity (CHS). Results: We demonstrate that NMP-MSC express posterior HOX genes and exhibit characteristics similar to those of bone marrow MSC (BMSC), and NMP-MSC derived from different hPSC lines show high level of similarity in global gene expression profiles. More importantly, NMP-MSC display much stronger immunomodulatory activity than BMSC in vitro and in vivo, as revealed by decreased inflammatory cell infiltration and diminished production of pro-inflammatory cytokines in inflamed tissue of CHS models. Conclusion: Our results identify NMP as a new source of MSC and suggest that functional and homogeneous NMP-MSC could serve as a candidate for MSC-based therapies.