Age-related alterations in myelin are a prominent feature of brain aging, yet how myelin-associated markers and oligodendrocyte lineage cell populations change across the primate lifespan remains incompletely characterized. Here, we provide a multimodal, cross-sectional analysis of myelin-related imaging and cellular markers in the prefrontal cortex (PFC) of age-matched both male and female rhesus macaques across postnatal development and aging using a multimodal approach combining magnetic resonance imaging (MRI), histological analysis, immunohistochemistry, and RNAscope in situ hybridization. We quantified regional gray and white matter volumes and myelin water fraction measures in prefrontal cortex (PFC) subregions BA9 and BA46 across four age groups: 5, 10, 15, and 30 years. Myelin water fraction and regional brain volumes exhibited age-dependent increases from childhood through adolescence, peaking at 15 years, followed by a decline in aged animals. Histological analyses revealed age-associated changes in myelin organization and the presence of myelin fragments within Iba1-positive microglia, along with dynamic alterations in the density of cells expressing oligodendrocyte lineage-associated markers, including Olig2 and oligodendrocyte precursor cell (OPC)-associated markers, in BA9 and BA46. OPC density displayed a nonlinear, ageassociated pattern across developmental and aging stages, coinciding temporally with changes in myelin-associated imaging measures. Our findings define an age-related framework of myelin alterations and oligodendrocyte lineage markers in the primate prefrontal cortex. This work establishes a reference dataset for oligodendrocyte lineage dynamics across the lifespan in a translationally relevant primate model, providing a foundation for future mechanistic and interventional studies of myelin maintenance during brain aging.

Exosomes are nanoscale particles that participate in multiple biological processes and are secreted by various cell types. Exosomes derived from dermal papilla cells (DPC-Exos) regulate hair follicle (HF) growth and development. In this study, HF development-related genes were significantly expressed in low-passage dermal papilla cells (DPCs). Low-passage DPC-Exos promoted hair follicle stem cell (HFSC) proliferation. After the collection of DPC-Exos, miRNA sequencing identified 36 differentially expressed (DE) miRNAs between low-passage and high-passage DPC-Exos. Among these, miR-218-5p was significantly upregulated in low-passage DPC-Exos and dysregulated HF growth and development-related gene expression in HFSCs. Furthermore, the transport mechanism of exosomal miR-218-5p from DPCs is into HFSCs was verified. RNA sequencing of HFSCs treated with exosomal miR-218-5p identified differentially expressed genes (DEGs). The results indicated involvement of miR-218-5p in signaling pathways related to HF growth and development. Additionally, in vitro HF organ culture experiments demonstrated that exosomal miR-218-5p actively promotes hair growth. In summary, low-passage DPC-Exos enhance HFSC proliferation. Exosomal miR-218-5p may serve as a biomarker and therapeutic target for human hair disorders and as a tool to improve wool production in mammals.

Decorin (DCN) is a member of the small leucine-rich proteoglycan family within the extracellular matrix, playing a role in the growth and development of hair follicle (HF). Exosomes serve as significant mediators of intercellular communication and are involved in the cyclic regeneration of HF. Exosomes derived from dermal papilla cells (DPC-Exos) are essential for the cycling and regrowth of HF. The present study demonstrated that DCN treatment significantly enhances the proliferation of DPCs, thereby promoting hair follicle growth. miRNA sequencing revealed 442 differentially expressed exosomal miRNAs. The regulatory mechanism of exosomal miR-129-2-3p, an up-regulated differential miRNA, was further investigated. The study identified its role in transporting DPCs to HFSCs through DPC-Exos. miR-129-2-3p has been shown to suppress the expression of genes associated with HF growth and development, lower the expression of genes and proteins downstream of the TGF-(3 signaling pathway, promote HFSC proliferation, and decrease HFSC apoptosis. Furthermore, miR129-2-3p displayed an antagonistic effect on activating the TGF-(3/SMAD3 signaling pathway induced by SRI011381. The findings indicate that DCN-mediated DPC-Exos influence HF growth and development through the miR-129-2-3p/SMAD3/TGF-(3 regulatory axis. These results may facilitate novel strategies for the diagnosis and treatment of human hair disorders, in addition to enhancing industrial wool production.

The application of isothiazolinones as antimicrobial agents has caused prevalent pollution of marine environment. However, the developmental toxicity and endocrine disrupting effects of different isothiazolinone analogs to marine organisms remain largely elusive. In the present study, marine medaka embryos were exposed to 0, 1, 3, and 10 μg/L of six representative isothiazolinone analogs, including isothiazole, methylisothiazolinone (MIT), methylchloroisothiazolinone (MCI), octylisothiazolinone (OIT), benzisothiazolinone (BIT), and dichlorocthylisothiazolinone (DCOIT), after which the anomalies in early embryogenesis and endocrine homeostasis were examined. In vivo results showed that OIT, BIT, and DCOIT were potently estrogenic, which was characterized by the higher estradiol (E2) content and remarkable elevation of E2/testosterone ratio in larval medaka. Correlation analysis found significantly positively relationship among OIT, BIT, and DCOIT, indicating their similar modes of toxicity. Besides, in vitro exposure using H295R cells was performed to gain more insights into endocrine disrupting mechanisms, further confirming the multiple disturbances of DCOIT in reproductive endocrine cascades, consisting of MAPK proteins, aromatase, and sex hormones. Overall, the present findings underscore the high susceptibility of marine organisms to the developmental and endocrine toxicity of isothiazolinones, especially during early embryonic stages. In the future, the marine ecological risks of isothiazolinones need to be evaluated urgently, thus facilitating chemical lifecycle management.

Traumatic brain injury (TBI) is a recognized global public health problem. However, there are still limitations in the available therapeutic approaches and a lack of clinically effective drugs. Therefore, an in-depth exploration of the secondary pathological mechanism of TBI and the identification of new effective drugs are urgently needed. Cannabidiol (CBD), a component derived from the cannabis plant, has potential therapeutic effects on neurological diseases and has received increasing attention. However, few reports on CBD intervention in TBI patients exist. Here, we use the Feeney free-fall method to establish a rat TBI model. CBD significantly improves neurological deficit scores, neuronal damage and blood-brain barrier permeability in rats and significantly inhibits the expressions of the brain injury markers S-100β and NSE. Mechanistically, CBD attenuates TBI-induced astrocyte activation, reduces inflammation, and attenuates the expressions of inflammatory prostaglandin system indicators. The use of TG6-10-1 (EP2 inhibitor) and H-89 (PKA inhibitor) indicates that CBD attenuates TBI-induced neurological damage via the PGE 2-EP2-cAMP-PKA signaling pathway. Overall, this research provides a novel drug candidate for the treatment of clinical brain trauma.

Decorin (DCN) is a member of the small leucine-rich proteoglycan family within the extracellular matrix, playing a role in the growth and development of hair follicle (HF). Exosomes serve as significant mediators of intercellular communication and are involved in the cyclic regeneration of HF. Exosomes derived from dermal papilla cells (DPC-Exos) are essential for the cycling and regrowth of HF. The present study demonstrated that DCN treatment significantly enhances the proliferation of DPCs, thereby promoting hair follicle growth. miRNA sequencing revealed 442 differentially expressed exosomal miRNAs. The regulatory mechanism of exosomal miR-129-2-3p, an up-regulated differential miRNA, was further investigated. The study identified its role in transporting DPCs to HFSCs through DPC-Exos. miR-129-2-3p has been shown to suppress the expression of genes associated with HF growth and development, lower the expression of genes and proteins downstream of the TGF-β signaling pathway, promote HFSC proliferation, and decrease HFSC apoptosis. Furthermore, miR-129-2-3p displayed an antagonistic effect on activating the TGF-β/SMAD3 signaling pathway induced by SRI-011381. The findings indicate that DCN-mediated DPC-Exos influence HF growth and development through the miR-129-2-3p/SMAD3/TGF-β regulatory axis. These results may facilitate novel strategies for the diagnosis and treatment of human hair disorders, in addition to enhancing industrial wool production.

Colorectal cancer (CRC) and its metastatic form (mCRC) demonstrate considerable biological and clinical heterogeneity. By analyzing transcriptomic data from CRC and mCRC patients, we identified significant differences in gene expression profiles between the two. Our study focused on immune-related differentially expressed genes, which enabled the classification of CRC patients into four distinct subgroups based on their gene expression patterns. These subgroups exhibited marked differences in overall survival (OS) and immune infiltration levels, with Group 1 characterized by a robust immune response.To refine prognostic assessment, we employed a LASSO regression model to select core genes and developed a risk scoring system with promising clinical utility. Furthermore, methylation analysis uncovered notable epigenetic distinctions between CRC and mCRC, particularly involving the SALL1 gene and its methylation sites. Among these, the methylation level at the cg13755795 site emerged as an independent prognostic biomarker, offering predictive value for patient outcomes.Our findings provide a comprehensive view of the transcriptomic and epigenetic differences between CRC and mCRC, identify novel prognostic biomarkers and therapeutic targets, and propose potential strategies for personalized prognosis prediction and targeted therapy. This work contributes valuable insights into immune regulatory mechanisms and supports the development of advanced treatment approaches for colorectal cancer.

The gut microbiome, commonly termed as a "super organ", plays a crucial role in the modulation of various biological functions associated with metabolism, endocrinology, immunology, and neurology. However, gut microbiome is extremely susceptible to the risks of environmental pollutants, which will drive gut microbial community to dysbiosis. Simultaneously, restoring healthy gut microbiome can protect the hosts from the health hazards of pollutants. It is increasingly verified that probiotics, prebiotics, and fecal microbiota transplantation (FMT) are efficacious measures to manipulate and remediate gut microecosystem. Among various probiotic strains, lactic acid bacteria are the most extensively applied in toxicity mitigation, which is characterized by shaping gut microbiota structure and metabolism, increasing gut epithelial barrier integrity, promoting fecal elimination of pollutants, suppressing inflammation symptoms, and then improving host systemic physiology. Prebiotics are dietary fibers that cannot be digested by the host, but can be fermented by specific gut bacteria to produce short chain fatty acids, which are identified as the key effect molecules in the manifestation of prebiotic toxicity mitigation actions. In addition, by transplanting the entire community of healthy gut microbiota, FMT also shows effective performances in counteracting the adverse effects of environmental pollutants and recovering host animal health. Intriguingly, FMT from young donors is even found to inhibit the toxic disturbances in healthy aging progression. Based on current evidence, this review summarized the findings about using probiotics, prebiotics, and FMT to manipulate gut microbiota and alleviate the health impairment of environmental pollutants. Key mechanistic insights into the interactive behaviors were underlined. Furthermore, the challenges and future directions in harnessing gut microbiota manipulation as a novel therapeutic approach to mitigate pollutant-induced toxicities were postulated. This review is expected to advocate comprehensive scientific research and literally favor the application of health intervention strategies.

OBJECTIVE:The ovary, as an important reproductive organ, tightly regulates the litter size of rabbits through its complex network of genes. This study aims to identify candidate genes related to litter size in rabbits through RNA sequencing and to analyze the regulatory effects of C-X-C motif chemokine ligand 12 (CXCL12) on granulosa cells (GCs). METHODS:This study used ovarian transcriptome sequencing to identify differentially expressed genes between the ovarian tissues of New Zealand female rabbits with high (H) and low (L) litter sizes. In addition, a new candidate gene which was highly expressed in group H, namely the chemokine ligand CXCL12, was selected for further verification of biological functions. RESULTS:The cell counting kit-8 assay and flow cytometry analysis showed that CXCL12 can promote GCs proliferation but inhibit their apoptosis. Furthermore, quantitative reverse transcription polymerase chain reaction and western blotting indicated that CRABP1 regulated genes (PCNA, CCND1, CDK2, Bcl-2 and Bax) and proteins (CCND1, PCNA, Bcl-2 and Bax) related to cell cycle and cell proliferation. In addition, it can also regulate the expression levels of genes (TAF4B, CITED1, WNT2, WNT10B, and HSD17B1) and proteins (CITED1 and WNT10B) related to follicle development and litter size. Finally, it was found that CXCL12 targeted the CXCR4 receptor to activate the JAK/STAT signaling pathway. CONCLUSION:We utilized bioinformatics to screen 184 genes potentially associated with litter size in New Zealand female rabbits. Among these, CXCL12 plays a role in regulating the expression of cell cycle-related genes, promoting GCs proliferation. As a result, CXCL12 emerges as a promising candidate marker for selecting high litter size female rabbits in future breeding and production practices.

Dermal papilla cells (DPCs) are crucial for the growth and development of hair follicles (HF). (-)-Epigallocatechin-3-gallate (EGCG) is the primary catechin identified in green tea, which has antioxidant effects and regulates cell activity. This study demonstrates that EGCG could promote the proliferation of DPCs. In addition, EGCG treatment significantly upregulated the expression of PCNA, CCND1, HIF-1 alpha, VEGFA, and Bcl-2 mRNAs in DPCs, while significantly reducing the gene expression of Bax. The optimal concentration of EGCG addition was screened. When detecting the antioxidant ability of DPCs, treatment with 0.5 mu M EGCG could intensify the relative activity of catalase, superoxide dismutase, and glutathione, promoting the antioxidant ability and migration of DPCs. Subsequently, the differentially expressed genes (DEGs) associated with the EGCG treatment in DPCs were identified by RNA sequencing, revealing 21 DEGs, including VEGFA, POSTN, CLU, SERPINE2, and NPY. As the candidate gene, the role of VEGFA in regulating HF growth and development was investigated. Immunofluorescence staining revealed that EGCG treatment enhanced the fluorescence intensity of VEGFA and CLU in DPCs. After VEGFA overexpression and knockdown in DPCs, it was found to regulate the HF growth and the expression of development-related genes, enhance the expression of proliferating cell nuclear antigen, and promote DPCs proliferation. EGCG could also rescue the siRNA-VEGFA effect in DPCs. Thus, this study demonstrates that EGCG possibly regulates cell viability in DPCs by inducing VEGFA expression level, and provides a reference for exploring the mechanism of HF growth and the treatment of hair-related illnesses.

Ataxia-telangiectasia (A-T) is a hereditary neurodegenerative disorder caused by mutations in the ATM (ataxia-telangiectasia mutated) gene. Although existing rodent models reproduce some of the multi-systemic features of A-T, they notably fail to recapitulate the severe neurological manifestations, particularly the profound cerebellar atrophy and associated ataxia. To address this limitation, we have generated ATM-deficient rhesus macaques using CRISPR-Cas9. These macaques exhibit hallmark features of A-T, including growth retardation, lymphopenia, elevated a-fetoprotein levels, oculocutaneous telangiectasias, heightened sensitivity to ionizing radiation, and most critically, cerebellar atrophy, Purkinje cell loss, and early-stage cerebellar neurodegeneration leading to significant motor impairments. Single-nucleus transcriptomic profiling of the cerebellum revealed pronounced gene expression changes associated with ATM deficiency, particularly in molecular layer interneurons (MLIs), which are implicated in Purkinje cell loss. This non-human primate model provides deeper insights into the pathogenesis of A-T and represents a promising and valuable platform for developing therapeutic strategies.

Particulate materials arising from road-deposited sediments (RDS) are an essential target for the control and management of surface runoff pollution. However, the heterogeneity of urban spaces hinders the identification and quantification of particulate pollution, which is challenging when formulating precise control measures. To elucidate the factors that drive particulate pollution in heterogeneous urban spaces, the accumulation of RDS on dry days and the total suspended solids during six natural rainfall events were investigated across three urban-rural spatial units (central urban, central suburban, and remote suburban). The underlying surface type (asphalt or cement roads) and particle size composition jointly determined the spatial heterogeneity in the static accumulation and dynamic output loads of RDS during rainfall. These two factors explained 59.6% and 18.9% of the spatial heterogeneity, respectively, according to principal component analysis. A novel CPSI exponential wash-off equation that incorporates particle size composition and underlying surface type was applied. It precisely described the spatial heterogeneity of RDS wash-off loads, the estimated values exhibiting event mean concentration errors of 10.8-18.2%. When coupled with the M(V) curve, this CPSI exponential wash-off equation more precisely split the initial volume of runoff: a lower total volume (17.6-38.0%) was shown to carry a higher proportion of the load (70.0-93.7%) compared to the traditional coupled exponential wash-off equation (volume: 31.6-49.0%, load: 37-90%). This study provides a new approach to characterizing RDS wash-off processes and splitting initial runoff in heterogeneous spaces.

Transplanting young feces into the aged was found to effectively counteract the endocrine disrupting effects of perfluorobutanesulfonate (PFBS) pollutant, showing promise in the maintenance of healthy aging. However, the interactive mechanisms between young fecal transplantation and PFBS endocrine disruption during aging remain unclear. In this follow-up study, aged zebrafish were administered young donor feces and then exposed to environmentally relevant concentrations of PFBS (0 and 100 μg/L). Alterations in the holistic estrobolome along gut-liver axis were investigated. The results showed that PFBS singular exposure significantly increased blood estradiol concentration in the aged, inducing an estrogenic activity. Concentrations of other estrogen forms, including estrone and estriol, were also disrupted by PFBS. Interestingly, young fecal transplant effectively mitigated the estrogenic toxicity of PFBS and largely restored estrogen equilibrium. After PFBS exposure, the transcriptions of estrogen metabolic genes were consistently upregulated in aged livers, causing the accumulation of 2-methoxyestradiol-3-methylether metabolite. In contrast, aged livers coexposed to young fecal transplant and PFBS enhanced the glucuronidation process, successfully facilitating the elimination and detoxification of estrogen metabolites. In aged gut, PFBS exposure inhibited β-glucuronidase enzyme activity, implying the suppression of estrogen deconjugation and recycle. However, in the combined group, β-glucuronidase activity was significantly stimulated, thus reestablishing estrobolome dynamics. Overall, current findings provide mechanistic insights into the antagonistic interaction between young fecal transplant and PFBS on reproductive endocrinology. Gut microbiota manipulation appears appealing to maintain healthy aging progression albeit the interruption of environmental xenobiotics.

This study investigated the regulatory effect of alternative spliceosomes of the fibroblast growth factor 5 (FGF5) gene on hair follicle (HF) growth and development in rabbits. The FGF5 alternative spliceosomes (called FGF5-X1, FGF5-X2, FGF5-X3) were cloned. The overexpression vector and siRNA of spliceosomes were transfected into dermal papilla cells (DPCs) to analyze the regulatory effect on DPCs. The results revealed that FGF5-X2 and FGF5-X3 overexpression significantly decreased LEF1 mRNA expression (p < 0.01). FGF5-X1 overexpression significantly reduced CCND1 expression (p < 0.01). FGF5-X1 and FGF5-X2 possibly downregulated the expression level of FGF2 mRNA (p < 0.05), and FGF5-X3 significantly downregulated the expression level of FGF2 mRNA (p < 0.01). The FGF5 alternative spliceosomes significantly downregulated the BCL2 mRNA expression level in both cases (p < 0.01). FGF5-X1 and FGF5-X2 significantly increased TGFβ mRNA expression (p < 0.01). All three FGF5 alternative spliceosomes inhibited DPC proliferation. In conclusion, the expression profile of HF growth and development-related genes can be regulated by FGF5 alternative spliceosomes, inhibiting the proliferation of DPCs and has an influence on the regulation of HF growth in rabbits. This study provides insights to further investigate the mechanism of HF development in rabbits via FGF5 regulation.

In commercial rabbit breeding, litter size is a crucial reproductive trait. This trait directly determines the reproductive ability of female rabbits and is crucial for evaluating the production efficiency. We here compared differentially expressed proteins of in the ovary tissue from New Zealand female rabbits with high (H) and low (L) litter sizes by using 4D label-free quantitative proteomic technology and identified 92 differential proteins. The biological functions of these proteins were revealed through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Most distributions of GO and KEGG were related to reproduction, growth development, and metabolism. Furthermore, a novel candidate gene cellular retinoic acid binding protein-1 (CRABP1), which was highly expressed in the L group, was selected for further biological function verification. The Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis revealed that CRABP1 can promote granulosa cell (GC) apoptosis and inhibit GC proliferation. Furthermore, qRT-PCR and western blotting analysis revealed that CRABP1 regulates the genes (HSD17B1, Wnt-10b, FSHR, TAF4B, BMP15, and BMP6) and protein (Wnt-10b) associated with steroid hormone synthesis and follicle development. The PCR product direct sequencing method revealed single nucleotide polymorphisms in the core promoter region of CRABP1. Luciferase activity assays revealed that the transcriptional activity of the GG genotype was significantly higher than that of the TT or TG genotype. Different genotypes are accompanied by changes in transcription factors, which indicates that T-359G polymorphism can regulate CRABP1 expression. In general, we identified litter size-related genes and revealed the mechanism underlying the effect of CRABP1 on litter size. CRABP1 serves as a key factor in the reproductive capacity of rabbits and can act as a molecular biomarker for the breeding of New Zealand rabbits.

Premature ovarian failure (POF) is characterized by a significant decline in the ovarian follicle pool and oocyte reserve, alongside an increase in the number of low-quality oocytes and apoptosis of granulosa cells (GCs). Exosome-derived miRNA plays a regulatory role in crucial cellular activities and contributes to the onset and progression of POF. In this study, we successfully established a rabbit model of POF and conducted in vitro and in vivo experiments that confirmed DiI-labeled Pla-Exos (exosomes derived from plasma) could enter the follicle through blood circulation, with GCs capable of uptaking these exosomes. Our RNA-seq analysis revealed elevated expression of miR-10a-5p in Pla-Exos from POF rabbits. Moreover, our findings demonstrate that exosomal miR-10a-5p suppresses GCs proliferation and induces apoptosis via the mitochondrial pathway. Additionally, exosomal miR-10a-5p inhibits the TrkB/Akt/mTOR signaling pathway by downregulating BDNF expression, thereby modulating the expression levels of proteins and genes associated with the cell cycle, follicle development, and GCs senescence. In conclusion, our study highlights the role of Pla-Exos miR-10a-5p in promoting rabbit POF through the TrkB/Akt/mTOR signaling pathway by targeting BDNF. These findings provide new insights into potential therapeutic targets for POF, offering valuable references for addressing concerns related to female reproductive function.

Perfluoroalkyl acids (PFAAs) of different chemical speciation were previously found to cause diverse toxicity. However, the toxicological mechanisms depending on chemical speciation are still largely unknown. In this follow-up study, zebrafish embryos were acutely exposed to only one concentration at 4.67 mu M of the acid and salt of representative PFAAs, including perfluorooctanoic acid (PFOA), perfluorobutane carboxylic acid (PFBA), and perfluorobutanesulfonic acid (PFBS), till 96 h post -fertilization (hpf), aiming to gain more mechanistic insights. High -throughput proteomics found that PFAA acid and salt exerted discriminative effects on protein expression pattern. Bioinformatic analyses based on differentially expressed proteins underlined the developmental cardiotoxicity of PFOA acid with regard to cardiac muscle contraction, vascular smooth muscle contraction, adrenergic signaling in cardiomyocytes, and multiple terms related to myocardial contraction. PFOA salt and PFBS acid merely disrupted the cardiac muscle contraction pathway, while cardiac muscle cell differentiation was significantly enriched in PFBA acid -exposed zebrafish larvae. Consistently, under PFAA exposure, especially PFOA and PFBS acid forms, transcriptional levels of key genes for cardiogenesis and the concentrations of troponin and epinephrine associated with myocardial contraction were significantly dysregulated. Moreover, a transgenic line Tg ( my17: GFP ) expressing green fluorescent protein in myocardial cells was employed to visualize the histopathology of developing heart. PFOA acid concurrently caused multiple deficits in heart morphogenesis and function, which were characterized by the significant increase in sinus venosus and bulbus arteriosus distance (SV-BA distance), the induction of pericardial edema, and the decrease in heart rate, further confirming the stronger toxicity of PFOA acid than the salt counterpart on heart development. Overall, this study highlighted the developmental cardiotoxicity of PFAAs, with potency ranking PFOA > PFBS > PFBA. The acid forms of PFAAs induced stronger cardiac toxicity than their salt counterparts, providing an additional insight into the structure -toxicity relationship.

The antifoulant 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) is an emerging pollutant in the marine environment, which may disrupt the thyroid endocrine system. However, DCOIT toxicity in relation to thyroid endocrine disruption and the underlying mechanisms remains largely unclear. In this study, in vivo, in silico, in vitro, and ex vivo assays were performed to clarify DCOIT's thyroid toxicity. First, marine medaka (Oryzias melastigma) were exposed to environmentally realistic concentrations of DCOIT for an entire life cycle. The results demonstrated that DCOIT exposure potently stimulated the hypothalamic-pituitary-thyroid axis, characterized by hyperthyroidism symptom induction and prevalent key gene and protein upregulation in the brain. Moreover, the in silico and in vitro results evidenced that DCOIT could bind to thyroid hormone receptor beta (TR beta) and interact synergistically with triiodothyronine, thus promoting GH3 cell proliferation. The CUT&Tag experiment found that DCOIT interfered with the affinity fingerprint of TR beta to target genes implicated in thyroid hormone signaling cascade regulation. Furthermore, ex vivo, Chem-seq revealed that DCOIT directly bound to the genomic sequences of thyrotropin-releasing hormone receptor b and thyroid-stimulating hormone receptor in marine medaka brain tissues. In conclusion, the current multifaceted evidence confirmed that DCOIT has a strong potency for thyroid endocrine system disruption and provided comprehensive insights into its toxicity mechanisms.

The surge in demand for experimental monkeys has led to a rapid increase in their costs. Consequently, there is a growing need for a cost-effective model of Parkinson disease (PD) that exhibits all core clinical and pathologic phenotypes. Evolutionarily, tree shrews (Tupaia belangeri) are closer to primates in comparison with rodents and could be an ideal species for modeling PD. To develop a tree shrew PD model, we used the 1-methyl-4-phenylpyridinium (MPP+), a metabolite derived from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, to induce lesions in dopaminergic neurons of the unilateral substantia nigra. The induced tree shrew model consistently exhibited and maintained all classic clinical manifestations of PD for a 5-month period. The symptoms included bradykinesia, rest tremor, and postural instability, and ∼50% individuals showed apomorphine-induced rotations, a classic phenotype of unilateral PD models. All these are closely resembled the ones observed in PD monkeys. Meanwhile, this model was also sensitive to L-dopa treatment in a dose-dependent manner, which suggested that the motor deficits are dopamine dependent. Immunostaining showed a significant loss of dopaminergic neurons (∼95%) in the lesioned substantia nigra, which is a crucial PD pathological marker. Moreover, a control group of nigral saline injection did not show any motor deficits and pathological changes. Cytomorphologic analysis revealed that the size of nigral dopaminergic neurons in tree shrews is much bigger than that of rodents and is close to that of macaques. The morphologic similarity may be an important structural basis for the manifestation of the highly similar phenotypes between monkey and tree shrew PD models. Collectively, in this study, we have successfully developed a PD model in a small animal species that faithfully recapitulated the classic clinical symptoms and key pathological indicators of PD monkeys, providing a novel and low-cost avenue for evaluation of PD treatments and underlying mechanisms.

Granulosa cells (GCs) are the key components of ovarian follicles and regulate the maturation, communication, growth, and development of oocytes. GCs have great potential as human therapeutic models and in livestock breeding. In this study, we established an immortalized cell line (Im-RGCs) by transforming primary rabbit granulosa cells (Pri-RGCs) with lentivirus-mediated simian virus 40 Large T (SV40LT). Morphologically, Im-RGCs were indistinguishable from Pri-RGCs and maintained intact cell structure as observed by H&E staining. Also, Im-RGCs exhibited no significant change in cell proliferation, viability, and growth. Furthermore, GC-specific markers, such as FSHR , StAR , CYP11A1 , and CYP19A1 , were examined by PCR, immunofluorescence, and Western blotting. ELISA and karyotype analysis showed that Im-RGCs can synthesize steroid hormones and maintain the normal number of chromosomes during the infinite passage. Furthermore, soft-agar cloning and nude mice tumorigenic experiments indicated the absence of any malignancy transformation in Im-RGCs. In conclusion, we successfully established the immortalized granulosa cell line of rabbit follicles that can be used for biological, animal husbandry, and female reproductive research.