SOX2 Gene Research Articles

A rare Coffin-Siris syndrome induced by SOX11: a de novo nonsense variant of short stature.

Coffin-Siris syndrome is a clinically elusive and rare genetic disease characterized by a wide range of clinical manifestations. This study deeply analyzed and identified the clinical phenotype and genetic variant location in a pediatric patient with Coffin-Siris syndrome, aiming to enhance the understanding of this syndrome and assist in its screening and diagnosis. A combination of advanced diagnostic tools, including high-throughput whole-exome sequencing (WES) and first-generation sequencing technologies, was employed to ascertain the etiology of the disease in the child. The clinical phenotype was characterized by stunted growth, reduced stature, spina bifida, enuresis, and a ventricular septal defect. WES revealed a de novo variant in the SOX11 gene locus (c.700G > T), identified as pathogenic. It is noteworthy that this variant has not been previously reported. The combination of clinical presentation and genetic testing results supports that the patient suffers from Coffin-Siris syndrome due to a genetic variant in the SOX11 gene. This de novo variant expands our understanding of human gene variation, which is conducive to genetic counseling and screening for early diagnosis of Coffin-Siris syndrome.

Primary vulvar and vaginal adenocarcinomas of intestinal-type are closer to colorectal adenocarcinomas than to carcinomas of Müllerian origin

Primary vulvar and vaginal adenocarcinomas of intestinal-type (VVAIts) are very rare tumors, displaying morphological and immunohistochemical overlap with colorectal adenocarcinomas. However, their immunoprofile and genomics are poorly studied, and their origin is still debated. Herein, we studied a series of 4 vulvar and 4 vaginal adenocarcinomas of intestinal-type using a large panel of immunohistochemistry, and DNA and RNA sequencing with clustering analyses. All tumors shared a similar morphology with colorectal adenocarcinomas and diffuse CK20 and CDX2 expression. SATB2 diffuse positivity was observed in 62.5% of tumors and CK7 in 82.5%, while PAX8, SOX17, p16, estrogen and progesterone receptors were always negative. A p53 mutated-type expression was observed in 75% of tumors. All tumors were MMR proficient. No HPV DNA nor pathogenic transcript fusions were detected. The most frequent molecular alterations were TP53 and KRAS variants in 71.4% and 42.9%, respectively. The transcriptomic analysis highlighted a robust VVAIts cluster distinct from endocervical, ovarian, lung, thyroid, salivary glands, breast, and renal carcinomas, but failed to differentiate vulvar from vaginal intestinal-type tumors. On two different clustering analyses, VVAIts clustered altogether, very close to colorectal adenocarcinomas. Compared to endocervical adenocarcinomas of intestinal-type, VVAIts had a significantly lower expression of SOX17 and epithelial-mesenchymal transition (EMT) genes, and a higher MAP-Kinase pathway gene expression. These results suggest that Müllerian structures leading to cervical adenocarcinomas may undergo intestinal-type transdifferentiation via an EMT phenomenon. Conversely, MAP-Kinase pathway activation in VVAIts, which plays a major role in colorectal adenocarcinomas, may indicate a close relationship in the carcinogenesis of these tumors. Our results indicate that adenocarcinomas of intestinal-type, in distal vagina or vestibular vulva, might be a unique and single entity, probably originating from cloacogenic embryonic remnants and/or ectopic colorectal mucosae inclusions. An open question would be to explore the efficacy of systemic drugs prescribed in colorectal cancers, in VVAIts.

Synergistic integration of plant derived galactomannan and MXene to produce multifunctional nanocomposites with antibacterial and osteogenic properties

This study proposes to combine plant-derived galactomannan and MXene to form an organic-inorganic hydrogel network with integrative antibacterial and osteogenic properties. Oxidized galactomannan (OxGa) was blended with N-succinyl chitosan (NSC) and varying concentrations of Mxene, owing to its high reactivity and biocompatibility. The results indicated that Mxene-loaded OxGa/NSC scaffolds exhibited biomimetic topography, adequate mechanical features and excellent physicochemical properties with strong antibacterial properties against pathogenic microbes. The cell culture experiments showed dose-dependent cytotoxic behaviour. An optimized MXene content of ≤ 4 mg/ml revealed no cytotoxicity and augmented the proliferation of osteoblast cells. Similar results were obtained in gene expression analysis where ALP, COL1A1, RUNX2, and SOX2 genes showed up-regulation. In addition, the chorioallantoic membrane (CAM) assay also illustrated augmentation of angiogenesis without any toxicity. The overall results highlight the dual performance of OxGa/NSC-MXene scaffolds to exhibit anti-infection with simultaneous osteogenic properties, which is purely determined by the concentration of MXene. Therefore, regulating MXene concentration can serve as a chemical switch in imparting adequate antibacterial functions with the ability to allow new osseous generation. Our findings on the newly designed Mxene-loaded OxGa/NSC scaffolds can be a promising biomaterial for bone-related infections with a concurrent ability to promote osteogenesis.

Up-Regulation of miR-625-5p Correlates with Suppressed Sox2, Increased Apoptosis, and Cell Cycle Arrest via The PI3K/AKT Signalling Pathway in Acute Myeloid Leukaemia

Background: Up-regulation of the microRNA-625 and abnormal expression of the Sox2 gene have been studied and seen in several tumors. Few reports have also shown the aberrant expression of miR-625 and Sox2 expression in various cancers. Several studies have also confirmed that phosphatidylinositol 3' -kinase /protein kinase B pathways regulate hematological malignancies, including Acute Myeloid Leukemia (AML). Thus, this study aimed to investigate the effects of mir-625 up-regulation on proliferation, apoptosis, and cell cycle by targeting the Sox2 gene via the downstream Akt signaling pathway and cell cycle regulators, such as p21, p27, and cyclin E in the KG-1 cell line. Materials and Methods: Cells obtained from the KG-1 cell line were cultured and transfected with plasmid DNA (miR-625) and scrambled as the control using the Lonza electroporation system. Flow cytometry was used to evaluate cell cycle, proliferation, and apoptosis. Relative gene expression was validated by qRT-PCR. All data were analyzed using graph pad prism 7.01 and REST 2009. Results: KG-1 cells transfected with the mir625-GFP construct showed decreased proliferation, increased apoptosis, and induced cell cycle arrest. Low levels of Sox2, p21, cyclin E, and up-regulation of p27 were confirmed and validated by qRT-PCR ( P < 0.05 ). Conclusion: MiR-625 can be a promising approach to aid in the treatment of AML. However, further studies are required in this field

Induction of chronic asthma up regulated the transcription of senile factors in male rats

BackgroundThe main characteristic of asthma is chronic inflammation. We examined cellular senescence by histology and molecular assay in the lungs of a rat model of asthma. This model comprises sensitization by several intraperitoneal injections of ovalbumin with aluminium hydroxide, followed by aerosol challenges every other day.ResultsData showed that asthma induction caused histological changes including, hyperemia, interstitial pneumonia, fibrinogen clots, and accumulation of inflammatory cells in the pleura. There is an elevation of IL-1β and NF-kB proteins in the asthmatic group (P < 0.001) compared to the control group. The expression of ß-galactosidase increased (P < 0.01), while the expression of Klotho and Sox2 genes was decreased in the lung tissue of the asthmatic group (P < 0.01).ConclusionTaken together, these findings suggest that asthmatic conditions accelerated the cellular senescence in the lung tissue.

Novel variants in the SOX11 gene: clinical description of seven new patients.

Pathogenic SOX11 variants have been associated with intellectual developmental disorder with microcephaly, and with or without ocular malformations or hypogonadotropic hypogonadism (HH) (IDDMOH, OMIM # 615866). In this article, we report seven new patients with de novo SOX11 variants. Five of the variants are missense, one nonsense, and one whole-gene deletion, most of them are novel variants. The main clinical features included neurodevelopmental delay (7/7) and intellectual disability (5/7), autism/attention deficit hyperactivity disorder (5/7), microcephaly (4/7), short stature (4/7), hypotonia (4/7), and clinodactyly of the 5th fingers (5/7). HH was confirmed in two female patients with primary amenorrhea, nonvisualized/prepubertal size of the uterus, and nonvisualized ovaries. Two of the male patients presented with micropenis, two had cryptorchidism, and one had decreased testicular size, which are suggestive findings of HH. This article contributes to the clinical characterization of patients with SOX11 variants and supports the role of this gene in HH.

Flowcytometric Based Analysis of Sox4 Gene Expression-An Early Transcription Factor Influenced by 5-Azacytidine and Compare with EpCAM in Circulating Tumor Cells Isolated from Breast Cancer Patients

Flowcytometric Based Analysis of Sox4 Gene Expression-An Early Transcription Factor Influenced by 5-Azacytidine and Compare with EpCAM in Circulating Tumor Cells Isolated from Breast Cancer Patients

Combination of microRNA and suicide gene for targeting Glioblastoma: Inducing apoptosis and significantly suppressing tumor growth in vivo

Glioblastoma (GBM), a grade IV brain tumor, presents a severe challenge in treatment and eradication due to its high genetic variability and the existence of stem-like cells with self-renewal potential. Conventional therapies fall short of preventing recurrence and fail to extend the median survival of patients significantly. However, the emergence of gene therapy, which has recently obtained significant clinical outcomes, brings hope. It has the potential to be a suitable strategy for the treatment of GBM. Notably, microRNAs (miRNAs) have been noticed as critical players in the development and progress of GBM. The combined usage of hsa-miR-34a and Cytosine Deaminase (CD) suicide gene and 5-fluorocytosine (5FC) prodrug caused cytotoxicity against U87MG Glioma cells in vitro. The apoptosis and cell cycle arrest rates were measured by flow cytometry. The lentiviral vector generated overexpression of CD/miR-34a in the presence of 5FC significantly promoted apoptosis and caused cell cycle arrest in U87MG cells. The expression level of the BCL2, SOX2, and P53 genes, target genes of hsa-miR-34a, was examined by quantitative real-time PCR. The treatment led to a substantial downregulation of Bcl2 and SOX2 genes while elevating the expression levels of Caspase7 and P53 genes compared to the scrambled control. The hsa-miR-34a hindered the proliferation of GBM cancer cells and elevated apoptosis through the P53–miR-34a–Bcl2 axis. The CD suicide gene with 5FC treatment demonstrated similar results to miR-34a in the apoptosis, cell cycle, and real-time assays. The combination of CD and miR-34a produced a synergistic effect. In vivo, anti-GBM efficacy evaluation in rats bearing intracranial C6 Glioma cells revealed a remarkable induction of apoptosis and a significant inhibition of tumor growth compared with the scrambled control. The simultaneous use of CD/miR-34a with 5FC almost entirely suppressed tumor growth in rat models. The combined application of hsa-miR-34a and CD suicide gene against GBM tumors led to significant induction of apoptosis in U87MG cells and a considerable reduction in tumor growth in vivo.

Abstract Introduction of a novel pathogenic variant (c.1684G&gt;A) in the SOX5 gene associated with Lamb– Shaffer syndrome in a family from north of Iran

So far, different types of SOX5 variants have been reported in patients with LAMSHF syndrome, which are mainly clustered in the HMG domain. The LAMSHF syndrome has a broad variety of clinical manifestations such as developmental delay, speech delay, intellectual disability, and behavioral disturbances. In this article, we aim to present three cases with Lamb–Shaffer syndrome who are heterozygotes for a novel variant (c.1684G&gt;A) in the SOX5 gene in a family from the north of Iran. A 38-year-old male case with moderate mental retardation and strabismus, with a head circumference size of 56 cm, was tested for genetic diagnosis. The results of wholeexome sequencing (WES) indicated the c.1684G&gt;A pathogenic variant (NM_006940.6) in the SOX5 gene in a heterozygote state. Family analysis showed that the proband’s sister and father, who have similar symptoms, also carry the detected variant. Like the previous cases, the presented cases with a missense variant in the HMGdomain also have a mild phenotype. The introduction of new patients, especially with new pathogenic variants, is fundamental to increasing our knowledge about the disease and possible genotype–phenotype correlations.

Clinical cases series and pathogenesis of Lamb-Shaffer syndrome in China

BackgroundLamb-Shaffer syndrome (LAMSHF, OMIM: 616803) is a rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, poor expressive speech, which is attributed to haploinsufficiency by heterozygous variants of SOX5 gene (SRY-Box Transcription Factor 5, HGNC: 11201) on chromosome 12p12. A total of 113 cases have been reported in the world, however, only 3 cases have been reported.in China. Here, we aimed to report novel variants of SOX5 gene and provide examples for clinical diagnosis by reporting the clinical phenotype of a series of Chinese patients with LAMSHF.MethodsThis study retrospectively collected the information of families of LAMSHF patients in China. Whole Exome Sequencing (WES) were performed to confirm the diagnosis of 4 children with unexplained developmental delay or epilepsy. A minigene splicing assay was used to verify whether the splice variant affected splicing. Meanwhile, a literature review was conducted to analyze the clinical and genetic characteristics of patients with LAMSHF.ResultsThree of the LAMSHF patients had a de novo heterozygous mutation in the SOX5 gene respectively, c.290delC (p.Pro97fs*30), chr12:23686019_24048958del, c.1772-1C > A, and the remaining one had a mutation inherited from his father, c.1411C > T (p.Arg471*). The main clinical manifestations of these children were presented with global developmental delays, and one of them also had seizures. And the results of the minigene experiment indicated that the splice variant, c.1772-1C > A, transcribed a novel mRNA product which leaded to the formation of a truncated protein.ConclusionsThrough a comprehensive review and analysis of existing literature and this study showed intellectual disability, speech delay and facial dysmorphisms were common clinical manifestation, while the seizures and EEG abnormalities were rare (21/95, 22.16%). Notably, we represent the largest sample size of LAMSHF in Asia that encompasses previously unreported SOX5 gene mutation, and a minigene testing have been conducted to validate the pathogenicity of the c.1772-1C > A splice variant. The research further expands the phenotype and genotype of LAMSHF while offers novel insights for potential pathogenicity of genes locus.

Effects of Withania somnifera (L.) Dunal in acute pulmonary pathophysiology in a rat model of smoke-induced lung injury and role of IRS-1 and SOX-2

The respiratory structure has a broad capacity to undergo the mechanism of regeneration. The recent study was intended to determine the efficacy of Withania somnifera (L.) Dunal and expression levels of IRS-1 and SOX-2 genes in the smoke-induced Pulmonary Injury. The present study included 3 groups (n = 9): Normal/negative control (NC), positive control/disease control (PC), and treatment group (TG; treated orally with 350 mg/kg of ethanol extract). Lung injury was induced in PC and TG groups in rats by cigarette smoke (4 CG/day). Decapitation (n = 3) was done on the 14th, 18th, and 21st day of treatment. Phenolic acid quantification by HPLC-UV/VIS showed a significant concentration of p-coumaric acid (130.2 mg/kg) that may also contribute to the extract's efficacy. Hematological parameters (leukocytes, hemoglobin, hematocrit) and serum oxidative parameters (total oxidant status and malondialdehyde) were significantly improved (P ≤ 0.05) in the TG compared to the PC group. Moreover, the total antioxidant capacity, total plasma protein, albumin, globulin, and platelet count significantly decreased in the PC while increasing in the treatment group (P ≤ 0.05). Histology showed damaged histological structures in the PC group, while there was obvious regeneration of architectural damage in the TG group. The IRS-1 and SOX-2 genes were up-regulated in the PC group, indicating the role of IRS-1 and SOX-2 gene expression in tissue homeostasis and regeneration in smoke-induced Pulmonary Injury. These results rationalize the traditional use of W. somnifera in pulmonary diseases and encourage further studies to exploit it in the pharmaceutical industry.

Evaluation of Tumorigenic Properties of MDA-MB-231 Cancer Stem Cells Cocultured with Telocytes and Telocyte-Derived Mitochondria Following miR-146a Inhibition.

Telocytes have some cytoplasmic extensions called telopodes, which are thought to play a role in mitochondrial transfer in intercellular communication. Besides, it is hypothesized that telocytes establish cell membrane-mediated connections with breast cancer cells in coculture and may contribute to the survival of neoplastic cell clusters together with other stromal cells. The aim of this study is to investigate the contribution of telocytes and telocyte-derived mitochondria, which have also been identified in breast tumors, to the tumor development of breast cancer stem cells (CSCs) via miR-146a-5p. The isolation/characterization of telocytes from bone marrow mononuclear cells and the isolation of mitochondria from these cells were performed, respectively. In the next step, CSCs were isolated from the MDA-MB-231 cell line and were characterized. Then, miR-146a-5p expressions of CSCs were inhibited by anti-miR-146a-5p. The epithelial-mesenchymal transition (EMT) was determined by evaluating changes in vimentin protein levels and was evaluated by analyzing BRCA1, P53, SOX2, E-cadherin, and N-cadherin gene expression changes. Our results showed that miR-146a promoted stemness and oncogenic properties in CSCs. EMT (N-cadherin, vimentin, E-cadherin) and tumorigenic markers (BRCA1, P53, SOX2) of CSCs decreased after miR-146a inhibition. Bone marrow-derived telocytes and mitochondria derived from telocytes favored the reduction of CSC aggressiveness following this inhibition.

The Effect of Bone Marrow Mesenchymal Stem Cells on Nestin and Sox-2 Gene Expression and Spatial Learning (Percent Alternation Y-Maze Test) against AlCl3-Induced Alzheimer's-like Pathology in a Rat Model.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by gradual cognitive impairment, including loss of synapses and nerve cells involved in learning, memory, and habit formation processes. Bone Marrow Mesenchymal Stem Cells (BM-MSCs) are multipotent cells. Because of their self-renewable, differentiation, and immunomodulatory capabilities, they are commonly used to treat many disorders. Hence, the current study intends to examine the effect of BM-MSCs transplantation on Aluminum chloride (AlCl3)-induced cognitive problems, an experimental model resembling AD's hallmarks in rats. The study was conducted in 2022 at The Biomedical Laboratory Faculty of Medicine, Andalas University, Indonesia. Adult male Wistar rats (three groups: negative control; no intervention+treatment with PBS; positive control: AlCl3+treatment with aqua dest; AlCl3+BM-MSCs: AlCl3+treatment with BM-MSCs, n=5 each) were treated daily with AlCl3 orally for five days. Stem cells were intraperitoneally injected into rats at a dose of 1x106 cells/rat. The same quantity of phosphate-buffered saline was given to the control group. One month after stem cell injection, the rat brain tissue was removed and placed in the film bottles that had been created. The expression of neural progenitor cell markers, including nestin and sex-determining Y-box 2 (SOX-2), was analyzed using real-time polymerase chain reaction (RT-PCR). Rats' cognitive and functional memory were examined using Y-maze. Data were analyzed using SPSS software (version 26.0) with a one-way analysis of variance (ANOVA) test. The gene expression of nestin (29.74±0.42), SOX-2 (31.44±0.67), and percent alternation of Y-maze (67.04±2.28) increased in the AlCl3+BM-MSCs group compared to that in the positive control group. RT-PCR analysis indicated that nestin (P<0.001) and SOX-2 (P<0.001) were significantly enhanced in the AlCl3+BM-MSCs group compared to the positive control group. This group also indicated an increased percent alternation of Y-maze (P<0.001) in the AlCl3+BM-MSCs group compared to the positive control group. Due to its potential effects on cell therapy, BM-MSCs were found effective in a rat model of AD on the impairment of the rats' behavior and increased expression of neural progenitor cell markers.

Identification of placenta-specific protein 1 (PLAC-1) expression on human PC-3 cell line-derived prostate cancer stem cells compared to the tumor parental cells

Placenta-specific protein 1 (PLAC-1) is a gene primarily expressed in the placenta and the testis. Interestingly, it is also found to be expressed in many solid tumors, and it is involved in malignant cell features. However, no evidence has been reported regarding the relationship between PLAC-1 and cancer stem cells (CSCs). In the current research, we explored the expression of the PLAC-1 molecule in prostate cancer stem cells (PCSCs) derived from the human PC-3 cell line. The enrichment of PCSCs was achieved using a three-dimensional cell culture technique known as the sphere-formation assay. To confirm the identity of PCSCs, we examined the expression of genes associated with stemness and pluripotency, such as SOX2, OCT4, Nanog, C-Myc, and KLF-4, as well as stem cell differentiation molecules like CD44 and CD133. These evaluations were conducted in both the PCSCs and the original tumor cells (parental cells) using real-time PCR and flow cytometry. Subsequently, we assessed the expression of the PLAC-1 molecule in both enriched cells and parental tumor cells at the gene and protein levels using the same techniques. The tumor cells from the PC-3 cell line formed spheroids with CSC characteristics in a non-adherent medium. The expression of SOX2, OCT4, Nanog, and C-Myc genes (p < 0.01), and the molecules CD44 and CD133 (p < 0.05) were significantly elevated in PCSCs compared to the parental cells. The expression of the PLAC-1 molecule in PCSCs showed a significant increase compared to the parental cells at both gene (p < 0.01) and protein (p < 0.001) levels. In conclusion, it was indicated for the first time that PLAC-1 is up-regulated in PCSCs derived from human PC-3 cell line. This study may propose PLAC-1 as a potential target in targeted therapies, which should be confirmed through further studies.

Implications of a De Novo Variant in the SOX12 Gene in a Patient with Generalized Epilepsy, Intellectual Disability, and Childhood Emotional Behavioral Disorders.

SRY-box transcription factor (SOX) genes, a recently discovered gene family, play crucial roles in the regulation of neuronal stem cell proliferation and glial differentiation during nervous system development and neurogenesis. Whole exome sequencing (WES) in patients presenting with generalized epilepsy, intellectual disability, and childhood emotional behavioral disorder, uncovered a de novo variation within SOX12 gene. Notably, this gene has never been associated with neurodevelopmental disorders. No variants in known genes linked with the patient's symptoms have been detected by the WES Trio analysis. To date, any MIM phenotype number associated with intellectual developmental disorder has not been assigned for SOX12. In contrast, both SOX4 and SOX11 genes within the same C group (SoxC) of the Sox gene family have been associated with neurodevelopmental disorders. The variant identified in the patient here described was situated within the critical high-mobility group (HMG) functional site of the SOX12 protein. This domain, in the Sox protein family, is essential for DNA binding and bending, as well as being responsible for transcriptional activation or repression during the early stages of gene expression. Sequence alignment within SoxC (SOX12, SOX4 and SOX11) revealed a high conservation rate of the HMG region. The in silico predictive analysis described this novel variant as likely pathogenic. Furthermore, the mutated protein structure predictions unveiled notable changes with potential deleterious effects on the protein structure. The aim of this study is to establish a correlation between the SOX12 gene and the symptoms diagnosed in the patient.

Dexamethasone-tamoxifen combination exerts synergistic therapeutic effects in tamoxifen-resistance breast cancer cells.

Tamoxifen (TAM) is a key player in estrogen receptor-positive (ER+) breast cancer (BC); however, ∼30% of patients experience relapse and a lower survival rate due to TAM resistance. TAM resistance was related to the over expression of SOX-2 gene, which is regulated by the E2F3 transcription factor in the Wnt signaling pathway. It was suggested that SOX-2 overexpression was suppressed by dexamethasone (DEX), a glucocorticoid commonly prescribed to BC patients. The aim of the present study is to explore the effect of combining DEX and TAM on the inhibition of TAM-resistant LCC-2 cells (TAMR-1) through modulating the E2F3/SOX-2-mediated Wnt signaling pathway. The effect of the combination therapy on MCF-7 and TAMR-1 cell viability was assessed. Drug interactions were analyzed using CompuSyn and SynergyFinder softwares. Cell cycle distribution, apoptotic protein expression, gene expression levels of SOX-2 and E2F3, and cell migration were also assessed. Combining DEX with TAM led to synergistic inhibition of TAMR-1 cell proliferation and migration, induced apoptosis, reduced SOX-2 and E2F3 expression and was also associated with S and G2-M phase arrest. Therefore, combining DEX with TAM may present an effective therapeutic option to overcome TAM resistance, by targeting the E2F3/SOX-2/Wnt signaling pathway, in addition to its anti-inflammatory effect.

Impact of gallbladder hypoplasia on hilar hepatic ducts in biliary atresia

BackgroundBiliary atresia (BA) is an intractable disease of unknown cause that develops in the neonatal period. It causes jaundice and liver damage due to the destruction of extrahepatic biliary tracts,. We have found that heterozygous knockout mice of the SRY related HMG-box 17 (Sox17) gene, a master regulator of stem/progenitor cells in the gallbladder wall, exhibit a condition like BA. However, the precise contribution of hypoplastic gallbladder wall to the pathogenesis of hepatobiliary disease in Sox17 heterozygous embryos and human BA remains unclear.MethodsWe employed cholangiography and histological analyses in the mouse BA model. Furthermore, we conducted a retrospective analysis of human BA.ResultsWe show that gallbladder wall hypoplasia causes abnormal multiple connections between the hilar hepatic bile ducts and the gallbladder-cystic duct in Sox17 heterozygous embryos. These multiple hilar extrahepatic ducts fuse with the developing intrahepatic duct walls and pull them out of the liver parenchyma, resulting in abnormal intrahepatic duct network and severe cholestasis. In human BA with gallbladder wall hypoplasia (i.e., abnormally reduced expression of SOX17), we also identify a strong association between reduced gallbladder width (a morphometric parameter indicating gallbladder wall hypoplasia) and severe liver injury at the time of the Kasai surgery, like the Sox17-mutant mouse model.ConclusionsTogether with the close correlation between gallbladder wall hypoplasia and liver damage in both mouse and human cases, these findings provide an insight into the critical role of SOX17-positive gallbladder walls in establishing functional bile duct networks in the hepatic hilus of neonates.

Value of SOX1 and PAX1 Gene Methylation Detection in Secondary Triage of High-Grade Cervical Lesions

Objective To evaluate the value of SOX1 and PAX1 gene methylation detection in the secondary triage of high-grade cervical lesions.Methods Exfoliated cervical cells were collected from 122 patients tested positive for human papilloma virus (HPV) and subjected to thin-prep cytologic test (TCT) and SOX1/PAX1 gene methylation tests.Results The HPV test combined with TCT showed the sensitivity of 95.24% and the specificity of 23.75% for detecting cervical intraepithelial neoplasia (CIN) grade 2 and above (CIN2+).After the addition of the SOX1/PAX1 gene methylation detection in secondary triage,the sensitivity for detecting CIN2+ was 83.33%,which had no statistically significant difference from the sensitivity of TCT combined with HPV test (P=0.078).However,the specificity reached 77.50%,which was significantly higher than that of HPV test combined with TCT (P<0.001).The SOX1/PAX1 gene methylation level in the CIN2+ group was higher than those in the normal cervical tissue and the CIN1 group(P<0.001).The cut-off values of SOX1 and PAX1 gene methylation for CIN2+ detection were -11.81 and -11.98,respectively.Conclusion Adding the detection of SOX1/PAX1 gene methylation in secondary triage significantly improves the efficiency and accuracy of CIN2+ detection.

In vitro developmental competence of bovine demi-embryos generated by blastomere separation and blastocyst bisection.

The efficiency of bovine invitro embryo production can be significantly improved by splitting embryos at different stages. However, the blastocyst quality of invitro-produced demi-embryos remains unexplored. The objective of this research was to compare embryo developmental rates and quality of bovine demi-embryos produced by two different strategies: (a) embryo bisection (BSEC) and (b) 2-cell blastomere separation (BSEP). To determine demi-embryos quality, we evaluated total blastocyst cell number and proportion of SOX2+ cells. Additionally, the expression of SOX2, NANOG, OCT4, CDX2, IFNT, BAX and BCL genes and let-7a and miRNA-30c Micro RNAs was analysed. BSEP resulted in improved blastocyst development, higher ICM cells and a significantly higher expression of IFNΤ than demi-embryos produced by BSEC. Let-7a, which is associated with low pregnancy establishment was detected in BSEC, while miRNA-30c expression was observed in all treatments. In conclusion, BSEP of 2-cell embryos is more efficient to improve invitro bovine embryo development and to produce good quality demi-embryos based on ICM cell number and the expression pattern of the genes explored compared to BSEC.

17β-estradiol activates SOX6 to balance the anabolism and catabolism via estrogen receptor 2 in chondrocyte.

We investigated the influence of 17β-estradiol (17β-E2) on cartilage extracellular matrix (ECM) homeostasis in postmenopausal women. We focused on the roles of estrogen receptors (ESR) and SOX6 in 17β-E2-mediated stimulation of ECM metabolism during chondrocyte (CH) degeneration. We compared the expression of anabolic genes (collagen II and aggrecan) and catabolic genes (MMPs and TIMPs) in IL-1β-induced CH degeneration in vitro, with and without 17β-E2 supplementation. We separately silenced the SOX6, ESR1, and ESR2 genes in CHs to determine their impact on 17β-E2 treatment. Additionally, we used Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) and luciferase assays to investigate protein-DNA interactions within ESR2 and SOX6-promoter complexes. After three days of IL-1β treatment, ESR1/2, SOX6, collagen II, aggrecan, and TIMP1/3 were decreased, while MMP3/9/13 were increased. The addition of 17β-E2 partially reversed these effects, but silencing SOX6, ESR1, or ESR2 weakened the protective effects of 17β-E2. Silencing ESR2, but not ESR1, abolished the upregulation of SOX6 induced by 17β-E2. ESR2 was found to bind the SOX6 promoter and regulate SOX6 expression. 17β-E2 upregulates SOX6 through ESR2 mediation, and the synergistic effect of 17β-E2 and ESR2 on SOX6 balances ECM metabolism in CHs.