Serpin family E member 1 enhances myometrium contractility by increasing ATP production during labor.

The uterine contraction during labor, a process with repetitive hypoxia and high energy consumption, is essential for successful delivery. However, the molecular mechanism of myometrial contraction regulation is unknown. Serpin family E member 1 (SERPINE1), one of the most upregulated genes in laboring myometrium in both transcriptome and proteome, was highlighted in our previous study. Here, we confirmed SERPINE1 is upregulated in myometrium during labor. Blockade of SERPINE1 using small interfering RNA (siRNA) or inhibitor (Tiplaxtinin) under hypoxic conditions in myocytes or myometrium in vitro showed a decrease contractility, which was achieved by regulating ATP production. Chromatin immunoprecipitation (ChIP-seq), Co-immunoprecipitation (Co-IP), and glutathione-S-transferase (GST) pull down explored that the promoter of SERPINE1 is directly activated by hypoxia-inducible factor-1α (HIF-1α) and SERPINE1 interacts with ATP Synthase Peripheral Stalk Subunit F6 (ATP5PF). Together they enhance hypoxia driven myometrial contraction by maintaining ATP production in the key oxidative phosphorylation pathway. The results provide new insight for uterine contraction regulation, and potential novel therapeutic targets for labor management.

Exploring myometrial microenvironment changes at the single-cell level from nonpregnant to term pregnant states.

The microenvironment and cell populations within the myometrium play crucial roles in maintaining uterine structural integrity and protecting the fetus during pregnancy. However, the specific changes occurring at the single-cell level in the human myometrium between nonpregnant (NP) and term pregnant (TP) states remain unexplored. In this study, we used single-cell RNA sequencing (scRNA-Seq) and spatial transcriptomics (ST) to construct a transcriptomic atlas of individual cells in the myometrium of NP and TP women. Integrated analysis of scRNA-Seq and ST data revealed spatially distinct transcriptional characteristics and examined cell-to-cell communication patterns based on ligand-receptor interactions. We identified and categorized 87,845 high-quality individual cells into 12 populations from scRNA-Seq data of 12 human myometrium tissues. Our findings demonstrated alterations in the proportions of five subpopulations of smooth muscle cells in TP. Moreover, an increase in monocytic cells, particularly M2 macrophages, was observed in TP myometrium samples, suggesting their involvement in the anti-inflammatory response. This study provides unprecedented single-cell resolution of the NP and TP myometrium, offering new insights into myometrial remodeling during pregnancy.NEW & NOTEWORTHY Using single-cell RNA sequencing and spatial transcriptomics, the myometrium was examined at the single-cell level during pregnancy. We identified spatially distinct cell populations and observed alterations in smooth muscle cells and increased M2 macrophages in term pregnant women. These findings offer unprecedented insights into myometrial remodeling and the anti-inflammatory response during pregnancy. The study advances our understanding of pregnancy-related myometrial changes.

STAT3 drives the expression of HIF1alpha in cancer cells through a novel super-enhancer.

Aerobic glycolysis is one of the major hallmarks of malignant tumors. This metabolic reprogramming benefits the rapid proliferation of cancer cells, facilitates the formation of tumor microenvironment to support their growth and survival, and impairs the efficacy of various tumor therapies. Therefore, the elucidation of the mechanisms driving aerobic glycolysis in tumors represents a pivotal breakthrough in developing therapeutic strategies for solid tumors. HIF1α serves as a central regulator of aerobic glycolysis with elevated mRNA and protein expression across multiple tumor types. However, the mechanisms contributing to this upregulation remain elusive. This study reports the identification of a novel HIF1α super enhancer (HSE) in multiple cancer cells using bioinformatics analysis, chromosome conformation capture (3C), chromatin immunoprecipitation (ChIP), and CRISPR/Cas9 genome editing techniques. Deletion of HSE in cancer cells significantly reduces the expression of HIF1α, glycolysis, cell proliferation, colony and tumor formation ability, confirming the role of HSE as the enhancer of HIF1α in cancer cells. Particularly, we demonstrated that STAT3 promotes the expression of HIF1α by binding to HSE. The discovery of HSE will help elucidate the pathways driving tumor aerobic glycolysis, offering new therapeutic targets and potentially resolving the bottleneck in solid tumor treatment.

Upregulated TIMP1 facilitates and coordinates myometrial contraction by decreasing collagens and cell adhesive capacity during human labor.

Myometrial contraction is one of the key events involved in parturition. Increasing evidence suggests the importance of the extracellular matrix (ECM) in this process, in addition to the functional role of myometrial smooth muscle cells, and our previous study identified an upregulated tissue inhibitor of metalloproteinase 1 (TIMP1) in human laboring myometrium compared to nonlabor samples. This study aimed to further explore the potential role of TIMP1 in myometrial contraction. First, we confirmed increased myometrial TIMP1 levels in labor and during labor with cervical dilation using transcriptomic and proteomic analyses, followed by real-time PCR, western blotting, and immunohistochemistry. Then, a cell contraction assay was performed to verify the decreased contractility after TIMP1 knockdown in vitro. To further understand the underlying mechanism, we used RNA-sequencing analysis to reveal the upregulated genes after TIMP1 knockdown; these genes were enriched in collagen fibril organization, cell adhesion, and ECM organization. Subsequently, a human matrix metalloproteinase (MMP) array and collagen staining were performed to determine the TIMPs, MMPs and collagens in laboring and nonlabor myometrium. A real-time cell adhesion assay was used to detect cell adhesive capacity. The results showed upregulated MMP8 and MMP9, downregulated collagens, and attenuated cell adhesive capacity in laboring myometrium, while lower MMP levels and higher collagen levels and cell adhesive capacity were observed in nonlabor. Moreover, TIMP1 knockdown led to restoration of cell adhesive capacity. Together, these results indicate that upregulated TIMP1 during labor facilitates and coordinates myometrial contraction by decreasing collagen and cell adhesive capacity, which may provide effective strategies for the regulation of myometrial contraction.

Retinoic acid receptor gamma is required for proliferation of pancreatic cancer cells.

Despite the expectation that retinoic acid receptor could be the potential therapeutic targets for pancreatic cancers, there has been the lack of information about the role and the impact of retinoic acid receptor gamma (RARγ, RARG) on pancreatic cancer, unlike other two RARs. Herein, we applied TCGA and GEO database to show that the expression and prognosis of RARG is closely related to pancreatic cancer, which demonstrates that RARG is commonly overexpressed in human pancreatic cancer and is an independent diagnostic marker predicting the poor prognosis of pancreatic cancer patients. In addition, we demonstrated that the reduction in the expression of RARG in human pancreatic cancer cells dramatically suppress their proliferation and tumor growth in vivo, partially attributable to the downregulation of tumor-supporting biological processes such as cell proliferation, antiapoptosis and metabolism and the decreased expression of various oncogenes like MYC and STAT3. Mechanistically, RARG binds on the promoters of MYC, STAT3, and SLC2A1 which is distinguished from well-known conventional Retinotic acid response elements (RAREs) and that the binding is likely to be responsible for the epigenetic activation in the level of chromatin, assessed by the measurement of deposition of the gene activation marker histone H3 K27 acetylation (H3K27ac) using ChIP-qPCR. In this study, we reveal that RARG plays important role in the tumorigenesis of pancreatic cancer and represents new therapeutic targets for human pancreatic cancer.

Golgi Reassembly Stacking Protein 2 Modulates Myometrial Contractility during Labor by Affecting ATP Production.

The mechanism of maintaining myometrial contractions during labor remains unclear. Autophagy has been reported to be activated in laboring myometrium, along with the high expression of Golgi reassembly stacking protein 2 (GORASP2), a protein capable of regulating autophagy activation. This study aimed to investigate the role and mechanism of GORASP2 in uterine contractions during labor. Western blot confirmed the increased expression of GORASP2 in laboring myometrium. Furthermore, the knockdown of GORASP2 in primary human myometrial smooth muscle cells (hMSMCs) using siRNA resulted in reduced cell contractility. This phenomenon was independent of the contraction-associated protein and autophagy. Differential mRNAs were analyzed using RNA sequencing. Subsequently, KEGG pathway analysis identified that GORASP2 knockdown suppressed several energy metabolism pathways. Furthermore, reduced ATP levels and aerobic respiration impairment were observed in measuring the oxygen consumption rate (OCR). These findings suggest that GORASP2 is up-regulated in the myometrium during labor and modulates myometrial contractility mainly by maintaining ATP production.

HIF-1α is essential for the augmentation of myometrial contractility during labor†.

Uterine contraction is crucial for a successful labor and the prevention of postpartum hemorrhage. It is enhanced by hypoxia; however, its underlying mechanisms are yet to be elucidated. In this study, transcriptomes revealed that hypoxia-inducible factor-1alpha was upregulated in laboring myometrial biopsies, while blockade of hypoxia-inducible factor-1alpha decreased the contractility of the myometrium and myocytes in vitro via small interfering RNA and the inhibitor, 2-methoxyestradiol. Chromatin immunoprecipitation sequencing revealed that hypoxia-inducible factor-1alpha directly binds to the genome of contraction-associated proteins: the promoter of Gja1 and Ptgs2, and the intron of Oxtr. Silencing the hypoxia-inducible factor-1alpha reduced the expression of Ptgs2, Gja1, and Oxtr. Furthermore, blockade of Gja1 or Ptgs2 led to a significant decrease in myometrial contractions in the hypoxic tissue model, whereas atosiban did not remarkably influence contractility. Our study demonstrates that hypoxia-inducible factor-1alpha is essential for promoting myometrial contractility under hypoxia by directly targeting Gja1 and Ptgs2, but not Oxtr. These findings help us to better understand the regulation of myometrial contractions under hypoxia and provide a promising strategy for labor management and postpartum hemorrhage treatment.

Proteomic and miRNA Profiles of Exosomes Derived from Myometrial Tissue in Laboring Women.

Myometrial contraction is essential for successful delivery. Recent studies have highlighted the vital roles of tissue-derived exosomes in disease diagnostic, prognostic, and therapeutic applications; however, the characteristics of uterine myometrium-derived exosomes are unclear. Here, we successfully isolated exosomes from myometrial tissues, human myometrial smooth muscle cells (HMSMCs), and human umbilical vein endothelial cells (HUVECs), then performed quantitative liquid chromatography-tandem mass spectrometry and miRNA sequencing to investigate the cargo of the exosomes. Fifty-two proteins and five miRNAs were differentially expressed (DE) in term non-labor and term labor myometrium-derived exosomes. Among them, seven proteins (SERPINE1, THBS1, MGAT1, VIM, FGB, FGG, and VWF) were differentially expressed both in the myometrial exosomes and tissues, three miRNAs (miR-363-3p, miR-203a-3p, and miR-205-5p) target 13 DE genes. The top three miRNA derived from HMSMCs (miR-125b-1-3p, miR-337-5p, and miR-503-5p) and HUVECs (miR-663a, miR-4463, and miR-3622a-5p) were identified. Two proteins, GJA1 and SLC39A14, exist in female blood exosomes and are highly expressed in HMSMCs exosomes, are also upregulated in the laboring myometrium, which verified increased in laboring blood samples, might be novel potential biomarkers for myometrial activation. The proteomic and miRNA profile of exosomes derived from laboring myometrium revealed some molecules in the exosomes that affect the intercellular communication and the function of the myometrium.

Exploring the Expression Differences Between Professionals and Laypeople Toward the COVID-19 Vaccine: Text Mining Approach.

BACKGROUND: COVID-19 is still rampant all over the world. Until now, the COVID-19 vaccine is the most promising measure to subdue contagion and achieve herd immunity. However, public vaccination intention is suboptimal. A clear division lies between medical professionals and laypeople. While most professionals eagerly promote the vaccination campaign, some laypeople exude suspicion, hesitancy, and even opposition toward COVID-19 vaccines. OBJECTIVE: This study aims to employ a text mining approach to examine expression differences and thematic disparities between the professionals and laypeople within the COVID-19 vaccine context. METHODS: We collected 3196 answers under 65 filtered questions concerning the COVID-19 vaccine from the China-based question and answer forum Zhihu. The questions were classified into 5 categories depending on their contents and description: adverse reactions, vaccination, vaccine effectiveness, social implications of vaccine, and vaccine development. Respondents were also manually coded into two groups: professional and laypeople. Automated text analysis was performed to calculate fundamental expression characteristics of the 2 groups, including answer length, attitude distribution, and high-frequency words. Furthermore, structural topic modeling (STM), as a cutting-edge branch in the topic modeling family, was used to extract topics under each question category, and thematic disparities were evaluated between the 2 groups. RESULTS: Laypeople are more prevailing in the COVID-19 vaccine-related discussion. Regarding differences in expression characteristics, the professionals posted longer answers and showed a conservative stance toward vaccine effectiveness than did laypeople. Laypeople mentioned countries more frequently, while professionals were inclined to raise medical jargon. STM discloses prominent topics under each question category. Statistical analysis revealed that laypeople preferred the "safety of Chinese-made vaccine" topic and other vaccine-related issues in other countries. However, the professionals paid more attention to medical principles and professional standards underlying the COVID-19 vaccine. With respect to topics associated with the social implications of vaccines, the 2 groups showed no significant difference. CONCLUSIONS: Our findings indicate that laypeople and professionals share some common grounds but also hold divergent focuses toward the COVID-19 vaccine issue. These incongruities can be summarized as "qualitatively different" in perspective rather than "quantitatively different" in scientific knowledge. Among those questions closely associated with medical expertise, the "qualitatively different" characteristic is quite conspicuous. This study boosts the current understanding of how the public perceives the COVID-19 vaccine, in a more nuanced way. Web-based question and answer forums are a bonanza for examining perception discrepancies among various identities. STM further exhibits unique strengths over the traditional topic modeling method in statistically testing the topic preference of diverse groups. Public health practitioners should be keenly aware of the cognitive differences between professionals and laypeople, and pay special attention to the topics with significant inconsistency across groups to build consensus and promote vaccination effectively.

MicroRNA-379 mediates pigmentation, migration and proliferation of melanocytes by targeting the insulin-like growth factor 1 receptor.

Melanogenesis, migration and proliferation of melanocytes are important factors that determine the hair colours of mammals. MicroRNAs (miRNAs) have been shown to be closely related to these processes. In melanocytes of alpacas, insulin-like growth factor 1 (IGF1) has been shown to improve melanogenesis through the cyclic AMP (cAMP) pathway. miR-379 was predicted to target insulin-like growth factor (IGF) receptor 1 (IGF1R), which binds to IGF1. Therefore, we hypothesized that miR-379 could mediate melanogenesis, migration and proliferation of melanocytes. Here, we report that miR-379 was highly expressed in alpaca melanocytes. Subsequent overexpression of miR-379 in alpaca melanocytes led to the generation of the phenotype of melanogenesis, proliferation and migration. In addition, the expression of genes related to these phenotypes in melanocytes was detected. Our results showed that miR-379 targets IGF1R in melanocytes. The overexpression of miR-379 stimulated dendrite extension or elongation and limited the perinuclear distribution of melanin, but inhibited melanogenesis via cAMP response element (CRE)-binding protein (CREB)/microphthalmia-associated transcription factor (MITF) pathway. miR-379 attenuated melanocyte migration by downregulating the focal adhesion kinase (FAK) and enhanced melanocyte proliferation by upregulating protein kinase B (AKT). These observations suggest the involvement of miR-379 in the physiological regulation of melanocytes, mediated by targeting IGF1R on insulin receptor (IR) compensation and subsequent crosstalk.

The Genetics Analysis of Molecular Pathogenesis for Alzheimer's Disease.

INTRODUCTION: The molecular pathogenesis of Alzheimer's disease (AD) is still not clear, and the relationship between gene expression profile for different brain regions has not been studied. OBJECTIVE: Bioinformatic analysis at the genetic level has become the best way for the pathogenesis research of AD, which can analyze the abovementioned relationship. METHODS: In this study, the datasets of AD were obtained from the Gene Expression Omnibus (GEO), and Qlucore Omics Explorer (QOE) software was used to screen differentially expressed genes of GSE36980 and GSE9770 and verify gene expression of GSE63060. The Gene Ontology (GO) function enrichment analysis of these selected genes was conducted by Database for Annotation, Visualization, and Integrated Discovery (DAVID), and then the gene/protein interaction network was established by STRING to find the related proteins. R language was used for drafting maps and plots. RESULTS: There were 20 differentially expressed genes related to AD selected from GSE36980 (p = 6.2e-6, q = 2.9422e-4) and GSE9770 (p = 3.3e-4, q = 0.016606). Their expression levels of the AD group were lower than those in the control group and varied among different brain regions. Cellular morphogenesis and establishment or maintenance of cell polarity were enriched, and LRRTM1 and RASAL1 were identified by the integration network. Moreover, the analysis of GSE63060 verified the expression level of LRRTM1 and RASAL1 in Alzheimer's patients, which was much lower than that in normal people aged >65 years. CONCLUSIONS: The pathogenesis of AD at molecular levels may link to cell membrane structures and signal transduction; hence, a list of 20 genes, including LRRTM1 and RASAL1,potentially are important for the discovery of treatment target or molecular marker of AD.

A Novel Nanobody Targeting Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Receptor-Binding Domain Has Potent Cross-Neutralizing Activity and Protective Efficacy against MERS-CoV.

The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) continues to infect humans and camels, calling for efficient, cost-effective, and broad-spectrum strategies to control its spread. Nanobodies (Nbs) are single-domain antibodies derived from camelids and sharks and are potentially cost-effective antivirals with small size and great expression yield. In this study, we developed a novel neutralizing Nb (NbMS10) and its human-Fc-fused version (NbMS10-Fc), both of which target the MERS-CoV spike protein receptor-binding domain (RBD). We further tested their receptor-binding affinity, recognizing epitopes, cross-neutralizing activity, half-life, and efficacy against MERS-CoV infection. Both Nbs can be expressed in yeasts with high yield, bind to MERS-CoV RBD with high affinity, and block the binding of MERS-CoV RBD to the MERS-CoV receptor. The binding site of the Nbs on the RBD was mapped to be around residue Asp539, which is part of a conserved conformational epitope at the receptor-binding interface. NbMS10 and NbMS10-Fc maintained strong cross-neutralizing activity against divergent MERS-CoV strains isolated from humans and camels. Particularly, NbMS10-Fc had significantly extended half-life in vivo; a single-dose treatment of NbMS10-Fc exhibited high prophylactic and therapeutic efficacy by completely protecting humanized mice from lethal MERS-CoV challenge. Overall, this study proves the feasibility of producing cost-effective, potent, and broad-spectrum Nbs against MERS-CoV and has produced Nbs with great potentials as anti-MERS-CoV therapeutics.IMPORTANCE Therapeutic development is critical for preventing and treating continual MERS-CoV infections in humans and camels. Because of their small size, nanobodies (Nbs) have advantages as antiviral therapeutics (e.g., high expression yield and robustness for storage and transportation) and also potential limitations (e.g., low antigen-binding affinity and fast renal clearance). Here, we have developed novel Nbs that specifically target the receptor-binding domain (RBD) of MERS-CoV spike protein. They bind to a conserved site on MERS-CoV RBD with high affinity, blocking RBD's binding to MERS-CoV receptor. Through engineering a C-terminal human Fc tag, the in vivo half-life of the Nbs is significantly extended. Moreover, the Nbs can potently cross-neutralize the infections of diverse MERS-CoV strains isolated from humans and camels. The Fc-tagged Nb also completely protects humanized mice from lethal MERS-CoV challenge. Taken together, our study has discovered novel Nbs that hold promise as potent, cost-effective, and broad-spectrum anti-MERS-CoV therapeutic agents.

MicroRNA-5110 regulates pigmentation by cotargeting melanophilin and WNT family member 1.

Mammalian pigmentation requires the production of melanin by melanocytes and its transfer to neighboring keratinocytes. These complex processes are regulated by several molecular pathways. Melanophilin ( MLPH) and WNT family member 1 ( WNT1), known to be involved in melanin transfer and melanin production, respectively, were predicted to be targets of microRNA-5110 using bioinformatics. In the current study, we investigated the effects of microRNA-5110 on pigmentation in alpaca ( Vicugna pacos) melanocytes. In situ hybridization identified high levels of microRNA-5110 in the cytoplasm of alpaca melanocytes. Luciferase activity assays confirmed that MLPH and WNT1 were targeted by microRNA-5110 in these cells. Overexpression and knockdown of microRNA-5110 in alpaca melanocytes downregulated and upregulated MLPH and WNT1 expression at the mRNA and protein levels, respectively. In addition, overexpression and knockdown of microRNA-5110 in alpaca melanocytes decreased and increased, respectively, the mRNA levels of the melanin transfer-related genes, rat sarcoma (RAS)-associated binding ( RAB27a) and myosin 5a ( MYO5a); the mRNA levels of microphthalmia-associated transcription factor ( MITF), tyrosinase ( TYR), and tyrosinase-related protein ( TYRP) 1; and the production of total alkali melanin and pheomelanin. In contrast, overexpression and knockdown of microRNA-5110 increased and decreased the mRNA levels of TYRP2, respectively. Overexpression of microRNA-5110 also increased eumelanin. These results indicate that microRNA-5110 regulates pigmentation in alpaca melanocytes by directly targeting MLPH and WNT1 to affect eumelanin production and transfer.-Yang, S., Liu, B., Ji, K., Fan, R., Dong, C. MicroRNA-5110 regulates pigmentation by cotargeting melanophilin and WNT family member 1.

Differential expression of lncRNAs and predicted target genes in normal mouse melanocytes and B16 cells.

Melanoma is a highly invasive and metastatic malignant skin tumor with poor prognosis. Although several widely studied pure melanoma cell lines are available, the precise mechanism underlying transformation of melanocyte to melanoma remains unclear. Long non-coding RNAs (lncRNAs) represent a vast category of non-coding RNA molecules, and increasing evidence suggests that lncRNAs are crucial for various biological processes, including those in the skin. Herein, lncRNA sequencing was performed on an Illumina HiSeq platform to identify lncRNAs expressed differently in murine B16 melanoma cells compared to normal mouse melanocytes. Using four computational approaches, 2319 lncRNAs were expressed in both normal melanocytes and B16 cells, with 373 being differentially expressed at a significant level. Of these, 136 lncRNAs were upregulated and 237 were downregulated. KEGG analyses revealed that 467 genes were target genes in the Wnt signalling pathway, TGF-beta signalling pathway, MAPK signalling pathway, NF-kappa B signalling pathway, melanoma and several other cancer-related regulatory pathways. From among the differentially expressed lncRNAs, lnc-13317.1 was found to play a role in the cell cycle in melanoma by targeting BRCA1. Thus, lnc-13317.1 might have therapeutic potential in melanoma treatment. The lncRNA profile described here highlights the importance of elucidating the exact function of these lncRNAs in the transformation of melanoma. Lnc-13317.1 might have therapeutic potential in melanoma treatment by targeting BRCA1.

MicroRNA 143-5p regulates alpaca melanocyte migration, proliferation and melanogenesis.

microRNAs (miRNAs) have been shown to be closely involved in the control of melanogenesis and hair colour in mammals. Previous data also indicate that miR-143 regulates cell growth in melanoma. Here, we aimed to investigate the role of miR-143-5p in alpaca melanocytes. We found that miR-143-5p was highly expressed in the cytoplasm of alpaca melanocytes as demonstrated by an in situ hybridization assay. Prediction analysis revealed that miR-143-5p could regulate TGF-ß-activated kinase 1 (TAK1) expression, which we confirmed by luciferase reporter assay, indicating that miR-143-5p controls TAK1 expression by directly targeting its 3' untranslated region (UTR). miR-143-5p overexpression decreased TAK1 expression, which led to increased melanocyte migration and proliferation, and downregulation of microphthalmia-associated transcription factor (MITF), which regulates melanin production. These results support a functional role for miR-143-5p in regulating alpaca melanocyte migration, proliferation and melanogenesis through direct targeting of TAK1.

The utility of "low current" stimulation threshold of intraoperative electromyography monitoring in predicting facial nerve function outcome after vestibular schwannoma surgery: a prospective cohort study of 103 large tumors.

To investigate the predictive utility of stimulation threshold (ST) of intraoperative electromyography monitoring for facial nerve (FN) outcomes among vestibular schwannoma (VS) patients postoperatively. The authors enrolled 103 unilateral VS patients who underwent surgical resection into a prospective cohort observational study from January 2013 to April 2015 in our hospital. ST values were used to categorize 81 patients into the "low current" (ST ≤ 0.05 mA) group and 22 patients into the control (ST > 0.05 mA) group. The FN function outcomes were summarized and correlated with these two groups at 1, 3, 6, and 12 months after surgery. Binary regression analysis revealed that the percentage of "good" FN outcome, defined by House-Brackmann (HB) classification of facial function (I-II), in the "low current" group was significantly higher than that of the control group (42.0 vs. 4.5% at 1 month, P = 0.015; 64.2 vs. 31.8% at 3 months, P = 0.024; 72.8 vs. 40.9% at 6 months, P = 0.021; 84.0 vs. 45.5% at 12 months, P = 0.002). Ordinal regression analysis showed that the distribution of HB scores was shifted in a favorable direction in the "low current" group at 1, 3, 6, and 12 months postoperatively. For patients with HB IV at the first month postoperative period, the recovery rate of the "low current" group was significantly higher than that of control group (P = 0.003). "Low current" can predict FN function outcomes better and has faster recovery rates than that of the control group.

FGF21 regulates melanogenesis in alpaca melanocytes via ERK1/2-mediated MITF downregulation.

Fibroblast growth factor 21 (FGF21) is known as a metabolic regulator to regulate the metabolism of glucose and lipids. However, the underlying mechanism of FGF21 on melanin synthesis remains unknown. Therefore, the current study investigates the effect of FGF21 on melanogenesis in alpaca melanocytes. We transfected the FGF21 into alpaca melanocytes, then detected the melanin contents, protein and mRNA levels of pigmentation-related genes in order to determine the melanogenesis-regulating pathway of FGF21. The results showed that FGF21 overexpression suppressed melanogenesis and decreased the expression of the major target genes termed microphthalmia-associated transcription factor (MITF) and its downstream genes, including tyrosinase (TYR) and tyrosinase-related protein 2 (TRP2). However FGF21 increased the expression of phospho-extracellular signal-regulated kinase (p-Erk1/2). In contrast, FGF21-siRNA, a small interference RNA mediating FGF21 silencing, abolished the inhibition of melanogenesis. Altogether, FGF21 may decrease melanogenesis in alpaca melanocytes via ERK activation and subsequent MITF downregulation, which is then followed by the suppression of melanogenic enzymes and melanin production.

Functional outcome and complications after the microsurgical removal of giant vestibular schwannomas via the retrosigmoid approach: a retrospective review of 16-year experience in a single hospital.

BACKGROUND: Intracranial vestibular schwannoma still remain to be difficulty for its unique microsurgical technique and preservation of neuro-function, as well as reducing common complications that may arise in surgery. METHODS: We consecutively enrolled 657 unilateral giant (>4 cm diameter) vestibular schwannoma patients treated in Huashan Hospital via the suboccipital retrosigmoid approach in the past 16 years. The extension of tumor removal, surgical mortality, facial nerve function, hearing, and the other main short and long-term complications were the studied parameters. RESULTS: Gross total resection was performed in 556 patients (84.6%); near-total resection was achieved in 99 patients (15.1%). The mortality rate is 0.6%. The main short-term complications included 'new' deafness (47.6%), intracranial infection (7.6%), lower cranial nerve defects (7.5%) and pneumonia (6.2%). The facial nerve was preserved anatomically in 589 cases (89.7%). Good facial nerve functional outcome (House-Brackmann Grades I and II) postoperatively was achieved in 216 patients (32.9%). Other 308 cases (46.9%) were House-Brackmann grade III, and 133 patients (20.2%) were House-Brackmann grade IV-VI. Follow-up data were available for 566 of the 657 patients (86.1%). The common long-term complications were hearing loss (85.2%), facial paralysis (HB grade IV-VI, 24.4%) and facial numbness (15.7%). CONCLUSIONS: Trends in the data lead the authors to suggest that the microsurgical technique, intraoperative nerve monitoring, and multidisciplinary cooperation, were the keys to improving prognostic outcomes in giant intracranial vestibular schwannoma patients.

Assessing the Capabilities of Generative Pretrained Transformer-4 in Addressing Open-Ended Inquiries of Oral Cancer.

INTRODUCTION AND AIMS: In the face of escalating oral cancer rates, the application of large language models like Generative Pretrained Transformer (GPT)-4 presents a novel pathway for enhancing public awareness about prevention and early detection. This research aims to explore the capabilities and possibilities of GPT-4 in addressing open-ended inquiries in the field of oral cancer. METHODS: Using 60 questions accompanied by reference answers, covering concepts, causes, treatments, nutrition, and other aspects of oral cancer, evaluators from diverse backgrounds were selected to evaluate the capabilities of GPT-4 and a customized version. A P value under .05 was considered significant. RESULTS: Analysis revealed that GPT-4 and its adaptations notably excelled in answering open-ended questions, with the majority of responses receiving high scores. Although the median score for standard GPT-4 was marginally better, statistical tests showed no significant difference in capabilities between the two models (P > .05). Despite statistical significance indicated diverse backgrounds of evaluators have statistically difference (P < .05), a post hoc test and comprehensive analysis demonstrated that both editions of GPT-4 demonstrated equivalent capabilities in answering questions concerning oral cancer. CONCLUSIONS: GPT-4 has demonstrated its capability to furnish responses to open-ended inquiries concerning oral cancer. Utilizing this advanced technology to boost public awareness about oral cancer is viable and has much potential. When it's unable to locate pertinent information, it will resort to their inherent knowledge base or recommend consulting professionals after offering some basic information. Therefore, it cannot supplant the expertise and clinical judgment of surgical oncologists and could be used as an adjunctive evaluation tool.

Chinese medicine PaBing-II protects human iPSC-derived dopaminergic neurons from oxidative stress.

Background: PaBing-II Formula (PB-II) is a traditional Chinese medicine for treating Parkinson's disease (PD). However, owing to the complexity of PB-II and the difficulty in obtaining human dopaminergic neurons (DAn), the mechanism of action of PB-II in PD treatment remains unclear. The aim of this study was to investigate the mechanisms underlying the therapeutic benefits of PB-II in patients with PD. Methods: hiPSCs derived DAn were treated with H2O2 to construct the DAn oxidative damage model. SwissTargetPrediction was employed to predict the potential targets of the main compounds in serum after PB-II treatment. Metascape was used to analyze the pathways. Sprague-Dawley rats were used to construct the 6-hydroxydopamine (6-OHDA)-induced PD model, and the duration of administration was four weeks. RNA sequencing was used for Transcriptome analysis to find the signal pathways related to neuronal damage. The associated inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). We identified PB-II as an Nrf2 activator using antioxidant-responsive element luciferase assay in MDA-MB-231 cells. Results: In vitro experiments showed that the treatment of PB-II-treated serum increased the percentage of TH+ cells, decreased inflammation and the apoptosis, reduced cellular reactive oxygen species, and upregulated the expression of Nrf2 and its downstream genes. Pathway analysis of the RNA-seq data of samples before and after the treatment with PB-II-treated serum identified neuron-associated pathways. In vivo experiments demonstrated that PB-II treatment of PD rat model could activate the Nrf2 signaling pathway, protect the midbrain DAn, and improve the symptoms in PD rats. Conclusion: PB-II significantly protects DAn from inflammation and oxidative stress via Nrf2 pathway activation. These findings elucidate the roles of PB-II in PD treatment and demonstrate the application of hiPSC-derived DAn in research of Chinese medicine.