FGF-2 mRNA Research Articles

METTL3 affects the biological function of lung adenocarcinoma through the FGF2/PI3K/AKT /mTOR pathway.

This study aims to investigate the role of the m6A regulatory factor METTL3 in LUAD. By examining the expression of METTL3 in LUAD and conducting cellular functional experiments, the biological functions of METTL3 were discussed. mRNA-seq and MeRIP-qPCR were used to identify downstream target genes and pathways. The expression level of METTL3 in LUAD is lower than that in the control group. The downregulation of METTL3 promoted the proliferation, migration, and invasion of LUAD cells, while overexpression of METTL3 results in the opposite effects. Furthermore, we found that FGF2 was negatively regulated by METTL3. Inhibiting FGF2 reversed the tumor-promoting effects caused by METTL3 downregulation in LUAD cells. Silencing METTL3 enhanced the stability of FGF2 mRNA. Silencing FGF2 resulted in reduced activity of the PI3K/AKT/mTOR signaling pathway in METTL3 knockdown LUAD cells. In summary, our findings unveil an intricate signaling network involving METTL3/FGF2/PI3K/AKT/mTOR in LUAD and provide valuable insights into the molecular mechanisms underlying tumor progression, thus holding significant implications for targeted therapy and advancing LUAD research.

Expression Profiles of Fatty Acid Transporters and the Role of n-3 and n-6 Polyunsaturated Fatty Acids in the Porcine Endometrium.

Fatty acids (FAs) are important for cell membrane composition, eicosanoid synthesis, and metabolic processes. Membrane proteins that facilitate FA transport into cells include FA translocase (also known as CD36) and FA transporter proteins (encoded by SLC27A genes). The present study aimed to examine expression profiles of FA transporters in the endometrium of cyclic and early pregnant gilts on days 3 to 20 after estrus and the possible regulation by conceptus signals and polyunsaturated FAs (PUFAs). The effect of PUFAs on prostaglandin (PG) synthesis and transcript abundance of genes related to FA action and metabolism, angiogenesis, and immune response was also determined. Day after estrus and reproductive status of animals affected FA transporter expression, with greater levels of CD36, SLC27A1, and SLC27A4 observed in pregnant than in cyclic gilts. Conceptus-conditioned medium and/or estradiol-17β stimulated SLC27A1 and CD36 expression. Among PUFAs, linoleic acid decreased SLC27A1 and SLC27A6 mRNA expression, while arachidonic, docosahexaenoic, and eicosapentaenoic acids increased SLC27A4 transcript abundance. Moreover, arachidonic acid stimulated ACOX1, CPT1A, and IL1B expression and increased PGE2 and PGI2 secretion. In turn, α-linolenic acid up-regulated VEGFA, FGF2, FABP4, and PPARG mRNA expression. These results indicate the presence of an active transport of FAs in the porcine endometrium and the role of PUFAs as modulators of the uterine activity during conceptus implantation.

Curcumin Reduces Hypoxia/Reperfusion Injury of Cardiomyocytes byStimulating Vascular Endothelial Cells to Secrete FGF2.

Endothelial cells (ECs) can provide cell protection for cardiomyocytes (CMs) under hypoxia-reoxygenation (HR) conditions by secreting derived factors. This study aimed to explore the role of curcumin (CUR) in ECs for protecting CMs from HR injury. A co-culture system for ECs and CMs was set up, and subjected to HR. The transcription, expression, and secretion of FGF2 were detected by RT-qPCR, western blot, and ELISA, respectively. siRNAs specifically targeting FGF2 were transfected into ECs. FGF2 receptor- specific inhibitors (AZD4547) were used to treat CMs. The co-culture with ECs did not affect the proliferation of CMs, while CUR and ECs co-culture had a synergistic effect on promoting the proliferation of CMs in HR. Furthermore, the co-culture with ECs did not affect the apoptosis and autophagy of CMs in HR. However, the co-culture of ECs after CUR treatment inhibited the apoptosis and autophagy of CMs in HR. CUR treatment significantly enhanced FGF2 mRNA, protein, and secretion levels of ECs in HR. In addition, CUR treatment increased FGF2 levels in the CMs medium in the ECs and CMs co-culture system. The reduction of FGF2 levels in the medium and the inhibition of FGF2 receptors significantly inhibited the proliferation of CMs and significantly promoted the apoptosis and autophagy of CMs in HR. Focusing on the protective effects of CUR and ECs on cardiomyocytes is of great significance for the treatment of clinical myocardial HR injury.

Osteogenic differentiation by MC3T3-E1 pre-osteoblasts is enhanced more on wet-chemically surface-modified 3D-printed poly-e-caprolactone scaffolds than on plasma-assisted modified scaffolds

3D-Printed poly-є-caprolactone (PCL)-scaffolds are safe for cell support, but their hydrophobicity, bioinertness, and smooth surface limits bioactive/biomimetic performance. This can be overcome by providing biophysicochemical and biomechanical signals using amine (NH2) or carboxyl (COOH)-surface functionalization via wet-chemical treatment or plasma-assisted modification, but the alteration extent and hence bone-cell activity is unknown. We aimed to investigate the influence of NH2 or COOH-surface functionalization via wet-chemical treatment or plasma-assisted modification on biophysicochemical and biomechanical properties of 3D-printed PCL-scaffolds and osteogenic activity. In PCL/NH2 and PCL/COOH scaffolds, only wet-chemical treatment increased void size and surface-roughness, but both treatments reduced water contact angle. Wet-chemical treatment decreased, but plasma-assisted modification increased the elastic modulus. Finite-element modeling revealed that in all scaffolds, maximum von Mises stress under 2% compression-strain did not surpass yield stress for bulk material, indicating excellent mechanical stability and fracture resistance. Wet-chemical treatment and plasma-assisted modification increased pre-osteoblast proliferation, alkaline phosphatase activity, and mineral deposition. Wet-chemical treatment increased Fgf2 mRNA, while both treatments increased Cox2 mRNA. Only wet-chemical treatment increased collagen production. In conclusion, NH2 and COOH-surface functionalization of 3D-printed PCL-scaffolds via wet-chemical treatment was superior to plasma-assisted modification in enhancing osteogenic activity, and is therefore more promising for in vivo bone formation.

Regulation of Hair Follicle Growth and Development by Different Alternative Spliceosomes of FGF5 in Rabbits.

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.

Abstract TMP113: RNA Sequencing Reveals Novel Pericytic MiR-15a/16-1 Targets in Post-Stroke Cerebral Angiogenesis

Introduction: Angiogenesis actively contributes to post-stroke functional recovery and improves long-term survival in stroke patients. Previously, we demonstrated that endothelium-targeted deletion of miR-15a/16-1 promotes post-stroke angiogenesis by enhancing classic pro-angiogenic factors and their receptors, and genetic deletion of miR-15a/16-1 in pericytes likewise promotes post-stroke functional recovery by stimulating cerebral angiogenesis. Here, we further investigate the underlying mechanisms and downstream targets of pericytic miR-15a/16-1 in cerebral angiogenesis after ischemic stroke. Methods: Pericyte-miR15a/16-1 conditional knockout mice (Pericyte-miR-15a/16-1 cKO) and wild-type (WT) controls were subjected to 1h MCAO followed by 7d reperfusion. Cerebral microvessels were extracted and subjected to RNA-seq to identify the significant differentially expressed genes (DEGs) that related to miR-15a/16-1 and angiogenesis among experimental groups. TargetScan and miRDB were used to predict potential miR-15a/16-1 downstream targets. Primary mouse brain vascular pericytes (mBVPs) were treated with lentivirus to achieve loss- or gain-of-miR-15a/16-1 function, and subjected to OGD 8h and reperfusion 24h. Pro-angiogenic factors were further verified by dual-luciferase reporter assay, qPCR, and western blotting. Results: RNA-seq analysis showed 289 upregulated genes (P &lt; 0.05 &amp; at least one CPM &gt; 1) and 399 upregulated genes from 100 positive enriched gene sets (GESA) in cerebral microvessels of pericyte-miR-15a/16-1 cKO mice compared to WT controls 7d after MCAO. By comparing to miR-15a/16-1 potential target database from TargetScan and miRDB, 9 angiogenic genes were identified. Further biochemical analysis revealed that Pappa2, Fgf9, Islr, and Ccr2 mRNA and protein expression are significantly increased in cerebral microvessels of cKO mice and mBVPs with loss-of-miR-15a/16-1 function. Furthermore, dual-luciferase assay results verified that loss- or gain-of-miR-15a/16-1 function significantly increased or decreased luciferase reporter activity of these four genes, respectively. Conclusion: Our findings reveal novel pericytic miR-15a/16-1 mediated angiogenic targets in ischemic stroke.

Expression Status of Rap1 Pathway-Related Genes in Liver Metastases Compared with Corresponding Primary Colorectal Cancer.

Understanding molecular networks of CRLM is an ongoing area of research. In this study, paired CRC tissue and adjacent noncancerous tissue from 15 non-metastatic CRC patients and paired CRC tissue and matched liver metastatic tissues from 15 CRLM patients along with their adjacent noncancerous tissues were evaluated. We assessed Rap1 pathway-related genes including NRAS, FGF-1, NGF, and KDR expression by qRT-PCR and their protein status by Western blot. In CRLM patients, NRAS, FGF1, and KDR mRNA and protein were expressed at higher levels in metastatic than in CRC primary tumor and adjacent noncancerous tissue (p < 0.05). In non-metastatic patients, NRAS, FGF1, KDR, and NGF gene expression did not differ between CRC primary tumor-and adjacent noncancerous tissue (p > 0.05). ROC curve analysis showed a reasonable diagnostic accuracy of NRAS, FGF1, KDR, and FGF for the discrimination of metastatic patients from non- metastatic ones on analysis of their primary tumors. The data suggest that further functional studies on Rap1-related genes' role in CRLM are needed. In conclusion, the present data broaden our knowledge about specific molecular characteristics of CRLM. An increased understanding of the molecular features of metastasis has the potential to create more successful treatment, or prevention, of metastasis, especially in multimodal primary tumor treatment.

A chemo-mechanical model of endoderm movements driving elongation of the amniote hindgut.

Although mechanical and biochemical descriptions of development are each essential, integration of upstream morphogenic cues with downstream tissue mechanics remains understudied during vertebrate morphogenesis. Here, we developed a two-dimensional chemo-mechanical model to investigate how mechanical properties of the endoderm and transport properties of fibroblast growth factor (FGF) regulate avian hindgut morphogenesis in a coordinated manner. Posterior endoderm cells convert a gradient of FGF ligands into a contractile force gradient, leading to a force imbalance that drives collective cell movements that elongate the forming hindgut tube. We formulated a 2D reaction-diffusion-advection model describing the formation of an FGF protein gradient as a result of posterior displacement of cells transcribing unstable Fgf8 mRNA during axis elongation, coupled with translation, diffusion and degradation of FGF protein. The endoderm was modeled as an active viscous fluid that generates contractile stresses in proportion to FGF concentration. With parameter values constrained by experimental data, the model replicates key aspects of hindgut morphogenesis, suggests that graded isotropic contraction is sufficient to generate large anisotropic cell movements, and provides new insight into how chemo-mechanical coupling across the mesoderm and endoderm coordinates hindgut elongation with axis elongation.

Circulating FGF18 is decreased in pleural mesothelioma but not correlated with disease prognosis.

Pleural mesothelioma (PM) is a relatively rare malignancy with limited treatment options and dismal prognosis. We have previously found elevated FGF18 expression in PM tissue specimens compared with normal mesothelium. The objective of the current study was to further explore the role of FGF18 in PM and evaluate its suitability as a circulating biomarker. FGF18 mRNA expression was analyzed by real-time PCR in cell lines and in silico in datasets from the Cancer Genome Atlas (TCGA). Cell lines overexpressing FGF18 were generated by retroviral transduction and cell behavior was investigated by clonogenic growth and transwell assays. Plasma was collected from 40 PM patients, six patients with pleural fibrosis, and 40 healthy controls. Circulating FGF18 was measured by ELISA and correlated to clinicopathological parameters. FGF18 showed high mRNA expression in PM and PM-derived cell lines. PM patients with high FGF18 mRNA expression showed a trend toward longer overall survival (OS) in the TCGA dataset. In PM cells with low endogenous FGF18 expression, forced overexpression of FGF18 resulted in reduced growth but increased migration. Surprisingly, despite the high FGF18 mRNA levels observed in PM, circulating FGF18 protein was significantly lower in PM patients and patients with pleural fibrosis than in healthy controls. No significant association of circulating FGF18 with OS or other disease parameters of PM patients was observed. FGF18 is not a prognostic biomarker in PM. Its role in PM tumor biology and the clinical significance of decreased plasma FGF18 in PM patients warrant further investigation.

Transcriptomic and in vivo approaches introduced human iPSC-derived microvesicles for skin rejuvenation

The skin undergoes the formation of fine lines and wrinkles through the aging process; also, burns, trauma, and other similar circumstances give rise to various forms of skin ulcers. Induced pluripotent stem cells (iPSCs) have become promising candidates for skin healing and rejuvenation due to not stimulating inflammatory responses, low probability of immune rejection, high metabolic activity, good large-scale production capacity and potentials for personalized medicine. iPSCs can secrete microvesicles (MVs) containing RNA and proteins responsible for the normal repairing process of the skin. This study aimed to evaluate the possibility, safety and effectiveness of applying iPSCs-derived MVs for skin tissue engineering and rejuvenation applications. The possibility was assessed using the evaluation of the mRNA content of iPSC-derived MVs and the behavior of fibroblasts after MV treatment. Investigating the effect of microvesicle on stemness potential of mesenchymal stem cells was performed for safety concerns. In vivo evaluation of MVs was done in order to investigate related immune response, re-epithelialization and blood vessel formation to measure effectiveness. Shedding MVs were round in shape distributed in the range from 100 to 1000 nm in diameter and positive for AQP3, COL2A, FGF2, ITGB, and SEPTIN4 mRNAs. After treating dermal fibroblasts with iPSC-derived MVs, the expressions of collagens Iα1 and III transcripts (as the main fibrous extracellular matrix (ECM) proteins) were upregulated. Meanwhile, the survival and proliferation of MV treated fibroblasts did not change significantly. Evaluation of stemness markers in MV treated MSCs showed negligible alteration. In line with in vitro results, histomorphometry and histopathology findings also confirmed the helpful effect of MVs in skin regeneration in the rat burn wound models. Conducting more investigations on hiPSCs-derived MVs may lead to produce more efficient and safer biopharmaceutics for skin regeneration in the pharmaceutical market.

Thermodynamically Favorable Interactions between eIF4E Binding Domain of eIF4GI with Structured 5'-Untranslated Regions Drive Cap-Independent Translation of Selected mRNAs.

During cellular stress conditions, particularly those seen in multiple cancers, canonical cap-dependent translation is suppressed and a subset of cellular mRNAs (e.g., those encoding FGF-9, HIF-1α, and p53, among others) is known to translate in a cap-independent manner. Human eIF4GI specifically binds to the highly structured 5'-untranslated regions (5'UTRs) of these mRNAs to promote cap-independent translation. The thermodynamics of these protein-RNA interactions have not been explored, and such information will aid in understanding the basic interactions and in potential design of therapeutic drugs. Using fluorescence quenching-based assays and site-directed mutagenesis, we determined the thermodynamic properties of three eIF4GI constructs binding to the 5'UTRs of FGF-9, HIF-1α, and p53 mRNA. These three constructs were designed to explore the importance of the eIF4E binding domain of eIF4GI, which has been shown to be important in binding and selectivity. eIF4GI557-1599, containing the eIF4E binding domain, had higher binding enthalpy (-21 to -14 kJ mol-1 higher), suggesting increased hydrogen bonding, whereas for eIF4GI682-1599 lacking the eIF4E binding domain, binding was entropically favored (TΔS/ΔG of 46-85%), suggesting hydrophobic forces and/or less specific binding. A third construct where a cluster of positively charged amino acids was changed to neutral amino acids showed intermediate properties. Circular dichroism spectra confirmed the significant role of eIF4E binding domain in stable bond formation between eIF4GI and mRNAs via conformational changes. Together, these data contribute to a better understanding of the molecular forces involved in eIF4GI-mRNA recognition and elucidate properties important for the design of small molecules to mediate these interactions.

Role of FGF10/FGFR2b Signaling in Homeostasis and Regeneration of Adult Lacrimal Gland and Corneal Epithelium Proliferation.

Fibroblast growth factor 10 (FGF10) is involved in eye, meibomian, and lacrimal gland (LG) development, but its function in adult eye structures remains unknown. This study aimed to characterize the role of FGF10 in homeostasis and regeneration of adult LG and corneal epithelium proliferation. Quantitative reverse transcription PCR was used for analysis of FGF10 expression in both early postnatal and adult mouse LG, and RNA sequencing was used to analyze gene expression during LG inflammation. FGF10 was injected into the LG of two mouse models of Sjögren's syndrome and healthy controls. Flow cytometry, BrdU cell proliferation assay, immunostaining, and hematoxylin and eosin staining were used to evaluate the effects of FGF10 injection on inflammation and cell proliferation in vivo. Mouse and human epithelial cell cultures were treated with FGF10 in vitro, and cell viability was assessed using WST-8 and adenosine triphosphate (ATP) quantification assays. The level of Fgf10 mRNA expression was lower in adult LG compared to early postnatal LG and was downregulated in chronic inflammation. FGF10 injection into diseased LGs significantly increased cell proliferation and decreased the number of B cells. Mouse and human corneal epithelial cell cultures treated with FGF10 showed significantly higher cell viability and greater cell proliferation. FGF10 appears to promote regeneration in damaged adult LGs. These findings have therapeutic potential for developing new treatments for dry eye disease targeting the ability of the cornea and LG to regenerate.

Development of lacrimal gland organoids from iPSC derived multizonal ocular cells.

Lacrimal gland plays a vital role in maintaining the health and function of the ocular surface. Dysfunction of the gland leads to disruption of ocular surface homeostasis and can lead to severe outcomes. Approaches evolving through regenerative medicine have recently gained importance to restore the function of the gland. Using human induced pluripotent stem cells (iPSCs), we generated functional in vitro lacrimal gland organoids by adopting the multi zonal ocular differentiation approach. We differentiated human iPSCs and confirmed commitment to neuro ectodermal lineage. Then we identified emergence of mesenchymal and epithelial lacrimal gland progenitor cells by the third week of differentiation. Differentiated progenitors underwent branching morphogenesis in the following weeks, typical of lacrimal gland development. We were able to confirm the presence of lacrimal gland specific acinar, ductal, and myoepithelial cells and structures during weeks 4-7. Further on, we demonstrated the role of miR-205 in regulation of the lacrimal gland organoid development by monitoring miR-205 and FGF10 mRNA levels throughout the differentiation process. In addition, we assessed the functionality of the organoids using the β-Hexosaminidase assay, confirming the secretory function of lacrimal organoids. Finally, metabolomics analysis revealed a shift from amino acid metabolism to lipid metabolism in differentiated organoids. These functional, tear proteins secreting human lacrimal gland organoids harbor a great potential for the improvement of existing treatment options of lacrimal gland dysfunction and can serve as a platform to study human lacrimal gland development and morphogenesis.

Vascular Distribution and Expression Patterns of Angiogenic Factors in Caruncle during the Early Stage of Pregnancy in Goats (Capra hircus).

The placenta is a temporary maternal−fetal organ, and its maternal placenta (caruncle) is essential for fetal growth and development. The exchange function of the placenta requires vascular development (angiogenesis). However, the angiogenesis of the caruncle is poorly understood in goats during the early stage of pregnancy. Here, we investigated the vascular distribution, mRNA expression of major angiogenic factors, and the methylation levels of ANGPT2 in the goat caruncle. It showed that CAD (capillary area density), CSD (capillary surface density), and APC (area per capillary) increased gradually, while CND (capillary number density) showed an insignificant change, probably due to the variability between animals. The proportion of proliferating cells was observed to be very high (>26%) and increased (p < 0.002) approximately 2-fold from day 20 to 60 of pregnancy. Furthermore, the expression patterns of major angiogenic factors changed during the early stage of pregnancy. Interestingly, we discovered an absolute correlation between the mRNA for ANGPT2, TEK, FGF2, and vascular distribution. Subsequently, we evaluated the DNA methylation of ANGPT2, where we found that mean methylation was negatively correlated with CAD. The methylation at the CpG sites, such as CpG 4/18, CpG 9.10.11, and CpG 15, showed significant changes during the early stage of pregnancy. Thus, our findings suggest that the methylation of ANGPT2 may be involved in the regulation of caruncle angiogenesis during the early stage of pregnancy.

Effectiveness of topical administration of platelet-rich plasma on the healing of methicillin-resistant Staphylococcus aureus-infected full-thickness wound model

This study aimed to investigate the wound-healing activity of animal platelet-rich plasma (PRP) in wounds infected with methicillin-resistant Staphylococcus aureus (MRSA) in rats. After wound induction, the rats were divided into three groups: noninfected animals treated with PRP (PRP group), MRSA-infected animals treated with mupirocin (standard control group), and MRSA-infected animals treated with PRP (MRSA+PRP group). Scratch assays, MTT test, and live/dead cells were also investigated. Total bacterial count, parameters of wound area, histopathological assessment, and expressions of IL-1β, TNF-α, iNOS, PDGF, FGF-2, and TGF-β mRNA levels and immunofluorescent staining of CD31 and collagen type 1 were assessed. The results showed that culture with PRP increased migration. PRP only showed cytotoxicity in a concentration of 100%. Topical application of PRP (50 µL) reduced the wound area and total bacterial count compared with the control group (P<0.05). The mRNA levels of IL-1β, TNF-α, and iNOS expression on days 7 and 14 (P<0.05) decreased in the treated groups compared with control rats. The mRNA levels of PDGF and TGF-β expression (P<0.05) increased in the treatment groups compared with control rats on days 3 and 7 (P<0.05). FGF-2 expression was significantly higher in the treated groups compared with the control group on days 7 and 14 (P<0.05). Moreover, positive expressions of macrophage colony-stimulating factor (M-CSF), CD31, collagen type 1 and cytokeratin proteins keratinocyte proliferation, and re-epithelization were significantly (P<0.05) increased in both PRP and MRSA+PRP-treated groups compared with the control groups on days 7 and 14. Topical administration of PRP accelerated the wound healing in MRSA-infected wound by decreasing the inflammation and improving the proliferative phase.

The effects of follicle stimulating hormone (FSH)-induced controlled ovarian hyperstimulation and nutrition on implantation-related gene expression in caruncular tissues of non-pregnant sheep

Disturbances at the conceptus-maternal interface can have detrimental effects on pregnancy outcome. Additionally, changes in body condition and exogenously administered gonadotropins could affect ovarian and uterine function, including cell proliferation and ovulation rates, and alter endometrial receptivity. In ruminants, endometrial caruncles maintain placental function via interaction with fetal chorionic cotyledons. Here, the effects of feeding regimens on the expression of selected genes known to be involved in uterine receptivity were investigated in the caruncles of control and FSH-superovulated ewes. Sheep were grouped according to their diet: control fed (CF), overfed (OF) or underfed (UF), and were either superovulated with FSH (SOV) or untreated (CON, naturally cycling) (n = 3–5/group). Caruncular samples for the assessment of the transcript levels of 11 target genes were collected at either the early (day 5) or mid-luteal (day 10) phases of the luteal lifespan, resulting in 12 groups of animals. The day of the estrous cycle affected the expression of ITGAV, ITGB3, FGF10 and IGFBP3 mRNA. There was lower expression of MUC1, and higher expression of FGF10, ITGB3 and FN1, on day 10 in CF_SOV animals. Compared with CF, expression of integrins (ITGB3, ITGA5 and ITGA4) was higher in OF and UF, and higher transcript levels of HGF and IGFBP3 in UF animals on day 10. Expression of ITGA5, ITGB1, -3, -5 and MUC1 was greater in OF_SOV than CF_SOV at day 10. In conclusion, it appears that imbalanced nutrition, by altering the expression of genes responsible for intercellular communication, cell adhesion, and encoding for growth factors, could affect the uterine responsiveness to exogenously applied hormonal stimulation and, likely, uterine receptivity.

A deletion variant within the FGF5 gene in goats is associated with gene expression levels and cashmere growth.

The FGF5 gene has been associated with the regulation of fibre length in mammals, including cashmere goats. A deletion variant at ~14 kb downstream of the FGF5 gene showed significant divergence between cashmere and non-cashmere goats in previous studies. In this study, we designed specific primers to genotype the deletion variant. The results of gel electrophoresis and Sanger sequencing revealed that a 507-bp deletion mutation is located at 95 454 685-95 455 191 of chromosome 6 in goats. Genotyping data from a large panel of 288 goats showed that the deletion at the FGF5 gene locus appeared to be associated with cashmere length. The deletion variant was close to fixation (frequency 0.97) in cashmere goats. Furthermore, electrophoretic mobility shift assays for evaluating DNA-protein interaction and mRNA expression levels of FGF5 suggested that the deletion variant may serve as a cis-acting element by specifically binding transcription factors to mediate quantitative changes in FGF5 mRNA expression. Our study illustrates how a structural mutation of the FGF5 gene has contributed to the cashmere growth phenotype in domestic goats. The deletion mutation within the FGF5 gene could potentially serve as a molecular marker of cashmere growth in cashmere goat breeding.

F1A‐CreERT2 Mice: Targeting and Tracing Cardiomyocytes with Fgf1 Expression in Adult Mouse

Fibroblast growth factor 1 (FGF1) regulates many biological and homeostatic processes, including obesity and metabolic syndrome. In mice, Fgf1 gene contains at least three upstream promoters and their respective adjacent untranslated exons that spliced to the first protein coding exon mutually exclusively, giving rise to different Fgf1 mRNA variants. Among them, the Fgf1A transcript is predominantly expressed in the heart. FGF1 can induce cardiomyocyte regeneration and cardiogenesis in vitro and in vivo. Here, we generated a novel mouse line Fgf1A promoter (F1A)‐driven inducible Cre recombinase (CreERT2). We firstly demonstrated that the highest mRNA expression of CreERT2 were detected in the heart specifically of F1A‐CreERT2 mice, similar to that of Fgf1A mRNA. The F1A‐CreERT2 mice were crossed with ROSA26 mice, and the F1 mice were analyzed. The LacZ‐positive signals were detected exclusively in the heart after tamoxifen administration. The CreERT2‐mediated recombination in the tissues is monitored through LacZ‐positive signals, indicating the in situ localization of F1A‐positive cells. Consistently, these F1A‐positive cells with RFP‐positive signals or LacZ‐positive blue signals were co‐localized with cardiomyocytes expressing cardiac troponin T, suggesting cardiomyocyte‐specific activation of Fgf1A promoter. Our data suggested that the F1A‐CreERT2 mouse line could be used for time‐dependent and lineage tracing of Fgf1A‐expressing cells in vivo. F1A‐CreERT2 line is a valuable tool for in vivo lineage tracing of Fgf1A‐expressing cells during heart development and will facilitate the elucidation of the physiological and pathological role of Fgf1A in heart failure and metabolic syndrome.

Fibroblast Growth Factor 9 as a Potential Biomarker for Schizophrenia

Preclinical and clinical studies have suggested that fibroblast growth factor (FGF) system contributed to the onset and development of schizophrenia (SCZ). However, there was no strong clinical evidence to link an individual FGF with SCZ. In this study, we aim to measure blood FGF9 levels in the patients with SCZ with and/or without medication, and test whether FGF9 has a potential to be a biomarker for SCZ. We recruited 130 patients with SCZ and 111 healthy individuals, and the ELISA and qRT-PCR assays were used to measure serum FGF9 levels in the participants. ELISA assay demonstrated that serum FGF9 protein levels were dramatically reduced in first-episode, drug-free patients, but not in chronically medicated patients when compared to healthy control subjects. Further analysis showed that treatment of the first-episode, drug-free SCZ patients with antipsychotics for 8 weeks significantly increased the serum FGF9 levels. In addition, we found that blood FGF9 mRNA levels were significantly lower in first-onset SCZ patients than controls. Under the receiver operating characteristic curve, the optimal cutoff values for FGF9 protein level as an indicator for diagnosis of drug-free SCZ patients was projected to be 166.4 pg/ml, which yielded a sensitivity of 0.955 and specificity of 0.86, and the area under the curve was 0.973 (95% CI, 0.954-0.993). Furthermore, FGF9 had good performance to discriminate between drug-free SCZ patients and chronically medicated patients, the optimal cutoff value for FGF9 concentration was projected to be 165.035 pg/ml with a sensitivity of 0.86 and specificity of 0.919, and the AUC was 0.968 (95% CI, 0.944, 0.991). Taken together, our results for the first time demonstrated the dysregulation of FGF9 in SCZ, and FGF9 has the potential to be served as a biomarker for SCZ.

CircITGB6 promotes ovarian cancer cisplatin resistance by resetting tumor-associated macrophage polarization toward the M2 phenotype

BackgroundPlatinum resistance is a major challenge in the clinical treatment of advanced ovarian cancer (OC). Accumulating evidence shows that the tumor-promotive M2 macrophage is linked to the limiting chemotherapy efficacy...