Flavonoids, gut microbiota, and host lipid metabolism.

Flavonoids are widely distributed in nature and have a variety of beneficial biological effects, including antioxidant, anti-inflammatory, and anti-obesity effects. All of these are related to gut microbiota, and flavonoids also serve as a bridge between the host and gut microbiota. Flavonoids are commonly used to modify the composition of the gut microbiota by promoting or inhibiting specific microbial species within the gut, as well as modifying their metabolites. In turn, the gut microbiota extensively metabolizes flavonoids. Hence, this reciprocal relationship between flavonoids and the gut microbiota may play a crucial role in maintaining the balance and functionality of the metabolism system. In this review, we mainly highlighted the biological effects of antioxidant, anti-inflammatory and antiobesity, and discussed the interaction between flavonoids, gut microbiota and lipid metabolism, and elaborated the potential mechanisms on host lipid metabolism.

Long-term outcomes of anti-vascular endothelial growth factor therapy with and without posterior scleral reinforcement on myopic maculopathy in myopic choroidal neovascularization eyes.

BACKGROUND: Anti-vascular endothelial growth factor (anti-VEGF) therapy is used for myopic choroidal neovascularization (mCNV). Patchy chorioretinal atrophy (pCRA) enlargement has been reported in mCNV cases associated with vision loss. Our aim was to compare the long-term effectiveness of anti-VEGF therapy alone versus anti-VEGF followed by posterior scleral reinforcement (PSR) in controlling myopic maculopathy in mCNV eyes. METHODS: We performed a retrospective review of the medical records of 95 high myopia patients (refractive error ≥ 6.00 diopters, axial length ≥ 26.0 mm) with mCNV. Patients were treated with anti-VEGF alone (group A) or anti-VEGF followed by PSR (group B). The following data were collected: refractive error, best corrected visual acuity (BCVA), ophthalmic fundus examination, ocular coherence tomography and ocular biometry at 12 and 24 months pre- and postoperatively. The primary outcomes were changes in pCRA and BCVA. RESULTS: In 26 eyes of 24 patients, the mean pCRA size significantly increased from baseline (0.88 ± 1.69 mm2) to 12 months (1.57 ± 2.32 mm2, t = 3.249, P = 0.003) and 24 months (2.17 ± 2.79 mm2, t = 3.965, P = 0.001) postoperatively. The increase in perilesional pCRA in group B (n = 12) was 98.2% and 94.2% smaller than that in group A (n = 14) at 12 and 24 months (Beta 0.57 [95% CI 0.01, 191 1.13], P = 0.048). In group B, 7 eyes (58.3%) gained more than 2 lines of BCVA compared with only 4 eyes (28.6%) in group A at 24 months. CONCLUSION: Anti-VEGF therapy followed by PSR achieved better outcomes than anti-VEGF therapy alone in controlling the development of myopic maculopathy in mCNV and may constitute a better treatment option by securing a better long-term VA outcome.

Internet addiction and suicidal ideation among Chinese college students: the mediating role of psychotic-like experiences.

Background: Individuals with Internet addiction (IA) are at significant risk of suicide-related behaviors. This study aimed to investigate the relationships among IA, psychotic-like experiences (PLEs), and suicidal ideation (SI) among college students. Methods: A total of 5,366 college students (34.4% male, mean age 20.02 years) were assessed using the self-compiled sociodemographic questionnaires, Revised Chinese Internet Addiction Scale (CIAS-R), 15-item Positive subscale of the Community Assessment of Psychic Experiences (CAPE-P15), Self-rating Idea of Suicide Scale (SIOSS), and 2-item Patient Health Questionnaire (PHQ-2). Results: The prevalence of IA and SI were 9.3 and 12.1% among Chinese college students, respectively. There were direct effects of IA and PLEs on SI. The total effect of IA on SI was 0.18 (p < 0.001). PLEs mediated the relationship between IA and SI (Indirect effect = 0.07). Conclusion: IA had both direct and indirect effects on SI. These findings enable us to elucidate the mechanism of how IA influences individual SI, which can provide vital information for developing and implementing targeted interventions and strategies to alleviate SI among Chinese college students.

Sorafenib induces ferroptosis by promoting TRIM54-mediated FSP1 ubiquitination and degradation in hepatocellular carcinoma.

BACKGROUND: Ferroptosis is a unique form of regulated cell death that provided a new opportunity for cancer therapy. Ferroptosis suppressor protein 1 (FSP1) is a key regulator in the NAD(P)H/FSP1/CoQ10 antioxidant system, which sever as an oxide redox enzyme to scavenge harmful lipid hydroperoxides and escape from ferroptosis in cells. This study aimed to investigate the role of FSP1 on sorafenib-induced ferroptosis and disclosed the underlying mechanisms. METHODS: Cell viability, malondialdehyde (MDA), glutathione (GSH), and lipid reactive oxygen species levels were assessed using indicated assay kits. The levels of FSP1 and glutathione peroxidase 4 (GPX4) in the patients with HCC were analyzed based on the database. Western blot and quantitative real-time PCR were performed to detect the protein and mRNA expression. Co-immunoprecipitation was applied to detect the interaction between proteins. Tumor xenograft experiments were used to evaluate whether overexpression of FSP1-inhibited sorafenib-induced ferroptosis in vivo. RESULTS: We verified that sorafenib-induced ferroptosis in HCC. Furthermore, we found that sorafenib decreased the protein level of FSP1, and knockdown FSP1 rendered HCC cells susceptible to sorafenib-induced ferroptosis. Co-immunoprecipitation and ubiquitination assays showed that sorafenib accelerated the TRIM54-mediated FSP1 ubiquitination and degradation. Sorafenib-induced ferroptosis was abrogated by TRIM54 suppression. Mechanically, sorafenib-promoted TRIM54 ubiquitinated and degraded FSP1 by means of the ERK pathway. Moreover, FSP1 enhanced tumor development and decreased HCC cellular susceptibility to sorafenib in vivo. CONCLUSIONS: Sorafenib facilitated the TRIM54-mediated FSP1 ubiquitination through the ERK pathway, thereby inducing ferroptosis in HCC cells.

The alleviating effect of ellagic acid on DSS-induced colitis via regulating gut microbiomes and gene expression of colonic epithelial cells.

The anti-inflammatory effect of ellagic acid (EA) and its possible underlying mechanism in dextran sulfate sodium (DSS)-induced mouse chronic colonic inflammation were studied. It was observed that EA administration significantly alleviated the colonic inflammation phenotypes, including decreasing the disease activity index (DAI), enhancing the body weight loss, and improving the shortened length of the colon and pathological damage of colon tissue. Additionally, EA reshaped the constitution of the gut microbiota by elevating the ratio of Bacteroidetes along with Bacteroides and Muribaculaceae, while decreasing the proportion of Firmicutes. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2) revealed that the metabolic function of the gut microbiota was also changed. Furthermore, mouse colon transcriptome analysis showed that the tight junction and peroxisome proliferator-activated receptor (PPAR) signaling pathways were activated and the expressions of related genes were upregulated after EA intervention. These results showed that EA could remodel the gut bacterial composition, change the intestinal epithelial cell gene expressions in mice, and consequently improve the colonic inflammatory symptoms.

Effects of pre-anthesis low-temperature stress on the mineral components in wheat grains.

Introduction: The nutritional value of wheat is important to human health. Despite minerals being essential nutrients for the human body, they are often neglected in consideration of the nutritional quality of cereal grains. Extreme low-temperature events have become more frequent due to the current environmental unpredictability, and it is yet unknown how the mineral components in grains are affected by low temperature. Methods: To provide valuable information for enhancing the nutritional quality of wheat under potential climatic conditions, we treated different cold-sensitive wheat cultivars at four low-temperature levels during the individual and combined stages of jointing and booting in controlled-environment phytotrons. Results and Discussion: In general, the contents of P, K, Ca, and Zn in the cold-sensitive cultivar (Yangmai16) and K in the cold-tolerant cultivar (Xumai30) were enhanced by low temperature. However, the accumulation of minerals in mature grains was reduced under low-temperature treatment, except for P, Ca, and Zn in Yangmai16. In addition, the mineral content and accumulation in Yangmai16 (except for Fe) were more susceptible to low temperature during the combined stages, while the mineral content and accumulation of K, Fe, and Zn in Xumai30 were more susceptible to low temperature during the booting stage. Moreover, Yangmai16 under extremely low temperatures (T3 and T4) during booting and Xumai30 under all low-temperature treatments during the combined stages had lower comprehensive evaluation values. These findings offer a crucial reference for enhancing the nutritional quality of wheat grains under climate change.

Interventions of river network structures on urban aquatic microplastic footprint from a connectivity perspective.

Microplastic footprint in urban river networks can be disturbed by multiple urbanization features, and regional river structures are generally overlooked. In this research, we analyzed the distribution of microplastics and potential impact pattern of river structures on it in a typical urban river network in Nanjing, China. Surface waters of the river network were jointly detected by multiple methods, and the Renkonen similarity index was used to study spatial variabilities of microplastics characteristics. Microplastics were ubiquitous and abundant, showing five (>50 µm) and six (20∼50 µm) hotspots, and heterogeneities in the shape and type of microplastics larger than 100 µm were prominent, presumably influenced by river network scale and connectivity. River structure parameters associated with network connectivity were obtained by combining graph theory and an entropy-based set-pair analysis model. Aiming at the action pathway of river structures, by using correlation and partial least squares regression analysis, we found that river node (confluences and sluices) ratio, river frequency, river network density, and water system circularity were significantly positively correlated with microplastic abundance, and confluences with poor connectivity had a greater indirect intervention intensity on the microplastic distribution. The land use characteristics dominated the fitting of microplastic abundance, which was about 1.2 times better than river structures, and the comprehensive land use intensity and river network connectivity were the critical factors, respectively. Potential ecological risks of microplastics were evaluated, resulting in relatively severe levels. This study proposed targeted measures to control urban microplastic pollution by combining the perspective of river network characteristics. To summarize, our exploration of microplastic footprint based on urban river network structures from the perspective of river network connectivity provides new insights into microplastic management.

PAK5 potentiates slug transactivation of N-cadherin to facilitate metastasis of renal cell carcinoma.

Renal cell carcinoma (RCC) is an aggravating cancer with a poor prognosis and a high rate of metastasis. PAK5, a p21-activated kinases, has shown to be overexpressed in a variety of cancers, including RCC. In previous studies, we discovered that PAK5 regulates cell migration and invasion in RCC cell lines. However, the underlying mechanisms remain obscure. In this study, we consolidated that PAK5 confers a pro-metastatic phenotype RCC cells in vitro and exacerbates metastasis in vivo. High PAK5 expression was associated with an advanced TNM stage and a lower overall survival. Furthermore, PAK5 increases the expression level of N-cadherin. In terms of mechanism, PAK5 bound to Slug and phosphorylated it at serine 87. As a result, phosphorylated Slug transactivated N-cadherin, accelerating the epithelial-mesenchymal transition. Collectively, Slug is a novel PAK5 substrate, and PAK5-mediated phosphorylation of Slug-S87 increases N-cadherin and the pro-metastatic phenotype of RCC, implying that phosphorylated Slug-S87 could be a therapeutic target in progressive RCC.

HPV E7-drived ALKBH5 promotes cervical cancer progression by modulating m6A modification of PAK5.

Human papillomavirus (HPV) infection is a causative agent of cervical cancer (CC). N6-methyladenosine (m6A) modification is implicated in carcinogenesis and tumor progression. However, the involvement of m6A modification in HPV-involved CC remains unclear. Here we showed that HPV E6/7 oncoproteins affected the global m6A modification and E7 specifically promoted the expression of ALKBH5. We found that ALKBH5 was significantly upregulated in CC and might serve as a valuable prognostic marker. Forced expression of ALKBH5 enhanced the malignant phenotypes of CC cells. Mechanistically, we discovered that E7 increased ALKBH5 expression through E2F1-mediated activation of the H3K27Ac and H3K4Me3 histone modifications, as well as post-translational modification mediated by DDX3. ALKBH5-mediated m6A demethylation enhanced the expression of PAK5. The m6A reader YTHDF2 bound to PAK5 mRNA and regulated its stability in an m6A-dependent manner. Moreover, ALKBH5 promoted tumorigenesis and metastasis of CC by regulating PAK5. Overall, our findings herein demonstrate a significant role of ALKBH5 in CC progression in HPV-positive cells. Thus, we propose that ALKBH5 may serve as a prognostic biomarker and therapeutic target for CC patients.

Corrigendum: The amino acids sensing and utilization in response to dietary aromatic amino acid supplementation in LPS-induced inflammation piglet model.

[This corrects the article DOI: 10.3389/fnut.2021.819835.].

Heptamethoxyflavone Alleviates Metabolic Syndrome in High-Fat Diet-Fed Mice by Regulating the Composition, Function, and Metabolism of Gut Microbiota.

3,5,6,7,8,3',4'-Heptamethoxyflavone (HMF) could prevent obesity and hyperlipidemia, but its effects on gut microbiota and fecal metabolites remain unclear. Here, the effect of HMF on metabolic syndrome (MS) was evaluated in high-fat diet (HFD)-fed mice, and its underlying mechanisms were revealed by integrative metagenomic and metabolomic analyses. We demonstrated that HMF could effectively ameliorate HFD-induced MS by alleviating body-weight gain, fat accumulation, hepatic steatosis, and lipid and glucose abnormalities. HMF significantly altered the gut microbiota composition in HFD-fed mice with enrichment of short-chain fatty acid (SCFA)- and bile acid-producing beneficial bacteria and inhibition of harmful bacteria. Also, HMF improved microbial functions by up-regulating bile acid metabolism and down-regulating fatty acid metabolism and inflammatory response-related pathways. Consistent with the gut microbial changes, HMF altered the fecal metabolite profile of HFD-fed mice, mainly characterized by increasing SCFA and several bile acid levels as well as lowering several lysophospholipids and fatty acid levels. Correlation analysis indicated that three key species Faecalibaculum rodentium, Collinsella aerofaciens, and Lactobacillus fermentum and the increase in microbial metabolites, i.e., SCFAs and secondary bile acids, might play a positive role in alleviating MS. Our results suggested that HMF alleviated HFD-induced MS possibly by modulating the composition, function, and metabolism of gut microbiota.

Scalar topological photonic nested meta-crystals and skyrmion surface states in the light cone continuum.

Topological photonics is rapidly expanding. However, discovering three-dimensional topological electromagnetic systems can be more challenging than electronic systems for two reasons. First, the vectorial nature of electromagnetic waves results in complicated band dispersions, and simple tight-binding-type predictions usually fail. Second, topological electromagnetic surface modes inside the light cone have very low quality factors (Q factors). Here, we propose the concept of scalar topological photonics to address these challenges. Our approach is experimentally validated by employing a nested meta-crystal configuration using connected coaxial waveguides. They exhibit scalar-wave-like band dispersions, making the search for photonic topological phases an easier task. Their surface states have skyrmion-like electric field distributions, resulting in a whole, bright surface state band inside the light cone continuum. As such, the topological surface states in our three-dimensional nested crystals can be exposed to air, making such systems well-suited for practical applications.

The nutritional and functional properties of 1-oleoyl-2-palmitoyl-3-linoleoylglycerol-rich oil: promoting early-life growth and intestinal health with alterations in the intestinal microbiota of Micropterus salmoides.

1-Oleoyl-2-palmitoyl-3-linoleoylglycerol (OPL), a key structural lipid in the breast milk fat, plays a critical role in providing nutrients and energy for infants. OPL is more abundant in Chinese breast milk fat and might be better for Chinese infants' growth. However, few studies have investigated the effect of OPL on the growth and intestinal health of the organism in early life. OPL-rich oil with 45.77% OPL was prepared by immobilized lipase-catalyzed synthesis and purification. The effects of OPL on the nutritional properties and the regulation of intestinal microbiota in early life were further investigated in vivo (Micropterus salmoides). Dietary OPL-rich oil significantly increased the juvenile fish weight gain rate, protein content, and muscular polyunsaturated fatty acids, which in turn markedly altered the muscle texture in springiness and cohesiveness. Dietary OPL-rich oil could also protect intestinal tissues by significantly increasing fish intestinal fold height, mucosal thickness, and intestinal wall thickness. Furthermore, dietary OPL-rich oil regulated intestinal microbiota. Particularly, OPL significantly increased the probiotics (Cetobacterium_sp014250685, Streptomyces_mutabilis, Saccharopolyspora_spinosa, and Nocardiopsis_kunsanensis) and reduced the potential pathogens (Staphylococcus_nepalensis, Salmonella_enterica, the Candidatus_berkiella). The structured OPL significantly promoted fish growth and improved nutritional composition due to its higher bioavailability relative to tripalmitate (PPP). Moreover, OPL significantly improved the growth, cholesterol metabolism, and intestinal health than the mixed oil (MO), which was attributed to the higher palmitic acid content in the sn-2 position. Overall, the structure of triacylglycerols and its distribution of fatty acids affected early growth and intestinal health, and OPL was more effective in the improvement of juvenile growth and intestinal health.

COPS6 promotes tumor progression and reduces CD8+ T cell infiltration by repressing IL-6 production to facilitate tumor immune evasion in breast cancer.

Due to poor T cell infiltration, tumors evade immune surveillance. Increased CD8+ T cell infiltration in breast cancer suggests a satisfactory response to immunotherapy. COPS6 has been identified as an oncogene, but its role in regulating antitumor immune responses has not been defined. In this study, we investigated the impact of COPS6 on tumor immune evasion in vivo. Tumor transplantation models were established in C57BL/6 J mice and BALB/c nude mice. Flow cytometry was conducted to identify the role of COPS6 on tumor-infiltrating CD8+ T cells. By analyzing the TCGA and GTEx cohort, we found that COPS6 expression was significantly up-regulated in a variety of cancers. In human osteosarcoma cell line U2OS and non-small cell lung cancer cell line H1299, we showed that p53 negatively regulated COPS6 promoter activity. In human breast cancer MCF-7 cells, COPS6 overexpression stimulated p-AKT expression as well as the proliferation and malignant transformation of tumor cells, whereas knockdown of COPS6 caused opposite effects. Knockdown of COPS6 also significantly suppressed the growth of mouse mammary cancer EMT6 xenografts in BALB/c nude mice. Bioinformatics analysis suggested that COPS6 was a mediator of IL-6 production in the tumor microenvironment and a negative regulator of CD8+ T cell tumor infiltration in breast cancer. In C57BL6 mice bearing EMT6 xenografts, COPS6 knockdown in the EMT6 cells increased the number of tumor-infiltrating CD8+ T cells, while knockdown of IL-6 in COPS6KD EMT6 cells diminished tumor infiltrating CD8+ T cells. We conclude that COPS6 promotes breast cancer progression by reducing CD8+ T cell infiltration and function via the regulation of IL-6 secretion. This study clarifies the role of p53/COPS6/IL-6/CD8+ tumor infiltrating lymphocytes signaling in breast cancer progression and immune evasion, opening a new path for development of COPS6-targeting therapies to enhance tumor immunogenicity and treat immunologically "cold" breast cancer.

Optimization of HS-SPME-GC-MS for the Determination of Volatile Flavor Compounds in Ningxiang Pork.

This study attempts to explore the suitable conditions for the detection of volatile flavor compounds (VFCs) in Ningxiang pork by headspace solid-phase microextraction and gas chromatography-mass spectrometry (HS-SPME-GC-MS). Ningxiang pigs were harvested from a slaughterhouse and a longissimus dorsi sample was collected from each animal. The VFCs of Ningxiang pork can be strongly impacted by the detection conditions (columns, weight of meat samples, heat treatment time, equilibrium conditions, and extraction conditions) that need to be optimized. Our results also provided the optimal test conditions: weighing 5 g of meat samples, grinding for 30 s in a homogenizer, heat treatment at 100 °C for 30 min, equilibration at 70 °C for 30 min, and extraction at 100 °C for 50 min. Furthermore, the feasibility and representativeness of the test method were confirmed based on principal component analysis and a comparison of the three pork VFCs. These findings offer researchers a unified and efficient pretreatment strategy to research pork VFCs.

Identification and functional analysis of three novel osteogenic peptides isolated from tilapia scale collagen hydrolysate.

On the basis of our previous study that 133 peptides were identified from the tilapia scale peptide-calcium chelate, the potential osteogenic peptide monomers through the calcium-binding properties of peptides and molecular docking were screened, and the osteogenic activity and active mechanism of the peptides were further researched in this study. Three highly osteogenic peptides GPAGPHGPVG (844.4191 Da), APDPFRMY (995.4534 Da), and TPERYY (827.3813 Da) were screened. Molecular docking showed that the three osteogenic peptides had the same interaction sites in the epidermal growth factor receptor (EGFR), namely ARG 285, GLN 8, GLY 317, THR 406, and HIS 409. Compared to the blank control group, within 50 µg/mL of GPAGPHGPVG, APDPFRMY, and TPERYY increased the proliferation of MC3T3-E1 cells by changing the cell proportion in the S and G2/M phases, and the alkaline phosphatase (ALP) activity of MC3T3-E1 cells treated with 50 µg/mL of the three active peptides increased by 25%, 37%, and 56%, respectively. The three active peptides at 10 µg/mL concentration significantly promoted the mineralization of osteoblasts, and the mineralized calcium nodules increased by 166%, 161%, and 111%, respectively. TPERYY significantly increased the expression of osteogenic genes (osteocalcin (OCN), type I collagen (Col I α) and transcription factor (OSX)). Moreover, TPERYY significantly increased the mRNA and protein expression of ß-catenin to 1.39 and 2.6 times of the blank control group, respectively, while decreased the mRNA and protein expression of glycogen synthesis kinase (GSK3ß) to 1.6 and 2.3 times of the blank control group, respectively. This study provides a theoretical basis for using GPAGPHGPVG, APDPFRMY, and TPERYY peptides as functional foods to prevent osteoporosis.

UPLC-QTOF/MS Metabolomics and Biochemical Assays Reveal Changes in Hepatic Nutrition and Energy Metabolism during Sexual Maturation in Female Rainbow Trout (Oncorhynchus mykiss).

Mobilization and repartition of nutrients and energy are prerequisites for the normal sexual maturity of broodstock. However, there are few studies on the mechanisms of hepatic nutrients and energy metabolism during sexual maturation in female rainbow trout (Oncorhynchus mykiss). This study investigated hepatic metabolite changes and explored the potential nutritional regulation mechanism between mature and immature female rainbow trout by combining UPLC-QTOF/MS metabolomics and biochemical assays. It was observed that hepatic biochemical assays differed considerably between the two groups, such as glucose, triglycerides, hexokinase, lipase, and aspartate aminotransferase. Liver metabolomics showed that various differential metabolites involved in amino acid and lipid metabolism markedly increased, suggesting the enhancement of lipid metabolism and amino acid anabolism in the liver provides the necessary material basis for ovarian development. Meanwhile, glycogen catabolism and glycolysis hold the key to maintaining organismal energy homeostasis with normal sexual maturation of female rainbow trout. Overall, the results from this study suggested that the liver undergoes drastic reprogramming of the metabolic profile in response to mobilization and repartition of nutrients and energy during the sexual maturation of female rainbow trout. This study further deepened the understanding of the reproductive biology of rainbow trout, and provided the theoretical basis and practical ramifications for nutritional requirements of breeding high-quality broodstock in the artificial propagation of rainbow trout.

The Immediate Effect of Backward Walking on External Knee Adduction Moment in Healthy Individuals.

Backward walking (BW) has been recommended as a rehabilitation intervention to prevent, manage, or improve diseases. However, previous studies showed that BW significantly increased the first vertical ground reaction force (GRF) during gait, which might lead to higher loading at the knee. Published reports have not examined the effects of BW on medial compartment knee loading. The objective of this study was to investigate the effects of BW on external knee adduction moment (EKAM). Twenty-seven healthy adults participated in the present study. A sixteen-camera three-dimensional VICON gait analysis system, with two force platforms, was used to collect the EKAM, KAAI, and other biomechanical data during BW and forward walking (FW). The first (P < 0.001) and second (P < 0.001) EKAM peaks and KAAI (P=0.02) were significantly decreased during BW when compared with FW. The BW significantly decreased the lever arm length at the first EKAM peak (P=0.02) when compared with FW. In conclusion, BW was found to be a useful strategy for reducing the medial compartment knee loading even though the first peak ground reaction force was significantly increased.

Alternative splicing of HSPA12A pre-RNA by SRSF11 contributes to metastasis potential of colorectal cancer.

BACKGROUND: Dysregulation of alternative splicing (AS) induced by serine/arginine-rich proteins has recently been linked to cancer metastasis. Nonetheless, as a member of the serine/arginine-rich protein family, the involvement of SRSF11 in colorectal cancer (CRC) is unknown. METHODS: The TCGA dataset and clinical samples were used to assess SRSF11 expression levels in CRC. For SRSF11, functional experiments were conducted both in vitro and in vivo. RNA-seq technology was used to analyze and screen SRSF11-triggered AS events, which were then confirmed by in vivo UV crosslinking and immunoprecipitation (CLIP) and mini-gene reporter assays. Jalview software was used to determine the preferential binding motif with relation to exon skipping (ES) events. Furthermore, coimmunoprecipitation (Co-IP) and Phospho-tag SDS-PAGE experiments were used to investigate PAK5-mediated phosphorylation regulation on SRSF11, and in vitro kinase experiments validated the interaction. RESULTS: In CRC, SRSF11 was discovered to be overexpressed and associated with a poor prognosis. And SRSF11 played a pro-metastatic role in vitro and in vivo. By screening SRSF11-regulated AS events, we identified the binding motif of SRSF11-triggered splicing-switching of HSPA12A AS, which specifically regulated HSPA12A AS by directly binding to a motif in exon 2. Mechanistically, the HSPA12A transcript with exon 2 retention increased N-cadherin expression by promoting RNA stability. Furthermore, the oncogenic kinase PAK5 phosphorylated SRSF11 at serine 287, protecting it from ubiquitination degradation. CONCLUSIONS: SRSF11 exerts pro-metastatic effects in CRC by inhibiting the AS of HSPA12A pre-RNA. Our findings point to SRSF11-regulated HSPA12A splicing as a novel relationship between SRSF11-regulated splicing and CRC metastasis and suggest a PAK5/SRSF11/HSPA12A axis as a potential therapeutic target and prognostic biomarker in CRC.

Ocular Perfusion Pressure in 7- and 12-Year-Old Chinese Children: The Anyang Childhood Eye Study.

Purpose: The purpose of this study was to report the distribution of mean ocular perfusion pressure (MOPP) and its associated factors in Chinese children. Methods: We enrolled 3048 grade 1 students and 2258 grade 7 students of the Anyang Childhood Eye Study in central China. Systolic and diastolic blood pressure (SBP and DBP) were recorded with a digital automatic sphygmomanometer. Intraocular pressure (IOP) was assessed by a non-contact tonometer. MOPP was calculated as 2/3 × (DBP + 1/3[SBP - DBP]) - IOP. Risk factors for myopia were obtained through a questionnaire survey. Results: The MOPP was 33.83 ± 6.37 mm Hg (mean ± SD) in grade 1, which was lower than 36.99 ± 6.80 mm Hg in grade 7 (P < 0.001). Compared with myopic eyes, non-myopic eyes had higher MOPP in grade 7 (37.72 ± 6.72 mm Hg versus 36.58 ± 6.57 mm Hg, P < 0.001) and in grade 1 (33.88 ± 6.29 mm Hg versus 33.12 ± 7.03 mm Hg, P = 0.12). Multivariable analysis showed that higher MOPP was associated with less myopia (P < 0.001), higher body mass index (BMI; P < 0.001), thinner central corneal thickness (P < 0.001), less time on near work (P < 0.001), and more time on sleeping (P = 0.04). Conclusions: MOPP was higher in children of older age, with higher BMI, less time on near work, and more time on sleeping, and was higher in eyes with less myopia. Translational Relevance: We found that MOPP might be an indicator for the detection of myopia development.