DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells.

Epithelial barrier dysfunction and crypt destruction are hallmarks of inflammatory bowel disease (IBD). Intestinal stem cells (ISCs) residing in the crypts play a crucial role in the continuous self-renewal and rapid recovery of intestinal epithelial cells (IECs). However, how ISCs are dysregulated in IBD remains poorly understood. Here, we observe reduced DHX9 protein levels in IBD patients, and mice with conditional DHX9 depletion in the intestinal epithelium (Dhx9ΔIEC) exhibit an increased susceptibility to experimental colitis. Notably, Dhx9ΔIEC mice display a significant reduction in the numbers of ISCs and Paneth cells. Further investigation using ISC-specific or Paneth cell-specific Dhx9-deficient mice demonstrates the involvement of ISC-expressed DHX9 in maintaining epithelial homeostasis. Mechanistically, DHX9 deficiency leads to abnormal R-loop accumulation, resulting in genomic instability and the cGAS-STING-mediated inflammatory response, which together impair ISC function and contribute to the pathogenesis of IBD. Collectively, our findings highlight R-loop-mediated genomic instability in ISCs as a risk factor in IBD.

Clinical significance of small extracellular vesicles in cholangiocarcinoma.

Cholangiocarcinoma is an aggressive and heterogeneous malignancy originating from the bile duct epithelium. It is associated with poor prognosis and high mortality. The global incidence of cholangiocarcinoma is rising, and there is an urgent need for effective early diagnosis and treatment strategies to reduce the burden of this devastating tumor. Small extracellular vesicles, including exosomes and microparticles, are nanoscale vesicles formed by membranes that are released both normally and pathologically from cells, mediating the intercellular transfer of substances and information. Recent studies have demonstrated the involvement of small extracellular vesicles in numerous biological processes, as well as the proliferation, invasion, and metastasis of tumor cells. The present review summarizes the tumorigenic roles of small extracellular vesicles in the cholangiocarcinoma microenvironment. Owing to their unique composition, accessibility, and stability in biological fluids, small extracellular vesicles have emerged as ideal biomarkers for use in liquid biopsies for diagnosing and outcome prediction of cholangiocarcinoma. Specific tissue tropism, theoretical biocompatibility, low clearance, and strong biological barrier penetration of small extracellular vesicles make them suitable drug carriers for cancer therapy. Furthermore, the potential value of small extracellular vesicle-based therapies for cholangiocarcinoma is also reviewed.

Role of lens in early refractive development: evidence from a large cohort of Chinese children.

AIMS: To document longitudinal changes in spherical equivalent refraction (SER) and related biometric factors during early refractive development. METHODS: This was a prospective cohort study of Chinese children, starting in 2018 with annual follow-ups. At each visit, children received cycloplegic autorefraction and ocular biometry measurements. Lens power (LP) was calculated using Bennett's formula. Children were divided into eight groups based on baseline age: the 3-year-old (n=426, 49.77% girls), 4-year-old (n=834, 47.36% girls), 6-year-old (n=292, 46.58% girls), 7-year-old (n=964, 43.46% girls), 9-year-old (n=981, 46.18% girls), 10-year-old (n=1181, 46.32% girls), 12-year-old (n=504, 49.01%) and 13-year-old (n=644, 42.70%) age groups. RESULTS: This study included right-eye data from 5826 children. The 3-year-old and 4-year-old age groups demonstrated an inflection point in longitudinal SER changes at a mild hyperopic baseline SER (+1 to +2 D), with children with more myopic SER showing hyperopic refractive shifts while those with more hyperopic SER showing myopic shifts. The hyperopic shift in SER was mainly attributed to rapid LP loss and was rarely seen in the older age groups. Axial elongation accelerated in the premyopia stage, accompanied by a partially counter-balancing acceleration of LP loss. For children aged 3-7 years, those with annual SER changes <0.25 D were all mildly hyperopic at baseline (mean: 1.23 D, 95% CI 1.20 to 1.27 D). CONCLUSION: Our findings suggest that during early refractive development, refractions cluster around or above +1.00 D. There is a pushback process in which increases in the rate of LP occur in parallel with increases in axial elongation.

Simulation and On-Site Detection of the Failure Characteristics of Overlying Strata under the Mining Disturbance of Coal Seams with Thin Bedrock and Thick Alluvium.

When mining deep coal seams with thin bedrock and thick alluvium, the collapse and fracture of thin bedrock layers may cause geological disasters, such as water inrush and sand inrush of the mining face. Comprehensively obtaining the response data of coal mining and reasonably analyzing the failure characteristics of overlying strata are helpful in guiding safe production. In this study, the caving zone heights of overlying strata are obtained by field detection during layered mining. Then, the caving zone heights during the once-full-height mining are evaluated by theoretical analysis. Further, the force and failure characteristics of coal-rock structures under different mining conditions are compared by the simulation detection and analysis. Finally, the results of on-site observation, theoretical analysis, and simulation detection are compared and discussed, and an optimized mining technology is proposed to ensure safe mining. The research shows the caving zone heights of on-site and simulation detections are, respectively, 14.65 m and 13.5 m during bottom-layer mining, which is larger than the caving zone heights of the top-layer coal mining. During once-full-height mining, the maximum caving zone height of simulation detection is 21 m, which is in between two standard results. For the mechanical responses of an aquiclude clay layer under thick loose alluvium, the maximum disturbance displacement of clay aquiclude is 5.8 m during layered mining, which is slightly larger than the disturbance displacement of once full-height mining; however, the maximum stress of the clay layer is 25 MPa during once-full-height mining, which is larger than the maximum stress of clay layer during layered mining. For the clay aquiclude failure, the clay layer during layered mining is in the deflection deformation area, and there is no obvious fracture structure to inrush the water and sand of thick loose alluvium; however, the clay layer during once-full-height mining is prone to produce obvious fracture structure. Therefore, the layered mining technology can effectively reduce and prevent the water/sand inrush disaster of mining working face.

Association between body stature with ocular biometrics and refraction among Chinese preschoolers.

PURPOSE: To evaluate the association of body stature with ocular biometrics and refraction in preschool children. METHODS: A cross-sectional, school-based study was conducted in Shenzhen, China. Preschool children aged 3 to 6 from 10 randomly-selected kindergartens were recruited. Ocular biometric parameters, including axial length (AL), anterior chamber depth (ACD), vitreous chamber depth (VCD), corneal radius curvature (CR), axial length to corneal radius ratio (AL-to-CR ratio) and lens thickness (LT) were measured using non-contact partial-coherence laser interferometry. Cycloplegic refractions were obtained by a desktop autorefractor. Body height and weight were measured using standard procedures. The association between body stature and ocular biometrics were analyzed with univariable and multivariable regression model. RESULTS: A total of 373 preschoolers were included. AL, ACD, VCD, CR, and AL-to-CR ratio, were positively associated with height and weight (p < 0.05), whereas LT was negatively associated with height and weight (p < 0.01). No association was observed between stature and central cornea thickness and refraction. After adjusted for age and gender in a multivariable regression model, AL had positive associations with height (p < 0.01) and weight (p < 0.01). However, refraction had no significant association with stature parameters. CONCLUSION: Taller and heavier preschoolers had eyes with longer AL, deeper vitreous chamber, and flatter cornea. The significant associations between body stature and ocular biometric parameters reveal the driving influence of body development on the growth of eyeballs in preschoolers.

TBC1D5 reverses the capability of HIF-2α in tumor progression and lipid metabolism in clear cell renal cell carcinoma by regulating the autophagy.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is known for abnormal lipid metabolism and widespread activation of HIF-2α. Recently, the importance of autophagy in ccRCC has been focused, and it has potential connections with HIF-2α and lipid metabolism. However, the specific regulatory mechanism between HIF-2α, autophagy, and lipid metabolism in ccRCC is still unclear. METHODS: In this study, Bioinformatics Analysis and Sequencing of the whole transcriptome were used to screen our target. The expression of TBC1D5 in renal clear cell carcinoma was confirmed by database analysis, immunohistochemistry, PCR and Western blot. The effects of TBC1D5 on tumor cell growth, migration, invasion and lipid metabolism were examined by CCK8, Transwell and oil red staining, and the mechanism of TBC1D5 on autophagy was investigated by Western blot, fluorescence microscopy and electron microscopy. Chloroquine and rapamycin were used to verified the key role of autophagy in effects of TBC1D5 on tumor cell. The regulatory mechanism of TBC1D5 in renal clear cell carcinoma (RCC) was investigated by shhif-2α, shTBC1D5, mimic, inhibitor, ChIP and Luciferase experiments. The animal model of ccRCC was used to evaluate the biological function of TBC1D5 in vivo. RESULTS: In this study, TBC1D5 was found to be an important bridge between autophagy and HIF-2α. Specifically, TBC1D5 is significantly underexpressed in ccRCC, serving as a tumor suppressor which inhibits tumor progression and lipid accumulation, and is negatively regulated by HIF-2α. Further research has found that TBC1D5 regulates the autophagy pathway to reverse the biological function of HIF-2α in ccRCC. Mechanism studies have shown that HIF-2α regulates TBC1D5 through hsa-miR-7-5p in ccRCC, thereby affecting tumor progression and lipid metabolism through autophagy. CONCLUSIONS: Our research reveals a completely new pathway, HIF-2α/hsa-miR-7-5p/TBC1D5 pathway affects ccRCC progression and lipid metabolism by regulating autophagy.

Using choroidal thickness to detect myopic macular degeneration.

AIM: To explore the usage of choroidal thickness measured by swept-source optical coherence tomography (SS-OCT) to detect myopic macular degeneration (MMD) in high myopic participants. METHODS: Participants with bilateral high myopia (≤-6 diopters) were recruited from a subset of the Guangzhou Zhongshan Ophthalmic Center-Brien Holden Vision Institute High Myopia Cohort Study. SS-OCT was performed to determine the choroidal thickness, and myopic maculopathy was graded by the International Meta-Analysis for Pathologic Myopia (META-PM) Classification. Presence of MMD was defined as META-PM category 2 or above. RESULTS: A total of 568 right eyes were included for analysis. Eyes with MMD (n=106, 18.7%) were found to have older age, longer axial lengths (AL), higher myopic spherical equivalents (SE), and reduced choroidal thickness in each Early Treatment Diabetic Retinopathy Study (ETDRS) grid sector (P<0.001). The area under the receiver operating characteristic (ROC) curves (AUC) for subfoveal choroidal thickness (0.907) was greater than that of the model, including age, AL, and SE at 0.6249, 0.8208, and 0.8205, respectively. The choroidal thickness of the inner and outer nasal sectors was the most accurate indicator of MMD (AUC of 0.928 and 0.923, respectively). An outer nasal sector choroidal thickness of less than 74 µm demonstrated the highest odds of predicting MMD (OR=33.8). CONCLUSION: Choroidal thickness detects the presence of MMD with high agreement, particularly of the inner and outer nasal sectors of the posterior pole, which appears to be a biometric parameter more precise than age, AL, or SE.

A mouse model to distinguish NLRP6-mediated inflammasome-dependent and -independent functions.

The NOD-like receptor (NLR) family pyrin domain containing 6 (NLRP6) serves as a sensor for microbial dsRNA or lipoteichoic acid (LTA) in intestinal epithelial cells (IECs), and initiating multiple pathways including inflammasome pathway and type I interferon (IFN) pathway, or regulating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. NLRP6 can exert its function in both inflammasome-dependent and inflammasome-independent manners. However, there is no tool to distinguish the contribution of individual NLRP6-mediated pathway to the physiology and pathology in vivo. Here, we validated that Arg39 and Trp50 residues in the pyrin domain (PYD) of murine NLRP6 are required for ASC recruitment and inflammasome activation, but are not important for the RNA binding and PYD-independent NLRP6 oligomerization. We further generated the Nlrp6R39E&W50E mutant mice, which showed reduced inflammasome activation in either steady state intestine or during viral infection. However, the type I IFN production in cells or intestine tissue from Nlrp6R39E&W50E mutant mice remain normal. Interestingly, NLRP6-mediated inflammasome activation or the IFN-I production seems to play distinct roles in the defense responses against different types of RNA viruses. Our work generated a useful tool to study the inflammasome-dependent role of NLRP6 in vivo, which might help to understand the complexity of multiple pathways mediated by NLRP6 in response to the complicated and dynamic environmental cues in the intestine.

Four-Year Progression of Myopic Maculopathy in Children and Adolescents With High Myopia.

Importance: Individuals with high myopia younger than 18 years are at relatively high risk of progressively worsening myopic maculopathy. Additional studies are needed to investigate the progression of myopic maculopathy in this age group, as well as the risk factors associated with progression. Objective: To investigate the 4-year progression of myopic maculopathy in children and adolescents with high myopia, and to explore potential risk factors. Design, Setting, and Participants: This hospital-based observational study with 4-year follow-up included a total of 548 high myopic eyes (spherical power -6.00 or less diopters) of 274 participants aged 7 to 17 years. Participants underwent comprehensive ophthalmic examination at baseline and 4-year follow-up. Myopic maculopathy was accessed by the International Photographic Classification and Grading System. The data analysis was performed from August 1 to 15, 2023. Main Outcomes and Measures: The progression of myopic maculopathy progression over 4 years and associated risk factors. Results: The 4-year progression of myopic maculopathy was found in 67 of 548 eyes (12.2%) of 274 participants (138 girls [50.4%] at baseline and 4-year follow-up) with 88 lesion changes, including new signs of the tessellated fundus in 16 eyes (18.2%), diffuse atrophy in 12 eyes (13.6%), patchy atrophy in 2 eyes (2.3%), lacquer cracks in 9 eyes (10.2%), and enlargement of diffuse atrophy in 49 eyes (55.7%). By multivariable analysis, worse best-corrected visual acuity (odds ratio [OR], 6.68; 95% CI, 1.15-38.99; P = .04), longer axial length (AL) (OR, 1.73; 95% CI, 1.34-2.24; P < .001), faster AL elongation (OR, 302.83; 95% CI, 28.61-3205.64; P < .001), and more severe myopic maculopathy (diffuse atrophy; OR, 4.52; 95% CI, 1.98-10.30; P < .001 and patchy atrophy; OR, 3.82; 95% CI, 1.66-8.80; P = .002) were associated with myopic maculopathy progression. Conclusions and Relevance: In this observational study, the progression of myopic maculopathy was observed in approximately 12% of pediatric high myopes for 4 years. The major type of progression was the enlargement of diffuse atrophy. Risk factors for myopic maculopathy progression were worse best-corrected visual acuity, longer AL, faster AL elongation, and more severe myopic maculopathy. These findings support consideration of follow-up in these individuals and trying to identify those at higher risk for progression.

Photocatalytic selective synthesis of (E)-ß-aminovinyl sulfones and (E)-ß-amidovinyl sulfones using Ru(bpy)3Cl2 as the catalyst.

Selectively producing a variety of valuable compounds using controlled chemical reactions starting from a common material is an appealing yet complex concept. Herein, a photocatalytic approach for the selective synthesis of (E)-ß-aminovinyl sulfones and (E)-ß-amidovinyl sulfones from allenamides and sodium sulfinates was established. This reaction exhibits the traits of an eco-friendly solvent and adjustable amide cleavage, and can accommodate a diverse range of substrates with exceptional functional group tolerance. Based on control experiments and deuterium labeling experiments, a plausible radical reaction pathway is proposed.

Evaluating the efficacy and timing of blood purification modalities in early-stage hyperlipidemic acute pancreatitis treatment.

Hypertriglyceridemia-induced acute pancreatitis (HTG-AP) is characterized by a violent cytokine storm-driven inflammation and is associated with a predisposition to severe disease. The treatment strategy for HTG-AP consists mainly of conventional symptomatic and lipid-lowering treatments. For early-stage HTG-AP, blood purification (BP) can rapidly and effectively reduce serum triglyceride and inflammatory cytokine levels, block the development of systemic inflammatory response syndrome, and improve patient outcomes. Currently, the primary modalities for BP in patients with HTG-AP include plasma exchange, hemoperfusion, and hemofiltration. When using BP to treat patients with HTG-AP, a comprehensive analysis incorporating the elevated lipid levels and severity of the patient's condition contributes to the selection of different treatment modes. Moreover, the timing of the treatment is also imperative. Early intervention is associated with a better prognosis for patients with HTG-AP requiring lipid-lowering treatment.

Photocatalytic Radical Cascade Dehalogenation/Carbo-cyclization/Sulfonylation Leading to Indole- and Benzofuran-Based Benzylic Sulfones.

This study presents a convenient approach to the synthesis of indole- and benzofuran-based benzylic sulfones using unactivated alkynes containing aryl iodides and sodium sulfinates under visible light irradiation. The procedure involves a sequential series of dehalogenation, carbo-cyclization, and radical sulfonylation. Plausible insights into the reaction mechanism are derived from control experiments, leading to the proposal of a radical cascade reaction pathway.

LncRNA FTO-IT1 promotes glycolysis and progression of hepatocellular carcinoma through modulating FTO-mediated N6-methyladenosine modification on GLUT1 and PKM2.

BACKGROUND: Long non-coding RNAs (LncRNAs) have been extensively studied to play essential roles in tumor progression. However, more in-depth studies are waiting to be solved on how lncRNAs regulate the progression of hepatocellular carcinoma (HCC). METHODS: Different expression levels of lncRNAs in HCC cells were compared by analysis of Gene Expression Omnibus and The Cancer Genome Atlas databases. The effects of lncRNA FTO Intronic Transcript 1 (FTO-IT1) on HCC cells were assessed by gain- and loss-of-function experiments. Colony formation assay, Edu assay, glucose uptake and lactic acid production assay were performed to evaluate the regulation of proliferation and glycolysis of HCC cells by FTO-IT1. The binding between protein interleukin enhancer binding factor 2/3 (ILF2/ILF3) and FTO-IT1 was determined by RNA pull-down, mass spectroscopy and RNA immunoprecipitation experiments. RNA stability assay, quantitative reverse transcription PCR and Western blot were employed to determine the regulatory mechanisms of FTO-IT1 on fat mass and obesity-associated (FTO). Methylated RNA immunoprecipitation assay was used to assessed the regulation of key enzymes of glycolysis by FTO. The role of FTO-IT1/FTO in vivo was confirmed via xenograft tumor model. RESULTS: LncRNA FTO-IT1, an intronic region transcript of FTO gene, was highly expressed in HCC and associated with poor prognosis of patients with HCC. FTO-IT1 was related to proliferation and glycolysis of HCC cells, and contributed to the malignant progression of HCC by promoting glycolysis. Mechanistically, FTO-IT1 induced stabilization of FTO mRNA by recruiting ILF2/ILF3 protein complex to 3'UTR of FTO mRNA. As a demethylase for N6-methyladenosine (m6A), FTO decreased m6A modification on mRNAs of glycolysis associated genes including GLUT1, PKM2, and c-Myc which alleviated the YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-mediated mRNA degradation. Therefore, the upregulated expression of FTO-IT1 leaded to overexpression of GLUT1, PKM2, and c-Myc by which enhanced glycolysis of HCC. Meanwhile, it was found that c-Myc transcriptional regulated expression of FTO-IT1 by binding to its promoter area under hypo-glucose condition, forming a reciprocal loop between c-Myc and FTO-IT1. CONCLUSIONS: This study identified an important role of the FTO-IT1/FTO axis mediated m6A modification of glycolytic genes contributed to glycolysis and tumorigenesis of HCC, and FTO-IT1 might be served as a new therapeutic target for HCC.

Preparation of basic magnesium carbonate nanosheets modified pumice and its adsorption of heavy metals.

Heavy metal pollution in wastewater poses a grave danger to the environment and the human body. Pumice is a mineral with abundant reserves and low prices, and its prospect of heavy metal adsorbent is very broad. In this work, we modified pumice with basic magnesium carbonate nanosheets by a convenient hydrothermal synthesis. The adsorption capacity of heavy metals is greatly improved. The effects of different pH and adsorption dosages are investigated. All the optimum pH values for Cu2+, Pb2+, and Cd2+ are 5. The adsorption of three kinds of ions conforms to the quasi-second-order adsorption kinetics model. The theoretical adsorption capacities of Cu2+, Pb2+, and Cd2+, which are calculated by the Langmuir model, are 235.29 mg/L, 595.24 mg/L, and 370.34 mg/L, respectively. The adsorption of Cu2+ and Cd2+ fit the Langmuir model better. The Freundlich model is fitted well with the adsorption of Pb2+. In the experiment simulating real wastewater, the adsorption capacity of heavy metals is not affected. It also shows good reusability in three regeneration cycles. And Mg5(CO3)4(OH)2·4H2O@pumice adsorption column showed the good removal efficiency of three heavy metals at different concentrations and different spatial velocities in the column experiment. Thus, it is believed that the Mg5(CO3)4(OH)2·4H2O@pumice is a promising adsorbent for the efficient removal of heavy metals.

Longitudinal Changes in Axial Length and Spherical Equivalent in Children and Adolescents With High Myopia.

Purpose: To investigate longitudinal changes in axial length (AL) and spherical equivalent (SE) in children and adolescents with high myopia and to explore associated risk factors. Methods: This was a longitudinal, observational cohort study of highly myopic participants (aged 7-17 years) to evaluate the mean rates of change in AL and SE. Mixed effects regression models were used to explore the risk factors. Results: The sample consisted of 293 participants (mean age at the baseline, 13.63 ± 2.66 years; mean AL, 27.03 ± 1.30 mm diopters; mean SE, -8.99 ± 2.30 diopters) who were followed for 7.09 ± 1.64 years. Pathological myopia (PM) was present in 11.95% of the participants at the baseline. Over the follow-up period, the mean AL and SE progression rates were 0.13 mm/y (95% CI, 0.12-0.14) and -0.36 diopters/y (95% CI, -0.39 to -0.34). The multivariate analysis showed that the AL elongation and myopic SE progression decreased significantly after age 11 (ß = -0.080, P < 0.001; ß = 0.146, P < 0.001), increased with a greater baseline SE (ß = -0.006, P = 0.014; ß = 0.017, P = 0.005), and accelerated in children and adolescents who had PM at the baseline (ß = 0.043, P = 0.011; ß = -0.097, P = 0.025). Conclusions: A significant association was found between acceleration of AL elongation and myopic SE progression among the children and adolescents with age, especially those younger than 11 years, and the presence of PM.

Effect of Extracurricular After-School Physical Activities on Academic Performance of Schoolchildren: A Cluster Randomized Clinical Trial.

Importance: The beneficial effects of increasing outdoor physical activity time on children's myopia onset and physical well-being are widely acknowledged. However, in countries with competitive educational systems, such as China, parents and school administrators may be relatively reluctant to increase the extracurricular physical activity time for children due to concerns that this action will compromise children's academic performance. Objective: To investigate whether additional extracurricular physical activity time after school compromises the academic performance of schoolchildren. Design, Setting, and Participants: This cluster randomized clinical trial was conducted from October 2020 to June 2021 in Yudu, Jiangxi, China. Eligible children in grades 3 and 4 from 24 elementary schools were randomized to the intervention or control group. Primary analysis was conducted in the full sample using the intention-to-treat principle. Interventions: The intervention group received 2 hours of after-school physical activity time outdoors on school days. The control group was free to arrange their after-school activity. Main Outcomes and Measures: The primary outcome was the between-group mean difference in mathematics test scores at the end of 1 academic year, with a noninferiority margin of -3.3 points. Standardized mathematics tests, physical fitness assessments (in reference to the 2018 National Physical Fitness Survey Monitoring Programme in China), and cycloplegic autorefraction were performed at baseline and the end of 1 academic year. Myopia was defined as a cycloplegic spherical equivalent refraction of -0.5 diopters or less in either eye. Results: A total of 2032 children (mean [SD] age, 9.22 [0.62] years; 1040 girls [51.2%]) from 24 schools were randomized to the intervention group (12 schools; 1012 children) or control group (12 schools; 1020 children). The mean (SD) mathematics score at the end of 1 academic year was 78.01 (17.56) points in the intervention group and 77.70 (17.29) points in the control group. The adjusted between-group mean difference was 0.65 points (95% CI, -2.85 to 4.15). The adjusted between-group mean difference in physical fitness score was 4.95 points (95% CI, 3.56-6.34; P < .001) and -1.90% (95% CI, -18.72% to 14.91%; P > .99) in myopia incidence. Conclusions and Relevance: Results of this trial indicate that, compared with the control practice of free play after school, adding 2 hours of extracurricular physical activity outdoors after school was noninferior in academic performance and had superior efficacy in improving physical fitness. Trial Registration: ClinicalTrials.gov Identifier: NCT04587765.

Pancreatic Acinar Cells-Derived Sphingosine-1-Phosphate Contributes to Fibrosis of Chronic Pancreatitis via Inducing Autophagy and Activation of Pancreatic Stellate Cells.

BACKGROUND & AIMS: Studies have demonstrated that activated pancreatic stellate cells (PSCs) play a crucial role in pancreatic fibrogenesis in chronic pancreatitis (CP); however, the precise mechanism for PSCs activation has not been fully elucidated. We analyzed the role of injured pancreatic acinar cells (iPACs) in the activation of PSCs of CP. METHODS: Sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling was evaluated in experimental CP induced by cerulein injection or pancreatic duct ligation, as well as in PACs injured by cholecystokinin. The activation of PSCs and pancreatic fibrosis in CP samples was evaluated by immunohistochemical and immunofluorescence analyses. In vitro coculture assay of iPACs and PSCs was created to evaluate the effect of the SPHK1/S1P pathway and S1P receptor 2 (SIPR2) on autophagy and activation of PSCs. The pathogenesis of CP was assessed in SPHK1-/- mice or PACs-specific SPHK1-knockdown mice with recombinant adeno-associated virus serotypes 9-SPHK1-knockdown, as well as in mice treated with inhibitor of SPHK1 and S1P receptor 2 (S1PR2). RESULTS: SPHK1/S1P was remarkably increased in iPACs and acinar cells in pancreatic tissues of CP mice. Meanwhile, the pathogenesis, fibrosis, and PSCs activation of CP was significantly prevented in SPHK1-/- mice and recombinant adeno-associated virus serotypes 9-SPHK1-knockdown mice. Meanwhile, iPACs obviously activated PSCs, which was prevented by SPHK1 knockdown in iPACs. Moreover, iPACs-derived S1P specifically combined to S1PR2 of PSCs, by which modulated 5' adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin pathway and consequently induced autophagy and activation of PSCs. Furthermore, hypoxia-inducible factor 1-α and -2α promoted SPHK1 transcription of PACs under hypoxia conditions, which is a distinct characteristic of the CP microenvironment. Coincidently, inhibition of SPHK1 and S1PR2 activity with inhibitor PF-543 and JTE-013 obviously impeded pancreatic fibrogenesis of CP mice. CONCLUSIONS: The activated SPHK1/S1P pathway in iPACs induces autophagy and activation of PSCs by regulating the S1PR2/5' adenosine monophosphate-activated protein kinase/mammalian target of rapamycin pathway, which promotes fibrogenesis of CP. The hypoxia microenvironment might contribute to the cross talk between PACs and PSCs in pathogenesis of CP.

An unusual case of abdominal pain: psychogenic vomiting complicated by spontaneous pneumomediastinum.

BACKGROUND: Spontaneous pneumomediastinum (SPM) was defined by the appearance of free air in the mediastinum that was not preceded by trauma, surgery, or other medical procedures. Among the numerous manifestations of SPM, abdominal pain had seldom been described. CASE PRESENTATION: A 25-year-old man presented to the emergency department with nausea, vomiting, and abdominal pain for 7 days. The presenting clinical features and the radiological results were suggestive of psychogenic vomiting with spontaneous pneumomediastinum in a patient who suffered from abdominal pain. CONCLUSIONS: The special feature of this case was the elucidation of a rare cause of abdominal pain, which should be differentiated in patients with vomiting combined with abdominal pain. The importance of this case was that its recognition may prevent unnecessary procedures to rule out or treat other causes of abdominal pain.

Metabolic stress-induced reciprocal loop of long noncoding RNA ZFAS1 and ZEB1 promotes epithelial-mesenchymal transition and metastasis of pancreatic cancer cells.

Pancreatic cancer (PC) development faces significant metabolic stress due to metabolic reprogramming and a distinct hypovascular nature, often leading to glucose and glutamine depletion. However, the adaption mechanisms by which PC adapts to these metabolic challenges have not yet been completely explored. Here, we found that metabolic stress induced by glucose and glutamine deprivation led to an overexpression of ZNFX1 antisense RNA 1 (ZFAS1). This overexpression played a significant role in instigating PC cell epithelial-mesenchymal transition (EMT) and metastasis. Mechanistically, ZFAS1 enhanced the interaction between AMPK, a key kinase, and ZEB1, the primary regulator of EMT. This interaction resulted in the phosphorylation and subsequent stabilization of ZEB1. Interestingly, ZEB1 also reciprocally influenced the transcription of ZFAS1 by binding to its promoter. Furthermore, when ZFAS1 was depleted, the nutrient deprivation-induced EMT of PC cells and lung metastasis in nude mice were significantly inhibited. Our investigations also revealed that ZFAS1-rich exosomes released from cells suffering glucose and glutamine deprivation promoted the EMT and metastasis of recipient PC cells. Corroborating these findings, a correlated upregulation of ZFAS1 and ZEB1 expression was observed in PC tissues and was associated with a poor overall survival rate for patients. Our findings highlight the involvement of a long noncoding RNA-driven metabolic adaptation in promoting EMT and metastasis of PC, suggesting ZFAS1 as a promising novel therapeutic target for PC metabolic treatment.

Impact of Cataract Surgery on Income in Rural Southern China: The SUCCESS Randomized Controlled Trial.

PURPOSE: Visual impairment from cataracts is closely associated with low income, but trial evidence regarding the impact of surgery on income is lacking. We investigated whether cataract surgery could increase personal income. DESIGN: A 2-arm, parallel-group, open-label, randomized controlled trial (ClinicalTrials.gov, NCT03020056). METHODS: Persons aged 50 years or older in rural Guangdong, China, with best-corrected visual acuity <6/19 in both eyes due to cataracts were randomly assigned (1:1) to receive surgery within 4 weeks (intervention group), or 1 year later (control group). All participants were interviewed at baseline and end-line regarding demographic characteristics, income, and quality of life. RESULTS: Among the 292 eligible persons (5.40%, mean age = 74.0 y, 61.0% women) randomly assigned to intervention (n = 146) or control (n = 146) groups, 12 participants (8.22%) in the intervention group and 1 (0.68%) in the control did not receive the allocated intervention. By study closeout, 18 participants (6.16%) were lost to follow-up. The mean 1-year income increase of the intervention group ($2469-$3588; change = $1119) was significantly larger than that of the controls ($2258-$2052; change = $-206), a between-group difference of $1325 (relative increase = 54.0%; 95% CI = $739 to $1911; P < 0.001). In multivariable modeling, intervention group membership was associated with greater income increase (ß = 1143.2; 95% CI = 582.0 to 1704.3; P < 0.001). Greater improvement in best-corrected visual acuity was associated with income increase in univariable modeling (ß = 1626.9; 95% CI = 1083.6 to 2170.1; P < 0.001). CONCLUSIONS: Cataract surgery substantially increases personal income in rural China, offering a strategy for poverty alleviation. The strong association between increased income and change in visual acuity enhances the biological plausibility of the result.