Gly-ß-MCA is a potent anti-cholestasis agent against "human-like" hydrophobic bile acid-induced biliary injury in mice.

Cholestasis is a chronic liver disease with limited therapeutic options. Hydrophobic bile acid-induced hepatobiliary injury is a major pathological driver of cholestasis progression. This study investigates the anti-cholestasis efficacy and mechanisms of action of glycine-conjugated ß-muricholic acid (Gly-ß-MCA). We use female Cyp2c70 KO mice, a rodent cholestasis model that does not produce endogenous muricholic acid (MCA) and exhibits a "human-like" hydrophobic bile acid pool and female-dominant progressive hepatobiliary injury and portal fibrosis. The efficacy of Gly-ß-MCA and ursodeoxycholic acid (UDCA), the first line drug for cholestasis, on cholangiopathy and portal fibrosis are compared. At a clinically relevant dose, Gly-ß-MCA shows comparable efficacy as UDCA in reducing serum transaminase, portal inflammation and ductular reaction, and better efficacy than UDCA against portal fibrosis. Unlike endogenous bile acids, orally administered Gly-ß-MCA is absorbed at low efficiency in the gut and enters the enterohepatic circulation mainly after microbiome-mediated deconjugation, which leads to taurine-conjugated MCA enrichment in bile that alters enterohepatic bile acid pool composition and reduces bile acid pool hydrophobicity. Gly-ß-MCA also promotes fecal excretion of endogenous hydrophobic bile acids and decreases total bile acid pool size, while UDCA treatment does not alter total bile acid pool. Furthermore, Gly-ß-MCA treatment leads to gut unconjugated MCA enrichment and reduces gut hydrophobic lithocholic acid (LCA) exposure. In contrast, UDCA treatment drives a marked increase of LCA flux through the large intestine. In conclusion, Gly-ß-MCA is a potent anti-cholestasis agent with potential clinical application in treating human cholestasis.

Analysis of size effect and its influencing factors of brittle red sandstone with different heights.

We carried out uniaxial compression tests on brittle red sandstone with different heights. The test results show that the uniaxial compressive strength of rock sample increases first and then tends to be stable with the increase of the size, which is approximately stable between 75 and 81 MPa. Both elastic energy and dissipated energy increase with the increase of rock sample size. In order to further analyze the mechanism behind these phenomena, we combined advanced numerical simulation and theoretical analysis to explain these phenomena, and systematically analyzed the end face effect as one of the key factors affecting the uniaxial compression characteristics of brittle red sandstone for the first time. Small sized rock samples are very sensitive to end effect. The middle of the large sized rock samples is in a uniform compression state, and the effect of end effect is weakend. When there are rigid pads at both ends of the rock sample, there is an obvious elastic vertebral body during the loading process of the rock sample. The bearing capacity of rock samples with rigid pads is greater than that of rock samples without rigid pads, and the energy released during instantaneous failure of rock samples without rigid pads is greater than that of rock samples with rigid pads. The findings of this paper make a valuable contribution to establishing optimal study sample sizes and advancing the utilization of laboratory test mechanics parameters in engineering applications.

Pulmonary endometriosis presenting as multiple nodules and pseudocavities.

Pulmonary endometriosis is a rare disease of uncertain pathogenesis which generally presents with the cyclic clinical symptoms and catamenial changes noticed on computer tomography during menstruation. We report a case of a 33-year-old woman with recurrent hemoptysis for 1 year. The patient did not exhibit a temporal relationship between her periods and the onset of hemoptysis. A chest computed tomography scan showed multiple pseudocavities in the lower lobe of the right lung and multiple nodules in both lower lobes of the lungs. The right lower lobe wedge resection was performed. Postoperative pathological examination showed pulmonary endometriosis which is a rare cause of hemoptysis.

Cullin 3 RING E3 ligase inactivation causes NRF2-dependent NADH reductive stress, hepatic lipodystrophy, and systemic insulin resistance.

Cullin RING E3 ligases (CRL) have emerged as key regulators of disease-modifying pathways and therapeutic targets. Cullin3 (Cul3)-containing CRL (CRL3) has been implicated in regulating hepatic insulin and oxidative stress signaling. However, CRL3 function in liver pathophysiology is poorly defined. Here, we report that hepatocyte Cul3 knockout results in rapid resolution of steatosis in obese mice. However, the remarkable resistance of hepatocyte Cul3 knockout mice to developing steatosis does not lead to overall metabolic improvement but causes systemic metabolic disturbances. Liver transcriptomics analysis identifies that CRL3 inactivation causes persistent activation of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant defense pathway, which also reprograms the lipid transcriptional network to prevent TG storage. Furthermore, global metabolomics reveals that NRF2 activation induces numerous NAD+-consuming aldehyde dehydrogenases to increase the cellular NADH/NAD+ ratio, a redox imbalance termed NADH reductive stress that inhibits the glycolysis-citrate-lipogenesis axis in Cul3 knockout livers. As a result, this NRF2-induced cellular lipid storage defect promotes hepatic ceramide accumulation, elevates circulating fatty acids, and worsens systemic insulin resistance in a vicious cycle. Hepatic lipid accumulation is restored, and liver injury and hyperglycemia are attenuated when NRF2 activation and NADH reductive stress are abolished in hepatocyte Cul3/Nrf2 double-knockout mice. The resistance to hepatic steatosis, hyperglycemia, and NADH reductive stress are observed in hepatocyte Keap1 knockout mice with NRF2 activation. In summary, our study defines a critical role of CRL3 in hepatic metabolic regulation and demonstrates that the CRL3 downstream NRF2 overactivation causes hepatic metabolic maladaptation to obesity and insulin resistance.

Deletion of hepatocyte cysteine dioxygenase type 1, a bile acid repressed gene, enhances glutathione synthesis and ameliorates acetaminophen hepatotoxicity.

Liver is a major organ that metabolizes sulfur amino acids cysteine, which is the substrate for the synthesis of many essential cellular molecules including GSH, taurine, and coenzyme A. Bile acid-activated farnesoid x receptor (FXR) inhibits cysteine dioxygenase type 1 (CDO1), which mediates hepatic cysteine catabolism and taurine synthesis. To define the impact of bile acid inhibition of CDO1 on hepatic sulfur amino acid metabolism and antioxidant capacity, we developed hepatocyte-specific CDO1 knockout mice (Hep-CDO1 KO) and hepatocyte specific CDO1 transgenic mice (Hep-CDO1 Tg). Liver metabolomics revealed that genetic deletion of hepatic CDO1 reduced de novo taurine synthesis but had no impact on hepatic taurine abundance or bile acid conjugation. Consistent with reduced cysteine catabolism, Hep-CDO1 KO mice showed increased hepatic cysteine abundance but unaltered methionine cycle intermediates and coenzyme A synthesis. Upon acetaminophen overdose, Hep-CDO1 KO mice showed increased GSH synthesis capacity and alleviated liver injury. In contrast, hepatic CDO1 overexpression in Hep-CDO1 Tg mice stimulated hepatic cysteine to taurine conversion, resulting in reduced hepatic cysteine abundance. However, Hep-CDO1 Tg mice and WT showed similar susceptibility to acetaminophen-induced liver injury. Hep-CDO1 Tg mice showed similar hepatic taurine and coenzyme A compared to WT mice. In summary, these findings suggest that bile acid and FXR signaling inhibition of CDO1-mediated hepatic cysteine catabolism preferentially modulates hepatic GSH synthesis capacity and antioxidant defense, but has minimal effect on hepatic taurine and coenzyme A abundance. Repression of hepatic CDO1 may contribute to the hepatoprotective effects of FXR activation under certain pathologic conditions.

Comparing letrozole and mifepristone pre-treatment in medical management of first trimester missed miscarriage: a prospective open-label non-inferiority randomised controlled trial.

OBJECTIVE: To investigate whether letrozole pre-treatment is non-inferior to mifepristone pre-treatment, followed by misoprostol, for complete evacuation in the medical treatment of first-trimester missed miscarriage. DESIGN: Prospective open-label non-inferiority randomised controlled trial. SETTING: A university-affiliated hospital. POPULATION: We recruited 294 women diagnosed with first-trimester missed miscarriage who opted for medical treatment. METHODS: Participants were randomly assigned to: (i) the mifepristone group, who received 200 mg mifepristone orally followed 24-48 h later by 800 µg misoprostol vaginally; or (ii) the letrozole group, who received 10 mg letrozole orally once-a-day for 3 days, followed by 800 µg misoprostol vaginally on the third (i.e. last) day of letrozole administration. MAIN OUTCOME MEASURES: The primary outcome was the rate of complete evacuation without surgical intervention at 42 days post-treatment. Secondary outcomes included induction-to-expulsion interval, adverse effects, women's satisfaction, number of doses of misoprostol required, duration of vaginal bleeding, pain score on the day of misoprostol administration and other adverse events. RESULTS: The complete evacuation rates were 97.8% (95% CI 95.1%-100%) and 97.2% (95% CI 94.4%-99.9%) in the letrozole and mifepristone groups, respectively (p ≤ 0.001 for non-inferiority). The mean induction-to-tissue expulsion interval in the letrozole group was longer compared with the mifepristone group (15.4 vs 9.0 h) (p = 0.03). The letrozole group had less heavy post-treatment bleeding and an earlier return of menses. There were no statistically significant differences in the number of doses of misoprostol required, the duration of vaginal bleeding, the pain score on the day of misoprostol administration and the rate of other adverse events between the two groups. The majority of the women (91.2% and 93.9% in the letrozole and mifepristone groups, respectively) were satisfied with their treatment option. CONCLUSIONS: Letrozole is non-inferior to mifepristone as a pre-treatment, followed by misoprostol, for the medical treatment of first-trimester missed miscarriage.

Integration with carbon capture technology enables a positive carbon balance for sustainable rice paddy remediation with calcium­silicon composites.

In situ stabilization technologies based on lime-derived materials are extensively used for remediating Cd-contaminated paddy soils. However, the environmental impacts and carbon budget associated with these technologies throughout the paddy soil remediation life cycle are gaining increasing attention. Herein, through paddy field trials, two representative lime-derived materials, quicklime and calcium-silicon composite (Ca/Si), are evaluated for their remediation effectiveness and environmental sustainability in the remediation of Cd-contaminated soils. The results demonstrate that both quicklime and Ca/Si can reduce Cd bioavailability and enable the safe use of rice grain. Nevertheless, the life cycle assessment score of the quicklime case is 4.4 times that of the Ca/Si case, indicating that the quicklime case has a greater negative impact on the environment. Furthermore, the net ecosystem carbon budget analysis reveals that both lime-derived materials exhibit outward carbon emissions throughout their life cycle, in which the carbon emission of the quicklime case (-20.2 t CO2-eq/ha) is 20 times that of the Ca/Si case (-1 t CO2-eq/ha). Moreover, the implementation of carbon capture technology results in the Ca/Si case achieving a positive carbon budget and contributing to a carbon neutrality plan. Conversely, the quicklime case falls short, affording only a 24.8 % reduction in carbon emissions. Overall, this study provides valuable insights into the environmental sustainability of different lime-derived materials for paddy soil remediation and carbon mitigation.

Glycine-ß-Muricholic Acid Improves Liver Fibrosis and Gut Barrier Function by Reducing Bile Acid Pool Size and Hydrophobicity in Male Cyp2c70 Knockout Mice.

Cyp2c70 knockout mice lack the enzyme that produces muricholic acids and show a "human-like" hydrophobic bile acid pool-induced hepatobiliary injury. In this study, we investigated the potential anti-cholestasis effect of glycine-conjugated ß muricholic acid (G-ß-MCA) in male Cyp2c70 KO mice based on its hydrophilic physiochemical property and signaling property as an farnesoid X receptor (FXR) antagonist. Our results showed that G-ß-MCA treatment for 5 weeks alleviated ductular reaction and liver fibrosis and improved gut barrier function. Analysis of bile acid metabolism suggested that exogenously administered G-ß-MCA was poorly absorbed in the small intestine and mostly deconjugated in the large intestine and converted to taurine-conjugated MCA (T-MCA) in the liver, leading to T-MCA enrichment in the bile and small intestine. These changes decreased the biliary and intestine bile acid hydrophobicity index. Furthermore, G-ß-MCA treatment decreased intestine bile acid absorption via unknown mechanisms, resulting in increased fecal bile acid excretion and a reduction in total bile acid pool size. In conclusion, G-ß-MCA treatment reduces the bile acid pool size and hydrophobicity and improves liver fibrosis and gut barrier function in Cyp2c70 KO mice.

Regulation of Monocyte Activation by PPARα Through Interaction With the cGAS-STING Pathway.

Monocyte activation plays an important role in diabetic complications such as diabetic retinopathy (DR). However, the regulation of monocyte activation in diabetes remains elusive. Fenofibrate, an agonist of peroxisome proliferator-activated receptor-α (PPARα), has shown robust therapeutic effects on DR in patients with type 2 diabetes. Here we found that PPARα levels were significantly downregulated in monocytes from patients with diabetes and animal models, correlating with monocyte activation. Fenofibrate attenuated monocyte activation in diabetes, while PPARα knockout alone induced monocyte activation. Furthermore, monocyte-specific PPARα overexpression ameliorated, while monocyte-specific PPARα knockout aggravated monocyte activation in diabetes. PPARα knockout impaired mitochondrial function while also increasing glycolysis in monocytes. PPARα knockout increased cytosolic mitochondrial DNA release and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in monocytes under diabetic conditions. STING knockout or STING inhibitor attenuated monocyte activation induced by diabetes or by PPARα knockout. These observations suggest that PPARα negatively regulates monocyte activation through metabolic reprogramming and interaction with the cGAS-STING pathway.

Transformation kinetics of exogenous nickel in a paddy soil during anoxic-oxic alteration: Roles of organic matter and iron oxides.

Nickel is generally released from flooded soils; however, the key Ni transformation processes in soils that are freshly contaminated by Ni2+ during anoxic-oxic alteration remain unclear. We developed a kinetic model to investigate the Ni transformation in paddy soils under anoxic and oxic conditions based on the results of the seven-step sequential extraction, determination of dissolved and soil organic matter, and surface site quantification, which provide the kinetic data of different Ni fractions, organic matter, and reactive sites for modeling. The dissolved, exchangeable, and specifically adsorbed Ni was gradually transferred to fulvic complex, humic complex, Fe-Mn oxide bound, and sulfide bound Ni after 40 d of anoxic incubation due to the increase in pH and soil surface sites, which were mainly induced by Fe(III) oxide reduction and soil organic matter release. The introduction of oxygen triggered a rapid release of Ni, which was ascribed to the decrease in pH and soil surface sites caused by Fe(II) oxidation and carbon re-immobilization. Kinetic modeling demonstrated that complexation with soil organic matter dominated Ni immobilization under anoxic conditions, while organic matter and Fe-Mn oxides contributed similarly to Ni release under oxic conditions, although the majority of Ni remained complexed with soil organic matter. These findings are important for the evaluation and prediction of Ni behavior in paddy soils with exogenous Ni during flooding-drainage practices.

Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice.

Therapeutic reduction of hydrophobic bile acids exposure is considered beneficial in cholestasis. The Cyp2c70 KO mice lack hydrophilic muricholic acids and have a human-like hydrophobic bile acid pool resulting in hepatobiliary injury. This study investigates if combining an apical sodium-dependent bile acid transporter inhibitor GSK2330672 (GSK) and fibroblast growth factor-15 (FGF15) overexpression, via simultaneous inhibition of bile acid synthesis and gut bile acid uptake, achieves enhanced therapeutic efficacy in alleviating hepatobiliary injury in Cyp2c70 KO mice. The effects of GSK, adeno-associated virus (AAV)-FGF15, and the combined treatment on bile acid metabolism and cholangiopathy were compared in Cyp2c70 KO mice. In female Cyp2c70 KO mice with more severe cholangiopathy than male Cyp2c70 KO mice, the combined treatment was more effective in reversing portal inflammation, ductular reaction, and fibrosis than AAV-FGF15, while GSK was largely ineffective. The combined treatment reduced bile acid pool by ∼80% compared to ∼50% reduction by GSK or AAV-FGF15, and enriched tauro-conjugated ursodeoxycholic acid in the bile. Interestingly, the male Cyp2c70 KO mice treated with AAV-FGF15 or GSK showed attenuated cholangiopathy and portal fibrosis but the combined treatment was ineffective despite reducing bile acid pool. Both male and female Cyp2c70 KO mice showed impaired gut barrier integrity. AAV-FGF15 and the combined treatment, but not GSK, reduced gut exposure to lithocholic acid and improved gut barrier function. In conclusion, the combined treatment improved therapeutic efficacy against cholangiopathy than either single treatment in the female but not male Cyp2c70 KO mice by reducing bile acid pool size and hydrophobicity.

Dark Side of Ammonium Nitrogen in Paddy Soil with Low Organic Matter: Stimulation of Microbial As(V) Reduction and As(III) Transfer from Soil to Rice Grains.

The bioavailability of arsenic (As) is influenced by ammonium (NH4+-N) fertilization, but the underlying mechanisms controlling As transformation in soil-rice systems are still not fully understood. The effects of two NH4+-N fertilizers, urea and NH4HCO3, on the transformation of As in a paddy soil with low organic matter content and transfer in rice plants were investigated. Treatments with urea and NH4HCO3 significantly increased arsenite (As(III)) concentration in porewater, bioavailable As in rhizosphere soil, and the relative abundance of the As(V) respiratory reductase gene (arrA) and As(III) methyltransferase gene (arsM). Furthermore, the relative expression of As transporter genes in rice roots, such as OsLsi1, OsLsi2, and OsLsi3, was upregulated, and the translocation efficiency of As(III) from rice roots to brown rice was promoted. Subsequently, As(III) accumulation in brown rice significantly increased. Therefore, attention should be paid to As-contaminated paddy fields with NH4+-N fertilization.

Insight into universality and characteristics of nitrate reduction coupled with arsenic oxidation in different paddy soils.

Nitrate reduction coupled with arsenic (As) oxidation strongly influences the bioavailability and toxicity of As in anaerobic environments. In the present study, five representative paddy soils developed from different parent materials were used to investigate the universality and characteristics of nitrate reduction coupled with As oxidation in paddy soils. Experimental results indicated that 99.8 % of highly toxic aqueous As(III) was transformed to dissolved As(V) and Fe-bound As(V) in the presence of nitrate within 2-8 d, suggesting that As was apt to be reserved in its low-toxic and nonlabile form after nitrate treatment. Furthermore, nitrate additions also significantly induced the higher abundance of 16S rRNA and As(III) oxidase (aioA) genes in the five paddy soils, especially in the soils developed from purple sand-earth rock and quaternary red clay, which increased by 10 and 3-5 times, respectively, after nitrate was added. Moreover, a variety of putative novel nitrate-dependent As(III)-oxidizing bacteria were identified based on metagenomic analysis, mainly including Aromatoleum, Paenibacillus, Microvirga, Herbaspirillum, Bradyrhizobium, Azospirillum. Overall, all these findings indicate that nitrate reduction coupled with As(III) oxidation is an important nitrogen-As coupling process prevalent in paddy environments and emphasize the significance of developing and popularizing nitrate-based biotechnology to control As pollution in paddy soils and reduce the risk of As compromising food security.

Chromium transformation driven by iron redox cycling in basalt-derived paddy soil with high geological background values.

The flooding and drainage of paddy fields has great effects on the transformation of heavy metals, however, the transformation of Cr in basalt-derived paddy soil with high geological background values was less recognized. The typical basalt-derived paddy soil was incubated under alternating redox conditions. The Cr fractions and the dynamics of Fe/N/S/C were examined. The HCl-extractable Cr increased under anaerobic condition and then decreased during aerobic stage. The UV-vis spectra of the supernatant showed that amounts of colloids were released under anaerobic condition, and then re-aggregated during aerobic phase. The scanning transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) revealed that Fe oxides were reduced and became dispersed during anaerobic stage, whereas Fe(II) was oxidized and recrystallized under aerobic condition. Based on these results, a kinetic model was established to further distinguish the relationship between the transformation of Cr and Fe. During anaerobic phase, the reduction of Fe(III) oxides not only directly released the structurally bound Cr, but also enhanced the breakdown of soil aggregation and dissolution of organic matter causing indirect mobilization of Cr. During aerobic phase, the oxidation of Fe(II) and further recrystallization of newly formed Fe(III) oxides might induce the re-aggregation of soil colloids and further incorporation of Cr. In addition, the kinetic model of Cr and Fe transformation was further verified in the pot experiment. The model-based findings demonstrated that the Cr transformation in the basalt-derived paddy soil with high geological background values was highly driven by redox sensitive iron cycling.

Distinct arsenic uptake feature in rice reveals the importance of N fertilization strategies.

The environmental behavior of arsenic (As) is commonly affected by the biogeochemical processes of iron (Fe) and nitrogen (N). In this study, field experiments were conducted to explore As uptake in rice and As translation and distribution in As-contaminated iron-rich paddy soils after applying different forms of N fertilizers, including urea (CO(NH2)2), ammonium bicarbonate (NH4HCO3), nitrate of potash (KNO3), and ammonium bicarbonate + nitrate of potash (NH4HCO3 + KNO3). The results indicated that applying nitrate N fertilizer inhibited the reduction and dissolution of As-bearing iron minerals and promoted microbial-mediated As(III) oxidation in flooded soil, thus reducing the soil As bioavailability. The concentrations of total As and inorganic As ratio (iAs/TAs) in rice grain decreased by 32.4 % and 15.4 %, respectively. However, the application of ammonium nitrogen promoted the reductive dissolution of As-bearing iron minerals and stimulated microbial As(V) reduction in flooded soil, leading to the release of As from soil to porewater. The total As concentration and inorganic As uptake ratio in rice grain increased by 20.1 % and 6.2 %, respectively, when urea was applied, and by 29.6 % and 10.5 %, respectively, when ammonium bicarbonate was applied. However, the simultaneous application of NH4+ and NO3- had no significant effect on As concentration in rice grain and its transformation in paddy soils. Ammonium nitrogen enhanced the organic As concentration in rice grain because the increased As(III) promoted As methylation in soil. In contrast, nitrate decreased the organic As uptake by rice grain because the decreased As(III) diminished As methylation in soil. The results provide reasonable N fertilization strategies for regulating the As biogeochemical process and reducing the risk of As contamination in rice.

The emerging role of long non-coding RNAs in schizophrenia.

Schizophrenia (SZ) is a severe psychiatric disorder which is contributed by both genetic and environmental factors. However, at present, its specific pathogenesis is still not very clear, and there is a lack of objective and reliable biomarkers. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) are involved in the pathophysiology of several psychiatric disorders, including SZ, and hold promise as potential biomarkers and therapeutic targets for psychiatric disorders. In this review, we summarize and discuss the role of lncRNAs in the pathogenesis of SZ and their potential value as biomarkers and therapeutic targets.

TFEB regulates sulfur amino acid and coenzyme A metabolism to support hepatic metabolic adaptation and redox homeostasis.

Fatty liver is a highly heterogenous condition driven by various pathogenic factors in addition to the severity of steatosis. Protein insufficiency has been causally linked to fatty liver with incompletely defined mechanisms. Here we report that fatty liver is a sulfur amino acid insufficient state that promotes metabolic inflexibility via limiting coenzyme A availability. We demonstrate that the nutrient-sensing transcriptional factor EB synergistically stimulates lysosome proteolysis and methionine adenosyltransferase to increase cysteine pool that drives the production of coenzyme A and glutathione, which support metabolic adaptation and antioxidant defense during increased lipid influx. Intriguingly, mice consuming an isocaloric protein-deficient Western diet exhibit selective hepatic cysteine, coenzyme A and glutathione deficiency and acylcarnitine accumulation, which are reversed by cystine supplementation without normalizing dietary protein intake. These findings support a pathogenic link of dysregulated sulfur amino acid metabolism to metabolic inflexibility that underlies both overnutrition and protein malnutrition-associated fatty liver development.

Exploration of the relationship between hippocampus and immune system in schizophrenia based on immune infiltration analysis.

Immune dysfunction has been implicated in the pathogenesis of schizophrenia (SZ). Despite previous studies showing a broad link between immune dysregulation and the central nervous system of SZ, the exact relationship has not been completely elucidated. With immune infiltration analysis as an entry point, this study aimed to explore the relationship between schizophrenia and the immune system in more detail from brain regions, immune cells, genes, and pathways. Here, we comprehensively analyzed the hippocampus (HPC), prefrontal cortex (PFC), and striatum (STR) between SZ and control groups. Differentially expressed genes (DEGs) and functional enrichment analysis showed that three brain regions were closely related to the immune system. Compared with PFC and STR, there were 20 immune-related genes (IRGs) and 42 immune pathways in HPC. The results of immune infiltration analysis showed that the differential immune cells in HPC were effector memory T (Tem) cells. The correlation of immune-related DEGs (IDEGs) and immune cells further analysis showed that NPY, BLNK, OXTR, and FGF12, were moderately correlated with Tem cells. Functional pathway analysis indicated that these four genes might affect Tem by regulating the PI3K-AKT pathway and the neuroactive ligand-receptor interaction pathway. The receiver operating characteristic curve (ROC) analysis results indicated that these four genes had a high diagnostic ability (AUC=95.19%). Finally, the disease animal model was successfully replicated, and further validation was conducted using the real-time PCR and the western blot. These results showed that these gene expression changes were consistent with our previous expression profiling. In conclusion, our findings suggested that HPC in SZ may be more closely related to immune disorders and modulate immune function through Tem, PI3K-Akt pathway, and neuroactive ligand-binding receptor interactions. To the best of our knowledge, the Immucell AI tool has been applied for the first time to analyze immune infiltration in SZ, contributing to a better understanding of the role of immune dysfunction in SZ from a new perspective.

Seawater intrusion induced cadmium activation via altering its distribution and transformation in paddy soil.

Seawater intrusion can cause environmental risks to paddy soils around estuaries, but the impacts on the availability of heavy metals are still unclear. River water and sea water were collected along the river of an estuary. A stirred-flow experiment was conducted to examine the Cd desorption behavior in Cd-contaminated paddy soil. While the pH increased with increasing salinity levels, more Cd was released with increasing salinity, suggesting that Cd competition by cations and complexation by anions, but not pH, dominated the release of Cd from soils. Moreover, paddy soil was incubated at different salinities under alternating redox conditions. The availability of Cd, as indicated by the diffusive gradients in thin film (DGT), became relatively high with increasing salinity levels during the initial anaerobic and later aerobic stages. The available Cd fractions substantially decreased under anaerobic condition, and then rapidly increased under aerobic condition. When oxygen was introduced into the system, Cd associated with organic matter and Fe-Mn oxides were released, and oxidative dissolution of Cd sulfides was observed, especially in the high salinity treatment. Seawater intrusion affects biogeochemical cycles and can promote rapid export of NH4+, Fe2+, and SO42- in paddy soils, especially in soils with high salinity. Our findings demonstrated that the high salinity content in paddy soil significantly enhanced the availability of Cd, especially during the drainage stage.

LncRNA NEAT1 Promotes the Malignant Progression of Colorectal Cancer by Targeting ZEB1 via miR-448.

Background: Long noncoding RNAs have been associated with various types of malignant tumors; however, the specific role of long noncoding RNAs in tumorigenesis still remains unclear in colorectal cancer. Here, we aim to elucidate the role of long noncoding RNA nuclear paraspeckle assembly transcript 1 in the malignant progression of colorectal cancer and investigate its underlying mechanisms. Methods: Real-time polymerase chain reaction was used to detect the expression of nuclear paraspeckle assembly transcript 1 in colorectal cancer tissues and cells. Cell Counting Kit-8 assay was used to determine the effect of nuclear paraspeckle assembly transcript 1 in proliferation. Transwell assay was used to explore the role of nuclear paraspeckle assembly transcript 1 in metastasis. Bioinformatics method was used to predict the core nuclear paraspeckle assembly transcript 1 interaction network. Real-time polymerase chain reaction was used to detect nuclear paraspeckle assembly transcript 1 and miR-448 expression levels. Western blotting was used to detect the expression levels of ZEB1. Luciferase assay was used to verify the relationship among nuclear paraspeckle assembly transcript 1, miR-448, and ZEB1. The effect of nuclear paraspeckle assembly transcript 1 on tumor growth was detected by tumorigenesis test in nude mice. Results: Long noncoding RNA-nuclear paraspeckle assembly transcript 1 was up-regulated in colorectal cancer tissues and cells. Knocking down of nuclear paraspeckle assembly transcript 1 can suppress colorectal cancer proliferation and invasion, and caused a reduction of ZEB1 expression and an increase of miR-448 expression. Furthermore, knockdown of nuclear paraspeckle assembly transcript 1 regulated miR-448/ZEB1 axis to inhibit the expression of ZEB1. miR-448 silencing can reverse the effect of nuclear paraspeckle assembly transcript 1 knockdown. Conclusion: Our result demonstrated that long noncoding RNA nuclear paraspeckle assembly transcript 1 promotes proliferation and invasion of colorectal cancer by targeting miR-448 to promote the expression of ZEB1, which may play a significant role in the tumorigenesis of colorectal cancer.