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Background: Endoplasmic reticulum stress (ERS)-related genes are related to tumor growth, metastasis, and immunotherapy response. In this paper, we tried to identify ERS-related genes related to immunotherapy in colon cancer. Methods: ERS-related genes were downloaded from the Molecular Signatures Database (MSigDB) and GeneCards websites. Normal and tumor samples of the colon were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), and Gene Expression Omnibus (GEO) databases. A risk model based on gene coefficients was constructed by using the least absolute shrinkage and selection operator (LASSO) regression. The inherent biological process differences between risk groups were explored by Gene Ontology (GO) and gene set enrichment analysis (GSEA). ESTIMATE and single-sample GSEA (ssGSEA) algorithms were used to analyze the correlation between tumor microenvironment (TME) and immune checkpoint and risk score. The semi-inhibitory concentration (IC50) values of chemotherapeutic drugs between risk groups were calculated to evaluate the sensitivity of immunotherapy. Results: The pathway analysis showed that the ERS risk model was relevant to biosynthesis and metabolism. Consistent clustering based on the ERS-related differentially expressed genes (DEGs) demonstrated that the samples divided into three clusters had significant clinicopathological differences. A risk model consisting of six ERS-related genes was established. The model was verified on GSE39582 and GSE17536 testing datasets. The results showed that ERS risk model was significantly related to TME and immune checkpoint, and these genes enhanced the immunotherapy ability of colon cancer. Conclusions: We established a risk model with ERS-related genes (PMM2, STC2, EIF2AK1, HSPA1A, SLC8A1, KCNQ1), which enhance the sensitivity of immunotherapy for colon cancer. These may provide a new perspective for the treatment of colon cancer.
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OBJECTIVE OF THE STUDY: Hepatocellular carcinoma (HCC) stands as the third leading cause of cancer-related mortality globally. Metastasis, responsible for treatment failures, underscores the urgency to comprehend molecular drivers of invasion and migration. Central to the invasive and migratory processes underlying metastasis is the protein Talin1. However, the role and underlying mechanisms governing Talin1's involvement in HCC have remained elusive. METHODS: A total of 100 HCC specimens were collected from patients who underwent hepatectomy in our center. The expression level of talin1 was measured to evaluate the correlationship of talin1 and the development of HCC. In vitro and in vivo experiments were conducted to verify the characteristic of talin1 in HCC. RNA-seq and bioinformatics analysis were performed to identify the downstream signal pathway of talin1 and their impact on HCC development. RESULTS: Here, we reported elevated levels of Talin1 mRNA and protein in HCC tissues. Meanwhile, downregulation of Talin1 significantly reduced the HCC cell proliferation and metastasis in vitro and in vivo. Furthermore, elevating NRG-1, a downstream target of Talin1, enhanced metastasis of HCC cells. More importantly, attenuation of Talin1 inhibited HCC progression through decreasing the stabilization of NRG1 mRNA, consequently regulating the expression of NRG1 and its involvement in mediating the PI3K/AKT pathway. CONCLUSION: Taken together, Talin1 regulates cellular proliferation, metastasis, and invasiveness by modulating NRG1/PI3K/AKT axis, suggesting that Talin1 emerges as a promising candidate for treating HCC.
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Adopting biomass energy as an alternative to fossil fuels for electricity production presents a viable strategy to address the prevailing energy deficits and environmental concerns, although it faces challenges related to suboptimal energy efficiency levels. This study introduces a novel combined cooling and power (CCP) system, incorporating an externally fired gas turbine (EFGT), steam Rankine cycle (SRC), absorption refrigeration cycle (ARC), and organic Rankine cycle (ORC), aimed at boosting the efficiency of biomass integrated gasification combined cycle systems. Through the development of mathematical models, this research evaluates the system's performance from both thermodynamic and exergoeconomic perspectives. Results show that the system could achieve the thermal efficiency, exergy efficiency, and levelized cost of exergy (LCOE) of 70.67%, 39.13%, and 11.67 USD/GJ, respectively. The analysis identifies the combustion chamber of the EFGT as the component with the highest rate of exergy destruction. Further analysis on parameters indicates that improvements in thermodynamic performance are achievable with increased air compressor pressure ratio and gas turbine inlet temperature, or reduced pinch point temperature difference, while the LCOE can be minimized through adjustments in these parameters. Optimized operation conditions demonstrate a potential 5.7% reduction in LCOE at the expense of a 2.5% decrease in exergy efficiency when compared to the baseline scenario.
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STUDY QUESTION: Is preconception depression associated with time to pregnancy (TTP) and infertility? SUMMARY ANSWER: Couples with preconception depression needed a longer time to become pregnant and exhibited an increased risk of infertility. WHAT IS KNOWN ALREADY: Preconception depression in women contributes to impaired fertility in clinical populations. However, evidence from the general population-especially based on couples-is relatively scant. STUDY DESIGN SIZE DURATION: A couple-based prospective preconception cohort study was performed in 16 premarital examination centers between April 2019 and June 2021. The final analysis included 16 521 couples who tried to conceive for ≤6 months at enrollment. Patients with infertility were defined as those with a TTP ≥12 months and those who conceived through ART. PARTICIPANTS/MATERIALS SETTING METHODS: Couples' depression was assessed using the Patient Health Questionnaire-9 at baseline. Reproductive outcomes were obtained via telephone at 6 and 12 months after enrollment. Fertility odds ratios (FORs) and infertility risk ratios (RRs) in different preconception depression groups were analyzed using the Cox proportional-hazard models and logistic regression, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 16 521 couples analyzed, 10 834 (65.6%) and 746 (4.5%) couples achieved pregnancy within the first 6 months and between the 6th and 12th months, respectively. The median (P25, P75) TTP was 3.0 (2.0, 6.0) months. The infertility rate was 13.01%. After adjusting for potential confounders, in the individual-specific analyses, we found that preconception depression in women was significantly related to reduced odds of fertility (FOR = 0.947, 95% CI: 0.908-0.988), and preconception depression in either men or women was associated with an increased risk of infertility (women: RR = 1.212, 95% CI: 1.076-1.366; men: RR = 1.214, 95% CI: 1.068-1.381); in the couple-based analyses, we found that-compared to couples where neither partner had depression-the couples where both partners had depression exhibited reduced fertility (adjusted FOR = 0.904, 95% CI: 0.838-0.975). The risk of infertility in the group where only the woman had depression and both partners had depression increased by 17.8% (RR = 1.178, 95% CI: 1.026-1.353) and 46.9% (RR = 1.469, 95% CI: 1.203-1.793), respectively. LIMITATIONS REASONS FOR CAUTION: Reporting and recall bias were unavoidable in this large epidemiological study. Some residual confounding factors-such as the use of anti-depressants and other medications, sexual habits, and prior depressive and anxiety symptoms-remain unaddressed. We used a cut-off score of 5 to define depression, which is lower than prior studies. Finally, we assessed depression only at baseline, therefore we could not detect effects of temporal changes in depression on fertility. WIDER IMPLICATIONS OF THE FINDINGS: This couple-based study indicated that preconception depression in individuals and couples negatively impacts couples' fertility. Early detection and intervention of depression to improve fertility should focus on both sexes. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants from the National Natural Science Foundation of China (No. 82273638) and the National Key Research and Development Program of China (No. 2018YFC1004201). All authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
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Electrochemical carbon dioxide reduction reaction (eCO2RR) to generate syngas is an appealing strategy for CO2 net reduction. However, it suffers from the inferior faradaic efficiency (FE), selectivity, and difficult modulation of hydrogen/carbon monoxide (H2/CO) ratio. To address these issues, a series of magnesium-nickel (Mg-Ni) dual atomic catalysts with different Ni contents are fabricated on the nitrogen-doped carbon matrix (MgNiX-NC DACs) by one-step pyrolysis. MgNi5-NC electrocatalyst generates 0.51-0.79 H2/CO ratios in a potential range of -0.6 to -1.0 V vs. reversible hydrogen electrode (RHE) and the total FE reaches 100 % with good stability. While a wider range of H2/CO (0.95-4.34) is achieved for MgNi3-NC electrocatalyst in the same overpotential range, which is suitable for typical downstream thermochemical reactions. Introduction of Ni species accelerates the generation of CO, however, there is much less influence on the H2 production as compared with Mg-based single atomic electrocatalyst. According to the experimental results and density functional theory (DFT) calculations, the synergistic effect between Mg and Ni achieves the satisfied results rather than each one fulfill its own duty for selective producing H2 and CO, respectively. This work introduces a feasible approach to develop atomic catalysts on main group metal for more controllable CO2RR.
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The rapid expansion of green areas in China has enhanced carbon sinks, but it also presents challenges regarding increased biogenic volatile organic compound (BVOC) emissions. This study examines the impact of greening trends on BVOC emissions in China from 1985 to 2001 and from 2001 to 2022, focusing on evaluating long-term trends in BVOC emissions within eight afforestation project areas during these two periods. Emission factors for 62 dominant tree species and provincial Plant Functional Types were updated. The BVOC emission inventories were developed for China at a spatial resolution of 27 km × 27 km using the Model of Emissions of Gases and Aerosols from Nature. The national BVOC emissions in 2018 were estimated at 54.24 Tg, with isoprene, monoterpenes, sesquiterpenes, and other BVOC contributing 26.94 Tg, 2.29 Tg, 0.44 Tg, and 24.57 Tg, respectively. Over the past 37 years, BVOC emissions experienced a slow growth rate of 1.7 % (0.79 Tg) during 1985-2001, followed by a significant increase of 12 % (6 Tg) from 2001 to 2022. BVOC emissions in the eight afforestation project areas increased by 2 % and 20 % during the two periods. From 2001 to 2022, at the regional scale, the Shelterbelt program for the middle reaches of the Yellow River area exhibited the largest rate of increase (43 %) in BVOC emissions. The Shelterbelt program for the upper and middle reaches of the Yangtze River made the most largest contribution (45 %) to the national increase in BVOC emissions. Afforestation projects have shifted towards planting more broadleaf trees than needleleaf trees from 2001 to 2022, and there also showed a change from herbaceous plants to broadleaf trees. These trends have led to higher average emission factors for vegetation, resulting in increased BVOC emissions. It underscores the importance of considering BVOC emissions when evaluating afforestation initiatives, emphasizing the need to balancing ecological benefits with potential atmospheric consequences.
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Contaminantes Atmosféricos , Monitoreo del Ambiente , Compuestos Orgánicos Volátiles , China , Compuestos Orgánicos Volátiles/análisis , Contaminantes Atmosféricos/análisis , Bosques , Árboles , Contaminación del Aire/estadística & datos numéricos , Agricultura ForestalRESUMEN
The metal-semiconductor (M-S) contact is usually an Ohmic contact or a Schottky contact, which greatly affects the electronic properties of devices, and it remains a huge challenge to realize a low-resistance Ohmic contact in a metal-semiconductor junction (MSJ). Herein, we systematically studied the band structures, electrostatic potential, charge transfer, Schottky barrier height of carriers, effective carrier masses, and tunneling probability of carriers of a germanene (Ge)/GaAs MSJ. The transition from the Schottky to the Ohmic contact can be caused by applying certain biaxial strains or electric fields, which weakens the Fermi level pinning (FLP) effect and reduces contact resistance. Meanwhile, the electron injection efficiency of Ge/(GaAs)As MSJ (PTB > 27%) is far superior to that of other two-dimensional (2D) vdW MSJs. This work indicates that Ge/GaAs heterostructures are the most compatible for applying high-effective 2D electronic nanodevices under controllable conditions.
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BACKGROUND: Biomonitoring-based epidemiological studies on prenatal antibiotic exposure and behavioral problems in preschoolers are lacking. The present study aimed to investigate the relationship between prenatal antibiotic exposure and internalizing and externalizing problems in preschoolers. METHODS: Data from 2449 mother-child pairs were analyzed. Urine samples were repeatedly collected across three trimesters, and 43 antibiotics and 2 metabolites were measured, including preferred as veterinary antibiotics (PVAs), VAs, preferred as human antibiotics and human antibiotics. Preschoolers' internalizing and externalizing problems were evaluated by the Achenbach Child Behavior Checklist. Poisson regression models with generalized estimating equations were used to estimate risk ratios (RRs) and 95 % confidence intervals (CIs) for preschoolers' internalizing, externalizing and total problems across tertiles of antibiotic concentrations during three periods of pregnancy, and performed several subgroup analyses. RESULTS: First-trimester urinary oxytetracycline (RR = 1.69, 95%CI: 1.20, 2.39, P-FDR = 0.011), tetracycline (RR = 1.91, 95%CI: 1.36, 2.68, P-FDR < 0.001), doxycycline (RR = 1.66, 95%CI: 1.28, 2.17, P-FDR < 0.001) and PVAs (RR = 1.79, 95%CI: 1.29, 2.48, P-FDR < 0.001) concentrations in the highest tertile were related to an elevated risk of internalizing problems compared with concentrations in the lowest tertile. First-trimester urinary doxycycline concentrations in the third tertile were also associated with an increased risk of externalizing problems compared with the first tertile (RR = 2.00, 95%CI: 1.28, 3.15, P-FDR = 0.042). Compared with concentrations in the lowest tertile, first-trimester urinary doxycycline (RR = 1.63, 95%CI: 1.19, 2.22, P-FDR = 0.028) and PVAs (RR = 1.67, 95%CI: 1.14, 2.43, P-FDR = 0.047) concentrations in the middle tertile were related to an increased risk of total problems. Furthermore, the type of main caregiver and children's outdoor activities time modified the relationships between specific prenatal antibiotic exposure and preschoolers' behavioral problems. CONCLUSIONS: Exposure to specific antibiotics during the first trimester may be related to an increased risk of internalizing and externalizing problems in preschoolers.
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Doxiciclina , Efectos Tardíos de la Exposición Prenatal , Embarazo , Femenino , Humanos , Estudios de Cohortes , Estudios Prospectivos , Antibacterianos/efectos adversos , Monitoreo Biológico , Efectos Tardíos de la Exposición Prenatal/epidemiologíaRESUMEN
As a typical industrial and agricultural province, Shandong is one of China's most seriously air-polluted regions. One comprehensive ammonia emission inventory with a high spatial resolution (1 km × 1 km) for 136 county-level administrative divisions in Shandong from 2000 to 2020 is developed based on county-level activity data with the corrected and updated emission factors of seventy-seven subcategories. Annual ammonia emissions decrease from 1003.3 Gg in 2000 to 795.9 Gg in 2020, with an annual decrease rate of 1.2 %. Therein, the ammonia emissions associated with livestock and farmland ecosystems in 2020 account for 50.8 % and 32.9 % of the provincial total ammonia emission, respectively. Laying hen and wheat are the livestock and crop with the highest ammonia emissions, accounting for 23.3 % and 36.3 % of ammonia emissions from livestock and the application of synthetic fertilizers, respectively. Furthermore, waste treatment, humans and vehicles are the top three ammonia emission sources in urban areas, accounting for 5.0 %, 4.7 % and 1.3 % of total ammonia emissions, respectively. The spatial distribution of grids with high ammonia emissions is consistent with the distribution of intensive farms. Significant emission intensity areas mainly concentrate in western Shandong (e.g., Caoxian of Heze, Qihe of Dezhou, Yanggu of Liaocheng, Liangshan of Jining) due to the large area of arable land and the high levels of agricultural activity. Overall, prominent seasonal variability characteristics of ammonia emission are observed. Ammonia emissions tend to be high in summer and low in winter, and the August to January-emission ratio is 5.6. The high temperature and fertilization for maize are primarily responsible for Shandong's increase in ammonia emissions in summer. Finally, the validity of the estimates is further evaluated using uncertainty analysis and comparison with previous studies. This study can provide information to determine preferentially effective PM2.5 control strategies.
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Peripheral nerve regeneration and functional recovery rely on the chemical, physical, and structural properties of nerve guidance conduits (NGCs). However, the limited support for long-distance nerve regeneration and axonal guidance has hindered the widespread use of NGCs. This study introduces a novel nerve guidance conduit with oriented lateral walls, incorporating multi-walled carbon nanotubes (MWCNTs) within core-shell fibers prepared in a single step using a modified electrohydrodynamic (EHD) printing technique to promote peripheral nerve regeneration. The structured conduit demonstrated exceptional stability, mechanical properties, and biocompatibility, significantly enhancing the functionality of NGCs. In vitro cell studies revealed that RSC96 cells adhered and proliferated effectively along the oriented fibers, demonstrating a favorable response to the distinctive architectures and properties. Subsequently, a rat sciatic nerve injury model demonstrated effective efficacy in promoting peripheral nerve regeneration and functional recovery. Tissue analysis and functional testing highlighted the significant impact of MWCNT concentration in enhancing peripheral nerve regeneration and confirming well-matured aligned axonal growth, muscle recovery, and higher densities of myelinated axons. These findings demonstrate the potential of oriented lateral architectures with coaxial MWCNT fibers as a promising approach to support long-distance regeneration and encourage directional nerve growth for peripheral nerve repair in clinical applications.
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Nanotubos de Carbono , Regeneración Nerviosa , Traumatismos de los Nervios Periféricos , Ratas Sprague-Dawley , Nervio Ciático , Animales , Regeneración Nerviosa/fisiología , Nanotubos de Carbono/química , Ratas , Nervio Ciático/fisiología , Nervio Ciático/lesiones , Traumatismos de los Nervios Periféricos/terapia , Andamios del Tejido/química , Regeneración Tisular Dirigida/métodos , Axones/fisiología , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacologíaRESUMEN
Mutations in genes that disrupt centrosome structure or function can cause congenital kidney developmental defects and lead to fibrocystic pathologies. Yet, it is unclear how defective centrosome biogenesis impacts renal progenitor cell physiology. Here, we examined the consequences of impaired centrosome duplication on kidney stromal progenitor cell growth, differentiation, and fate. Conditional deletion of the ciliopathy gene Cep120, which is essential for centrosome duplication, in the stromal mesenchyme resulted in reduced abundance of interstitial lineages including pericytes, fibroblasts and mesangial cells. These phenotypes were caused by a combination of delayed mitosis, activation of the mitotic surveillance pathway leading to apoptosis, and changes in both Wnt and Hedgehog signaling that are key for differentiation of stromal cells. Cep120 ablation resulted in small hypoplastic kidneys with medullary atrophy and delayed nephron maturation. Finally, Cep120 and centrosome loss in the interstitium sensitized kidneys of adult mice, causing rapid fibrosis after renal injury via enhanced TGF-ß/Smad3-Gli2 signaling. Our study defines the cellular and developmental defects caused by loss of Cep120 and aberrant centrosome biogenesis in the embryonic kidney stroma.
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Proteínas Hedgehog , Riñón , Ratones , Animales , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Riñón/patología , Diferenciación Celular/genética , Células del Estroma , Células Madre , Proteínas de Ciclo Celular/metabolismoRESUMEN
Few studies have explored the relationship between antibiotic exposure and sleep in newlyweds. We applied the actor-partner interdependence moderation model to estimate the relationships of antibiotic exposure with nighttime sleep duration (weekday, weekend, and average sleep durations) and daytime sleepiness in newlyweds. We found that 99.0% of the 2698 enrolled individuals were exposed to at least one antibiotic. Among the newlyweds, exposure to florfenicol (ß, - 0.077; 95% confidence interval [CI], - 0.143, - 0.011), exposure to chloramphenicols (- 0.086 [- 0.160, - 0.011]), and exposure to veterinary antibiotics (VAs) (- 0.106 [- 0.201, - 0.010]) were negatively associated with weekday sleep duration. Florfenicol, chloramphenicols, and VAs were also inversely related to average sleep duration in the newlyweds. Ciprofloxacin and cyadox exposure was significantly associated with an increase of 0.264 (0.030, 0.497) and (0.375 [0.088, 0.663]) Epworth Sleepiness Scale (ESS) scores in the newlyweds, respectively. Gender moderated the actor-partner effects of erythromycin and tetracyclines on the newlyweds' weekday sleep duration and ESS scores. Overall, exposure to florfenicol, chloramphenicols, and VAs shortened weekday and average sleep durations of newlyweds. Exposure to ciprofloxacin and cyadox promoted daytime sleepiness. Gender moderated the actor-partner effects of specific antibiotics on the weekday sleep duration and ESS scores of the newlyweds.
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Trastornos de Somnolencia Excesiva , Duración del Sueño , Tianfenicol/análogos & derivados , Humanos , Antibacterianos , Sueño , CiprofloxacinaRESUMEN
The intestinal microbiota drives the maturation of the immune system, which is essential for maintaining lifetime homeostasis. Whether fecal microbiota transplantation can promote the development of the immune system in chicks? On days 1, 3, and 5, the post-hatch Hy-line Brown chicks were treated with fecal suspension from breeding hens. Intestinal length, blood biochemical indicators, the morphology of immune organs, and intestinal immunity-related indicators were focused on days 7 and 14. Short-chain fatty acids were determined by gas chromatography. We discovered that fecal microbial transplantation significantly increased the area of the follicles and medulla from the bursa of Fabricius, as well as the area of the medulla, cortex, and both ratios from the thymus on 14 d, the concentration of butyric acid in feces, the levels of immunologically active substances (transforming growth factor-ß, interleukin 10, forkhead box protein P3, G-Protein Coupled Receptor 43, immunoglobulin A, etc.) in serum or the intestine, and the number of goblet cells. Correlation analysis indicated that short-chain fatty acids, as metabolites of the gut microbiota, were correlated with intestinal immunity. In short, fecal microbiota transplantation regulated early intestinal immunity, which provided the possibility for the processing and utilization of gut microbiota as germplasm resources. IMPACT STATEMENT: Modern management of eggs causes the normal vertical transmission of microbiota from hens to be significantly reduced. The risk of environmental threats to newborn chicks is raised. The microbial community helps to mature the immune system of chicks and protect them from pathogen invasion. We still have doubts about whether transplanting the microbiota can regulate gut immunity. Using the gut microbiota of hens as an excellent resource to improve the immunity of chicks may provide new ideas for the development of the poultry industry.
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Pollos , Trasplante de Microbiota Fecal , Animales , Femenino , Trasplante de Microbiota Fecal/métodos , Ácidos Grasos Volátiles , Ácido Butírico , InmunidadRESUMEN
A fundamental problem in tissue morphogenesis is identifying how subcellular signaling regulates mesoscale organization of tissues. The primary cilium is a paradigmatic organelle for compartmentalized subcellular signaling. How signaling emanating from cilia orchestrates tissue organization-especially, the role of cilia-generated effectors in mediating diverse morpho-phenotypic outcomes-is not well understood. In the hedgehog pathway, bifunctional GLI transcription factors generate both GLI-activators (GLI-A) and GLI-repressors (GLI-R). The formation of GLI-A/GLI-R requires cilia. However, how these counterregulatory effectors coordinate cilia-regulated morphogenetic pathways is unclear. Here we determined GLI-A/GLI-R requirements in phenotypes arising from lack of hedgehog pathway repression (derepression) during mouse neural tube and skeletal development. We studied hedgehog pathway repression by the GPCR GPR161, and the ankyrin repeat protein ANKMY2 that direct cAMP/protein kinase-A signaling by cilia in GLI-R generation. We performed genetic epistasis between Gpr161 or Ankmy2 mutants, and Gli2/Gli3 knockouts, Gli3R knock-in and knockout of Smoothened, the hedgehog pathway transducer. We also tested the role of cilia-generated signaling using a Gpr161 ciliary localization knock-in mutant that is cAMP signaling competent. We found that the cilia-dependent derepression phenotypes arose in three modes: lack of GLI-R only, excess GLI-A formation only, or dual regulation of either lack of GLI-R or excess GLI-A formation. These modes were mostly independent of Smoothened. The cAMP signaling-competent non-ciliary Gpr161 knock-in recapitulated Gpr161 loss-of-function tissue phenotypes solely from lack of GLI-R only. Our results show complex tissue-specific GLI-effector requirements in morphogenesis and point to tissue-specific GLI-R thresholds generated by cilia in hedgehog pathway repression. Broadly, our study sets up a conceptual framework for rationalization of different modes of signaling generated by the primary cilium in mediating morphogenesis in diverse tissues.
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Proteínas Hedgehog , Factores de Transcripción de Tipo Kruppel , Ratones , Animales , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Transducción de Señal/genética , Morfogénesis/genética , Factores de Transcripción/metabolismo , Cilios/metabolismo , Proteínas Portadoras/metabolismoRESUMEN
Mutations that disrupt centrosome biogenesis or function cause congenital kidney developmental defects and fibrocystic pathologies. Yet how centrosome dysfunction results in the kidney disease phenotypes remains unknown. Here, we examined the consequences of conditional knockout of the ciliopathy gene Cep120, essential for centrosome duplication, in the nephron and collecting duct progenitor niches of the mouse embryonic kidney. Cep120 loss led to reduced abundance of both cap mesenchyme and ureteric bud populations, due to a combination of delayed mitosis, increased apoptosis and premature differentiation of progenitor cells. These defects resulted in dysplastic kidneys at birth, which rapidly formed cysts, displayed increased interstitial fibrosis and decline in kidney function. RNA sequencing of embryonic and postnatal kidneys from Cep120-null mice identified changes in the pathways essential for development, fibrosis and cystogenesis. Our study defines the cellular and developmental defects caused by centrosome dysfunction during kidney morphogenesis and identifies new therapeutic targets for patients with renal centrosomopathies.
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Riñón , Enfermedades Renales Poliquísticas , Animales , Humanos , Ratones , Riñón/metabolismo , Nefronas/metabolismo , Centrosoma/metabolismo , Enfermedades Renales Poliquísticas/metabolismo , Ratones Noqueados , Fibrosis , Proteínas de Ciclo Celular/metabolismoRESUMEN
BACKGROUND: The successful launch of icaritin, a therapeutic drug for liver cancer derived from Epimedium brevicornu, has provided new impetus for the development of prenylated flavonoids in the field of oncology. Flemingia macrophylla is reported to contain characteristic prenylated flavonoids which can regulate the p53 protein. We aimed to isolate these constituents and conduct activity evaluation, structure-activity relationship, and mechanism studies to provide candidate compounds for antitumor drug development. METHODS: In this study, chromatographic techniques combined with spectroscopic methods were used to separate, purify, and identify the constituents of Flemingia macrophylla methanol extract. The cytotoxic activity of the constituents was evaluated using an MTT assay with A549 and H1975 cells as the model. The binding mechanism between the compounds and the p53 protein was investigated with molecular docking and validated with cellular thermal shift assay (CETSA). Western blotting (WB) was employed to detect the expression of p53 protein and apoptosis-related proteins in cells. RESULTS: Chiral HPLC separation of racemates 1 and 7 provided two pairs of undescribed enantiomers (1a/1b and 7a/7b), along with eight known compounds (2 - 9) isolated from Flemingia macrophylla roots. Their structures were elucidated by spectroscopic analysis, and the absolute configurations of the enantiomers were determined from experimental and calculated electronic circular dichroism data. Compounds 1 - 7, and the non-prenyl analogues 10 - 13, were evaluated for cytotoxic activity against the human lung cancer A549 and H1975 cell line. Compounds 5 - 7 displayed better cytotoxicity than the positive control icaritin in A549 and H1975, with IC50 values ranging from 4.50 to 19.83 µmol·L-1 and < 5 µmol·L-1, respectively. The structure-activity relationships of the chromone or flavonoid analogues against A549 cells were discussed. Molecular docking results demonstrated that compound 7a has strong interaction with p53 and WB indicated that 7a induced apoptosis by increasing the p53 protein, decreasing the anti-apoptotic protein Bcl-2, and activating the caspase family in A549 cells. These results suggest that prenylated flavonoids are potential p53 protein activators. CONCLUSION: This study demonstrates that Flemingia macrophylla is rich in prenylated flavonoid constituents, among which compounds 5 and 7 exhibited significant cytotoxic activity against A549 cells and served as reference candidates for the design and development of prenylated compounds as antitumor therapeutic drugs.
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Only few studies have assessed the health effects due to preconception exposure to antibiotics among childbearing couples. This study investigated the status of preconception exposure to antibiotics among childbearing couples in Anhui, associated with health risks, and influencing factors. Overall, 1500 childbearing couples were randomly selected from the Reproductive Health of Childbearing Couples - Anhui Cohort (RHCC-AC). The urinary levels of 40 antibiotics and 2 metabolites were determined, and specific gravity (SG) adjusted concentrations of antibiotics were measured to assess health risks. Generalized linear models were used to assess the associations of urinary SG-adjusted concentration of antibiotics with demographic parameters and diet frequency. The total detection rates of all antibiotics were 98.9 % and 99.3 % in wives and husbands, respectively. The detection rates of veterinary antibiotics (VAs) and preferred as VAs (PVAs) were above 90 %. Among eight antibiotics, sulfonamides (95.1 %) and fluoroquinolones (87.6 %) had the highest detection rates in couples. Approximately four-fifths of couples were simultaneously exposed to at least three different antibiotics, and more than half of them were exposed to low concentrations of antibiotics. 8.9 % and 9.2 % of wives and husbands had hazard index value of antibiotics exposure greater than 1. Antibiotic concentrations were associated with residence, sampling season, and diet frequency. In Anhui, nearly 98 % of childbearing couples have environmental exposure to antibiotics, and VAs and PVAs are the primary antibiotics. More than 8 % of couples had health risks due to antibiotic exposure. Several potential determinants of urinary antibiotics deserve more attention in future research.
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Antibacterianos , Exposición a Riesgos Ambientales , Humanos , Antibacterianos/orina , Sulfanilamida , FluoroquinolonasRESUMEN
Methylmercury (MeHg) produced in rice paddies is the main source of MeHg accumulation in rice, resulting in high risk of MeHg exposure to humans and wildlife. Net MeHg production is affected by Hg(II) reduction and MeHg demethylation, but it remains unclear to what extent these processes influence net MeHg production, as well as the role of the microbial guilds involved. We used isotopically labeled Hg species and specific microbial inhibitors in microcosm experiments to simultaneously investigate the rates of Hg(II) and MeHg transformations, as well as the key microbial guilds controlling these processes. Results showed that Hg(II) and MeHg reduction rate constants significantly decreased with addition of molybdate or BES, which inhibit sulfate-reduction and methanogenesis, respectively. This suggests that both sulfate-reduction and methanogenesis are important processes controlling Hg(II) and MeHg reduction in rice paddies. Meanwhile, up to 99% of MeHg demethylation was oxidative demethylation (OD) under the incubation conditions, suggesting that OD was the main MeHg degradative pathway in rice paddies. In addition, [202Hg(0)/Me202Hg] from the added 202Hg(NO3)2 was up to 13.9%, suggesting that Hg(II) reduction may constrain Hg(II) methylation in rice paddies at the abandoned Hg mining site. This study improves our understanding of Hg cycling pathways in rice paddies, and more specifically how reduction processes affect net MeHg production and related microbial metabolisms.
Asunto(s)
Mercurio , Compuestos de Metilmercurio , Oryza , Humanos , Desmetilación , SulfatosRESUMEN
The surface ozone (O3) spatiotemporal distribution, variations, and its causes in Ji'nan from 2015 to 2020 were revealed based on the air quality monitoring network data and satellite retrievals from the Ozone Monitoring Instrument (OMI). The results showed that the ozone concentration in Ji'nan gradually increased from 2015 to 2020. The annual 90th percentile of the daily maximum 8-h average (MDA8) O3(namely the annual evaluation value) and the MDA8 O3(April-September) increased by 4.8 µg·(m3·a)-1 and 3.8 µg·(m3·a)-1, respectively. The trend of the ozone levels in the high-concentration range increased faster than that in the low-concentration range. The MDA8 in June increased by 7.4 µg·(m3·a)-1, and the rate range of increases was 2.6-3.9 µg·(m3·a)-1 in the cool seasons (December-February); thus, the O3 control in winter cannot be ignored. It is apparent from the diurnal variations in ozone from 2015 to 2020 in April-September that the average ozone levels have risen in recent years. The growth rate in the daytime was higher than that at night. The capacity of photochemical production has been increasing, especially in recent years. Additionally, it is noteworthy that the peak time for ozone levels occurred approximately 1-2 h earlier. The disparity of ozone concentrations among different stations gradually decreased in recent years. Compared with that in 2015, the range of areas with high O3 concentrations in 2019-2020 was further expanded. The significant positive trends in MDA8-90th and MDA8 (April-September) were observed in 16.1% and 22.6% of the monitoring sites in Ji'nan (P<0.05), most of which were located in urban areas and the suburbs close to urban areas. The temporal and spatial changes in ozone in Jinan had been affected by the changes in VOCs and NOx emissions since 2015. Satellite remote sensing data from 2015 to 2020 revealed that the NO2 tropospheric columns (April-September) showed reductions of 20.6%, with a decreasing rate of 0.3×1015 mole·(cm2·a)-1, especially in the urban areas and suburbs. The detected variation trends of tropospheric HCHO were weak and insignificant, which suggested that the decrease in NOx emissions was much greater than the decrease in VOCs emissions, and the gap had become more obvious in the urban areas. With responses to precursor emissions, the chemical sensitivity of O3 formation had been changing. The VOCs-limited regimes continuously decreased, and the mixed NOx/VOCs-sensitive regimes and NOx-limited regimes increased. In general, such an extremely inappropriate control ratio of ozone precursor NOx/VOCs led to an overall trend of slow increasing fluctuations of O3 in Ji'nan. The findings clearly indicate that the reduction of VOCs in Ji'nan was far from sufficient, and strengthening the current control of VOCs emissions is an effective measure to control the growth trend of O3 pollution in Ji'nan in the near future, especially in urban and surrounding suburban areas.