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Initiation of eukaryotic chromosome replication follows a spatiotemporal program. The current model suggests that replication origins compete for a limited pool of initiation factors. However, it remains to be answered how these limiting factors are preferentially recruited to early origins. Here, we report that Dbf4 is enriched at early origins through its interaction with forkhead transcription factors Fkh1 and Fkh2. This interaction is mediated by the Dbf4 C terminus and was successfully reconstituted in vitro. An interaction-defective mutant, dbf4ΔC, phenocopies fkh alleles in terms of origin firing. Remarkably, genome-wide replication profiles reveal that the direct fusion of the DNA-binding domain (DBD) of Fkh1 to Dbf4 restores the Fkh-dependent origin firing but interferes specifically with the pericentromeric origin activation. Furthermore, Dbf4 interacts directly with Sld3 and promotes the recruitment of downstream limiting factors. These data suggest that Fkh1 targets Dbf4 to a subset of noncentromeric origins to promote early replication in a manner that is reminiscent of the recruitment of Dbf4 to pericentromeric origins by Ctf19.
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Proteínas de Ciclo Celular/metabolismo , Factores de Transcripción Forkhead/metabolismo , Origen de Réplica/fisiología , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Ciclo Celular/genética , Replicación del ADN/genética , Proteínas de Unión al ADN/metabolismo , Genoma Fúngico/genética , Mutación , Proteínas Nucleares/metabolismo , Transporte de Proteínas , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Origen de Réplica/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
BACKGROUND & AIMS: NOTCH signaling in liver sinusoidal endothelial cells (LSECs) regulates liver fibrosis, a pathological feature of chronic liver diseases. POFUT1 is an essential regulator of NOTCH signaling. Here, we investigated the role of LSEC-expressed POFUT1 in liver fibrosis. METHODS: Endothelial-specific Pofut1 knockout mice were generated and experimental liver fibrosis was induced by chronic carbon tetrachloride exposure or common bile duct ligation. Liver samples were assessed by ELISA, histology, electron microscopy, immunostaining and RNA in situ hybridization. LSECs and hepatic stellate cells (HSCs) were isolated for gene expression analysis by RNA sequencing, qPCR, and western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSEC cultures. Liver single-cell RNA sequencing datasets from patients with cirrhosis and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies. RESULTS: POFUT1 loss promoted injury-induced LSEC capillarization and HSC activation, leading to aggravated liver fibrosis. RNA sequencing analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of patients with cirrhosis. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to those treated with supernatant from control LSECs, and this effect was attenuated by knockdown of fibrinogen or by pharmacological inhibition of fibrinogen receptor signaling, altogether suggesting that LSEC-derived fibrinogen induced the activation of HSCs. Mechanistically, POFUT1 loss augmented fibrinogen expression by enhancing NOTCH/HES1/STAT3 signaling. CONCLUSIONS: Endothelial POFUT1 prevents injury-induced liver fibrosis by repressing the expression of fibrinogen, which functions as a profibrotic paracrine signal to activate HSCs. Therapies targeting the POFUT1/fibrinogen axis offer a promising strategy for the prevention and treatment of fibrotic liver diseases. IMPACT AND IMPLICATIONS: Paracrine signals produced by liver vasculature play a major role in the development of liver fibrosis, which is a pathological hallmark of most liver diseases. Identifying those paracrine signals is clinically relevant in that they may serve as therapeutic targets. In this study, we discovered that genetic deletion of Pofut1 aggravated experimental liver fibrosis in mouse models. Moreover, fibrinogen was identified as a downstream target repressed by Pofut1 in liver endothelial cells and functioned as a novel paracrine signal that drove liver fibrosis. In addition, fibrinogen was found to be relevant to cirrhosis and may serve as a potential therapeutic target for this devastating human disease.
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Células Endoteliales , Fibrinógeno , Células Estrelladas Hepáticas , Cirrosis Hepática , Ratones Noqueados , Animales , Humanos , Masculino , Ratones , Tetracloruro de Carbono/toxicidad , Tetracloruro de Carbono/efectos adversos , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Fibrinógeno/metabolismo , Fibrinógeno/biosíntesis , Fibrinógeno/genética , Células Estrelladas Hepáticas/metabolismo , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/genética , Receptores Notch/metabolismo , Receptores Notch/fisiología , Transducción de SeñalRESUMEN
This study aims to explore the impact and underlying mechanism of sulforaphane (SFN) intervention on the migration and invasion of lung adenocarcinoma induced by 7, 8-dihydroxy-9, 10-epoxy-benzo (a) pyrene (BPDE). Human lung adenocarcinoma A549 cells were exposed to varying concentrations of BPDE (0.25, 0.50, and 1.00 µM) and subsequently treated with 5 µM SFN. Cell viability was determined using CCK8 assay, while migration and invasion were assessed using Transwell assays. Lentivirus transfection was employed to establish NLRP12 overexpressing A549 cells. ELISA was utilized to quantify IL-33, CXCL12, and CXCL13 levels in the supernatant, while quantitative real-time PCR (qRT-PCR) and Western Blot were used to analyze the expression of NLRP12 and key factors associated with canonical and non-canonical NF-κB pathways. Results indicated an increase in migratory and invasive capabilities, concurrent with heightened expression of IL-33, CXCL12, CXCL13, and factors associated with both canonical and non-canonical NF-κB pathways. Moreover, mRNA and protein levels of NLRP12 were decreased in BPDE-stimulated A549 cells. Subsequent SFN intervention attenuated BPDE-induced migration and invasion of A549 cells. Lentivirus-mediated NLRP12 overexpression not only reversed the observed phenotype in BPDE-induced cells but also led to a reduction in the expression of critical factors associated with both canonical and non-canonical NF-κB pathways. Collectively, we found that SFN could inhibit BPDE-induced migration and invasion of A549 cells by upregulating NLRP12, thereby influencing both canonical and non-canonical NF-κB pathways.
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Adenocarcinoma del Pulmón , Movimiento Celular , Isotiocianatos , Neoplasias Pulmonares , Invasividad Neoplásica , Sulfóxidos , Humanos , Isotiocianatos/farmacología , Sulfóxidos/farmacología , Movimiento Celular/efectos de los fármacos , Células A549 , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/toxicidad , Anticarcinógenos/farmacología , FN-kappa B/metabolismo , Supervivencia Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
Nitrous oxide (N2O) emissions from livestock manure contribute significantly to the growth of atmospheric N2O, a powerful greenhouse gas and dominant ozone-depleting substance. Here, we estimate global N2O emissions from livestock manure during 1890-2020 using the tier 2 approach of the 2019 Refinement to the 2006 IPCC Guidelines. Global N2O emissions from livestock manure increased by ~350% from 451 [368-556] Gg N year-1 in 1890 to 2042 [1677-2514] Gg N year-1 in 2020. These emissions contributed ~30% to the global anthropogenic N2O emissions in the decade 2010-2019. Cattle contributed the most (60%) to the increase, followed by poultry (19%), pigs (15%), and sheep and goats (6%). Regionally, South Asia, Africa, and Latin America dominated the growth in global emissions since the 1990s. Nationally, the largest emissions were found in India (329 Gg N year-1), followed by China (267 Gg N year-1), the United States (163 Gg N year-1), Brazil (129 Gg N year-1) and Pakistan (102 Gg N year-1) in the 2010s. We found a substantial impact of livestock productivity, specifically animal body weight and milk yield, on the emission trends. Furthermore, a large spread existed among different methodologies in estimates of global N2O emission from livestock manure, with our results 20%-25% lower than those based on the 2006 IPCC Guidelines. This study highlights the need for robust time-variant model parameterization and continuous improvement of emissions factors to enhance the precision of emission inventories. Additionally, urgent mitigation is required, as all available inventories indicate a rapid increase in global N2O emissions from livestock manure in recent decades.
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Ganado , Estiércol , Óxido Nitroso , Óxido Nitroso/análisis , Estiércol/análisis , Animales , Contaminantes Atmosféricos/análisisRESUMEN
INTRODUCTION: Owing to the antioxidant and anti-inflammatory effects, flavonoids can influence the initiation and development of atherosclerosis, but the underlying mechanisms remain largely undetermined. This study aimed to evaluate the associations between dietary flavonoids and carotid calcification in patients with ischemic stroke. METHODS: This study screened consecutive patients with ischemic stroke via Nanjing Stroke Registry Program from February 2016 to April 2021. A semiquantitative food frequency questionnaire was used to evaluate dietary consumption of flavonoids and other nutritional components. Presence and degree of carotid calcification were determined according to Agatston scores on computer tomography angiography. Logistic regression was performed to evaluate the association between dietary flavonoids (total flavonoids, flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, and isoflavones) and carotid calcification. RESULTS: Of the 601 enrolled patients, 368 (61.2%) were detected with carotid calcification. Patients with high intake of total flavonoids (the fifth quintile) had a 52% lower carotid calcification risk than those with low intake (the first quintile; odds ratio [OR] = 0.48; 95% confidence interval [CI], 0.26-0.90; p = 0.007 for trends) after adjusting for major confounders. Patients with high intake of flavan-3-ols (the fifth quintile) had a 51% lower carotid calcification risk than those with low intake (the first quintile; OR = 0.49; 95% CI, 0.25-0.97; p = 0.016 for trends). CONCLUSION: Dietary flavonoid intake is associated with carotid calcification, and, therefore, may influence the risk of stroke occurrence and recurrence.
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Flavonas , Accidente Cerebrovascular Isquémico , Humanos , Flavonoides/efectos adversos , Antocianinas , Flavonoles , Dieta/efectos adversos , Polifenoles , Factores de RiesgoRESUMEN
BACKGROUND AND PURPOSE: Microbial infection has been associated with thrombogenesis. This study aimed to detect bacterium-specific genes and other signatures in thrombi from patients with acute ischemic stroke and to relate these signatures to clinical characteristics. METHODS: Blood samples were collected before thrombectomy procedures, and thrombus samples were obtained during the procedure. Identification and classification of bacteria in the samples were accomplished using 16 S rRNA gene sequencing. Bacterium-specific structures were observed with transmission electron microscopy. Bacterium-specific biomarkers were detected through immunohistochemical staining. RESULTS: 16 S rRNA gene was detected in 32.1% of the thrombus samples from 81 patients. Bacillus (0.04% vs. 0.00046%, p = 0.003), Parabacteroides (0.20% vs. 0.09%, p = 0.029), Prevotella (1.57% vs. 0.38%, p = 0.010), Streptococcus (1.53% vs. 0.29%, p = 0.001), Romboutsia (0.18% vs. 0.0070%, p = 0.029), Corynebacterium (1.61% vs. 1.26%, p = 0.026) and Roseburia (0.53% vs. 0.05%, p = 0.005) exhibited significantly higher abundance in thrombi compared to arterial blood. Bacteria-like structures were observed in 22 (27.1%), while whole bacteria-like structures were observed in 7 (8.6%) thrombi under transmission electron microscopy. Immunohistochemical staining detected bacterium-specific monocyte/macrophage markers in 51 (63.0%) out of 81 thrombi. Logistic regression analysis indicated that alcohol consumption was associated with a higher bacteria burden in thrombi (odds ratio = 3.19; 95% CI, 1.10-9.27; p = 0.033). CONCLUSION: Bacterial signatures usually found in the oral cavity and digestive tract were detected in thrombi from patients with ischemic stroke. This suggests a potential involvement of bacterial infection in the development of thrombosis. Long-term alcohol consumption may potentially enhance this possibility.
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Dwarf bamboo (Indocalamus decorus) is an O3-tolerant plant species. To identify the possible mechanism and response of leaf morphological, antioxidant, and anatomical characteristics to elevated atmospheric O3 (EO3) concentrations, we exposed three-year-old I. decorus seedlings to three O3 levels (low O3-LO: ambient air; medium O3-MO: Ambient air+70 ppb high O3-HO: Ambient air+140 ppb O3) over a growing season using open-top chambers. Leaf shape and stomatal characteristics, and leaf microscopic structure of I. decorus were examined. The results indicated that 1) the stomata O3 flux (Fst) of HO decreased more rapidly under EO3 as the exposure time increased. The foliar O3 injury of HO and MO occurred when AOT40 was 26.62 ppm h and 33.20 ppm h, respectively, 2) under EO3, leaf number, leaf mass per area, leaf area, and stomata length/width all decreased, while leaf thickness, stomatal density, width, and area increased compared to the control, 3) MDA and total soluble protein contents all showed significantly increase under HO (36.57% and 32.77%) and MO(31.91% and 19.52%) while proline contents only increased under HO(33.27%). 4) MO and HO increased bulliform cells numbers in the leaves by 6.28% and 23.01%, respectively. HO reduced the transverse area of bulliform cells by 13.73%, while MO treatments had no effect, and 5) the number of fusoid cells interspace, the transverse area of fusoid cells interspace, and mesophyll thickness of HO significantly increased by 11.16%, 28.58%, and 13.42%, respectively. In conclusion, I. decorus exhibits strong O3 tolerance characteristics, which stem from adaptions in the leaf's morphological, structural, antioxidant, and anatomical features. One critical attribute was the enlargement of the bulliform cell transverse area and the transverse area of fusoid cells interspace that drove this resistance to O3. Local bamboo species with high resistance to O3 pollution thus need to be promoted for sustained productivity and ecosystem services in areas with high O3 pollution.
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Contaminantes Atmosféricos , Ozono , Hojas de la Planta , Hojas de la Planta/anatomía & histología , Hojas de la Planta/efectos de los fármacos , Ozono/toxicidad , Contaminantes Atmosféricos/toxicidad , Contaminantes Atmosféricos/análisis , Poaceae/efectos de los fármacos , Poaceae/anatomía & histología , Estomas de Plantas/efectos de los fármacos , Estomas de Plantas/anatomía & histologíaRESUMEN
The increasing production and prevalence of antimony (Sb)-related products raise concerns regarding its potential hazards to reproductive health. Upon environmental exposure, Sb reportedly induces testicular toxicity during spermatogenesis; moreover, it is known to affect various testicular cell populations, particularly germline stem cell populations. However, the cell-cell communication resulting from Sb exposure within the testicular niche remains poorly understood. To address this gap, herein we analyzed testicular single-cell RNA sequencing data from Sb-exposed Drosophila. Our findings revealed that the epidermal growth factor receptor (EGFR) and WNT signaling pathways were associated with the stem cell niche in Drosophila testes, which may disrupt the homeostasis of the testicular niche in Drosophila. Furthermore, we identified several ligand-receptor pairs, facilitating the elucidation of intercellular crosstalk involved in Sb-mediated reproductive toxicology. We employed scRNA-seq analysis and conducted functional verification to investigate the expression patterns of core downstream factors associated with EGFR and WNT signatures in the testes under the influence of Sb exposure. Altogether, our results shed light on the potential mechanisms of Sb exposure-mediated testicular cell-lineage communications.
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Drosophila , Testículo , Masculino , Animales , Testículo/metabolismo , Drosophila/metabolismo , Antimonio/toxicidad , Antimonio/metabolismo , Comunicación Celular , Receptores ErbB/metabolismo , Análisis de Secuencia de ARNRESUMEN
The effects of volatile organic compounds on urban air quality and the ozone have been widely acknowledged, and the contributions of relevant biogenic sources are currently receiving rising attentions. However, inventories of biogenic volatile organic compounds (BVOCs) are in fact limited for the environmental management of megacities. In this study, we provided an estimation of BVOC emissions and their spatial characteristics in a typical urbanized area, Shenzhen megacity, China, based on an in-depth vegetation investigation and using remote sensing data. The total BVOC emission in Shenzhen in 2019 was estimated to be 3.84 × 109 g C, of which isoprene contributed to about 24.4%, monoterpenes about 44.4%, sesquiterpenes about 1.9%, and other VOCs (OVOCs) about 29.3%. Metropolitan BVOC emissions exhibited a seasonal pattern with a peak in July and a decline in January. They were mainly derived from the less built-up areas (88.9% of BVOC emissions). Estimated BVOCs comprised around 5.2% of the total municipal VOC emissions in 2019. This percentage may increase as more green spaces emerge and anthropogenic emissions decrease in built-up areas. Furthermore, synergistic effects existed between BVOC emissions and relevant vegetation-based ecosystem services (e.g., air purification, carbon fixation). Greening during urban sprawl should be based on a trade-off between BVOC emissions and ecosystem benefits of urban green spaces. The results suggested that urban greening in Shenzhen, and like other cities as well, need to account for BVOC contributions to ozone. Meanwhile, greening cites should adopt proactive environmental management by using plant species with low BVOC emissions to maintain urban ecosystem services while avoid further degradation to ozone pollution.
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Contaminantes Atmosféricos , Ozono , Compuestos Orgánicos Volátiles , Compuestos Orgánicos Volátiles/análisis , Contaminantes Atmosféricos/análisis , Árboles/metabolismo , Ecosistema , Monitoreo del Ambiente , ChinaRESUMEN
Ecological restoration projects (ERPs) are an indispensable component of natural climate solutions and have proven to be very important for reversing environmental degradation in vulnerable regions and enhancing ecosystem services. However, the level of enhancement would be inevitably influenced by global drought and rising CO2 , which remain less investigated. In this study, we took the Beijing-Tianjin sand source region (which has experienced long-term ERPs), China, as an example and combined the process-based Biome-BGCMuSo model to set multiple scenarios to address this issue. We found ERP-induced carbon sequestration (CS), water retention (WR), soil retention (SR), and sandstorm prevention (SP) increased by 22.21%, 2.87%, 2.35%, and 28.77%, respectively. Moreover, the ecosystem services promotion from afforestation was greater than that from grassland planting. Approximately 91.41%, 98.13%, and 64.51% of the increased CS, SR, and SP were contributed by afforestation. However, afforestation also caused the WR to decline. Although rising CO2 amplified ecosystem services contributed by ERPs, it was almost totally offset by drought. The contribution of ERPs to CS, WR, SR, and SP was reduced by 5.74%, 32.62%, 11.74%, and 14.86%, respectively, under combined drought and rising CO2 . Our results confirmed the importance of ERPs in strengthening ecosystem services provision. Furthermore, we provide a quantitative way to understand the influence rate of drought and rising CO2 on ERP-induced ecosystem service dynamics. In addition, the considerable negative climate change impact implied that restoration strategies should be optimized to improve ecosystem resilience to better combat negative climate change impacts.
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Dióxido de Carbono , Ecosistema , Sequías , China , Beijing , Suelo , Cambio ClimáticoRESUMEN
INTRODUCTION: Endothelial dysfunction (ED) may result in parenchymal injury and therefore worsen the outcomes of ischemic stroke. This study aimed to determine whether ED could predict parenchymal hematoma (PH) in ischemic stroke patients treated with endovascular thrombectomy (EVT). METHODS: Patients with large artery occlusion in the anterior circulation and treated with EVT were prospectively enrolled from 2 stroke centers. Serum soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, soluble E-selectin, and von Willebrand factor (vWF) were tested and summed to a standardized score to reflect the levels of ED. PH was diagnosed according to the Heidelberg Bleeding Classification. RESULTS: Of the 325 enrolled patients (mean age, 68.6 years; 207 men), 41 (12.6%) developed PH. Patients with PH had higher concentrations of soluble E-selectin, vWF, and ED sum score. After adjusting for demographic characteristics, National Institutes of Health Stroke Scale score, pretreatment Alberta stroke program early computed tomography score, and other potential confounders, the increased ED burden was associated with PH (odds ratio, 1.432; 95% confidence interval, 1.031-1.988; p = 0.032). Similar significant results were found in the sensitivity analysis. The multiple-adjusted spline regression model showed a linear association between the total ED score and PH (p = 0.001 for linearity). Adding the ED score to the conventional model significantly improved the risk prediction of PH (net reclassification improvement = 25.2%, p = 0.001; integrated discrimination index = 2.9%; p = 0.001). CONCLUSIONS: This study demonstrated that ED might be related to PH. Introducing the ED score could increase the reliability of the PH risk model for stroke patients treated with EVT.
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Isquemia Encefálica , Procedimientos Endovasculares , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Masculino , Humanos , Anciano , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/terapia , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/terapia , Selectina E , Reproducibilidad de los Resultados , Factor de von Willebrand , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/terapia , Trombectomía/efectos adversos , Trombectomía/métodos , Hematoma/etiología , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Acute kidney injury (AKI) refers to a tricky clinical disease, known by its high morbidity and mortality, with no real specific medicine for AKI. The carbonization product from Pollen Typhae (i.e., Pu-huang in China) has been extensively employed in clinic, and it is capable of relieving the renal damage and other diseases in China since acient times. RESULTS: Inspired by the carbonization process of Traditional Chinese Medicine (TCM), a novel species of carbon dots derived from Pollen Typhae (PT-CDs) was separated and then collected using a one-pot pyrolysis method. The as-prepared PT-CDs (4.85 ± 2.06 nm) with negative charge and abundant oxygenated groups exhibited high solubility, and they were stable in water. Moreover, the rhabdomyolysis (RM)-induced AKI rat model was used, and it was first demonstrated that PT-CDs had significant activity in improving the level of BUN and CRE, urine volume and kidney index, and histopathological morphology in RM-induced AKI rats. It is noteworthy that interventions of PT-CDs significantly reduced degree of inflammatory reaction and oxidative stress, which may be correlated with the basial potential mechanism of anti-AKI activities. Furthermore, cytotoxicity assay and biosafety evaluation exhibited high biocompatibility of PT-CDs. CONCLUSION: This study offers a novel relieving strategy for AKI based on PT-CDs and suggests its potential to be a related candidate for clinical applications.
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Lesión Renal Aguda , Rabdomiólisis , Ratas , Animales , Carbono/farmacología , Ratas Sprague-Dawley , Lesión Renal Aguda/patología , Riñón/patología , Rabdomiólisis/patologíaRESUMEN
Most cells involved in atherosclerosis release extracellular vesicles (EVs), which can carry bioactive substances to downstream tissues via circulation. We hypothesized that EVs derived from atherosclerotic plaques could promote atherogenesis in remote locations, a mechanism that mimics the blood metastasis of cancer. Ldlr gene knockout (Ldlr KO) rats were fed on a high cholesterol diet and underwent partial carotid ligation to induce local atherosclerosis. EVs were separated from carotid artery tissues and downstream blood of carotid ligation by centrifugation. MiRNA sequencing and qPCR were then performed to detect miRNA differences in EVs from rats with and without induced carotid atherosclerosis. Biochemical analyses demonstrated that EVs derived from atherosclerosis could increase the expression of ICAM-1, VCAM-1, and E-selectin in endothelial cells in vitro. EVs derived from atherosclerosis contained a higher level of miR-23a-3p than those derived from controls. MiR-23a-3p could promote endothelial inflammation by targeting Dusp5 and maintaining ERK1/2 phosphorylation in vitro. Inhibiting EV release could attenuate atherogenesis and reduce macrophage infiltration in vivo. Intravenously administrating atherosclerotic plaque-derived EVs could induce intimal inflammation, arterial wall thickening and lumen narrowing in the carotids of Ldlr KO rats, while simultaneous injection of miR-23a-3p antagomir could reverse this reaction. The results suggested that EVs may transfer atherosclerosis to remote locations by carrying proinflammatory factors, particularly miR-23a-3p.
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Aterosclerosis , Vesículas Extracelulares , MicroARNs , Placa Aterosclerótica , Animales , Antagomirs/metabolismo , Aterosclerosis/metabolismo , Células Endoteliales/metabolismo , Vesículas Extracelulares/metabolismo , Inflamación/patología , MicroARNs/genética , MicroARNs/metabolismo , Placa Aterosclerótica/metabolismo , RatasRESUMEN
Casposase, a homolog of Cas1 integrase, is encoded by a superfamily of mobile genetic elements known as casposons. While family 2 casposase has been well documented in both function and structure, little is known about the other three casposase families. Here, we studied the family 1 casposase lacking the helix-turn-helix (HTH) domain from Candidatus Nitrosopumilus koreensis AR1 (Ca. N. koreensis). The determinants for integration by Ca. N. koreensis casposase were extensively investigated, and it was found that a 13-bp target site duplication (TSD) sequence, a minimal 3-bp leader and three different nucleotides of the TSD sequences are indispensable for target specific integration. Significantly, the casposase can site-specifically integrate a broad range of terminal inverted repeat (TIR)-derived oligonucleotides ranging from 7-nt to â¼4000-bp, and various oligonucleotides lacking the 5'-TTCTA-3' motif at the 3' end of TIR sequence can be integrated efficiently. Furthermore, similar to some Cas1 homologs, the casposase utilizes a 5'-ATAA-3' motif in the TSD as a molecular ruler to dictate nucleophilic attack at 9-bp downstream of the end of the ruler during the spacer-side integration. By characterizing the family 1 Ca. N. koreensis casposase, we have extended our understanding on mechanistic similarities and evolutionary connections between casposons and the adaptation elements of CRISPR-Cas immunity.
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Proteínas Asociadas a CRISPR/genética , Integrasas/genética , Integrasas/metabolismo , Secuencias Repetidas Terminales/genética , Archaea/genética , Sistemas CRISPR-Cas/genética , Elementos Transponibles de ADN/genética , Secuencias Hélice-Giro-Hélice/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Oligonucleótidos/genéticaRESUMEN
BACKGROUND: In calcaneal fractures, the percutaneous screw fixation (PSF) is currently considered to be the better choice, but it is difficult to accurately place the screw into the sustentaculum tali (ST) during the operation. In this study, the ideal entry point, angle, diameter and length of the screw were calculated by simulating the operation process. METHODS: We retrospectively collected the calcaneus computed tomography (CT) scans of 180 adults, DICOM-formatted CT-scan images of each patient were imported into Mimics software to establish calcaneus model. Virtual screws were placed on the lateral of the posterior talar articular surface (PTAS), the lateral edge of the anterior process of calcaneus (APC), and the calcaneal tuberosity, respectively, the trajectory and size of the screws were calculated. RESULTS: The mean maximum diameter of the PTAS screw was 42.20 ± 3.71 mm. The vertical distance between the midpoint of the APC optimal screw trajectory and the lowest point of the tarsal sinus was 10.67 ± 1.84 mm, and the distance between the midpoint of the APC optimal screw trajectory and the calcaneocuboid joint was 5 mm ~ 19.81 ± 2.08 mm. The mean maximum lengths of APC screws was 44.69 ± 4.81 mm, and the Angle between the screw and the coronal plane of the calcaneus from proximal to distal was 4.72°±2.15° to 20.52°±3.77°. The optimal point of the maximum diameter of the calcaneal tuberosity screw was located at the lateral border of the achilles tendon endpoint. The mean maximum diameters of calcaneal tuberosity screws was 4.46 ± 0.85 mm, the mean maximum lengths of screws was 65.31 ± 4.76 mm. We found gender-dependent differences for the mean maximum diameter and the maximum length of the three screws. CONCLUSIONS: The study provides effective positioning for percutaneous screw fixation of calcaneal fractures. For safer and more efficient screw placement, we suggest individualised preoperative 3D reconstruction simulations. Further biomechanical studies are needed to verify the function of the screw.
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Traumatismos del Tobillo , Calcáneo , Fracturas Óseas , Adulto , Humanos , Calcáneo/diagnóstico por imagen , Calcáneo/cirugía , Estudios Retrospectivos , Fijación Interna de Fracturas/métodos , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/cirugía , Tornillos ÓseosRESUMEN
Urbanization-induced phenological changes have received considerable attention owing to their implications for determining urban ecosystem productivity and predicting the response of plants and ecosystem carbon cycles to future climate change. However, inconsistent rural-urban gradients in plant phenology remain, and phenological drivers other than temperature are poorly understood. In this study, we simultaneously observed the micro-climate and spring leaf phenology of seven woody plant species at 13 parks along a rural-urban gradient in Beijing, China. The minimum (Tmin) and mean (Tmean) air temperature and the minimum (VPDmin) and mean (VPDmean) vapor pressure deficit increased significantly along the rural-urban gradient, but the maximum air temperature (Tmax) and maximum vapor pressure deficit (VPDmax) did not. All observed leaf phenological phases for the seven species were significantly advanced along the rural-urban gradient by 0.20 to 1.02 days/km. Advances in the occurrence of leaf phenological events were significantly correlated with increases in Tmean (accounting for 57-59% variation), Tmin (21-26%), VPDmin (12-16%), and VPDmean (3-5%), but not with changes in Tmax or VPDmax. Advances in spring leaf phenology along the rural-urban gradient differed between non-native species and native species and between shrubs and trees. The reason may be mainly that the sensitivities of spring leaf phenology to micro-climate differ with species origin and growth form. This study highlights that urbanization-induced increases in Tmean and Tmin are the major contributors to advances in spring leaf phenology along the rural-urban gradient, exerting less influence on native species than on non-native species.
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Ecosistema , Árboles , Beijing , Temperatura , Estaciones del Año , Plantas , Hojas de la Planta , Cambio ClimáticoRESUMEN
Today, cardiovascular diseases threaten human health worldwide. In clinical practice, it has been concluded that analyzing the pulse waveform can provide clinically valuable information for the diagnosis of cardiovascular diseases. Accordingly, continuous and accurate monitoring of the pulse wave is essential for the prevention and detection of cardiovascular diseases. Wearable triboelectric nanogenerators (TENGs) are emerging as a pulse wave monitoring biotechnology due to their compelling characteristics, including being self-powered, light-weight, and wear-resistant, as well as featuring user-friendliness and superior sensitivity. Herein, a comprehensive review is conducted on the progress of wearable TENGs for pulse wave monitoring. Firstly, the four modes of operation of TENG are briefly described. Secondly, TENGs for pulse wave monitoring are classified into two categories, namely wearable flexible film-based TENG sensors and textile-based TENG sensors. Next, the materials, fabrication methods, working mechanisms, and experimental performance of various TENG-based sensors are summarized. It concludes by comparing the characteristics of the two types of TENGs and discussing the potential development and challenges of TENG-based sensors in the diagnosis of cardiovascular diseases and personalized healthcare.
Asunto(s)
Enfermedades Cardiovasculares , Dispositivos Electrónicos Vestibles , Humanos , Enfermedades Cardiovasculares/diagnóstico , Frecuencia Cardíaca , Biotecnología , Monitoreo FisiológicoRESUMEN
Sphingolipids are the structural components of membrane lipid bilayers and act as signaling molecules in many cellular processes. Serine palmitoyltransferase (SPT) is the first committed and rate-limiting enzyme in the de novo sphingolipids biosynthetic pathway. The core SPT enzyme is a heterodimer consisting of LONG-CHAIN BASE1 (LCB1) and LCB2 subunits. SPT activity is inhibited by orosomucoid proteins and stimulated by small subunits of SPT (ssSPTs). However, whether LCB1 is modified and how such modification might regulate SPT activity have to date been unclear. Here, we show that activation of MITOGEN-ACTIVATED PROTEIN KINASE 3 (MPK3) and MPK6 by upstream MKK9 and treatment with Flg22 (a pathogen-associated molecular pattern) increases SPT activity and induces the accumulation of sphingosine long-chain base t18:0 in Arabidopsis thaliana, with activated MPK3 and MPK6 phosphorylating AtLCB1. Phosphorylation of AtLCB1 strengthened its binding with AtLCB2b, promoted its binding with ssSPTs, and stimulated the formation of higher order oligomeric and active SPT complexes. Our findings therefore suggest a novel regulatory mechanism for SPT activity.
Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Serina C-Palmitoiltransferasa/metabolismo , Arabidopsis/metabolismo , Fosforilación , Esfingolípidos/metabolismo , Proteínas/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas de Arabidopsis/metabolismoRESUMEN
Here, we report the synthesis of two-dimensional (2D) layered metal-organic framework (MOF) nanoparticle (NP) superstructures via an ice-templating strategy. MOF NP monolayers and bilayers can be obtained by regulating the concentration of colloidal MOF NPs without any external fields during self-assembly. Adjacent polyhedral MOF NPs are packed and aligned through crystalline facets, resulting in the formation of a quasi-ordered array superstructure. The morphology of the MOF layers is well preserved when subjected to pyrolysis, and the obtained carbon NPs have hollow interiors driven by the outward contraction of MOF precursors during pyrolysis. With the advantages of large surface areas, hierarchical porosity, high exposure of active sites, and fast electron transport of the 2D layered structure, the mono- and bilayered carbon NP superstructures show better oxygen reduction activity than isolated carbon particles in alkaline media. Our work demonstrates that ice-templating is a powerful strategy to fabricate superstructures of various MOFs and their derivatives.
RESUMEN
As a group of typical endocrine disrupters, phthalates are simultaneously present in a variety of environmental media and enter human body through multiple exposure pathways. In this study, field monitoring data were used to characterize the skin-air (Klg ), dust-air (Kd ), and PM2.5 -air (Kp ) partition coefficients of DiBP, DnBP, and DEHP. The median values of log(Klg ) in the summer and winter were 7.654 and 7.932, 7.265 and 7.902, 9.419 and 9.015 for DiBP, DnBP, and DEHP, respectively, and Klg was significantly higher in the winter. The median Kd (m3 /mg) in the summer (0.036-0.151 for DiBP, 0.021-0.036 for DnBP and 1.479-4.069 for DEHP) were significantly higher than the counterparts in the winter (0.027-0.065 for DiBP, 0.022-0.245 for DnBP, and 0.140-3.250 for DEHP). In addition, Kd was associated with material of surface and residence time of dust. The Kp values (m3 /µg) of DiBP, DnBP, and DEHP in the summer (0.053, 0.015, and 0.021) were also significantly higher than the counterparts in the winter (0.011, 0.004, and 0.025). The partition of phthalates was influenced by built environment, such as temperature, humidity, ventilation, indoor chemistry, smoking, and building age. Except Klg , there was substantial discrepancy between the estimates of K with empirical equations and the values of K based on field monitoring data in our study.