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The tree shrew ( Tupaia belangeri) has long been proposed as a suitable alternative to non-human primates (NHPs) in biomedical and laboratory research due to its close evolutionary relationship with primates. In recent years, significant advances have facilitated tree shrew studies, including the determination of the tree shrew genome, genetic manipulation using spermatogonial stem cells, viral vector-mediated gene delivery, and mapping of the tree shrew brain atlas. However, the limited availability of tree shrews globally remains a substantial challenge in the field. Additionally, determining the key questions best answered using tree shrews constitutes another difficulty. Tree shrew models have historically been used to study hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, myopia, and psychosocial stress-induced depression, with more recent studies focusing on developing animal models for infectious and neurodegenerative diseases. Despite these efforts, the impact of tree shrew models has not yet matched that of rodent or NHP models in biomedical research. This review summarizes the prominent advancements in tree shrew research and reflects on the key biological questions addressed using this model. We emphasize that intensive dedication and robust international collaboration are essential for achieving breakthroughs in tree shrew studies. The use of tree shrews as a unique resource is expected to gain considerable attention with the application of advanced techniques and the development of viable animal models, meeting the increasing demands of life science and biomedical research.

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Investigación Biomédica , Animales , Investigación Biomédica/tendencias , Tupaiidae , Modelos Animales de Enfermedad , Tupaia , Modelos Animales

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OBJECTIVES: Remnant cholesterol (RC) is thought to be an important pathogenic risk factor for atherosclerosis, however, the relationship between RC and acute ischemic stroke (AIS) is still unclear. This study aimed to determine whether fasting blood RC level is an independent risk factor for AIS. MATERIALS AND METHODS: A retrospective analysis was performed on 650 patients with AIS and 598 healthy controls during the same time period. The association between RC and AIS was investigated using binary logistic regression, and the relationship between RC and AIS risk was demonstrated using Restricted Cubic Splines (RCS). RESULTS: RC was significantly higher in the AIS group compared with control group, and was an independent risk factor for AIS when the covariates were not adjusted;After adjusting some covariates, RC was still an independent risk factor for AIS. The RCS analysis found the risk was non-linear: when RC concentration was less than 0.69 mol/L, the risk of AIS increased with the elevation of RC, and when RC concentration was more than or equal to 0.69 mol/L, the risk of AIS was insignificant with the elevation of RC. Correlation analysis revealed that RC was associated with diabetes and fasting glucose. Further analysis revealed that the incidence of AIS in diabetic patients increased significantly with the increase of RC, and RCS analysis revealed that the risk of AIS in diabetic patients increased with the increase of RC when RC was more than 1.15 mol/L. CONCLUSIONS: This study confirms RC as an independent risk factor for AIS, which highlights a distinct non-linear association between RC levels and AIS risk. These findings suggest the need for targeted AIS risk assessment strategies, especially in diabetic patients, and underscore the relevance of RC as a biomarker in AIS risk stratification.

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Biomarcadores , Glucemia , Colesterol , Accidente Cerebrovascular Isquémico , Regulación hacia Arriba , Humanos , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/diagnóstico , Anciano , Factores de Riesgo , Biomarcadores/sangre , Colesterol/sangre , Medición de Riesgo , Glucemia/metabolismo , Incidencia , Diabetes Mellitus/sangre , Diabetes Mellitus/epidemiología , Diabetes Mellitus/diagnóstico , Pronóstico

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To control of phosphorus release from soil after farmland inundation around the lake and reservoir， calcium modified biochar （Ca-BC） was prepared using the coprecipitation method. Through X-ray photoelectron spectroscopy （XPS）， X-ray polycrystalline powder diffraction （XRD）， adsorption experiments， and simulated culture experiments， the effects of Ca-based biochar on the fraction of soil phosphorus （P） and its stabilization mechanism were studied. The results showed that the adsorption process of Ca-based modified biochar conformed to Langmuir （R2 = 0.940） and the first-order adsorption kinetic model （R2 = 0.961）， indicating that the P adsorption was a single-layer adsorption dominated by chemical action， and the maximum adsorption capacity was 267.93 mg·g-1. The simulated culture experiment indicated that when the modified biochar was 1%， the exchangeable fraction of phosphorus in the soil decreased from 7.42% to 4.59%. The XRD results demonstrated that Ca3（PO4）2 and hydroxyapatite absorption peaks appeared after adsorbed phosphorus on biochar， which proved that phosphate formed a relatively stable crystal precipitation. As shown in the XPS spectrum analysis， the carbonyl functional groups participated in the phosphorus fixation process， which improved the adsorption capacity of biochar for phosphorus. In general， when the concentration of Ca-based modified biochar was greater than 1%， it had a good fixation capacity for phosphorus release and had potential application value for controlling phosphorus release in soil.

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Objective:To analyze the effect of acidic or alkaline diluents of the direct dilution method on the results of multiple elements measurement in whole blood by inductively coupled plasma mass spectrometry (ICP-MS) and to explore the possibility whether the two diluents can be substituted for each other in elemental measurement results.Methods:A total of 162 human whole blood samples collected from the National Human Biomonitoring Programme in August 2018 were used for dilution with different diluents followed by centrifugation, then the supernatants of the samples were measured by ICP-MS. The methodological characteristics of the two pre-treatment methods including acidic diluent (0.1% nitric acid+0.01% tralatone solution) and alkaline diluent (0.05% n-butanol+0.01% tralatone+1% ammonium hydroxide solution) were evaluated separately. Spearman correlation coefficient analysis was used for the correlation of 19 elements results in whole blood measured by 2 diluents, then, Passing-Bablok linear regression and Bland-Altman plots were used to evaluate the consistency of the 19 elements results in 162 whole blood samples between the two diluents.Results:The methodological data of 19 elements using the two diluents were good, with the limits of quantification (LOQ) of the 19 elements were 0.1-15.8 μg/L for acidic diluents and 0.3-19.2 μg/L for alkaline diluents, and the linear correlation coefficients of the standard curves of the 19 elements using the acidic and alkaline diluents were all≥0.995. Except for strontium, cadmium, tin, and thallium, the recovery percents of the 19 elements were all in the range of 80%-120%, and for all elements the total coefficients of variation of within-and between-run in the acidic and alkaline diluents were 0.5%-12.4%. The correlation coefficients of the two diluents for the measured values of chromium, manganese, cobalt, zinc, copper, arsenic, selenium, strontium, molybdenum, silver, cadmium, antimony, barium, mercury, and lead were relatively strong ( R2>0.8), while the correlation coefficients of vanadium, nickel, tin, and thallium were relatively weak ( R2<0.8). For the vanadium, cadmium, tin, barium, and mercury, 95% confidence intervals of slopes were<1. The 95% confidence intervals of intercepts of chromium, nickel, arsenic, silver, barium, and mercury contain point 0. The Bland-Altman plot showed that vanadium, chromium, arsenic, strontium, silver, cadmium, tin, and mercury have good consistency in using acidic and alkaline diluents. Conclusion:The results of the mean values measured with the 2 diluents differed among different elements and could not be completely substituted.

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This study introduces robust screening methodology for the efficient design of delafossite CuM1-xM'xO2 solid-solution photocatalysts using band-structure engineering. The investigation not only reveals the formation rules for various CuM1-xM'xO2 solid solutions but also highlights the dependence on both lattice compatibility and thermodynamic stability. Moreover, the study uncovers the nonlinear relationship between composition and band gaps in these solid solutions, with the bowing coefficient determined by the substitution constituents. By optimizing the constituent elements of the conduction band edge and adjusting solubility, the band structure of CuM1-xM'xO2 samples can be fine-tuned to the visible light region. Among the examined photocatalysts, CuAl0.5Ga0.5O2 exhibits the highest H2 evolution rate by striking a balance between visible-light absorption and sufficient reduction potential, showing improvements of 28.8 and 6.9 times those of CuAlO2 and CuGaO2, respectively. Additionally, CuGa0.9In0.1O2 demonstrates enhanced electron migration and surpasses CuGaO2 in H2 evolution due to a reduction in the effective mass of photogenerated electrons. These findings emphasize the pivotal role of theoretical predictions in synthesizing CuM1-xM'xO2 solid solutions and underscore the importance of rational substitution constituents in optimizing light absorption, reduction potentials, and effective mass for efficient hydrogen production.

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Chemical oxygen demand (COD) is an important index used to assess organic oxygen consumption pollution. To explore COD composition in the natural water in Baiyangdian Lake, the main composition, source, and influencing factors of oxygen-consuming organic substances in the water body were revealed through physical continuous classification, three-dimensional fluorescence, and other methods. The results showed that the COD of the two waters was affected by dissolved organic substances (protein-like and humus-like organic matters) with size of less than 220 nm (59%-93%), and inorganic substances had little effect on COD. The source of organic matter in overlying water was primarily affected by endophytic vegetation decomposition, sediment release (the release flux of TOC was in the range of 1.55-2.28 mg·(m2·d)-1), and other endogenous sources (biological index>0.8), as well as by land-based sources such as reed platform and artificial pollution (1.4

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Background and Aims: In this study, we aimed to evaluate the diagnostic values of alpha-fetoprotein (AFP), soluble AXL (sAXL), des-γ-carboxy prothrombin (DCP), the aspartate aminotransferase-to-platelet ratio index (APRI), and the gamma-glutamyl transpeptidase-to-platelet ratio (GPR) in hepatocellular carcinoma (HCC) and the possible underlying mechanisms of the correlations between them. Methods: We collected serum samples from 190, 128, and 75 patients with HCC, cirrhosis, and chronic viral hepatitis, and from 82 healthy subjects. Serum levels of AFP, sAXL, and DCP were determined, and APRI and GPR values were calculated. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic value of single and combined biomarkers. Results: We detected significant differences between the HCC group and other groups regarding serum AFP, sAXL, DCP, and APRI levels. GPR significantly differed between the HCC group and other groups, except for the liver cirrhosis group. AFP, sAXL, DCP, APRI, and GPR had positive correlations with each other, and AFP showed a higher area under the curve (AUC) and Youden index values, while APRI and DCP showed the highest sensitivity and specificity. Also, when AFP was combined with sAXL, DCP, APRI, and GRP, the highest AUC (0.911) and a higher net reclassification improvement value were obtained compared with those obtained for the individual biomarkers. Conclusions: AFP, sAXL, DCP, APRI, and GPR are independent risk factors for HCC, and the diagnostic performance of AFP combined with sAXL, DCP, APRI, and GPR for HCC diagnosis was superior to that of the individual biomarkers.

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Synapse loss in medial prefrontal cortex (mPFC) has been implicated in stress-related mood disorders, such as depression. However, the exact effect of synapse elimination in the depression and how it is triggered are largely unknown. Through repeated longitudinal imaging of mPFC in the living brain, we found both presynaptic and postsynaptic components were declined, together with the impairment of synapse remodeling and cross-synaptic signal transmission in the mPFC during chronic stress. Meanwhile, chronic stress also induced excessive microglia phagocytosis, leading to engulfment of excitatory synapses. Further investigation revealed that the elevated complement C3 during the stress acted as the tag of synapses to be eliminated by microglia. Besides, chronic stress induced a reduction of the connectivity between the mPFC and neighbor regions. C3 knockout mice displayed significant reduction of synaptic pruning and alleviation of disrupted functional connectivity in mPFC, resulting in more resilience to chronic stress. These results indicate that complement-mediated excessive microglia phagocytosis in adulthood induces synaptic dysfunction and cortical hypo-connectivity, leading to stress-related behavioral abnormality.

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Microglía , Derrota Social , Ratones , Animales , Sinapsis , Ratones Noqueados , Plasticidad Neuronal

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Purpose: To explore the relationship between blood-brain barrier (BBB) leakage and brain structure in non-brain metastasis lung cancer (LC) by magnetic resonance imaging (MRI) as well as to indicate the possibility of brain metastasis (BM) occurrence. Patients and methods: MRI were performed in 75 LC patients and 29 counterpart healthy peoples (HCs). We used the Patlak pharmacokinetic model to calculate the average leakage in each brain region according to the automated anatomical labeling (AAL) atlas. The thickness of the cortex and the volumes of subcortical structures were calculated using the FreeSurfer base on Destrieux atlas. We compared the thickness of the cerebral cortex, the volumes of subcortical structures, and the leakage rates of BBB, and evaluated the relationships between these parameters. Results: Compared with HCs, the leakage rates of seven brain regions were higher in patients with advanced LC (aLC). In contrast to patients with early LC (eLC), the cortical thickness of two regions was decreased in aLCs. The volumes of twelve regions were also reduced in aLCs. Brain regions with increased BBB penetration showed negative correlations with thinner cortices and reduced subcortical structure volumes (P<0.05, R=-0.2 to -0.50). BBB penetration was positively correlated with tumor size and with levels of the tumor marker CYFRA21-1 (P<0.05, R=0.2-0.70). Conclusion: We found an increase in BBB permeability in non-BM aLCs that corresponded to a thinner cortical thickness and smaller subcortical structure volumes. With progression in LC staging, BBB shows higher permeability and may be more likely to develop into BM.

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The morphological characteristics of Cd, Cr, Cu, Ni, Pb, and Zn in sediments were analyzed using an improved BCR extraction method in four water types of Baiyangdian Lake:watercourse, trench, lake surface, and fish pond. The potential ecological risk index, secondary and primary phases, and risk assessment codes were used to systematically assess the pollution level and ecological risk of heavy metals in surface sediments. The results showed that:① the mean contents of heavy metals Cd, Cu, and Zn in the sediments were 0.37, 28.49, and 83.08 mg·kg-1, respectively, 94.91%, 73.91%, and 46.39% of which exceeded the soil background value. ② Cd was dominated by the non-residual fraction (F1+F2+F3) with a fraction ranging from 54% to 97%, whereas Cr was dominated by the residual fraction (F4) with a mass fraction ranging from 87% to 99%. Cu, Ni, Pb, and Zn were mainly in the fraction of residual fraction. In the non-residual fraction, Cu and Ni were mainly in the oxidizable fraction (F3) state, whereas Pb and Zn were mainly in the reducible fraction (F2) state. ③ The RAC risk assessment results showed that there were 68.97%, 39.89%, 54.84%, and 49.78% points in channel, trench, open water, and fish pond samples, respectively, of Cd at high risk. The Cu, Ni, and Pb were at low risk. In general, the overall heavy metal pollution level in Baiyangdian Lake was low, but Cd had ecological risk and high bioavailability in the Fuhe River of the Nanliuzhuang area and the Baigouyin River.

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Metales Pesados , Contaminantes Químicos del Agua , Cadmio , Monitoreo del Ambiente , Sedimentos Geológicos , Lagos , Plomo , Metales Pesados/análisis , Agua , Contaminantes Químicos del Agua/análisis

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BACKGROUND: Hyperglycemia has been widely reported to induce vascular senescence. We have previously demonstrated that angiotensin II (Ang II) could promote brain vascular smooth muscle cell (VSMC) senescence, and its type 2 (AT2) receptor deletion could enhance VSMC senescence. Therefore, we examined the possible cross-talk between Ang II and hyperglycemia on VSMC senescence, and the roles of AT2 receptor agonist, compound 21 (C21) on it. METHODS: Aortic VSMCs were prepared from adult male mice and stimulated with Ang II and/or high glucose (Glu) and/or C21 and/or an autophagy inhibitor, 3-methyladenine (3-MA), and/or an autophagy agonist, rapamycin (RAP) for the indicated times. Cellular senescence, oxidative stress, and protein expressions were evaluated. RESULTS: Combination treatment with Ang II and Glu synergistically increased the proportion of VSMC senescent area compared with control group and each treatment alone, which was almost completely attenuated by C21 treatment. Moreover, combination treatment induced significant changes in the levels of superoxide anion, the expressions of p21 and pRb, and the ratio of LC3B II/I expression, which were also significantly attenuated by C21 treatment. The proportion of VSMC senescent area and the levels of superoxide anion by combination treatment were increased after 3-MA treatment, and the proportion of senescent area and the expressions of p21 and pRb were decreased after RAP treatment, both of which were further attenuated by C21 treatment. CONCLUSIONS: Ang II and hyperglycemia synergistically promoted VSMC senescence, at least partly through the participation by autophagy, oxidative stress, and p21-pRb pathway, which could be inhibited by C21.

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Angiotensina II , Hiperglucemia , Angiotensina II/metabolismo , Angiotensina II/farmacología , Animales , Proteínas Portadoras/metabolismo , Células Cultivadas , Senescencia Celular/fisiología , Glucosa/metabolismo , Glucosa/farmacología , Hiperglucemia/inducido químicamente , Hiperglucemia/metabolismo , Imidazoles , Masculino , Ratones , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Receptor de Angiotensina Tipo 2 , Sirolimus/metabolismo , Sirolimus/farmacología , Sulfonamidas , Superóxidos/metabolismo , Superóxidos/farmacología , Tiofenos

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Núcleo Accumbens , Aprendizaje Inverso , Animales , Encéfalo , Función Ejecutiva , Tupaia

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BACKGROUND: The incidence of gastric cancer is high. The number of dissected lymph nodes was an independent factor affecting prognosis. Although preoperative labeling is helpful in lymph nodes resection, there are no guidelines for when to perform preoperative labeling. AIM: To investigate the role of nanocarbon in lymph node dissection during gastrectomy, and to discuss the relationship between the timing of preoperative injection of carbon nanoparticles and the extent of lymph node dissection. METHODS: A prospective analysis was performed on the clinical data of 307 patients with advanced gastric cancer who underwent laparoscopic surgery in the General Surgery Department of Weifang People's Hospital between June 2018 and February 2021. The patients were randomly divided into experimental group and control group based on whether they received preoperative nanocarbon injection or not. The experimental group was divided into different groups according to the preoperative labeling time. The number of dissected lymph nodes and the number of lymph nodes with black staining were compared in each group after surgery, and the role of nanocarbon in the number of dissected lymph nodes, pathological staging, and the relationship with prognosis were discussed. RESULTS: The average number of dissected lymph nodes in the experimental group was higher than that in the control group. In the experimental group, the number of lymph node dissections and number of black-staining lymph nodes in the nanocarbon-labeling group at 2 d and 1 d before surgery were higher than in the labeling group on the day before surgery (P < 0.05). CONCLUSION: Preoperative nanocarbon labeling can safely and effectively guide lymph node dissection. To improve the detection rate of lymph nodes is conducive to subsequent comprehensive anti-tumor therapy.

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Evolutionarily conserved DDB1-and CUL4-associated factor 13 (DCAF13) is a recently discovered substrate receptor for the cullin RING-finger ubiquitin ligase 4 (CRL4) E3 ubiquitin ligase that regulates cell cycle progression. DCAF13 is overexpressed in many cancers, although its role in breast cancer is currently elusive. In this study we demonstrate that DCAF13 is overexpressed in human breast cancer and that its overexpression closely correlates with poor prognosis, suggesting that DCAF13 may serve as a diagnostic marker and therapeutic target. We knocked down DCAF13 in breast cancer cell lines using CRISPR/Cas9 and found that DCAF13 deletion markedly reduced breast cancer cell proliferation, clone formation, and migration both in vitro and in vivo. In addition, DCAF13 deletion promoted breast cancer cell apoptosis and senescence, and induced cell cycle arrest in the G1/S phase. Genome-wide RNAseq analysis and western blotting revealed that loss of DCAF13 resulted in both mRNA and protein accumulation of p53 apoptosis effector related to PMP22 (PERP). Knockdown of PERP partially reversed the hampered cell proliferation induced by DCAF13 knockdown. Co-immunoprecipitation assays revealed that DCAF13 and DNA damage-binding protein 1 (DDB1) directly interact with PERP. Overexpression of DDB1 significantly increased PERP polyubiquitination, suggesting that CRL4DCAF13 E3 ligase targets PERP for ubiquitination and proteasomal degradation. In conclusion, DCAF13 and the downstream effector PERP occupy key roles in breast cancer proliferation and potentially serve as prognostics and therapeutic targets.

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Neoplasias de la Mama , Factor XIII , Neoplasias de la Mama/genética , Proliferación Celular/genética , Proteínas Cullin/genética , Factor XIII/genética , Factor XIII/metabolismo , Femenino , Genes Supresores de Tumor , Humanos , Proteínas de la Membrana/metabolismo , Proteínas de Unión al ARN/genética , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación

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A novel three-dimensional CdII coordination framework, namely, poly[{µ-bis[4-(2-methylimidazol-1-yl)phenyl] ether-κ2N3:N3'}(µ-naphthalene-1,4-dicarboxylato-κ3O1:O4,O4')cadmium(II)], [Cd(C12H6O4)(C20H18N4O)]n or [Cd(1,4-NDC)(BMIOPE)]n, where 1,4-H2NDC is naphthalene-1,4-dicarboxylic acid and BMIOPE is bis[4-(2-methylimidazol-1-yl)phenyl] ether, has been prepared and characterized by single-crystal X-ray diffraction, elemental analysis, IR spectroscopy and thermogravimetric analysis. The compound displays a novel fourfold interpenetrating diamond-like network. In addition, it not only shows a strong fluorescence emission in the solid state, but also exhibits excellent photocatalytic activity for the degradation of methylene blue (MB) at room temperature.

RESUMEN

The distribution of inorganic nitrogen across the sediment-water interface in Baiyangdian Lake, the largest shallow lake in North China, was examined during the low temperature period. Furthermore, the influence of inorganic nitrogen diffusion flux in sediment porewater on the overlying water quality was analyzed. The results showed that the mean TN concentration in the surface water ranged from 4.83 to 8.23 mg·L-1, the mean NH4+-N concentration ranged from 0.21 to 0.34 mg·L-1, and the mean NO3--N concentration ranged from 0.01 to 2.75 mg·L-1. TN exceeds the Class V water quality standard for surface water, indicating serious pollution. The mean TN content of the sediments ranged from 681 to 4365 mg·kg-1, of which TON was the main form of TN, accounting for 61.6%-93.1%. NH4+-N was the main form of TIN, with a mean content ranging from 28.9 to 116.3 mg·kg-1, and a mean NO3--N content of between 5.2 and 23.7 mg·kg-1, which is relatively low. The NH4+-N concentration in the porewater was 3 to 16 times that of the overlying water, showing a gradual accumulation trend. The diffusion flux ranges of NH4+-N, NO3--N, and NO2--N across the sediment-water interface were -0.55-4.09, -1.44-3.67, and -0.88-0.04 mg·(m2·d)-1, respectively. There was still a potential release risk during the low temperature period. A large amount of NH4+-N accumulated in the sediments during the low-temperature period, which may affect the quality of the overlying water after the temperature rises. Therefore, studying the distribution of nitrogen across the sediment-water interface, and the risk of internal release of inorganic nitrogen during the low temperature period, is of great significance for improving water quality in Baiyangdian Lake and understanding the internal nitrogen pollution of shallow lakes.

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Brain capillaries are crucial for cognitive functions by supplying oxygen and other nutrients to and removing metabolic wastes from the brain. Recent studies have demonstrated that constriction of brain capillaries is triggered by beta-amyloid (Aß) oligomers via endothelin-1 (ET1)-mediated action on the ET1 receptor A (ETRA), potentially exacerbating Aß plaque deposition, the primary pathophysiology of Alzheimer's disease (AD). However, direct evidence is still lacking whether changes in brain capillaries are causally involved in the pathophysiology of AD. Using APP/PS1 mouse model of AD (AD mice) relative to age-matched negative littermates, we identified that reductions of density and diameter of hippocampal capillaries occurred from 4 to 7 months old while Aß plaque deposition and spatial memory deficit developed at 7 months old. Notably, the injection of ET1 into the hippocampus induced early Aß plaque deposition at 5 months old in AD mice. Conversely, treatment of ferulic acid against the ETRA to counteract the ET1-mediated vasoconstriction for 30 days prevented reductions of density and diameter of hippocampal capillaries as well as ameliorated Aß plaque deposition and spatial memory deficit at 7 months old in AD mice. Thus, these data suggest that reductions of density and diameter of hippocampal capillaries are crucial for initiating Aß plaque deposition and spatial memory deficit at the early stages, implicating the development of new therapies for halting or curing memory decline in AD.

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Enfermedad de Alzheimer/tratamiento farmacológico , Precursor de Proteína beta-Amiloide , Capilares/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Ácidos Cumáricos/administración & dosificación , Presenilina-1 , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Capilares/patología , Disfunción Cognitiva/genética , Disfunción Cognitiva/patología , Hipocampo/irrigación sanguínea , Hipocampo/efectos de los fármacos , Hipocampo/patología , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Presenilina-1/genética

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Renin-angiotensin system (RAS) has important roles in cardiovascular disease. Angiotensin II (Ang II) and angiotensin-(1-7) (Ang-(1-7)) are major effector peptides of RAS. However, the roles of Ang II type 2 receptor (AT2R) need to be further explored and the roles of Ang-(1-7) are still not very clear on vascular calcification (VC). Therefore, we hypothesized they have effects on preventing VC in vivo and in vitro. VC model is established by inorganic phosphate (IP) cultured with vascular smooth muscle cells (VSMC) for in vitro study and by 5/6 nephrectomy in mice for in vivo study. Increased calcified nodules by Alizarin Red S staining and mRNA expressions of bone morphogenetic protein-2 (BMP-2) and osteocalcin (OCN) by reverse transcription polymerase chain reaction in calcified WT VSMC were significantly inhibited in calcified AT2R overexpression (SmAT2) VSMC or after Ang-(1-7) treatment. After 5/6 nephrectomy, the ratio of positive and total area by Alizarin Red S and von Kossa staining and mRNA expressions of BMP-2 and OCN were significantly increased in ApoE/AT2R knockout mice compared with apolipoprotein E knockout mice, and which were significantly inhibited with Ang-(1-7) administration. Both AT2R and Ang-(1-7) have the effects on preventing VC induced by IP, at least in part through inhibiting BMP-2, OCN expressions, and in which Ang-(1-7) had protective roles mainly through Mas receptor rather than AT2R.

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Sistema Renina-Angiotensina , Calcificación Vascular , Angiotensina II , Animales , Humanos , Ratones , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/metabolismo , Calcificación Vascular/prevención & control

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Metastasis-associated protein 2 (MTA2) is frequently amplified in many types of cancers; however, the role and underlying molecular mechanism of MTA2 in esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we reported that MTA2 is highly expressed in ESCC tissue and cells, and is closely related to the malignant characteristics and poor prognosis of patients with ESCC. Through in vitro and in vivo experiments, we demonstrated that MTA2 significantly promoted ESCC growth, metastasis, and epithelial-mesenchymal transition (EMT) progression. This integrative analysis combined with expression microarray showed that MTA2 could interact with eukaryotic initiation factor 4E (EIF4E), which positively regulates the expression of Twist, known as a master regulator of EMT. Moreover, the results of chromatin immunoprecipitation revealed that MTA2 was recruited to the E-cadherin promoter by Twist, which reduced the acetylation level of the promoter region and thus inhibited expression of E-cadherin, and subsequently promoted the aggressive progression of ESCC. Collectively, our study provided novel evidence that MTA2 plays an aggressive role in ESCC metastasis by a novel EIF4E-Twist positive feedback loop, which may provide a potential therapeutic target for the management of ESCC.

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Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , Factor 4E Eucariótico de Iniciación/metabolismo , Histona Desacetilasas/metabolismo , Proteínas Nucleares/genética , Proteínas Represoras/metabolismo , Proteína 1 Relacionada con Twist/genética , Animales , Antígenos CD/genética , Cadherinas/genética , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/secundario , Carcinoma de Células Escamosas de Esófago/cirugía , Esofagectomía , Esófago/patología , Esófago/cirugía , Factor 4E Eucariótico de Iniciación/genética , Retroalimentación Fisiológica , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Histona Desacetilasas/genética , Humanos , Estimación de Kaplan-Meier , Masculino , Ratones , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , Pronóstico , Regiones Promotoras Genéticas , Proteínas Represoras/genética , Proteína 1 Relacionada con Twist/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

BACKGROUND: Amyloid-ß (Aß) induces cerebrovascular damage and is reported to stimulate endothelial cell senescence. We previously demonstrated that angiotensin II (Ang II)-promoted vascular senescence. We examined the possible cross-talk between Ang II and Aß in regulating brain vascular smooth muscle cell (BVSMC) senescence. METHODS: BVSMCs were prepared from adult male mice and stimulated with Ang II (0, 0.1, 1, 10, and 100 nmol/l) and/or Aß 1-40 (0, 0.1, 0.3, 0.5, 1, 3, and 5 µmol/l) for the indicated times. Cellular senescence was evaluated by senescence-associated ß-galactosidase staining. RESULTS: Treatment with Ang II (100 nmol/l) or Aß (1 µmol/l) at a higher dose increased senescent cells compared with control at 6 days. Treatment with Ang II (10 nmol/l) or Aß (0.5 µmol/l) at a lower dose had no effect on senescence whereas a combined treatment with lower doses of Ang II and Aß significantly enhanced senescent cells. This senescence enhanced by lower dose combination was markedly blocked by valsartan (Ang II type 1 receptor inhibitor) or TAK-242 (Aß receptor TLR4 inhibitor) treatment. Moreover, lower dose combination caused increases in superoxide anion levels and p-ERK expression for 2 days, NF-κB activity, p-IκB, p-IKKα/ß, p16 and p53 expression for 4 days, and an obvious decrease in pRb expression. These changes by lower dose combination, except in p-IκB expression and NF-κB activity, were significantly inhibited by pretreatment with U0126 (ERK inhibitor). CONCLUSIONS: Ang II and Aß synergistically promoted BVSMC senescence at least due to enhancement of the p-ERK-p16-pRb signaling pathway, oxidative stress, and NF-κB/IκB activity.

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Péptidos beta-Amiloides , Angiotensina II , Senescencia Celular , Péptidos beta-Amiloides/farmacología , Angiotensina II/farmacología , Animales , Encéfalo/metabolismo , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Masculino , Ratones , Músculo Liso Vascular/metabolismo