RESUMEN
Nuclear pore complexes (NPCs) mediate the nucleocytoplasmic transport of macromolecules. Here we provide a structure of the isolated yeast NPC in which the inner ring is resolved by cryo-EM at sub-nanometer resolution to show how flexible connectors tie together different structural and functional layers. These connectors may be targets for phosphorylation and regulated disassembly in cells with an open mitosis. Moreover, some nucleoporin pairs and transport factors have similar interaction motifs, which suggests an evolutionary and mechanistic link between assembly and transport. We provide evidence for three major NPC variants that may foreshadow functional specializations at the nuclear periphery. Cryo-electron tomography extended these studies, providing a model of the in situ NPC with a radially expanded inner ring. Our comprehensive model reveals features of the nuclear basket and central transporter, suggests a role for the lumenal Pom152 ring in restricting dilation, and highlights structural plasticity that may be required for transport.
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Adaptación Fisiológica , Poro Nuclear/metabolismo , Saccharomyces cerevisiae/fisiología , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Fluorescencia , Simulación del Acoplamiento Molecular , Membrana Nuclear/metabolismo , Poro Nuclear/química , Proteínas de Complejo Poro Nuclear/química , Proteínas de Complejo Poro Nuclear/metabolismo , Dominios Proteicos , Reproducibilidad de los Resultados , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMEN
The Paf1 complex (Paf1C) is a conserved transcription elongation factor that regulates transcription elongation efficiency, facilitates co-transcriptional histone modifications, and impacts molecular processes linked to RNA synthesis, such as polyA site selection. Coupling of the activities of Paf1C to transcription elongation requires its association with RNA polymerase II (Pol II). Mutational studies in yeast identified Paf1C subunits Cdc73 and Rtf1 as important mediators of Paf1C association with Pol II on active genes. While the interaction between Rtf1 and the general elongation factor Spt5 is relatively well-understood, the interactions involving Cdc73 have not been fully elucidated. Using a site-specific protein cross-linking strategy in yeast cells, we identified direct interactions between Cdc73 and two components of the Pol II elongation complex, the elongation factor Spt6 and the largest subunit of Pol II. Both of these interactions require the tandem SH2 domain of Spt6. We also show that Cdc73 and Spt6 can interact in vitro and that rapid depletion of Spt6 dissociates Paf1 from chromatin, altering patterns of Paf1C-dependent histone modifications genome-wide. These results reveal interactions between Cdc73 and the Pol II elongation complex and identify Spt6 as a key factor contributing to the occupancy of Paf1C at active genes in Saccharomyces cerevisiae.
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Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Proteínas Nucleares/metabolismo , Factores de Elongación de Péptidos/metabolismo , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética , Factores de Elongación Transcripcional/genética , Factores de Elongación Transcripcional/metabolismoRESUMEN
Wild-type (WT) mice maintain viable levels of blood glucose even when adipose stores are depleted by 6 d of 60% calorie restriction followed by a 23-h fast (hereafter designated as "starved" mice). Survival depends on ghrelin, an octanoylated peptide hormone. Mice that lack ghrelin suffer lethal hypoglycemia when subjected to the same starvation regimen. Ghrelin is known to stimulate secretion of growth hormone (GH), which in turn stimulates secretion of IGF-1 (insulin-like growth factor-1). In the current study, we found that starved ghrelin-deficient mice had a 90% reduction in plasma IGF-1 when compared with starved WT mice. Injection of IGF-1 in starved ghrelin-deficient mice caused a twofold increase in glucose production and raised blood glucose to levels seen in starved WT mice. Increased glucose production was accompanied by increases in plasma glycerol, fatty acids and ketone bodies, and hepatic triglycerides. All of these increases were abolished when the mice were treated with atglistatin, an inhibitor of adipose tissue triglyceride lipase. We conclude that IGF-1 stimulates adipose tissue lipolysis in starved mice and that this lipolysis supplies energy and substrates that restore hepatic gluconeogenesis. This action of IGF-1 in starved mice is in contrast to its known action in inhibiting adipose tissue lipase in fed mice. Surprisingly, the ghrelin-dependent maintenance of plasma IGF-1 in starved mice was not mediated by GH. Direct injection of GH into starved ghrelin-deficient mice failed to increase plasma IGF-1. These data call attention to an unsuspected role of IGF-1 in the adaptation to starvation.
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Glucemia , Factor I del Crecimiento Similar a la Insulina , Inanición , Adaptación Fisiológica , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/enzimología , Tejido Adiposo/metabolismo , Animales , Glucemia/metabolismo , Ácidos Grasos/sangre , Ghrelina/metabolismo , Gluconeogénesis , Glicerol/sangre , Hormona del Crecimiento/metabolismo , Factor I del Crecimiento Similar a la Insulina/análisis , Factor I del Crecimiento Similar a la Insulina/metabolismo , Cuerpos Cetónicos/sangre , Lipasa/antagonistas & inhibidores , Lipasa/metabolismo , Lipólisis , Hígado/metabolismo , Ratones , Compuestos de Fenilurea/farmacología , Inanición/sangre , Inanición/metabolismo , Triglicéridos/metabolismoRESUMEN
Characterization of histone proteoforms with various post-translational modifications (PTMs) is critical for a better understanding of functions of histone proteoforms in epigenetic control of gene expression. Mass spectrometry (MS)-based top-down proteomics (TDP) is a valuable approach for delineating histone proteoforms because it can provide us with a bird's-eye view of histone proteoforms carrying diverse combinations of PTMs. Here, we present the first example of coupling capillary zone electrophoresis (CZE), ion mobility spectrometry (IMS), and MS for online multi-dimensional separations of histone proteoforms. Our CZE-high-field asymmetric waveform IMS (FAIMS)-MS/MS platform identified 366 (ProSight PD) and 602 (TopPIC) histone proteoforms from a commercial calf histone sample using a low microgram amount of histone sample as the starting material. CZE-FAIMS-MS/MS improved the number of histone proteoform identifications by about 3 folds compared to CZE-MS/MS alone (without FAIMS). The results indicate that CZE-FAIMS-MS/MS could be a useful tool for comprehensive characterization of histone proteoforms with high sensitivity.
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Histonas , Espectrometría de Masas en Tándem , Espectrometría de Masas en Tándem/métodos , Espectrometría de Movilidad Iónica , Procesamiento Proteico-Postraduccional , Electroforesis Capilar/métodosRESUMEN
Mass spectrometry (MS)-based top-down proteomics (TDP) analysis of histone proteoforms provides critical information about combinatorial post-translational modifications (PTMs), which is vital for pursuing a better understanding of epigenetic regulation of gene expression. It requires high-resolution separations of histone proteoforms before MS and tandem MS (MS/MS) analysis. In this work, for the first time, we combined SDS-PAGE-based protein fractionation (passively eluting proteins from polyacrylamide gels as intact species for mass spectrometry, PEPPI-MS) with capillary zone electrophoresis (CZE)-MS/MS for high-resolution characterization of histone proteoforms. We systematically studied the histone proteoform extraction from SDS-PAGE gel and follow-up cleanup as well as CZE-MS/MS, to determine an optimal procedure. The optimal procedure showed reproducible and high-resolution separation and characterization of histone proteoforms. SDS-PAGE separated histone proteins (H1, H2, H3, and H4) based on their molecular weight and CZE provided additional separations of proteoforms of each histone protein based on their electrophoretic mobility, which was affected by PTMs, for example, acetylation and phosphorylation. Using the technique, we identified over 200 histone proteoforms from a commercial calf thymus histone sample with good reproducibility. The orthogonal and high-resolution separations of SDS-PAGE and CZE made our technique attractive for the delineation of histone proteoforms extracted from complex biological systems.
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Mass spectrometry (MS)-based top-down proteomics (TDP) has revolutionized biological research by measuring intact proteoforms in cells, tissues, and biofluids. Capillary zone electrophoresis-tandem MS (CZE-MS/MS) is a valuable technique for TDP, offering a high peak capacity and sensitivity for proteoform separation and detection. However, the long-term reproducibility of CZE-MS/MS in TDP remains unstudied, which is a crucial aspect for large-scale studies. This work investigated the long-term qualitative and quantitative reproducibility of CZE-MS/MS for TDP for the first time, focusing on a yeast cell lysate. Over 1000 proteoforms were identified per run across 62 runs using one linear polyacrylamide (LPA)-coated separation capillary, highlighting the robustness of the CZE-MS/MS technique. However, substantial decreases in proteoform intensity and identification were observed after some initial runs due to proteoform adsorption onto the capillary inner wall. To address this issue, we developed an efficient capillary cleanup procedure using diluted ammonium hydroxide, achieving high qualitative and quantitative reproducibility for the yeast sample across at least 23 runs. The data underscore the capability of CZE-MS/MS for large-scale quantitative TDP of complex samples, signaling its readiness for deployment in broad biological applications. The MS RAW files were deposited in ProteomeXchange Consortium with the data set identifier of PXD046651.
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Proteoma , Espectrometría de Masas en Tándem , Espectrometría de Masas en Tándem/métodos , Proteoma/análisis , Saccharomyces cerevisiae/química , Proteómica/métodos , Proyectos Piloto , Reproducibilidad de los Resultados , Electroforesis Capilar/métodos , Proteínas de Unión al ADNRESUMEN
Methane (CH4) carboxylation with carbon dioxide (CO2) into acetic acid (CH3COOH) is an ideal chemical reaction to utilize both greenhouse gases with 100% atom efficiency but remains a great challenge under mild conditions. Herein, we introduce a concept of water (H2O) radiocatalysis for efficient and selective aqueous-phase CH4 carboxylation with CO2 into CH3COOH at room temperature. H2O radiolysis occurs under γ-ray radiation to produce ·OH radicals and hydrated electrons that efficiently react with CH4 and CO2, respectively, to produce ·CH3 radicals and ·CO2- species facilely coupling to produce CH3COOH. CH3COOH selectivity as high as 96.9 and 96.6% calculated respectively from CH4 and CO2 and a CH3COOH production rate of as high as 121.9 µmol·h-1 are acquired. The water radiocatalysis driven by γ-rays is also applicable to selectively produce organic acids from other hydrocarbons and CO2.
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BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer and is highly lethal. Clonorchis sinensis (C. sinensis) infection is an important risk factor for iCCA. Here we investigated the clinical impact and underlying molecular characteristics of C. sinensis infection-related iCCA. METHODS: We performed single-cell RNA sequencing, whole-exome sequencing, RNA sequencing, metabolomics and spatial transcriptomics in 251 patients with iCCA from three medical centers. Alterations in metabolism and the immune microenvironment of C. sinensis-related iCCAs were validated through an in vitro co-culture system and in a mouse model of iCCA. RESULTS: We revealed that C. sinensis infection was significantly associated with iCCA patients' overall survival and response to immunotherapy. Fatty acid biosynthesis and the expression of fatty acid synthase (FASN), a key enzyme catalyzing long-chain fatty acid synthesis, were significantly enriched in C. sinensis-related iCCAs. iCCA cell lines treated with excretory/secretory products of C. sinensis displayed elevated FASN and free fatty acids. The metabolic alteration of tumor cells was closely correlated with the enrichment of tumor-associated macrophage (TAM)-like macrophages and the impaired function of T cells, which led to formation of an immunosuppressive microenvironment and tumor progression. Spatial transcriptomics analysis revealed that malignant cells were in closer juxtaposition with TAM-like macrophages in C. sinensis-related iCCAs than non-C. sinensis-related iCCAs. Importantly, treatment with a FASN inhibitor significantly reversed the immunosuppressive microenvironment and enhanced anti-PD-1 efficacy in iCCA mouse models treated with excretory/secretory products from C. sinensis. CONCLUSIONS: We provide novel insights into metabolic alterations and the immune microenvironment in C. sinensis infection-related iCCAs. We also demonstrate that the combination of a FASN inhibitor with immunotherapy could be a promising strategy for the treatment of C. sinensis-related iCCAs. IMPACT AND IMPLICATIONS: Clonorchis sinensis (C. sinensis)-infected patients with intrahepatic cholangiocarcinoma (iCCA) have a worse prognosis and response to immunotherapy than non-C. sinensis-infected patients with iCCA. The underlying molecular characteristics of C. sinensis infection-related iCCAs remain unclear. Herein, we demonstrate that upregulation of FASN (fatty acid synthase) and free fatty acids in C. sinensis-related iCCAs leads to formation of an immunosuppressive microenvironment and tumor progression. Thus, administration of FASN inhibitors could significantly reverse the immunosuppressive microenvironment and further enhance the efficacy of anti-PD-1 against C. sinensis-related iCCAs.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Clonorquiasis , Clonorchis sinensis , Ácidos Grasos , Microambiente Tumoral , Colangiocarcinoma/inmunología , Colangiocarcinoma/parasitología , Animales , Clonorchis sinensis/inmunología , Clonorchis sinensis/fisiología , Clonorquiasis/inmunología , Neoplasias de los Conductos Biliares/inmunología , Neoplasias de los Conductos Biliares/parasitología , Ratones , Microambiente Tumoral/inmunología , Humanos , Ácidos Grasos/metabolismo , Acido Graso Sintasa Tipo I/genética , Acido Graso Sintasa Tipo I/antagonistas & inhibidores , Acido Graso Sintasa Tipo I/metabolismo , Masculino , Femenino , Línea Celular Tumoral , Modelos Animales de Enfermedad , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismoRESUMEN
Renewable energy technologies, such as water splitting, heavily depend on the oxygen evolution reaction (OER). Nanolaminated ternary compounds, referred to as MAX phases, show great promise for creating efficient electrocatalysts for OER. However, their limited intrinsic oxidative resistance hinders the utilization of conductivity in Mn+1Xn layers, leading to reduced activity. In this study, a method is proposed to improve the poor inoxidizability of MAX phases by carefully adjusting the elemental composition between Mn+1Xn layers and single-atom-thick A layers. The resulting Ta2FeC catalyst demonstrates superior performance compared to conventional Fe/C-based catalysts with a remarkable record-low overpotential of 247 mV (@10 mA cm-2) and sustained activity for over 240 h. Notably, during OER processing, the single-atom-thick Fe layer undergoes self-reconstruction and enrichment from the interior of the Ta2FeC MAX phase toward its surface, forming a Ta2FeC@Ta2C@FeOOH heterostructure. Through density functional theory (DFT) calculations, this study has found that the incorporation of Ta2FeC@Ta2C not only enhances the conductivity of FeOOH but also reduces the covalency of FeâO bonds, thus alleviating the oxidation of Fe3+ and O2-. This implies that the Ta2FeC@Ta2C@FeOOH heterostructure experiences less lattice oxygen loss during the OER process compared to pure FeOOH, leading to significantly improved stability. These results highlight promising avenues for further exploration of MAX phases by strategically engineering M- and A-site engineering through multi-metal substitution, to develop M2AX@M2X@AOOH-based catalysts for oxygen evolution.
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BACKGROUND: The obesity paradox has been reported among older adults. However, whether the favorable effect of obesity is dependent on metabolic status remains largely unknown. We aimed to explore the association of metabolic obesity phenotypes and their changes with all-cause mortality among the Chinese oldest-old population. METHODS: This prospective cohort study included 1207 Chinese oldest old (mean age: 91.8 years). Metabolic obesity phenotypes were determined by central obesity and metabolic status, and participants were classified into metabolically healthy obesity (MHO), metabolically unhealthy obesity (MUO), metabolically healthy non-obesity (MHN), and metabolically unhealthy non-obesity (MUN). The hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by Cox regression models. RESULTS: During 5.3 years of follow-up, 640 deaths were documented. Compared with non-obesity, obesity was associated with a decreased mortality risk among participants with metabolically healthy (HR, 0.75; 95% CI, 0.63-0.91) while this association was insignificant among metabolically unhealthy. Compared to MHO, MHN (HR, 1.27; 95% CI, 1.06-1.53) and MUN (HR, 1.49; 95% CI, 1.10-2.02) were significantly associated with an increased mortality risk. Compared to those with stable MHO, those transited from MHO to MUO demonstrated a higher mortality risk (HR, 1.81; 95% CI, 1.06-3.11). CONCLUSIONS: MHO predicts better survival among the Chinese oldest-old population. These findings suggest that ensuring optimal management of metabolic health is beneficial and taking caution in weight loss based on the individual body weight for the metabolically healthy oldest-old adults.
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BACKGROUND: Atherogenic index of plasma (AIP), a marker of atherosclerosis and cardiovascular disease (CVD). However, few studies have investigated association between AIP and all-cause mortality and specific-mortality in the general population. METHODS: This study included data from 14,063 American adults. The exposure variable was the AIP, which was defined as log10 (triglycerides/high-density lipoprotein cholesterol). The outcome variables included all-cause mortality and specific-mortality. Survey-weighted cox regressions were performed to evaluate the relation between AIP and all-cause mortality and specific-mortality. Weighted restricted cubic spline was conducted to examin the non-linear relationship. RESULTS: During 10 years of follow-up, we documented 2,077, 262, 854, and 476 cases of all-cause mortality, diabetes mortality, CVD mortality and cancer mortality, respectively. After adjustment for potential confounders, we found that atherogenic index of plasma (AIP) was significantly associated with an increased risk of diabetes mortality when comparing the highest to the lowest quantile of AIP in female (p for trend = 0.001) or participants older than 65 years (p for trend = 0.002). AIP was not significantly associated with all-cause mortality, CVD mortality and cancer mortality (p > 0.05). Moreover, a non-linear association was observed between AIP and all-cause mortality in a U-shape (p for non-linear = 0.0011), while a linear relationship was observed with diabetes mortality and non-diabetes mortality (p for linear < 0.0001). CONCLUSIONS: In this study, there is a no significant association between high AIP levels and a high risk of all-cause and cardiovascular mortality. Besides, a higher AIP was significantly associated with an increased risk of diabetes mortality, which only found in women older than 65 years. AIP was associated with all-cause mortality in a U-shape. This association could be explained by the finding that higher AIP predicted a higher risk of death from diabetes, and that lower AIP predicted a higher risk of death from non-diabetes causes.
We used a large national database and a prospective cohort study with a long follow-up period. Higher AIP was significantly associated with an increased risk of diabetes mortality, only in women older than 65 years. There is a no significant association between high AIP levels and a high risk of all-cause and cardiovascular mortality. AIP was associated with all-cause mortality in a U-shape. This finding suggest that controlling AIP levels may have a positive effect on reducing diabetes mortality.
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Aterosclerosis , Biomarcadores , Causas de Muerte , HDL-Colesterol , Diabetes Mellitus , Triglicéridos , Humanos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Medición de Riesgo , Biomarcadores/sangre , Aterosclerosis/mortalidad , Aterosclerosis/sangre , Aterosclerosis/diagnóstico , Factores de Riesgo , Factores de Tiempo , Adulto , Diabetes Mellitus/mortalidad , Diabetes Mellitus/sangre , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , HDL-Colesterol/sangre , Estados Unidos/epidemiología , Triglicéridos/sangre , Pronóstico , Neoplasias/mortalidad , Neoplasias/sangre , Neoplasias/diagnóstico , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnósticoRESUMEN
Limbal stem cell deficiency (LSCD) is a clinically challenging eye disease caused by damage to limbal stem cells (LSCs). Currently, the international consensus classifies LSCD into three clinical stages based on the disease severity. However, no existing animal models attempt to replicate the varying degrees of LSCD observed in clinical cases. The present study demonstrates an easy-to-create, reproducible, and reliable mouse model of graded LSCD. To achieve mild, moderate, or severe LSCD, filter paper rings with a variety of central angles (90°, 180°, or 270°) are utilized to deliver alkali burns to different sizes of the limbal area (1, 2, or 3 quarters). The animal model has successfully resulted in the development of clinical signs and pathological manifestations in escalating severity that are similarly observed in the three clinical stages of LSCD. Our study thus provides new insights into distinct pathological features underlying different grades of LSCD and serves as a new tool for further exploring the disease mechanisms and developing new effective therapeutics for repairing damaged LSCs.
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Quemaduras Químicas , Enfermedades de la Córnea , Modelos Animales de Enfermedad , Quemaduras Oculares , Limbo de la Córnea , Células Madre , Animales , Limbo de la Córnea/patología , Ratones , Células Madre/patología , Enfermedades de la Córnea/patología , Quemaduras Químicas/patología , Quemaduras Oculares/inducido químicamente , Quemaduras Oculares/patología , Ratones Endogámicos C57BL , Femenino , Deficiencia de Células Madre LimbaresRESUMEN
Multimode emission of Mn2+ for multimode fluorescence anticounterfeiting is achieved by cation site and interstitial occupancy in Ca2-xMgxGe7O16. The rings in Ca2-xMgxGe7O16 have a significant distortion for Mn2+ ions to enter the ring interstitials with a luminescence center at 665 nm, which is supported by XRD refinement results and first-principles calculations. The interstitial Mn2+ ion has good thermal stability with an activation energy of 0.36 eV. Surprisingly, these two luminescence centers, the cation site Mn and the interstitial Mn, have an obvious afterglow, and the disappearing afterglow will reappear by heating or irradiating with the 980 nm laser. The afterglow is significantly enhanced, as MnO2 is used as the manganese source, which is explained in detail by the thermal luminescence spectrum. Finally, Ca2-xMgxGe7O16:Mn2+ fully demonstrates its excellent prospects in fluorescent anticounterfeiting, information encryption, and optical information storage.
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Acute coronary syndrome (ACS) remains a major cause of morbidity and mortality, despite many improvements in its prevention and management. Lipid management is an important aspect of secondary prevention after ACS. Previous studies indicate that the early use of intensive statin therapy in patients with ACS may alleviate the risk of recurrent cardiovascular events and mortality. However, many patients do not reach the target low-density lipoprotein cholesterol (LDL-C) level of < 55 mg/dL with statin monotherapy, and muscle-related adverse effects caused by statins hinder adherence to treatment. Novel non-statin agents are recommended for patients who cannot achieve the target LDL-C levels with high-intensity statin therapy and those with statin intolerance. The combination of statins and non-statins may synergistically affect intensively lowering LDL-C through different mechanisms, which could lead to better cardiovascular outcomes than statin monotherapy. However, it remains uncertain whether the early use of combination lipid-lowering therapy is more beneficial. The present review summarizes the benefits of intensive statin monotherapy and their early combination with non-statin medications including ezetimibe, PCSK9 inhibitors, inclisiran, and bempedoic acid (BDA) in the management of ACS.
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BACKGROUND: Primary osteoporosis (POP) is recognized as a "silent disease" and often ignored. This meta-analysis aimed to determine the prevalence of POP in the Chinese population over the past 20 years to raise awareness of the disease's epidemiology, which is hoped to help prevent and treat the condition better. METHODS: Eight English and three Chinese language databases were searched systematically from January 2002 to December 2023. Relevant data were analysed using Stata 16.0. Meta-regression and subgroup analyses were performed to explore causes of heterogeneity. A funnel plot was further drawn in combination with Egger and Begg tests to determine publication bias. RESULTS: A total of 45 studies (241,813 participants) were included. The meta-analysis revealed that the overall prevalence of POP in the Chinese population was 18.2% (95% CI: 14.7-21.7%), showing a positive correlation with age. Specifically, prevalence rates were 23.4% (18.3-28.5%) in women and 11.5% (9.1-13.9%) in men. A notable increase was observed within the span of 20 years (16.9% before 2010 and 20.3% in 2011-2020). Notably, regional variations were observed, with southern China reporting a lower prevalence of 16.4% compared to 20.2% in northern China. Meta-regression suggested that sample size significantly influenced the estimation of point prevalence (P = 0.037). CONCLUSIONS: Over the past two decades, there has been an increase in the prevalence of POP within the Chinese population. The growing prevalence of older individuals and women further highlights the urgency for tailored disease prevention and control measures.
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Osteoporosis , Humanos , China/epidemiología , Prevalencia , Osteoporosis/epidemiología , Femenino , Masculino , Persona de Mediana Edad , AncianoRESUMEN
Medial arterial calcification (MAC) accompanying chronic kidney disease (CKD) leads to increased vessel wall stiffness, myocardial ischemia, heart failure, and increased cardiovascular morbidity and mortality. Unfortunately, there are currently no drugs available to treat MAC. The natural polyphenol epigallocatechin-3-gallate (EGCG) has been demonstrated to protect against cardiovascular disease; however, whether EGCG supplementation inhibits MAC in CKD remains unclear. In this study, we utilize a CKD-associated MAC model to investigate the effects of EGCG on vascular calcification and elucidate the underlying mechanisms involved. Our findings demonstrate that EGCG treatment significantly reduces calcium phosphate deposition and osteogenic differentiation of VSMCs in vivo and in vitro in a dose-dependent manner. In addition, through RNA sequencing (RNA-seq) analysis, we show a significant activation of the transcription factor JunB both in CKD mouse arteries and in osteoblast-like VSMCs. Notably, EGCG effectively suppresses CKD-associated MAC by inhibiting the activity of JunB. In addition, overexpression of JunB can abolish while knockdown of JunB can enhance the inhibitory effect of EGCG on the osteogenic differentiation of VSMCs. Furthermore, EGCG supplementation inhibits MAC in CKD via modulation of the JunB-dependent Ras/Raf/MEK/ERK signaling pathway. In conclusion, our study highlights the potential therapeutic value of EGCG for managing CKD-associated MAC, as it mitigates this pathological process through targeted inactivation of JunB.
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AIM: To explore the prevalence of kinesiophobia in older patients with primary osteoporosis and analyze its influencing factors. METHODS: A cross-sectional survey was conducted among 221 older patients with primary osteoporosis in a general hospital in Kunming, China. Data were collected through a sociodemographic-clinical questionnaire, Tampa Scale for Kinesiophobia-11 (TSK-11), Global Pain Scale (GPS), Five Facets Mindfulness Questionnaire-Short Form (FFMQ-SF), and Hospital Anxiety and Depression Scale (HADS). SPSS 27.0 software was utilized for univariate and binary logistic regression analyses. RESULTS: The findings revealed that the prevalence of kinesiophobia in this study was 57.01 %. Age, history of fractures, chronic obstructive pulmonary disease (COPD), lumbar disc herniation, chronic pain, mindfulness, anxiety, and depression were identified as significant influencing factors of kinesiophobia in the binary logistic regression analyses. CONCLUSION: Healthcare professionals should be attentive to occurrence of kinesiophobia. Timely measures should be implemented to improve pain, anxiety and depression, and employ mindfulness interventions to mitigate kinesiophobia.
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Osteoporosis , Trastornos Fóbicos , Humanos , Estudios Transversales , Femenino , Masculino , Anciano , Prevalencia , Osteoporosis/psicología , Encuestas y Cuestionarios , China/epidemiología , Trastornos Fóbicos/psicología , Trastornos Fóbicos/epidemiología , Depresión/psicología , Depresión/epidemiología , Ansiedad/psicología , Ansiedad/epidemiología , Persona de Mediana Edad , Anciano de 80 o más Años , KinesiofobiaRESUMEN
The ammonium exceedance discharge from sewage treatment plants has a great risk to the stable operation of subsequent constructed wetlands (CWs). The effects of high ammonium shocks on submerged macrophytes and epiphytic biofilms on the leaves of submerged macrophytes in CWs were rarely mentioned in previous studies. In this paper, the 16S rRNA sequencing method was used to investigate the variation of the microbial communities in biofilms on the leaves of Vallisneria natans plants while the growth characteristics of V. natans plants were measured at different initial ammonium concentrations. The results demonstrated that the total chlorophyll and soluble sugar synthesis of V. natans plants decreased by 51.45% and 57.16%, respectively, and malondialdehyde content increased threefold after 8 days if the initial NH4+-N concentration was more than 5 mg/L. Algal density, bacterial quantity, dissolved oxygen, and pH increased with high ammonium shocks. The average removal efficiencies of total nitrogen and NH4+-N reached 73.26% and 83.94%, respectively. The heat map and relative abundance analysis represented that the relative abundances of phyla Proteobacteria, Cyanobacteria, and Bacteroidetes increased. The numbers of autotrophic nitrifiers and heterotrophic nitrification aerobic denitrification (HNAD) bacteria expanded in biofilms. In particular, HNAD bacteria of Flavobacterium, Hydrogenophaga, Acidovorax, Acinetobacter, Pseudomonas, Aeromonas, and Azospira had higher abundances than autotrophic nitrifiers because there were organic matters secreted from declining leaves of V. natans plants. The analysis of the nitrogen metabolic pathway showed aerobic denitrification was the main nitrogen removal pathway. Thus, the nitrification and denitrification bacterial communities increased in epiphytic biofilms on submerged macrophytes in constructed wetlands while submerged macrophytes declined under ammonium shock loading.
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Compuestos de Amonio , Cianobacterias , Desnitrificación , Nitrógeno/análisis , Humedales , ARN Ribosómico 16S , Nitrificación , BiopelículasRESUMEN
Mass spectrometry (MS)-based top-down characterization of integral membrane proteins (IMPs) is crucial for understanding their functions in biological processes. However, it is technically challenging due to their low solubility in typical MS-compatible buffers. In this work, for the first time, we developed an efficient capillary zone electrophoresis (CZE)-tandem MS (MS/MS) method for the top-down proteomics (TDP) of IMPs enriched from mouse brains. Our technique employs a sample buffer containing 30% (v/v) formic acid and 60% (v/v) methanol for solubilizing IMPs and utilizes a separation buffer of 30% (v/v) acetic acid and 30% (v/v) methanol for maintaining the solubility of IMPs during CZE separation. Single-shot CZE-MS/MS identified 51 IMP proteoforms from the mouse brain sample. Coupling size exclusion chromatography (SEC) to CZE-MS/MS enabled the identification of 276 IMP proteoforms from the mouse brain sample containing 1-4 transmembrane domains. This proof-of-concept work demonstrates the high potential of CZE-MS/MS for the large-scale TDP of IMPs.
Asunto(s)
Metanol , Espectrometría de Masas en Tándem , Animales , Ratones , Proteómica , Electroforesis Capilar , Proteínas de la Membrana , Encéfalo , Proteínas de Unión al ADNRESUMEN
BACKGROUND: Epicardial adipose tissue (EAT) has been suggested to exert deleterious effects on myocardium and cardiovascular disease (CVD) consequence. We evaluated the associations of EAT thickness with adverse outcomes and its potential mediators in the community. METHODS: Participants without heart failure (HF) who had undergone cardiac magnetic resonance (CMR) to measure EAT thickness over the right ventricular free wall from the Framingham Heart Study were included. The correlation of EAT thickness with 85 circulating biomarkers and cardiometric parameters was assessed in linear regression models. The occurrence of HF, atrial fibrillation, coronary heart disease (CHD), and other adverse events was tracked since CMR was implemented. Their associations with EAT thickness and the mediators were evaluated using Cox regression and causal mediation analysis. RESULTS: Of 1554 participants, 53.0% were females. Mean age, body mass index, and EAT thickness were 63.3 years, 28.1 kg/m2, and 9.8 mm, respectively. After fully adjusting, EAT thickness positively correlated with CRP, LEP, GDF15, MMP8, MMP9, ORM1, ANGPTL3, and SERPINE1 and negatively correlated with N-terminal pro-B-type natriuretic peptide (NT-proBNP), IGFBP1, IGFBP2, AGER, CNTN1, and MCAM. Increasing EAT thickness was associated with smaller left ventricular end-diastolic dimension, thicker left ventricular wall thickness, and worse global longitudinal strain (GLS). During a median follow-up of 12.7 years, 101 incident HF occurred. Per 1-standard deviation increment of EAT thickness was associated with a higher risk of HF (adjusted hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.19-1.72, P < 0.001) and the composite outcome consisting of myocardial infarction, ischemic stroke, HF, and death from CVD (adjusted HR [95% CI], 1.23 [1.07-1.40], P = 0.003). Mediation effect in the association between thicker EAT and higher risk of HF was observed with NT-proBNP (HR [95% CI], 0.95 [0.92-0.98], P = 0.011) and GLS (HR [95% CI], 1.04 [1.01-1.07], P = 0.032). CONCLUSIONS: EAT thickness was correlated with inflammation and fibrosis-related circulating biomarkers, cardiac concentric change, myocardial strain impairment, incident HF risk, and overall CVD risk. NT-proBNP and GLS might partially mediate the effect of thickened EAT on the risk of HF. EAT could refine the assessment of CVD risk and become a new therapeutic target of cardiometabolic diseases. TRIAL REGISTRATION: URL: https://clinicaltrials.gov . Identifier: NCT00005121.