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Antiasmáticos , Anticorpos Monoclonais Humanizados , Asma , Doença Pulmonar Obstrutiva Crônica , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Resultado do Tratamento , Masculino , Asma/tratamento farmacológico , Asma/diagnóstico , Asma/fisiopatologia , Feminino , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Antiasmáticos/uso terapêutico , Pessoa de Meia-Idade , Idoso , Pulmão/fisiopatologia , Pulmão/efeitos dos fármacos , Fatores de Tempo , Estudos Retrospectivos , Volume Expiratório ForçadoRESUMO
Modifying catalyst surface with small molecular-additives presents a promising avenue for enhancing electrocatalytic performance. However, challenges arise in preserving the molecular-additives and maximizing their tuning effect, particularly at high current-densities. Herein, we develop an effective strategy to preserve the molecular-additives on electrode surface by applying a thin protective layer. Taking 4-dimethylaminopyridine (DMAP) as an example of a molecular-additive, the hydrophobic protection layer on top of the DMAP-functionalized Cu-catalyst effectively prevents its leaching during CO2 electroreduction (CO2R). Consequently, the confined DMAP molecules substantially promote the CO2-to-multicarbon conversion at low overpotentials. For instance, at a potential as low as -0.47 V vs. reversible hydrogen electrode, the DMAP-functionalized Cu exhibits over 80% selectivity towards multi-carbon products, while the pristine Cu shows only ~35% selectivity for multi-carbon products. Notably, ethanol appears as the primary product on DMAP-functionalized Cu, with selectivity approaching 50% at a high current density of 400 mA cm-2. Detailed kinetic analysis, in-situ spectroscopies, and theoretical calculations indicate that DMAP-induced electron accumulations on surface Cu-sites decrease the reaction energy for C-C coupling. Additionally, the interactions between DMAP and oxygenated intermediates facilitate the ethanol formation pathway in CO2R. Overall, this study showcases an effective strategy to guide future endeavors involving molecular tuning effects.
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BACKGROUND: Hyperkalemia is a known complication of chronic kidney disease (CKD); however, it is not known whether hyperkalemia directly contributes to CKD progression and the risk of death. Clarifying the extent to which hyperkalemia is associated with CKD progression and mortality can inform clinical practice and guide future research. The objective of this study was to quantify the risks of CKD progression and mortality associated with hyperkalemia in patients with stages 3b/4 CKD. METHODS: This was a real-world, exact and propensity score-matched, observational cohort study using data (January 2016-December 2021) from Optum's deidentified Market Clarity Data, a large US integrated insurance claims/electronic medical record database. The study included matched adult patients with stages 3b/4 CKD with and without hyperkalemia, not regularly treated with an intestinal potassium (K+) binder. Measured outcomes were CKD progression and all-cause mortality. CKD progression was defined as diagnosis of CKD stage 4 (if stage 3b at index), CKD stage 5 or kidney failure, or receipt of dialysis or kidney transplantation. RESULTS: After matching, there were 6,619 patients in each of the hyperkalemia and non-hyperkalemia cohorts, with a mean (standard deviation) follow-up time of 2.12 (1.42) years. Use of any renin-angiotensin-aldosterone system inhibitors (RAASi) during baseline was common (75.9%) and most patients had CKD stage 3b (71.2%). Patients with hyperkalemia had a 1.60-fold (95% confidence interval [CI] 1.50, 1.71) higher risk of CKD progression and a 1.09-fold (1.02, 1.16) higher risk of all-cause mortality relative to patients without hyperkalemia. Relative risks of CKD progression associated with hyperkalemia were similar within the subset of patients receiving RAASi and across CKD stages, and when alternative definitions of CKD progression were used. CONCLUSIONS: Patients with CKD stages 3b/4 and hyperkalemia experienced significantly higher risks of CKD progression and all-cause mortality than propensity score-matched patients without hyperkalemia.
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Dysfunction of pancreatic δ cells contributes to the etiology of diabetes. Despite their important role, human δ cells are scarce, limiting physiological studies and drug discovery targeting δ cells. To date, no directed δ-cell differentiation method has been established. Here, we demonstrate that fibroblast growth factor (FGF) 7 promotes pancreatic endoderm/progenitor differentiation, whereas FGF2 biases cells towards the pancreatic δ-cell lineage via FGF receptor 1. We develop a differentiation method to generate δ cells from human stem cells by combining FGF2 with FGF7, which synergistically directs pancreatic lineage differentiation and modulates the expression of transcription factors and SST activators during endoderm/endocrine precursor induction. These δ cells display mature RNA profiles and fine secretory granules, secrete somatostatin in response to various stimuli, and suppress insulin secretion from in vitro co-cultured ß cells and mouse ß cells upon transplantation. The generation of human pancreatic δ cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation studies in diabetes.
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Diferenciação Celular , Células-Tronco Pluripotentes , Humanos , Animais , Camundongos , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/citologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Somatostatina/metabolismo , Células Secretoras de Somatostatina/citologia , Endoderma/citologia , Endoderma/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Pâncreas/citologia , Pâncreas/metabolismo , Somatostatina/metabolismo , Linhagem da Célula , Insulina/metabolismo , Secreção de InsulinaRESUMO
The two-dimensional (2D) honeycomb lattice has attracted intensive research interest due to the appearance of Dirac-type band structures as the consequence of two sublattices in the honeycomb structure. Introducing strong spin-orbit coupling (SOC) leads to a gap opening at the Dirac point, transforming the honeycomb lattice into a 2D topological insulator as a platform for the quantum spin Hall effect (QSHE). In this work, we realize a 2D honeycomb-structured film with tellurium, the heaviest nonradioactive element in Group VI, namely, tellurene, via molecular beam epitaxy. We revealed the gap opening of 160 meV at the Dirac point due to the strong SOC in the honeycomb-structured tellurene by angle-resolved photoemission spectroscopy. The topological edge states of tellurene are detected via scanning tunneling microscopy/spectroscopy. These results demonstrate that tellurene is a novel 2D honeycomb lattice with strong SOC, and they unambiguously prove that tellurene is a promising candidate for a room-temperature QSHE system.
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The messenger RNA (mRNA) vaccines hold great significance in contagion prevention and cancer immunotherapy. However, safely and effectively harnessing innate immunity to stimulate robust and durable adaptive immune protection is crucial, yet challenging. In this study, we synthesized a library of stimuli-responsive bivalent ionizable lipids (srBiv iLPs) with smart molecular blocks responsive to esterase, H2O2, cytochrome P450, alkaline phosphatase, nitroreductase, or glutathione (GSH), aiming to leverage physiological cues to trigger fast lipid degradation, promote mRNA translation, and induce robust antitumor immunity via reactive oxygen species (ROS)-mediated boosting. After subcutaneous immunization, esterase-responsive vaccine (eBiv-mVac) was rapidly internalized and transported into the draining lymph nodes. It then underwent fast decaging and self-immolative degradation in esterase-rich antigen-presenting cells, releasing sufficient mRNA for antigen translation and massive reactive quinone methides to elevate ROS levels. This resulted in broad activation of innate immunity to boost T cell response, prompting a large number of primed antigen-specific CD8+ T cells to circulate and infiltrate into tumors (>1000-fold versus unvaccinated control), thereby orchestrating innate and adaptive immunity to control tumor growth. Moreover, by further combining our vaccination strategy with immune checkpoint blockade, we demonstrated a synergism that significantly amplified the magnitude and function of antigen-specific CD8+ T cells. This, in turn, caused potent systemic antitumor efficacy and prolonged survival with high complete response rate in xenograft and metastasis models. Overall, our generalized stimuli-responsive mRNA delivery platform promises a paradigm shift in the design of potent vaccines for cancer immunotherapy, as well as effective and precise carriers for gene editing, protein replacement, and cell engineering.
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Linfócitos T CD8-Positivos , Imunidade Inata , Espécies Reativas de Oxigênio , Espécies Reativas de Oxigênio/metabolismo , Imunidade Inata/efeitos dos fármacos , Animais , Linfócitos T CD8-Positivos/imunologia , Camundongos , Vacinas de mRNA/química , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/química , RNA Mensageiro/imunologia , RNA Mensageiro/genética , Humanos , Camundongos Endogâmicos C57BLRESUMO
Metal phosphide-containing materials have emerged as a potential candidate of nonprecious metal-based catalysts for alkaline oxygen evolution reaction (OER). While it is known that metal phosphide undergoes structural evolution, considerable debate persists regarding the effects of dynamics on the surface activation and morphological stability of the catalysts. In this study, we synthesize NiP x -FeO x core-shell nanocatalysts with an amorphous NiP x core designed for enhanced OER activity. Using ex situ X-ray absorption spectroscopy, we elucidate the local structural changes as a function of the cyclic voltammetry cycles. Our studies suggest that the presence of corner-sharing octahedra in the FeO x shell improves structural rigidity through interlayer cross-linking, thereby inhibiting the diffusion of OH-/H2O. Thus, the FeO x shell preserves the amorphous NiP x core from rapid oxidation to Ni3(PO4)2 and Ni(OH)2. On the other hand, the incorporation of Ni from the core into the FeO x shell facilitates absorption of hydroxide ions for OER. As a result, Ni/Fe(OH) x at the surface oxidizes to the active γ-(oxy)hydroxide phase under the applied potentials, promoting OER. This intriguing synergistic behavior holds significance as such a synthetic route involving the FeO x shell can be extended to other systems, enabling manipulation of surface adsorption and diffusion of hydroxide ions. These findings also demonstrate that nanomaterials with core-shell morphologies can be tuned to leverage the strength of each metallic component for improved electrochemical activities.
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Stress has been shown to promote the development and persistence of binge eating behaviors. However, the neural circuit mechanisms for stress-induced binge-eating behaviors are largely unreported. The endogenous dynorphin (dyn)/kappa opioid receptor (KOR) opioid neuropeptide system has been well established to be a crucial mediator of the anhedonic component of stress. Here, we aimed to dissect the basis of dynorphinergic control of stress-induced binge-like eating behavior. We first established a mouse behavioral model for stress-induced binge-like eating behaviors. We found that mice exposed to stress increased their food intake of familiar palatable food (high fat, high sugar, HPD) compared to non-stressed mice. Following a brain-wide analysis, we isolated robust cFos-positive cells in the Claustrum (CLA), a subcortical structure with highly abundant KOR expression, following stress-induced binge-eating behavior. We report that KOR signaling in CLA is necessary for this elevated stress-induced binge eating behavior using local pharmacology and local deletion of KOR. In vivo calcium recordings using fiber photometry revealed a disinhibition circuit structure in the CLA during the initiation of HPD feeding bouts. We further established the dynamics of endogenous dynorphinergic control of this behavior using a genetically encoded dynorphin biosensor, Klight. Combined with 1-photon single-cell calcium imaging, we report significant heterogeneity with the CLA population during stress-induced binge eating and such behavior attenuates local dynorphin tone. Furthermore, we isolate the anterior Insular cortex (aIC) as the potential source of endogenous dynorphin afferents in the CLA. By characterizing neural circuits and peptidergic mechanisms within the CLA, we uncover a pathway that implicates endogenous opioid regulation stress-induced binge eating.
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MicroRNAs (miRNAs) are increasingly recognized as potential biomarkers for the early diagnosis of cancer. However, the concurrent detection of multiple miRNAs in biological samples presents a significant challenge due to their high homogeneity and low abundance. This study introduced a novel approach combining strand displacement amplification (SDA) with microchip electrophoresis (MCE) for the simultaneous quantitation of trace levels of three miRNAs associated with cancer: miRNA-21, miRNA-145, and miRNA-221. Specifically designed probes were utilized to selectively capture the target miRNAs, thereby initiating the SDA process in a single solution without cross-interference. Under optimized conditions, the SDA-MCE method achieved the limit of detection (LOD) as low as 0.02 fM (S/N = 3) and the limit of quantitation (LOQ) as low as 0.1 fM across a broad linear range spanning from 0.1 fM to 1 pM. The SDA reaction was completed in approximately 1.5 h, and all target products were separated within 135 s through MCE. Application of this method for the simultaneous detection of these three miRNAs in human lung cancer cell samples yielded satisfactory results. Featuring high sensitivity, rapid analysis, minimal reagent consumption, and straightforward operation, the proposed MCE-SDA strategy holds considerable promise for multi-miRNAs detection applications.
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Eletroforese em Microchip , Limite de Detecção , MicroRNAs , Técnicas de Amplificação de Ácido Nucleico , MicroRNAs/análise , Eletroforese em Microchip/métodos , Humanos , Técnicas de Amplificação de Ácido Nucleico/métodos , Linhagem Celular Tumoral , Neoplasias Pulmonares/genéticaRESUMO
Vat photopolymerization (VP), as an additive manufacturing process, has experienced significant growth due to its high manufacturing precision and excellent surface quality. This method enables the fabrication of intricate shapes and structures while mitigating the machining challenges associated with non-oxide ceramics, which are known for their high hardness and brittleness. Consequently, the VP process of non-oxide ceramics has emerged as a focal point in additive manufacturing research areas. However, the absorption, refraction, and reflection of ultraviolet light by non-oxide ceramic particles can impede light penetration, leading to reduced curing thickness and posing challenges to the VP process. To enhance the efficiency and success rate of this process, researchers have explored various aspects, including the parameters of VP equipment, the composition of non-oxide VP slurries, and the surface modification of non-oxide particles. Silicon carbide and silicon nitride are examples of non-oxide ceramic particles that have been successfully employed in VP process. Nonetheless, there remains a lack of systematic induction regarding the curing mechanisms and key influencing factors of the VP process in non-oxide ceramics. This review firstly describes the curing mechanism of the non-oxide ceramic VP process, which contains the chain initiation, chain polymerization, and chain termination processes of the photosensitive resin. After that, the impact of key factors on the curing process, such as the wavelength and power of incident light, particle size, volume fraction of ceramic particles, refractive indices of photosensitive resin and ceramic particles, incident light intensity, critical light intensity, and the reactivity of photosensitive resins, are systematically discussed. Finally, this review discusses future prospects and challenges in the non-oxide ceramic VP process. Its objective is to offer valuable insights and references for further research into non-oxide ceramic VP processes.
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The modified coconut shell biochars (MCSBCs) were fabricated and their adsorptions for Pb(II) were evaluated, in which waste coconut shell was used as the raw material, both ZnCl2 and KMnO4 were applied as the inorganic modifiers. FT-IR spectra, TGA, SEM and BET techniques were utilized to characterize their properties. It was spotted that the thermal stability of UCSBC could arrive at 500 °C. The BET specific surface areas of both Zn- and Mn-modified MCSBCs (485.137, 476.734 m2/g) were highly decreased as compared with that of UCSBC (3528.78 m2/g). In contrast, the average pore diameters of both Zn- and Mn-modified MCSBCs (3.295, 3.803 nm) were smaller than that of UCSBC (3.814 nm). These findings reveal that the modification of CSBC didn't change its pore size. Their adsorptions for Pb(II) were performed and some controlling factors involving pH, contact time, starting concentration and temperature were explored. Moreover, the experiment data were fitted via linear and non-linear techniques. It was found that the Langmuir maximal adsorption amounts of un-modified coconut shell biochar (UCSBC), Zn-modified and Mn-modified MCSBCs for Pb(II) could reach 31.653, 86.547 and 93.666 mg/g, respectively. Two-parameter kinetic models exposed that Pb(II) adsorption on UCSBC, Zn-modified and Mn-modified MCSBCs obeyed both the Lagergren first-order (non-linear R2 = 0.990, 0.954, 0.953, respectively) and Avrami fractional-order (non-linear R2 = 0.989, 0.946, 0.945, respectively) kinetic models. Two-parameter and three-parameter isotherm models verified that Pb(II) adsorption on UCSBC, Zn-modified and Mn-modified MCSBCs followed the Langmuir (non-linear R2 = 0.992, 0.997, 0.993, respectively) as well as Sips (non-linear R2 = 0.992, 0.997, 0.992, respectively) isotherm models. The computation of thermodynamic parameters evidenced that the modification of UCSBC via KMnO4 and ZnCl2 can effectively rise its adsorption for Pb(II), exhibiting promising applications in the handling of metal-bearing water.
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Liver fibrosis, a progressive process of fibrous scarring, results from the accumulation of extracellular matrix proteins (ECM). If left untreated, it often progresses to diseases such as cirrhosis and hepatocellular carcinoma. Lycorine, a natural alkaloid derived from medicinal plants, has shown diverse bioactivities by targeting JAK2/STAT3 signaling, but its pharmacological effects and potential molecular mechanisms in liver fibrosis remains largely unexplored. The purpose of this study is to elucidate the pharmacological activity and molecular mechanism of lycorine in anti-hepatic fibrosis. Findings indicate that lycorine significantly inhibited hepatic stellate cells (HSCs) activation by reducing the expression of α-SMA and collagen-1. In vivo, lycorine treatment alleviated carbon tetrachloride (CCl4) -induced mice liver fibrosis, improving liver function, decreasing ECM deposition, and inhibiting fibrosis-related markers' expression. Mechanistically, it was found that lycorine exerts protective activity through the JAK2/STAT3 and PI3K/AKT signaling pathways, as evidenced by transcriptome sequencing technology and small molecule inhibitors. These results underscore lycorine's potential as a therapeutic drug for liver fibrosis.
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Alcaloides de Amaryllidaceae , Tetracloreto de Carbono , Células Estreladas do Fígado , Janus Quinase 2 , Cirrose Hepática , Fenantridinas , Proteínas Proto-Oncogênicas c-akt , Fator de Transcrição STAT3 , Transdução de Sinais , Animais , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Alcaloides de Amaryllidaceae/farmacologia , Tetracloreto de Carbono/toxicidade , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Masculino , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Cirrose Hepática/metabolismo , Fenantridinas/farmacologia , Fenantridinas/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos Endogâmicos C57BL , Linhagem CelularRESUMO
Forkhead box protein J1 (FOXJ1), a member of the forkhead family, is an important transcription factor regulating multiciliated cell differentiation and motile ciliogenic program. Here, we established a FOXJ1- EGFP knock-in human embryonic stem cell (hESC) line by inserting a P2A-EGFP gene cassette of FOXJ1 using CRISPR/Cas9 system. The reporter cell line retained a normal karyotype, expressed comparable pluripotent marker genes, and maintained differentiation potential. This reporter cell line enables live identification of multiciliated cells during the general lung differentiation and will be a valuable tool for studying the multiciliated cell differentiation, ciliogenesis and mechanism of related pulmonary diseases.
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Sistemas CRISPR-Cas , Fatores de Transcrição Forkhead , Células-Tronco Embrionárias Humanas , Humanos , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Fluorescência Verde/genética , Linhagem Celular , Diferenciação Celular , Técnicas de Introdução de Genes/métodos , Marcação de Genes/métodos , Genes ReporterRESUMO
BACKGROUND: Inflammation and obesity are the risk factors for hyperlipidaemia. Nonetheless, research regarding the association between dietary live microbes intake and hyperlipidaemia is lacking. Therefore, this study focused on revealing the relationship between them and mediating roles of inflammation and obesity. METHODS: Totally 16,677 subjects were enrolled from the National Health and Nutrition Examination Survey (NHANES) (1999-2010 and 2015-2020). To explore the correlation between live microbes and hyperlipidaemia as well as blood lipid levels, respectively, multiple logistic regression and linear regression were employed. Furthermore, the mediating roles of body mass index (BMI), C-reactive protein (Crp) and their chain effect were explored through mediating analysis. RESULTS: High dietary live microbes intake was the protective factor for hyperlipidaemia. In addition, high dietary live microbes intake exhibited a positive relationship to the high-density lipoprotein cholesterol (HDL-C) among males (ß = 2.52, 95% CI: 1.29, 3.76, P < 0.0001) and females (ß = 2.22, 95% CI: 1.05, 3.38, P < 0.001), but exhibited a negative correlation with triglyceride (TG) levels in males (ß = -7.37, 95% CI: -13.16, -1.59, P = 0.02) and low-density lipoprotein cholesterol (LDL-C) levels in females (ß = -2.75, 95% CI: -5.28, -0.21, P = 0.02). Crp, BMI and their chain effect mediated the relationship between live microbes with HDL-C levels. Moreover, BMI and the chain effect mediated the relationship between live microbes with LDL-C levels. CONCLUSION: Dietary live microbes intake is related to a lower hyperlipidaemia risk. Crp, BMI and their chain effect make a mediating impact on the relationship.
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Índice de Massa Corporal , Proteína C-Reativa , HDL-Colesterol , Hiperlipidemias , Triglicerídeos , Humanos , Proteína C-Reativa/metabolismo , Masculino , Hiperlipidemias/sangue , Hiperlipidemias/dietoterapia , Feminino , Pessoa de Meia-Idade , Adulto , Triglicerídeos/sangue , HDL-Colesterol/sangue , Fatores de Risco , Obesidade/sangue , Obesidade/dietoterapia , Inquéritos Nutricionais , Inflamação/sangue , Dieta , LDL-Colesterol/sangueRESUMO
Background: Ventilator-Associated Pneumonia (VAP) severely impacts stroke patients' prognosis after endovascular treatment. Hence, this study created a nomogram to predict the occurrence of VAP after endovascular treatment. Methods: The individuals with acute ischemic stroke and large vessel occlusion (AIS-LVO) who received mechanical ventilation and endovascular therapy between July 2020 and August 2023 were included in this retrospective study. The predictive model and nomogram were generated by performing feature selection optimization using the LASSO regression model and multifactor logistic regression analysis and assessed the evaluation, verification and clinical application. Results: A total of 184 individuals (average age 61.85 ± 13.25 years, 73.37% male) were enrolled, and the rate of VAP occurrence was found to be 57.07%. Factors such as the Glasgow Coma Scale (GCS) score, duration of stay in the Intensive Care Unit (ICU), dysphagia, Fazekas scale 2 and admission diastolic blood pressure were found to be associated with the occurrence of VAP in the nomogram that demonstrating a strong discriminatory power with AUC of 0.862 (95% CI, 0.810-0.914), and a favorable clinical net benefit. Conclusion: This nomogram, comprising GCS score, ICU duration, dysphagia, Fazekas scale 2 and admission diastolic blood pressure, can aid clinicians in predicting the identification of high-risk patients for VAP following endovascular treatment in large vessel occlusion stroke.
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INTRODUCTION: The contribution of individual and combined inflammatory markers for the prognosis of acute ischemic stroke (AIS) remains elusive. This study investigated the effect of systemic inflammatory response index (SIRI), and neutrophil to high-density lipoprotein ratio (NHR), which is mediated by fasting blood glucose (FBG), on 90-day prognosis of patients with AIS. METHODS: In this pre-specified substudy of an observational cohort study, 2,828 patients with AIS were enrolled from the Nanjing Stroke Registry between January 2017 and July 2021. Peripheral venous blood was collected from patients fasting for at least 8 h within 24 h of admission to gather information on the following parameters: neutrophil count, lymphocyte count, monocyte count, HDL level, and fasting blood glucose level. Then, the SIRI and NHR values were calculated. Following this, the correlation among SIRI, NHR, and modified Rankin Scale (mRS) scores 90 days after onset was examined via univariate and multivariate logistic analyses. Lastly, mediation analysis was performed to examine the relationship between systematic inflammatory response and study outcomes mediated by FBG. RESULTS: SIRI and NHR were both negatively correlated with clinical outcomes (p < 0.05). Logistic regression analysis revealed that SIRI and NHR were independently associated with poor outcomes after adjusting for potential confounders. Subgroup analyses further validated these correlations. Meanwhile, mediation analysis corroborated that FBG partially mediated the associations between SIRI and a poor prognosis at 90 days (indirect effect estimate = 0.0038, bootstrap 95% CI 0.001-0.008; direct effect estimate = 0.1719, bootstrap 95% CI 0.1258-0.2179). Besides, FBG also played a mediating role between NHR and poor outcomes (indirect effect estimate = 0.0066, bootstrap 95% CI 0.002-0.120; direct effect estimate = 0.1308, bootstrap 95% CI 0.0934-0.1681). CONCLUSION: Our study demonstrated that SIRI and NHR are positively associated with poor clinical and mortality outcomes at 90 days in AIS patients, which was partially mediated by FBG.
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Escherichia coli (E. coli) plays an important ecological role, and is a useful bioindicator to recognize the evolution of resistance in human, animal and environment. Recently, extended-spectrum ß-lactamases (ESBL) producing E.coli has posed a threat to public health. Generally, captive healthy giant pandas are not exposed to antibiotics; however, they still acquire antimicrobial resistant bacteria. In order to understand whether there is an exchange of resistance genes within the ecosystems of captive giant pandas, this study explored resistance characteristics of 330 commensal E. coli isolates from feces of giant pandas, the surroundings, and breeders. Isolates from different sources showed similar resistance phenotype, and ESBL/AmpC-producing isolates showed more profound resistance to antibiotics than non-ESBL/AmpC-producing isolates (P<0.05). Furthermore, the occurrence of broad-spectrum ß-lactamase related resistance genes and colistin resistance genes was detected, and isolates phylogenetic typing and multilocus sequence typing (MLST) were applied in this study. Seven different ß-lactamase resistance genes (blaCTX-M-55, blaCTX-M-15, blaCTX-M-27, blaCTX-M-65, blaTEM-1, blaOXA-1 and blaCMY) and mcr-1 were found in 68 ESBL/AmpC-producing isolates. blaCTX-M-55 (48.53 %) was found the most predominant resistance genes, followed by blaTEM-1 (19.12 %) and blaCTX-M-27 (16.18 %). Nonetheless, blaCTX-M-55 was commonly detected in the isolates from giant pandas (63.16 %), the surroundings (43.48 %), and breeders (33.33 %). However, there were no carbapenemase genes detected in this study. mcr-1 was harbored in only one isolate from giant panda. Forty-five tansconjugants were successfully obtained in the conjugation experiments. The presence of antimicrobial resistance and related resistance genes tested were observed in the transconjugants. The results indicated that 52.63 % of the isolates from giant panda 73.91 % of the isolates from surroundings, and 100 % of the isolates from breeders were phylogroup A. Total of 27 sequence types (ST) were recognized from the isolate by MLST and found that ST48 (19/68; 27.94 %) was the predominant ST type, especially in the isolates from giant pandas and the surroundings. In conclusion, commensal ESBL/AmpC-producing E. coli becomes a reservoir of ESBL resistance genes, which is a potential threaten to health of giant pandas. The interaction between giant pandas, surroundings and breeders contribute to development of resistant phenotypes and genotypes which might transfer across species or the surroundings easily; hence, strict monitoring based on a "One Health" approach is recommended.
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Antibacterianos , Proteínas de Bactérias , Escherichia coli , Fezes , Tipagem de Sequências Multilocus , Ursidae , beta-Lactamases , Animais , Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , beta-Lactamases/genética , Ursidae/microbiologia , China , Antibacterianos/farmacologia , Fezes/microbiologia , Proteínas de Bactérias/genética , Ecossistema , Filogenia , Testes de Sensibilidade Microbiana , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/veterinária , Farmacorresistência Bacteriana Múltipla/genética , Farmacorresistência Bacteriana/genéticaRESUMO
Glucose and lipid metabolic disorders (GLMDs), such as diabetes, dyslipidemia, metabolic syndrome, nonalcoholic fatty liver disease, and obesity, are significant public health issues that negatively impact human health. The endoplasmic reticulum (ER) plays a crucial role at the cellular level for lipid and sterol biosynthesis, intracellular calcium storage, and protein post-translational modifications. Imbalance and dysfunction of the ER can affect glucose and lipid metabolism. As an essential trace element, selenium contributes to various human physiological functions mainly through 25 types of selenoproteins (SELENOs). At least 10 SELENOs, with experimental and/or computational evidence, are predominantly found on the ER membrane or within its lumen. Two iodothyronine deiodinases (DIOs), DIO1 and DIO2, regulate the thyroid hormone deiodination in the thyroid and some external thyroid tissues, influencing glucose and lipid metabolism. Most of the other eight members maintain redox homeostasis in the ER. Especially, SELENOF, SELENOM, and SELENOS are involved in unfolded protein responses; SELENOI catalyzes phosphatidylethanolamine synthesis; SELENOK, SELENON, and SELENOT participate in calcium homeostasis regulation; and the biological significance of thioredoxin reductase 3 in the ER remains unexplored despite its established function in the thioredoxin system. This review examines recent research advances regarding ER SELENOs in GLMDs and aims to provide insights on ER-related pathology through SELENOs regulation.
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Retículo Endoplasmático , Metabolismo dos Lipídeos , Selenoproteínas , Selenoproteínas/metabolismo , Humanos , Retículo Endoplasmático/metabolismo , Animais , Metabolismo dos Lipídeos/fisiologia , Transtornos do Metabolismo dos Lipídeos/metabolismo , Transtornos do Metabolismo dos Lipídeos/patologia , Transtornos do Metabolismo de Glucose/metabolismo , Transtornos do Metabolismo de Glucose/patologia , Glucose/metabolismoRESUMO
Introduction: The incidence of biliary system diseases has been continuously increasing in the past decade. Biliary system diseases bring a heavy burden to humanity and society. However, the specific etiology and pathogenesis are still unknown. The biliary system, as a bridge between the liver and intestine, plays an indispensable role in maintaining the physiological metabolism of the body. Therefore, prevention and treatment of biliary diseases are crucial. It is worth noting that the microorganisms participate in the lipid metabolism of the bile duct, especially the largest proportion of intestinal bacteria. Methods: We systematically reviewed the intestinal microbiota in patients with gallstones (GS), non-calculous biliary inflammatory, and biliary tract cancer (BTC). And searched Pubmed, Embase and Web of science for research studies published up to November 2023. Results: We found that the abundance of Faecalibacterium genus is decreased in GS, primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and BTC. Veillonella, Lactobacillus, Streptococcus and Enterococcus genus were significantly increased in PSC, PBC and BTC. Interestingly, we found that the relative abundance of Clostridium was generally reduced in GS, PBC and BTC. However, Clostridium was generally increased in PSC. Discussion: The existing research mostly focuses on exploring the mechanisms of bacteria targeting a single disease. Lacking comparison of multiple diseases and changes in bacteria during the disease process. We hope to provide biomarkers forearly diagnosis of biliary system diseases and provide new directions for the mechanism of intestinal microbiota in biliary diseases.
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Doenças Biliares , Microbioma Gastrointestinal , Humanos , Doenças Biliares/microbiologia , Bactérias/classificação , Bactérias/isolamento & purificação , Bactérias/metabolismo , Cálculos Biliares/microbiologia , Faecalibacterium , Lactobacillus , Sistema Biliar/microbiologia , Neoplasias do Sistema Biliar/microbiologia , Clostridium/isolamento & purificação , Colangite Esclerosante/microbiologia , Enterococcus , Streptococcus/isolamento & purificaçãoRESUMO
The angiotensin-converting enzyme 2 (ACE2) is a primary cell surface viral binding receptor for SARS-CoV-2, so finding new regulatory molecules to modulate ACE2 expression levels is a promising strategy against COVID-19. In the current study, we utilized islet organoids derived from human embryonic stem cells (hESCs), animal models and COVID-19 patients to discover that fibroblast growth factor 7 (FGF7) enhances ACE2 expression within the islets, facilitating SARS-CoV-2 infection and resulting in impaired insulin secretion. Using hESC-derived islet organoids, we demonstrated that FGF7 interacts with FGF receptor 2 (FGFR2) and FGFR1 to upregulate ACE2 expression predominantly in ß cells. This upregulation increases both insulin secretion and susceptibility of ß cells to SARS-CoV-2 infection. Inhibiting FGFR counteracts the FGF7-induced ACE2 upregulation, subsequently reducing viral infection and replication in the islets. Furthermore, retrospective clinical data revealed that diabetic patients with severe COVID-19 symptoms exhibited elevated serum FGF7 levels compared to those with mild symptoms. Finally, animal experiments indicated that SARS-CoV-2 infection increased pancreatic FGF7 levels, resulting in a reduction of insulin concentrations in situ. Taken together, our research offers a potential regulatory strategy for ACE2 by controlling FGF7, thereby protecting islets from SARS-CoV-2 infection and preventing the progression of diabetes in the context of COVID-19.