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Immobilization of imidazole molecules as proton carriers into MOFs to facilitate proton conduction is a general strategy for developing high proton conductive materials. Herein, we designed two imidazole substituted phthalic acid ligands and constructed two novel MOFs, {[Zr6(OH)16(H3L1)4]Cl8·20H2O}n [Zr-MOF; H3L1 = 2-(1H-imidazol-4-yl) methylaminoterephthalic acid] and {Gd(HCOO)(H2L2)2}n [Gd-MOF; H3L2 = 5-(1H-imidazol-4-yl)methylaminoisophthalic acid] and fully studied their porous nature, stability and water-assisted proton conduction. The resulting Zr-MOF exhibits a high proton conductivity of 1.82 × 10-2 S cm-1 at 98% RH and 80 °C, while Gd-MOF has a proton conductivity of 3.01 × 10-3 S cm-1 at 98% RH and 60 °C.
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The gut-brain axis has recently emerged as a crucial link in the development and progression of Parkinson's disease (PD). Dysregulation of the gut microbiota has been implicated in the pathogenesis of this disease, sparking growing interest in the quest for non-invasive biomarkers derived from the gut for early PD diagnosis. Herein, an artificial intelligence-guided gut-microenvironment-triggered imaging sensor (Eu-MOF@Au-Aptmer) to achieve non-invasive, accurate screening for various stages of PD is presented. The sensor works by analyzing α-Syn in the gut using deep learning algorithms. By monitoring changes in α-Syn, the sensor can predict the onset of PD with high accuracy. This work has the potential to revolutionize the diagnosis and treatment of PD by allowing for early intervention and personalized treatment plans. Moreover, it exemplifies the promising prospects of integrating artificial intelligence (AI) and advanced sensors in the monitoring and prediction of a broad spectrum of diseases and health conditions.
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Inteligencia Artificial , Microbioma Gastrointestinal , Enfermedad de Parkinson , Enfermedad de Parkinson/diagnóstico por imagen , Humanos , Biomarcadores/metabolismo , Aprendizaje Profundo , Eje Cerebro-Intestino , Animales , Técnicas Biosensibles/métodosRESUMEN
The pancreatic ß cell synthesizes, packages, and secretes insulin in response to glucose-stimulation to maintain blood glucose homeostasis. Under diabetic conditions, a subset of ß cells fail and lose expression of key transcription factors (TFs) required for insulin secretion. Among these TFs is Pancreatic and duodenal homeobox 1 (PDX1), which recruits a unique subset of transcriptional coregulators to modulate its activity. Here we describe a novel interacting partner of PDX1, the Staphylococcal Nuclease and Tudor domain-containing protein (SND1), which has been shown to facilitate protein-protein interactions and transcriptional control through diverse mechanisms in a variety of tissues. PDX1:SND1 interactions were confirmed in rodent ß cell lines, mouse islets, and human islets. Utilizing CRISPR-Cas9 gene editing technology, we deleted Snd1 from the mouse ß cell lines, which revealed numerous differentially expressed genes linked to insulin secretion and cell proliferation, including limited expression of Glp1r. We observed Snd1 deficient ß cell lines had reduced cell expansion rates, GLP1R protein levels, and limited cAMP accumulation under stimulatory conditions, and further show that acute ablation of Snd1 impaired insulin secretion in rodent and human ß cell lines. Lastly, we discovered that PDX1:SND1 interactions were profoundly reduced in human ß cells from donors with type 2 diabetes (T2D). These observations suggest the PDX1:SND1 complex formation is critical for controlling a subset of genes important for ß cell function and is targeted in diabetes pathogenesis.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Animales , Humanos , Ratones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Endonucleasas/genética , Endonucleasas/metabolismo , Expresión Génica , Regulación de la Expresión Génica , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Transactivadores/genética , Transactivadores/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Dominio TudorRESUMEN
BACKGROUND: Cholangitis is common in patients with biliary atresia following Kasai portoenterostomy (KPE). The prompt use of empiric antibiotics is essential due to the lack of identified microorganisms. The authors aimed to validate a severity grading system to guide empiric antibiotic therapy in the management of post-KPE cholangitis. MATERIALS AND METHODS: This multicenter, prospective, randomized, open-label study recruited patients with post-KPE cholangitis and was conducted from January 2018 to December 2019. On admission, patients were categorized into mild, moderate, and severe cholangitis according to the severity grading system. Patients in the mild cholangitis group were randomized to receive cefoperazone sodium tazobactam sodium (CSTS) or meropenem (MEPM). Patients with severe cholangitis were randomized to treatment with MEPM or a combination of MEPM plus immunoglobulin (MEPM+IVIG). Patients with moderate cholangitis received MEPM. RESULTS: The primary endpoint was duration of fever (DOF). Secondary outcomes included blood culture, length of hospital stay, incidence of recurrent cholangitis, jaundice clearance rate, and native liver survival (NLS). For mild cholangitis, DOF, and length of hospital stay were similar between those treated with CSTS or MEPM (all P >0.05). In addition, no significant difference in recurrence rate, jaundice clearance rate, and NLS was observed between patients treated with CSTS and MEPM at 1-month, 3-month, and 6-month follow-up. In patients with moderate cholangitis, the DOF was 36.00 (interquartile range: 24.00-48.00) h. In severe cholangitis, compared with MEPM, MEPM+IVIG decreased DOF and improved liver function by reducing alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and direct bilirubin at 1-month follow-up. However, recurrence rate, jaundice clearance rate, and NLS did not differ significantly between MEPM+IVIG and MEPM at 1-month, 3-month, and 6-month follow-up. CONCLUSIONS: In patients with post-KPE cholangitis, MEPM is not superior to CSTS for the treatment of mild cholangitis. However, MEPM+IVIG treatment was associated with better short-term clinical outcomes in patients with severe cholangitis.
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Atresia Biliar , Colangitis , Ictericia , Niño , Humanos , Lactante , Portoenterostomía Hepática/efectos adversos , Estudios Prospectivos , Inmunoglobulinas Intravenosas , Atresia Biliar/cirugía , Atresia Biliar/complicaciones , Colangitis/tratamiento farmacológico , Colangitis/etiología , Ictericia/complicaciones , Antibacterianos/uso terapéutico , Meropenem , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Background: Hirschsprung-associated enterocolitis (HAEC) is a common and life-threatening complication of Hirschsprung's disease (HSCR), which can occur before and after surgery. The aim of this study was to identify the risk factors associated with the development of HAEC. Methods: We retrospectively reviewed the medical records of HSCR patients admitted to the Children's Hospital of Shanxi Province, China, between January 2011 and August 2021. Diagnosis of HAEC was made using a scoring system with cutoff values ≥4 and included the patient's history, physical examination, and radiological and laboratory findings. The results are shown as frequency (%). The chi-square test was used to analyze a single factor with a significance level of P < 0.05. Logistic regression analysis was used to analyze multiple factors. Results: A total of 324 patients were included in this study, with 266 males and 58 females. In total, 34.3% (111/324) of patients had HAEC, including 85 males and 26 females; 18.9% (61/324) of patients had preoperative HAEC; and 15.4% (50/324) of patients had postoperative HAEC within one year after surgery. Gender, age at definitive therapy, and feeding methods were not found to be associated with preoperative HAEC in univariate analysis. Respiratory infection was associated with preoperative HAEC (P = 0.00003). No association was found between gender and age at definitive therapy and postoperative HAEC. Postoperative HAEC was associated with microcytic hypochromic anemia (P = 0.00058), preoperative history of HAEC (P = 0.00120), the creation of a preoperative stoma (P = 0.00097), long segment or total colon HSCR (P = 0.00057), and hypoalbuminemia (P = 0.03225). Regression analysis showed that microcytic hypochromic anemia (OR=2.716, 95% CI = 1.418-5.203, P = 0.003), preoperative history of HAEC (OR=2.814, 95% CI = 1.429-5.542, P = 0.003), the creation of a preoperative stoma (OR=2.332, 95% CI = 1.003-5.420, P = 0.049), and long segment or total colon HSCR (OR=2.167, 95% CI = 1.054-4.456, P = 0.035) were associated with postoperative HAEC. Conclusion: This study revealed that the incidence of preoperative HAEC at our hospital was associated with respiratory infections. In addition, microcytic hypochromic anemia, preoperative history of HAEC, the creation of a preoperative stoma, and long segment or total colon HSCR were risk factors of postoperative HAEC. The most important finding of this study was that microcytic hypochromic anemia was a risk factor for postoperative HAEC, which has been rarely reported. Further studies with larger sample sizes are necessary to confirm these findings.
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The development of disease detection by biosensors represents one of the key components of medical science. However, millions of people are still misdiagnosed each year due to the poor efficacy and thermal instability of biosensors. Using horseradish peroxidase (HRP) as a paradigm, we offer a rational design strategy to optimize the thermostability and activity of biosensors by biomimetic mineralization. To overcome the weak thermostability of the biosensor, the mineralization of Fe-MOF forms an armor on HRP that protects against high temperature. Additionally, the biomimetic mineralization HRP@Fe-MOF can double-catalyze the TMB/H2O2 chromogenic system for color development. The biosensor can also be recycled through simple heat treatment due to the thermally stable aptamer and biomimetic mineralization HRP@Fe-MOF. The optical biosensor based on this sensitive spectral transformation was successfully developed for the measurement of AßO with an outstanding linear range (0.0001-10 nM) and a low limit of detection (LOD) of 0.03 pM. This promising platform will open up new avenues for the detection of AßO in the early diagnosis of Alzheimer's disease (AD).
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Enfermedad de Alzheimer , Técnicas Biosensibles , Humanos , Peroxidasa de Rábano Silvestre , Biomimética , Peróxido de Hidrógeno , Enfermedad de Alzheimer/diagnósticoRESUMEN
G protein-coupled receptors (GPCRs) in intestinal enteroendocrine cells (EECs) respond to nutritional, neural, and microbial cues and modulate the release of gut hormones. Here we show that Gpr17, an orphan GPCR, is co-expressed in glucagon-like peptide-1 (GLP-1)-expressing EECs in human and rodent intestinal epithelium. Acute genetic ablation of Gpr17 in intestinal epithelium improves glucose tolerance and glucose-stimulated insulin secretion (GSIS). Importantly, inducible knockout (iKO) mice and Gpr17 null intestinal organoids respond to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP). In an in vitro EEC model, overexpression or agonism of Gpr17 reduces voltage-gated calcium currents and decreases cyclic AMP (cAMP) production, and these are two critical factors regulating GLP-1 secretion. Together, our work shows that intestinal Gpr17 signaling functions as an inhibitory pathway for GLP-1 secretion in EECs, suggesting intestinal GPR17 is a potential target for diabetes and obesity intervention.
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Células Enteroendocrinas/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Mucosa Intestinal/metabolismo , Proteínas del Tejido Nervioso/genética , Receptores Acoplados a Proteínas G/genética , Animales , Glucemia/análisis , Calcio/metabolismo , Línea Celular , AMP Cíclico/metabolismo , Diabetes Mellitus/patología , Femenino , Polipéptido Inhibidor Gástrico/metabolismo , Prueba de Tolerancia a la Glucosa , Células HEK293 , Células HeLa , Humanos , Incretinas/metabolismo , Insulina/metabolismo , Secreción de Insulina/fisiología , Mucosa Intestinal/citología , Masculino , Ratones , Ratones Noqueados , Obesidad/patología , Receptores de la Hormona Gastrointestinal/metabolismoRESUMEN
Insulin resistance impairs postprandial glucose uptake through glucose transporter type 4 (GLUT4) and is the primary defect preceding type 2 diabetes. We previously generated an insulin-resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in the muscle, adipose, and neuronal subpopulations. However, the rate of diabetes in GIRKO mice remained low prior to 6 months of age on normal chow diet (NCD), suggesting that additional factors/mechanisms are responsible for adverse metabolic effects driving the ultimate progression of overt diabetes. In this study, we characterized the metabolic phenotypes of the adult GIRKO mice acutely switched to high-fat diet (HFD) feeding in order to identify additional metabolic challenges required for disease progression. Distinct from other diet-induced obesity (DIO) and genetic models (e.g., db/db mice), GIRKO mice remained leaner on HFD feeding, but developed other cardinal features of insulin resistance syndrome. GIRKO mice rapidly developed hyperglycemia despite compensatory increases in ß-cell mass and hyperinsulinemia. Furthermore, GIRKO mice also had impaired oral glucose tolerance and a limited glucose-lowering benefit from exendin-4, suggesting that the blunted incretin effect contributed to hyperglycemia. Secondly, GIRKO mice manifested severe dyslipidemia while on HFD due to elevated hepatic lipid secretion, serum triglyceride concentration, and lipid droplet accumulation in hepatocytes. Thirdly, GIRKO mice on HFD had increased inflammatory cues in the gut, which were associated with the HFD-induced microbiome alterations and increased serum lipopolysaccharide (LPS). In conclusion, our studies identified important gene/diet interactions contributing to diabetes progression, which might be leveraged to develop more efficacious therapies.
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Diabetes Mellitus Tipo 2 , Dieta Alta en Grasa , Intolerancia a la Glucosa , Transportador de Glucosa de Tipo 4 , Hiperglucemia , Resistencia a la Insulina , Animales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Transportador de Glucosa de Tipo 4/biosíntesis , Transportador de Glucosa de Tipo 4/metabolismo , Hiperglucemia/sangre , Hiperglucemia/etiología , Hiperglucemia/metabolismo , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
GPR17 is a G-protein-coupled receptor (GPCR) implicated in the regulation of glucose metabolism and energy homeostasis. Such evidence is primarily drawn from mouse knockout studies and suggests GPR17 as a potential novel therapeutic target for the treatment of metabolic diseases. However, links between human GPR17 genetic variants, downstream cellular signaling, and metabolic diseases have yet to be reported. Here, we analyzed GPR17 coding sequences from control and disease cohorts consisting of individuals with adverse clinical metabolic deficits including severe insulin resistance, hypercholesterolemia, and obesity. We identified 18 nonsynonymous GPR17 variants, including eight variants that were exclusive to the disease cohort. We characterized the protein expression levels, membrane localization, and downstream signaling profiles of nine GPR17 variants (F43L, V96M, V103M, D105N, A131T, G136S, R248Q, R301H, and G354V). These nine GPR17 variants had similar protein expression and subcellular localization as wild-type GPR17; however, they showed diverse downstream signaling profiles. GPR17-G136S lost the capacity for agonist-mediated cAMP, Ca2+, and ß-arrestin signaling. GPR17-V96M retained cAMP inhibition similar to GPR17-WT, but showed impaired Ca2+ and ß-arrestin signaling. GPR17-D105N displayed impaired cAMP and Ca2+ signaling, but unaffected agonist-stimulated ß-arrestin recruitment. The identification and functional profiling of naturally occurring human GPR17 variants from individuals with metabolic diseases revealed receptor variants with diverse signaling profiles, including differential signaling perturbations that resulted in GPCR signaling bias. Our findings provide a framework for structure-function relationship studies of GPR17 signaling and metabolic disease.
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Síndrome Metabólico/genética , Mutación Missense , Receptores Acoplados a Proteínas G/genética , Transducción de Señal , Calcio/metabolismo , AMP Cíclico/metabolismo , Células HEK293 , Humanos , Transporte de Proteínas , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , beta-Arrestinas/metabolismoRESUMEN
High-fat diet (HFD) has been shown to accelerate Alzheimer's disease (AD) pathology, but the exact molecular and cellular mechanisms remain incompletely understood. Moreover, it is unknown whether AD mice are more susceptible to HFD-induced metabolic dysfunctions. To address these questions, we used 5xFAD mice as an Alzheimer's disease model to study the physiological and molecular underpinning between HFD-induced metabolic defects and AD pathology. We systematically profiled the metabolic parameters, the gut microbiome composition, and hippocampal gene expression in 5xFAD and wild type (WT) mice fed normal chow diet and HFD. HFD feeding impaired energy metabolism in male 5xFAD mice, leading to increased locomotor activity, energy expenditure, and food intake. 5xFAD mice on HFD had elevated circulating lipids and worsened glucose intolerance. HFD caused profound changes in gut microbiome compositions, though no difference between genotype was detected. We measured hippocampal mRNAs related to AD neuropathology and neuroinflammation and showed that HFD elevated the expression of apoptotic, microglial, and amyloidogenic genes in 5xFAD mice. Pathway analysis revealed that differentially regulated genes were involved in insulin signaling, cytokine signaling, cellular stress, and neurotransmission. Collectively, our results showed that 5xFAD mice were more susceptible to HFD-induced metabolic dysregulation and suggest that targeting metabolic dysfunctions can ameliorate AD symptoms via effects on insulin signaling and neuroinflammation in the hippocampus.
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Enfermedad de Alzheimer/metabolismo , Proteínas Amiloidogénicas/metabolismo , Dieta Alta en Grasa/efectos adversos , Inflamación Neurogénica/metabolismo , Transducción de Señal/fisiología , Enfermedad de Alzheimer/etiología , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Ingestión de Alimentos/fisiología , Metabolismo Energético/fisiología , Microbioma Gastrointestinal/genética , Expresión Génica , Genotipo , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/etiología , Hipocampo/metabolismo , Inflamación , Insulina/metabolismo , Lípidos/sangre , Locomoción/fisiología , Masculino , Ratones , Microglía/metabolismo , Inflamación Neurogénica/etiología , ARN Mensajero/metabolismo , Factores de Riesgo , Transmisión Sináptica/genéticaRESUMEN
To early effectively detect amyloid-beta (Aß) oligomers, a label-free reusable aptasensor was designed. This aptasensor based on a luminescent nanoscale lanthanum-based metal-organic framework (L-MOF)-armored single-stranded DNA antibody (MOF-armored-anti-DNA antibody) as signal tags and aptamer bound to magnetic beads (Apt-MB) as capture probe. The reusable aptasensor combines signal tag and capture probe with antigen-antibody interaction. When the reusable aptasensor is formed, the strong fluorescence intensity of L-MOF will "turn off" by photo-induced electron transfer from excited states to an unfilled d shell of iron cations on the nanoparticle surface. Upon the presence of Aß oligomers in serum samples, they can be especially distinguished with the Aß oligomers aptamer in capture probes and then signal tags are released into the solution for developing the fluorescence aptasensor under excitation/emission 365 nm/430 nm. Meanwhile, the aptamer was recovered from the complex of Aß oligomers/Apt-MB by heat treatment. When the temperature returns to room temperature, the recovered aptamer in the capture probe can once again bound to the MOF-armored-anti-DNA antibody for reuse. The label-free reusable aptasensor system detection has high sensitivity and selectivity toward Aß oligomers (LOD = 0.4 pg/mL) and an excellent linear range (0.001-100 ng/mL). This strategy is a fruitful step for the development of reusable aptasensor and may turn on new avenues for the applications of Aß oligomer detection in clinical diagnosis.Graphical abstract.
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Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/sangre , Aptámeros de Nucleótidos/química , Técnicas Biosensibles/métodos , Péptidos beta-Amiloides/química , Anticuerpos Inmovilizados/inmunología , Aptámeros de Nucleótidos/inmunología , ADN de Cadena Simple/química , ADN de Cadena Simple/inmunología , Colorantes Fluorescentes/química , Humanos , Separación Inmunomagnética , Lantano/química , Límite de Detección , Nanopartículas de Magnetita/química , Estructuras Metalorgánicas/química , Estructura Cuaternaria de Proteína , Espectrometría de FluorescenciaRESUMEN
A new enantioselective Michael addition between 3-(3-hydroxy-1H-pyrazol-1-yl)oxindole, a new synthon generated from isatin N,N'-cyclic azomethine imine 1,3-dipole, and ß-nitrostyrene has been disclosed. A series of chiral 3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl) disubstituted oxindoles were obtained in excellent results (up to 97% yield, up to 94% ee) with moderate to good diastereoselectivities (up to 4.3:1 dr).
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AIM: We evaluated the demographic of biliary atresia (BA) children from twins family and aimed to investigated what it can add to the twins' literature and our understanding of the disease. METHODS: This study contains 11 medical centers in mainland China and the medical record of twins with BA was retrospectively analyzed from January 2012 to December 2018. Follow-up was carried out by out-patient review and questionnaire. RESULTS: The study included 19 twin pairs in whom there was discordance for BA. Sixteen (84.2%) affected twin underwent Kasai Procedure (KP); median age at KP was 78 (49-168) days. There were ten affected twins that became jaundice-free at 3 months post-KP, and eight occurred with different degrees of cholangitis post-KP. Six affected twins received Liver Transplantation (LT) successfully. The 2 year native liver survival rate and the 2 year overall survival rate of affected twins were 61.1 and 94.4%, respectively. There were three affected monozygotic (MZ) twins and one healthy co-twin with BA-associated congenital malformations, all of which were cardiac malformations. The number of virus infection of affected MZ twins was significantly more (p = 0.04) than affected dizygotic (DZ) twin. CONCLUSIONS: Discordance for BA in 19 pairs of twins supported that BA may be related to genetic phenotype or penetrance. The difference in genetic background between MZ and DZ affects the susceptibility of the host to virus infection. High acceptance of KP (84.2%) in our study implied a high motivation for treatment for twins with BA. Delays of KP (78 days) in affected twin may be related to the postnatal gradual onset and the late diagnosis.
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Atresia Biliar/cirugía , Portoenterostomía Hepática/métodos , Gemelos Monocigóticos , Atresia Biliar/epidemiología , China/epidemiología , Enfermedades en Gemelos , Femenino , Humanos , Recién Nacido , Trasplante de Hígado , Masculino , Morbilidad/tendencias , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia/tendenciasRESUMEN
An abnormal [3 + 2]-cycloaddition and highly effective and convenient one-step preparation of tetracyclic bispirooxindoles containing two all-carbon quaternary spirocenters from isatin N,N'-cyclic azomethine imine 1,3-dipole and 3-methyleneoxindole in the presence of catalytic organic base has been disclosed. A variety of bispirooxindoles bearing a dinitrogen heterocycle with four adjacent cycles have been obtained in excellent yields (up to 95%) and diastereoselectivities (>99:1) under mild conditions.
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Amyloid-beta (Aß) oligomers causing neuron damage are regarded as potential therapeutic targets and diagnostic markers for Alzheimer's disease (AD). A homogeneous turn-on fluorometric aptasensor is described for Aß oligomers. It is highly selective and non-invasive and based on (a) the use of a luminescent metal-organic framework carrying aptamer-modified AuNPs (L-MOF/Apt-Au) as tracking agent, and (b) enzyme-assisted target recycling signal amplification. The tracking agent does not emit fluoresce by fluorescence resonance energy transfer (FRET) between the luminescent MOF as donor and Apt-Au as the acceptor under the excitation wavelength of 466 nm. When Aß oligomers are added to the tracking agent solution, the Apt-Au on tracking agent can preferentially bind with Aß oligomers and then be released. This turns the "off" signal of the luminescent MOF tracer to the "on" state. The enzyme (Rec Jf exonuclease) added into the supernatant further improves sensitivity due to enzyme-assisted target-recycling signal amplification. The assay has an excellent linear response to Aß oligomers from 1.0 pM to 10 nM, with a detection limit of 0.3 pM. This homogeneous turn-on fluorometric method is expected to have potential and applications in clinical diagnosis. Graphical abstractSchematic representation of fluorometric assay for amyloid-ß oligomers based on luminescence metal-organic framework nanocomposites as tracking agent with exonuclease-assisted target recycling.
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Péptidos beta-Amiloides/análisis , Aptámeros de Nucleótidos , Fluorometría/métodos , Estructuras Metalorgánicas/química , Reciclaje/métodos , Enfermedad de Alzheimer/diagnóstico , Técnicas Biosensibles/métodos , Exonucleasas , Oro , Humanos , Límite de Detección , Nanopartículas del Metal/químicaRESUMEN
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BACKGROUND: Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) control energy homeostasis by sensing hormonal and nutrient cues and activating secondary melanocortin sensing neurons. We identified the expression of a G protein-coupled receptor, Gpr17, in the ARH and hypothesized that it contributes to the regulatory function of POMC neurons on metabolism. METHODS: In order to test this hypothesis, we generated POMC neuron-specific Gpr17 knockout (PGKO) mice and determined their energy and glucose metabolic phenotypes on normal chow diet (NCD) and high-fat diet (HFD). RESULTS: Adult PGKO mice on NCD displayed comparable body composition and metabolic features measured by indirect calorimetry. By contrast, PGKO mice on HFD demonstrated a sexually dimorphic phenotype with female PGKO mice displaying better metabolic homeostasis. Notably, female PGKO mice gained significantly less body weight and adiposity (p < 0.01), which was associated with increased energy expenditure, locomotor activity, and respiratory quotient, while males did not have an overt change in energy homeostasis. Though PGKO mice of both sexes had comparable glucose and insulin tolerance, detailed analyses of liver gene expression and serum metabolites indicate that PGKO mice could have reduced gluconeogenesis and increased lipid utilization on HFD. To elucidate the central-based mechanism(s) underlying the better-preserved energy and glucose homeostasis in PGKO mice on HFD, we examined the electrophysiological properties of POMC neurons and found Gpr17 deficiency led to increased spontaneous action potentials. Moreover, PGKO mice, especially female knockouts, had increased POMC-derived alpha-melanocyte stimulating hormone and beta-endorphin despite a comparable level of prohormone POMC in their hypothalamic extracts. CONCLUSIONS: Gpr17 deficiency in POMC neurons protects metabolic homeostasis in a sex-dependent manner during dietary and aging challenges, suggesting that Gpr17 could be an effective anti-obesity target in specific populations with poor metabolic control.
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Peso Corporal/fisiología , Encéfalo/metabolismo , Resistencia a la Insulina/fisiología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Envejecimiento/metabolismo , Animales , Dieta Alta en Grasa , Metabolismo Energético/fisiología , Femenino , Homeostasis/fisiología , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Actividad Motora/fisiología , Proteínas del Tejido Nervioso/genética , Receptores Acoplados a Proteínas G/genética , Factores SexualesRESUMEN
Surface recombination at the photoanode/electrolyte junction seriously impedes photoelectrochemical (PEC) performance. Through coating of photoanodes with oxygen evolution catalysts, the photocurrent can be enhanced; however, current systems for water splitting still suffer from high recombination. We describe herein a novel charge transfer system designed with BiVO4 as a prototype. In this system, porphyrins act as an interfacial-charge-transfer mediator, like a volleyball setter, to efficiently suppress surface recombination through higher hole-transfer kinetics rather than as a traditional photosensitizer. Furthermore, we found that the introduction of a "setter" can ensure a long lifetime of charge carriers at the photoanode/electrolyte interface. This simple interface charge-modulation system exhibits increased photocurrent density from 0.68 to 4.75â mA cm-2 and provides a promising design strategy for efficient photogenerated charge separation to improve PEC performance.
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A visualization strategy is described for the detection of clenbuterol (CLB). It is using of antibody against dsDNA and G-quadruplex/hemin labeled on a metal organic framework of type MIL-101(Fe) (G-quadruplex/hemin-anti-DNA/MIL-101) acting as a peroxidase mimetic, and magnetic beads modified with aptamer and complementary DNA (MB/Apt-cDNA) as capture probes. The detection reagent was prepared via the reactions between the double stranded DNA (Apt-cDNA) in capture probes and anti-DNA in peroxidase mimetic. In the presence of CLB, the aptamer on the magnetic beads preferentially binds CLB, and the peroxidase mimetic is released to the supernatant after magnetic separation. The released peroxidase mimetic can catalyze the TMB/H2O2 chromogenic system under mild conditions. This leads to the development of a blue-green coloration whose absorbance is measured at 650 nm. The detection limit is as low as 34 fM of CLB. The method was applied to the determination of CLB in pork samples and gave results that were consistent with data obtained with an ELISA kit. Graphical abstract A visualization strategy is described for the detection of clenbuterol. The selectivity of detection system for clenbuterol is excellent compared with other interferents. The method was applied to the determination of CLB in pork samples.
Asunto(s)
Agonistas Adrenérgicos beta/análisis , Clenbuterol/análisis , Contaminación de Alimentos/análisis , Carne Roja/análisis , Porcinos , Agonistas Adrenérgicos beta/química , Animales , Anticuerpos/química , Aptámeros de Nucleótidos/química , Biomimética , Clenbuterol/química , Colorimetría , ADN/química , ADN/inmunología , G-Cuádruplex , Hemina/química , Hierro/química , Fenómenos Magnéticos , Estructuras Metalorgánicas/química , Peroxidasa/químicaRESUMEN
BACKGROUND: Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. RESULTS: We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. CONCLUSION: In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.