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ABSTRACT: Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem or progenitor cells. AML prognosis remains poor owing to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is often dysregulated in AML. We found that although PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-AKT signaling promotes nuclear factor erythroid 2-related factor 2 (NRF2) nuclear accumulation, which induces 6-phosphogluconate dehydrogenase (PGD) and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3Kγ impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3Kγ in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3Kγ pathway may, therefore, eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.
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Fosfatidilinositol 3-Quinasa Clase Ib , Leucemia Mieloide Aguda , Células Madre Neoplásicas , Vía de Pentosa Fosfato , Animales , Humanos , Ratones , Autorrenovación de las Células , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Vía de Pentosa Fosfato/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de SeñalRESUMEN
Nutrients are not only organic compounds fueling bioenergetics and biosynthesis, but also key chemical signals controlling growth and metabolism. Nutrients enormously impact the production of reactive oxygen species (ROS), which play essential roles in normal physiology and diseases. How nutrient signaling is integrated with redox regulation is an interesting, but not fully understood, question. Herein, we report that superoxide dismutase 1 (SOD1) is a conserved component of the mechanistic target of rapamycin complex 1 (mTORC1) nutrient signaling. mTORC1 regulates SOD1 activity through reversible phosphorylation at S39 in yeast and T40 in humans in response to nutrients, which moderates ROS level and prevents oxidative DNA damage. We further show that SOD1 activation enhances cancer cell survival and tumor formation in the ischemic tumor microenvironment and protects against the chemotherapeutic agent cisplatin. Collectively, these findings identify a conserved mechanism by which eukaryotes dynamically regulate redox homeostasis in response to changing nutrient conditions.
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Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Nutrientes/metabolismo , Fosforilación/fisiología , Superóxido Dismutasa-1/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Daño del ADN/fisiología , Metabolismo Energético/fisiología , Femenino , Células HEK293 , Humanos , Células MCF-7 , Ratones Endogámicos BALB C , Ratones Desnudos , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
MOTIVATION: Alternative polyadenylation (APA) is a widespread post-transcriptional regulatory mechanism across all eukaryotes. With the accumulation of genome-wide APA sites, especially those with single-cell resolution, it is imperative to develop easy-to-use visualization tools to guide APA analysis. RESULTS: We developed an R package called vizAPA for visualizing APA dynamics from bulk and single-cell data. vizAPA implements unified data structures for APA data and genome annotations. vizAPA also enables identification of genes with differential APA usage across biological samples and/or cell types. vizAPA provides four unique modules for extensively visualizing APA dynamics across biological samples and at the single-cell level. vizAPA could serve as a plugin in many routine APA analysis pipelines to augment studies for APA dynamics. AVAILABILITY AND IMPLEMENTATION: https://github.com/BMILAB/vizAPA.
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Regulación de la Expresión Génica , Poliadenilación , Eucariontes , Regiones no Traducidas 3'RESUMEN
Actin cytoskeleton is essential for root hair formation. However, the underlying molecular mechanisms of actin dynamics in root hair formation in response to abiotic stress are largely undiscovered. Here, genetic analysis showed that actin-depolymerizing protein ADF7 and actin-bundling protein VILLIN1 (VLN1) were positively and negatively involved in root hair formation of Arabidopsis respectively. Moreover, RT-qPCR, GUS staining, western blotting, and genetic analysis revealed that ADF7 played an important role in inhibiting the expression and function of VLN1 during root hair formation. Filament actin (F-actin) dynamics observation and actin pharmacological experiments indicated that ADF7-inhibited-VLN1 pathway led to the decline of F-actin bundling and thick bundle formation, as well as the increase of F-actin depolymerization and turnover to promote root hair formation. Furthermore, the F-actin dynamics mediated by ADF7-inhibited-VLN1 pathway was associated with the reactive oxygen species (ROS) accumulation in root hair formation. Finally, ADF7-inhibited-VLN1 pathway was critical for osmotic stress-induced root hair formation. Our work demonstrates that ADF7 inhibits VLN1 to regulate F-actin dynamics in root hair formation in response to osmotic stress, providing the novel evidence on the F-actin dynamics and their molecular mechanisms in root hair formation and in abiotic stress.
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Proteínas de Arabidopsis , Arabidopsis , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Actinas/genética , Actinas/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Destrina/metabolismo , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Presión Osmótica , Raíces de Plantas/genética , Raíces de Plantas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND & AIMS: Diagnosing gastric cancer (GC) while the disease remains eligible for surgical resection is challenging. In view of this clinical challenge, novel and robust biomarkers for early detection thus improving prognosis of GC are necessary. The present study is to develop a blood-based long noncoding RNA (LR) signature for the early-detection of GC. METHODS: The present 3-step study incorporated data from 2141 patients, including 888 with GC, 158 with chronic atrophic gastritis, 193 with intestinal metaplasia, 501 healthy donors, and 401 with other gastrointestinal cancers. The LR profile of stage I GC tissue samples were analyzed using transcriptomic profiling in discovery phase. The extracellular vesicle (EV)-derived LR signature was identified with a training cohort (n = 554) and validated with 2 external cohorts (n = 429 and n = 504) and a supplemental cohort (n = 69). RESULTS: In discovery phase, one LR (GClnc1) was found to be up-regulated in both tissue and circulating EV samples with an area under the curve (AUC) of 0.9369 (95% confidence interval [CI], 0.9073-0.9664) for early-stage GC (stage I/II). The diagnostic performance of this biomarker was further confirmed in 2 external validation cohorts (Xi'an cohort, AUC: 0.8839; 95% CI: 0.8336-0.9342; Beijing cohort, AUC: 0.9018; 95% CI: 0.8597-0.9439). Moreover, EV-derived GClnc1 robustly distinguished early-stage GC from precancerous lesions (chronic atrophic gastritis and intestinal metaplasia) and GC with negative traditional gastrointestinal biomarkers (CEA, CA72-4, and CA19-9). The low levels of this biomarker in postsurgery and other gastrointestinal tumor plasma samples indicated its GC specificity. CONCLUSIONS: EV-derived GClnc1 serves as a circulating biomarker for the early detection of GC, thus providing opportunities for curative surgery and improved survival outcomes.
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Gastritis Atrófica , Neoplasias Gástricas , Humanos , Biomarcadores de Tumor/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirugía , Gastritis Atrófica/diagnóstico , Gastritis Atrófica/genética , Antígeno CA-19-9 , Detección Precoz del Cáncer , MetaplasiaRESUMEN
Anodes with high capacity and long lifespan play an important role in the advanced batteries. However, none of the existing anodes can meet these two requirements simultaneously. Lithium (Li)-graphite composite anode presents great potential in balancing these two requirements. Herein, the working mechanism of Li-graphite composite anode is comprehensively investigated. The capacity decay features of the composite anode are different from those of Li ion intercalation in Li ion batteries and Li metal deposition in Li metal batteries. An intercalation and conversion hybrid storage mechanism are proposed by analyzing the capacity decay ratios in the composite anode with different initial specific capacities. The capacity decay models can be divided into four stages including Capacity Retention Stage, Relatively Independent Operation Stage, Intercalation & Conversion Coupling Stage, Pure Li Intercalation Stage. When the specific capacity is between 340 and 450 mAh g-1, its capacity decay ratio is between that of pure intercalation and conversion model. These results intensify the comprehensive understandings on the working principles in Li-graphite composite anode and present novel insights in the design of high-capacity and long-lifespan anode materials for the next-generation batteries.
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Biomass-derived materials generally exhibit uniform and highly-stable hierarchical porous structures that can hardly be achieved by conventional chemical synthesis and artificial design. When used as electrodes for rechargeable batteries, these structural and compositional advantages often endow the batteries with superior electrochemical performances. This review systematically introduces the innate merits of biomass-derived materials and their applications as the electrode for advanced rechargeable batteries, including lithium-ion batteries, sodium-ion batteries, potassium-ion batteries, and metal-sulfur batteries. In addition, biomass-derived materials as catalyst supports for metal-air batteries, fuel cells, and redox-flow batteries are also included. The major challenges for specific batteries and the strategies for utilizing biomass-derived materials are detailly introduced. Finally, the future development of biomass-derived materials for advanced rechargeable batteries is prospected. This review aims to promote the development of biomass-derived materials in the field of energy storage and provides effective suggestions for building advanced rechargeable batteries.
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High power 509 nm continuous-wave (CW) lasers have important applications in science and communication. Here we demonstrate a robust high-power single-frequency 509 nm laser system based on nonlinear phase demodulation technique and single-pass second harmonic generation (SHG) configuration. In experiments, the single-frequency fundamental wave at 1018 nm was linewidth-broadened by an electro-optical modulator and then amplified to 207 W in a ytterbium-doped fiber amplifier. In subsequent single-pass SHG stage, over 20 W CW single-frequency 509 nm laser was generated in a LiB3O5 crystal with a SHG efficiency of 9.7%. To the best of our knowledge, this is the highest reported power for CW single-frequency 509 nm laser, which could be used for advanced underwater optical communication and preparation of cesium Rydberg state.
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The relative intensity noise (RIN) characteristics of a continuous-wave diamond Raman laser are investigated for the first time. The results reveal the parasitic stimulated Brillouin scattering (SBS) that usually occurred with higher-order spatial modes in the diamond Raman resonator is a pivotal factor impacting the Raman longitudinal modes and deteriorating the RIN level. The diamond Raman laser automatically switches to single-longitudinal-mode operation and the RIN level is significantly decreased in the frequency range of 200â Hz to 1â MHz after the parasitic SBS is effectively suppressed through inserting a spatial aperture or a χ(2) nonlinear crystal into the cavity. Due to the introduction of additional nonlinear loss to the high intensity Raman fluctuations and the non-lasing spontaneous Raman modes, the χ(2) nonlinear crystal enables better performance in the RIN-level reduction compared to the spatial aperture which can only achieve SBS inhibition. The RIN reduction routes are well suited for various crystalline Raman media to achieve high power and low intensity noise laser at different wavelengths.
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BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) and SGLT1 inhibitors may have additional beneficial metabolic effects on circulating metabolites beyond glucose regulation, which could contribute to a reduction in the burden of cerebral small vessel disease (CSVD). Accordingly, we used Mendelian Randomization (MR) to examine the role of circulating metabolites in mediating SGLT2 and SGLT1 inhibition in CSVD. METHODS: Genetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations. RESULTS: A lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively. CONCLUSIONS: SGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.
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Biomarcadores , Enfermedades de los Pequeños Vasos Cerebrales , Análisis de la Aleatorización Mendeliana , Transportador 1 de Sodio-Glucosa , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Transportador 2 de Sodio-Glucosa , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Transportador 1 de Sodio-Glucosa/genética , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Transportador 1 de Sodio-Glucosa/metabolismo , Enfermedades de los Pequeños Vasos Cerebrales/genética , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/tratamiento farmacológico , Enfermedades de los Pequeños Vasos Cerebrales/sangre , Enfermedades de los Pequeños Vasos Cerebrales/metabolismo , Factores de Riesgo , Transportador 2 de Sodio-Glucosa/metabolismo , Transportador 2 de Sodio-Glucosa/genética , Biomarcadores/sangre , Medición de Riesgo , Hemoglobina Glucada/metabolismo , Variantes Farmacogenómicas , Resultado del Tratamiento , Fenotipo , Hemorragia Cerebral/genética , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/epidemiología , Factores Protectores , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Predisposición Genética a la EnfermedadRESUMEN
Muscle degeneration following rotator cuff tendon tearing is characterized by fatty infiltration and fibrosis. While tools exist for the characterization of fat, the ability to noninvasively assess muscle fibrosis is limited. The purpose of this study was to evaluate the capability of quantitative ultrashort echo time T1 (UTE-T1) and UTE magnetization transfer (UTE-MT) mapping with and without fat suppression (FS) for the differentiation of injured and control rotator cuff muscles and for the detection of fibrosis. A rat model of chronic massive rotator cuff tearing (n = 12) was used with tenotomy of the right supraspinatus and infraspinatus tendons and silicone implants to prevent healing. Imaging was performed on a 3-T scanner, and UTE-T1 mapping with and without FS and UTE-MT with and without FS for macromolecular fraction (MMF) mapping was performed. At 20 weeks postinjury, T1 and MMF were measured in the supraspinatus and infraspinatus muscles of the injured and contralateral, internal control sides. Histology was performed and connective tissue fraction (CTF) was measured, defined as the area of collagen-rich extracellular matrix divided by the total muscle area. Paired t-tests and correlation analyses were performed. Significant differences between injured and control sides were found for CTF in the supraspinatus (mean ± SD, 14.5% ± 3.9% vs. 11.3% ± 3.7%, p = 0.01) and infraspinatus (17.0% ± 5.4% vs. 12.5% ± 4.6%, p < 0.01) muscles, as well as for MMF using UTE-MT FS in the supraspinatus (9.7% ± 0.3% vs. 9.5% ± 0.2%, p = 0.04) and infraspinatus (10.9% ± 0.8% vs. 10.1% ± 0.5%, p < 0.01) muscles. No significant differences between sides were evident for T1 without or with FS or for MMF using UTE-MT. Only MMF using UTE-MT FS was significantly correlated with CTF for both supraspinatus (r = 0.46, p = 0.03) and infraspinatus (r = 0.51, p = 0.01) muscles. Fibrosis occurs in rotator cuff muscle degeneration, and the UTE-MT FS technique may be helpful to evaluate the fibrosis component, independent from the fatty infiltration process.
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Manguito de los Rotadores , Tendones , Animales , Ratas , Manguito de los Rotadores/diagnóstico por imagen , Manguito de los Rotadores/patología , Atrofia Muscular , Imagen por Resonancia Magnética/métodos , Tejido Adiposo/patologíaRESUMEN
Selected gold complexes have been regarded as promising anti-cancer agents because they can bind with protein targets containing thiol or selenol moieties, but their clinical applications were hindered by the unbiased binding towards off-target thiol-proteins. Recently, a novel gold(III)-hydride complex (abbreviated as 1) with visible light-induced thiol reactivity has been reported as potent photo-activated anticancer agents (Angew. Chem. Int. Ed., 2020, 132, 11139). To explore new strategies to stimuli this potential antitumor drug, the effect of oriented external electric fields (OEEFs) on its geometric structure, electronic properties, and chemical reactivity was systematically investigated. Results reveal that imposing external electric fields along the Au-H bond of 1 can effectively activate this bond, which is conducive to its dissociation and the binding of Au site to potential targets. Hence, this study provides a new OEEF-strategy to activate this reported gold(III)-hydride, revealing its potential application in electrochemical therapy. We anticipate this work could promote the development of more electric field-activated anticancer agents. However, further experimental research should be conducted to verify the conclusions obtained in this work.
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Antineoplásicos , Oro , Oro/química , Antineoplásicos/química , Electricidad , Compuestos de SulfhidriloRESUMEN
BACKGROUND: Colony-stimulating factor 1 receptor (CSF1R)-related disorder (CRD) is a rare autosomal dominant disease. The clinical and genetic characteristics of Chinese patients have not been elucidated. OBJECTIVE: The objective of the study is to clarify the core features and influence factors of CRD patients in China. METHODS: Clinical and genetic-related data of CRD patients in China were collected. Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Sundal MRI Severity Score were evaluated. Whole exome sequencing was used to analyze the CSF1R mutation status. Patients were compared between different sexes, mutation types, or mutation locations. RESULTS: A total of 103 patients were included, with a male-to-female ratio of 1:1.51. The average age of onset was (40.75 ± 8.58). Cognitive impairment (85.1%, 86/101) and parkinsonism (76.2%, 77/101) were the main clinical symptoms. The most common imaging feature was bilateral asymmetric white matter changes (100.0%). A total of 66 CSF1R gene mutants (22 novel mutations) were found, and 15 of 92 probands carried c.2381 T > C/p.I794T (16.30%). The MMSE and MoCA scores (17.0 [9.0], 11.90 ± 7.16) of female patients were significantly lower than those of male patients (23.0 [10.0], 16.36 ± 7.89), and the white matter severity score (20.19 ± 8.47) of female patients was significantly higher than that of male patients (16.00 ± 7.62). There is no statistical difference in age of onset between male and female patients. CONCLUSIONS: The core manifestations of Chinese CRD patients are progressive cognitive decline, parkinsonism, and bilateral asymmetric white matter changes. Compared to men, women have more severe cognitive impairment and imaging changes. c.2381 T > C/p.I794T is a hotspot mutation in Chinese patients. © 2024 International Parkinson and Movement Disorder Society.
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Mutación , Fenotipo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , China/epidemiología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Mutación/genética , Genotipo , Disfunción Cognitiva/genética , Imagen por Resonancia Magnética , Trastornos Parkinsonianos/genética , Anciano , Edad de Inicio , Adulto Joven , Receptor de Factor Estimulante de Colonias de MacrófagosRESUMEN
Rheumatoid arthritis (RA) patients have a high prevalence for depression. On the other hand, comorbid with depression is associated with worse prognosis for RA. However, little is known about the underlying mechanisms for the comorbidity between RA and depression. It remains to be elucidated which brain region is critically involved in the development of depression in RA, and whether alterations in the brain may affect pathological development of RA symptoms. Here, by combining clinical and animal model studies, we show that in RA patients, the level of depression is significantly correlated with the severity of RA disease activity and affects patients' quality of life. The collagen antibody-induced arthritis (CAIA) mouse model of RA also develops depression-like behaviors, accompanied by hyperactivity and alterations in gene expression reflecting cerebrovascular disruption in the lateral habenula (LHb), a brain region critical for processing negative valence. Importantly, inhibition of the LHb not only alleviates depression-like behaviors, but also results in rapid remission of RA symptoms and amelioration of RA-related pathological changes. Together, our study highlights a critical but previously overlooked contribution of hyperactive LHb to the comorbidity between RA and depression, suggesting that targeting LHb in conjunction with RA treatments may be a promising strategy for RA patients comorbid with depression.
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Artritis Experimental , Artritis Reumatoide , Habénula , Animales , Ratones , Humanos , Depresión/epidemiología , Calidad de Vida , Artritis Reumatoide/complicaciones , ComorbilidadRESUMEN
The consumption of a high-fat diet (HFD) has been implicated in the etiology of obesity and various neuropsychiatric disturbances, including anxiety and depression. Compelling evidence suggests that far-infrared ray (FIR) possesses beneficial effects on emotional disorders. However, the efficacy of FIR therapy in addressing HFD-induced anxiety and the underlying mechanisms remain to be elucidated. Here, we postulate that FIR emitted from a graphene-based therapeutic device may mitigate HFD-induced anxiety behaviors. The graphene-FIR modify the gut microbiota in HFD-mice, particularly by an enriched abundance of beneficial bacteria Clostridiaceae and Erysipelotrichaceae, coupled with a diminution of harmful bacteria Lachnospiraceae, Anaerovoracaceae, Holdemania and Marvinbryantia. Graphene-FIR also improved intestinal barrier function, as evidenced by the augmented expression of the tight junction protein occludin and G protein-coupled receptor 43 (GPR43). In serum level, we observed the decreased free fatty acids (FFA), lipopolysaccharides (LPS), diamine oxidase (DAO) and D-lactate, and increased the glucagon-like peptide-2 (GLP-2) levels in graphene-FIR mice. Simultaneously, inflammatory cytokines IL-6, IL-1ß, and TNF-α manifested a decrease subsequent to graphene-FIR treatment in both peripheral and central system. Notably, graphene-FIR inhibited over expression of astrocytes and microglia. We further noticed that the elevated the BDNF and decreased TLR4 and NF-κB expression in graphene-FIR group. Overall, our study reveals that graphene-FIR rescued HFD-induced anxiety via improving the intestine permeability and the integrity of blood-brain barrier, and reduced inflammatory response by down regulating TLR4/NF-κB inflammatory pathway.
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Ansiedad , Dieta Alta en Grasa , Microbioma Gastrointestinal , Grafito , Ratones Endogámicos C57BL , Animales , Dieta Alta en Grasa/efectos adversos , Masculino , Grafito/uso terapéutico , Grafito/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Ansiedad/etiología , Ansiedad/metabolismo , Rayos Infrarrojos/uso terapéutico , Obesidad/metabolismo , Ratones , Enfermedades Neuroinflamatorias/metabolismo , Ratones Obesos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacosRESUMEN
BACKGROUND: Cerebral small vessel injury, including loss of endothelial tight junctions, endothelial dysfunction, and blood-brain barrier breakdown, is an early and typical pathology for Alzheimer's disease, cerebral amyloid angiopathy, and hypertension-related cerebral small vessel disease. Whether there is a common mechanism contributing to these cerebrovascular alterations remains unclear. Studies have shown an elevation of BACE1 (ß-site amyloid precursor protein cleaving enzyme 1) in cerebral vessels from cerebral amyloid angiopathy or Alzheimer's disease patients, suggesting that vascular BACE1 may involve in cerebral small vessel injury. METHODS: To understand the contribution of vascular BACE1 to cerebrovascular impairments, we combined cellular and molecular techniques, mass spectrometry, immunostaining approaches, and functional testing to elucidate the potential pathological mechanisms. RESULTS: We observe a 3.71-fold increase in BACE1 expression in the cerebral microvessels from patients with hypertension. Importantly, we discover that an endothelial tight junction protein, occludin, is a completely new substrate for endothelial BACE1. BACE1 cleaves occludin with full-length occludin reductions and occludin fragment productions. An excessive cleavage by elevated BACE1 induces membranal accumulation of caveolin-1 and subsequent caveolin-1-mediated endocytosis, resulting in lysosomal degradation of other tight junction proteins. Meanwhile, membranal caveolin-1 increases the binding to eNOS (endothelial nitric oxide synthase), together with raised circulating Aß (ß-amyloid peptides) produced by elevated BACE1, leading to an attenuation of eNOS activity and resultant endothelial dysfunction. Furthermore, the initial endothelial damage provokes chronic reduction of cerebral blood flow, blood-brain barrier leakage, microbleeds, tau hyperphosphorylation, synaptic loss, and cognitive impairment in endothelial-specific BACE1 transgenic mice. Conversely, inhibition of aberrant BACE1 activity ameliorates tight junction loss, endothelial dysfunction, and memory deficits. CONCLUSIONS: Our findings establish a novel and direct relationship between endothelial BACE1 and cerebral small vessel damage, indicating that abnormal elevation of endothelial BACE1 is a new mechanism for cerebral small vessel disease pathogenesis.
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Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Enfermedades de los Pequeños Vasos Cerebrales , Hipertensión , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide , Animales , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Caveolina 1/genética , Caveolina 1/metabolismo , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/metabolismo , Humanos , Hipertensión/complicaciones , Ratones , Ratones Transgénicos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ocludina/metabolismo , Proteínas de Uniones Estrechas , Uniones Estrechas/metabolismoRESUMEN
Perioperative sleep disturbance may increase delirium risk. However, the role of perioperative sleep disturbance in delirium following total joint arthroplasty remains unclear. This prospective cohort study aimed to observe the delirium risk in patients with sleep disturbances. After excluding pre-existing sleep disturbances, older patients scheduled for total joint arthroplasty from July 17, 2022, to January 12, 2023, were recruited. Preoperative sleep disturbance or postoperative sleep disturbance was defined as a Chinese version of the Richards-Campbell Sleep Questionnaire (RCSQ) score of <50 during hospitalisation. A cut-off score of 25 was used to classify the severity of sleep disturbance. The primary outcome was the incidence of postoperative delirium. In all, 11.6% of cohort patients (34/294) developed delirium. After multivariate analysis, a preoperative Day 1 RCSQ score of ≤25 (odds ratio [OR] 3.62, 95% confidence interval [CI] 1.19-10.92; p = 0.02), occurrence of sleep disturbances (OR 2.76, 95% CI 1.19-6.38; p = 0.02) and RCSQ score of ≤25(OR 2.91, 95% CI 1.33-6.37; p = 0.007) postoperatively were strong independent predictors of delirium. After sensitivity analysis for daily delirium, a postoperative Day 1 RCSQ score of ≤25 (OR 9.27, 95% CI 2.72-36.15; p < 0.001) was associated with a greater risk of delirium on postoperative Day 1, with a reasonable discriminative area under the curve of 0.730. We concluded that postoperative but not preoperative sleep disturbances may be an independent factor for delirium risk. Sleep disturbance on the first night after surgery was a good predictor of subsequent delirium, no matter the nature of self-reported sleep disturbance.
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Metal-organic framework (MOF)-based mixed-matrix membranes (MMMs) represent a class of composite membranes that seamlessly integrate the properties of MOF fillers and polymer matrix into a hybrid system and have been widely used in countless advanced technologies. However, there remains a need for scalable and simple manufacturing techniques that can fabricate a MOF-based MMM with uniform dispersion. Herein, a series of MMMs with well-dispersed MOFs are constructed by a soft spray technique. In brief, by uniformly spraying metal ions onto the surface of a mixed solution containing polyvinylpyrrolidone (PVP) and organic ligands, a free-standing MMM is synthesized at the miscible liquid-liquid interface, facilitated by the dual function of metal ions. Moreover, soft spray technology can also introduce multifunctional materials into the MMM to customize performance. We have successfully introduced carbon black into a MOF-based MMM by soft spray, resulting in MMMs with excellent photothermal effects. The resulted MOF-based MMM exhibits favorable catalytic performance in the condensation reaction of benzaldehyde with primary amines, and the MOF-based MMM modified with carbon black significantly boosts the endothermic CO2 conversion. The work opens a new avenue for the development of MOF-based MMMs with a promising future.
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BACKGROUND: Brain-heart infusion agar supplemented with 4 µg/mL of vancomycin (BHI-V4) was commonly used for the detection of heterogeneous (hVISA) and vancomycin-intermediate Staphylococcus aureus (VISA). However, its diagnostic value remains unclear. This study aims to compare the diagnostic accuracy of BHI-V4 with population analysis profiling with area under the curve (PAP-AUC) in hVISA/VISA. METHODS: The protocol of this study was registered in INPLASY (INPLASY2023120069). The PubMed and Cochrane Library databases were searched from inception to October 2023. Review Manager 5.4 was used for data visualization in the quality assessment, and STATA17.0 (MP) was used for statistical analysis. RESULTS: In total, eight publications including 2153 strains were incorporated into the meta-analysis. Significant heterogeneity was evident although a threshold effect was not detected across the eight studies. The summary receiver operating characteristic (SROC) was 0.77 (95% confidence interval [CI], 0.74-0.81). The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic score and diagnostic odds ratio were 0.59 (95% CI: 0.46-0.71), 0.96 (95%CI: 0.83-0.99), 14.0 (95% CI, 3.4-57.1), 0.43 (95%CI, 0.32-0.57), 3.48(95%CI, 2.12-4.85) and 32.62 (95%CI, 8.31-128.36), respectively. CONCLUSION: Our study showed that BHI-V4 had moderate diagnostic accuracy for diagnosing hVISA/VISA. However, more high-quality studies are needed to assess the clinical utility of BHI-V4.
Asunto(s)
Antibacterianos , Pruebas de Sensibilidad Microbiana , Infecciones Estafilocócicas , Staphylococcus aureus , Vancomicina , Humanos , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/diagnóstico , Vancomicina/farmacología , Antibacterianos/farmacología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/aislamiento & purificación , Sensibilidad y Especificidad , Resistencia a la Vancomicina , Medios de Cultivo , Área Bajo la CurvaRESUMEN
Pollutants in human milk are critical for evaluating maternal internal exposure and infant external exposure. However, most studies have focused on a limited range of pollutants. Here, 15 pooled samples (prepared from 467 individual samples) of human milk from three areas of the Yangtze River Delta (YRD) in China were analyzed by gas chromatography quadrupole time-of-flight mass spectrometry. In total, 171 compounds of nine types were preliminarily identified. Among these, 16 compounds, including 2,5-di-tert-butylhydroquinone and 2-tert-butyl-1,4-benzoquinone, were detected in human milk for the first time. Partial least-squares discriminant analysis identified ten area-specific pollutants, including 2-naphthylamine, 9-fluorenone, 2-isopropylthianthrone, and benzo[a]pyrene, among pooled human milk samples from Shanghai (n = 3), Jiangsu Province (n = 6), and Zhejiang Province (n = 6). Risk index (RI) values were calculated and indicated that legacy polycyclic aromatic hydrocarbons (PAHs) contributed only 20% of the total RIs for the identified PAHs and derivatives, indicating that more attention should be paid to PAHs with various functional groups. Nine priority pollutants in human milk from the YRD were identified. The most important were 4-tert-amylphenol, caffeine, and 2,6-di-tert-butyl-p-benzoquinone, which are associated with apoptosis, oxidative stress, and other health hazards. The results improve our ability to assess the health risks posed by pollutants in human milk.