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AIM: To compare relative peripheral refraction (RPR) in Chinese school children with different refractive errors using multispectral refraction topography (MRT). METHODS: A total of 713 eyes of primary school children [172 emmetropia (E), 429 low myopia (LM), 80 moderate myopia (MM), and 32 low hypermetropia (LH)] aged 10 to 13y were analyzed. RPRs were measured using MRT without mydriasis. MRT results showed RPR at 0-15° (RPR 0-15), 15°-30° (RPR 15-30), and 30°-45° (RPR 30-45) annular in the inferior (RPR-I), superior (RPR-S), nasal (RPR-N), and temporal (RPR-T) quadrants. Spherical equivalent (SE) was detected and calculated using an autorefractor. RESULTS: There were significant differences of RPR 15-30 between groups MM [0.02 (-0.12; 0.18)] and LH [-0.13 (-0.36; 0.12)] (P<0.05), MM and E [-0.06 (-0.20; 0.10)] (P<0.05), and LM [-0.02 (-0.15; 0.15)] and E (P<0.05). There were also significant differences of RPR 30-45 between groups MM [0.45 (0.18; 0.74)] and E [0.29 (-0.09; 0.67)] (P<0.05), and LM [0.44 (0.14; 0.76)] and E (P<0.001). RPR values increased from the hyperopic to medium myopic group in each annular. There were significant differences of RPR-S between groups MM [-0.02 (-0.60; 0.30)] and E [-0.44 (-0.89; -0.04)] (P<0.001), and LM [-0.28 (-0.71; 0.12)] and E (P<0.05). There were also significant differences of RPR-T between groups MM [0.37 (0.21; 0.78)] and LH [0.14 (-0.52; 0.50)] (P<0.05), LM [0.41 (0.06; 0.84)] and LH (P<0.05), and LM and E [0.29 (-0.10; 0.68), P<0.05]. A Spearman's correlation analysis showed a negative correlation between RPR and SE in the 15°-30° (P=0.005), 30°-45° (P<0.05) annular (P=0.002), superior (P<0.001), and temporal (P=0.001) quadrants. CONCLUSION: Without pupil dilation, values for RPR 15-30, 30-45, RPR-S, and T shows significant differences between myopic eyes and emmetropia, and the differences are negatively correlated with SE.
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AIM: To investigate the impact of hsa_circ_0007482 on the proliferation and apoptosis of human pterygium fibroblasts (HPFs) and its correlation with the severity grades of pterygium. METHODS: Pterygium and normal conjunctival tissues were collected from the superior area of the same patient's eye (n=33). The correlation between pterygium severity and hsa_circ_0007482 expression using quantitative reverse-transcription polymerase chain reaction (RT-qPCR) were analyzed. Three distinct siRNA sequences targeting hsa_circ_0007482, along with a negative control sequence, were transfected into HPFs. Cell proliferation was assessed using the cell counting kit-8. Expression levels of Ki67, proliferating cell nuclear antigen (PCNA), Cyclin D1, Bax, B-cell lymphoma-2 (Bcl-2), and Caspase-3 were measured via RT-qPCR. Immunofluorescence staining was employed to detect Ki67 and vimentin expressions. Apoptosis was evaluated using flow cytometry. RESULTS: Hsa_circ_0007482 expression was significantly higher in pterygium tissues compared to normal conjunctival tissues (P<0.001). Positive correlations were observed between hsa_circ_0007482 expression and pterygium severity, thickness, and vascular density. Knockdown of hsa_circ_0007482 inhibited cell proliferation, reducing the mRNA expression of Ki67, PCNA, and Cyclin D1 in HPFs. Hsa_circ_0007482 knockdown induced apoptosis, increasing mRNA expression levels of Bax and Caspase-3, while decreasing Bcl-2 expression in HPFs. Additionally, hsa_circ_0007482 knockdown attenuated vimentin expression in HPFs. CONCLUSION: The downregulation of hsa_circ_0007482 effectively hampers cell proliferation and triggers apoptosis in HPFs. There are discernible positive correlations detected between the expression of hsa_circ_0007482 and the severity of pterygium.
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The existing surgery timetable is very simple, not user-friendly, and has very limited information. This article outlines the creation of a surgical dynamic dashboard for users, using Microsoft Power BI. The dashboard was developed based on in-depth interviews with the surgical team members to determine their requirements. The outcome of dashboard was evaluated by 5-likert scale questionnaire to measure satisfaction of all surgical team members. All team members were very satisfied with the dashboard compared to the existing surgery timetable. In addition, with the function of auto-generated analytic reports through data criteria selection on the dashboard saved time on manually generating reports. This study supports to replace the existing surgery timetable by the user-centric and real time surgical dashboard.
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Interfaz Usuario-Computador , HumanosRESUMEN
Sestrin2 is a highly conserved protein that can be induced under various stress conditions. Researches have revealed that the signaling pathway of the mammalian target of rapamycin (mTOR) is essential in modulating both glucose and lipid metabolism. However, the precise involvement of Sestrin2 in the hypothalamus, particularly in pro-opiomelanocortin (POMC) neurons, in control of energy homeostasis remains uncertain. In this study, we aimed to investigate the functional role of Sestrin2 in hypothalamic POMC neurons in regulation of energy balance, as well as revealing the underlying mechanisms. Therefore, cre-dependent AAV virus encoding or silencing Sestrin2 was injected into the hypothalamic ARC of pomc-cre transgenic mice. The results demonstrated that Sestrin2 overexpression in POMC neurons ameliorated high-fat diet (HFD)-induced obesity and increased energy expenditure. Conversely, Sestrin2 deficiency in POMC neurons predisposed mice to HFD induced obesity. Additionally, the thermogenesis of brown adipose tissue and lipolysis of inguinal white adipose tissue were both enhanced by the increased sympathetic nerve innervation in Sestrin2 overexpressed mice. Further exploration revealed that Sestrin2 overexpression inhibited the mTOR signaling pathway in hypothalamic POMC neurons, which may account for the alleviation of systematic metabolic disturbance induced by HFD in these mice. Collectively, our findings demonstrate that Sestrin2 in POMC neurons plays a pivotal role in maintaining energy balance in a context of HFD-induced obesity by inhibiting the mTOR pathway, providing new insights into how hypothalamic neurons respond to nutritional signals to protect against obesity-associated metabolic dysfunction.
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Hyperplasia of mammary glands (HMG) is considered a precancerous condition with a risk of malignant transformation, highlighting the necessity of proactive treatment in the early stages. Transdermal drug delivery offers significant advantages such as painlessness, absence of first-pass effect, and good patient compliance. However, the unique structure of the breast requires transdermal formulations for treating mammary hyperplasia to exhibit higher levels of safety and comfort. We have formulated an ancient topical formula called 'Muxiang Bing,' comprising traditional Chinese medicines Aucklandiae Radix (AR) and Rehmanniae Radix (RR), for the treatment of HMG. This formula has been transformed into a gel paster in the form of nipple cover for trans-nipple-areola delivery. In our investigations, we observed that the optimal formulation of the Muxiang gel plaster demonstrated enhanced permeation facilitated by AR's effect on RR. Furthermore, pre-treatment with the Muxiang gel plaster improved mammary tissue morphology, hormone levels, oxidative stress, aberrant cell proliferation, and damage in rat models, thus preventing and ameliorating mammary hyperplasia. The Muxiang gel plaster exhibited low skin irritability in rats, and long-term use did not cause harm to their internal organs or blood cells, indicating its safety and efficacy.
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Administración Cutánea , Medicamentos Herbarios Chinos , Geles , Hiperplasia , Pezones , Ratas Sprague-Dawley , Animales , Femenino , Pezones/efectos de los fármacos , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacocinética , Ratas , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/patología , Absorción Cutánea , Enfermedades de la Mama/tratamiento farmacológicoRESUMEN
BACKGROUND: Obese asthma is an asthma phenotype that causes more severe lung inflammation and airway hyperresponsiveness than allergic asthma and it is resistant to conventional therapy. Involucrasin B (IB) is a dihydroflavonoid isolated from Shuteria involucrata (Wall.) Wight & Arn., a traditional "Dai" and "Wa" medicine was used in southern China to treat the "phlegm and wetness of sputum" (obesity disease) as well as lung inflammation. However, whether IB can ameliorate obese asthma remains unclear, and the underlying mechanisms and molecular expression in obese asthma specifically targeted by IB are still not fully understood. METHODS: An in vivo C57BL/6 J mouse model of obese asthma was established using house dust mites (HDMs) and high-fat diet (HFD) as inducers to evaluate the therapeutic effect of IB. An in vitro cell culture of human THP-1 monocytic cell culture was used to investigate the effect of IB after the treatment with lipopolysaccharide (LPS) and palmitic acid (PA). RESULTS: In vivo, we found that intervention with IB improved airway hyperresponsiveness and lung histopathology and significantly inhibited the secretion of relevant inflammatory factors, such as interleukin (IL)-1ß, IL-17A, and IL-22 in bronchoalveolar lavage fluid, and total-IgE and HDM-IgE in serum compared with the model group (HFD+HDM). The findings indicate that IB could decrease the expression of granulocyte receptor 1 (Gr-1) and neutrophil extracellular traps (NETs) in lung tissue, as well as the expression of NLR family pyrin domain containing 3 (NLRP3) and inducible nitric oxide synthase in M1 macrophages (M1). IB also reduced the population of ILC3/Th17 cells, which are responsible for producing IL-17A, a crucial mediator of neutrophil-mediated inflammation, confirming that the therapeutic effect of IB in obesity-related asthma was related to neutrophils and M1 cells. In addition, IB regulated lipid metabolism and inhibited the production of macrophages in adipose tissue. The in vitro results revealed that IB inhibited the secretion of IL-1ß, IL-18, and tumor necrosis factor-α (TNF-α) from THP-1 cells, and the expression of NLRP3-related protein in THP-1 cells compared with the model groups (LPS, PA, and LPS+PA), confirming that the action of IB involved the TLR4-NF-κB-NLRP3 pathway. CONCLUSION: This study demonstrated the therapeutic effect of IB in obese asthma for the first time and further clarified its mechanistic pathway as the TLR4-NF-κB-NLRP3 pathway.
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Asma , Ratones Endogámicos C57BL , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Obesidad , Receptor Toll-Like 4 , Animales , Asma/tratamiento farmacológico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Humanos , Obesidad/tratamiento farmacológico , FN-kappa B/metabolismo , Receptor Toll-Like 4/metabolismo , Ratones , Modelos Animales de Enfermedad , Masculino , Células THP-1 , Lipopolisacáridos , Dieta Alta en Grasa , Transducción de Señal/efectos de los fármacos , Pulmón/efectos de los fármacos , Pyroglyphidae , Inflamación/tratamiento farmacológicoRESUMEN
PURPOSE: To explore the pathogenesis of oocyte maturation defects. METHODS: Whole exome sequencing was conducted to identify potential variants, which were then confirmed within the pedigree through Sanger sequencing. The functional characterization of the identified variants responsible for the disease, including their subcellular localization, protein levels, and interactions with other proteins, was verified through transient transfection in HeLa cells in vitro. Additionally, we employed real-time RT-PCR and single-cell RNA sequencing to examine the impact of ZFP36L2 pathogenic variants on mRNA metabolism in both HeLa cells and mouse or human oocytes. RESULTS: A novel compound heterozygous variant in ZFP36L2 (c.186T > G, p.His62Gln and c.869 C > T, p.Pro290Leu) was discovered in a patient with oocyte maturation defects. Our findings indicate that these variants lead to compromised binding capacity of the ZFP36L2-CONT6L complex and impaired mRNA degradation in HeLa cells and mouse oocytes. Furthermore, we characterized the changes in the human oocyte transcriptome associated with ZFP36L2 variants, with a particular emphasis on cell division, mitochondrial function, and ribosome metabolism. CONCLUSIONS: This study broadens the mutation spectrum of ZFP36L2 and constitutes the first report of human oocyte transcriptome alterations linked to ZFP36L2 variants. In conjunction with existing knowledge of ZFP36L2, our research lays the groundwork for genetic counseling aimed at addressing female infertility.
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Infertilidad Femenina , Oocitos , Humanos , Femenino , Oocitos/crecimiento & desarrollo , Oocitos/metabolismo , Oocitos/patología , Ratones , Células HeLa , Infertilidad Femenina/genética , Infertilidad Femenina/patología , Animales , Secuenciación del Exoma , Linaje , Heterocigoto , Oogénesis/genética , Tristetraprolina/genética , Tristetraprolina/metabolismo , Mutación/genética , AdultoRESUMEN
ZnSeTe quantum dots (QDs) attract growing interest owing to their low threats to health and the environment. They are widely applied as emitters in displays and lighting devices. Previous findings have indicated that inorganic halides are excellent candidates for surface ligands on QDs. By incorporating inorganic halides during the synthesis process, the photoluminescence (PL) intensity and quantum yield (QY) of QDs can be significantly enhanced. However, the alteration of surface states in QDs induced by zinc halide modification and the mechanism of formation of trap-state radiative recombination processes have been less discussed. Herein, we proposed a synthesis strategy for ZnSeTe/ZnSe/ZnSeS/ZnS core/shell/shell/shell QDs modified with ZnCl2, and by comparing the morphology and elemental composition of QDs with different amounts of ZnCl2 added, we revealed the regulatory mechanism of nanocrystal growth in the presence of ZnCl2. QDs with modification of ZnCl2 exhibited broad yellow fluorescence, distinct from the intrinsic blue emission. Through spectroscopic and surface ligand analyses, we attributed this yellow emission to the intermediate state energy levels caused by the defects on the surface. Finally, we used the QDs with broad linewidth emission to fabricate a simple white-light-emitting diode (WLED). This work provided new insights into the role of inorganic ligands and the use of a single emitting material in solid-state lighting devices.
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The issue of urban renewal is complex and multifaceted. In this study, six specialists in the construction industry were invited to conduct audio interviews, which were compiled into verbatim text. The key phrases were extracted by Grounded theory, and three levels of coding were retrieved. The data were categorized into ten accelerating urban renewal factors in three constructs to establish an Analytic Hierarchy Process framework. Using institutional theory to construct outcomes based on grounded theory, transforming these into specific urban renewal relation issue elements. 113 AHP questionnaires were collected from five types of specialists, including practitioners, professionals, participants in urban renewal, academics, and government staff. The results show that relaxing the plot ratio control and incentives is ranked No. 1 by practitioners, participants in urban renewal, professionals, and academics, indicating that the factor is highly valued by specialists but neglected by government staff. Secondly, practitioners, academics, participants in urban renewal, and professionals identified incentives and rewards for urban renewal and enhancing the trust and credibility of urban renewal projects as crucial factors. However, the government staff showed a different weighting. This indicates that government staff is determined to accelerate urban renewal. Finally, the suggestion of this study is in line with the views of the specialists interviewed, who suggest that the government should hold public hearings regularly and seriously to listen to people and specialists. Only through public hearings can all parties reach a consensus. The government should consolidate the views of all parties to amend or enact a bill on urban renewal that is more in line with the changes of the times, including appropriately relaxing the control of building plot ratio and other accelerating factors, to promote urban renewal in Taiwan.
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ETHNOPHARMACOLOGICAL RELEVANCE: As a representative local medicinal herb produced in China, Vladimiriae Radix (VR) has been proven to exert hepatoprotective and choleretic effects, with particular therapeutic efficacy in cholestatic liver injury (CLI), as demonstrated by the VR extract (VRE). However, the quality markers (Q-markers) of VRE for the treatment of CLI remain unclear. AIM OF THE STUDY: A new strategy based on the core element of "efficacy" was proposed, using a combination of spectrum-effect relationship, pharmacokinetics, and molecular docking methods to select and confirm Q-markers of VRE. MATERIAL AND METHODS: First, the HPLC fingerprinting of 10 batches of VRE was studied, and the in vivo pharmacological index of anti-CLI in rats was determined. The spectrum-effect relationship was utilized as a screening method to identify the Q-markers of VRE. Secondly, Q-markers were used as VRE pharmacokinetic markers to measure their concentrations in normal and CLI rat plasma, and to analyze their disposition. Finally, molecular docking was utilized to predict the potential interaction between the identified Q-markers and crucial targets of CLI. RESULTS: The fingerprints of 10 batches of VRE was established. The in vivo pharmacological evaluation of rats showed that VRE had a significant therapeutic effect on CLI. The spectrum-effect correlation analysis showed that costunolide (COS) and dehydrocostus lactone (DEH) were the Q-markers of VRE anti-CLI. The pharmacokinetic results showed that AUC(0-t), Cmax, CLZ/F, and VZ/F of COS and DEH in CLI rats had significant differences (P < 0.01). They were effectively absorbed into the blood plasma of CLI rats, ensuring ideal bioavailability, and confirming their role as Q-markers. Molecular docking results showed that COS, DEH had good affinity with key targets (FXR, CAR, PXR, MAPK, TGR5, NRF2) for CLI treatment (Binding energy < -4.52 kcal mol-1), further verifying the correctness of Q-marker selection. CONCLUSIONS: In this study, through the combination of experimental and theoretical approaches from the aspects of pharmacodynamic expression, in vivo process rules, and interaction force prediction, the therapeutic effect of VRE and Q-markers (COSãDEH) were elucidated. Furthermore, a new idea based on the principle of "efficacy" was successfully proposed for screening and evaluating Q-markers.
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Simulación del Acoplamiento Molecular , Ratas Sprague-Dawley , Animales , Masculino , Ratas , Colestasis/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Extractos Vegetales/farmacocinética , Extractos Vegetales/farmacología , Extractos Vegetales/química , Raíces de Plantas/química , Biomarcadores/sangreRESUMEN
Background: Polyphyllin, a natural compound derived primarily from the Paris genus, manifests its anticancer properties. Extensive research on its therapeutic potential in cancers has been reported. However, there is no systematical analysis of the general aspects of research on polyphyllin by bibliometric analysis. The aim of this study is to visualize emerging trends and hotspots and predict potential research directions in this field. Methods: In this study, we collected relevant research articles from the Web of Science Core Collection Bibliometrics. Using R-bibliometrix, we analyzed the research status, hotspots, frontiers, and development trends of polyphyllin in high-incidence cancers. To conduct a comprehensive visual analysis, CiteSpace and VOSviewer were used for visual analysis of authors, countries, institutions, keywords, and co-cited references within the published articles. Results: A total of 257 articles focusing on the research of polyphyllin in high-incidence cancers were retrieved from the WOSCC database, covering the period from 2005 to 2023. The analysis revealed a consistent increasing trend in annual publications during this timeframe. Notably, China emerged as the most productive country, with Tianjin University leading the institutions. The Journal of Ethnopharmacology stood out as the most prominent journal in this field, while Gao WY emerged as the most prolific author. Polyphyllin VI, polyphyllin II, and polyphyllin VII have emerged as the latest research hotspots. Additionally, the investigation of autophagy and its associated mechanisms has gained significant attention as a novel research direction. Conclusion: This study presents a novel visualization of the research on polyphyllin saponins in the field of highly prevalent cancers using bibliometric analysis. The investigation of polyphyllin D has emerged as a primary focus in this field, with lung cancer, breast cancer, and liver cancer being the key areas of current research. Lastly, polyphyllin saponins show potential application in the field of cancer.
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AIMS: This scoping review was conducted to provide a comprehensive summary of how electroencephalogram (EEG) and event-related potentials (ERPs) have been used in nursing research, with the goal of mapping the themes and methods of nursing research involving EEGs or ERPs as a measurement tool. METHODS: The eligibility criteria were determined according to the Population, Concept, and Context principle. A systematic electronic search of articles in the PubMed, Web of Science, Embase, CINAHL, APA PsycInfo, and Scopus databases was carried out for the period from database establishment to November 21, 2022. The included studies were analyzed using descriptive statistics and content analysis. RESULTS: The review process culminated in 45 articles, evidencing an increasing trend and dispersion characteristics of EEG in nursing research and reflecting five thematic domains of inquiry related to nursing. There was a deficiency of detailed reports of EEG recording and data analysis parameters in nursing research. The common EEG bands in nursing research were Delta, Theta, Alpha, Beta, Gamma. The ERP components used frequently were P3, P2, N1, N2, P1, N170, and feedback-related negativity. CONCLUSIONS: The wide variety of EEG components used show broad potential for studying nursing questions. In the future, it will be necessary to increase the depth of the research content, the repeatability of the experiment and the standardization of the report. Nursing researchers should give full play to the characteristics of nursing and establish a systematic and complete EEG research system for nursing.
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Electroencefalografía , Investigación en Enfermería , Humanos , Potenciales Evocados/fisiologíaRESUMEN
Dendrobium nobile is a traditional Chinese herb with anti-inflammatory, antioxidant, and neuroprotective properties. However, its antiaging effects are unclear. Herein, we studied the aging-related functions and the mechanism of action of the alcohol extract of Dendrobium nobile (DnAE) in the model organism Caenorhabditis elegans. The results indicated that 1 mg/mL DnAE slowed lipofuscin accumulation, decreased the levels of reactive oxygen species, elevated superoxide dismutase activity, enhanced oxidative and heat stress resistance, extended the lifespan of nematodes, protected their dopamine neurons from 6-hydroxydopamine-induced neurodegeneration, and reduced Aß-induced neurotoxicity. DnAE upregulated the mRNA expression of the transcription factors DAF-16 and HSF-1, promoted the nuclear localization of DAF-16, and enhanced the fluorescence intensity of HSP-16.2. However, it had no effect on the lifespan of DAF-16 mutants. Thus, DnAE can significantly extend lifespan, enhance heat stress tolerance, and delay age-related diseases through a DAF-16-dependent pathway.
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Proteínas de Caenorhabditis elegans , Dendrobium , Animales , Longevidad , Caenorhabditis elegans , Dendrobium/metabolismo , Estrés Oxidativo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factores de Transcripción del Choque Térmico/metabolismo , Etanol/metabolismo , Factores de Transcripción Forkhead/metabolismoRESUMEN
AIMS: To map the themes and methods of nursing researches involving eye-tracking as a measurement, and offer suggestion for future nursing research using eye-tracking. DESIGN: We conducted a scoping review following the methodology outlined in the JBI Manual for Evidence Synthesis on scoping reviews. METHODS: Eligibility criteria were established based on Population (involving nursing or nursing students), Concept (utilizing eye-tracking as a research method), and Context (in any setting). Articles were retrieved from the PubMed, Web of Science, Embase, CINAHL, APA PsycInfo, and Scopus databases, spanning from database inception to November 17, 2023. The included studies were analysed using descriptive statistics and content analysis. RESULTS: After duplicates were removed, 815 citations were identified from searches of electronic databases and other resources, and 66 met the inclusion criteria finally. Thirty-eight studies were conducted in a simulated environment. Five application domains were identified, and most of the studies (N = 50) were observational. The domains found in our review did not cover all topics of nursing research in the same depth. Additionally, 39 studies did not solely explicate eye-tracking data but instead integrated behavioural measures, scales/questionnaires, or other physiological data. CONCLUSIONS: Eye-tracking emerges as a significant research tool in uncovering visual behaviour, particularly in nursing research focused on nursing education. This study not only summarized the application and interpretation of eye-tracking data but also recognized its potential in advancing clinical nursing research and practice. To effectively harness the capabilities of eye-tracking in elucidating cognitive processes, future research should aim for a clearer grasp of the theoretical underpinnings of the addressed research problems and methodological choices. It is crucial to emphasize the standardization of eye-tracking method reporting and ensuring data quality. No Patient or Public Contribution.
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Educación en Enfermería , Investigación en Enfermería , Estudiantes de Enfermería , Humanos , Tecnología de Seguimiento Ocular , Competencia ClínicaRESUMEN
Glaucoma, an irreversible blinding eye disease, is currently unclear whose pathological mechanism is. This study investigated how transient receptor potential cation channel subfamily V member 1 (TRPV1), 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCγ1), and P2X purinoceptor 7 (P2X7) modulate the levels of intracellular calcium ions (Ca2+) and adenosine triphosphate (ATP) in Müller cells and retinal ganglion cells (RGCs) under conditions of elevated intraocular pressure (IOP). Müller cells were maintained at hydrostatic pressure (HP). TRPV1- and PLCG1-silenced Müller cells and P2X7-silenced RGCs were constructed by transfection with short interfering RNA (siRNAs). RGCs were cultured with the conditioned media of Müller cells under HP. A mouse model of chronic ocular hypertension (COH) was established and used to investigate the role of TRPV1 in RGCs in vivo. Müller cells and RGCs were analyzed by ATP release assays, intracellular calcium assays, CCK-8 assays, EdU (5-ethynyl-2'-deoxyuridine) staining, TUNEL staining, flow cytometry, and transmission electron microscopy. In vivo changes in inner retinal function were evaluated by hematoxylin and eosin (H&E) staining and TUNEL staining. Western blot analyses were performed to measure the levels of related proteins. Our data showed that HP increased the levels of ATP and Ca2+ influx in Müller cells, and those increases were accompanied by the upregulation of TRPV1 and p-PLCγ1 expression. Suppression of TRPV1 or PLCG1 expression in Müller cells significantly decreased the ATP levels and intracellular Ca2+ accumulation induced by HP. Knockdown of TRPV1, PLCG1, or P2X7 significantly decreased apoptosis and autophagy in RGCs cultured in the conditioned media of HP-treated Müller cells. Moreover, TRPV1 silencing decreased RGC apoptosis and autophagy in the in vivo model of COH. Collectively, inhibition of TRPV1/PLCγ1 and P2X7 expression may be a useful therapeutic strategy for managing RGC death in glaucoma.
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Calcio , Supervivencia Celular , Células Ependimogliales , Glaucoma , Presión Hidrostática , Fosfolipasa C gamma , Células Ganglionares de la Retina , Canales Catiónicos TRPV , Animales , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Glaucoma/patología , Glaucoma/metabolismo , Glaucoma/genética , Ratones , Células Ependimogliales/metabolismo , Células Ependimogliales/patología , Fosfolipasa C gamma/metabolismo , Fosfolipasa C gamma/genética , Calcio/metabolismo , Supervivencia Celular/genética , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Presión Intraocular , Adenosina Trifosfato/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/genética , Masculino , Apoptosis , Células CultivadasRESUMEN
Objective: Brain radiotherapy often results in impairment of hypothalamic-pituitary (HT-P) function, which in turn causes secretory dysfunction of related hormones. In this paper, the frequency of metastasis in the HT-P area and its high-risk factors in patients with brain metastasis were retrospectively analyzed, and thus provide experimental evidence for protecting HT-P area during whole brain radiotherapy (WBRT). Methods: A retrospective analysis was performed on the data of patients with brain metastasis diagnosed by cranial magnetic resonance imaging (MRI) at the First Hospital of Lanzhou University from 2017 to 2020. The anatomical positions of the hypothalamus and pituitary were delineated, followed by their expansion by 5 mm outwards, respectively, in the three-dimensional direction, and the hypothalamus +5 mm and pituitary +5 mm were obtained as the avoidance area, in which the frequency of brain metastasis was evaluated. Univariate and multivariate logistic regression models were used to analyze the high risk factors of brain metastasis in HT-P area. Results: A total of 3,375 brain metastatic lesions from 411 patients were included in the analysis. The rates of brain metastasis in the hypothalamus +5 mm and pituitary +5 mm in the whole group of cases were 2.9% (12/411) and 1.5% (6/411) respectively; the frequency of lesions was 0.4% (13/3375) and 0.2% (6/3375) respectively. Univariate and multivariate analyses showed that the number of brain metastases (OR = 14.946; 95% CI = 4.071-54.880; p < 0.001), and the occurrence of brain metastasis in the pituitary (OR = 13.331; 95% CI = 1.511-117.620; p = 0.020) were related to brain metastasis in the hypothalamus, and that the only relevant factor for brain metastasis in the pituitary was the occurrence of that in the hypothalamus (OR = 0.069; 95% CI = 0.010-0.461; p = 0.006). There was no correlation between tumor pathological types, the maximum diameter, the total volume of brain metastatic lesions and the risk of brain metastasis in hypothalamus and pituitary. Conclusion: The frequency of brain metastasis in the HT-P area is extremely low. The risk of brain metastases in the hypothalamus is correlated with their number. The larger the number of metastatic lesions, the higher the frequency of brain metastasis. Protection of the HT-P area during WBRT may be unlikely to compromise the tumor recurrence rate for patients with a relatively small number of brain metastases.
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As a subclass of the biopharmaceutical classification system (BCS) class II, basic drugs (BCS IIB) exhibit pH-dependent solubility and tend to generate supersaturation in the gastrointestinal tract, leading to less qualified in vitro-in vivo correlation (IVIVC). This study aims to develop a physiologically based multi-cup dissolution approach to improve the evaluation of the supersaturation for a higher quality of IVIVC and preliminarily explores the molecular mechanism of supersaturation and precipitation of ketoconazole affected by Polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA) and hydroxypropyl methyl-cellulose (HPMC). The concentration of ketoconazole in each cup of the dynamic gastrointestinal model (DGIM) was measured using fiber optical probes. Molecular interactions between ketoconazole and PVPVA or HPMC were simulated by Materials Studio. The results demonstrated that PVPVA and HPMC improved and maintained the supersaturation of ketoconazole. PVPVA exhibited superior precipitation inhibitory effect on ketoconazole molecule aggregation due to slightly stronger van der Waals forces as well as unique electrostatic forces, thereby further enhancing in vitro drug absorption, which correlated well with in vivo drug absorption. Compared with a conventional dissolution apparatus paddle method, the DGIM improved the mean prediction error through the IVIVC from 19.30% to 9.96%, reaching the qualification criteria. In conclusion, the physiologically based multi-cup dissolution approach enables improved evaluation of supersaturation in gastrointestinal transportation of BCS IIB drug ketoconazole, enabling screening screen precipitation inhibitors and achieving qualified IVIVC for drug formulation studies.
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Productos Biológicos , Cetoconazol , Solubilidad , Cetoconazol/farmacología , Simulación de Dinámica Molecular , Productos Biológicos/farmacología , Absorción Intestinal , Administración OralRESUMEN
Ulcerative colitis (UC) is a difficult-to-cure and recurrent inflammatory bowel disease, and it is difficult to maintain long-term results with a single drug. Inspired by clinical medication in traditional Chinese medicine, we used berberine hydrochloride (BBH) and dehydrocostus lactone (DEH) in combination for the first time and focused on studying their mechanism of treating UC based on gut microbiota. Therefore, we evaluated the therapeutic effects of BBH and DEH on DSS-induced UC mice using ELISA, HE and AB-PAS staining, 16s rDNA amplicon sequencing technology, and fecal transplantation experiments (FMT). In this study, the combination of BBH and DEH significantly relieved symptoms, colonic inflammation, and intestinal barrier damage of DSS-induced UC mice, and they did not show antagonism. In addition, the co-administration of BBH and DEH altered the composition and function of gut microbiota, with BBH increasing the abundance of key beneficial bacterial genus Akkermansia and DEH aiming to enhance species diversity and supplying intestinal proteins to prevent overconsumption. Furthermore, our data showed that BBH and DEH improve the levels of short-chain fatty acids, which also proved the positive regulation of gut microbiota by BBH and DEH. Finally, the FMT confirmed the strong correlation between BBH, DEH, and the gut microbiota. In conclusion, the co-administration of BBH and DEH protected the intestinal barrier and reduced inflammatory damage by regulating gut microbiota, targeting the key beneficial bacterial genus Akkermansia, and maintaining a normal supply of intestinal proteins.
Asunto(s)
Berberina , Colitis Ulcerosa , Colitis , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Animales , Ratones , Colitis Ulcerosa/tratamiento farmacológico , Berberina/uso terapéutico , Colon , Sulfato de Dextran , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Microglia play a pivotal role in neuroinflammation, while obesity triggers hypothalamic microglia activation and inflammation. Sirt6 is an important regulator of energy metabolism in many peripheral tissues and hypothalamic anorexic neurons. However, the exact mechanism for microglia Sirt6 in controlling high-fat diet-induced obesity remain unknown. METHODS: Microglia Sirt6 expression levels under various nutritional conditions were measured in the hypothalamus of mice. Also, microglia Sirt6-deficient mice were provided various diets to monitor metabolic changes and hypothalamic inflammatory response. Besides, RNA-seq and Co-IP of microglia with Sirt6 alterations were conducted to further investigate the detailed mechanism by which Sirt6 modulated microglia activity. RESULTS: We found that Sirt6 was downregulated in hypothalamic microglia in mice given a high-fat diet (HFD). Additionally, knockout of microglia Sirt6 exacerbated high-fat diet-induced hypothalamic microglial activation and inflammation. As a result, mice were more prone to obesity, exhibiting a decrease in energy expenditure, impaired glucose tolerance, insulin and leptin resistance, and increased food intake. In vitro, Sirt6 overexpression in BV2 cells displayed protective effects against oleic acid and palmitic acid treatment-derived inflammatory response. Mechanically, Sirt6 deacetylated and stabilised NRF2 to increase the expression of anti-oxidative genes and defend against reactive oxygen species overload. Pharmacological inhibition of NRF2 eliminated the beneficial modulating effects of Sirt6 on microglial activity. CONCLUSION: Collectively, our results revealed that microglial Sirt6 was a primary contributor of microglial activation in the central regulation of obesity. Thus, microglial Sirt6 may be an important therapeutic target for obesity.