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SARS-CoV-2 variants acquire mutations in the spike protein that promote immune evasion1 and affect other properties that contribute to viral fitness, such as ACE2 receptor binding and cell entry2,3. Knowledge of how mutations affect these spike phenotypes can provide insight into the current and potential future evolution of the virus. Here we use pseudovirus deep mutational scanning4 to measure how more than 9,000 mutations across the full XBB.1.5 and BA.2 spikes affect ACE2 binding, cell entry or escape from human sera. We find that mutations outside the receptor-binding domain (RBD) have meaningfully affected ACE2 binding during SARS-CoV-2 evolution. We also measure how mutations to the XBB.1.5 spike affect neutralization by serum from individuals who recently had SARS-CoV-2 infections. The strongest serum escape mutations are in the RBD at sites 357, 420, 440, 456 and 473; however, the antigenic effects of these mutations vary across individuals. We also identify strong escape mutations outside the RBD; however, many of them decrease ACE2 binding, suggesting they act by modulating RBD conformation. Notably, the growth rates of human SARS-CoV-2 clades can be explained in substantial part by the measured effects of mutations on spike phenotypes, suggesting our data could enable better prediction of viral evolution.
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Análisis Mutacional de ADN , Evolución Molecular , Aptitud Genética , Evasión Inmune , Mutación , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , Enzima Convertidora de Angiotensina 2/metabolismo , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Sitios de Unión , COVID-19/inmunología , COVID-19/virología , Aptitud Genética/genética , Evasión Inmune/genética , Pruebas de Neutralización , Unión Proteica , Dominios Proteicos/genética , SARS-CoV-2/genética , SARS-CoV-2/inmunología , SARS-CoV-2/clasificación , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/inmunología , Internalización del Virus , Células HEK293RESUMEN
BACKGROUND & AIMS: CT-P13 subcutaneous (SC), an SC formulation of the intravenous (IV) infliximab biosimilar CT-P13 IV, creates a unique exposure profile. The LIBERTY studies aimed to demonstrate superiority of CT-P13 SC vs placebo as maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Two randomized, placebo-controlled, double-blind studies were conducted in patients with moderately to severely active CD or UC and inadequate response or intolerance to corticosteroids and immunomodulators. All patients received open-label CT-P13 IV 5 mg/kg at weeks 0, 2, and 6. At week 10, clinical responders were randomized (2:1) to CT-P13 SC 120 mg or placebo every 2 weeks until week 54 (maintenance phase) using prefilled syringes. (Co-) primary end points were clinical remission and endoscopic response (CD) and clinical remission (UC) at week 54 (all-randomized population). RESULTS: Overall, 396 patients with CD and 548 patients with UC received induction treatment. At week 54 in the CD study, statistically significant higher proportions of CT-P13 SC-treated patients vs placebo-treated patients achieved clinical remission (62.3% vs 32.1%; P < .0001) and endoscopic response (51.1% vs 17.9%; P < .0001). In the UC study, clinical remission rates at week 54 were statistically significantly higher with CT-P13 SC vs placebo (43.2% vs 20.8%; P < .0001). Achievement of key secondary end points was significantly higher with CT-P13 SC vs placebo across both studies. CT-P13 SC was well tolerated, with no new safety signals identified. CONCLUSIONS: CT-P13 SC was more effective than placebo as maintenance therapy and was well tolerated in patients with moderately to severely active CD or UC who responded to CT-P13 IV induction. CLINICALTRIALS: gov, Numbers: NCT03945019 (CD) and NCT04205643 (UC).
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The inherent limitations of lithium (Li)-ion batteries have sparked interest in exploring alternative technologies, especially those relying on metallic anodes: monovalent Li and divalent zinc (Zn), magnesium (Mg), and calcium (Ca) metals. In particular, Mg and Ca metal batteries offer significant advantages based on the natural abundance of their raw materials and high energy-storage capabilities resulting from the bivalency of the carrier ions. Yet, these battery systems are far from commercialization, and the lack of reliable electrolytes constitutes a primary concern. The formation of ion-insulating passivation layers on these metallic anodes and their inferior desolvation kinetics have long been recognized as formidable hurdles in the way of optimizing the electrolyte composition. These impediments call for innovative strategies in electrolyte engineering and an extensive analysis of the resulting solid-electrolyte-interphase (SEI) layer. In this review, we introduce recent pioneering studies of divalent Mg and Ca metal batteries that have been concerned with these issues. This review particularly focuses on drawing an analogy with Li and Zn metal batteries in terms of the relative advancement and by benchmarking against the strategies developed for these analogous systems. The areas of interest include a fundamental understanding of the thermodynamics and evolution of the morphology of metallic anodes, a correlation between the electrolyte and SEI compositions, state-of-the-art electrolyte strategies to realize reversible (de)plating of Mg and Ca, and new perspectives on the SEI properties and their relevance to corrosion and the calendar life. We finally encourage researchers in the community to delve into these emerging areas by linking with successful stories in the analogous systems, but identifying distinct aspects of Mg and Ca batteries that still require attention.
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The human-specific bacterial pathogen group A Streptococcus (GAS) is a significant cause of morbidity and mortality. Macrophages are important to control GAS infection, but previous data indicate that GAS can persist in macrophages. In this study, we detail the molecular mechanisms by which GAS survives in THP-1 macrophages. Our fluorescence microscopy studies demonstrate that GAS is readily phagocytosed by macrophages, but persists within phagolysosomes. These phagolysosomes are not acidified, which is in agreement with our findings that GAS cannot survive in low pH environments. We find that the secreted pore-forming toxin Streptolysin O (SLO) perforates the phagolysosomal membrane, allowing leakage of not only protons but also large proteins including the lysosomal protease cathepsin B. Additionally, GAS recruits CD63/LAMP-3, which may contribute to lysosomal permeabilization, especially in the absence of SLO. Thus, although GAS does not inhibit fusion of the lysosome with the phagosome, it has multiple mechanisms to prevent proper phagolysosome function, allowing for persistence of the bacteria within the macrophage. This has important implications for not only the initial response but also the overall functionality of the macrophages, which may lead to the resulting pathologies in GAS infection. Our data suggest that therapies aimed at improving macrophage function may positively impact patient outcomes in GAS infection.
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Proteínas Bacterianas , Lisosomas , Macrófagos , Streptococcus pyogenes , Estreptolisinas , Streptococcus pyogenes/inmunología , Humanos , Macrófagos/microbiología , Macrófagos/inmunología , Macrófagos/metabolismo , Lisosomas/metabolismo , Lisosomas/microbiología , Estreptolisinas/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Fagosomas/microbiología , Fagosomas/metabolismo , Células THP-1 , Fagocitosis , Infecciones Estreptocócicas/inmunología , Infecciones Estreptocócicas/microbiología , Infecciones Estreptocócicas/metabolismo , Catepsina B/metabolismo , Concentración de Iones de HidrógenoRESUMEN
OBJECTIVE: To describe the characteristics of research training and scholarly activity during pediatrics residency in Canada and identify facilitators and barriers to resident scholarly activity. STUDY DESIGN: We conducted a mixed-methods, cross-sectional survey of pediatrics residents in Canada from April to June 2023. Trainees and medical education experts developed the 55-item survey, pilot tested, and distributed electronically to residents in all 17 Canadian residency programs. Responses were complemented with program-level data from pediatrics residency program directors. RESULTS: Of 644 Canadian pediatrics residents, 230 (36%) responded. Resident respondents conducted various types of scholarly projects, including retrospective clinical study (22%), qualitative research (15%), quality improvement (13%), and medical education research (12%). Discordance between the field of career interests and primary scholarly projects was common. Among respondents, 20% had abstracts accepted at national or international conferences, and 12% had manuscripts submitted to peer-reviewed journals. Resident respondents' self-perceived progress in their scholarly projects were discrepant from their actual progress. Key themes related to barriers and facilitators to scholarly activity included protected time for research, mentorship, and research skills training. CONCLUSIONS: The research training and scholarly activity of pediatrics residents in Canada is variable. Establishing national standards, implementing progress monitoring mechanisms with tailored support, and offering flexible protected research time are important next steps.
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BACKGROUND: For patients with left upper lobe lesions, the functional benefit of left upper division segmentectomy over left upper lobectomy remains controversial. This study evaluated the clinical and functional outcomes after these two procedures. METHODS: This retrospective study included 135 patients with left upper lobe lesions (left upper lobectomy, 110; left upper division segmentectomy, 25). Propensity score matching was used to compare the two groups. Spirometry and computed tomography volume assessments were performed to evaluate bronchus angle and tortuosity. Short-term clinical respiratory symptoms were assessed via medical record reviews. RESULTS: Patients in both groups had similar preoperative characteristics, apart from tumor size (left upper division segmentectomy, 1.6 ± 0.9 cm; left upper lobectomy, 2.8 ± 1.7 cm; p = 0.002). After propensity score matching, both groups had similar preoperative spirometry and pathological results. The postoperative spirometry results were similar; however, the left upper division segmentectomy group had a significantly smaller decrease in left-side computed tomography lung volume compared with that in the left upper lobectomy group (left upper division segmentectomy, 323.6 ± 521.4 mL; left upper lobectomy, 690.7 ± 332.8 mL; p = 0.004). The left main bronchus-curvature index was higher in the left upper lobectomy group (left upper division segmentectomy, 1.074 ± 0.035; left upper lobectomy, 1.097 ± 0.036; p = 0.013), and more patients had persistent cough in the left upper lobectomy group (p = 0.001). CONCLUSIONS: Left upper division segmentectomy may be a promising option for preventing marked bronchial angulation and decreasing postoperative persistent cough in patients with left upper lobe lung cancer.
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Bronquios , Neoplasias Pulmonares , Neumonectomía , Humanos , Masculino , Femenino , Neumonectomía/métodos , Estudios Retrospectivos , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico por imagen , Bronquios/cirugía , Bronquios/patología , Persona de Mediana Edad , Anciano , Estudios de Seguimiento , Tomografía Computarizada por Rayos X , Pronóstico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Pulmón/cirugía , Pulmón/diagnóstico por imagenRESUMEN
BACKGROUND: Advancements in the diagnosis, treatment, and surveillance of castration-resistant prostate cancer (CRPC) have progressed considerably, but a new biomarker that combines existing clinical and pathological data could be useful for a more precise diagnosis and prognosis. Some investigations have found that extracellular vesicle (EV)-derived miRNAs play crucial roles in various types of malignant tumors. The objective of this study was to explore EV miRNA and identify its biologic function as a biomarker for the diagnosis and prognosis of CRPC. METHODS: Plasma samples were collected from five healthy donors (Control, CT) and 17 CRPC patients, categorizing into two groups based on their endocrine treatment response: partial response (PR; n = 10) and progressive disease (PD; n = 7). Candidate extracellular vesicle (EV) miRNAs were identified using miRNA microarray and RT-qPCR. The biological functions of the selected miRNAs were evaluated using the MTT assay, wound healing assay, trans-well assay, and RNA sequencing in CRPC cells after transient miRNA expression. RESULTS: Microarray analysis revealed a significant downregulation of EV-miR-6880-5p in the PD samples compared to both CT and PR samples (p < 0.01). The expression of EV-miR-6880-5p in CRPC patients was decreased compared with that CT group (p = 0.0336) using RT-qPCR. In the PR group, EV-miR-6880-5p was increased at follow-up compared with the baseline (p = 0.2803), while in the PD group, it decreased at follow-up compared with the baseline samples (p = 0.4356). Furthermore, overexpression of miR-6880-5p hampered cell proliferation, migration, and invasion, downregulated pathways associated with tumor progression, and simultaneously upregulated pathways associated with cell growth and apoptosis in CRPC cells. CONCLUSIONS: EV-miR-6880-5p shows promise as a prognostic biomarker in patients with CRPC. Further, prospective validations are necessary to evaluate the potential of these candidate miRNAs.
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Biomarcadores de Tumor , Vesículas Extracelulares , Regulación Neoplásica de la Expresión Génica , MicroARNs , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , MicroARNs/sangre , MicroARNs/genética , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Pronóstico , Anciano , Persona de Mediana Edad , Línea Celular Tumoral , Proliferación Celular , Perfilación de la Expresión Génica/métodos , Movimiento Celular/genéticaRESUMEN
BACKGROUND: Ultrasound-guided transversus abdominis plane (TAP) block is commonly used for pain control in laparoscopic cholecystectomy. However, significant pain persists, affecting patient recovery and sleep quality on the day of surgery. We compared the analgesic effect of ultrasound-guided TAP block with or without rectus sheath (RS) block in patients undergoing laparoscopic cholecystectomy using the visual analog scale (VAS) scores. METHODS: The study was registered before patient enrollment at the Clinical Research Information Service (registration number: KCT0006468, 19/08/2021). 88 American Society of Anesthesiologist physical status I-III patients undergoing laparoscopic cholecystectomy were divided into two groups. RS-TAP group received right lateral and right subcostal TAP block, and RS block with 0.2% ropivacaine (30 mL); Bi-TAP group received bilateral and right subcostal TAP block with same amount of ropivacaine. The primary outcome was visual analogue scale (VAS) for 48 h postoperatively. Secondary outcomes included the use of rescue analgesics, cumulative intravenous patient-controlled analgesia (IV-PCA) consumption, patient satisfaction, sleep quality, and incidence of adverse events. RESULTS: There was no significant difference in VAS score between two groups for 48 h postoperatively. We found no difference between the groups in any of the secondary outcomes: the use of rescue analgesics, consumption of IV-PCA, patient satisfaction with postoperative pain control, sleep quality, and the incidence of postoperative adverse events. CONCLUSION: Both RS-TAP and Bi-TAP blocks provided clinically acceptable pain control in patients undergoing laparoscopic cholecystectomy, although there was no significant difference between two combination blocks in postoperative analgesia or sleep quality.
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Músculos Abdominales , Colecistectomía Laparoscópica , Bloqueo Nervioso , Dolor Postoperatorio , Ropivacaína , Ultrasonografía Intervencional , Humanos , Colecistectomía Laparoscópica/métodos , Femenino , Masculino , Ultrasonografía Intervencional/métodos , Bloqueo Nervioso/métodos , Persona de Mediana Edad , Dolor Postoperatorio/prevención & control , Dolor Postoperatorio/tratamiento farmacológico , Ropivacaína/administración & dosificación , Adulto , Anestésicos Locales/administración & dosificación , Dimensión del Dolor/métodos , Recto del Abdomen/inervación , Recto del Abdomen/diagnóstico por imagen , Satisfacción del Paciente , Analgesia Controlada por el Paciente/métodos , AncianoRESUMEN
PURPOSE: We sought to compare three intubation methods using different intubation techniques/tube materials for tube advancement from the nasal cavity into the oral cavity during nasotracheal intubation. METHODS: We conducted a randomized clinical trial with adult patients scheduled to undergo elective surgery requiring nasotracheal intubation for general anesthesia. Participants were randomly allocated to a polyvinyl chloride (PVC) tube group (group P), PVC tube attached to a rubber catheter group (group PR), or velvet-soft PVC tube group (group V). Tracheal intubation was then performed based on group allocation. The primary outcome was the first-attempt success rate of tube advancement into the oral cavity; secondary outcomes included the time required for tube advancement into the oral cavity, total intubation time, and the incidence of epistaxis. RESULTS: A total of 149 patients were included in the study. The first-attempt success rate in group V (90%) was significantly higher than that in group P (58%) (odds ratio, 6.5; 95% confidence interval [CI], 2.2 to 19.2), but similar to that in group PR (100%). The mean (standard deviation) time required for tube advancement into the oral cavity was significantly shorter in group V (16 [13] sec) than in group PR [40 (10) sec; 95% CI of mean difference, 17 to 30] and group P (26 [16] sec; 95% CI of mean difference, 3 to 16). Total intubation time was longest in group PR. Epistaxis occurred the least in group V. CONCLUSIONS: Among the three intubation techniques/tube materials for nasotracheal intubation, the velvet-soft PVC tube provided the highest first-attempt success rate, most expeditious advancement into the oral cavity, and lowest incidence of epistaxis. STUDY REGISTRATION: ClinicalTrials.gov (NCT04695444); first submitted 30 December 2020.
RéSUMé: OBJECTIF: Nous avons cherché à comparer trois méthodes d'intubation utilisant différentes techniques d'intubation / matériaux de sondes pour l'avancement de la sonde de la cavité nasale dans la cavité buccale pendant l'intubation nasotrachéale. MéTHODE: Des patient·es devant recevoir une intubation nasotrachéale ont été réparti·es au hasard dans un groupe avec sondes en polychlorure de vinyle (PVC) (groupe P), un groupe avec sondes en PVC attachées à un cathéter en caoutchouc (groupe PR) ou un groupe avec sondes en PVC doux comme du velours (groupe V). L'intubation trachéale a ensuite été réalisée en fonction de l'affectation du groupe. Le critère d'évaluation principal était le taux de réussite de la première tentative d'avancement de la sonde dans la cavité buccale; les critères d'évaluation secondaires comprenaient le temps nécessaire à l'avancement de la sonde dans la cavité buccale, la durée totale de l'intubation et l'incidence d'épistaxis. RéSULTATS: Au total, 149 patient·es ont été inclus·es dans l'étude. Le taux de réussite de l'intubation à la première tentative était significativement plus élevé dans le groupe V (90 %) que dans le groupe P (58 %) (rapport de cotes, 6,5; intervalle de confiance à 95 % [IC], 2,2 à 19,2), mais similaire à celui du groupe PR (100 %). Le temps moyen (écart type) nécessaire pour l'avancement de la sonde dans la cavité buccale était significativement plus court dans le groupe V (16 [13] sec) que dans le groupe PR (40 [10] sec; IC 95 % de la différence moyenne, 17 à 30) et dans le groupe P (26 [16] sec; IC 95 % de la différence moyenne, 3 à 16). La durée totale d'intubation était la plus longue dans le groupe PR. C'est dans le groupe V que l'épistaxis a été la moins fréquente. CONCLUSION: Parmi les trois techniques d'intubation/matériaux de sonde pour l'intubation nasotrachéale, le tube en PVC doux comme du velours a fourni le taux de réussite de première tentative le plus élevé, l'avancement le plus rapide dans la cavité buccale et l'incidence d'épistaxis la plus faible. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT04695444); première soumission le 30 décembre 2020.
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Anestesia General , Epistaxis , Intubación Intratraqueal , Humanos , Intubación Intratraqueal/métodos , Intubación Intratraqueal/instrumentación , Masculino , Femenino , Persona de Mediana Edad , Adulto , Epistaxis/etiología , Anestesia General/métodos , Cloruro de Polivinilo , Cavidad Nasal , Factores de Tiempo , Boca , AncianoRESUMEN
AIM: Cholesterol homeostasis is associated with Alzheimer's disease (AD). Despite the multitude of cholesterol metabolites, little is known about which metabolites are directly involved in AD pathogenesis and can serve as its potential biomarkers. METHODS: To identify "hit" metabolites, steroid profiling was conducted in mice with different age, diet, and genotype and also in humans with normal cognition, mild cognitive impairment, and AD using gas chromatography-mass spectrometry. Then, using one of the "hit" molecules (7ß-hydroxycholesterol; OHC), molecular and histopathological experiment and behavioral testing were conducted in normal mice following its intracranial stereotaxic injection to see whether this molecule drives AD pathogenesis and causes cognitive impairment. RESULTS: The serum levels of several metabolites, including 7ß-OHC, were increased by aging in the 3xTg-AD unlike normal mice. Consistently, the levels of 7ß-OHC were increased in the hairs of patients with AD and were correlated with clinical severity. We found that 7ß-OHC directly affects AD-related pathophysiology; intrahippocampal injection of 7ß-OHC induced astrocyte and microglial cell activation, increased the levels of pro-inflammatory cytokines (TNF-alpha, IL-1ß, IL-6), and enhanced amyloidogenic pathway. Mice treated with 7ß-OHC also exhibited deficits in memory and frontal/executive functions assessed by object recognition and 5-choice serial reaction time task, respectively. CONCLUSIONS: Our results suggest that 7ß-OHC could serve as a convenient, peripheral biomarker of AD. As directly involved in AD pathogenesis, 7ß-OHC assay may help actualize personalized medicine in a way to identify an at-risk subgroup as a candidate population for statin-based AD treatment.
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Enfermedad de Alzheimer , Biomarcadores , Disfunción Cognitiva , Hidroxicolesteroles , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/patología , Hidroxicolesteroles/sangre , Animales , Ratones , Biomarcadores/sangre , Humanos , Disfunción Cognitiva/sangre , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Masculino , Anciano , Ratones Transgénicos , Femenino , Ratones Endogámicos C57BL , Hipocampo/metabolismo , Hipocampo/patología , Modelos Animales de EnfermedadRESUMEN
STATEMENT OF PROBLEM: Prostheses printed on a 3-dimensional (3D) printer need to undergo the postpolymerization process, which can increase the working time. However, it has been not suggested for reducing workload and improving the properties of prostheses in dental clinical practice. PURPOSE: The purpose of this in vitro study was to evaluate how the printing temperature impacts the dimensional accuracy and fracture load of 3D printed fixed dental prostheses (FDPs). MATERIAL AND METHODS: Dental prostheses were printed at room temperature (RT), 50°C, and 70°C using a stereolithography 3D printer. Subsequently, after rinsing away residual monomer, the printed parts underwent the green condition (it was not subjected to any postprocessing) and postpolymerization. The mechanical properties of the printed FDPs were determined by loading to fracture (n=6). To evaluate their clinical applicability, the dimensional accuracy and fit of FDPs fabricated at various resin polymerization temperatures were measured (n=6). The 1-way analysis of variance was used to perform statistical comparisons, followed by the Tukey honestly significant difference test (α=.05). RESULTS: The specimens printed at RT and 50°C were better than those printed at 70°C in terms of dimensional accuracy and fit (P<.05). Nonetheless, the dimensional accuracy and fit of the specimens printed at 70°C were clinically acceptable. The fracture load of the 3-unit FDPs depended significantly on the printing temperature. CONCLUSIONS: The dimensional accuracy and fracture load of the 70°C group were acceptable for FDP fabrication. Thus, the temperature of 70°C without postprocessing may help make the procedure more efficient.
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Prótesis Dental , Estereolitografía , Temperatura , Diseño Asistido por Computadora , Polimerizacion , Ensayo de Materiales , Impresión TridimensionalRESUMEN
STATEMENT OF PROBLEM: Improvement in the mechanical properties of 3-dimensional (3D) printed dental prostheses is necessary to prevent wear caused by an antagonist or fracture. However, how different printing temperatures affect their mechanical properties is unclear. PURPOSE: The purpose of this in vitro study was to evaluate the mechanical properties of 3D printed parts fabricated at different printing temperatures. MATERIAL AND METHODS: Photopolymer specimens were fabricated at 3 different temperatures (room temperature, 50 °C, and 70 °C) using a stereolithography 3D printer. After rinsing to remove the residual monomer, the specimens were divided into 2 groups: with or without postprocessing. The viscosity of the photopolymerization resin was measured while the temperature was increased. Furthermore, the double-bond conversion (DBC) of the printed part was evaluated (n=3). Mechanical properties were investigated via dynamic mechanical analysis (n=1) and tensile testing (n=5). Statistical comparisons were performed via 1-way analysis of variance, followed by the Tukey honestly significant difference test (α=.05). RESULTS: The DBC rates of the green condition group increased from 66.67% to 86.33% with increasing temperature. In addition, these specimens exhibited improved mechanical properties and reduced residual monomer levels. CONCLUSIONS: Specimens fabricated at a temperature of 70 °C exhibited mechanical properties suitable for clinical application.
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Impresión Tridimensional , Estereolitografía , Temperatura , Polimerizacion , Ensayo de Materiales , Propiedades de SuperficieRESUMEN
Aqueous zinc-ion batteries (AZIBs) are receiving increasing attention for power-grid energy storage systems. Nevertheless, warranting long-term reversible operation is not trivial owing to uncontrolled interfacial phenomena related to zinc dendritic growth and parasitic reactions. Herein, the addition of hexamethylphosphoramide (HMPA) to the electrolyte revealed the surface overpotential (|ηs|) to be a key metric of the reversibility. HMPA adsorbs onto active sites on the zinc metal surface, raising the surface overpotential toward lowering the nucleation energy barrier and decreasing the critical size (rcrit) of nuclei. We also correlated the observed interface-to-bulk properties by the Wagner (Wa) dimensionless number. The controlled interface enables a Zn|V6O13 full cell to retain 75.97% capacity for 2000 cycles, with a capacity loss of only 1.5% after 72 h resting. Our study not only delivers AZIBs with unparalleled cycling and storage performance but also proposes surface overpotential as a key descriptor regarding the sustainability of AZIB cycling and storage.
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Ischemia-reperfusion (IR) injury, a leading cause of acute kidney injury (AKI), is still without effective therapies. Succinate accumulation during ischemia followed by its oxidation during reperfusion leads to excessive reactive oxygen species (ROS) and severe kidney damage. Consequently, the targeting of succinate accumulation may represent a rational approach to the prevention of IR-induced kidney injury. Since ROS are generated primarily in mitochondria, which are abundant in the proximal tubule of the kidney, we explored the role of pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial enzyme, in IR-induced kidney injury using proximal tubule cell-specific Pdk4 knockout (Pdk4ptKO) mice. Knockout or pharmacological inhibition of PDK4 ameliorated IR-induced kidney damage. Succinate accumulation during ischemia, which is responsible for mitochondrial ROS production during reperfusion, was reduced by PDK4 inhibition. PDK4 deficiency established conditions prior to ischemia resulting in less succinate accumulation, possibly because of a reduction in electron flow reversal in complex II, which provides electrons for the reduction of fumarate to succinate by succinate dehydrogenase during ischemia. The administration of dimethyl succinate, a cell-permeable form of succinate, attenuated the beneficial effects of PDK4 deficiency, suggesting that the kidney-protective effect is succinate-dependent. Finally, genetic or pharmacological inhibition of PDK4 prevented IR-induced mitochondrial damage in mice and normalized mitochondrial function in an in vitro model of IR injury. Thus, inhibition of PDK4 represents a novel means of preventing IR-induced kidney injury, and involves the inhibition of ROS-induced kidney toxicity through reduction in succinate accumulation and mitochondrial dysfunction.
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Daño por Reperfusión , Ácido Succínico , Ratones , Animales , Ácido Succínico/farmacología , Especies Reactivas de Oxígeno , Ratones Noqueados , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Isquemia/tratamiento farmacológico , Riñón , Mitocondrias , ReperfusiónRESUMEN
Aggregated and hyperphosphorylated Tau is one of the pathological hallmarks of Alzheimer's disease. Tau is a polyampholytic and intrinsically disordered protein (IDP). In this paper, we present for the first time experimental results on the ionic strength dependence of the radius of gyration (Rg) of human Tau 4RS and 4RL isoforms. Synchrotron X-ray scattering revealed that 4RS Rg is regulated from 65.4 to 58.5 Å and 4RL Rg is regulated from 70.9 to 57.9 Å by varying ionic strength from 0.01 to 0.592 M. The Rg of 4RL Tau is larger than 4RS at lower ionic strength. This result provides an insight into the ion-responsive nature of intrinsically disordered and polyampholytic Tau, and can be implicated to the further study of Tau-Tau and Tau-tubulin intermolecular structure in ionic environments.
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Proteínas Intrínsecamente Desordenadas , Sincrotrones , Humanos , Rayos XRESUMEN
Aptamers are single-stranded oligonucleotides that bind to a specific target with high affinity, and are widely applied in biomedical diagnostics and drug development. However, the use of aptamers has largely been limited to simple binders or inhibitors that interfere with the function of a target protein. Here, we show that an aptamer can also act as a positive allosteric modulator that enhances the activation of a receptor by stabilizing the binding of a ligand to that receptor. We developed an aptamer, named IR-A43, which binds to the insulin receptor, and confirmed that IR-A43 and insulin bind to the insulin receptor with mutual positive cooperativity. IR-A43 alone is inactive, but, in the presence of insulin, it potentiates autophosphorylation and downstream signaling of the insulin receptor. By using the species-specific activity of IR-A43 at the human insulin receptor, we demonstrate that residue Q272 in the cysteine-rich domain is directly involved in the insulin-enhancing activity of IR-A43. Therefore, we propose that the region containing residue Q272 is a hotspot that can be used to enhance insulin receptor activation. Moreover, our study implies that aptamers are promising reagents for the development of allosteric modulators that discriminate a specific conformation of a target receptor.
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Antígenos CD/efectos de los fármacos , Aptámeros de Nucleótidos/farmacología , Receptor de Insulina/efectos de los fármacos , Regulación Alostérica , Animales , Antígenos CD/química , Antígenos CD/metabolismo , Células Cultivadas , Cricetinae , Glutamina/química , Humanos , Insulina/metabolismo , Ratones , Fosforilación , Unión Proteica , Conformación Proteica , Dominios Proteicos , Procesamiento Proteico-Postraduccional , Ratas , Receptor IGF Tipo 1/química , Receptor IGF Tipo 1/efectos de los fármacos , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/química , Receptor de Insulina/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/efectos de los fármacos , Proteínas Recombinantes/metabolismo , Técnica SELEX de Producción de Aptámeros , Estimulación QuímicaRESUMEN
BACKGROUND: There have been few reports comparing image quality and radiation dose of aorta computed tomography angiography (CTA) between the high-pitch and the hybrid technique. PURPOSE: To compare the image quality and radiation dose among non-electrocardiogram (ECG)-gated high-pitch CTA and hybrid ECG-gated CTA of the aorta using 512-slice CT. MATERIAL AND METHODS: This retrospective study included 110 patients who underwent non-ECG-gated high-pitch CTA (group 1) or hybrid ECG-gated CTA (group 2) of the entire aorta. Interpretability, image noise, contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), and the mean effective radiation dose were compared. RESULTS: The mean image noise of the whole aorta was significantly lower (15.7 ± 1.8 HU vs. 16.5 ± 1.2 HU, P = 0.008) in group 1 than in group 2. The CNR (22.3 ± 4.7 vs. 20.0 ± 3.9, Pâ <â 0.001) and SNR (26.5 ± 4.9 vs. 23.2 ± 4.0, Pâ <â 0.001) were higher in group 2 compared with group 1. Neither group showed a significant difference in interpretability of the ascending aorta, cardiac chamber, aortic valve, right ostium, and left ostium (all P = 1). The mean effective radiation dose was significantly lower in group 1 than in group 2 (3.5 ± 0.9 mSv vs. 4.3 ± 0.8 mSv, Pâ <â 0.001). CONCLUSION: The non-ECG-gated high-pitch technique shows significantly improved CNR and SNR due to reduced noise with lower radiation exposure. The interpretability of the cardiac structure, ascending aorta, aortic valve, and both ostia did not differ significantly between the two groups.
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Aorta , Angiografía por Tomografía Computarizada , Humanos , Angiografía por Tomografía Computarizada/métodos , Aortografía/métodos , Estudios Retrospectivos , Dosis de Radiación , Aorta/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Electrocardiografía/métodos , Válvula Aórtica , Angiografía Coronaria/métodosRESUMEN
BACKGROUND: Although it is known that a substantial proportion of the population experience loneliness, the consequence of loneliness remains unclear by countries and ages. Accordingly, this study aimed to assess the association between loneliness and suicidality in the general population of Korea. METHOD: A total of 5,511 Koreans aged 18-79 completed a tablet-assisted personal interview using the Korean version of the Composite International Diagnostic Interview and responded to questions about loneliness and lifetime suicidal ideation, plans, and attempts. A logistic regression analysis was used to examine the association between loneliness and suicidality. RESULTS: Approximately one-third of the Korean general population reported loneliness. Being older, never married, widowed, separated, or divorced, unemployed, and having a part-time job were all significantly related to loneliness. After adjusting for sociodemographic factors, individuals with loneliness were significantly associated with increased suicidal ideation (adjusted odd ratio [aOR], 4.05; 95% confidence interval [CI], 3.36-4.88), suicidal plans (aOR, 4.91; 95% CI, 3.34-7.21), and suicidal attempts (aOR, 4.82; 95% CI, 3.03-7.66). Even after adjusting for sociodemographic factors and mental disorders, suicidality remained statistically significant. Moreover, frequent, moderate-to-severe, and long-term loneliness were all associated with increased ORs for suicidality, regardless of sociodemographic factors and mental disorders. CONCLUSION: Loneliness was associated with suicidal ideation, plans, and attempts. This study lays the foundation for public health policymakers to establish early intervention and mental health care support for lonely people.
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Ideación Suicida , Suicidio , Humanos , Prevalencia , Soledad , República de Corea/epidemiologíaRESUMEN
BACKGROUND AND AIM: prokinetics could eradicate small intestinal bacterial overgrowth. This study aimed to evaluate the efficacy of mosapride, rifaximin and a combination of mosapride and rifaximin for the treatment of small intestinal bacterial overgrowth. METHODS: we randomly assigned patients with functional dyspepsia diagnosed with small intestinal bacterial overgrowth in a 1:1:1 ratio to receive mosapride, rifaximin or a combination of both for two weeks. The hydrogen-methane glucose breath test and symptom questionnaire were surveyed before and after the treatment. Primary outcome was eradication rate of small intestinal bacterial overgrowth. Secondary outcomes were changes in the gas concentration, symptoms and safety. RESULTS: the eradication rates were 17.2 % (5/29) for mosapride, 32.1 % (9/28) for rifaximin, and 34.6 % (9/26) for the combined groups, with no significant differences among the three groups. Total hydrogen concentration during the glucose breath test significantly decreased in the rifaximin group (p = 0.001). Total methane concentration significantly decreased in the rifaximin and combined groups (p = 0.005). Significant symptomatic improvements were observed in chest and abdominal discomfort with mosapride, in flatulence with rifaximin, and in chest discomfort with the combined groups. Adverse events were similar between the groups. CONCLUSIONS: rifaximin has an advantage of reducing gas, whereas mosapride can help to decrease breath hydrogen concentration. Certain intestinal symptoms improved with mosapride alone or combined with rifaximin.
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Dispepsia , Humanos , Rifaximina/uso terapéutico , Dispepsia/diagnóstico , Dispepsia/tratamiento farmacológico , Glucosa , Intestino Delgado/microbiología , Resultado del Tratamiento , Pruebas Respiratorias , Hidrógeno , MetanoRESUMEN
Prostate cancer (PCa) is the most commonly diagnosed malignancy among men in developed countries. The five-year survival rate for men diagnosed with early-stage PCa is approximately 100%, while it is less than 30% for castration-resistant PCa (CRPC). Currently, the detection of prostate-specific antigens as biomarkers for the prognosis of CRPC is criticized because of its low accuracy, high invasiveness, and high false-positive rate. Therefore, it is important to identify new biomarkers for prediction of CRPC progression. Extracellular vesicles (EVs) derived from tumors have been highlighted as potential markers for cancer diagnosis and prognosis. Specifically, urinary EVs directly reflect changes in the pathophysiological conditions of the urogenital system because it is exposed to prostatic secretions. Thus, detecting biomarkers in urinary EVs provides a promising approach for performing an accurate and non-invasive liquid biopsy for CPRC. In this study, we effectively isolated urinary EVs with low protein impurities using size-exclusion chromatography combined with ultrafiltration. After EV isolation and characterization, we evaluated the miRNAs in urinary EVs from healthy donors and patients with CRPC. The results indicated that miRNAs (miR-21-5p, miR-574-3p, and miR-6880-5p) could be used as potential biomarkers for the prognosis of CRPC. This analysis of urinary EVs contributes to the fast and convenient prognosis of diseases, including CRPC, in the clinical setting.