Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.751
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Cell ; 175(1): 133-145.e15, 2018 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-30220454

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis (NASH) in response to elevated endoplasmic reticulum (ER) stress. Whereas the onset of simple steatosis requires elevated de novo lipogenesis, progression to NASH is triggered by accumulation of hepatocyte-free cholesterol. We now show that caspase-2, whose expression is ER-stress inducible and elevated in human and mouse NASH, controls the buildup of hepatic-free cholesterol and triglycerides by activating sterol regulatory element-binding proteins (SREBP) in a manner refractory to feedback inhibition. Caspase-2 colocalizes with site 1 protease (S1P) and cleaves it to generate a soluble active fragment that initiates SCAP-independent SREBP1/2 activation in the ER. Caspase-2 ablation or pharmacological inhibition prevents diet-induced steatosis and NASH progression in ER-stress-prone mice. Caspase-2 inhibition offers a specific and effective strategy for preventing or treating stress-driven fatty liver diseases, whereas caspase-2-generated S1P proteolytic fragments, which enter the secretory pathway, are potential NASH biomarkers.


Asunto(s)
Caspasa 2/fisiología , Lipogénesis/fisiología , Proproteína Convertasas/fisiología , Serina Endopeptidasas/fisiología , Animales , Colesterol/metabolismo , Retículo Endoplásmico/fisiología , Estrés del Retículo Endoplásmico/fisiología , Hígado Graso/fisiopatología , Células HEK293 , Hepatocitos/metabolismo , Humanos , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Proproteína Convertasas/metabolismo , Serina Endopeptidasas/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Triglicéridos/metabolismo
2.
Cell ; 173(4): 864-878.e29, 2018 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-29681454

RESUMEN

Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/efectos de los fármacos , Neoplasias Pulmonares/patología , Bibliotecas de Moléculas Pequeñas/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Familia 4 del Citocromo P450/deficiencia , Familia 4 del Citocromo P450/genética , Descubrimiento de Drogas , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Glucocorticoides/farmacología , Proteínas Facilitadoras del Transporte de la Glucosa/antagonistas & inhibidores , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Mutación , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptor Notch2/genética , Receptor Notch2/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo
3.
Nat Immunol ; 18(7): 780-790, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28553951

RESUMEN

The acquisition of a protective vertebrate immune system hinges on the efficient generation of a diverse but self-tolerant repertoire of T cells by the thymus through mechanisms that remain incompletely resolved. Here we identified the endosomal-sorting-complex-required-for-transport (ESCRT) protein CHMP5, known to be required for the formation of multivesicular bodies, as a key sensor of thresholds for signaling via the T cell antigen receptor (TCR) that was essential for T cell development. CHMP5 enabled positive selection by promoting post-selection thymocyte survival in part through stabilization of the pro-survival protein Bcl-2. Accordingly, loss of CHMP5 in thymocyte precursor cells abolished T cell development, a phenotype that was 'rescued' by genetic deletion of the pro-apoptotic protein Bim or transgenic expression of Bcl-2. Mechanistically, positive selection resulted in the stabilization of CHMP5 by inducing its interaction with the deubiquitinase USP8. Our results thus identify CHMP5 as an essential component of the post-translational machinery required for T cell development.


Asunto(s)
Diferenciación Celular/inmunología , Complejos de Clasificación Endosomal Requeridos para el Transporte/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Timocitos/inmunología , Animales , Proteína 11 Similar a Bcl2/inmunología , Endopeptidasas/inmunología , Immunoblotting , Inmunoprecipitación , Ratones , Microscopía Electrónica de Transmisión , Microscopía Fluorescente , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/inmunología , Linfocitos T/citología , Timocitos/citología , Ubiquitina Tiolesterasa/inmunología
4.
Cell ; 148(5): 1051-64, 2012 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-22385968

RESUMEN

How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders.


Asunto(s)
Proteínas del Tejido Nervioso/metabolismo , Neurogénesis , Esquizofrenia/metabolismo , Transducción de Señal , Ácido gamma-Aminobutírico/metabolismo , Animales , Dendritas/metabolismo , Susceptibilidad a Enfermedades , Femenino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Análisis de la Célula Individual , Simportadores de Cloruro de Sodio-Potasio/genética , Simportadores de Cloruro de Sodio-Potasio/metabolismo , Miembro 2 de la Familia de Transportadores de Soluto 12
5.
PLoS Biol ; 21(4): e3002051, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37014914

RESUMEN

Detoxification, scavenging, and repair systems embody the archetypical antioxidant defenses of prokaryotic and eukaryotic cells. Metabolic rewiring also aids with the adaptation of bacteria to oxidative stress. Evolutionarily diverse bacteria combat the toxicity of reactive oxygen species (ROS) by actively engaging the stringent response, a stress program that controls many metabolic pathways at the level of transcription initiation via guanosine tetraphosphate and the α-helical DksA protein. Studies herein with Salmonella demonstrate that the interactions of structurally related, but functionally unique, α-helical Gre factors with the secondary channel of RNA polymerase elicit the expression of metabolic signatures that are associated with resistance to oxidative killing. Gre proteins both improve transcriptional fidelity of metabolic genes and resolve pauses in ternary elongation complexes of Embden-Meyerhof-Parnas (EMP) glycolysis and aerobic respiration genes. The Gre-directed utilization of glucose in overflow and aerobic metabolism satisfies the energetic and redox demands of Salmonella, while preventing the occurrence of amino acid bradytrophies. The resolution of transcriptional pauses in EMP glycolysis and aerobic respiration genes by Gre factors safeguards Salmonella from the cytotoxicity of phagocyte NADPH oxidase in the innate host response. In particular, the activation of cytochrome bd protects Salmonella from phagocyte NADPH oxidase-dependent killing by promoting glucose utilization, redox balancing, and energy production. Control of transcription fidelity and elongation by Gre factors represent important points in the regulation of metabolic programs supporting bacterial pathogenesis.


Asunto(s)
Estrés Oxidativo , Salmonella , Salmonella/genética , Estrés Oxidativo/genética , Oxidación-Reducción , NADPH Oxidasas/metabolismo , Glucosa/metabolismo
6.
Nature ; 582(7813): 511-514, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32581381

RESUMEN

Decrease in processing speed due to increased resistance and capacitance delay is a major obstacle for the down-scaling of electronics1-3. Minimizing the dimensions of interconnects (metal wires that connect different electronic components on a chip) is crucial for the miniaturization of devices. Interconnects are isolated from each other by non-conducting (dielectric) layers. So far, research has mostly focused on decreasing the resistance of scaled interconnects because integration of dielectrics using low-temperature deposition processes compatible with complementary metal-oxide-semiconductors is technically challenging. Interconnect isolation materials must have low relative dielectric constants (κ values), serve as diffusion barriers against the migration of metal into semiconductors, and be thermally, chemically and mechanically stable. Specifically, the International Roadmap for Devices and Systems recommends4 the development of dielectrics with κ values of less than 2 by 2028. Existing low-κ materials (such as silicon oxide derivatives, organic compounds and aerogels) have κ values greater than 2 and poor thermo-mechanical properties5. Here we report three-nanometre-thick amorphous boron nitride films with ultralow κ values of 1.78 and 1.16 (close to that of air, κ = 1) at operation frequencies of 100 kilohertz and 1 megahertz, respectively. The films are mechanically and electrically robust, with a breakdown strength of 7.3 megavolts per centimetre, which exceeds requirements. Cross-sectional imaging reveals that amorphous boron nitride prevents the diffusion of cobalt atoms into silicon under very harsh conditions, in contrast to reference barriers. Our results demonstrate that amorphous boron nitride has excellent low-κ dielectric characteristics for high-performance electronics.

7.
Nat Mater ; 23(6): 834-843, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38532072

RESUMEN

Liquid crystal elastomers hold promise in various fields due to their reversible transition of mechanical and optical properties across distinct phases. However, the lack of local phase patterning techniques and irreversible phase programming has hindered their broad implementation. Here we introduce laser-induced dynamic crosslinking, which leverages the precision and control offered by laser technology to achieve high-resolution multilevel patterning and transmittance modulation. Incorporation of allyl sulfide groups enables adaptive liquid crystal elastomers that can be reconfigured into desired phases or complex patterns. Laser-induced dynamic crosslinking is compatible with existing processing methods and allows the generation of thermo- and strain-responsive patterns that include isotropic, polydomain and monodomain phases within a single liquid crystal elastomer film. We show temporary information encryption at body temperature, expanding the functionality of liquid crystal elastomer devices in wearable applications.

8.
Mol Ther ; 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-39066480

RESUMEN

Multiple pathogenic single-nucleotide polymorphisms (SNPs) have been identified as contributing factors in the aggravation of cancer prognosis and emergence of drug resistance in various cancers. Here, we targeted mutated EGFR and TP53 oncogenes harboring single-nucleotide missense mutations (EGFR-T790M and TP53-R273H) that are associated with gefitinib resistance. Co-delivery of adenine base editor (ABE) and EGFR- and TP53-SNP specific single-guide RNA via adenovirus (Ad) resulted in precise correction of the oncogenic mutations with high accuracy and efficiency in vitro and in vivo. Importantly, compared with a control group treated only with gefitinib, an EGFR inhibitor, co-treatment with Ad/ABE targeting SNPs in TP53 and EGFR in combination with gefitinib increased drug sensitivity and suppressed abnormal tumor growth more efficiently. Taken together, these results indicate that ABE-mediated correction of dual oncogenic SNPs can be an effective strategy for the treatment of drug-resistant cancers.

9.
Nano Lett ; 24(37): 11462-11468, 2024 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-39239915

RESUMEN

As atomic-scale etching and deposition processes become necessary for manufacturing logic and memory devices at the sub-5 nm node, the limitations of conventional plasma technology are becoming evident. For atomic-scale processes, precise critical dimension control at the sub-1 nm scale without plasma-induced damage and high selectivity between layers are required. In this paper, a plasma with very low electron temperature is applied for damage-free processing on the atomic scale. In plasmas with an ultralow electron temperature (ULET, Te < 0.5 eV), ion energies are very low, and the ion energy distribution is narrow. The absence of physical damage in ULET plasma is verified by exposing 2D structural material. In the ULET plasma, charging damage and radiation damage are also expected to be suppressed due to the extremely low Te. This ULET plasma source overcomes the limitations of conventional plasma sources and provides insights to achieve damage-free atomic-scale processes.

10.
J Infect Dis ; 229(6): 1878-1882, 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38366017

RESUMEN

Tuberculosis (TB) remains a major threat to global public health. Various measures at the national level have been implemented to control TB, and no evidence with long-term effectiveness has yet been evaluated on TB control programs. We confirmed the long-term effectiveness of the TB control programs in reducing overall burden in South Korea using interrupted time series analysis. Our finding suggests that, along with the public-private mix, relieving the economic burden of people with TB may complement achieving the End TB Strategy. For countries currently developing strategies for TB control, results may provide important insights in effective TB control.


Asunto(s)
Análisis de Series de Tiempo Interrumpido , Tuberculosis , República de Corea/epidemiología , Humanos , Tuberculosis/prevención & control , Tuberculosis/epidemiología , Tuberculosis/economía , Adulto , Femenino , Masculino , Persona de Mediana Edad , Adulto Joven , Adolescente , Anciano
11.
J Infect Dis ; 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38679784

RESUMEN

Rotavirus is linked to severe childhood gastroenteritis and neurological complications, but its impact on neurodevelopment remains uncertain. We examined data from 1,420,941 Korean children born between 2009 and 2011, using the Korean National Health Insurance System. At age 6, we assessed neurodevelopmental outcomes using the validated Korean Developmental Test, covering six major domains. Utilizing propensity score-based Inverse Probability Weighting to ensure covariates including considering covariates including sex, birth weight, changes in body weight from birth to 4-6 months of age, head circumference at 4-6 months of age, residence at birth, economic status, infant feeding types, and birth year. The main analysis that encompassed 5,451 children with rotavirus hospitalization and 310,874 unexposed individuals reveled heightened odds of suspected delays in fine motor skills and cognition among exposed children. Our results suggest an association between rotavirus-related hospitalization in infancy and suspected delays in fine motor function and cognition in 6-year-olds.

12.
Circulation ; 148(20): 1570-1581, 2023 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-37850383

RESUMEN

BACKGROUND: Although venoarterial extracorporeal membrane oxygenation (VA-ECMO) is beneficial for the treatment of profound cardiogenic shock, peripheral VA-ECMO cannulation can increase left ventricular afterload, thus compromising myocardial recovery. We investigated whether early routine left ventricular unloading can reduce 30-day mortality compared with the conventional approach in patients with cardiogenic shock undergoing VA-ECMO. METHODS: This randomized clinical trial involved 116 patients with cardiogenic shock undergoing VA-ECMO from March 2021 to September 2022 at Chonnam National University Hospital, Gwangju, South Korea. The patients were randomly assigned to undergo either early routine left ventricular unloading with transseptal left atrial cannulation within 12 hours after randomization (n=58) or the conventional approach, which permitted rescue transseptal left atrial cannulation in case of an increased left ventricular afterload (n=58). The primary outcome was all-cause mortality within 30 days. RESULTS: All 116 randomized patients (mean age, 67.6±13.5 years; 34 [29.3%] women) completed the trial. At 30 days, all-cause death had occurred in 27 (46.6%) patients in the early group and 26 (44.8%) patients in the conventional group (hazard ratio, 1.02 [95% CI, 0.59-1.74]; P=0.942). Crossover to rescue transseptal left atrial cannulation occurred in 29 patients (50%) in the conventional group according to a clear indication. Time to rescue transseptal cannulation in the conventional group was a median of 21.8 (interquartile range, 12.4-52.2) hours after randomization. There were no significant differences in other secondary outcomes between the 2 groups except for a shorter time to disappearance of pulmonary congestion in the early group (median, 3 [interquartile range, 2-6] versus 5 [interquartile range, 3-7] days; P=0.027). CONCLUSIONS: Among patients with cardiogenic shock undergoing VA-ECMO, early routine left ventricular unloading with transseptal left atrial cannulation did not reduce 30-day mortality compared with the conventional strategy, which permitted rescue transseptal left atrial cannulation. These findings should be cautiously interpreted until the results of multicenter trials using other unloading modalities become available. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04775472.


Asunto(s)
Fibrilación Atrial , Oxigenación por Membrana Extracorpórea , Humanos , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Masculino , Choque Cardiogénico , Oxigenación por Membrana Extracorpórea/métodos , Ventrículos Cardíacos , Atrios Cardíacos , Estudios Retrospectivos
13.
Immunology ; 173(1): 93-105, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38778445

RESUMEN

Cytokines of the common-γ receptor chain (γc) family are crucial for T-cell differentiation and dysregulation of γc cytokine pathways is involved in the pathogenesis of autoimmune diseases. There is increasing evidence that the availability of the γc receptor (CD132) for the associated receptor chains has implications for T-cell functions. Here we studied the influence of differential γc expression on the expression of the IL-2Rα (CD25), the IL-7Rα (CD127) and the differentiation of activated naïve T cells. We fine-tuned the regulation of γc expression in human primary naïve T cells by lentiviral transduction using small hairpin (sh)RNAs and γc cDNA. Differential γc levels were then analysed for effects on T-cell phenotype and function after activation. Differential γc expression markedly affected IL-2Rα and IL-7Rα expression on activated naïve T cells. High γc expression (γc-high) induced significantly higher expression of IL-2Rα and re-expression of IL-7Rα after activation. Inhibition of γc caused lower IL-2Rα/IL-7Rα expression and impaired proliferation of activated naïve T cells. In contrast, γc-high T cells secreted significantly higher concentrations of effector cytokines (i.e., IFN-γ, IL-6) and showed higher cytokine-receptor induced STAT5 phosphorylation during initial stages as well as persistently higher pSTAT1 and pSTAT3 levels after activation. Finally, accelerated transition towards a CD45RO expressing effector/memory phenotype was seen especially for CD4+ γc-high naïve T cells. These results suggested that high expression of γc promotes expression of IL-2Rα and IL-7Rα on activated naïve T cells with significant effects on differentiation and effector cytokine expression.


Asunto(s)
Diferenciación Celular , Activación de Linfocitos , Humanos , Diferenciación Celular/inmunología , Subunidad gamma Común de Receptores de Interleucina/genética , Subunidad gamma Común de Receptores de Interleucina/metabolismo , Receptores de Interleucina-7/metabolismo , Receptores de Interleucina-7/genética , Células Cultivadas , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Transducción de Señal , Fosforilación , Factor de Transcripción STAT5/metabolismo , Regulación de la Expresión Génica
14.
J Cell Biochem ; 125(2): e30518, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38224182

RESUMEN

Excessive bone-resorbing osteoclast activity during bone remodeling is a major feature of bone diseases, such as osteoporosis. Therefore, the inhibition of osteoclast formation and bone resorption can be an effective therapeutic target for various bone diseases. Gryllus biomaculatus (GB) has recently been approved as an alternative food source because of its high nutritional value and environmental sustainability. Traditionally, GB has been known to have various pharmacological properties, including antipyretic and blood pressure-lowering activity, and it has recently been reported to have various biological activities, including protective effects against inflammation, oxidative stress, insulin resistance, and alcohol-induced liver injury. However, the effect of GB on osteoclast differentiation and bone metabolism has not yet been demonstrated. In this study, we confirmed the inhibitory effect of GB extract (GBE) on the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation. To determine the effect of GBE on RANKL-induced osteoclast differentiation and function, we performed TRAP and F-actin staining, as well as a bone-resorbing assay. The intracellular mechanisms of GBE responsible for the regulation of osteoclastogenesis were revealed by Western blot analysis and quantitative real-time polymerase chain reaction. We investigated the relationship between GBE and expression of osteoclast-specific molecules to further elucidate the underlying mechanisms. It was found that GBE significantly suppressed osteoclastogenesis by decreasing the phosphorylation of Akt, p38, JNK, and ERK, as well as Btk-PLCγ2 signaling, in pathways involved in early osteoclastogenesis as well as through the subsequent suppression of c-Fos, NFATc1, and osteoclastogenesis-specific marker genes. Additionally, GBE inhibited the formation of F-actin ring-positive osteoclasts and bone resorption activity of mature osteoclasts. Our findings suggest that GBE is a potential functional food and therapeutic candidate for bone diseases involving osteoclasts.


Asunto(s)
Resorción Ósea , Osteoclastos , Ligando RANK , Humanos , Actinas/metabolismo , Resorción Ósea/tratamiento farmacológico , Diferenciación Celular , Ligandos , FN-kappa B/metabolismo , Factores de Transcripción NFATC/metabolismo , Osteoclastos/metabolismo , Ligando RANK/antagonistas & inhibidores , Ligando RANK/metabolismo
15.
Biochem Biophys Res Commun ; 735: 150629, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39260332

RESUMEN

Interferon-gamma (IFN-γ) was found to increase in the synovial fluid of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). However, few studies have been conducted to elucidate the role of IFN-γ in cartilage metabolism and regeneration. In this study, we investigated whether cartilage regeneration is driven by interferon-stimulated gene 15 (ISG15) under the control of IFN-γ. IFN-γ significantly increased ITS-induced chondrogenic differentiation of ATDC5 cells. Knockdown of IFN-γ receptor (IFN-γR) inhibited IFN-γ-induced chondrogenic differentiation and reduced ACAN and Col II expression. In addition, ISG15 expression was highly elevated in response to IFN-γ, whereas its expression was downregulated by knockdown of IFN-γR, indicating that ISG15 is closely related to IFN-γ signaling. Furthermore, chondrogenic differentiation and expression of ACAN and Col II were significantly reduced following knockdown of ISG15 in ATDC5 cells despite the presence of IFN-γ. ISGylation of cellular proteins found in chondrogenic differentiated cells was related to activation of IFN-γ signaling. In addition, ISG15/ISGylation was significantly observed in the regenerated cartilage tissue 7 days after FTCI of young mice compared with sham control. Our findings showed that upregulation of ISG15 and/or ISGylation of cellular proteins may play a critical role in cartilage regeneration through activation of IFN-γ signaling.

16.
Am J Gastroenterol ; 2024 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-39315687

RESUMEN

INTRODUCTION: Anti-tumor necrosis factor (anti-TNF) therapy may improve insulin sensitivity, and its impact during pregnancy remains unclear. We aimed to assess the risk of gestational diabetes mellitus (GDM) associated with anti-TNF treatment among pregnant women with inflammatory bowel disease (IBD). METHODS: This nationwide cohort study included patients with IBD in Korea from 2010 to 2021. Anti-TNF exposure was identified from the last menstrual period (LMP) to LMP+140 days. The development of GDM was assessed from LMP+141 days to delivery. We performed overlap weighting to balance the covariates and used a generalized linear mixed model to measure the risk ratio (RR) and 95% confidence intervals (CIs). The anti-TNF group was compared with the unexposed group, as well as with the immunosuppressant, 5-aminosalicylate, and untreated groups. RESULTS: A total of 3,695 pregnancies in women with IBD were identified, of which 338 (9.2%) were exposed to anti-TNFs. GDM was found in 7.1% of the pregnancies exposed to anti-TNFs as compared with 11.0% of those unexposed. The crude and weighted RR for GDM risk were 0.64 (95% CI 0.43-0.96) and 0.68 (0.55-0.84), respectively. The weighted RR when compared with the immunosuppressant, 5-aminosalicylate, and untreated groups were 0.70 (0.41-1.18), 0.71 (0.52-0.95), and 0.85 (0.59-1.24), respectively. DISCUSSION: This nationwide cohort reported a decreased risk of GDM among patients who used anti-TNFs during early pregnancy compared to those unexposed. GDM risk may become a consideration in the decision-making process when choosing treatment options for pregnant women with a risk factor for GDM.

17.
BMC Med ; 22(1): 123, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38486297

RESUMEN

BACKGROUND: Several neurological manifestations shortly after a receipt of coronavirus infectious disease 2019 (COVID-19) vaccine have been described in the recent case reports. Among those, we sought to evaluate the risk of encephalitis and meningitis after COVID-19 vaccination in the entire South Korean population. METHODS: We conducted self-controlled case series (SCCS) analysis using the COVID-19 immunization record data from the Korea Disease Control Agency between February 2021 and March 2022, linked with the National Health Insurance Database between January 2021 and October 2022. We retrieved all medical claims of adults aged 18 years or older who received at least one dose of COVID-19 vaccines (BNT162b2, mRNA-1273, ChAdOx1-S, or Ad26.COV2.S), and included only those who had a diagnosis record for encephalitis or meningitis within the 240-day post-vaccination period. With day 0 defined as the date of vaccination, risk window was defined as days 1-28 and the control window as the remainder period excluding the risk windows within the 240-day period. We used conditional Poisson regression to estimate the incidence rate ratios (IRR) with 95% confidence intervals (CI), stratified by dose and vaccine type. RESULTS: From 129,956,027 COVID-19 vaccine doses administered to 44,564,345 individuals, there were 251 and 398 cases of encephalitis and meningitis during the risk window, corresponding to 1.9 and 3.1 cases per 1 million doses, respectively. Overall, there was an increased risk of encephalitis in the first 28 days of COVID-19 vaccination (IRR 1.26; 95% CI 1.08-1.47), which was only significant after a receipt of ChAdOx1-S (1.49; 1.03-2.15). For meningitis, no increased risk was observed after any dose of COVID-19 vaccine (IRR 1.03; 95% CI 0.91-1.16). CONCLUSIONS: Our findings suggest an overall increased risk of encephalitis after COVID-19 vaccination. However, the absolute risk was small and should not impede COVID-19 vaccine confidence. No significant association was found between the risk of meningitis and COVID-19 vaccination.


Asunto(s)
COVID-19 , Enfermedades Transmisibles , Encefalitis , Meningitis , Adulto , Humanos , Vacunas contra la COVID-19/efectos adversos , Ad26COVS1 , Vacuna BNT162 , COVID-19/epidemiología , COVID-19/prevención & control , Meningitis/epidemiología , Meningitis/etiología , República de Corea/epidemiología , Vacunación/efectos adversos , ChAdOx1 nCoV-19
18.
BMC Med ; 22(1): 335, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39148087

RESUMEN

BACKGROUND: Concomitant use of clopidogrel and proton pump inhibitor (PPI) is common, but PPI may reduce the antiplatelet effects of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We evaluated the impact of PPI use on clinical outcomes in post-PCI patients, by incorporating P2Y12 reaction unit (PRU) and CYP2C19 genotyping results. METHODS: From a multicenter registry of patients who underwent PCI with drug-eluting stent implantation and received clopidogrel-based dual antiplatelet therapy (DAPT), patients who were prescribed a PPI at the time of PCI (PPI users) were compared to those who were not (non-users). The primary outcome included all-cause death, myocardial infarction, stent thrombosis, or cerebrovascular accident at 12 months. Major bleeding (Bleeding Academic Research Consortium [BARC] types 3-5) and gastrointestinal (GI) bleeding (BARC types 3-5) were important secondary outcomes. The adjusted outcomes were compared using a 1:1 propensity-score (PS) matching and competing risk analysis. RESULTS: Of 13,160 patients, 2,235 (17.0%) were prescribed PPI, with an average age of 65.4 years. PPI users had higher on-treatment PRU levels than non-users. After PS matching, the primary outcome occurred in 51 patients who were PPI users (cumulative incidence, 4.7%) and 41 patients who were non-users (cumulative incidence, 3.7%; log-rank p = 0.27). In carriers of both CYP2C19 loss-of-function alleles, PPI use was linked to an increased risk of the primary outcome (hazard ratio, 3.22; 95% confidence interval, 1.18-8.78). The incidence of major bleeding and GI bleeding (BARC types 3-5) was comparable between PPI users and non-users in the PS-matched cohort. CONCLUSIONS: In post-PCI patients receiving clopidogrel-based DAPT, PPI use was not linked to an increased risk of adverse cardiac and cerebrovascular events, but there was a small but significant increase in on-treatment PRU. Future research using a more individualized approach would further elucidate these interactions and guide evidence-based clinical practices.


Asunto(s)
Clopidogrel , Citocromo P-450 CYP2C19 , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Inhibidores de la Bomba de Protones , Humanos , Clopidogrel/uso terapéutico , Clopidogrel/efectos adversos , Clopidogrel/administración & dosificación , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/administración & dosificación , Masculino , Femenino , Stents Liberadores de Fármacos/efectos adversos , Anciano , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Intervención Coronaria Percutánea/efectos adversos , Citocromo P-450 CYP2C19/genética , Resultado del Tratamiento , Sistema de Registros , Pueblos del Este de Asia
19.
Small ; 20(24): e2307200, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38197540

RESUMEN

Uniform lithium deposition is essential to hinder dendritic growth. Achieving this demands even seed material distribution across the electrode, posing challenges in correlating the electrode's surface structure with the uniformity of seed material distribution. In this study, the effect of periodic surface and facet orientation on seed distribution is investigated using a model system consisting of a wrinkled copper (Cu)/graphene structure with a [100] facet orientation. A new methodology is developed for uniformly distributed silver (Ag) nanoparticles over a large area by controlling the surface features of Cu substrates. The regularly arranged Ag nanoparticles, with a diameter of 26.4 nm, are fabricated by controlling the Cu surface condition as [100]-oriented wrinkled Cu. The wrinkled Cu guides a deposition site for spherical Ag nanoparticles, the [100] facet determines the Ag morphology, and the presence of graphene leads to spacings of Ag seeds. This patterned surface and high lithiophilicity, with homogeneously distributed Ag nanoparticles, lead to uniform Li+ flux and reduced nucleation energy barrier, resulting in excellent battery performance. The electrochemical measurements exhibit improved cyclic stability over 260 cycles at 0.5 mA cm-2 and 100 cycles at 1.0 mA cm-2 and enhanced kinetics even under a high current density of 5.0 mA cm-2.

20.
Small ; 20(6): e2305311, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37798936

RESUMEN

Structural engineering and hybridization of heterogeneous 2D materials can be effective for advanced supercapacitor. Furthermore, architectural design of electrodes particularly with vertical construction of structurally anisotropic graphene nanosheets, can significantly enhance the electrochemical performance. Herein, MXene-derived TiO2 nanocomposites hybridized with vertical graphene is synthesized via CO2 laser irradiation on MXene/graphene oxide nanocomposite film. Instantaneous photon energy by laser irradiation enables the formation of vertical graphene structures on nanocomposite films, presenting the controlled anisotropy in free-standing film. This vertical structure enables improved supercapacitor performance by forming an open structure, increasing the electrolyte-electrode interface, and creating efficient electron transport path. In addition, the effective oxidation of MXene nanosheets by instantaneous photon energy leads to the formation of rutile TiO2 . TiO2 nanoparticles directly generated on graphene enables the effective current path, which compensates for the low conductivity of TiO2 and enables the functioning of an effective supercapacitor by utilizing its pseudocapacitive properties. The resulting film exhibits excellent specific areal capacitance of 662.9 mF cm-2 at a current density of 5 mA cm-2 . The film also shows superb cyclic stability during 40 000 repeating cycles, maintaining high capacitance. Also, the pseudocapacitive redox reaction kinetics is evaluated, showing fast redox kinetics with potential for high-performance supercapacitor applications.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA