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The mammalian cytoplasmic multi-tRNA synthetase complex (MSC) is a depot system that regulates non-translational cellular functions. Here we found that the MSC component glutamyl-prolyl-tRNA synthetase (EPRS) switched its function following viral infection and exhibited potent antiviral activity. Infection-specific phosphorylation of EPRS at Ser990 induced its dissociation from the MSC, after which it was guided to the antiviral signaling pathway, where it interacted with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity. This interaction blocked PCBP2-mediated ubiquitination of MAVS and ultimately suppressed viral replication. EPRS-haploid (Eprs+/-) mice showed enhanced viremia and inflammation and delayed viral clearance. This stimulus-inducible activation of MAVS by EPRS suggests an unexpected role for the MSC as a regulator of immune responses to viral infection.
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Aminoacil-tRNA Sintetases/metabolismo , Resistência à Doença/imunologia , Interações Hospedeiro-Patógeno/imunologia , Viroses/imunologia , Viroses/metabolismo , Aminoacil-tRNA Sintetases/química , Aminoacil-tRNA Sintetases/genética , Animais , Antivirais/farmacologia , Modelos Animais de Doenças , Imunidade Inata , Camundongos , Camundongos Knockout , Peptídeos/farmacologia , Fosforilação , Ligação Proteica , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/metabolismo , Infecções por Vírus de RNA/virologia , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/imunologia , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Ubiquitinação , Viroses/virologia , Replicação ViralRESUMO
Toxin- and drug-induced tubulointerstitial nephritis (TIN), characterized by interstitial infiltration of immune cells, frequently necessitates dialysis for patients due to irreversible fibrosis. However, agents modulating interstitial immune cells are lacking. Here, we addressed whether the housekeeping enzyme glutamyl-prolyl-transfer RNA synthetase 1 (EPRS1), responsible for attaching glutamic acid and proline to transfer RNA, modulates immune cell activity during TIN and whether its pharmacological inhibition abrogates fibrotic transformation. The immunological feature following TIN induction by means of an adenine-mixed diet was infiltration of EPRS1high T cells, particularly proliferating T and γδ T cells. The proliferation capacity of both CD4+ and CD8+ T cells, along with interleukin-17 production of γδ T cells, was higher in the kidneys of TIN-induced Eprs1+/+ mice than in the kidneys of TIN-induced Eprs1+/- mice. This discrepancy contributed to the fibrotic amelioration observed in kidneys of Eprs1+/- mice. TIN-induced fibrosis was also reduced in Rag1-/- mice adoptively transferred with Eprs1+/- T cells compared to the Rag1-/- mice transferred with Eprs1+/+ T cells. The use of an EPRS1-targeting small molecule inhibitor (bersiporocin) under clinical trials to evaluate its therapeutic potential against idiopathic pulmonary fibrosis alleviated immunofibrotic aggravation in TIN. EPRS1 expression was also observed in human kidney tissues and blood-derived T cells, and high expression was associated with worse patient outcomes. Thus, EPRS1 may emerge as a therapeutic target in toxin- and drug-induced TIN, modulating the proliferation and activity of infiltrated T cells.
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Aminoacil-tRNA Sintetases , Nefrite Intersticial , Insuficiência Renal , Animais , Humanos , Camundongos , Aminoacil-tRNA Sintetases/metabolismo , Linfócitos T CD8-Positivos , Proliferação de Células , Fibrose , Proteínas de Homeodomínio , Nefrite Intersticial/induzido quimicamente , Nefrite Intersticial/genética , Nefrite Intersticial/tratamento farmacológicoRESUMO
BACKGROUND & AIMS: Chronic HCV infection results in abnormal immunological alterations, which are not fully normalized after viral elimination by direct-acting antiviral (DAA) treatment. Herein, we longitudinally examined phenotypic, transcriptomic, and epigenetic alterations in peripheral blood regulatory T (Treg) cells from patients with chronic HCV infection before, during, and after DAA treatment. METHODS: Patients with chronic genotype 1b HCV infection who achieved sustained virologic response by DAA treatment and age-matched healthy donors were recruited. Phenotypic characteristics of Treg cells were investigated through flow cytometry analysis. Moreover, the transcriptomic and epigenetic landscapes of Treg cells were analyzed using RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin with sequencing) analysis. RESULTS: The Treg cell population - especially the activated Treg cell subpopulation - was expanded in peripheral blood during chronic HCV infection, and this expansion was sustained even after viral clearance. RNA sequencing analysis revealed that viral clearance did not abrogate the inflammatory features of these Treg cells, such as Treg activation and TNF signaling. Moreover, ATAC-seq analysis showed inflammatory imprinting in the epigenetic landscape of Treg cells from patients, which remained after treatment. These findings were further confirmed by intracellular cytokine staining, demonstrating that Treg cells exhibited inflammatory features and TNF production in chronic HCV infection that were maintained after viral clearance. CONCLUSIONS: Overall, our results showed that during chronic HCV infection, the expanded Treg cell population acquired inflammatory features at phenotypic, transcriptomic, and epigenetic levels, which were maintained even after successful viral elimination by DAA treatment. Further studies are warranted to examine the clinical significance of sustained inflammatory features in the Treg cell population after recovery from chronic HCV infection. IMPACT AND IMPLICATIONS: During chronic HCV infection, several immune components are altered both quantitatively and qualitatively. The recent introduction of direct-acting antivirals has led to high cure rates. Nevertheless, we have demonstrated that inflammatory features of Treg cells are maintained at phenotypic, transcriptomic, and epigenetic levels even after successful DAA treatment. Further in-depth studies are required to investigate the long-term clinical outcomes of patients who have recovered from chronic HCV infection.
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OBJECTIVES: To develop a model for predicting flares after tapering the dose of tumour necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). METHODS: Data were obtained from the Korean College of Rheumatology Biologics and Targeted Therapy Registry. In total, 526 patients who received the standard-dose TNFi for at least 1 year and tapered their dose were included in the derivation cohort. The main outcome was a flare occurrence defined as an Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) score of ≥ 2.1 after 1 year of TNFi tapering. The final prediction model was validated using an independent cohort. RESULTS: Among 526 patients, 127 (24.1%) experienced flares. The final prediction model included negative human leucocyte antigen B27 (ß = 1.088), inflammatory back pain (ß = 1.072), psoriasis (ß = 1.567), family history of SpA (ß = 0.623), diabetes mellitus (ß = 1.092), TNFi tapering by ≥ 50% of the standard-dose (ß = 0.435), ASDAS-CRP at tapering (ß = 1.029), and Bath Ankylosing Spondylitis Functional Index score at tapering (ß = 0.194) as covariates. It showed an excellent discrimination performance (AUC = 0.828). According to the predictive risk, patients were classified into three groups (low-, intermediate-, and high-risk). The probabilities of flares in these groups were 4.5%, 18.1%, and 61.8%, respectively. The performance of the model in the validation cohort was also comparable. CONCLUSION: The established prediction model accurately predicted the risk of flares after TNFi dose tapering in patients with axSpA using eight simple clinical parameters, which could be helpful to select appropriate patients for tapering their TNFi without flare in daily clinical practice.
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PURPOSE: We examined whether gender identity and sexual orientation were associated with seven health-related behaviours, and with co-occurrence and clustering of these behaviours among British adolescents. METHODS: Millennium Cohort Study (age 17 wave) provided data on the exposures, gender identity (male, female, genderqueer) and sexual orientation (heterosexual, bisexual, gay or lesbian, or other), and seven self-reported health-related behaviours (binge drinking, drug use, no consumption of breakfast, no consumption of fruits or vegetables, physical inactivity, poor sleep, and smoking or vaping). Poisson regressions examined associations between the exposures and single behaviours (reporting prevalence ratios (PRs)); and multinomial logistic regressions were used for behavioural cumulative co-occurrence score (reporting PRs). Cluster patterns were identified using Ward's agglomerative hierarchical cluster analysis while associations with cluster membership were performed using logistic regressions (reporting odds ratios (ORs)). RESULTS: Our sample included 6022 adolescents (55.4% female, 1.5% genderqueer, 11.6% non-heterosexual). Adolescents who identified as genderqueer had the highest prevalence of not eating breakfast (PR: 60.5% [95%CI 48.4-71.4]) and poor sleep (68.7% [95%CI 55.6-79.3]). Those who identified as bisexual had a higher PR of co-occurring behaviours (2.46 [95%CI 1.39-4.27]). Among the three clusters identified (1: Multiple risk behaviours; 2: Physical inactivity and binge drinking; 3: Poor diet and physical inactivity), adolescents who identified as genderqueer or other sexual orientation showed the highest prevalence in cluster 3. CONCLUSION: Gender and sexual minority British adolescents showed a higher prevalence of risky health-related behaviours, and higher risk of co-occurring behaviours. Physical inactivity and poor diet behaviours commonly clustered together for these groups.
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A new monoterpenoid, neoroseoside (1), along with two previously reported compounds, 2â³-O-α-l-rhamnosyl-6-C-fucosylluteolin (2) and farobin A (3) were isolated from the Zea mays. The structure of compound 1 was determined through the analysis spectroscopic data, including mass spectrometry (MS), infrared (IR) spectroscopy, and nuclear magnetic resonance (NMR) data. The absolute configurations of 1 were deduced from the comparing the values of optical rotations and from the interpretation of electronic circular dichroism (ECD) spectra. Compounds 2 and 3 displayed moderate antibacterial activity against Streptococcus mutans ATCC 25175 (inhibition rates 24 % and 28 %, respectively) and Streptococcus sobrinus ATCC 33478 (inhibition rate of 26 %), at a concentration of 100 µg/mL, whereas compound 1 did not have any significant antibacterial activities. The compounds 1-3 also showed anti-inflammatory activity on cytokine IL-6 and TNF-α.
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Antibacterianos , Testes de Sensibilidade Microbiana , Monoterpenos , Zea mays , Zea mays/química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Monoterpenos/farmacologia , Monoterpenos/química , Monoterpenos/isolamento & purificação , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Relação Estrutura-Atividade , Estrutura Molecular , Streptococcus mutans/efeitos dos fármacos , Interleucina-6/metabolismo , Interleucina-6/antagonistas & inibidores , Descoberta de Drogas , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Relação Dose-Resposta a Droga , Streptococcus/efeitos dos fármacosRESUMO
OBJECTIVES: To investigate the epidemiological features of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in South Korea. METHODS: We identified the index cases of GPA and MPA using the 2010-2018 Korean National Health Insurance Service database and the Rare Intractable Disease registry for the entire Korean population. Each disease's incidence and prevalence rates and trends over time were analysed. To assess the impact of disease on morbidity and mortality, a comparator group comprising the general population was established using nearest-neighbour matching by age, sex, income, and comorbidity index, at a 5:1 ratio. Morbidity outcomes included the initiation of renal replacement therapy and admission to the intensive care unit. RESULTS: We identified 546 and 795 patients with GPA and MPA, respectively. The incidence rates of both diseases increased with age, with peak incidence rates observed among patients aged ≥70 years. The incidence of MPA increased continuously over time, whereas that of GPA showed no significant changes. During the observation period, 132 (28.7%) and 277 (41.1%) patients in the GPA and MPA groups, respectively, died, which were significantly higher than that in the general population (standardised mortality ratio: 3.53 and 5.58, respectively) and comparator group (hazard ratio: 4.02 and 5.64, respectively). Higher mortality and morbidity rates were observed among patients with MPA than among those with GPA. CONCLUSIONS: In South Korea, the incidence of MPA has increased over time. Although both GPA and MPA had high rates of mortality and morbidity, MPA has a poorer prognosis than GPA.
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Granulomatose com Poliangiite , Humanos , República da Coreia/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Incidência , Adulto , Resultado do Tratamento , Prevalência , Granulomatose com Poliangiite/epidemiologia , Granulomatose com Poliangiite/mortalidade , Granulomatose com Poliangiite/terapia , Poliangiite Microscópica/epidemiologia , Poliangiite Microscópica/mortalidade , Poliangiite Microscópica/terapia , Poliangiite Microscópica/diagnóstico , Sistema de Registros , Adulto Jovem , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/epidemiologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Fatores de Tempo , Bases de Dados Factuais , Distribuição por Idade , Idoso de 80 Anos ou mais , Adolescente , Terapia de Substituição Renal , Fatores de RiscoRESUMO
BACKGROUND: Adherence to the 24-h movement guidelines is associated with various health benefits, but given the novelty of these integrative recommendations, little is known about year-to-year trends in guideline adherence in adolescents. This study investigated trends of adherence to the 24-h movement guidelines among US adolescents. METHODS: Data from 2011 to 2019 cycles of the Youth Risk Behavior Surveillance System were used, which included 62 589 US adolescents aged 14-17 years (female: unweighted sample size = 31 876, 51%; weighted% = 50.1%). Participants self-reported their demographic information (i.e., sex, age, race/ethnicity), physical activity, screen time and sleep duration. Meeting the 24-h movement guidelines was operationalized as simultaneously engaging in 60 min or more of moderate-to-vigorous physical activity, no more than 2 h of screen time, and 8-10 h of sleep per day. Trend analysis was used to examine the secular changes in adherence to the integrated guidelines from 2011 to 2019. RESULTS: Downward trends in adherence to the 24-h movement guidelines were observed among adolescents from 2011 (3.6%) to 2019 (2.6%). After stratification by sex, age, and race/ethnicity, similar downward trends in the guideline adherence were observed in females and Black/African American adolescents. The lowest prevalence of meeting the individual guidelines was for the PA guidelines (25.6%). Movement guideline adherence was consistently lowest among females, older adolescents, and those who identified as Black/African American. CONCLUSIONS: Adherence to the 24-h movement guidelines has declined among US adolescents over the past decade. Interventions should prioritize an integrative approach that could increase concurrent adherence to each of the 24-h movement guideline, particularly among female, older and minority adolescents.
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Exercício Físico , Comportamento Sedentário , Humanos , Adolescente , Feminino , Estudos Transversais , Autorrelato , Sono , Fidelidade a DiretrizesRESUMO
PURPOSE: This study aimed to examine whether indirectly deterring elevator use through time-targeted Point-of-Decision Prompts (PODPs) efficiently increased stair usage in a university setting. METHODS: A quasi-experimental design (pre-post design) was employed over 2 weeks in September 2023. Baseline observations were conducted for 1 week prior to signage placement at two locations. The intervention in this study lasted for 1 week, immediately following baseline observations. Three hundred and thirty-one and 384 participants were observed during the baseline and intervention periods, respectively. Logistic regression analysis was used to examine the increase in the act of ascending the stairs. RESULTS: Our intervention, which focused on time-related messages, effectively increased stair usage among university students (coefficient = 0.435, p-value < 0.01). Furthermore, females (coefficient = -0.820, p-value < 0.05) and individuals aged ≥ 30 years (coefficient = 1.048, p-value < 0.01) were notably more likely to be influenced by our intervention than males and individuals aged < 30 years. CONCLUSION: Indirectly discouraging elevator use through time-targeted PODPs may amplify the effects of the previously employed time-related messages. Our findings suggested that a deterrence nudge should primarily be directed towards promoting stair usage among females or individuals aged ≥ 30 years.
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Promoção da Saúde , Subida de Escada , Estudantes , Humanos , Masculino , Feminino , Universidades , Adulto , Promoção da Saúde/métodos , Estudantes/psicologia , Estudantes/estatística & dados numéricos , Adulto Jovem , Elevadores e Escadas Rolantes , AdolescenteRESUMO
BACKGROUND: Chronic kidney disease (CKD) poses a significant health challenge, yet early detection remains difficult. Resting heart rate (RHR) has been shown to be a reliable indicator of type 2 diabetes, prompting interest in its potential as an independent predictor of CKD. This study aimed to investigate the association between RHR and CKD prevalence, as well as explore potential interactions between RHR and other risk factors for CKD in a sample of 25,246 adults. METHODS: Data from the Korean National Health and Nutrition Examination Survey (2011-2014) were utilized for this study, with 19,210 participants included after screening. Logistic regression analysis was employed to examine the relationship between RHR and CKD prevalence. Stratified analyses were conducted based on known risk factors for CKD. RESULTS: Participants with an RHR ≥ 90 bpm exhibited a 2.07-fold [95% confidence interval (CI): 1.28-3.34] and 2.22-fold (95% CI: 1.42-3.48) higher prevalence of CKD in men and women, respectively, compared to those with an RHR < 60 bpm. The association between RHR and CKD prevalence was particularly pronounced in younger participants (40-59 years vs. ≥ 60 years), individuals with diabetes (yes vs. no), and those with a longer duration of diabetes (≥ 7 years vs. < 7 years). CONCLUSION: Elevated RHR was found to be significantly associated with a higher prevalence of CKD in both men and women, independent of demographic, lifestyle, and medical factors. These findings suggest that RHR could serve as a valuable predictor for undiagnosed CKD.
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Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Adulto , Masculino , Humanos , Feminino , Diabetes Mellitus Tipo 2/epidemiologia , Inquéritos Nutricionais , Prevalência , Frequência Cardíaca/fisiologia , Fatores de Risco , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , República da Coreia/epidemiologiaRESUMO
Botanical extracts, widely used in cosmetics, pose a challenge to safety assessment due to their complex compositions. The threshold of toxicological concern (TTC) approach, offering a safe exposure level for cosmetic ingredients, proves to be a promising solution for ensuring the safety of cosmetic ingredients with low exposure level. We assessed the safety of Paeonia lactiflora root extract (PLR), commonly used in skin conditioning products, with the TTC. We identified 50 constituents of PLR extract from the USDA database and literature exploration. Concentration of each constituent of PLR extract was determined with the information from USDA references, literature, and experimental analysis. The genotoxicity of PLR and its constituents was assessed in vitro and in silico respectively. Cramer class of the constituents of the PLR extract was determined with Toxtree 3.1 extended decision tree using ChemTunes®. Systemic exposure of each constituent from leave-on type cosmetic products containing PLR at a 1% concentration was estimated and compared with respective TTC threshold. Two constituents exceeding TTC threshold were further analyzed for dermal absorption using in silico tools, which confirmed the safety of PLR extract in cosmetics. Collectively, we demonstrated that the TTC is a useful tool for assessing botanical extract safety in cosmetics.
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Cosméticos , Paeonia , Extratos Vegetais , Raízes de Plantas , Paeonia/química , Extratos Vegetais/toxicidade , Cosméticos/toxicidade , Raízes de Plantas/química , Medição de Risco , Humanos , Animais , Qualidade de Produtos para o Consumidor , Absorção Cutânea , Nível de Efeito Adverso não ObservadoRESUMO
This study aims to explore the potential inhibition effects of staurosporine isolated from a Streptomyces sp. SNC087 strain obtained from seawater on nasal polyps. Staurosporine possesses antimicrobial and antihypertensive activities. This research focuses on investigating the effects of staurosporine on suppressing the growth and development of nasal polyps and elucidating the underlying mechanisms involved. The experimental design includes in vitro and ex vivo evaluations to assess the inhibition activity and therapeutic potential of staurosporine against nasal polyps. Nasal polyp-derived fibroblasts (NPDFs) were stimulated with TGF-ß1 in the presence of staurosporine. The levels of α-smooth muscle actin (α-SMA), collagen type-I (Col-1), fibronectin, and phosphorylated (p)-Smad 2 were investigated using Western blotting. VEGF expression levels were analyzed in nasal polyp organ cultures treated with staurosporine. TGF-ß1 stimulated the production of Col-1, fibronectin, and α-SMA and was attenuated by staurosporine pretreatment. Furthermore, these inhibitory effects were mediated by modulation of the signaling pathway of Smad 2 in TGF-ß1-induced NPDFs. Staurosporine also inhibits the production of VEGF in ex vivo NP tissues. The findings from this study will contribute to a better understanding of staurosporine's role in nasal polyp management and provide insights into its mechanisms of action.
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Pólipos Nasais , Streptomyces , Humanos , Fibronectinas , Pólipos Nasais/tratamento farmacológico , Estaurosporina/farmacologia , Fator de Crescimento Transformador beta1 , Fator A de Crescimento do Endotélio VascularRESUMO
Although melanin protects against ultraviolet radiation, its overproduction causes freckles and senile lentigines. Recently, various biological effects of metabolites derived from marine microorganisms have been highlighted due to their potential for biological and pharmacological applications. In this study, we discovered the anti-melanogenic effect of Bacillus sp. APmarine135 and verified the skin-whitening effect. Fractions of APmarine135 showed the melanin synthesis inhibition effect in B16 melanoma cells, and 2,4,6-triphenyl-1-hexene was identified as an active compound. The melanogenic capacity of 2,4,6-triphenyl-1-hexene (1) was investigated by assessing the intracellular melanin content in B16 cells. Treatment with 5 ppm of 2,4,6-triphenyl-1-hexene (1) for 72 h suppressed the α-melanocyte-stimulating hormone (α-MSH)-induced intracellular melanin increase to the same level as in the untreated control group. Additionally, 2,4,6-triphenyl-1-hexene (1) treatment suppressed the activity of tyrosinase, the rate-limiting enzyme for melanogenesis. Moreover, 2,4,6-triphenyl-1-hexene (1) treatment downregulated tyrosinase, Tyrp-1, and Tyrp-2 expression by inhibiting the microphthalmia-associated transcription factor (MITF). Furthermore, 2,4,6-triphenyl-1-hexene (1) treatment decreased the melanin content in the three-dimensional (3D) human-pigmented epidermis model MelanoDerm and exerted skin-whitening effects. Mechanistically, 2,4,6-triphenyl-1-hexene (1) exerted anti-melanogenic effects by suppressing tyrosinase, Tyrp-1, and Tyrp-2 expression and activities via inhibition of the MITF. Collectively, these findings suggest that 2,4,6-triphenyl-1-hexene (1) is a promising anti-melanogenic agent in the cosmetic industry.
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Alcenos , Bacillus , Melaninas , Compostos de Terfenil , Humanos , Monofenol Mono-Oxigenase/metabolismo , Bacillus/metabolismo , Raios Ultravioleta/efeitos adversos , Linhagem Celular Tumoral , Fator de Transcrição Associado à Microftalmia/metabolismo , alfa-MSH/farmacologiaRESUMO
BACKGROUND: Relatives share more genomic regions than unrelated individuals, with closer relatives sharing more regions. This concept, paired with the increased availability of high-throughput single nucleotide polymorphism (SNP) genotyping technologies, has made it feasible to measure the shared chromosomal regions between individuals to assess their level of relation to each other. However, such techniques have remained in the conceptual rather than practical stages in terms of applying measures or indices. Recently, we developed an index called "genetic distance-based index of chromosomal sharing (GD-ICS)" utilizing large-scale SNP data from Korean family samples and demonstrated its potential for practical applications in kinship determination. In the current study, we present validation results from various real cases demonstrating the utility of this method in resolving complex familial relationships where information obtained from traditional short tandem repeats (STRs) or lineage markers is inconclusive. METHODS: We obtained large-scale SNP data through microarray analysis from Korean individuals involving 13 kinship cases and calculated GD-ICS values using the method described in our previous study. Based on the GD-ICS reference constructed for Korean families, each disputed kinship was evaluated and validated using a combination of traditional STRs and lineage markers. RESULTS: The cases comprised those A) that were found to be inconclusive using the traditional approach, B) for which it was difficult to apply traditional testing methods, and C) that were more conclusively resolved using the GD-ICS method. This method has overcome the limitations faced by traditional STRs in kinship testing, particularly in a paternity case with STR mutational events and in confirming distant kinship where the individual of interest is unavailable for testing. It has also been demonstrated to be effective in identifying various relationships without specific presumptions and in confirming a lack of genetic relatedness between individuals. CONCLUSION: This method has been proven effective in identifying familial relationships across diverse complex and practical scenarios. It is not only useful when traditional testing methods fail to provide conclusive results, but it also enhances the resolution of challenging kinship cases, which suggests its applicability in various types of practical casework.
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Linhagem , Polimorfismo de Nucleotídeo Único , Feminino , Humanos , Masculino , Cromossomos Humanos/genética , Genótipo , Repetições de Microssatélites/genética , República da Coreia , População do Leste Asiático/genéticaRESUMO
Background and Objectives: As modulators of the tumor microenvironment, macrophages have been extensively studied for their potential in developing anticancer strategies, particularly in regulating macrophage polarization towards an antitumorigenic (M1) phenotype rather than a protumorigenic (M2) one in various experimental models. Here, we evaluated the effect of PD98059, a mitogen-activated protein kinase kinase MAPKK MEK1-linked pathway inhibitor, on the differentiation and polarization of THP-1 monocytes in response to phorbol-12-myristate-13-acetate (PMA) under various culture conditions for tumor microenvironmental application. Materials and Methods: Differentiation and polarization of THP-1 were analyzed by flow cytometry and RT-PCR. Polarized THP-1 subsets with different treatment were compared by motility, phagocytosis, and so on. Results: Clearly, PMA induced THP-1 differentiation occurs in adherent culture conditions more than nonadherent culture conditions by increasing CD11b expression up to 90%, which was not affected by PD98059 when cells were exposed to PMA first (post-PD) but inhibited when PD98059 was treated prior to PMA treatment (pre-PD). CD11bhigh THP-1 cells treated with PMA and PMA-post-PD were categorized into M0 (HLA-DRlow and CD206low), M1 (HLA-DRhigh and CD206low), and M2 (HLA-DRlow and CD206high), resulting in an increased population of M1 macrophages. The transcription levels of markers of macrophage differentiation and polarization confirmed the increased M1 polarization of THP-1 cells with post-PD treatment rather than with PMA-only treatment. The motility and cytotoxicity of THP-1 cells with post-PD treatment were higher than THP-1 cells with PMA, suggesting that post-PD treatment enhanced the anti-tumorigenicity of THP-1 cells. Confocal microscopy and flow cytometry showed the effect of post-PD treatment on phagocytosis by THP-1 cells. Conclusions: We have developed an experimental model of macrophage polarization with THP-1 cells which will be useful for further studies related to the tumor microenvironment.
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Diferenciação Celular , Flavonoides , Macrófagos , Monócitos , Acetato de Tetradecanoilforbol , Humanos , Macrófagos/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Células THP-1 , Diferenciação Celular/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Citometria de Fluxo , Fagocitose/efeitos dos fármacosRESUMO
A valid assessment tool that measures active play is not yet available due to the sporadic and spontaneous nature of play, as well as the potential differences in how active play is understood and measured across different age groups, cultures, and contexts. The purpose of this review was to identify the scope and gaps in the measurement of active play based on data gathered from 68 countries that participated in the Global Matrix (GM) initiative, led by the Active Healthy Kids Global Alliance (AHKGA). GM is the global-level, biennial evaluation system of physical activity related behaviors among children and youth, including the Active Play indicator, and the sources of influence using letter grades (ranging between "A" and "F"). Based on the identified scope and gaps, this study offers recommendations for future research dedicated to the measurement/surveillance of active play. Out of the 68 countries involved in the previous GM (2014-22), 55% of the grades remained unassigned due to insufficient data on the Active Play indicator. The high number of unassigned grades, combined with the absence of valid measurement tool, highlight a need for a standardized measurement tool for improved global data generation of active play among children and youth. Our findings emphasize the need to address challenges in measuring active play. This review offers future considerations, research recommendations specific to the GM initiative, and two sets of age- and location-specific (indoor and outdoor settings) questionnaire items along with guidelines for its use. Together, these elements provide a roadmap for guiding future research and evaluation efforts on active play.
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OBJECTIVES: To investigate computer-aided quantitative scores from high-resolution CT (HRCT) images and determine their longitudinal changes and clinical significance in patients with idiopathic inflammatory myopathies (IIMs)-related interstitial lung disease (IIMs-ILD). METHODS: The clinical data and HRCT images of 80 patients with IIMs who underwent serial HRCT scans at least twice were retrospectively analysed. Quantitative ILD (QILD) scores (%) were calculated as the sum of the extent of lung fibrosis, ground-glass opacity, and honeycombing. The individual time-estimated ΔQILD between two consecutive scans was derived using a linear approximation of yearly changes. RESULTS: The baseline median QILD (interquartile range) scores in the whole lung were 28.1% (19.1-43.8). The QILD was significantly correlated with forced vital capacity (r = -0.349, P = 0.002) and diffusing capacity for carbon monoxide (r = -0.381, P = 0.001). For ΔQILD between the first two scans, according to the visual ILD subtype, QILD aggravation was more frequent in patients with usual interstitial pneumonia (UIP) than non-UIP (80.0% vs 44.4%, P = 0.013). Multivariable logistic regression analyses identified UIP was significantly related to radiographic ILD progression (ΔQILD >2%, P = 0.015). Patients with higher baseline QILD scores (>28.1%) had a higher risk of lung transplantation or death (P = 0.015). In the analysis of three serial HRCT scans (n = 41), dynamic ΔQILD with four distinct patterns (improving, worsening, convex and concave) was observed. CONCLUSION: QILD changes in IIMs-ILD were dynamic, and baseline UIP patterns seemed to be related to a longitudinal progression in QILD. These may be potential imaging biomarkers for lung function, changes in ILD severity and prognosis in IIMs-ILD.
Assuntos
Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Miosite , Humanos , Estudos Retrospectivos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Miosite/diagnóstico por imagemRESUMO
OBJECTIVES: To explore the course of lung function and RA disease activity and predictive factors for deteriorating lung function in patients with RA-interstitial lung disease (ILD). METHODS: The Korean Rheumatoid Arthritis-Interstitial Lung Disease cohort is a multicentre, prospective observational cohort. Patients with RA-ILD were enrolled and followed up annually for 3 years for RA disease activity and ILD status assessment. Group-based modelling was used to cluster a similar predicted percentage of forced vital capacity (FVC%) patterns into trajectories. RESULTS: This study included 140 patients who underwent at least two pulmonary function tests. Four distinctive trajectories for predicted FVC% were 'improving' [n = 11 (7.9%)], 'stable' [n = 68 (38.4%)], 'slowly declining' [n = 54 (48.6%)] and 'rapidly declining' [n = 7 (5.0%)]. Most (77.7%) patients maintained or improved to low RA disease activity. The lung function trajectory was not comparable to the RA disease activity trajectory. Age ≥70 years [relative risk (RR) 10.8 (95% CI 1.30, 89.71)] and early RA diagnosed within the preceding 2 years [RR 10.1 (95% CI 1.22, 84.2)] were associated with increased risk for rapidly declining predicted FVC%. The risk for deterioration or mortality increased in patients with a simultaneous diagnosis of RA and ILD within 24 weeks [RR 9.18 (95% CI 2.05, 41.0)] and the extent of lung involvement [RR 3.28 (95% CI 1.12, 9.60)]. CONCLUSION: Most patients with RA-ILD experienced stable or slowly declining lung function. In 5% of patients, predicted FVC% deteriorated rapidly, especially in older adults with early RA. The lung function trajectory was not comparable to the RA disease activity trajectory.
Assuntos
Artrite Reumatoide , Doenças Pulmonares Intersticiais , Humanos , Idoso , Estudos Retrospectivos , Artrite Reumatoide/complicações , Capacidade Vital , PulmãoRESUMO
OBJECTIVE: To examine the association between MTX, LEF and tacrolimus use and the progression of RA-associated interstitial lung disease (ILD). METHODS: The Korean RA-ILD cohort prospectively enrolled patients with RA-associated ILD at multiple centres from 2015 to 2018 and followed up with them for 3 years. ILD progression was defined by any of the followings: a decrease of ≥10% in forced vital capacity, a decrease of ≥15% in the diffusing capacity of the lung for carbon monoxide, or death from respiratory failure. RESULTS: Of 143 patients, 64 patients experienced ILD progression during a median follow-up period of 33 months. The use of MTX [adjusted hazard ratio (aHR), 1.06; 95% CI, 0.59, 1.89], LEF (aHR, 1.75; 95% CI, 0.88, 3.46) and tacrolimus (aHR, 0.94; 95% CI, 0.52, 1.72) did not increase the risk of ILD progression. However, the association between LEF use and the risk of ILD progression was significant in subgroups with poor lung function (aHR, 8.42; 95% CI, 2.61, 27.15). Older age, male sex, a shorter RA duration, higher RA disease activity and extensive disease at baseline were independently associated with ILD progression. CONCLUSION: None of the three treatments increased the risk of RA-associated ILD progression, except for LEF, which increased the risk of ILD progression in patients with severe ILD. The appropriate use of conventional synthetic disease-modifying antirheumatic drugs considering RA disease activity and ILD severity would be important for the management of RA-associated ILD.
Assuntos
Antirreumáticos , Artrite Reumatoide , Doenças Pulmonares Intersticiais , Humanos , Masculino , Metotrexato/efeitos adversos , Leflunomida/uso terapêutico , Tacrolimo/efeitos adversos , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/induzido quimicamente , Antirreumáticos/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/complicaçõesRESUMO
Background: Using a genetic risk score (GRS) to predict coronary heart disease (CHD) may detect disease earlier. The current study aims to assess whether GRS is associated with CHD incidence and whether it is clinically useful for improving prediction using traditional risk factors (TRFs) as well as family history. Methods: Data from a total of 48,941 participants in the Korean Genome and Epidemiology Study were analyzed in the current study. The weighted GRS was constructed using 55 single-nucleotide polymorphisms based on published genome-wide association studies. The association of GRS with incident CHD was analyzed using Cox proportional hazard model. Discrimination and reclassification were assessed to demonstrate the clinical utility of GRS. The analyses were performed separately by sex. Results: After adjusting for family history and TRFs, GRS was significantly associated with CHD incidence in men; compared to the low GRS group, men in the high GRS group had a 2.07-fold increased risk of CHD (95% confidence interval [CI]: 1.51-2.85). In men, the combination of TRFs, family history, and GRS had better performance than TRFs alone (C statistics for TRF-only model, 0.66, 95% CI, 0.64-0.69; C statistics for combination model, 0.68, 95% CI, 0.65-0.71; category-free reclassification index, 15%). In women, however, there was no significant association between GRS and CHD and no improvement between models. Conclusions: GRS was associated with CHD incidence and contributed to a small improvement of CHD prediction in men. The potential clinical use of GRS may not outweigh the value of family history.