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Multiple areas in the cerebellum have been reported to be engaged in reading. However, how these regions cooperate with the reading-related areas in the cerebrum remains unclear. Here, brain images of fifty-two adults were acquired via functional magnetic resonance imaging. By comparing the cerebellar activation across three localization tasks targeting orthographic, phonological, and semantic processing, we first identified three different reading-related areas in the cerebellum, biased toward orthography, phonology, and semantics, respectively. Then, functional connectivity (FC) analyses demonstrated that the mean FC between functionally corresponding areas across the cerebrum and cerebellum was greater than that between noncorresponding areas during silent word reading. FC patterns of functionally corresponding areas could significantly predict reading speed, with the FC driven from orthographic and semantic areas contributing the most. Effective FC analyses further showed that orthographic and semantic areas in the cerebellum had selective and direct connectivity to areas in the cerebrum with similar functional specificity. These results suggest that reading-related areas vary in their functions to reading, and cooperation between areas with corresponding functions was greater than that between noncorresponding areas. These findings emphasize the importance of functional cooperation between the cerebrum and cerebellum during reading from a new perspective.
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Cerebelo , Cerebro , Lectura , Mapeo Encefálico , Cerebelo/diagnóstico por imagen , Cerebelo/fisiología , Cerebro/diagnóstico por imagen , Cerebro/fisiología , Imagen por Resonancia Magnética , Semántica , Humanos , AdultoRESUMEN
Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare, low-grade soft tissue neoplasm preferentially arising in the extremities of young to middle-aged adults characterized histologically by a variegated appearance and absence of a distinctive immunophenotype. Herein we have evaluated a series of 73 cases of MIFS to define potential features and markers that may facilitate diagnosis. An immunohistochemical study with a large panel of antibodies showed strong positivity of the tumor cells for bcl-1 (94.5%), FXIIIa (89%), CD10 (80%), and D2-40 (56%). FISH and array comparative genomic hybridization (aCGH) were performed in a large subset of cases to investigate the utility for detecting the TGFBR3 and OGA t(1;10) rearrangement and BRAF abnormalities. Using a combination of FISH and/or aCGH, t(1;10) was detected in only 3 of 54 cases (5.5%). The aCGH study also demonstrated amplification of VGLL3 on chromosome 3 that was detected in 8 of 20 cases (40%). BRAF alterations were observed by FISH in 4 of 70 cases (5.7%) and correlated with gain of chromosome 3p12 (VGLL3). A novel fusion transcript involving exon 6 of ZNF335 and exon 10 of BRAF was identified in one case. Demonstration of amplification of VGLL3 on chromosome 3 in combination with expression of bcl-1 and FXIIIa may help support the diagnosis, however, due to their low specificity these markers are not sufficient for a definitive diagnosis in the absence of the appropriate clinical-pathological context. Until a more robust genetic or immunohistochemical signature is identified, the diagnosis of MIFS rests on its characteristic clinicopathological features.
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Biomarcadores de Tumor , Fibroblastos/química , Fibrosarcoma/química , Fibrosarcoma/genética , Inmunohistoquímica , Técnicas de Diagnóstico Molecular , Neoplasias de los Tejidos Blandos/química , Neoplasias de los Tejidos Blandos/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Hibridación Genómica Comparativa , Europa (Continente) , Femenino , Fibroblastos/patología , Fibrosarcoma/patología , Amplificación de Genes , Fusión Génica , Reordenamiento Génico , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Fenotipo , Neoplasias de los Tejidos Blandos/patología , Translocación Genética , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: Newborn infants are highly vulnerable to oxidative stress. Following birth asphyxia, oxidative injury due to ischemia-reperfusion can result in significant brain and heart damage, leading to death or long-term disability. STUDY QUESTION: The study objective was to evaluate the effectiveness of antioxidant gamma-L-glutamyl-L-cysteine (γGlu-Cys) in inhibiting oxidative injury to cultured embryonic cardiomyocytes (H9c2 cells). STUDY DESIGN: Control and γGlu-Cys-treated (0.5 mM) H9c2 cells were incubated under 6-hour ischemic conditions followed by 2-hour simulated reperfusion. MEASURES AND OUTCOMES: To quantify oxidative stress-induced apoptosis sustained by cardiomyocytes, lactate dehydrogenase (LDH) release and the presence of cytosolic cytochrome c were measured, as well as the number of secondary lysosomes visualized under electron microscopy. RESULTS: Compared to controls, H9c2 cells coincubated with γGlu-Cys during ischemia-reperfusion exhibited a significant reduction in both LDH release into the incubation medium [23.88 ± 4.08 (SE) vs. 9.95 ± 1.86% of total; P = 0.02] and the number of secondary lysosomes [0.070 ± 0.009 (SD) vs. 0.043 ± 0.004 per µm; P = 0.01]. Inhibition of LDH release with γGlu-Cys was the same (P = 0.67) as that of a caspase inhibitor. The significant increase in cytosolic cytochrome c (P = 0.01) after ischemia-reperfusion simulation further supports γGlu-Cys's role in apoptosis prevention. CONCLUSIONS: It is concluded that the glutathione precursor γGlu-Cys protects cultured embryonic cardiomyocytes from apoptosis-associated oxidative injury.
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Antioxidantes/farmacología , Asfixia Neonatal/tratamiento farmacológico , Dipéptidos/farmacología , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Animales , Antioxidantes/uso terapéutico , Apoptosis/efectos de los fármacos , Asfixia Neonatal/complicaciones , Línea Celular , Dipéptidos/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Embrión de Mamíferos , Humanos , Recién Nacido , Daño por Reperfusión Miocárdica/etiología , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos , RatasRESUMEN
BACKGROUND: Intestinal necrosis is the most serious complication of intussusception. The risk factors associated with intestinal necrosis in pediatric patients with intussusception have not been well characterized. OBJECTIVE: This study aimed to investigate the risk factors associated with intestinal necrosis in pediatric patients with failed non-surgical reduction for intussusception. METHODS: Hospitalized patients who failed the air-enema reduction for intussusception in the outpatient department and subsequently underwent surgery were retrospectively reviewed. All cases were categorized into two groups: intestinal necrosis group and non-intestinal necrosis group based on the surgical findings. Demographic and clinical features including the findings from the surgery were recorded and analyzed. Factors associated with intestinal necrosis were analyzed using univariate and multivariate unconditional logistic regression analyses. RESULTS: A total of 728 cases were included. Among them, 171 had intestinal necrosis at the time of surgery. The group with intestinal necrosis had a longer duration of symptom or length of illness (P = 0.000), and younger (P = 0.000) than the non-intestinal necrosis group. Complex/compound type of intussusceptions is more likely to have intestinal necrosis. Multivariate analysis showed that the presence of grossly bloody stool (OR = 2.12; 95% CI 1.19-3.76, P = 0.010) and duration of symptom (OR = 1.07; 95% CI 1.06-1.08, P = 0.000) were independent risk factors for intestinal necrosis in patients hospitalized for surgical reduction for intussusceptions. CONCLUSION: At time of admission, the presence of bloody stools and duration of symptom are the important risk factors for developing intestinal necrosis for those patients who failed non-surgical reduction. The length of illness has the highest sensitivity and specificity to correlate with intestinal necrosis. This finding may suggest that we should take the intussusception cases that have the longer duration of symptom directly to operation room for reduction.
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Intestinos/patología , Intususcepción/complicaciones , Intususcepción/terapia , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Intestinos/cirugía , Intususcepción/cirugía , Modelos Logísticos , Masculino , Necrosis , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
Normal development of ovarian follicles is critical for female reproduction and endocrine function. We have identified retinoic acid (RA) and the RA-degrading enzyme CYP26B1 as regulators of ovarian follicle development and showed that RA and a CYP26 inhibitor stimulated ovarian granulosa cell proliferation. The mechanism underpinning RA-dependent proliferation, however, is not known. The current study was designed to examine the role of intracellular calcium (Ca2+) signaling in mediating the effects of RA on primary mouse granulosa cell proliferation. In single-cell Ca2+ imaging experiments, treatment of cultured granulosa cells with RA increased the steady-state Ca2+ content of the endoplasmic reticulum (ER) stores. This correlated with increased store-operated Ca2+ entry (SOCE) and enhanced inositol 1,4,5-trisphosphate receptor (IP3R)-dependent Ca2+ release. In proliferation assays, RA treatment or Cyp26b1 knockdown stimulated proliferation, whereas Cyp26b1 overexpression inhibited proliferation. When RA was given together with 2-aminoethoxydiphenylborane (2-APB), a blocker of IP3R-dependent ER Ca2+ release and SOCE, with xestospongin C, a selective IP3R- receptor antagonist, or with 3,5-bis (trifluoromethyl)pyrazole (BTP-2), a specific SOCE blocker, the stimulatory effect of RA on cell proliferation was abolished. Further investigation showed that treatment with 2-APB or BTP-2 inhibited RA induction of RA response element (RARE) activation in granulosa cells, confirming an important role for Ca2+ signaling in mediating RA actions. Overall, these data support a model in which RA regulates ovarian follicle development by stimulating granulosa cell proliferation and that this stimulatory effect is at least in part driven by the modulation of Ca2+ signaling.
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The role of the antiapoptotic protein Bcl-xL in regulating mitochondrial Ca(2+) ([Ca(2+)]mito) handling was examined in wild-type (WT) and Bcl-xL knock-out (Bcl-xL-KO) mouse embryonic fibroblast cells. Inositol 1,4,5-trisphosphate-generating agonist evoked cytosolic Ca(2+) transients that produced a larger [Ca(2+)]mito uptake in WT cells compared with Bcl-xL-KO. In permeabilized cells, stepping external [Ca(2+)] from 0 to 3 µm also produced a larger [Ca(2+)]mito uptake in WT; moreover, the [Ca(2+)]mito uptake capacity of Bcl-xL-KO cells was restored by re-expression of mitochondrially targeted Bcl-xL. Bcl-xL enhancement of [Ca(2+)]mito uptake persisted after dissipation of the mitochondrial membrane potential but was absent in mitoplasts lacking an outer mitochondrial membrane. The outer membrane-localized voltage-dependent anion channel (VDAC) is a known Ca(2+) permeability pathway that directly interacts with Bcl-xL. Bcl-xL interacted with VDAC1 and -3 isoforms, and peptides based on the VDAC sequence disrupted Bcl-xL binding. Peptides reduced [Ca(2+)]mito uptake in WT but were without effect in Bcl-xL-KO cells. In addition, peptides reduced [Ca(2+)]mito uptake in VDAC1 and VDAC3 knock-out but not VDAC1 and -3 double knock-out mouse embryonic fibroblast cells, confirming that Bcl-xL interacts functionally with VDAC1 and -3 but not VDAC2. Thus, an interaction between Bcl-xL and VDAC promotes matrix Ca(2+) accumulation by increasing Ca(2+) transfer across the outer mitochondrial membrane.
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Calcio/metabolismo , Embrión de Mamíferos/metabolismo , Fibroblastos/metabolismo , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Proteínas Mitocondriales/metabolismo , Canales Aniónicos Dependientes del Voltaje/metabolismo , Proteína bcl-X/metabolismo , Animales , Células Cultivadas , Embrión de Mamíferos/citología , Fibroblastos/citología , Ratones , Ratones Noqueados , Mitocondrias/genética , Proteínas Mitocondriales/genética , Unión Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Canales Aniónicos Dependientes del Voltaje/genética , Proteína bcl-X/genéticaRESUMEN
Seed development is important for agriculture productivity. We demonstrate that brassinosteroid (BR) plays crucial roles in determining the size, mass, and shape of Arabidopsis (Arabidopsis thaliana) seeds. The seeds of the BR-deficient mutant de-etiolated2 (det2) are smaller and less elongated than those of wild-type plants due to a decreased seed cavity, reduced endosperm volume, and integument cell length. The det2 mutant also showed delay in embryo development, with reduction in both the size and number of embryo cells. Pollination of det2 flowers with wild-type pollen yielded seeds of normal size but still shortened shape, indicating that the BR produced by the zygotic embryo and endosperm is sufficient for increasing seed volume but not for seed elongation, which apparently requires BR produced from maternal tissues. BR activates expression of SHORT HYPOCOTYL UNDER BLUE1, MINISEED3, and HAIKU2, which are known positive regulators of seed size, but represses APETALA2 and AUXIN RESPONSE FACTOR2, which are negative regulators of seed size. These genes are bound in vivo by the BR-activated transcription factor BRASSINAZOLE-RESISTANT1 (BZR1), and they are known to influence specific processes of integument, endosperm, and embryo development. Our results demonstrate that BR regulates seed size and seed shape by transcriptionally modulating specific seed developmental pathways.
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Arabidopsis/fisiología , Brasinoesteroides/metabolismo , Semillas/fisiología , Proteínas de Arabidopsis/efectos de los fármacos , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Brasinoesteroides/farmacología , Sistema Enzimático del Citocromo P-450/genética , Proteínas de Unión al ADN , Regulación de la Expresión Génica de las Plantas , Proteínas de Homeodominio/genética , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Plantas Modificadas Genéticamente , Proteínas Quinasas/genética , Proteínas Represoras/genética , Semillas/anatomía & histología , Semillas/efectos de los fármacos , Factores de Transcripción/genéticaRESUMEN
OBJECTIVES: Butyrate is well known to induce apoptosis in differentiating intestinal epithelial cells. The present study was designed to examine the role of p38 mitogen-activated protein kinase (MAPK) in butyrate-induced intestinal barrier impairment. METHODS: The intestinal barrier was determined by measuring the transepithelial electrical resistance (TER) in a Caco-2 cell monolayer model. The permeability was determined by measuring transepithelial passage of fluorescein isothiocyanate-conjugated inulin (inulin-FITC). The morphology of the monolayers was examined with scanning electron microscopy. The apoptosis status was determined by annexin V-FITC labeling and flow cytometry. The activity of p38 MAPK was determined by the phosphorylation status of p38 with Western blotting. RESULTS: Butyrate at 5 mM increases the apoptosis rate of Caco-2 cells and induces impairment of intestinal barrier functions as determined by decreased TER and increased inulin-FITC permeability. Butyrate treatment activates p38 MAPK in a concentration- and time-dependent manner. SB203580, a specific p38 inhibitor, inhibits butyrate-induced Caco-2 cell apoptosis. Treatment of SB203580 significantly attenuates the butyrate-induced impairment of barrier functions in the Caco-2 cell monolayer model. CONCLUSIONS: p38 MAPK can be activated by butyrate and is involved in the butyrate-induced apoptosis and impairment of intestinal barrier function. Inhibition of p38 MAPK can significantly attenuate butyrate-induced intestinal barrier dysfunction.
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Apoptosis , Butiratos/efectos adversos , Absorción Intestinal , Enfermedades Intestinales/enzimología , Mucosa Intestinal/enzimología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Anexina A5/metabolismo , Apoptosis/efectos de los fármacos , Células CACO-2 , Impedancia Eléctrica , Inhibidores Enzimáticos/farmacología , Fluoresceína-5-Isotiocianato/metabolismo , Humanos , Imidazoles/farmacología , Absorción Intestinal/efectos de los fármacos , Enfermedades Intestinales/metabolismo , Mucosa Intestinal/metabolismo , Inulina/metabolismo , Permeabilidad , Fosforilación , Piridinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
OBJECTIVE: To assess the relative validity and reproducibility of the quantitative FFQ used in the Tzu Chi Health Study (TCHS). DESIGN: The reproducibility was evaluated by comparing the baseline FFQ with the 2-year follow-up FFQ. The validity was evaluated by comparing the baseline FFQ with 3 d dietary records and biomarkers (serum folate and vitamin B12). Median comparison, cross-classification and Spearman correlation with and without energy adjustment and deattenuation for day-to-day variation were assessed. SETTING: TCHS is a prospective cohort containing a high proportion of true vegetarians and part-time vegetarians (regularly consuming a vegetarian diet without completely avoiding meat). SUBJECT: Subsets of 103, seventy-eight and 1528 TCHS participants were included in the reproducibility, dietary record-validity and biomarker-validity studies, respectively. RESULTS: Correlations assessing the reproducibility for repeat administrations of the FFQ were in the range of 0·46-0·65 for macronutrients and 0·35-0·67 for micronutrients; the average same quartile agreement was 40%. The correlation between FFQ and biomarkers was 0·41 for both vitamin B12 and folate. Moderate to good correlations between the baseline FFQ and dietary records were found for energy, protein, carbohydrate, saturated and monounsaturated fat, fibre, vitamin C, vitamin A, K, Ca, Mg, P, Fe and Zn (average crude correlation: 0·47 (range: 0·37-0·66); average energy-adjusted correlation: 0·43 (range: 0·38-0·55); average energy-adjusted deattenuated correlation: 0·50 (range: 0·44-0·66)) with same quartile agreement rate of 39% (range: 35-45%), while misclassification to the extreme quartile was rare (average: 4% (range: 0-6%)). CONCLUSIONS: The FFQ is a reliable and valid tool to rank relative intake of major nutrients for TCHS participants.
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Encuestas sobre Dietas/normas , Dieta Vegetariana , Conducta Alimentaria , Evaluación Nutricional , Valor Nutritivo , Encuestas y Cuestionarios/normas , Adulto , Anciano , Biomarcadores/sangre , Registros de Dieta , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reproducibilidad de los Resultados , TaiwánRESUMEN
Purpose: Develop and validate a nomogram for predicting intestinal resection in pediatric intussusception suspecting intestinal necrosis. Patients & methods: Children with intussusception were retrospectively enrolled after a failed air-enema reduction in the outpatient setting and divided into two groups: the intestinal resection group and the non-intestinal resection group. The enrolled cases were randomly selected for training and validation sets with a split ratio of 3:1. A nomogram for predicting the risk of intestinal resection was visualized using logistic regression analysis with calibration curve, C-index, and decision curve analysis to evaluate the model. Results: A total of 547 cases were included in the final analysis, of which 414 had non-intestinal necrosis and 133 had intestinal necrosis and underwent intestinal resection. The training set consisted of 411 patients and the validation cohort included 136 patients. Through forward stepwise regression, four variables (duration of symptoms, C-reaction protein, white blood cells, ascites) were selected for inclusion in the nomogram with a concordance index 0.871 (95% confidence interval: 0.834-0.908). Conclusion: We developed a nomogram for predicting intestinal resection in children with intussusception suspecting intestinal necrosis after a failed air-enema based on multivariate regression. This nomogram could be directly applied to facilitate predicting intestinal resection in pediatric intussusception suspecting necrosis.
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Gestational diabetes mellitus (GDM) disrupts glucolipid metabolism, endangering maternal and fetal health. Despite limited research on its pathogenesis and treatments, we conducted a study using serum samples from GDM-diagnosed pregnant women. We performed metabolic sequencing to identify key small molecule metabolites and explored their molecular interactions with FGF21. We also investigated FGF21's impact on GDM using blood samples from affected women. Our analysis revealed a novel finding: elevated levels of L-Cystine in GDM patients. Furthermore, we observed a positive correlation between L-Cystine and FGF21 levels, and found that L-Cystine induces NRF2 expression via FGF21 for a period of 96 h. Under high glucose (HG) conditions, FGF21 upregulates NRF2 and downstream genes NQO1 and EPHX1 via AKT phosphorylation induced by activation of IRS1, enhancing endothelial function. Additionally, we confirmed that levels of FGF21, L-Cystine, and endothelial function at the third trimester were effectively enhanced through appropriate exercise and diet during pregnancy in GDM patients (GDM + ED). These findings suggest FGF21 as a potential therapeutic agent for GDM, particularly in protecting endothelial cells. Moreover, elevated L-Cystine via appropriate exercise and diet might be a potential strategy to enhance FGF21's efficacy.
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Cistina , Diabetes Gestacional , Factores de Crecimiento de Fibroblastos , Factor 2 Relacionado con NF-E2 , Transducción de Señal , Humanos , Diabetes Gestacional/metabolismo , Femenino , Embarazo , Factores de Crecimiento de Fibroblastos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Adulto , Transducción de Señal/efectos de los fármacos , Cistina/metabolismoRESUMEN
Oncolytic viruses are multifaceted tumor killers, which can function as tumor vaccines to boost systemic antitumor immunity. In previous study, we rationally designed a synthetic oncolytic adenovirus (SynOV) harboring a synthetic gene circuit, which can kill tumors in mouse hepatocellular carcinoma (HCC) models. In this study, we demonstrated that SynOV could sense the tumor biomarkers to lyse tumors in a dosage-dependent manner, and killed PD-L1 antibody resistant tumor cells in mouse model. Meanwhile, we observed SynOV could cure liver cancer and partially alleviate the liver cancer with distant metastasis by activating systemic antitumor immunity. To understand its high efficacy, it is essential to explore the cellular and molecular features of the remodeled tumor microenvironment (TME). By combining spatial transcriptome sequencing and single-cell RNA sequencing, we successfully depicted the remodeled TME at single cell resolution. The state transition of immune cells and stromal cells towards an antitumor and normalized status exemplified the overall cancer-suppressive TME after SynOV treatment. Specifically, SynOV treatment increased the proportion of CD8+ T cells, enhanced the cell-cell communication of Cxcl9-Cxcr3, and normalized the Kupffer cells and macrophages in the TME. Furthermore, we observed that SynOV could induce distant responses to reduce tumor burden in metastatic HCC patient in the Phase I clinical trial. In summary, our results suggest that SynOV can trigger systemic antitumor immunity to induce CD8+ T cells and normalize the abundance of immune cells to remodel the TME, which promises a powerful option to treat HCC in the future.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Viroterapia Oncolítica , Virus Oncolíticos , Ratones , Animales , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Adenoviridae/genética , Linfocitos T CD8-positivos , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Virus Oncolíticos/genética , Viroterapia Oncolítica/métodos , Modelos Animales de Enfermedad , Análisis de la Célula Individual , Microambiente TumoralAsunto(s)
Brasinoesteroides/metabolismo , Grano Comestible/crecimiento & desarrollo , Factores de Transcripción GATA/fisiología , Oryza/crecimiento & desarrollo , Proteínas de Plantas/fisiología , Grano Comestible/genética , Grano Comestible/metabolismo , Factores de Transcripción GATA/genética , Regulación de la Expresión Génica de las Plantas , Oryza/genética , Oryza/metabolismo , Proteínas de Plantas/genética , Plantas Modificadas GenéticamenteRESUMEN
Artificial RNA translation modulation usually relies on multiple components, such as RNA binding proteins (RBPs) or microRNAs (miRNAs) for off-switches and double-inverter cascades for on-switches. Recently, translational circular RNAs (circRNAs) were developed as promising alternatives for linear messenger RNAs (mRNAs). However, circRNAs still lack straightforward and programmable translation control strategies. Here, we rationally design a programmable miRNA-responsive internal ribosome entry site (IRES) translation activation and repression (PROMITAR) platform capable of implementing miRNA-based translation upregulation and downregulation in a single RNA construct. Based on the PROMITAR platform, we construct logic gates and cell-type classifier circRNAs and successfully identify desired mammalian cell types. We also demonstrate the potential therapeutic application of our platform for targeted cancer cell killing by encoding a cytotoxic protein in our engineered circRNAs. We expect our platform to expand the toolbox for RNA synthetic biology and provide an approach for potential biomedical applications in the future.
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MicroARNs , Animales , MicroARNs/genética , ARN Circular/genética , Regulación hacia Abajo , Sitios Internos de Entrada al Ribosoma , ARN Mensajero/genética , MamíferosRESUMEN
BACKGROUND: Anxiety has been characterized by disrupted processing of conflict control, while little is known about anticipatory processing of conflicts in anxiety. Anticipation is the key factor in both anxiety and cognitive control, especially under uncertain conditions. The current study therefore examined neurocomputational mechanisms of uncertain anticipation of conflict control in anxiety. METHODS: Twenty-six participants with high-trait anxiety and twenty-nine low-trait anxiety participants completed a cue-flanker task with functional magnetic resonance imaging. The hierarchical drift diffusion model (HDDM) was used to measure the cognitive computations during the task. To identify the neurocomputational mechanism of anticipatory control in anxiety, mediation analysis and dynamic causal modelling (DCM) analysis were conducted to examine the relationship between functional connectivity of brain networks and the parameters of HDDM. RESULTS: We found influences of regulatory signals from the dorsolateral prefrontal cortex to dorsal anterior cingulate cortex on decision threshold in low-trait anxiety (LTA), but not in high-trait anxiety (HTA), especially for the condition with uncertain cues. The results indicate deficient top-down anticipatory control of upcoming conflicts in anxious individuals. DCM and HDDM analyses revealed that lower decision threshold was associated with higher intrinsic connectivity of salience network (SN) in anxious individuals, suggesting that dysfunctional SN disrupts anticipation of conflict control under uncertainty in anxiety. CONCLUSIONS: Our results suggest hyperfunction of the SN underlies the deficient information accumulation during uncertain anticipation of upcoming conflicts in anxiety. Our findings shed new light on the mechanisms of anticipation processing and the psychopathology of anxiety.
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Recent advances in global gene sequencing technologies and the effect they have had on disease diagnosis, therapy, and research have fueled interest in technologies capable of more broadly profiling not only genes but proteins, metabolites, cells, and almost any other component of biological systems. Mass cytometry is one such technology, which enables simultaneous characterization of over 40 parameters per cell, significantly more than can be achieved by even the most state-of-the-art flow cytometers. This mini-review will focus on how mass cytometry has been utilized to help advance the field of neoplastic hematology. Common themes among published studies include better defining lineage sub-populations, improved characterization of tumor microenvironments, and profiling intracellular signaling across multiple pathways simultaneously in various cell types. Reviewed studies highlight potential applications for disease diagnosis, prognostication, response to therapy, measurable residual disease analysis, and identifying new therapies.
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BACKGROUND: To determine risk factors for intestinal necrosis in intussusception cases among children with failed non-surgical reduction for intussusception. METHODS: Totally, 540 hospitalized individuals with unsuccessful air-enema reduction in our hospital between November 2010 and November 2020 were assessed in this retrospective study. The 540 intussusception cases were divided into the intestinal necrosis and non-intestinal necrosis groups. Haemostatic parameters, demographic and clinical features were assessed. Predictors of intestinal necrosis were examined by univariable and multivariable logistic regression analyses. RESULTS: Of the 540 patients included, 113 showed intestinal necrosis. This intestinal necrosis group had a longer duration of symptom or length of illness, younger ages, higher platelet counts, fibrinogen amounts and d-dimer levels (all P = 0.000) compared with the non-intestinal necrosis group. Multivariable analysis revealed that duration of symptom (odds ratio (OR) 1.12; 95% confidence interval (CI) 1.16-1.23, P = 0.000), fibrinogen (OR 1.26; 95% CI 1.10-1.31, P = 0.010) and d-dimer (OR 2.07; 95% CI 1.91-2.28, P = 0.000) independently predicted intestinal necrosis in individuals undergoing surgical reduction for intussusception. Receiver operating characteristic curve analysis showed that d-dimer amounts had the largest area under the curve for predicting intestinal necrosis. CONCLUSION: On admission, long duration of symptom, high fibrinogen and d-dimer levels are critical risk factors for intestinal necrosis development in children with unsuccessful non-surgical reduction. d-Dimer levels have the best predictive value for intestinal necrosis.
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Hemostáticos , Intususcepción , Niño , Enema , Humanos , Lactante , Intususcepción/diagnóstico , Intususcepción/cirugía , Necrosis , Estudios RetrospectivosRESUMEN
Background/Aims: Diabetic foot ulcers (DFUs) present a major challenge in clinical practice, and hyperglycemia-induced angiogenesis disturbance and endothelial dysfunction likely exacerbate DFUs. The long-acting glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira) is a potential activator of AMP-activated protein kinase (AMPK) that appears to enhance endothelial function and have substantial pro-angiogenesis and antioxidant stress effects. Therefore, in this study, we aimed to investigate whether the protective role of Lira in diabetic wound healing acts against the mechanisms underlying hyperglycemia-induced endothelial dysfunction and angiogenesis disturbance. Methods: Accordingly, db/db mice were assessed after receiving subcutaneous Lira injections. We also cultured human umbilical vein endothelial cells (HUVECs) in either normal or high glucose (5.5 or 33 mM glucose, respectively) medium with or without Lira for 72 h. Results: An obvious inhibition of hyperglycemia-triggered endothelial dysfunction and angiogenesis disturbance was observed; follow by a promotion of diabetic wound healing under Lira treatment combined with restored hyperglycemia-impaired AMPK signaling pathway activity. AMPKα1/2 siRNA and Compound C (Cpd C), an inhibitor of AMPK, abolished both Lira-mediated endothelial protection and pro-angiogenesis action, as well as the diabetic wound healing promoted by Lira. Furthermore, hypoxia inducible factor-1α (Hif-1α; transcription factors of AMPK substrates) knockdown in HUVECs and db/db mice demonstrated that Lira activated AMPK to prevent hyperglycemia-triggered endothelial dysfunction and angiogenesis disturbance, with a subsequent promotion of diabetic wound healing that was Hif-1α-heme oxygenase-1 (HO-1) axis-dependent. Taken together, these findings reveal that the promotion of diabetic wound healing by Lira occurs via its AMPK-dependent endothelial protection and pro-angiogenic effects, which are regulated by the Hif-1α-HO-1 axis.
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OBJECTIVES: The naming convention in coagulation may cause confusion in electronic ordering systems, leading to inappropriate test orders. We implemented test utilization efforts and studied utilization before and after interventions for two specialty coagulation assays. METHODS: Two interventions were implemented: test names were changed from factor assay to activity, and residents reviewed all factor V and X requests. A retrospective review of factor V and X activity orders was performed for the period 1 year before and after interventions. RESULTS: After interventions, factor V and X activity orders decreased by approximately 40%. Resulted tests decreased by 53.8% and 47.8%, corresponding to reductions of $2,493.05 and $1,867.80 per year in laboratory charges for factor V and factor X activity, respectively. Abnormal factor V activity results increased from 45% to 59%. Factor V activity orders from outpatient clinics decreased by 21.6%. CONCLUSIONS: Simple interventions can reduce inappropriate specialty coagulation test orders and unnecessary costs.
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Pruebas de Coagulación Sanguínea/estadística & datos numéricos , Técnicas de Laboratorio Clínico/estadística & datos numéricos , Factor V/análisis , Factor X/análisis , Pruebas de Coagulación Sanguínea/economía , Técnicas de Laboratorio Clínico/economía , Factor V/genética , Inhibidores del Factor Xa/sangre , Humanos , Mutación , Estudios Retrospectivos , Procedimientos InnecesariosRESUMEN
PURPOSE: This study aimed to evaluate the mechanism by which miR-29c expression in fibroblasts regulates renal interstitial fibrosis. METHODS: We stimulated NRK-49F cells with TGF-ß1 to mimic the effects of fibrosis in vitro, while unilateral ureteral obstruction (UUO) was performed to obstruct the mid-ureter in mice. MiR-29c mimic or miR-29c inhibitor was used to mediate genes expressions in vitro. The recombinant adeno associated virus (rAAV) vectors carrying a FSP1 promoter that encodes miR-29c precursor or miR-29c inhibitor was used to mediate genes expressions in vivo, and a flank incision was made to expose the left kidney of each animal. RESULTS: In the present study, TGF-ß1 was demonstrated to regulate miR-29c expression through Wnt/ß-catenin signaling. In contrast, miR-29c appears to inhibit the Wnt/ß-catenin pathway by suppressing TPM1 expression. As suggested by this feedback mechanism, miR-29c may be a key fibrosis-related microRNA expressed by fibroblasts in TGF-ß1/Wnt/ß-catenin-driven renal fibrosis, and manipulation of miR-29c action may accordingly offer a potential therapeutic pathway for renal fibrosis treatment. CONCLUSION: MiR-29c expression was downregulated in UUO mouse kidneys as well as TGF-ß1-treated NRK-49F cells, which thus inhibits myofibroblast formation via targeting of TPM1. Additionally, the production of extracellular matrix (ECM) in renal fibroblasts appears to be controlled by the reciprocal regulation of miR-29c action and the Wnt/ß-catenin pathway.