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PURPOSE: QT interval prolongation is one of the most common electrocardiographic (ECG) abnormalities in patients with aneurysmal subarachnoid hemorrhage (aSAH). Whether corrected QT interval (QTc) prolongation is associated with perioperative cardiac events and dismal neurological outcome in mid to long-term follow-up in patients after aSAH is insufficiently studied and remains controversial. METHODS: We retrospectively studied the adult (≥ 18 years) patients admitted to our institution between Jan 2018 and Dec 2020 for aSAH who underwent intracranial aneurysm clipping or embolization. The patients were divided into 2 groups (normal and QTc prolongation groups) according to their QTc. To minimize the confounding bias, a propensity score matching (PSM) analysis was performed to compare the neurologic outcomes between patients with normal QTc and QTc prolongation. RESULTS: After screening, 908 patients were finally included. The patients were divided into 2 groups: normal QTc groups (n = 714) and long QTc group (n = 194). Female sex, hypokalemia, posterior circulation aneurysm, and higher Hunt-Hess grade were associated with QTc prolongation. In multiple regression analysis, older age, higher hemoglobin level, posterior circulation aneurysm, and higher Hunt-Hess grade were identified to be associated with worse outcome during 1-year follow-up. Before PSM, patients with QTc prolongation had higher rate of perioperative cardiac arrest or ventricular arrhythmias. After PSM, there was no statistical difference between normal and QTc prolongation groups in perioperative cardiac events. However, patients in the QTc prolongation group still had worse neurologic outcome during 1-year follow-up. CONCLUSIONS: QTc prolongation is associated with worse outcome in patients following SAH, which is independent of perioperative cardiac events.
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Embolización Terapéutica , Aneurisma Intracraneal , Síndrome de QT Prolongado , Hemorragia Subaracnoidea , Humanos , Masculino , Femenino , Estudios Retrospectivos , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/cirugía , Persona de Mediana Edad , Aneurisma Intracraneal/cirugía , Aneurisma Intracraneal/complicaciones , Síndrome de QT Prolongado/etiología , Embolización Terapéutica/métodos , Embolización Terapéutica/efectos adversos , Adulto , Anciano , Microcirugia/métodos , Microcirugia/efectos adversos , Resultado del Tratamiento , Electrocardiografía/métodosRESUMEN
PURPOSE: To investigate the effect of early enteral nutrition on outcomes of trauma patients in the intensive care unit (ICU). METHODS: Clinical data of trauma patients in the ICU of Daping Hospital, China from January 2012 to December 2017 was retrospectively analyzed, including patient age, gender, injury mechanism, injury severity score (ISS), nutritional treatment, postoperative complications (wound infection, abdominal abscess, anastomotic rupture, pneumonia), mortality, and adverse events (nausea, vomiting, abdominal distention). Only adult trauma patients who developed bloodstream infection after surgery for damage control were included. Patients were divided into early enteral nutrition group (<48 h) and delayed enteral nutrition group (control group, >48 h). Data of all trauma patients were collected by the same investigator. Data were expressed as frequency (percentage), mean ± standard deviation (normal distribution), or median (Q1, Q3) (non-normal distribution) and analyzed by Chi-square test, Student's t-test, or rank-sum test accordingly. Multiple logistic regression analysis was further adopted to investigate the significant variables with enteral nutrition. RESULTS: Altogether 876 patients were assessed and 110 were eligible for this study, including 93 males and 17 females, with the mean age of (50.0 ± 15.4) years. Traffic accidents (46 cases, 41.8%) and fall from height (31 cases, 28.2%) were the dominant injury mechanism. There were 68 cases in the early enteral nutrition group and 42 cases in the control group. Comparison of general variables between early enteral nutrition group and control group revealed significant difference regarding surgeries of enterectomy (1.5% vs. 19.0%, p = 0.01), ileum/transverse colon/sigmoid colostomy (4.4% vs. 16.3%, p = 0.01) and operation time (h) (3.2 (1.9, 6.1) vs. 4.2 (1.8, 8.8), p = 0.02). Other variables like ISS (p = 0.31), acute physiology and chronic health evaluation≥20 (p = 0.79), etc. had no obvious difference. Chi-square test showed a much better result in early enteral nutrition group than in control group regarding morality (0 vs. 11.9%, p = 0.03), length of hospital stay (days) (76.8 ± 41.4 vs. 81.4 ± 44.7, p = 0.01) and wound infection (10.3% vs. 26.2%, p = 0.03). Logistic regression analysis showed that the incidence of wound infection was related to the duration required to achieve the enteral nutrition standard (OR = 1.095, p = 0.002). Seventy-six patients (69.1%) achieved the nutritional goal within a week and 105 patients (95.5%) in the end. Trauma patients unable to reach the enteral nutrition target within one week were often combined with abdominal infection, peritonitis, bowel resection, intestinal necrosis, intestinal fistula, or septic shock. CONCLUSION: Early enteral nutrition for trauma patients in the ICU is correlated with less wound infection, lower mortality, and shorter hospital stay.
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Cuidados Críticos , Nutrición Enteral , Heridas y Lesiones/terapia , Adulto , Anciano , Humanos , Tiempo de Internación , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , Infección de Heridas/epidemiología , Infección de Heridas/prevención & control , Heridas y Lesiones/mortalidadRESUMEN
Lysophosphatidic acid (LPA) is a bioactive lysophospholipid, which plays a crucial role in the regulation of cell proliferation, migration, and differentiation. LPA exerts its biological effects mainly through binding to cell-surface LPA receptors (LPA1-6), which belong to the G protein-coupled receptor (GPCR) family. Recent studies suggest that cross-talk between receptor tyrosine kinases (RTKs) and GPCRs modulates GPCRs-mediated signaling. Tropomyosin receptor kinase A (TrkA) is a RTK, which mediates nerve growth factor (NGF)-induced biological functions including cell migration in neuronal and non-neuronal cells. Here, we show LPA1 transactivation of TrkA in murine lung epithelial cells (MLE12). LPA induced tyrosine phosphorylation of TrkA in both time- and dose-dependent manners. Down-regulation of LPA1 by siRNA transfection attenuated LPA-induced phosphorylation of TrkA, suggesting a cross-talk between LPA1 and TrkA. To investigate the molecular regulation of the cross-talk, we focused on the interaction between LPA1 and TrkA. We found that LPA induced interaction between LPA1 and TrkA. The LPA1/TrkA complex was localized on the plasma membrane and in the cytoplasm. The C-terminus of LPA1 was identified as the binding site for TrkA. Inhibition of TrkA attenuated LPA-induced phosphorylation of TrkA and LPA1 internalization, as well as lung epithelial cell migration. These studies provide a molecular mechanism for the transactivation of TrkA by LPA, and suggest that the cross-talk between LPA1 and TrkA regulates LPA-induced receptor internalization and lung epithelial cell migration.
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Movimiento Celular , Células Epiteliales/metabolismo , Receptor Cross-Talk , Receptor trkA/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo , Animales , Western Blotting , Línea Celular , Relación Dosis-Respuesta a Droga , Pulmón/citología , Lisofosfolípidos/farmacología , Ratones , Microscopía Fluorescente , Fosforilación/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Interferencia de ARN , Receptor trkA/genética , Receptores del Ácido Lisofosfatídico/genética , Activación Transcripcional/efectos de los fármacos , Tirosina/metabolismoRESUMEN
This study examined 70 Klebsiella pneumoniae isolates derived from companion animals with urinary tract infections in Taiwan. Overall, 81% (57/70) of the isolates carried extended-spectrum ß-lactamase (ESBL) and/or plasmid-encoded AmpC (pAmpC) genes. ESBL genes were detected in 19 samples, with blaCTX-M-1, blaCTX-M-9, and blaSHV being the predominant groups. pAmpC genes were detected in 56 isolates, with blaCIT and blaDHA being the predominant groups. Multilocus sequence typing revealed that sequence types (ST)11, ST15, and ST655 were prevalent. wabG, uge, entB, mrkD, and fimH were identified as primary virulence genes. Two isolates demonstrated a hypermucoviscosity phenotype in the string test. Antimicrobial susceptibility testing exhibited high resistance to ß-lactams and fluoroquinolones in ESBL-positive isolates but low resistance to aminoglycosides, sulfonamides, and carbapenems. Isolates carrying pAmpC genes exhibited resistance to penicillin-class ß-lactams. These findings provide valuable insights into the role of K. pneumoniae in the context of the concept of One Health.
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Infecciones por Klebsiella , Infecciones Urinarias , Animales , Klebsiella pneumoniae/genética , Enterobacteriaceae/genética , beta-Lactamasas/genética , Proteínas Bacterianas/genética , Mascotas , Antibacterianos/farmacología , beta-Lactamas , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/veterinaria , Infecciones Urinarias/epidemiología , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/veterinaria , Pruebas de Sensibilidad MicrobianaRESUMEN
Large quantities of semiconductor minerals on soil surfaces have a sensitive photoelectric response. These semiconductor minerals generate photo-electrons and photo-hole pairs that can stimulate soil oxidation-reduction reactions when exposed to sunlight. We speculated that the photocatalysis of semiconductor minerals would affect soil carbon cycles. As the main component of the carbon cycle, soil respiration from paddy soil is often ignored. Five rice cropping areas in China were chosen for soil sampling. Semiconductor minerals were measured, and three main semiconductor minerals including hematile, rutile, and manganosite were identified in the paddy soils. The identified semiconductor minerals consisted of iron, manganese, and titanium oxides. Content of Fe2O3, TiO2, and MnO in the sampled soil was between 4.21-14%, 0.91-2.72%, and 0.02-0.22%, respectively. Most abundant semiconductor mineral was found in the DBDJ rice cropping area in Jilin province, with the highest content of Fe2O3 of 14%. Soils from the five main rice cropping areas were also identified as having strong photoelectric response characteristics. The highest photoelectric response was found in the DBDJ rice cropping area in Jilin province with a maximum photocurrent density of 0.48 µA/cm2. Soil respiration was monitored under both dark and light (3,000 lux light density) conditions. Soil respiration rates in the five regions were (from highest to lowest): DBDJ > XNDJ > XBDJ > HZSJ > HNSJ. Soil respiration was positively correlated with semiconductor mineral content, and soil respiration was higher under the light treatment than the dark treatment in every rice cropping area. This result suggested that soil respiration was stimulated by semiconductor mineral photocatalysis. This analysis provided indirect evidence of the effect semiconductor mineral photocatalysis has on the carbon cycle within paddy soils, while exploring carbon conversion mechanisms that could provide a new perspective on the soil carbon cycle.
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Extended-spectrum-ß-lactamase (ESBL) and AmpC ß-lactamase are two enzymes commonly found in Enterobacteriaceae that confer resistance to major antibiotics, such as third-generation cephalosporins that are widely prescribed for both human and animals. We screened for Escherichia coli producing ESBL and plasmid-mediated AmpC ß-lactamase (pAmpC) from dogs and cats brought to National Taiwan University Veterinary Hospital, Taipei, Taiwan from 29 June 2020, to 31 December 2020. The genotypes and phylogenetic relatedness of these E. coli were also analyzed. Fifty samples of E. coli obtained from 249 bacterial isolates were included in this study. Among them, eight isolates had ESBL, seven had pAmpC, and one had both. Thirty-two percent (16/50) of E. coli isolates were resistant to third-generation cephalosporins. The detected ESBL genes included the blaCTX-M-1 and blaCTX-M-9 groups, and the blaCMY-2 group was the only gene type found in pAmpC. ESBL-producing E. coli belonged to the pathogenic phylogroup B2, and the sequence types (STs) were ST131 and ST1193. Three isolates were determined to be ST131-O25b, a highly virulent epidemic clone. The pAmpC-producing E. coli were distributed in multiple phylogroups, primarily the commensal phylogroup B1. The STs of the pAmpC-producing E. coli included ST155, ST315, ST617, ST457, ST767, ST372, and ST93; all of these have been reported in humans and animals. Imipenem was active against all the ESBL/pAmpC-producing E. coli; however, since in humans it is a last-resort antimicrobial, its use in companion animals should be restricted.
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OBJECTIVE: To compare the clinical outcomes of arthroscopic anterior cruciate ligament (ACL) reconstruction (ACLR) with a tibialis anterior allograft (TAA)versus hamstring tendon autograft (HTA) after 10 years follow-up. METHODS: A clinical data of 107 patients who underwent arthroscopic ACLR with a single bundle tendon between March 2007 and March 2010 was retrospectively analyzed. Among the patients, 48 patients were reconstructed with a tibialis anterior allograft (TAA group), including 26 males and 22 females, ranging in age from 16 to 38 years, with a mean of 27.2±6.2 years;59 patients were reconstructed with a hamstring tendon autograft (HTA group), including 31 males and 28 females, ranging in age from 16 to 40 years, with a mean of 28.0±7.6 years. The preoperative tibial anterior displacement and knee joint function, as well as knee joint stability, tibial anterior displacement and knee joint function at 10 years after operation were observed. Lachman test was used to evaluate the forward joint stability and pivot shift test to evaluate the rotational stability of the knee;KT-2000 side-to-side difference (SSD) was used to measure tibial anterior displacement;International Knee Documentation Committee(IKDC) score and Lysholm score were used to evaluate knee function. RESULTS: The incisions of both groups were healed by first intention, and no early complications occurred after operation. All patients were followed-up 10 to 13 years, the mean time was 11.7 years. There was no graft failure were found during the follow up period. The KT-2000 SSD of the TAA group and the HTA group at ten years after operation were 1.9±0.7 and 1.8±0.6 respectively, which were significantly improved than 8.8±0.9 and 8.6±1.0 preoperatively(P<0.05), but there were no significant difference between the two groups(P>0.05). The total Lysholm score of the TAA group and the HTA group at ten years after operation were 90.4±4.4 and 90.7±3.4 respectively, which were significantly improved than 51.4±13.3 and 51.2±14.6 preoperatively(P<0.05), but there were no significant difference between the two groups(P>0.05). The total IKDC score of the TAA group and the HTA group at ten years after operation were 91.5±4.1 and 90.9±3.2 respectively, which were significantly improved than 45.8±12.2 and 47.0±14.5 preoperatively(P<0.05), but there were no significant difference between the two groups(P>0.05). No significant difference were found between the two groups in Lachman test and pivot shift test at 10 years after operation (P>0.05). CONCLUSION: The TAA and HTA have equal long term effect in ACL reconstruction, doctors and patients can choose the graft according to the actual situation.
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Lesiones del Ligamento Cruzado Anterior , Reconstrucción del Ligamento Cruzado Anterior , Tendones Isquiotibiales , Adolescente , Adulto , Aloinjertos , Ligamento Cruzado Anterior/cirugía , Lesiones del Ligamento Cruzado Anterior/cirugía , Artroscopía , Autoinjertos , Femenino , Humanos , Articulación de la Rodilla/cirugía , Masculino , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Extended-spectrum ß-lactamases (ESBLs) are enzymes that mediate resistance to newer ß-lactam antibiotics, including extended-spectrum cephalosporins and monobactams. The production of ESBL is primarily plasmid mediated, and such plasmids often comprise the genes that encode resistance to other classes of antimicrobials, such as aminoglycosides and fluoroquinolones. Therefore, ESBL-producing microorganisms leave clinicians with limited therapeutic options in both human and veterinary medicine. Compared with human medicine, information regarding ESBL-producing microorganisms is limited in veterinary medicine. We screened for ESBL-producing Escherichia coli in dogs and cats admitted to National Taiwan University Veterinary Hospital, Taipei, from 2014 to 2017 and further analyzed the genotypes and phylogenetic traits of these ESBL producers. Double disk tests specified by the Clinical and Laboratory Standards Institute were performed on 283 E. coli isolates and revealed a total of 65 E. coli (54 from dogs and 11 from cats) with the ESBL phenotype (22.8%). bla CTX-M-1 group and bla CTX-M-2group were the most commonly identified ESBL gene groups. bla CTX-M-55 was the main ESBL gene within the bla CTX-M-1group, whereas the bla CTX-M-2group contained only bla CTX-M-124. The ESBL-producing E. coli were all resistant to ampicillin. The resistance rate to ceftiofur, doxycycline, enrofloxacin, and ciprofloxacin was 93.8, 73.8, 80, and 78.5%, respectively. Of the antibiotics tested, greater sensitivity to imipenem and gentamicin was noted. Multilocus sequence typing indicated that ST457, ST131, and ST648 were the most common sequence types. Our study identified eight ST131/O25b isolates, which is a global zoonotic clone of public health concern. The major ESBL genes of these clones were bla CTX-M-174 and bla CTX-M-194. Because companion animals such as dogs and cats are in close contact with humans, the characterization of ESBL producers originating from them is crucial from the perspective of both public health and veterinary medicine.
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RATIONALE: The ingestion of a foreign body (FB) with complete impaction of the esophagus is not common. Here we report a rare case of successful retrieval of a spherical stone in the esophagus of a man with mental retardation, using gallbladder grasping forceps and rigid endoscope. PATIENT CONCERNS: A mental retarded man came to the emergency department presenting with recurrent nausea, vomiting, and dysphagia after swallowing a spherical stone. He had previously undergone an FB extraction under general anesthesia by fiberoptic esophagoscopy, which failed. DIAGNOSIS: The diagnosis of FB ingestion was confirmed by anteroposterior plain film x-ray of the chest and chest computed tomography (CT), which showed the ingested spherical FB in the upper esophagus. INTERVENTIONS: After multiple failed attempts using other instruments, the FB was successfully removed with gallbladder grasping forceps through a rigid esophagoscope. OUTCOMES: The patient was discharged without any complications. The nasogastric tube was extubated at the 10-day follow-up. LESSONS SUBSECTIONS AS PER STYLE: For esophageal retrieval of uncommon FBs, the instrument used is crucial. We report our experience retrieving a large and spherical FB in the upper esophagus using gallbladder grasping forceps. This proved to be an effective strategy, eliminating the need for thoracotomy.
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Esofagoscopía/instrumentación , Esófago/lesiones , Cuerpos Extraños/cirugía , Instrumentos Quirúrgicos , Adulto , Esofagoscopía/métodos , Esófago/cirugía , Humanos , Discapacidad Intelectual/complicaciones , MasculinoRESUMEN
An important Salmonella serovar for both human and animals Salmonella Typhimurium possesses 13 gene clusters that have the potential to produce fimbrial structure, among which the type 1 fimbriae with the binding specificity to mannose residue is the most commonly found type. Six structural genes and five regulatory genes comprise the fim gene cluster that is responsible for the production of type 1 fimbriae in S. Typhimurium. The fimY gene encodes a positive regulator for type 1 fimbrial expression since a deletion in fimY abolished the production of fimbriae. The N-terminal portion of FimY contains amino acid residues that exhibit some similarity as those found in the proteins possessing the PilZ domain, which is engaged in cyclic di-GMP binding. A fimY allele that had a change from arginine to alanine at position 7 (R7A) or 7 and 11 (R7/11A) generated by site-directed mutagenesis in a 6 RRERH11 R motif near N-terminal, when cloned in pACYC184 and transformed into a fimY-deleted strain, decreased the expression of fimA and fimZ. The number of type 1 fimbriae in these two transformants was also less than those of the other transformants that contained different fimY alleles in pACYC184 when observed in electron microscopy. However, changing from arginine to alanine at position 11 (R11A) remained the same as the wild-type fimY allele. It is likely that the arginine at the 7th position of FimY is critical for its maximal activating activity upon fimZ. Another motif 83 DI85 SLWIEK91 G motif did not affect the function of FimY. Although FimY has the two aforementioned motifs, which contain some amino acids that are present within those of the PilZ domain proteins, secondary structure prediction analysis did not reveal that FimY has a conformation commonly observed in PilZ-like proteins. Therefore, FimY and PilZ domain proteins are not homologs. Further investigation for a detailed analysis of FimY is thus warranted.
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Arginina/genética , Proteínas Fimbrias/genética , Proteínas Fimbrias/metabolismo , Fimbrias Bacterianas/metabolismo , Genes Reguladores , Salmonella typhimurium/genética , Salmonella typhimurium/metabolismo , Análisis Mutacional de ADN , Familia de Multigenes , Mutagénesis Sitio-Dirigida , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación MissenseRESUMEN
Accumulated evidence reveals that microRNAs play vital roles in various tumors, including gliomas. MiRNAs have been shown to participate in multiple cellular functions, including cell proliferation, migration and apoptosis. Here, we investigate the potential role of a novel miRNA, miR-6807-3p, in glioma. A quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and western blot were applied to detect the expression of miR-6807-3p and its target molecule in glioma specimens and cultured cells. The direct targets of miR-6807-3p were predicted by bioinformatics software and were further verified by a luciferase reporter assay. The effects of miR-6807-3p on glioma cell proliferation, migration, cell apoptosis and the cell cycle of glioma cells were analyzed by the Cell-Counting Kit-8 (CCK-8) assay, a cell migration assay and flow cytometry assays. MiR-6807-3p was found to promote tumor growth and migration and inhibits apoptosis and cell cycle arrest in vitro, thus playing a tumor oncogenic role in the progression of glioma. Expression levels of miR-6807-3p were greatly upregulated in glioma specimens, and dachshund homolog 1 (DACH1) was ascertained as a direct target of miR-6807-3p, modulated by the expression of miR-6807-3p in glioma cells. Aberrant expression of DACH1 was associated with the clinical survival of glioma patients. Furthermore, overexpression of DACH1 rescued the promotive effects of miR-6807-3p in glioma. Based on these findings, a novel miR-6807-3p may act as a glioma enhancer by targeting DACH1.
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Neoplasias Encefálicas/genética , Proteínas del Ojo/genética , Glioma/genética , MicroARNs/genética , Factores de Transcripción/genética , Apoptosis/fisiología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Carcinogénesis/genética , Ciclo Celular/fisiología , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Proteínas del Ojo/biosíntesis , Proteínas del Ojo/metabolismo , Glioma/metabolismo , Glioma/patología , Humanos , MicroARNs/metabolismo , Factores de Transcripción/biosíntesis , Factores de Transcripción/metabolismo , Regulación hacia ArribaRESUMEN
Glioma is a common malignant human brain tumor. The progression of glioma is associated with dysregulation of various microRNAs. Previous studies have demonstrated that microRNA-26b-3p (miR-26b-3p) is correlated with the pathogenesis of various tumors, but the functional role of miR-26b-3p and its underlying mechanisms in glioma are not clear. Here, we found that overexpression of miR-26b-3p repressed cell migration and proliferation and promoted apoptosis. In contrast, the opposite effects were observed when miR-26b-3p was inhibited in glioma cells. Anthrax toxin receptor 1 (ANTXR1) was confirmed to be a downstream molecule of miR-26b-3p. Reintroduction of ANTXR1 with an ORF region rescued the suppressive effects of miR-26b-3p on proliferation and migration, and inhibited the apoptosis of glioma cells. Moreover, the downstream target of miR-26b-3p, ANTXR1, was increased in glioma tissues and was inversely correlated with miR-26b-3p. MiR-26b-3p and ANTXR1 were correlated with the severity of glioma. Taken together, these results demonstrate that miR-26b-3p is a critical modulator of glioma via its downstream molecule, ANTXR1. Further, the miR-26b-3p/ANTXR1 axis may serve as a treatment or diagnostic target in glioma.
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Phosphorylation affects ubiquitination, stability, and activity of transcriptional factors, thus regulating various cellular functions. E2F transcriptional factor 1 (E2F1) regulates paternally expressed imprinted gene 10 (Peg10) expression, thereby promoting cell proliferation. However, the effect of E2F1 stability on Peg10 expression and the molecular regulation of E2F1 stability by its phosphorylation have not been well demonstrated. Here, we describe a new pathway in which phosphorylation of E2F1 by GSK3ß increases E2F1 association with the deubiquitinating enzyme, ubiquitin-specific protease 11 (USP11), which removes K63-linked ubiquitin chains thereby preventing E2F1 degradation in the nuclei. Downregulation of USP11 increases E2F1 ubiquitination and reduces E2F1 stability and protein levels, thereby decreasing Peg10 mRNA levels. Physiologically, USP11 depletion suppresses cell proliferation and wound healing in lung epithelial cells, and these effects are reversed by E2F1 and PEG10 overexpression. Thus, our study reveals a new molecular model that phosphorylation promotes substrate stability through increasing its association with a deubiquitinating enzyme. The data suggest that GSK3ß and USP11 act in concert to modulate E2F1 abundance and PEG10 expression in lung epithelial cells to affect cell wound healing. This study provides new therapeutic targets to lessen lung injury by improving lung epithelial cell repair and remodeling after injury.
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Factor de Transcripción E2F1/metabolismo , Células Epiteliales/citología , Pulmón/citología , Proteínas/genética , Tioléster Hidrolasas/metabolismo , Regulación hacia Arriba , Células A549 , Proteínas Reguladoras de la Apoptosis , Línea Celular , Proliferación Celular , Proteínas de Unión al ADN , Regulación hacia Abajo , Células Epiteliales/metabolismo , Humanos , Pulmón/metabolismo , Fosforilación , Estabilidad Proteica , Proteolisis , Proteínas de Unión al ARN , Tioléster Hidrolasas/genética , UbiquitinaciónRESUMEN
Transforming growth factor ß-1 (TGFß-1)-induced phosphorylation of transcription factors Smad2 and Smad3 plays a crucial role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the molecular regulation of Smad2/Smad3 proteins stability remains a mystery. Here, we show that ubiquitin carboxyl-terminal hydrolase-L5 (UCHL5 or UCH37) de-ubiquitinates both Smad2 and Smad3, up-regulates their stability, and promotes TGFß-1-induced expression of profibrotic proteins, such as fibronectin (FN) and α-smooth muscle actin (α-SMA). Inhibition or down-regulation of UCHL5 reduced Smad2/Smad3 levels and TGFß-1-induced the expression of FN and α-SMA in human lung fibroblast. We demonstrate that Smad2 and Smad3 ubiquitination was diminished by over-expression of UCHL5, while it was enhanced by inhibition or down-regulation of UCHL5. UCHL5 is highly expressed in IPF lungs. UCHL5, Smad2, and Smad3 levels were increased in bleomycin-injured lungs. Administration of UCHL5 inhibitor, b-AP15, reduced the expression of FN, type I collagen, Smad2/Smad3, and the deposition of collagen in lung tissues in a bleomycin-induced model of pulmonary fibrosis. Our studies provide a molecular mechanism by which UCHL5 mitigates TGFß-1 signaling by stabilizing Smad2/Smad3. These data indicate that UCHL5 may contribute to the pathogenesis of IPF and may be a potential therapeutic target.
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Fibrosis Pulmonar Idiopática/metabolismo , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Animales , Bleomicina/toxicidad , Línea Celular , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Fibrosis Pulmonar Idiopática/etiología , Ratones , Ratones Endogámicos C57BL , Piperidonas/farmacología , Estabilidad Proteica/efectos de los fármacos , Proteolisis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteína Smad2/química , Proteína smad3/química , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ubiquitinación/efectos de los fármacosRESUMEN
Two-dimensional metasurface structures have recently been proposed to reduce the challenges of fabrication of traditional plasmonic metamaterials. However, complex designs and sophisticated fabrication procedures are still required. Here, we present a unique one-dimensional (1-D) metasurface based on bilayered metallic nanowire gratings, which behaves as an ideal polarized beam splitter, producing strong negative reflection for transverse-magnetic (TM) light and efficient reflection for transverse-electric (TE) light. The large anisotropy resulting from this TE-metal-like/TM-dielectric-like feature can be explained by the dispersion curve based on the Bloch theory of periodic metal-insulator-metal waveguides. The results indicate that this photon manipulation mechanism is fundamentally different from those previously proposed for 2-D or 3-D metastructures. Based on this new material platform, a novel form of metasurface holography is proposed and demonstrated, in which an image can only be reconstructed by using a TM light beam. By reducing the metamaterial structures to 1-D, our metasurface beam splitter exhibits the qualities of cost-efficient fabrication, robust performance, and high tunability, in addition to its applicability over a wide range of working wavelengths and incident angles. This development paves a foundation for metasurface structure designs towards practical metamaterial applications.
RESUMEN
To assess pancreatic perfusion in experimental chronic pancreatitis (CP) by dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). DCE MRI on a 1.5 T MR scanner was performed on 21 piglets with the ligation of pancreatic duct. They were divided into four groups based on pathology, including seven normal pigs and seven, three and four piglets with grade I, II and III CP, respectively. The signal intensity measured in the pancreatic body on DCE MRI was plotted against time to create a signal intensity-time (SI-T) curve for each piglet. The steepest slope (SS), time-to-peak (TTP) and peak enhancement ratio (PER) of the SI-T curve were noted. In the four groups, on the SI-T curve derived from DCE MRI, the SS was, respectively, 10.88 +/- 1.20, 10.59 +/- 1.02, 6.67 +/- 1.31 and 5.48 +/- 1.97%/s (F = 20.509, p = 0.000) from normal piglets to piglets with grade III CP. The TTP was 13.82 +/- 3.09, 12.31 +/- 5.52, 20.55 +/- 3.79 and 37.26 +/- 14.56 s (F = 10.681, p = 0.000) and the PER was 62.95 +/- 20.20, 60.44 +/- 20.00, 46.33 +/- 22.70 and 67.65 +/- 32.66% (F = 0.529, p = 0.668), respectively. The SS (r = -0.719, p = 0.000) and TTP (r = 0.538, p = 0.012) of the SI-T curve was correlated to the severity of CP, respectively. DCE MRI has a potential to diagnose moderate to advanced CP. The SS and TTP of the SI-T curve were correlated to the severity of CP.