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SignificanceA clear mechanistic understanding of metformin's antidiabetic effects is lacking. This is because suprapharmacological concentrations of metformin have been used in most studies. Using mouse models and human primary hepatocytes, we show that metformin, at clinically relevant doses, suppresses hepatic glucose production by activating a conserved regulatory pathway encompassing let-7, TET3, and a fetal isoform of hepatocyte nuclear factor 4 alpha (HNF4α). We demonstrate that metformin no longer has potent antidiabetic actions in a liver-specific let-7 loss-of-function mouse model and that hepatic delivery of let-7 ameliorates hyperglycemia and improves glucose homeostasis. Our results thus reveal an important role of the hepatic let-7/TET3/HNF4α axis in mediating the therapeutic effects of metformin and suggest that targeting this axis may be a potential therapeutic for diabetes.
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Hiperglucemia , Metformina , Animales , Modelos Animales de Enfermedad , Glucosa/metabolismo , Hepatocitos/metabolismo , Hiperglucemia/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Hígado/metabolismo , Metformina/uso terapéutico , RatonesRESUMEN
Mesenchymal gastrointestinal cancers are represented by the gastrointestinal stromal tumors (GISTs) which occur throughout the whole gastrointestinal tract, and affect human health and economy globally. Curative surgical resections and tyrosine kinase inhibitors (TKIs) are the main managements for localized GISTs and recurrent/metastatic GISTs, respectively. Despite multi-lines of TKIs treatments prolonged the survival time of recurrent/metastatic GISTs by delaying the relapse and metastasis of the tumor, drug resistance developed quickly and inevitably, and became the huge obstacle for stopping disease progression. Immunotherapy, which is typically represented by immune checkpoint inhibitors (ICIs), has achieved great success in several solid tumors by reactivating the host immune system, and been proposed as an alternative choice for GIST treatment. Substantial efforts have been devoted to the research of immunology and immunotherapy for GIST, and great achievements have been made. Generally, the intratumoral immune cell level and the immune-related gene expressions are influenced by metastasis status, anatomical locations, driver gene mutations of the tumor, and modulated by imatinib therapy. Systemic inflammatory biomarkers are regarded as prognostic indicators of GIST and closely associated with its clinicopathological features. The efficacy of immunotherapy strategies for GIST has been widely explored in pre-clinical cell and mouse models and clinical experiments in human, and some patients did benefit from ICIs. This review comprehensively summarizes the up-to-date advancements of immunology, immunotherapy and research models for GIST, and provides new insights and perspectives for future studies.
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Antineoplásicos , Neoplasias Gastrointestinales , Tumores del Estroma Gastrointestinal , Sarcoma , Animales , Ratones , Humanos , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/terapia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Gastrointestinales/terapia , Neoplasias Gastrointestinales/patología , Sarcoma/tratamiento farmacológico , Inmunoterapia , Antineoplásicos/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/uso terapéuticoRESUMEN
IbMYB1 is a transcription factor involved in the biosynthesis of anthocyanin in the purple-fleshed sweet potato. So far, few studies have investigated transcription factors that are upstream of the promoter IbMYB1-4. In this study, a yeast one-hybrid screening aimed at identifying transcription factors upstream of the promoter IbMYB1-4 was performed in the storage roots of the purple-fleshed sweet potato, and IbPDC, IbERF1, and IbPGP19 were identified as upstream binding proteins for the promoter IbMYB1-4. A dual luciferase reporter assay, and yeast one-hybrid assays, were employed to confirm the interaction of these binding proteins with promoters. IbERF1 was found to be an upstream transcription factor for the promoter IbMYB1, and is implicated in the biosynthesis of anthocyanin in the purple-fleshed sweet potato. IbERF1 plays a major role in the biosynthesis of anthocyanin in the purple-fleshed sweet potato.
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Gastrointestinal stromal tumors are the most common mesenchymal tumors of the digestive tract, most of which are sporadic, and familial GISTs with germline mutations are rarely seen. Here, we report a 26-year-old female with a germline p. W557R mutation in exon 11 of the KIT gene. The proband and her father and sister presented with multifocal GIST and pigmented nevi. All 3 patients underwent surgery and imatinib therapy. To date, only 49 kindreds with germline KIT mutations and 6 kindreds with germline PDGFRA mutations have been reported. Summarizing the reported kindreds, the majority of familial GISTs manifest as multiple primary GISTs complicated with special clinical manifestations, including cutaneous hyperpigmentation, dysphagia, mastocytosis, inflammatory fibrous polyps, and large hands. Familial GISTs are generally thought to exhibit TKI sensitivity similar to that of sporadic GISTs with the same mutation.
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Tumores del Estroma Gastrointestinal , Síndromes Neoplásicos Hereditarios , Femenino , Humanos , Adulto , Tumores del Estroma Gastrointestinal/diagnóstico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Pronóstico , Mesilato de Imatinib/uso terapéutico , Mutación , Mutación de Línea Germinal , Proteínas Proto-Oncogénicas c-kit/genéticaRESUMEN
GaAs-based oxide-confined vertical-cavity surface-emitting lasers (VCSELs) exhibit relatively low resistance against reliability-related damage. In order to gain a deeper understanding of the degradation and failure mechanism in oxide-confined VCSELs caused by electrostatic discharge (ESD)-induced defect proliferation, we investigated the effects of ESD stress on the degradation of optical-electrical characteristics and the evolution of defects in VCSELs under human body model test condition. The degradation threshold values for forward and reverse ESD pulse amplitudes were estimated to be 200â V and -50â V, respectively. Notably, VCSELs demonstrated greater sensitivity to reverse bias ESD compared to forward bias ESD. Analysis of optical emission and microstructure provided evidence that the device failure is attributed to an increase in ESD current density, leading to the multiplication of dark line defects (DLDs) originating from the edge of the device's oxide aperture. The formation of defects occurred suddenly in discrete events within small regions, rather than progressing gradually and uniformly. These defects propagated and led to damage across the entire active region. We believe that our results would be meaningful for improving the reliability of VCSEL in the future.
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In the field of diamond MESFETs, this work is what we believe to be the first to investigate the optoelectronic properties of hydrogen-terminated polycrystalline diamond MESFETs under visible and near-UV light irradiation. It is shown that the diamond MESFETs are well suited for weak light detection in the near-ultraviolet region around the wavelength of 368â nm, with a responsivity of 6.14 × 106 A/W and an external quantum efficiency of 2.1 × 107 when the incident light power at 368.7â nm is only 0.75 µW/cm2. For incident light at 275.1â nm, the device's sensitivity and EQE increase as the incident light power increases; at an incident light power of 175.32 µW/cm2 and a VGS of -1â V, the device's sensitivity is 2.9 × 105 A/W and the EQE is 1.3 × 106. For incident light in the wavelength range of 660â nm to 404â nm with an optical power of 70 µW/cm2, the device achieves an average responsivity of 1.21 × 105 A/W. This indicates that hydrogen-terminated polycrystalline diamond MESFETs are suitable for visible and near-UV light detection, especially for weak near-UV light detection. However, the transient response test of the device shows a long relaxation time of about 0.2 s, so it is not yet suitable for high-speed UV communication or detection.
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BACKGROUND: Left atrial appendage closure (LAAC) is a safe and effective method for preventing embolic events in patients with non-valvular atrial fibrillation. However, peri-device leaks (PDLs) are sometimes unavoidable. Controversy exists regarding whether PDLs lead to embolic events. OBJECTIVES: This study aimed to explore the association between PDLs and embolic events, including ischaemic stroke, transient ischaemic attacks (TIAs), and systemic embolism (SE). METHODS: We conducted a systematic search of the PubMed, Web of Science, MEDLINE, and Cochrane Library databases for studies published up to September 25, 2022, to compare the rate of ischaemic stroke/TIA/SE between the PDL group and the non-PDL group after LAAC. RESULTS: Thirteen studies comprising 54,405 patients were included in the meta-analysis. The PDL group detected by transoesophageal echocardiography (TEE) had a significantly higher rate of ischaemic stroke/TIA/SE than the non-PDL group (OR: 1.20, 95% CI: 1.08-1.33, p = 0.0009). However, no difference in ischaemic stroke/TIA/SE was found between the PDL and non-PDL subgroups of the cardiac computed tomography angiography (CCTA) group (OR: 1.12, 95% CI: 0.51-2.50, p = 0.77). CCTA and TEE showed different rates of PDL detection, with the CCTA group having a higher rate of PDL detection (p < 0.0001), especially for trivial leaks. CONCLUSIONS: PDL detected by TEE increases the risk of embolic events after LAAC. However, no association was found between PDL and ischaemic stroke/TIA/SE in the CCTA group, which showed a higher rate of PDL detection than TEE, particularly for trivial leaks. In the future, CCTA may be used to explore the relationship between PDL size and ischaemic stroke/TIA/SE.
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Apéndice Atrial , Fibrilación Atrial , Isquemia Encefálica , Embolia , Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Ataque Isquémico Transitorio/etiología , Cierre del Apéndice Auricular Izquierdo , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Isquemia Encefálica/etiología , Fibrilación Atrial/etiología , Accidente Cerebrovascular Isquémico/etiología , Embolia/etiología , Embolia/prevención & control , Apéndice Atrial/diagnóstico por imagen , Apéndice Atrial/cirugía , Resultado del Tratamiento , Ecocardiografía Transesofágica , Cateterismo Cardíaco/efectos adversosRESUMEN
MicroRNAs (miRNAs) regulate the translational potential of their mRNA targets and control many cellular processes. The key step in canonical miRNA biogenesis is the cleavage of the primary transcripts by the nuclear RNase III enzyme Drosha. Emerging evidence suggests that the miRNA biogenic cascade is tightly controlled. However, little is known whether Drosha is regulated. Here, we show that Drosha is targeted by stress. Under stress, p38 MAPK directly phosphorylates Drosha at its N terminus. This reduces its interaction with DiGeorge syndrome critical region gene 8 and promotes its nuclear export and degradation by calpain. This regulatory mechanism mediates stress-induced inhibition of Drosha function. Reduction of Drosha sensitizes cells to stress and increases death. In contrast, increase in Drosha attenuates stress-induced death. These findings reveal a critical regulatory mechanism by which stress engages p38 MAPK pathway to destabilize Drosha and inhibit Drosha-mediated cellular survival.
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Ribonucleasa III/fisiología , Estrés Fisiológico , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología , Transporte Activo de Núcleo Celular , Supervivencia Celular , Células HEK293 , Humanos , Fosforilación , Proteolisis , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/fisiología , Ribonucleasa III/genética , Ribonucleasa III/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: To investigate the changes and clinical significance of vascular endothelial injury markers in type 2 diabetes mellitus (T2DM) complicated with pulmonary embolism (PE). METHODS: This prospective study enrolled patients with T2DM hospitalized in one hospital from January 2021 to June 2022. Soluble thrombomodulin (sTM) (ELISA), von Willebrand factor (vWF) (ELISA), and circulating endothelial cells (CECs) (flow cytometry) were measured. PE was diagnosed by computed tomography pulmonary angiography (CTPA). RESULTS: Thirty participants were enrolled in each group. The plasma levels of sTM (151.22 ± 120.57 vs. 532.93 ± 243.82 vs. 1016.51 ± 218.00 pg/mL, P < 0.001) and vWF (9.63 ± 2.73 vs. 11.50 ± 2.17 vs. 18.02 ± 3.40 ng/mL, P < 0.001) and the percentage of CECs (0.17 ± 0.46 vs. 0.30 ± 0.08 vs. 0.56 ± 0.18%, P < 0.001) gradually increased from the control group to the T2DM group to the T2DM + PE group. sTM (OR = 1.002, 95%CI: 1.002-1.025, P = 0.022) and vWF (OR = 1.168, 95%CI: 1.168-2.916, P = 0.009) were associated with T2DM + PE. sTM > 676.68 pg/mL for the diagnosis of T2DM + PE achieved an AUC of 0.973, while vWF > 13.75 ng/mL achieved an AUC of 0.954. The combination of sTM and vWF above their cutoff points achieved an AUC of 0.993, with 100% sensitivity and 96.7% specificity. CONCLUSIONS: Patients with T2DM show endothelial injury and dysfunction, which were worse in patients with T2DM and PE. High sTM and vWF levels have certain clinical predictive values for screening T2DM accompanied by PE.
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Diabetes Mellitus Tipo 2 , Embolia Pulmonar , Humanos , Células Endoteliales , Diabetes Mellitus Tipo 2/complicaciones , Factor de von Willebrand/análisis , Estudios Prospectivos , Endotelio Vascular/química , BiomarcadoresRESUMEN
The performance of lead-acid batteries could be significantly increased by incorporating carbon materials into the negative electrodes. In this study, a modified carbon material developed via a simple high-temperature calcination method was employed as a negative electrode additive, and we have named it as follows: N-doped chitosan-derived carbon (NCC). The performance of this material was compared with a control battery containing activated carbon (AC). X-ray diffraction (XRD), scanning electron microscopy (SEM) and Raman spectroscopy were engaged in analyzing the crystal structure and morphology of the material. Afterwards, the electrochemical and battery performance was examined through cyclic voltammetry (CV), linear voltammetry (LSV) and constant current charge-discharge testing. Markedly, the electrode plate containing 1 wt.% NCC indicates the highest specific capacity (106.48 F g-1) as compared to the control battery, which is 1.56 times higher than the AC electrode plate and 4.75 times higher than the blank electrode plate. The linear voltammetry shows that the hydrogen precipitation current density of the 1 wt.% NCC electrode plate is only -0.028 A cm-2, a much higher value than that of the AC electrode plate. In addition, the simulated battery containing 1 wt.% NCC has a cycle life of 4324 cycles, which is 2.36 times longer than that of the same amount of additive AC battery (1834 cycles) and 5.34 times longer than that of the blank battery (809 cycles). In summary, NCC carbon has the advantage of extending the life of lead-acid batteries, rendering it a promising candidate for lead-acid battery additives.
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Mammal's milk is an abundantly foremost source of proteins, lipids, and micronutrients for human nutrition and health. Understanding the molecular mechanisms underlying synthesis of milk components provides practical benefits to improve the milk quality via systematic breeding program in mammals. Through RNAi with EEF1D in primary bovine mammary epithelial cells, we phenotypically observed aberrant formation of cytoplasmic lipid droplets and significantly decreased milk triglyceride level by 37.7%, and exploited the mechanisms by which EEF1D regulated milk lipid synthesis via insulin (PI3K-Akt), AMPK, and PPAR pathways. In the EEF1D CRISPR/Cas9 knockout mice, incompletely developed mammary glands at 9th day postpartum with small or unformed lumens, and significantly decreased triglyceride concentration in milk by 23.4% were observed, as well as the same gene expression alterations in the three pathways. For dairy cattle, we identified a critical regulatory mutation modifying EEF1D transcription activity, which interpreted 7% of the genetic variances of milk lipid yield and percentage. Our findings highlight the significance of EEF1D in mammary gland development and milk lipid synthesis in mammals.
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Lípidos/biosíntesis , Lipogénesis , Glándulas Mamarias Animales/metabolismo , Leche/metabolismo , Factor 1 de Elongación Peptídica/fisiología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Células Epiteliales/metabolismo , Femenino , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genéticaRESUMEN
Very few developed economies have a full free trade agreement (FTA) with China. This study employs one GTAP model and builds an extended environmental multi-region input-output model to investigate a hypothetical China-UK FTA, concerning embodied industrial emissions of SO2, PM2.5, NOX, and NH3. The economic sectors are also classified based on their embodied pollution intensity and trade advantage index under various FTA scenarios. Results show that the UK's GDP and welfare and China's welfare will increase, along with changes in their trade structures. Overall, this FTA brings about larger net impacts on embodied emissions of SO2 than on PM2.5, NOX and NH3, and both countries are net importers of the latter three pollutants. Key sectors such as non-metallic mineral products, chemical products, and agriculture are inclined to become less competitive and less polluting under the FTA. The inclusion of agri-food sectors exhibits slight counteracting effects in general. The findings are of policy importance as they provide insights into how best to target key sectors, seeking a balance between trade development and environmental protection. Supplementary Information: The online version contains supplementary material available at 10.1007/s10668-022-02612-z.
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In this study, the regulation of miR-15b-5p on myocardial ischemia reperfusion (I/R) injury-induced arrhythmia and myocardial apoptosis was investigated in mice. We observed the change in miR-15b-5p expression after mice suffered from myocardial I/R injury and the change in myocardial injury, infarct size, apoptosis, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD) and malondialdehyde (MDA) after down-regulation of miR-15b-5p expression. The negative regulation of miR-15b-5p to KCNJ2 as well as whether cardioprotective effect formed by miR-15b-5p down-regulation relied on the increase of KNCJ2 expression were measured by dual-luciferase reporter assay system. miR-15b-5p expression increased and KCNJ2 mRNA and protein expressions decreased after myocardial ischemia reperfusion (all P < 0.05). miR-15b-5p negatively regulated KCNJ2 in a targeted way. Down-regulating miR-15b-5p expression or increasing KCNJ2 expression significantly decreased the incidence of arrhythmia, infarct size and apoptosis after myocardial I/R and lowered MDA content in the myocardial tissue as well as IL-6 and TNF-α content in the blood (all P < 0.05). KCNJ2 gene knockout reversed the above cardioprotective effect formed by miR-15b-5p down-regulation (P < 0.05). Down-regulating miR-15b-5p expression or up-regulating KCNJ2 expression improves arrhythmia after mice suffered from myocardial I/R injury and inhibits myocardial apoptosis.
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Apoptosis , Arritmias Cardíacas/genética , Regulación hacia Abajo , MicroARNs/genética , Daño por Reperfusión Miocárdica/genética , Animales , Arritmias Cardíacas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Daño por Reperfusión Miocárdica/patología , Miocardio/patologíaRESUMEN
The precise manipulation of microcirculation in mice can facilitate mechanistic studies of brain injury and repair after ischemia, but this manipulation remains a technical challenge, particularly in conscious mice. We developed a technology that uses micromagnets to induce aggregation of magnetic nanoparticles to reversibly occlude blood flow in microvessels. This allowed induction of ischemia in a specific cortical region of conscious mice of any postnatal age, including perinatal and neonatal stages, with precise spatiotemporal control but without surgical intervention of the skull or artery. When combined with longitudinal live-imaging approaches, this technology facilitated the discovery of a feature of the ischemic cascade: selective loss of smooth muscle cells in juveniles but not adults shortly after onset of ischemia and during blood reperfusion.
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Isquemia Encefálica/inducido químicamente , Isquemia Encefálica/fisiopatología , Nanopartículas de Magnetita/efectos adversos , Animales , Isquemia Encefálica/tratamiento farmacológico , Arterias Cerebrales/efectos de los fármacos , Arterias Cerebrales/fisiopatología , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Modelos Animales de Enfermedad , Células HEK293 , Hipocampo/efectos de los fármacos , Humanos , Imagen por Resonancia Magnética/métodos , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/toxicidad , Ratones Endogámicos C57BL , Ratones Transgénicos , Microcirculación/efectos de los fármacos , Microvasos/efectos de los fármacos , Microvasos/fisiopatologíaRESUMEN
Major histocompatibility complex class I (MHC I) molecules are critically involved in defense against pathogens, and their high polymorphism is advantageous to a range of immune responses, especially in duck displaying biased expression of one MHC I gene. Here, we examined MHC I polymorphism in two duck (Anas platyrhynchos) breeds from China: Shaoxing (SX) and Jinding (JD). Twenty-seven unique UAA alleles identified from the MHC I genes of these breeds were analyzed concerning amino acid composition, homology, and phylogenetic relationships. Based on amino acid sequence homology, allelic groups of Anas platyrhynchos MHC I (Anpl-MHC I) were established and their distribution was analyzed. Then, highly variable sites (HVSs) in peptide-binding domains (PBD) were estimated and located in the three-dimensional structure of Anpl-MHC I. The UAA alleles identified showed high polymorphism, based on full-length sequence homology. By adding the alleles found here to known Anpl-MHC I genes from domestic ducks, they could be divided into 17 groups and four novel groups were revealed for SX and JD ducks. The UAA alleles of the two breeds were not divergent from the MHC I of other duck breeds, and HVSs were mostly located in the peptide-binding groove (PBG), suggesting that they might determine peptide-binding characteristics and subsequently influence peptide presentation and recognition. The results from the present study enrich Anpl-MHC I polymorphism data and clarify the distribution of alleles with different peptide-binding specificities, which might also accelerate effective vaccine development and help control various infections in ducks.
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Patos/genética , Antígenos de Histocompatibilidad Clase I/genética , Polimorfismo Genético , Alelos , Animales , Patos/inmunología , Antígenos de Histocompatibilidad Clase I/química , FilogeniaRESUMEN
BACKGROUND: Paratuberculosis is a contagious, chronic and enteric disease in ruminants, which is caused by Mycobacterium avium subspecies paratuberculosis (MAP) infection, resulting in enormous economic losses worldwide. There is currently no effective cure for MAP infection or a vaccine, it is thus important to explore the genetic variants that contribute to host susceptibility to infection by MAP, which may provide a better understanding of the mechanisms of paratuberculosis and benefit animal genetic improvement. Herein we performed a genome-wide association study (GWAS) to identify genomic regions and candidate genes associated with susceptibility to MAP infection in dairy cattle. RESULTS: Using Illumina Bovine 50 K (54,609 SNPs) and GeneSeek HD (138,893 SNPs) chips, two analytical approaches were performed, GRAMMAR-GC and ROADTRIPS in 937 Chinese Holstein cows, among which individuals genotyped by the 50 K chip were imputed to HD SNPs with Beagle software. Consequently, 15 and 11 significant SNPs (P < 5 × 10- 5) were identified with GRAMMAR-GC and ROADTDRIPS, respectively. A total of 10 functional genes were in proximity to (i.e., within 1 Mb) these SNPs, including IL4, IL5, IL13, IRF1, MyD88, PACSIN1, DEF6, TDP2, ZAP70 and CSF2. Functional enrichment analysis showed that these genes were involved in immune related pathways, such as interleukin, T cell receptor signaling pathways and inflammatory bowel disease (IBD), implying their potential associations with susceptibility to MAP infection. In addition, by examining the publicly available cattle QTLdb, a previous QTL for MAP was found to be overlapped with one of regions detected currently at 32.5 Mb on BTA23, where the TDP2 gene was anchored. CONCLUSIONS: In conclusion, we identified 26 SNPs located on 15 chromosomes in the Chinese Holstein population using two GWAS strategies with high density SNPs. Integrated analysis of GWAS, biological functions and the reported QTL information helps to detect positional candidate genes and the identification of regions associated with susceptibility to MAP traits in dairy cattle.
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Enfermedades de los Bovinos/genética , Predisposición Genética a la Enfermedad , Mycobacterium avium subsp. paratuberculosis , Paratuberculosis/genética , Polimorfismo de Nucleótido Simple/genética , Animales , Bovinos , Femenino , Estudio de Asociación del Genoma Completo/veterinariaRESUMEN
BACKGROUND/AIMS: Circular RNAs (circRNAs) are a class of long noncoding RNAs with a closed loop structure that regulate gene expression as microRNA sponges. CircRNAs are more enriched in brain tissue, but knowledge of the role of circRNAs in temporal lobe epilepsy (TLE) has remained limited. This study is the first to identify the global expression profiles and characteristics of circRNAs in human temporal cortex tissue from TLE patients. METHODS: Temporal cortices were collected from 17 TLE patients and 17 non-TLE patients. Total RNA was isolated, and high-throughput sequencing was used to profile the transcriptome of dysregulated circRNAs. Quantitative PCR was performed for the validation of changed circRNAs. RESULTS: In total, 78983 circRNAs, including 15.29% known and 84.71% novel circRNAs, were detected in this study. Intriguingly, 442 circRNAs were differentially expressed between the TLE and non-TLE groups (fold change≥2.0 and FDR≤0.05). Of these circRNAs, 188 were up-regulated, and 254 were down-regulated in the TLE patient group. Eight circRNAs were validated by real-time PCR. Remarkably, circ-EFCAB2 was intensely up-regulated, while circ-DROSHA expression was significantly lower in the TLE group than in the non-TLE group (P<0.05). Bioinformatic analysis revealed that circ-EFCAB2 binds to miR-485-5p to increase the expression level of the ion channel CLCN6, while circ-DROSHA interacts with miR-1252-5p to decrease the expression level of ATP1A2. CONCLUSIONS: The dysregulations of circRNAs may reflect the pathogenesis of TLE and circ-EFCAB2 and circ-DROSHA might be potential therapeutic targets and biomarkers in TLE patients.
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Epilepsia del Lóbulo Temporal/patología , ARN/metabolismo , Lóbulo Temporal/metabolismo , Adolescente , Adulto , Biomarcadores/metabolismo , Niño , Preescolar , Canales de Cloruro/genética , Canales de Cloruro/metabolismo , Biología Computacional , Regulación hacia Abajo , Electroencefalografía , Epilepsia del Lóbulo Temporal/diagnóstico , Epilepsia del Lóbulo Temporal/genética , Femenino , Regulación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , ARN Circular , Análisis de Secuencia de ARN , ATPasa Intercambiadora de Sodio-Potasio/genética , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Regulación hacia Arriba , Adulto JovenRESUMEN
Giant intrapetrous internal carotid aneurysms (petrous ICA aneurysm) are rare. A giant petrous ICA aneurysm presenting with otorrhagia and coil exposure to the external auditory meatus (EAM) after endovascular treatment has never been documented before. The authors report here a case of successful surgical trapping with bypass intervention of a giant petrous ICA aneurysm presenting with coil exposure after endovascular treatment. A 58-year-old man presented with persistent otorrhagia having been admitted to our hospital because of the recurrence of a giant petrous ICA aneurysm after repeated embolization treatments with coils. An electronic otoscope examination demonstrated that a piece of coil escaped into his right EAM. After multidisciplinary consultation, an extracranial-intracranial (EC-IC) bypass with ICA occlusion and coil removal with a closed EAM filling were performed in stages. The patient recovered quickly without any neurological deficits. A digital subtraction angiography confirmed the absence of the aneurysm and patency of the bypass graft.
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Prótesis Vascular/efectos adversos , Enfermedades de las Arterias Carótidas/cirugía , Procedimientos Endovasculares/métodos , Aneurisma Intracraneal/cirugía , Procedimientos Neuroquirúrgicos/métodos , Hueso Petroso/cirugía , Angiografía de Substracción Digital , Implantación de Prótesis Vascular , Conducto Auditivo Externo/diagnóstico por imagen , Embolización Terapéutica , Humanos , Masculino , Persona de Mediana Edad , RecurrenciaRESUMEN
OBJECTIVE: To determine the regulatory and molecular mechanism of lncRNA MALAT1 in response to sepsis induced by lipopolysaccharide (LPS) in rats. METHODS: The expressions of lncRNA MALAT1 and miR-146a in U937 cells and peripheral blood samples of the rats with and without LPS-induced sepsis were detected using quantitative real-time reverse transcription PCR (qRT-PCR). The relationship between lncRNA MALAT1 and miR-146a was affirmed through luciferase assay. The expressions of p-P65, P65, TNF-α and iNOS were tested by Western blot. The expressions of TNF-α and iNOS in the lung tissues of the rats were measured by immunohistochemistry. RESULTS: The rats with LPS-induced sepsis had higher expressions of lncRNA MALAT1 in U937 cells than those without sepsis (P<0.001). In comparison with scramble, si-MALAT1 attenuated the expression of lncRNA MALAT1 and increased the expression of miR-146a (P<0.001). MiR-146a was the target of lncRNA MALAT1. si-MALAT1 decreased the p-P65/P65 ratio and and the expressions of TNF-α and iNOS in the rats with LPS-induced sepsis. In contrast, miR-146a inhibitor increased p-P65/P65 ratio and the expressions of TNF-α and iNOS in the rats with LPS-induced septis (P<0.001). Co-transfection with si-MALAT1 attenuated the elevated level of p-P65/P65 ratio and expressions of TNF-α and iNOS resulting from miR-146a inhibitor (P<0.001). LPS and scramble decreased the expression of miR-146a and increased the p-P65/P65 ratio compared with the healthy controls (P<0.01). Compared with scramble, si-MALAT1 increased the expression of miR-146a and attenuated the p-P65/P65 ratio (P<0.01). Higher numbers of TNF-α and iNOS positive cells were found in those with LPS-induced sepsis and those with scramble interventions (P<0.001). Compared with scramble, si-MALAT1 reduced the number of TNF-α and iNOS positive cells (P<0.01). CONCLUSIONS: LncRNA MALAT1 modulates the immunoreaction of rats with LPS -induced sepsis by targeting miR-146a/NF-κB P65.