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Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1-/-Ctla4+/- mice, we identify clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1-/-Ctla4+/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8+ T cells. The cardiac-specific protein α-myosin, which is absent from the thymus3,4, was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8+ T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.
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Linfocitos T CD8-positivos , Inmunoterapia , Miocarditis , Miosinas Ventriculares , Animales , Ratones , Autoantígenos/inmunología , Linfocitos T CD8-positivos/inmunología , Antígeno CTLA-4/deficiencia , Antígeno CTLA-4/genética , Inmunoterapia/efectos adversos , Miocarditis/inducido químicamente , Miocarditis/etiología , Miocarditis/mortalidad , Miocarditis/patología , Miosinas Ventriculares/inmunologíaRESUMEN
Chemotherapy as a cornerstone of cancer treatment is slowly being edged aside owing to its severe side effects and systemic toxicity. In this case, nanomedicine has emerged as an effective tool to address these drawbacks. Herein, a biocompatible carrier based on bovine serum albumin (BSA) coated gadolinium oxide nanoparticles (Gd2O3@BSA) was fabricated for curcumin (CUR) delivery and its physicochemical features along with its potential anticancer activity against nasal squamous cell carcinoma were also investigated. It was found that the fabricated Gd2O3@BSA containing CUR (Gd2O3@BSA-CUR) had spherical morphology with hydrodynamic size of nearly 26 nm, zeta-potential of -36 mV and high drug (CUR) loading capacity. Drug release profile disclosed that the release of CUR from the prepared Gd2O3@BSA-CUR nanoparticles occurred in a sustained- and pH-dependent manner. Also, in vitro cytotoxicity analysis revealed that the fabricated Gd2O3@BSA nanoparticles possessed excellent biosafety toward HFF2 normal cells, while Gd2O3@BSA-CUR appeared to display the greatest anticancer potential against RPMI 2650 and CNE-1 cancer cell lines. The results also show that the Gd2O3@BSA nanoparticles were compatible with the blood cells with minor hemolytic effect (< 3%). The manufactured NPs were found to be completely safe for biological applications in an in vivo subacute toxicity study. Taken together, these finding substantiate the potential anticancer activity of Gd2O3@BSA-CUR nanoparticles against nasal squamous cell carcinoma, but the results obtained demand further studies to assess their full potential.
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Antineoplásicos , Carcinoma de Células Escamosas , Gadolinio , Albúmina Sérica Bovina , Gadolinio/química , Gadolinio/farmacología , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Carcinoma de Células Escamosas/tratamiento farmacológico , Albúmina Sérica Bovina/química , Línea Celular Tumoral , Animales , Curcumina/farmacología , Curcumina/química , Neoplasias Nasales/tratamiento farmacológico , Nanopartículas/química , Nanopartículas del Metal/química , Supervivencia Celular/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Liberación de Fármacos , Hemólisis/efectos de los fármacosRESUMEN
[This corrects the article DOI: 10.1007/s11032-024-01474-9.].
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Apyrase is a class of enzyme that catalyzes the hydrolysis of nucleoside triphosphates/diphosphates (NTP/NDP), which widely involved in regulation of plant growth and stress responses. However, apyrase family genes in maize have not been identified, and their characteristics and functions are largely unknown. In this study, we identified 16 apyrases (named as ZmAPY1-ZmAPY16) in maize genome, and analyzed their phylogenetic relationships, gene structures, chromosomal distribution, upstream regulatory transcription factors and expression patterns. Analysis of the transcriptome database unveiled tissue-specific and abiotic stress-responsive expression of ZmAPY genes in maize. qPCR analysis further confirmed their responsiveness to drought, heat, and cold stresses. Association analyses indicated that variations of ZmAPY5 and ZmAPY16 may regulate maize agronomic traits and drought responses. Our findings shed light on the molecular characteristics and evolutionary history of maize apyrase genes, highlighting their roles in various biological processes and stress responses. This study forms a basis for further exploration of apyrase functions in maize. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01474-9.
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Multifunctional materials with switchable magnetic and dielectric properties are crucial for the development of memory and sensor devices. Herein, we report a methoxy-bridged dinuclear iron-pyridyl complex [Fe2(4-picoline)4(NCS)4(µ-OCH3)2] (1), which shows simultaneous thermal-induced magnetic and dielectric switchings. Within the phase-transition temperature range, both magnetic switching and the dielectric anomaly were detected, in which the thermal hysteresis loops were 23 and 21 K, respectively. Detailed structural analyses revealed that these simultaneous switchings were rooted in the flexible rotatable ligands, which were actuated by readjusting the π-π intermolecular interactions between the pyridine ligands in the trans positions of the metal centers. These results were comprehensively investigated both experimentally and theoretically. This study presents a new guideline to control both the magnetic and dielectric properties of molecular complexes by external stimuli.
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BACKGROUND: The microenvironment of hypoxia is an important factor contributing to the development of glioblastoma (GBM). MicroRNA-588 and its potential target Roundabout-directed receptor 1 (ROBO1) have been reported to promote tumor invasion and proliferation in diseases such as gastric, pancreatic and hepatocellular carcinoma, while their function in GBM and response to hypoxic states remain elusive. METHODS: A microarray was leveraged to identify differentially expressed microRNAs in U251 glioma cells cultured under normoxic and hypoxic conditions. The expression of miR-588 was assessed using quantitative real-time PCR (qRTâPCR). Gain- and loss-of-function studies were used to evaluate the role of miR-588 under hypoxic and normoxic conditions. Cell invasion, migration, proliferation, and vasculogenic mimicry (VM) formation experiments were performed. The relationship between miR-588 and ROBO1 was confirmed using western blot and luciferase reporter assays. Intracranial xenograft tumor mouse models were used to study the function of miR-588 in vivo. RESULTS: The expression of miR-588 was significantly upregulated in hypoxic glioma cells relative to normoxic glioma cells. miR-588 inhibited the invasive, migratory and VM-forming abilities of glioma cells in vitro and in vivo. Mechanistically, roundabout guidance receptor 1 (ROBO1) is a direct, functionally relevant target of miR-588 in glioma. ROBO1 knockdown suppressed the expression of matrix metallopeptidase 2 (MMP2) and matrix metallopeptidase 9 (MMP9), thereby inhibiting the invasive, migratory and VM-forming abilities of glioma. CONCLUSIONS: MiR-588 regulated the behaviors of hypoxic glioma cells by targeting ROBO1. miR-588 can be used as a prognostic marker for glioma and has potential implications in glioma gene therapy.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Neoplasias Hepáticas , MicroARNs , Animales , Ratones , Humanos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Movimiento Celular/genética , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Glioma/metabolismo , MicroARNs/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/genética , Hipoxia/genética , Neoplasias Hepáticas/genética , Metaloproteasas/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Microambiente TumoralRESUMEN
PURPOSE: The purpose of this study was to prepare the novel mussel-derived ACE inhibitory peptides (MEPs) by enzymatic hydrolysis of Mytilus edulis and investigate their antihypertensive effects in vivo. METHODS: After assessing the stability of MEPs in vitro, we investigated the effect of MEPs on hypertension using spontaneously hypertensive rats (SHRs). Subsequently, MEPs were purified and identified by ultrafiltration, gel filtration chromatography and liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Our study demonstrated that MEPs could keep stable ACE inhibitory activity after treatment with heat, acid, alkali, metal ions and simulated gastrointestinal digestive fluid. Additionally, the animal experiments showed that both short-term and long-term treatment with MEPs resulted in a significant reduction in systolic and diastolic blood pressure in SHRs. Mechanistically, the results suggested that MEPs could reduce vascular remodeling, regulate renin-angiotensin system (RAS), and inhibit kidney and myocardial fibrosis. Finally, we isolated and identified five peptides from MEPs, with the peptide Ile-Leu-Thr-Glu-Arg showed the highest ACE inhibition rate. CONCLUSION: Our findings demonstrate the potential use of MEPs as active components in functional foods designed to lower blood pressure.
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Bivalvos , Hipertensión , Ratas , Animales , Ratas Endogámicas SHR , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/química , Cromatografía Liquida , Espectrometría de Masas en Tándem , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Antihipertensivos/química , Péptidos/farmacología , Hipertensión/tratamiento farmacológico , Presión Sanguínea , Bivalvos/química , Peptidil-Dipeptidasa ARESUMEN
KEY MESSAGE: Editing ZmGA20ox3 can achieve the effect similar to applying Cycocel, which can reduce maize plant height and enhance stress resistance. Drought stress, a major plant abiotic stress, is capable of suppressing crop yield performance severely. However, the trade-off between crop drought tolerance and yield performance turns out to be significantly challenging in drought-resistant crop breeding. Several phytohormones [e.g., gibberellin (GA)] have been reported to play a certain role in plant drought response, which also take on critical significance in plant growth and development. In this study, the loss-of-function mutations of GA biosynthesis enzyme ZmGA20ox3 were produced using the CRISPR-Cas9 system in maize. As indicated by the result of 2-year field trials, the above-mentioned mutants displayed semi-dwarfing phenotype with the decrease of GA1, and almost no yield loss was generated compared with wild-type (WT) plants. Interestingly, as revealed by the transcriptome analysis, differential expressed genes (DEGs) were notably enriched in abiotic stress progresses, and biochemical tests indicated the significantly increased ABA, JA, and DIMBOA levels in mutants, suggesting that ZmGA20ox3 may take on vital significance in stress response in maize. The in-depth analysis suggested that the loss function of ZmGA20ox3 can enhance drought tolerance in maize seedling, reduce Anthesis-Silking Interval (ASI) delay while decreasing the yield loss significantly in the field under drought conditions. The results of this study supported that regulating ZmGA20ox3 can improve plant height while enhancing drought resistance in maize, thus serving as a novel method for drought-resistant genetic improvement in maize.
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Resistencia a la Sequía , Edición Génica , Zea mays/fisiología , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fitomejoramiento , Sequías , Regulación de la Expresión Génica de las Plantas , Estrés Fisiológico/genéticaRESUMEN
Polyoxometalate (POM) anions were successfully integrated into Fe(II) spin crossover (SCO) system, which demonstrates an effective role in regulating spin-state switching properties. Specifically, three drastically different magnetic behaviors of Fe(II) ion in the identical cation [Fe(bpp)2]2+ were achieved by leveraging [Mo6O19]2-, [Mo8O26]4-, and [Na(Mo8O26)]3-, respectively.
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Two isostructural valence tautomeric (VT) complexes with different critical temperatures were prepared and fully investigated through a series of magnetic, structural, spectral, and differential scanning calorimetry evidence. The kinetic effect in the VT complex was observed for the first time through scan-rate-dependent studies and further validated by annealing tests.
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It was aimed at the therapeutic value of loop electrosurgical excision procedure (LEEP) under propofol intravenous anesthesia combined with nano-silver gel in chronic cervicitis. 100 patients with chronic cervicitis were selected and randomly divided into the control group with 50 cases (LEEP under intravenous anesthesia with fentanyl) and the experimental group with the other 50 cases (LEEP under propofol intravenous anesthesia combined with the nano-silver gel). It was suggested from the results that the mean arterial pressure (MAP) and heart rate (HR) (76.88±5.65mmHg, 75.45±5.06beats/min) of patients in the experimental group at T1 time were better than those of the control group (83.76±5.43mmHg, 68.31±5.28beats/min). Visual analogue scale (VAS) (1.85±0.73 points), onset time of anesthesia (0.56±0.21min), time to open eyes (2.45±1.38min) and time of consciousness recovery (5.22±1.42min) were all lower than those of the control group (2.83±0.79 points, 0.93±0.25min, 4.33±1.45min, and 7.15±1.34min, respectively). The incidence of adverse reactions, the effective rate of treatment, the time of wound healing, and the incidence of complications (6%, 94%, 23.83±2.05 days, and 6%, respectively) were all better than those of the control group (24%, 70%, 29.25±2.16 days, and 6%) (P<0.05). All in all, intravenous anesthesia with propofol was beneficial to perform LEEP better, and the combination of LEEP combined with nano-silver gel had an important value in the treatment of chronic cervicitis and was worthy of clinical promotion.
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Propofol , Cervicitis Uterina , Anestesia Intravenosa , Anestésicos Intravenosos , Electrocirugia , Femenino , Humanos , Propofol/uso terapéuticoRESUMEN
BACKGROUND: Radial artery cannulation is a crucial investigative procedure for measuring patients' blood pressure invasively and serial blood gases. However, radial artery cannulation can be challenging for medical residents, and it is necessary to establish a facile and straightforward teaching strategy. This study aimed to evaluate the efficiency of acoustic shadowing-facilitated ultrasound guidance on radial artery cannulation teaching for medical residents. METHODS: A total of 116 medical postgraduates who underwent standardized residency training programs in the Department of Anesthesiology were randomly divided into a new ultrasound-guided teaching group and a traditional ultrasound-guided teaching group. In the new ultrasound-guided teaching group, radial artery puncture technique was taught by acoustic shadowing-facilitated ultrasound guidance. The training included both theoretical and practical components. After the training, the success rate of the first puncture attempt, the success rate of the catheterization, the ultrasonic positioning time, and the catheterization time of the two groups were compared in a unified manner. A questionnaire on the subjective evaluation of the various aspects of the program by participants was conducted at the end of the training period. RESULTS: The study included 101 medical residents. The success rate for radial artery puncture at the first attempt in the new ultrasound-guided teaching group was 78.43%. It was significantly higher than that of the traditional ultrasound-guided group (58.00%, odds ratio = 0.380; 95% CI = 0.159 to 0.908; p = 0.027). The success rate for the first arterial catheterization in the new ultrasound-guided teaching group was significantly higher than that of the traditional ultrasound-guided group (74.51% vs. 52.00%, odds ratio = 0.371; 95% CI = 0.160 to 0.858; p = 0.019). The ultrasonic positioning time and catheterization time in minutes in the new ultrasound-guided teaching group were significantly shorter than that of the traditional ultrasound-guided group (14.36 ± 3.31 vs. 18.02 ± 4.95, p < 0.001; 10.43 ± 2.38 vs. 14.78 ± 8.02, p = 0.012). However, no significant differences were observed in the incidence of local hematomas and teaching satisfaction scores between the two groups. CONCLUSION: Acoustic shadowing facilitates ultrasound-guided radial artery puncture and catheterization is beneficial in the standardized training and teaching of residents. It improves the success rate of the first attempt at radial artery puncture and catheterization and shortens the time of ultrasound location and catheterization. TRIAL REGISTRATION: Registered in the Chinese Clinical Trial Registry on 28 May 2021. REGISTRATION NUMBER: ChiCTR2100046833 .
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Cateterismo Periférico , Arteria Radial , Acústica , Cateterismo Periférico/métodos , Humanos , Punciones/métodos , Arteria Radial/diagnóstico por imagen , Ultrasonografía Intervencional/métodosRESUMEN
Two-dimensional hexagonal boron nitride (h-BN) has received much attention owing to its unique properties and wide range of applications. However, the lack of sufficient active functional groups on the surface coupled with the extremely stable structure restricts the wide application of h-BN. We find that thionyl chloride can corrode commercially available h-BN and generate many through-holes in the thickness direction. Both X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FT-IR) show that the corroded h-BN contains reactive hydroxyl and a lot of amino groups. The corrosion mechanism is proposed and we conclude that H+ and OH- will affect the defect structure of the corroded h-BN by affecting the generation of boric acid. The thionyl chloride corroded h-BN could improve the thermal conductivity and DC breakdown strength of the composites because of the improved interface. This novel method about corroding h-BN through thionyl chloride is promising for the modification research of h-BN due to its simplicity and efficiency.
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Nasopharyngeal cancer is a malignancy developing from the nasopharynx epithelium due to smoking and nitrosamine-containing foods. Nasopharyngeal cancer is highly endemic to Southeast Asia. Eugenol and piperine have shown many anticancer activities on numerous cancer types, like colon, lung, liver, and breast cancer. In this study, we amalgamated eugenol and piperine loaded with a polyhydroxy butyrate/polyethylene glycol nanocomposite (Eu-Pi/PHB-PEG-NC) for better anticancer results against nasopharyngeal cancer (C666-1) cells. In the current study, nasopharyngeal cancer cell lines C666-1 were utilized to appraise the cytotoxic potential of Eug-Pip-PEG-NC on cell propagation, programmed cell death, and relocation. Eu-Pi/PHB-PEG-NC inhibits cellular proliferation on C666-1 cells in a dose-dependent manner, and when compared with 20 µg/ml, 15 µg/ml of loaded mixture evidently restrained the passage aptitude of C666-1 cells, this was attended with a downregulated expression of mitochondrial membrane potential. Treatment with 15 µg/ml Eu-Pi/PHB-PEG-NC suggestively amplified cell apoptosis in the C666-1 cells. Furthermore, its cleaved caspase-3, 8, and 9 and Bax gene expression was augmented and Bcl-2 gene expression was diminished after Eu-Pi/PHB-PEG-NC treatment. Additionally, our data established that the collective effect of Eu-Pi/PHB-PEG-NC loaded micelles inhibited the expansion of C666-1 cells augmented apoptosis connected with the intrusion of PI3K/Akt/mTOR signaling pathway.
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Alcaloides , Apoptosis/efectos de los fármacos , Benzodioxoles , Portadores de Fármacos , Eugenol , Nanocompuestos , Neoplasias Nasofaríngeas , Piperidinas , Alcamidas Poliinsaturadas , Transducción de Señal/efectos de los fármacos , Alcaloides/química , Alcaloides/farmacología , Benzodioxoles/química , Benzodioxoles/farmacología , Línea Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Elafina/metabolismo , Eugenol/química , Eugenol/farmacología , Humanos , Nanocompuestos/química , Nanocompuestos/uso terapéutico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Piperidinas/química , Piperidinas/farmacología , Polietilenglicoles/química , Polietilenglicoles/farmacología , Polihidroxialcanoatos/química , Polihidroxialcanoatos/farmacología , Alcamidas Poliinsaturadas/química , Alcamidas Poliinsaturadas/farmacología , Prohibitinas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Long non-coding RNA small nucleolar RNA host gene 7 (SNHG7) was reported to regulate the pathogenesis of ischemic stroke. The study aimed to disclose SNHG7 role in oxygen and glucose deprivation (OGD)-induced Neuro-2a (N2a) cell disorders. An OGD injury cell model was established using N2a cells. The expression of SNHG7, microRNA-134-5p (miR-134-5p) and fibroblast growth factor 9 (FGF9) was determined by quantitative real-time polymerase chain reaction. Protein expression was detected by western blot. Cell viability and Lactate Dehydrogenase (LDH) leakage were determined by cell counting kit-8 and LDH activity detection assays. Oxidative stress was investigated by Superoxide Dismutase and Catalase activity assays as well as Malondialdehyde and Reactive Oxygen Species detection kits. Cell apoptosis and caspase-3 activity were severally demonstrated by flow cytometry and caspase-3 activity assays. The interaction between miR-134-5p and SNHG7 or FGF9 was predicted by online databases, and identified by mechanism assays. OGD treatment decreased SNHG7 and FGF9 expression, but increased miR-134-5p expression. OGD treatment repressed cell viability, promoted LDH leakage and induced oxidative stress and apoptosis in N2a cells, which was rescued by SNHG7 overexpression. SNHG7 acted as a sponge for miR-134-5p, and regulated OGD-triggered cell damage by associating with miR-134-5p. Additionally, miR-134-5p depletion protected N2a cells from OGD-induced injury by targeting FGF9. Ectopic SNHG7 expression protected against OGD-induced neuronal cell injury by inducing FGF9 through sponging miR-134-5p, providing a novel therapeutic target for ischemic stroke.
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MicroARNs , ARN Largo no Codificante , Factor 9 de Crecimiento de Fibroblastos/metabolismo , Glucosa/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neuronas/metabolismo , Oxígeno/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Drought is a major abiotic stress that threatens global food security. Circular RNAs (circRNAs) are endogenous RNAs. How these molecules influence plant stress responses remains elusive. Here, a large-scale circRNA profiling identified 2174 and 1354 high-confidence circRNAs in maize and Arabidopsis, respectively, and most were differentially expressed in response to drought. A substantial number of drought-associated circRNA-hosting genes were involved in conserved or species-specific pathways in drought responses. Comparative analysis revealed that circRNA biogenesis was more complex in maize than in Arabidopsis. In most cases, maize circRNAs were negatively correlated with sRNA accumulation. In 368 maize inbred lines, the circRNA-hosting genes were enriched for single nucleotide polymorphisms (SNPs) associated with circRNA expression and drought tolerance, implying either important roles of circRNAs in maize drought responses or their potential use as biomarkers for breeding drought-tolerant maize. Additionally, the expression levels of circRNAs derived from drought-responsible genes encoding calcium-dependent protein kinase and cytokinin oxidase/dehydrogenase were significantly associated with drought tolerance of maize seedlings. Specifically, Arabidopsis plants overexpressing circGORK (Guard cell outward-rectifying K+ -channel) were hypersensitive to abscisic acid, but insensitive to drought, suggesting a positive role of circGORK in drought tolerance. We report the transcriptomic profiling and transgenic studies of circRNAs in plant drought responses, and provide evidence highlighting the universal molecular mechanisms involved in plant drought tolerance.
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Arabidopsis/metabolismo , ARN Circular/metabolismo , ARN de Planta/metabolismo , Estrés Fisiológico/fisiología , Zea mays/metabolismo , Aclimatación/genética , Aclimatación/fisiología , Arabidopsis/genética , Cruzamiento , Sequías , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Malondialdehído/metabolismo , Oxidorreductasas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/genética , Prolina/metabolismo , ARN Circular/genética , ARN de Planta/genética , Plantones , Análisis de Secuencia de ARN , Estrés Fisiológico/genética , Zea mays/genéticaRESUMEN
The thyroid hormone receptors (TRs) mediate thyroid hormone (T3 )-dependent gene expression. The nuclear import and export signals that direct TR shuttling are well characterized, but little is known about factors modulating nuclear retention. We used fluorescence-based nucleocytoplasmic scoring and fluorescence recovery after photobleaching in transfected cells to investigate whether Mediator subunits MED1 and MED13 play a role in nuclear retention of TR. When MED1 was overexpressed, there was a striking shift towards a greater nuclear localization of TRß1 and the oncoprotein v-ErbA, subtypes with cytosolic populations at steady-state, and TRß1 intranuclear mobility was reduced. For TRα1, there was no observable change in its predominantly nuclear distribution pattern or mobility. Consistent with a role for MED1 in nuclear retention, the cytosolic TRα1 and TRß1 population were significantly greater in MED1-/- cells, compared with MED1+/+ cells. Exposure to T3 and epidermal growth factor, which induces MED1 phosphorylation, also altered TR intranuclear dynamics. Overexpression of miR-208a, which downregulates MED13, led to a more cytosolic distribution of nuclear-localized TRα1; however, overexpression of MED13 had no effect on TRß1 localization. The known binding site of MED1 overlaps with a transactivation domain and nuclear export signal in helix 12 of TR's ligand-binding domain (LBD). Coimmunoprecipitation assays demonstrated that TR's LBD interacts directly with exportins 5 and 7, suggesting that binding of exportins and MED1 to TR may be mutually exclusive. Collectively, our data provide evidence that MED1 promotes nuclear retention of TR, and highlight the dual functionality of helix 12 in TR transactivation and nuclear export.
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Subunidad 1 del Complejo Mediador/metabolismo , Proteínas Oncogénicas v-erbA/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Transporte Activo de Núcleo Celular , Animales , Sitios de Unión , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Citosol/metabolismo , Fibroblastos/metabolismo , Expresión Génica , Genes erbA , Células HeLa , Humanos , Carioferinas/metabolismo , Complejo Mediador/metabolismo , Ratones , Fosforilación , Transporte de Proteínas , Receptores beta de Hormona Tiroidea/metabolismo , Hormonas Tiroideas/metabolismo , TransfecciónRESUMEN
Manipulating the collective molecular movements to implement macroscopic mechanical response of bulk material is attractive and challenging. Here, an organic-inorganic hybrid single crystal is synthesized, which exhibits a giant macroscopic shape transformation with a remarkable thermal hysteretic feature. The colossal anisotropic shape change, which manifests as an abrupt elongation of ca. 9 % along the crystallographic c-axis and a concomitant contraction of ca. 9 % in a perpendicular direction, is induced by a significant reorientation of imidazolium, accompanied with a substantial configurational variation in CuBr4 2- complex anions. The synergistic motions of both the molecular cations and anions engender a remarkable large thermal hysteresis (>30â K) in the shape transformation of the single crystal, implying that this material may play a role in alternating memory media. Furthermore, due to the stable crystal lattice, a single crystal that demonstrates naked-eye detectable large shape transformation was used as a thermal actuator to spontaneously control an electric circuit by temperature variation.
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BACKGROUND: Although incidence rates of postoperative neurocognitive disorder (PND) in aged individuals following noncardiac major surgery are rising as individuals are living longer, the mechanism of PND remains poorly understood. We wondered if mammalian target of rapamycin (mTOR) signaling might be associated with PND since mTOR controls some essential intracellular events. OBJECTIVE: To investigate whether surgery activates the mTOR signaling pathway in aged rats, leading to PND, and whether the mTOR inhibitor, rapamycin, can be used to alleviate PND. METHODS: We randomly assigned aged rats to four groups: normal control (C), isoflurane (I), surgery (S), and rapamycin (R). Then, we anesthetized Groups I, S, and R, following which, Groups S and R underwent a splenectomy. After surgery, Group R was administered rapamycin. We used the Morris water maze to test the rats' spatial learning and memory after surgery. RESULTS: In Group S, escape latency (ie, the time to find the platform) was markedly higher, and the ratio of swimming time in the target quadrant was lower, compared to the other groups. In Group R, escape latency was markedly lower as compared with Group S, and the ratio of swimming time in the target quadrant was higher. CONCLUSIONS: Our results indicate that an altered mTOR signaling pathway after a splenectomy causes PND in aged rats, which can be alleviated by rapamycin.
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Trastornos Neurocognitivos/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Factores de Edad , Animales , Humanos , Masculino , Trastornos Neurocognitivos/tratamiento farmacológico , Trastornos Neurocognitivos/etiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Sirolimus/farmacología , Esplenectomía/efectos adversos , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
As the core components of abscisic acid (ABA) signal pathway, Clade A PP2C (PP2C-A) phosphatases in ABA-dependent stress responses have been well studied in Arabidopsis. However, the roles and natural variations of maize PP2C-A in stress responses remain largely unknown. In this study, we investigated the expression patterns of ZmPP2C-As treated with multiple stresses and generated transgenic Arabidopsis plants overexpressing most of the ZmPP2C-A genes. The results showed that the expression of most ZmPP2C-As were dramatically induced by multiple stresses (drought, salt, and ABA), indicating that these genes may have important roles in response to these stresses. Compared with wild-type plants, ZmPP2C-A1, ZmPP2C-A2, and ZmPP2C-A6 overexpression plants had higher germination rates after ABA and NaCl treatments. ZmPP2C-A2 and ZmPP2C-A6 negatively regulated drought responses as the plants overexpressing these genes had lower survival rates, higher leaf water loss rates, and lower proline accumulation compared to wild type plants. The natural variations of ZmPP2C-As associated with drought tolerance were also analyzed and favorable alleles were detected. We widely studied the roles of ZmPP2C-A genes in stress responses and the natural variations detected in these genes have the potential to be used as molecular markers in genetic improvement of maize drought tolerance.