RESUMEN
Jasmonic acid (JA) and gibberellin (GA) coordinately regulate plant developmental programs and environmental cue responses. However, the fine regulatory network of the cross-interaction between JA and GA remains largely elusive. In this study, we demonstrate that MdNAC72 together with MdABI5 positively regulates anthocyanin biosynthesis through an exquisite MdNAC72-MdABI5-MdbHLH3 transcriptional cascade in apple. MdNAC72 interacts with MdABI5 to promote the transcriptional activation of MdABI5 on its target gene MdbHLH3 and directly activates the transcription of MdABI5. The MdNAC72-MdABI5 module regulates the integration of JA and GA signals in anthocyanin biosynthesis by combining with JA repressor MdJAZ2 and GA repressor MdRGL2a. MdJAZ2 disrupts the MdNAC72-MdABI5 interaction and attenuates the transcriptional activation of MdABI5 by MdNAC72. MdRGL2a sequesters MdJAZ2 from the MdJAZ2-MdNAC72 protein complex, leading to the release of MdNAC72. The E3 ubiquitin ligase MdSINA2 is responsive to JA and GA signals and promotes ubiquitination-dependent degradation of MdNAC72. The MdNAC72-MdABI5 interface fine-regulates the integration of JA and GA signals at the transcriptional and posttranslational levels by combining MdJAZ2, MdRGL2a, and MdSINA2. In summary, our findings elucidate the fine regulatory network connecting JA and GA signals with MdNAC72-MdABI5 as the core in apple.
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Ciclopentanos , Regulación de la Expresión Génica de las Plantas , Giberelinas , Malus , Oxilipinas , Proteínas de Plantas , Transducción de Señal , Ubiquitinación , Oxilipinas/metabolismo , Malus/genética , Malus/metabolismo , Ciclopentanos/metabolismo , Ubiquitinación/efectos de los fármacos , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Giberelinas/metabolismo , Proteolisis/efectos de los fármacos , Antocianinas/metabolismo , Unión Proteica/efectos de los fármacos , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Modelos BiológicosRESUMEN
Background: Diffusion magnetic resonance imaging (dMRI) has revealed microstructural changes in white matter (WM) in Huntington's disease (HD). Objective: To compare the validities of different dMRI, i.e., diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) in HD. Methods: 22 mutant huntingtin (mHTT) carriers and 14 controls were enrolled. Clinical assessments and dMRI were conducted. Based on CAG-Age Product (CAP) score, mHTT carriers were categorized into high CAP (hCAP) and medium and low CAP (m& lCAP) groups. Spearman analyses were used to explore correlations between imaging parameters in brain regions and clinical assessments. Receiver operating characteristic (ROC) was used to distinguish mHTT carriers from control, and define the HD patients at advanced stage. Results: Compared to controls, mHTT carriers exhibited WM changes in DKI and DTI. There were 22 more regions showing significant differences in HD detected by MK than FA. Only MK in five brain regions showed significantly difference between any two group, and negatively correlated with the disease burden (râ=â-0.80 to -0.71). ROC analysis revealed that MK was more sensitive and FA was more specific, while Youden index showed that the integration of FA and MK gave rise to higher authenticities, in distinguishing m& lCAP from controls (Youden Indexâ=â0.786), and discerning different phase of HD (Youden Indexâ=â0.804). Conclusions: Microstructural changes in WM occur at early stage of HD and deteriorate over the disease progression. Integrating DKI and DTI would provide the best accuracies for differentiating early HD from control and identifying advanced HD.
RESUMEN
In the present study, six new compounds namely, picralactones CH (1-6) along with nine known compounds (7-15) were isolated from the branches and leaves of Picrasma chinese P.Y. Chen. Their structures were determined with the help of spectroscopic techniques such as NMR, HR-ESI-MS, UV, IR and CD. Cytotoxicity of all compounds was evaluated against MDA-MB-231, SW-620 and HepG2 human cancer cell lines. Compound 4 showed cytotoxic activities.
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Antineoplásicos Fitogénicos , Picrasma , Hojas de la Planta , Cuassinas , Humanos , Estructura Molecular , Picrasma/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Hojas de la Planta/química , Línea Celular Tumoral , Cuassinas/farmacología , Cuassinas/aislamiento & purificación , Cuassinas/química , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Tallos de la Planta/química , Pueblos del Este de AsiaRESUMEN
Auxin/indole-3-acetic acid (AUX/IAA) and auxin response factor (ARF) proteins are important components of the auxin signalling pathway, but their ubiquitination modification and the mechanism of auxin-mediated anthocyanin biosynthesis remain elusive. Here, the ARF MdARF5-1 was identified as a negative regulator of anthocyanin biosynthesis in apple, and it integrates auxin and ethylene signals by inhibiting the expression of the ethylene response factor MdERF3. The auxin repressor MdIAA29 decreased the inhibitory effect of MdARF5-1 on anthocyanin biosynthesis by attenuating the transcriptional inhibition of MdERF3 by MdARF5-1. In addition, the E3 ubiquitin ligases MdSINA4 and MdSINA11 played negative and positive regulatory roles in anthocyanin biosynthesis by targeting MdIAA29 and MdARF5-1 for ubiquitination degradation, respectively. MdSINA4 destabilized MdSINA11 to regulate anthocyanin accumulation in response to auxin signalling. In sum, our data revealed the crosstalk between auxin and ethylene signals mediated by the IAA29-ARF5-1-ERF3 module and provide new insights into the ubiquitination modification of the auxin signalling pathway.
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Malus , Ubiquitina-Proteína Ligasas , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Malus/genética , Malus/metabolismo , Antocianinas , Ácidos Indolacéticos/metabolismo , Etilenos , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
The abnormal activation of the mTOR pathway is closely related to the occurrence and progression of cancer, especially colorectal cancer. In this study, a rational virtual screening strategy has been established and MT-5, a novel mTOR inhibitor with a quinoline scaffold, was obtained from the ChemDiv database. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 µM) and antiproliferative effects against various cancer cell lines, especially HCT-116 cells (IC50: 4.61 µM), and this was 2.2-fold more potent than that of the cisplatin control (IC50: 9.99 µM). Western blot, cell migration, cycle arrest, and apoptosis assays were performed with HCT-116 cells to investigate the potential anticancer mechanism of MT-5. Metabolic stability results in vitro indicated that MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, rat plasma, and liver microsomes. In addition, the key contribution of the residues around the binding pocket of MT-5 in binding to the mTOR protein was also investigated from a computational perspective.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Animales , Ratas , Inhibidores mTOR , Serina-Treonina Quinasas TOR , Células HCT116 , Neoplasias Colorrectales/tratamiento farmacológicoRESUMEN
BACKGROUND: Mechanical ventilation is applied to unload the respiratory muscles, but knowledge about transpulmonary driving pressure (ΔPL) is important to minimize lung injury. We propose a method to estimate ΔPL during neurally synchronized assisted ventilation, with a simple intervention of lowering the assist for one breath ("lower assist maneuver", LAM). METHODS: In 24 rabbits breathing spontaneously with imposed loads, titrations of increasing assist were performed, with two neurally synchronized modes: neurally adjusted ventilatory assist (NAVA) and neurally triggered pressure support (NPS). Two single LAM breaths (not sequentially, but independently) were performed at each level of assist by acutely setting the assist to zero cm H2O (NPS) or NAVA level 0 cm H2O/uV (NAVA) for one breath. NPS and NAVA titrations were followed by titrations in controlled-modes (volume control, VC and pressure control, PC), under neuro-muscular blockade. Breaths from the NAVA/NPS titrations were matched (for flow and volume) to VC or PC. Throughout all runs, we measured diaphragm electrical activity (Edi) and esophageal pressure (PES). We measured ΔPL during the spontaneous modes (PL_PES) and controlled mechanical ventilation (CMV) modes (PL_CMV) with the esophageal balloon. From the LAMs, we derived an estimation of ΔPL ("PL_LAM") using a correction factor (ratio of volume during the LAM and volume during assist) and compared it to measured ΔPL during passive (VC or PC) and spontaneous breathing (NAVA or NPS). A requirement for the LAM was similar Edi to the assisted breath. RESULTS: All animals successfully underwent titrations and LAMs for NPS/NAVA. One thousand seven-hundred ninety-two (1792) breaths were matched to passive ventilation titrations (matched Vt, r = 0.99). PL_LAM demonstrated strong correlation with PL_CMV (r = 0.83), and PL_PES (r = 0.77). Bland-Altman analysis revealed little difference between the predicted PL_LAM and measured PL_CMV (Bias = 0.49 cm H2O and 1.96SD = 3.09 cm H2O). For PL_PES, the bias was 2.2 cm H2O and 1.96SD was 3.4 cm H2O. Analysis of Edi and PES at peak Edi showed progressively increasing uncoupling with increasing assist. CONCLUSION: During synchronized mechanical ventilation, a LAM breath allows for estimations of transpulmonary driving pressure, without measuring PES, and follows a mathematical transfer function to describe respiratory muscle unloading during synchronized assist.
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Infecciones por Citomegalovirus , Soporte Ventilatorio Interactivo , Animales , Conejos , Respiración Artificial , Respiración con Presión Positiva , RespiraciónRESUMEN
The dysregulation of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been implicated in various human cancers, and isoform-selective inhibitors targeting PI3Kα have received significant interest in recent years. In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a). A detailed structure-activity relationship (SAR) study has identified the optimal compound 18a bearing a quinoxaline scaffold. Compared to the control 8a, 18a exhibited 4.4-fold more potent inhibitory activity against PI3Kα (IC50: 2.5 vs 11 nM) and better isoform-selective profiles over other PI3Ks. In addition, 18a showed a 1.5-fold more potent antiproliferative effect against HCT-116 cell lines (IC50: 3.79 vs 5.80 µM) and a better selectivity over the normal tissue cells. The potential antitumor mechanism and in vitro metabolic stability of 18a were also investigated. Notably, pharmacokinetic assays indicated that 18a had a higher plasma exposure, a higher maximum concentration and shorter elimination time compared to 8a.
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Neoplasias Colorrectales , Fosfatidilinositol 3-Quinasas , Humanos , Células HCT116 , Quinoxalinas/farmacología , Transducción de Señal , Neoplasias Colorrectales/tratamiento farmacológicoRESUMEN
PHR1 (PHOSPHATE STARVATION RESPONSE1) plays key roles in the inorganic phosphate (Pi) starvation response and in Pi deficiency-induced anthocyanin biosynthesis in plants. However, the post-translational regulation of PHR1 is unclear, and the molecular basis of PHR1-mediated anthocyanin biosynthesis remains elusive. In this study, we determined that MdPHR1 was essential for Pi deficiency-induced anthocyanin accumulation in apple (Malus × domestica). MdPHR1 interacted with MdWRKY75, a positive regulator of anthocyanin biosynthesis, to enhance the MdWRKY75-activated transcription of MdMYB1, leading to anthocyanin accumulation. In addition, the E3 ubiquitin ligase SEVEN IN ABSENTIA1 (MdSINA1) negatively regulated MdPHR1-promoted anthocyanin biosynthesis via the ubiquitination-mediated degradation of MdPHR1. Moreover, the protein kinase apple BRASSINOSTEROID INSENSITIVE2 (MdBIN2) phosphorylated MdPHR1 and positively regulated MdPHR1-mediated anthocyanin accumulation by attenuating the MdSINA1-mediated ubiquitination degradation of MdPHR1. Taken together, these findings not only demonstrate the regulatory role of MdPHR1 in Pi starvation induced anthocyanin accumulation, but also provide an insight into the post-translational regulation of PHR1.
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Malus , Malus/genética , Malus/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Antocianinas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ubiquitinación , Regulación de la Expresión Génica de las PlantasRESUMEN
Although DELLA protein destabilization mediated by post-translational modifications is essential for gibberellin (GA) signal transduction and GA-regulated anthocyanin biosynthesis, the related mechanisms remain largely unknown. In this study, we report the ubiquitination and phosphorylation of an apple DELLA protein MdRGL2a in response to GA signaling and its regulatory role in anthocyanin biosynthesis. MdRGL2a could interact with MdWRKY75 to enhance the MdWRKY75-activated transcription of anthocyanin activator MdMYB1 and interfere with the interaction between anthocyanin repressor MdMYB308 and MdbHLH3 or MdbHLH33, thereby promoting anthocyanin accumulation. A protein kinase MdCIPK20 was found to phosphorylate and protect MdRGL2a from degradation, and it was essential for MdRGL2a-promoting anthocyanin accumulation. However, MdRGL2a and MdCIPK20 were ubiquitinated and degraded by E3 ubiquitin ligases MdSINA1 and MdSINA2, respectively, both of which were activated in the presence of GA. Our results display the integration of SINA1/2 with CIPK20 to dynamically regulate GA signaling and will be helpful toward understanding the mechanism of GA signal transduction and GA-inhibited anthocyanin biosynthesis. The discovery of extensive interactions between DELLA and SINA and CIPK proteins in apple will provide reference for the study of ubiquitination and phosphorylation of DELLA proteins in other species.
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Arabidopsis , Malus , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Antocianinas/metabolismo , Arabidopsis/metabolismo , Proteínas Quinasas/metabolismo , Ubiquitinación , Malus/genética , Malus/metabolismo , Giberelinas/metabolismo , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
As a native honeybee species in East Asia, Apis cerana is essential for the stability of local agricultural and plant ecosystems by its' olfactory system for searching nectar and pollen sources. Odorant-binding proteins (OBPs) existing in the insect's olfactory system can recognize environmental semiochemicals. It was known that sublethal doses of neonicotinoid insecticides could still cause a variety of physiological and behavioral abnormalities in bees. However, the molecular mechanism of A. cerana sensing and response for insecticide has not been further investigated. In this study, we found an A. cerana OBP17 gene significantly up-regulated expressed after exposure to sublethal doses of imidacloprid based on the transcriptomics results. The spatiotemporal expression profiles showed that OBP17 was highly expressed in the legs. Competitive fluorescence binding assays showed that OBP17 had the special and high binding affinity to imidacloprid among the 24 candidate semiochemicals, and the KA value of OBP17 binding with imidacloprid reached the maximum (6.94 × 104 L/mol) at low-temperature. Thermodynamic analysis showed that the quenching mechanism changed from dynamic to static binding interaction with the increasing temperature. Meanwhile, the force changed from hydrogen bond and van der Waals force to hydrophobic interaction and electrostatic force, indicating the interaction exhibits variability and flexibility. Molecular docking showed that Phe107 contributed the most energy. RNA interference (RNAi) results showed that OBP17 knockdown significantly enhanced the electrophysiological response of the bees' forelegs to imidacloprid. Our study indicated that OBP17 could precisely touch and sense sublethal doses of neonicotinoid imidacloprid in the natural environment through its high expression in legs, and the upregulation expression of OBP17 exposure to imidacloprid probably implied that it participate in the detoxification processes of A. cerana. Also, our research enriches the theoretical knowledge of the sensing and detoxifying activities of non-target insects' olfactory sensory system to environmental sublethal doses of systemic insecticides.
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Insecticidas , Abejas , Animales , Insecticidas/toxicidad , Insecticidas/química , Simulación del Acoplamiento Molecular , Ecosistema , Neonicotinoides/toxicidad , Nitrocompuestos/toxicidad , Feromonas/metabolismoRESUMEN
Recently, the good physical and chemical properties, well-defined pore architectures, and designable topologies have made microporous organic networks (MONs) excellent potential candidates in high-performance liquid chromatography (HPLC). However, their superior hydrophobic structures restrict their application in the reversed-phase mode. To solve this obstacle and to expand the application of MONs in HPLC, we realized the thiol-yne "click" postsynthesis of a novel hydrophilic MON-2COOH@SiO2-MER (MER denotes mercaptosuccinic acid) microsphere for reversed-phase/hydrophilic interaction mixed-mode chromatography. SiO2 was initially decorated with MON-2COOH using 2,5-dibromoterephthalic acid and tetrakis(4-ethynylphenyl)methane as monomers, and MER was then grafted via thiol-yne click reaction to yield MON-2COOH@SiO2-MER microspheres (5 µm) with a pore size of ~1.3 nm. The -COOH groups in 2,5-dibromoterephthalic acid and the post-modified MER molecules considerably improved the hydrophilicity of pristine MON and enhanced the hydrophilic interactions between the stationary phase and analytes. The retention mechanisms of the MON-2COOH@SiO2-MER packed column were fully discussed with diverse hydrophobic and hydrophilic probes. Benefiting from the numerous -COOH recognition sites and benzene rings within MON-2COOH@SiO2-MER, the packed column exhibited good resolution for the separation of sulfonamides, deoxynucleosides, alkaloids, and endocrine-disrupting chemicals. A column efficiency of 27,556 plates per meter was obtained for the separation of gastrodin. The separation performance of the MON-2COOH@SiO2-MER packed column was also demonstrated by comparing with those of MON-2COOH@SiO2, commercial C18, ZIC-HILIC, and bare SiO2 columns. This work highlights the good potential of the thiol-yne click postsynthesis strategy to construct MON-based stationary phases for mixed-mode chromatography.
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Alcaloides , Dióxido de Silicio , Dióxido de Silicio/química , Cromatografía Líquida de Alta Presión/métodos , Alcaloides/análisis , Interacciones Hidrofóbicas e Hidrofílicas , Compuestos de Sulfhidrilo , Cromatografía de Fase Inversa/métodosRESUMEN
BACKGROUND: Ineffective effort (IE) is a frequent patient-ventilator asynchrony in invasive mechanical ventilation. This study aimed to investigate the incidence of IE and to explore its relationship with respiratory drive in subjects with acute brain injury undergoing invasive mechanical ventilation. METHODS: We retrospectively analyzed a clinical database that assessed patient-ventilator asynchrony in subjects with acute brain injury. IE was identified based on airway pressure, flow, and esophageal pressure waveforms collected at 15-min intervals 4 times daily. At the end of each data set recording, airway-occlusion pressure (P0.1) was determined by the airway occlusion test. IE index was calculated to indicate the severity of IE. The incidence of IE in different types of brain injuries as well as its relationship with P0.1 was determined. RESULTS: We analyzed 852 data sets of 71 subjects with P0.1 measured and undergoing mechanical ventilation for at least 3 d after enrollment. IE was detected in 688 (80.8%) data sets, with a median index of 2.2% (interquartile range 0.4-13.1). Severe IE (IE index ≥ 10%) was detected in 246 (28.9%) data sets. The post craniotomy for brain tumor and the stroke groups had higher median IE index and lower P0.1 compared with the traumatic brain injury group (2.6% [0.7-9.7] vs 2.7% [0.3-21] vs 1.2% [0.1-8.5], P = .002; 1.4 [1-2] cm H2O vs 1.5 [1-2.2] cm H2O vs 1.8 [1.1-2.8] cm H2O, P = .001). Low respiratory drive (P0.1 < 1.14 cm H2O) was independently associated with severe IE in the expiratory phase (IEE) even after adjusting for confounding factors by logistic regression analysis (odds ratio 5.18 [95% CI 2.69-10], P < .001). CONCLUSIONS: IE was very common in subjects with acute brain injury. Low respiratory drive was independently associated with severe IEE.
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Lesiones Encefálicas , Respiración Artificial , Humanos , Estudios Retrospectivos , Ventiladores Mecánicos , EspiraciónRESUMEN
Eastern honeybee Apis cerana has important ecological value for the cold flowering loquat flower pollination in early winter in East Asia. However, the low-temperature adaptive pollination mechanism has not yet been revealed. One odorant-binding protein, OBP2, had been found that could bind to some plant volatiles with strong affinity before. In this study, by using competitive fluorescence binding assay, we first measured the ligand-binding profiles of recombinant OBP2 protein with nine representative aroma chemical substances from loquat flowers. Thermodynamic results showed that three loquat volatiles, 4-Methoxybenzaldehyde, (E)-Ethyl cinnamate, and Methyl cinnamate, have the strongest binding affinity with OBP2 with the static process. And interestingly their binding affinity significantly increased at low temperature (285 K/12 °C) compared to high temperature (298 K/25 °C). In addition, site-directed mutagenesis results showed that Met55 and Lys51 may be the key amino acid sites in the electrostatic and hydrophobic interactions of OBP2 interacting with Methyl cinnamate, respectively. This study suggests that OBP2 is functionally similar and universal in binding to different flower volatiles at low temperatures. Our studies interpreted a novel olfactory mechanism of A. cerana sensing loquat floral volatiles in cold early winter, and enrich a theoretical molecular basis for the temperature-adaptive ecological mechanism of insects' pollination.
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Eriobotrya , Magnoliopsida , Receptores Odorantes , Abejas , Animales , Magnoliopsida/metabolismo , Receptores Odorantes/química , Proteínas RecombinantesRESUMEN
The AP2/ERF family is an important class of transcription factors involved in plant growth and various biological processes. One of the AP2/ERF transcription factors, RAP2.6L, participates in various stresses responses. However, the function of RAP2.6L is largely unknown in apples (Malus domestica). In this study, an apple gene homologous to Arabidopsis AtRAP2.6L, MdERF113, was analyzed by bioinformatic characterization, gene expression analysis and subcellular localization assessment. MdERF113 was highly expressed in the sarcocarp and was responsive to hormonal signals and abiotic stresses. MdERF113-overexpression apple calli were less sensitive to low temperature, drought, salinity, and abscisic acid than wild-type. Subcellular localization revealed that MdERF113 was a nuclear-localized transcription factor, and yeast experiments confirmed that MdERF113 has no autonomous activation activity. Overall, this study indicated that MdERF113 plays a role in regulating plant growth under abiotic conditions.
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Proteínas de Arabidopsis , Arabidopsis , Malus , Malus/metabolismo , Plantas Modificadas Genéticamente/metabolismo , Factores de Transcripción/metabolismo , Arabidopsis/metabolismo , Ácido Abscísico/metabolismo , Estrés Fisiológico/genética , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/metabolismo , Filogenia , Sequías , Proteínas de Arabidopsis/metabolismoRESUMEN
Nitrogen (N) is an essential element that plays an important role in crop biomass accumulation and quality formation. Increased crop yield is relied on excessive application of fertilizers, which usually leads to environmental pollution and unsustainable development. Thus, identification and characterization of genes involved in promoting nitrogen use efficiency is of high priority in crop breeding. The activity of nitrate reductase (NR) plays a critical role in nitrogen metabolism. In model plant Arabidopsis, NITRATE REDUCTASE 2 (NIA2), one of the two NRs, is responsible for about 90% of the NR activity. In this study, MdNIA2 gene in apple (Malus domestica) genome was screened out and identified by using AtNIA2 as bait. Phylogenetic analysis revealed that MdNIA2 had the closest evolutionary relationship with MbNIA from Malus baccata. Ectopic expression of MdNIA2 in Arabidopsis elevated the nitrogen use efficiency and increased root hair elongation and formation, resulting in promoted plant growth. Furthermore, the overexpression of MdNIA2 improved salt and drought tolerance in transgenic Arabidopsis and improved the salt tolerance of transgenic apple callus, and MdNIA2-reagualted NO metabolism might contribute to the abiotic stress tolerance. Overall, our data indicate the critical role of MdNIA2 in regulating nitrogen utilization efficiency and abiotic stress responses.
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Arabidopsis , Malus , Arabidopsis/metabolismo , Malus/metabolismo , Nitrato-Reductasa/genética , Nitrato-Reductasa/metabolismo , Nitratos/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Filogenia , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/metabolismo , Fitomejoramiento , Estrés Fisiológico/genética , Nitrógeno/metabolismo , Regulación de la Expresión Génica de las PlantasRESUMEN
BACKGROUND: A sealed abdominal interface was positioned below the diaphragm (the "NeoVest") to apply synchronized and proportional negative pressure ventilation (NPV) and was compared to positive pressure ventilation (PPV) using neurally adjusted ventilatory assist (NAVA). Both modes were controlled by the diaphragm electrical activity (Edi). METHODS: Eleven rabbits (mean weight 2.9 kg) were instrumented, tracheotomized, and ventilated with either NPV or PPV (sequentially) with different loads (resistive, dead space, acute lung injury). Assist with either PPV or NPV was titrated to reduce Edi by 50%. RESULTS: In order to achieve a 50% reduction in Edi, NPV required slightly more negative pressure (-8 to -12 cm H2O) than observed in PPV (+6 to +10 cm H2O). The efficiency of pressure transmission from the NeoVest into gastric pressure was 69.6% (range 61.3-77.4%). Swings in esophageal pressure were more negative during NPV than PPV, for all conditions, due to transmission of negative pressure. Transpulmonary pressure was lower during NPV. Transdiaphragmatic pressure swings were reduced similarly for PPV and NPV, suggesting equivalent unloading of the diaphragm. NPV did not affect hemodynamics. CONCLUSIONS: It is feasible to apply NPV sub-diaphragmatically in synchrony and in proportion to Edi in an animal model of respiratory distress. IMPACT: Negative pressure ventilation (NPV), for example, the "Iron Lung," may offer advantages over positive pressure ventilation. In the present work, we describe the "NeoVest," a system consisting of a sealed abdominal interface and a ventilator that applies NPV in synchrony and in proportion to the diaphragm electrical activity (Edi).
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Soporte Ventilatorio Interactivo , Síndrome de Dificultad Respiratoria , Animales , Conejos , Respiración Artificial , Diafragma , Respiración con Presión Positiva , Modelos AnimalesRESUMEN
Two new compounds verboncin A (1) and verboncin B (4) and 14 known compounds (2-3 and 5-16) were isolated from Verbena bonariensis, and these 14 compounds were first obtained from this plant. Their chemical structures were established by one and two-dimensional NMR and HRESIMS analysis and the results were compared with literature values. The absolute configuration of 1 was determined by calculating electronic circular dichroism (ECD). The cytotoxicity of some of the compounds against MCF-7, HCT-116, MDA-MB-231, and SW620 human cancer cell lines were evaluated, in which compound 4 showed negligible cytotoxic activity with an IC50 value of 68.08 ± 0.35 µM against the MCF-7 cell line.
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Verbena , Verbena/química , Humanos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Modelos MolecularesRESUMEN
Objective To forecast the future burden and its attributable risk factors of infective endocarditis (IE). Method We analyzed the disease burden of IE and its risk factors from 1990 to 2019 using the Global Burden of Disease 2019 database and projected the disease burden from 2020 to 2030 using a Bayesian age-period-cohort model. Results By 2030, the incidence of IE will increase uncontrollably on a global scale, with developed countries having the largest number of cases and developing countries experiencing the fastest growth. The affected population will be predominantly males, but the gender gap will narrow. The elderly in high-income countries will bear the greatest burden, with a gradual shift to middle-income countries. The incidence of IE in countries with middle/high-middle social-demographic indicators (SDI) will surpass that of high SDI countries. In China, the incidence rate and the number of IE will reach 18.07 per 100,000 and 451,596 in 2030, respectively. IE-associated deaths and heart failure will continue to impose a significant burden on society, the burden on women will increase and surpass that on men, and the elderly in high-SDI countries will bear the heaviest burden. High systolic blood pressure has become the primary risk factor for IE-related death. Conclusions This study provides comprehensive analyses of the disease burden and risk factors of IE worldwide over the next decade. The IE-associated incidence will increase in the future and the death and heart failure burden will not be appropriately controlled. Gender, age, regional, and country heterogeneity should be taken seriously to facilitate in making effective strategies for lowering the IE disease burden.
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Endocarditis , Insuficiencia Cardíaca , Masculino , Humanos , Femenino , Anciano , Carga Global de Enfermedades , Teorema de Bayes , Salud Global , Factores de Riesgo , Costo de EnfermedadRESUMEN
INTRODUCTION: Spontaneous hyperventilation (SHV) is common in aneurysmal subarachnoid haemorrhage (aSAH). The reduction in arterial partial pressure of carbon dioxide (PaCO2) may change the brain physiology, such as haemodynamics, oxygenation, metabolism and may lead to secondary brain injury. However, how to correct SHV safely and effectively in patients with aSAH has not been well investigated. The aim of this study is to investigate the efficacy and safety of remifentanil dose titration to correct hyperventilation in aSAH, as well as the effect of changes in PaCO2 on cerebral blood flow (CBF). METHODS AND ANALYSIS: This study is a prospective, single-centre, physiological study in patients with aSAH. The patients who were mechanically ventilated and who meet with SHV (tachypnoea combined with PaCO2 <35 mm Hg and pH >7.45) will be enrolled. The remifentanil will be titrated to correct the SHV. The predetermined initial dose of remifentanil is 0.02 µg/kg/min and will be maintained for 30 min, and PaCO2 and CBF will be measured. After that, the dose of remifentanil will be sequentially increased to 0.04, 0.06, and 0.08 µg/kg/min, and the measurements for PaCO2 and CBF will be repeated 30 min after each dose adjustment and will be compared with their baseline values. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University (KY 2021-006-02) and has been registered at ClinicalTrials.gov. The results of this study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04940273.