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Stomata in leaves regulate gas (carbon dioxide and water vapor) exchange and water transpiration between plants and the atmosphere. SLow Anion Channel 1 (SLAC1) mediates anion efflux from guard cells and plays a crucial role in controlling stomatal aperture. It serves as a central hub for multiple signaling pathways in response to environmental stimuli, with its activity regulated through phosphorylation via various plant protein kinases. However, the molecular mechanism underlying SLAC1 phosphoactivation has remained elusive. Through a combination of protein sequence analyses, AlphaFold-based modeling and electrophysiological studies, we unveiled that the highly conserved motifs on the N- and C-terminal segments of SLAC1 form a cytosolic regulatory domain (CRD) that interacts with the transmembrane domain(TMD), thereby maintaining the channel in an autoinhibited state. Mutations in these conserved motifs destabilize the CRD, releasing autoinhibition in SLAC1 and enabling its transition into an activated state. Our further studies demonstrated that SLAC1 activation undergoes an autoinhibition-release process and subsequent structural changes in the pore helices. These findings provide mechanistic insights into the activation mechanism of SLAC1 and shed light on understanding how SLAC1 controls stomatal closure in response to environmental stimuli.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Estômatos de Plantas , Transdução de Sinais , Fosforilação , Estômatos de Plantas/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Domínios Proteicos , MutaçãoRESUMO
OBJECTIVE: As the predominant complication in preterm infants, Bronchopulmonary Dysplasia (BPD) necessitates accurate identification of infants at risk and expedited therapeutic interventions for an improved prognosis. This study evaluates the potential of Monosaccharide Composite (MC) enriched with environmental information from circulating glycans as a diagnostic biomarker for early-onset BPD, and, concurrently, appraises BPD risk in premature neonates. MATERIALS AND METHODS: The study incorporated 234 neonates of ≤32 weeks gestational age. Clinical data and serum samples, collected one week post-birth, were meticulously assessed. The quantification of serum-free monosaccharides and their degraded counterparts was accomplished via High-performance Liquid Chromatography (HPLC). Logistic regression analysis facilitated the construction of models for early BPD diagnosis. The diagnostic potential of various monosaccharides for BPD was determined using Receiver Operating Characteristic (ROC) curves, integrating clinical data for enhanced diagnostic precision, and evaluated by the Area Under the Curve (AUC). RESULTS: Among the 234 neonates deemed eligible, BPD development was noted in 68 (29.06%), with 70.59% mild (48/68) and 29.41% moderate-severe (20/68) cases. Multivariate analysis delineated several significant risk factors for BPD, including gestational age, birth weight, duration of both invasive mechanical and non-invasive ventilation, Patent Ductus Arteriosus (PDA), pregnancy-induced hypertension, and concentrations of two free monosaccharides (Glc-F and Man-F) and five degraded monosaccharides (Fuc-D, GalN-D, Glc-D, and Man-D). Notably, the concentrations of Glc-D and Fuc-D in the moderate-to-severe BPD group were significantly diminished relative to the mild BPD group. A potent predictive capability for BPD development was exhibited by the conjunction of gestational age and Fuc-D, with an AUC of 0.96. CONCLUSION: A predictive model harnessing the power of gestational age and Fuc-D demonstrates promising efficacy in foretelling BPD development with high sensitivity (95.0%) and specificity (94.81%), potentially enabling timely intervention and improved neonatal outcomes.
Assuntos
Displasia Broncopulmonar , Recém-Nascido Prematuro , Lactente , Masculino , Feminino , Gravidez , Recém-Nascido , Humanos , Idade Gestacional , Displasia Broncopulmonar/complicações , Fucose , MonossacarídeosRESUMO
Human exposure to microplastics (MPs) continues to occur due to ingestion of contaminated food, water and air. Intake of MPs can pose potential health risks by interfering with the production and circulation of nutrients, leading to physiological stress (such as immune responses and metabolic abnormalities). Toxicity data of MPs based on healthy individuals may not be applicable to large populations of patients with chronic diseases represented by diabetes. Therefore, in this study, the response of diabetic mice was compared with that of healthy mice after exposure to polystyrene microplastics (PS-MPs), and interesting differences were observed. PS-MPs exposure significantly increased liver tissue damage, abnormal lipid metabolism, inflammatory effect, liver metabolic disorder and changes of intestinal microbial composition in diabetic mice. Moreover, PS-MPs overstated abnormal lipid metabolism in diabetic mice. The difference between the increased inflammation after exposure to PS-MPs in healthy and diabetic mice involves that the former is mainly modulated by gut microbes, while diabetic mice seem to be more susceptible to lipid metabolism disturbances. In addition, the size effect of MPs was also observed in diabetic mice. These results suggested that individuals with chronic diseases may be more sensitive to pollution due to altered homeostasis, and therefore disease status should be fully considered when assessing the health risk of pollutants.
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Diabetes Mellitus Experimental , Poluentes Ambientais , Poluentes Químicos da Água , Animais , Inflamação/induzido quimicamente , Metabolismo dos Lipídeos , Camundongos , Microplásticos/toxicidade , Plásticos/metabolismo , Poliestirenos/metabolismo , Poliestirenos/toxicidade , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidadeRESUMO
BACKGROUND: Abscisic acid (ABA) plays an important role in plant growth and adaptation through the ABA signaling pathway. The ABA-responsive element binding (AREB/ABF) family transcriptional factors are central regulators that integrate ABA signaling with various signaling pathways. It has long been known that ABA inhibits rhizobial infection and nodule formation in legumes, but the underlying molecular mechanisms remain elusive. RESULTS: Here, we show that nodulation is very sensitive to ABA and exogenous ABA dramatically inhibits rhizobial infection and nodule formation in soybean. In addition, we proved that GmbZIP1, an AREB/ABF transcription factor, is a major regulator in both nodulation and plant response to ABA in soybean. GmbZIP1 was specifically expressed during nodule formation and development. Overexpression of GmbZIP1 resulted in reduced rhizobial infection and decreased nodule number. Furthermore, GmbZIP1 is responsive to ABA, and ectopic overexpression of GmbZIP1 increased sensitivity of Arabidopsis plants to ABA during seed germination and postgerminative growth, and conferred enhanced drought tolerance of plants. Remarkably, we found that GmbZIP1 directly binds to the promoter of GmENOD40-1, a marker gene for nodule formation, to repress its expression. CONCLUSION: Our results identified GmbZIP1 as a node regulator that integrates ABA signaling with nodulation signaling to negatively regulate nodule formation.
Assuntos
Ácido Abscísico/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Glycine max/crescimento & desenvolvimento , Glycine max/genética , Desenvolvimento Vegetal/efeitos dos fármacos , Nodulação/efeitos dos fármacos , Rhizobium , Plantas Geneticamente Modificadas , Transdução de Sinais/efeitos dos fármacos , Fatores de TranscriçãoRESUMO
A focused SAR study was conducted on a series of N1-substituted pyrazolopyrimidinone PDE2 inhibitors to reveal compounds with excellent potency and selectivity. The series was derived from previously identified internal leads and designed to enhance steric interactions with key amino acids in the PDE2 binding pocket. Compound 26 was identified as a lead compound with excellent PDE2 selectivity and good physicochemical properties.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Fosfodiesterase/farmacologia , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Pirazóis/síntese química , Pirazóis/química , Pirimidinonas/síntese química , Pirimidinonas/química , Relação Estrutura-AtividadeRESUMO
The kinetic data of cyclopentadiene C5H6 oxidation reactions are significant for the construction of aromatics oxidation mechanism because cyclopentadiene C5H6 has been proved to be an important intermediate in the aromatics combustion. Kinetics for the elementary reactions on the potential energy surface (PES) relevant for the C5H6 + HO2 reaction are studied in this work. Stationary points on the PES are calculated by employing the CCSD(T)/cc-pVTZ//B3LYP/6-311G(d,p) level of theory. High-pressure limit and pressure-dependent rate constants for elementary reactions on this PES are calculated using conventional transition state theory (TST), variational transition-state theory (VTST) and Rice-Ramsberger-Kassel-Marcus/master equation (RRKM/ME) theory. In this work, the reaction channels for the C5H6 + HO2 reaction, which include H-abstraction channels from C5H6 by HO2 to form the C5H5 + H2O2 and the addition channels through well-skipping pathways to form the bimolecular products C5H7 + O2 or C5H6O + OH, or through C5H7O2 stabilization and its unimolecular decomposition to form the bimolecular products C5H7 + O2 or C5H6O + OH, namely sequential pathways, are studied. Also, the consuming reaction channels for the compounds C5H6O and C5H7 in the addition products are studied. The dominant reaction channels for these reactions are unraveled through comparing the energy barriers and rate constants of all elementary reactions and it is found: (1) HO2 addition to cyclopentadiene C5H6 is more important than direct H-abstraction. (2) in the HO2 addition channels, the well-skipping pathways and sequential pathways are competing and the well-skipping pathways will be favor in the higher pressures and the sequential pathways will be favor in the higher temperature. (3) The major consumption reaction channel for the five-member-ring compound C5H6O is the reaction channel to form C4H6 + CO and the major consumption reaction channel for the five-member-ring compound C5H7 is the reaction channel to form C3H5 + C2H2. High-pressure limit rate constants and pressure-dependent rate constants for elementary reactions on the PES are calculated, which will be useful in modeling the oxidation of aromatic compounds at low- and medium-temperatures.
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DELLA (GAI/RGA/RGL1/RGL2/RGL3) proteins are key negative regulators in GA (gibberellin) signaling and are involved in regulating plant growth as a response to environmental stresses. It has been shown that the DELLA protein PROCERA (PRO) in tomato promotes drought tolerance, but its molecular mechanism remains unknown. Here, we showed that the gai-1 (gibberellin insensitive 1) mutant (generated from the gai-1 (Ler) allele (with a 17 amino acid deletion within the DELLA domain of GAI) by backcrossing gai-1 (Ler) with Col-0 three times), the gain-of-function mutant of GAI (GA INSENSITIVE) in Arabidopsis, increases drought tolerance. The stomatal density of the gai-1 mutant was increased but its stomatal aperture was decreased under abscisic acid (ABA) treatment conditions, suggesting that the drought tolerance of the gai-1 mutant is a complex trait. We further tested the interactions between DELLA proteins and ABF2 (abscisic acid (ABA)-responsive element (ABRE)-binding transcription factors) and found that there was a strong interaction between DELLA proteins and ABF2. Our results provide new insight into DELLA proteins and their role in drought stress tolerance.
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Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , Estresse Fisiológico , Desidratação , Secas , Regulação da Expressão Gênica de Plantas , Mapeamento de Interação de Proteínas , Mapas de Interação de ProteínasRESUMO
In this paper, single molecular junctions of Para-phthalic acid and Meta-phthalic acid with Au electrodes were studied by STM break junction approach. Conductance values of 10-3.55 G0 and 10-3.70 G0 were found for Para-phthalic acid and Meta-phthalic acid, respectively. The conductance order between Para-phthalic acid and Meta-phthalic acid with Au is different from that with Cu, which can be contributed to the different coupling between molecules and electrodes; different through-space interaction is proposed for such phenomenon between Cu and Au electrodes. Furthermore, the breaking off distances can reflect the length of molecules. The current work presents the important role of electrode in single molecular junctions with different position anchoring groups.
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Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development.
Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Proliferação de Células , Relação Dose-Resposta a Droga , Humanos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been suggested to be related with the pathogenesis and progression of osteoarticular degenerations. This study therefore aimed to investigate the relationship between the polymorphism of the TRAIL gene and the pathogenesis and severity of intervertebral disc degeneration (IDD) via detection of serum TRAIL expression levels. MATERIAL AND METHODS: A total of 100 IDD patients in our hospital were recruited in the experimental group, while another cohort of 100 healthy individuals was employed as the control group. Blood samples collected from all people were quantified for TRAIL level using enzyme-linked immunosorbent assay (ELISA), in addition to allele and genotype frequency analysis via fluorescent PCR for TRAIL gene. RESULTS: At loci 1525 and 1529 in 3'-untranslated region (UTR) of 5th exon of TRAIL gene, 3 different genotypes were identified: experimental group had higher frequency of 1525CG/1595CC, 1525G and 1595C alleles, compared to the control group (p<0.05). Patients under Schneiderman grade IV had significantly higher allele frequency compared to those at grade II or III. Serum TRAIL level was also higher in the experimental group compared to the control group, and in grade IV patients compared to grade II or III patients (p<0.05). CONCLUSIONS: The G/C mutation at loci 1525/1595 of TRAIL gene may induce the progression of IDD, as the down-regulation of TRAIL can aggravate the severity of the disease.
Assuntos
Degeneração do Disco Intervertebral/genética , Polimorfismo Genético , Ligante Indutor de Apoptose Relacionado a TNF/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Ligante Indutor de Apoptose Relacionado a TNF/sangueRESUMO
Molybdenum disulfide (MoS2)-based materials for piezocatalysis are unsatisfactory due to their low actual piezoelectric coefficient and poor electrical conductivity. Herein, 1T/3R phase MoS2 grown in situ on multiwalled carbon nanotubes (MWCNTs) was proposed. MoS2@MWCNTs exhibited the interwoven morphology of thin nanoflowers and tubes, and the piezoelectric response of MoS2@MWCNTs was 4.07 times higher than that of MoS2 via piezoresponse force microscopy (PFM) characterization. MoS2@MWCNTs exhibited superior activity with a 91% degradation rate of norfloxacin (NOR) after actually working 24 min (as for rhodamine B, reached 100% within 18 min) by pulse-mode ultrasonic vibration-triggered piezocatalysis. It was found that piezocatalysis for removing pollutants was attributed to the synergistic effect of free radicals (â¢OH and O2â¢-) and nonfree radical (1O2, key role) pathways, together with the innergenerated-H2O2 promoting the degradation rate. 1O2 can be generated by electron transfer and energy transfer pathways. The presence of oxygen vacancies (OVs) induced the transformation of O2 to 1O2 by triplet energy transfer. The fast charge transfer in MoS2@MWCNTs heterostructure and the coexistence of sulfur vacancies and OVs enhanced charge carrier separation resulting in a prominent piezoelectric effect. This work opens up new avenues for the development of efficient piezocatalysts that can be utilized for environmental purification.
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Objective: This study aimed to investigate the correlation between serum 25-hydroxyvitamin D (25(OH)D) levels and retinopathy of prematurity (ROP) in premature infants one month after birth. Methods: Preterm infants (gestational age <32 weeks) admitted to the Affiliated Hospital of Qingdao University from 2017 to 2022 were divided into ROP and non-ROP groups based on ROP occurrence any stage. Serum 25(OH)D levels and clinical data were compared between the two groups at 1 month after birth, and the relationship between vitamin D levels and ROP was analyzed. Results: Among the 217 premature infants included, 55 (25.35%) were in the ROP group, and 162 (74.65%) were in the non-ROP group. The ROP group had lower gestational age and birth weight, longer invasive ventilation (IV), non-invasive ventilation (NIV), and oxygen therapy times compared to the non-ROP group. Apgar scores, cesarean delivery, and antenatal steroids ratios were lower in the ROP group, while sepsis and pulmonary surfactant utilization ratios were higher (all p < 0.05). Significant differences in serum 25-(OH)D levels were observed among children in the non-ROP group (14.20 ± 5.07â ng/ml), ROP treated group (7.891 ± 1.878â ng/ml), and untreated group (12.168 ± 4.354â ng/ml) (p < 0.001). Multivariate regression analysis identified antenatal steroids as protective factors and lower birth weight, serum 25-(OH)D levels, long-term invasive mechanical ventilation, and sepsis as independent risk factors for ROP in premature infants. Conclusion: Vitamin D, lower birth weight, long-term invasive mechanical ventilation, and sepsis were associated with incidence of ROP in preterm infants. Vitamin D was associated with the severity of ROP, emphasizing the importance of prudent vitamin D supplementation and regular monitoring of serum 25-(OH)D levels.
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OBJECTIVE: Intervertebral disc degeneration (IDD) represents one of the leading causes of low back pain. Research suggests the participation of LINC01116 in IDD progression. Herein, the current study explored the underlying mechanism of LINC01116 in IDD. METHODS: The differential expression patterns of LINC01116 in IDD and normal tissues were analyzed using the GEO database. Human nucleus pulposus (NP) cells were provided and treated with IL-1ß to establish IDD models in vitro. LINC01116 expression was detected and intervened. Indices such as cell proliferation, apoptosis, and extracellular matrix (ECM)-related factor expression were determined using CCK-8 assay, flow cytometry, and Western blotting. LINC01116 sublocation was identified by means of nuclear/cytosol fractionation assay. The binding relationships between LINC01116 and miR-9-5p and miR-9-5p and ZIC5 were verified by bioinformatics analysis, dual-luciferase assays, RNA immunoprecipitation (RIP) assay, and RNA-pull-down. Western blotting was conducted to measure the levels of the Wnt pathway key factors. RESULTS AND DISCUSSION: LINC01116 was highly expressed in the degenerative NP cells. Silencing of LINC01116 critically promoted degenerative NP cell proliferation and inhibited apoptosis and ECM loss. LINC01116 was located in the cytoplasm. In degenerative NP cell models, LINC01116 could competitively bind to miR-9-5p to elevate ZIC5 expression. LINC01116 induced NP cell apoptosis and impeded NP cell proliferation and ECM synthesis by inhibiting miR-9-5p and miR-9-5p targeted ZIC5. ZIC5 could effectively increase the levels of the Wnt pathway-related factors. CONCLUSION: Silencing LINC01116 blocked its adsorption of miR-9-5p as a sponge to promote the miR-9- 5p expression and inhibit ZIC5/Wnt activation, thus impacting NP cell biological functions.
Assuntos
Degeneração do Disco Intervertebral , MicroRNAs , Núcleo Pulposo , Humanos , Degeneração do Disco Intervertebral/genética , Via de Sinalização Wnt/genética , Células Cultivadas , MicroRNAs/genética , MicroRNAs/metabolismo , Apoptose/genética , Proliferação de Células/genética , Proteínas Wnt/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Microplastics (MPs) have gained significant attention due to their widespread presence in the environment. While studies have been conducted to investigate the risks associated with MPs, the potential effects of MPs on populations with varying dietary habits, such as dietary restriction (DR), remain largely undefined. The sensitivity of the body to invasive contaminants may increase due to insufficient food intake. Here, we aimed to investigate whether dietary restriction could affect the toxicity of MPs in mice. Following a 5-week exposure to 200 µg/L polystyrene microplastics (PSMPs), DR-PSMPs treatment group exhibited significant intestinal barrier dysfunction compared to ND-PSMPs treatment group, as determined by histopathological and biochemical analysis. Dietary restriction worsened liver oxidative stress and bile acid disorder in mice exposed to PSMPs. 16S rRNA sequencing analysis revealed that DR-PSMPs treatment caused alterations in gut microbiota composition, including the downregulation of probiotics abundance and upregulation of pathogenic bacteria abundance. The negative effects caused by PSMPs in mice with dietary restriction could attribute to increased MPs bioaccumulation, declined water intake, reduced probiotics abundance, and elevated pathogenic bacteria abundance, as well as the susceptibility of the dietary restriction individual. Our findings hint that the biological effects of contaminants could be affected by dietary habits.
Assuntos
Gastroenteropatias , Enteropatias , Poluentes Químicos da Água , Animais , Camundongos , Poliestirenos/toxicidade , Poliestirenos/química , Microplásticos/toxicidade , Microplásticos/química , Plásticos/toxicidade , RNA Ribossômico 16S , Fígado , Poluentes Químicos da Água/toxicidadeRESUMO
Quinoline derivatives are important heterocyclic compounds because of their natural occurrence and applications in pharmaceutical fields. In this paper, a sequence of propargyl-allenyl isomerization and aza-electrocyclization for the synthesis of polyfunctionalized quinolines are described.
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Alcadienos/química , Alcinos/química , Compostos Aza/química , Quinolinas/síntese química , Alcadienos/síntese química , Ciclização , Estrutura Molecular , Quinolinas/química , EstereoisomerismoRESUMO
The excessive apoptosis of nucleus pulposus (NP) cells is a major risk factor in the progress of cervical intervertebral disc degeneration (IVDD). In this study, we investigated the impact of miR-98 on apoptosis of NP cells and the potential molecular mechanisms. Lipopolysaccharide (LPS) was used to establish an NP cell IVDD model. The sponging effect of miR-98 on TRAIL 3'UTR was predicted by ENCORI and assessed by the dual-luciferase reporter gene system. The expression levels of miR-98, TRAIL, and TRAIL pathway-related genes were tested by qRT-PCR, Western blot, and immunofluorescence analysis. Cell apoptosis was analyzed by Hoechst 33258 staining and flow cytometry. Cell viability was analyzed by MTT assay. It was found that the expression level of miR-98 was downregulated, while the level of TRAIL was upregulated in IVDD tissues, and their levels were negatively and positively associated with the clinical MRI grade, respectively. The LPS treatment resulted in a significant decrease of the miR-98 expression level and an increase of the TRAIL expression level in NP cells. miR-98 reduced NP cell apoptosis under LPS treatment in vitro. miR-98 directly targeted TRAIL. Moreover, the mRNA and protein levels of DR5, FADD, cleaved caspase8, cleaved caspase3, and cleaved PARP were downregulated by miR-98 overexpression. Overexpression of TRAIL partially reversed the suppressive roles of miR-98 on cell apoptosis and activation of the TRAIL pathway. We concluded that miR-98 inhibited apoptosis of NP cells by inactivating the TRAIL pathway via targeting TRAIL in IVDD NP cells. These results indicated that miR-98 might be a therapeutic target for IVDD.
Assuntos
Degeneração do Disco Intervertebral , MicroRNAs , Núcleo Pulposo , Apoptose/genética , Humanos , Degeneração do Disco Intervertebral/genética , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Seed germination and seedling establishment are important for the reproductive success of plants, but seeds and seedlings typically encounter constantly changing environmental conditions. By inhibiting seed germination and post-germinative growth through the PYR1/PYL/RCAR ABA receptors and PP2C co-receptors, the phytohormone abscisic acid (ABA) prevents premature germination and seedling growth under unfavorable conditions. However, little is known about how the ABA-mediated inhibition of seed germination and seedling establishment is thwarted. Here, we report that ABA Signaling Terminator (ABT), a WD40 protein, efficiently switches off ABA signaling and is critical for seed germination and seedling establishment. ABT is induced by ABA in a PYR1/PYL/RCAR-PP2C-dependent manner. Overexpression of ABT promotes seed germination and seedling greening in the presence of ABA, whereas knockout of ABT has the opposite effect. We found that ABT interacts with the PYR1/PYL/RCAR and PP2C proteins, interferes with the interaction between PYR1/PYL4 and ABI1/ABI2, and hampers the inhibition of ABI1/ABI2 by ABA-bound PYR1/PYL4, thereby terminating ABA signaling. Taken together, our results reveal a core mechanism of ABA signaling termination that is critical for seed germination and seedling establishment in Arabidopsis.
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Ácido Abscísico/farmacologia , Arabidopsis/efeitos dos fármacos , Arabidopsis/metabolismo , Proteínas de Arabidopsis/efeitos dos fármacos , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/genética , Germinação/efeitos dos fármacos , Plantas Geneticamente Modificadas/efeitos dos fármacos , Plantas Geneticamente Modificadas/genética , Plântula/efeitos dos fármacos , Plântula/metabolismo , Sementes/efeitos dos fármacos , Sementes/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
A novel class of fused pyrazole-derived inhibitors of p38alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC(50) values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10 m and 10 q. Inhibitor 10 m was found to be efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of 0.1mg/kg while 10 q was found to have an ED(50) of 0.05-0.07 mg/kg.
Assuntos
Anti-Inflamatórios/química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirazóis/química , Piridonas/química , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Sítios de Ligação , Linhagem Celular , Simulação por Computador , Cristalografia por Raios X , Humanos , Interleucina-8/sangue , Lipopolissacarídeos/farmacologia , Masculino , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Piridonas/administração & dosagem , Piridonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Electrochemical scanning tunneling microscopy (EC-STM) has been applied to study the structure of the film formed by fusion of cholesterol suspensions and mixed dimyristoylphosphatidylcholine (DMPC)/cholesterol vesicles on a Au(111) electrode surface. It has been demonstrated that cholesterol molecules assemble at the gold support into several structures templated by the crystallography of the metal surface and involving flat or edge-on adsorbed molecules. Studies of the film formed by fusion of mixed DMPC/cholesterol vesicles revealed that ordered domains of either pure DMPC or pure cholesterol were formed. These results indicate that, at the metal surface, the molecules released by the rupture of a vesicle initially self-assemble into a well-ordered monolayer. The self-assembly is controlled by the hydrocarbon skeleton-metal surface interaction. In the case of mixed DMPC/cholesterol vesicles, the molecule-metal interactions induce segregation of the two components into single component domains. However, the molecule-metal interaction induced monolayer is a transient phenomenon. When more molecules accumulate at the surface, the molecule-molecule interactions dominate the assembly, and the monolayer is transformed into a bilayer.
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Colesterol/química , Dimiristoilfosfatidilcolina/química , Ouro/química , Bicamadas Lipídicas/química , Cátions , Eletroquímica , Eletrodos , Microscopia de Tunelamento , Propriedades de SuperfícieRESUMO
In this study, the feasibility of applying a magnetotactic bacterial isolate (MTB), Stenotrophomonas sp. to the removal of Au(III) was investigated. Biosorption experiments showed that Au(III) biosorption capacity exhibited no significant difference in the initial pH range of 1.0-5.5, while decreased more significantly in the initial pH range of 5.5-13.0. Langmuir isotherm indicated that the maximum Au(III) biosorption capacity of Stenotrophomonas sp. were 506, 369 and 308 mg g(-1) dry weight biomass at the initial pH values of 2.0, 7.0 and 12.0, respectively. Thiourea was proved to be an effective desorbent to recover Au from the MTB biomass and 91% Au adsorbed on the biomass could be recovered at equilibrium when the thiourea concentration was 0.8M. The magnetic separator developed by our research team used for separating Au loaded MTB biomass showed high separation efficiency, with 100% biomass removed at the magnetic intensity of 1200 Gs in 180 min. The analyses from FTIR and XRD further confirmed that the reduction of Au(III) to Au(0) by the reductants on the MTB biomass occurred, and the deposition of nano-crystal Au(0) particles, ranging from 24.7 to 31.4 nm, could be estimated on the biomass surface.