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Immune related adverse events (irAEs) after immune checkpoint blockade (ICB) therapy occur in a significant proportion of cancer patients. To date, the circulating mediators of ICB-irAEs remain poorly understood. Using non-targeted mass spectrometry, here we identify the circulating bio-active lipid linoleoyl-lysophosphatidylcholine (LPC 18:2) as a modulator of ICB-irAEs. In three independent human studies of ICB treatment for solid tumor, loss of circulating LPC 18:2 preceded the development of severe irAEs across multiple organ systems. In both healthy humans and severe ICB-irAE patients, low LPC 18:2 was found to correlate with high blood neutrophilia. Reduced LPC 18:2 biosynthesis was confirmed in preclinical ICB-irAE models, and LPC 18:2 supplementation in vivo suppressed neutrophilia and tissue inflammation without impacting ICB anti-tumor response. Results indicate that circulating LPC 18:2 suppresses human ICB-irAEs, and LPC 18:2 supplementation may improve ICB outcomes by preventing severe inflammation while maintaining anti-tumor immunity.
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Recent years have witnessed the explosive development of highly sensitive smart sensors based on conductive polymer foam materials. However, the design and development of multifunctional polymeric foam composites as smart sensors applied in complex solvent and oil environments remain a critical challenge. Herein, we design and synthesize vinyl-terminated polytrifluoropropylmethylsiloxane through anionic ring-opening polymerization to fabricate fluorosilicone rubber foam (FSiRF) materials with nanoscale wrinkled surfaces and reactive Si-H groups via a green and rapid chemical foaming strategy. Based on the strong adhesion between FSiRF materials and consecutive oxidized ketjen black (OKB) nano-network, multifunctional FSiRF nanocomposites were prepared by a dip-coating strategy followed by fluoroalkylsilane modification. The optimized F-OKB@FSiRF nanocomposites exhibit outstanding mechanical flexibility in wide-temperature range (100 cycle compressions from -20 to 200 °C), structure stability (no detached particles after being immersed into various aqueous solutions for up to 15 days), surface superhydrophobicity (water contact angle of 154° and sliding angle of â¼7°), and tunable electrical conductivity (from 10-5 to 10-2 S m-1). Additionally, benefiting from the combined actions of multiple lines of defense (low surface energy groups, physical barriers, and "shielding effect"), the F-OKB@FSiRF sensor presents excellent anti-swelling property and high sensitivity in monitoring both large-deformation and tiny vibrations generated by knocking the beaker, ultrasonic action, agitating, and sinking objects in weak-polar or nonpolar solvents. This work conceivably provides a chemical strategy for the fabrication of multifunctional polymeric foam nanocomposite materials as smart sensors for broad applications.
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BACKGROUND: Acute-on-chronic liver failure (ACLF) patients exhibit an imbalance in intestinal microbiota, and bile acids (BAs) can affect the composition of intestinal microbiota. Although Artificial liver support system (ALSS) is a treatment for ACLF, the impact of ALSS on intestinal microbiota and serum BA profiles of ACLF patients remains unclear. METHODS: A prospective study was conducted, which included 51 patients diagnosed with ACLF. These patients were stratified into two groups based on the utilization of an ALSS during their treatment period: a standard medical treatment group (SMT group), comprising 19 patients, and an ALSS combined with SMT group (ALSS group), comprising 32 patients. Blood and stool samples were collected from the patients on the day of admission and 14 days after treatment. Additionally, eight healthy controls were recruited, and their stool samples were also collected. The intestinal microbiota was sequenced using the 16S rRNA sequencing technique, while the serum BA profiles were determined using ultra-performance liquid chromatography/mass spectrometry. RESULTS: ACLF patients exhibited imbalances in intestinal microbiota and abnormalities in BA profiles. Compared to SMT alone, the combined ALSS and SMT was more effective in regulating intestinal microbiota imbalance and increasing the concentrations of ursodeoxycholic acid and glycoursodeoxycholic acid. Correlation analysis revealed a significant correlation between intestinal microbiota and Bas. Furthermore, the preliminary correlation heatmap indicated that the Faecalibaculum, Gemmiger, and taurochenodeoxycholic acid were associated with clinical improvement. CONCLUSIONS: Our study identified the compositional characteristics of the intestinal microbiota and serum BA in ACLF patients, emphasizing the impact of ALSS on both intestinal microbiota and serum BA profiles.
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Bioactive fatty acid-derived oxylipin molecules play key roles in mediating inflammation and oxidative stress, which underlie many chronic diseases. Circulating levels of fatty acids and oxylipins are influenced by both environmental and genetic factors; characterizing the genetic architecture of bioactive lipids could yield new insights into underlying biological pathways. Thus, we performed a genome wide association study (GWAS) of n=81 fatty acids and oxylipins in n=11,584 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants with genetic and lipidomic data measured at study baseline (58.6% female, mean age = 46.1 years, standard deviation = 13.8 years). Additionally, given the effects of central obesity on inflammation, we examined interactions with waist circumference using two-degree-of-freedom joint tests. Heritability estimates ranged from 0% to 47.9%, and 48 of the 81oxylipins and fatty acids were significantly heritable. Moreover, 40 (49.4%) of the 81 oxylipins and fatty acids had at least one genome-wide significant (p< 6.94E-11) variant resulting in 19 independent genetic loci involved in fatty acid and oxylipin synthesis, as well as downstream pathways. Four loci (lead variant minor allele frequency [MAF] range: 0.08-0.50), including the desaturase-encoding FADS and the OATP1B1 transporter protein-encoding SLCO1B1, exhibited associations with four or more fatty acids and oxylipins. The majority of the 15 remaining loci (87.5%) (lead variant MAF range = 0.03-0.45, mean = 0.23) were only associated with one oxylipin or fatty acid, demonstrating evidence of distinct genetic effects. Finally, while most loci identified in two-degree-of-freedom tests were previously identified in our main effects analyses, we also identified an additional rare variant (MAF = 0.002) near CARS2, a locus previously implicated in inflammation. Our analyses revealed shared and distinct genetic architecture underlying fatty acids and oxylipins, providing insights into genetic factors and motivating future multi-omics work to characterize these compounds and elucidate their roles in disease pathways.
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The application of Monitored Natural Attenuation (MNA) technology has been widespread, while there is a paucity of data on groundwater with multiple co-contaminants. This study focused on high permeability, low hydraulic gradient groundwater with co-contamination of benzene, toluene, ethylbenzene, and xylenes (BTEX), chlorinated aliphatic hydrocarbons (CAHs), and chlorinated aromatic hydrocarbons (CPs). The objective was to investigate the responses of microbial communities during natural attenuation processes. Results revealed greater horizontal variation in groundwater microbial community composition compared to vertical variation. The variation was strongly correlated with the total contaminant quantity (r = 0.722, p < 0.001) rather than individual contaminants. BTEX exerted a more significant influence on community diversity than other contaminants. The assembly of groundwater microbial communities was primarily governed by deterministic processes (ßNTI < -2) in high contaminant concentration zones, while stochastic processes (|ßNTI| < 2) dominated in low-concentration zones. Moreover, the microbial interactions shifted at different depths indicating the degradation rate variation in the vertical. This study makes fundamental contribution to the understanding for the effects of groundwater flow and material fields on indigenous microbial communities, which will provide a scientific basis for more precise adoption of microbial stimulation/augmentation to accelerate the rate of contaminant removal.
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Biodegradación Ambiental , Agua Subterránea , Contaminantes Químicos del Agua , Agua Subterránea/microbiología , Agua Subterránea/química , Contaminantes Químicos del Agua/análisis , Solventes/química , Microbiota , Bacterias/clasificación , Bacterias/metabolismo , Hidrocarburos Clorados/análisis , Derivados del Benceno/análisis , Microbiología del Agua , ARN Ribosómico 16S/genéticaRESUMEN
The bioremediation of chlorinated ethenes (CEs) contaminated groundwater is attracting increasingly attention in practical remediation projects. However, modelling of microbial metabolic processes under the constraints of substrate and environmental factors is inadequate. This study developed a new kinetic model, which incorporated the logistic model and Dual-Monod kinetic to represent the interaction between the controlled microbial growth and the bioavailable substrates in CE-contaminated groundwater. The proposed model was based on discrete observations to simulate microbial growth under the constraints of substrate and environmental conditions, reducing the amount of observational data required for the model. Meanwhile, the proposed model introduced two new kinetic parameters, the effective specific growth rate µeff and the real self-limiting coefficient of microbial growth keff,sl, to simplified the number of independent parameters. A parameter estimation method based on the quasi-Newton's algorithm for the proposed model was also developed. The model was validated based on the hypothetical data, experimental results, and a published dataset, demonstrated the successful simulation of microbial growth and the sequential biodegradation of PCE in groundwater systems (*E < 0.3). The monitoring duration and the sampling schedule have significant impacts on estimating the biological parameters, and large errors would be induced when the data from the periods of extremely low substrate concentration or microbial growth decline were involved in parameter estimation. The research suggested that the proposed kinetic model provided a new insight to express the limitation of microbial population growth due to the available substrates and environmental factors, and is hoping to be applied in actual CE-contaminated sites.
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Biodegradación Ambiental , Biotransformación , Agua Subterránea , Contaminantes Químicos del Agua , Agua Subterránea/química , Agua Subterránea/microbiología , Contaminantes Químicos del Agua/metabolismo , Contaminantes Químicos del Agua/análisis , Cinética , Hidrocarburos Clorados/metabolismoRESUMEN
Nitrochlorobenzene (NCB) is very common in pesticide and chemical industries, which has become a major problem in soil environment. However, the remediation of NCB contaminated soil is received finite concern. Using biochar as a substrate for nanoscale-zero valent iron (nZVI/p-BC) to activate peroxodisulfate (PDS), a novel heterogeneous oxidative system had been applied in the current study to remediate NCB contaminants in soil. The degradation efficiencies and kinetics of m-NCB, p-NCB, and o-NCB by various systems were contrasted in soil slurry. Key factors including the dosage of nZVI/p-BC, the molar ratio of nZVI/PDS, initial pH and temperature on degradation of NCB were further examined. The results confirmed that the nZVI/p-BC/PDS displayed the remarkable performance for removing NCB compared with other systems. Higher temperature with nZVI/PDS molar ratio of 2:1 under the acidic condition favored the reduction of NCB. The treatment for NCB with optimal conditions were evaluated for the engineering application. The mechanism of nZVI/p-BC/PDS indicated that electron transfer between p-BC and nZVI was responsible for activation of PDS, generating active species (SO4â¢-, â¢OH and 1O2) via both the free and non-free radical pathways. Experimental results revealed prominent availability of nZVI/p-BC/PDS system in remediation of actual contaminated field by NCB.
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A novel position-sensitive linear winding silicon drift detector (LWSDD) was designed and simulated. On the frontside (anode side), the collecting anodes were set on both sides of the detector, and an S-shaped linear winding cathode strip was arranged in the middle, which can realize independent voltage division and reduce the complexity of external bias resistor chain compared with the traditional linear silicon drift detector. The detectors were arranged in a butterfly shape, which increased the effective area of the detectors and improved the collection efficiency. The linear winding silicon drift detector can obtain one-dimensional position information by measuring the drift time of electrons. The 2D position information of the incident particle is obtained from the anodes coordinates of the readout signal. One-dimensional analytically exact solutions of electric potential and field were obtained for the first time for the linear winding silicon drift detector. The simulation results show that the electric potential distribution inside the detector is uniform, and the "drift channel" inside the detector points to the collecting anodes on both sides, which proves the reasonable and feasible design of the linear winding silicon drift detector.
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Understanding chromium (Cr) migration and dispersion patterns in the soil-groundwater system is critical for the control and remediation of subsurface Cr contamination. In this study, a typical Cr-contaminated site from the Pearl River Delta (PRD) in China was simulated with a three-dimensional (3D) sandbox experiment to investigate the migration and transformation behavior of Cr. Results revealed that under the combined influence of rainfall and groundwater flow, a complex flow field favorable for 3D migration and solute dispersion was formed. The flow field characteristics were influenced by water-table depth, which in turn affected Cr behavior in the system. Moreover, downward flow field expansion under low water-table conditions led to Cr vertical migration range expansion, causing greater contamination in the deep soil. The migration process was accompanied with Cr(VI) reduction, during which approximately 75 % of the total Cr was immobilized in soils. The reactive transport model achieved a good fit for Cr retention and morphological distribution in the solid phase. The model indicates that Cr is more readily transported and dispersed with groundwater, and Cr migrated and spread downstream by 15 m during the eighth year. Therefore, managing water-table depth could be a strategy to minimize the Cr vertical migration and contamination.
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JOURNAL/nrgr/04.03/01300535-202419110-00027/figure1/v/2024-03-08T184507Z/r/image-tiff Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer's disease. Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases, including Parkinson's and Huntington's diseases, however, the effect of Citri Reticulatae Semen on Alzheimer's disease remains unelucidated. In the current study, the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated. Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy. In addition, Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro, and suppress amyloid-beta-induced pathology such as paralysis, in a transgenic Caenorhabditis elegans in vivo model. Moreover, genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent. Most importantly, Citri Reticulatae Semen extract was confirmed to improve cognitive impairment, neuronal injury and amyloid-beta burden in 3×Tg Alzheimer's disease mice. As revealed by both in vitro and in vivo models, these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer's disease via its neuroprotective autophagic effects.
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In this study, a controllable equal-gap large-area silicon drift detector (L-SDD) is designed. The surface leakage current is reduced by reducing the SiO2-Si interface through the new controllable equal-gap design. The design of the equal gap also solves the problem whereby the gap widens due to the larger detector size in the previous SDD design, which leads to a large invalid area of the detector. In this paper, a spiral hexagonal equal-gap L-SDD of 1 cm radius is selected for design calculation, and we implement 3D modeling and simulation of the device. The simulation results show that the internal potential gradient distribution of the L-SDD is uniform and forms a drift electric field, with the direction of electron drift pointing towards the collecting anode. The L-SDD has an excellent electron drift channel inside, and this article also analyzes the electrical performance of the drift channel to verify the correctness of the design method of the L-SDD.
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Pulmonary arterial hypertension (PAH) is a rare and fatal vascular disease with heterogeneous clinical manifestations. To date, molecular determinants underlying the development of PAH and related outcomes remain poorly understood. Herein, we identify pulmonary primary oxysterol and bile acid synthesis (PPOBAS) as a previously unrecognized pathway central to PAH pathophysiology. Mass spectrometry analysis of 2,756 individuals across five independent studies revealed 51 distinct circulating metabolites that predicted PAH-related mortality and were enriched within the PPOBAS pathway. Across independent single-center PAH studies, PPOBAS pathway metabolites were also associated with multiple cardiopulmonary measures of PAH-specific pathophysiology. Furthermore, PPOBAS metabolites were found to be increased in human and rodent PAH lung tissue and specifically produced by pulmonary endothelial cells, consistent with pulmonary origin. Finally, a poly-metabolite risk score comprising 13 PPOBAS molecules was found to not only predict PAH-related mortality but also outperform current clinical risk scores. This work identifies PPOBAS as specifically altered within PAH and establishes needed prognostic biomarkers for guiding therapy in PAH.
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The contamination of abandoned chromium slag-contaminated sites poses serious threats to human health and the environment. Therefore, improving the understanding of their distribution characteristics and health risks by multiple information is necessary. This study explored the distribution, accumulation characteristic, and the role in the migration process of chromium. The results showed that the contents of total Cr and Cr (VI) ranged from 12.00 to 7400.00 mg/kg, and 0.25 to 2160.00 mg/kg, respectively. The average contents of both total Cr and Cr (VI) reached the highest value at the depth of 7-9 m, where the silt layer retaining total Cr and Cr (VI) was. The spatial distribution analysis revealed that the total contamination area percentages of total Cr and Cr (VI) reached 7.87% and 90.02% in the mixed fill layer, and reduced to 1.21% and 34.53% in the silty layer, and the same heavily polluted areas were located in the open chromium residue storage. Soil pH and moisture content were the major factors controlling the migration of total Cr and Cr(VI) in soils. Results of probabilistic health risk assessment revealed that carcinogenic risk was negligible for adults and children, and the sensitive analysis implied that the content of Cr(VI) was the predominant contributor to carcinogenic risk. The combination of chemical reduction and microbial remediation could be the feasible remediation strategy for soil Cr(VI) pollution. Overall, this study provides scientific information into the chromium post-remediation and pollution management for various similar chromium-contaminated sites.
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Contaminantes del Suelo , Humanos , Niño , Adulto , Contaminantes del Suelo/análisis , Cromo/análisis , Suelo , ChinaRESUMEN
Irrigation with water containing a variety of microcystins (MCs) may pose a potential threat to the normal growth of agricultural plants. To investigate the phytotoxicity of MC-LR at environmental concentrations on rice (Oryza sativa L.), the characteristics of uptake and accumulation in plant tissues, as well as a series of key physio-biochemical process changes in leaves of rice seedlings, were measured at concentrations of 0.10, 1.0, 10.0, and 50.0 µg·L-1 in hydroponic nutrient solutions for 7, 15, 20, and 34 days. Results showed that MC-LR could be detected in rice leaves and roots in exposure groups; however, a significant accumulation trend of MC-LR in plants (BCF > 1) was only found in the 0.10 µg·L-1 group. The time-course study revealed a biphasic response of O2â¢- levels in rice leaves to the exposure of MC-LR, which could be attributed to the combined effects of the antioxidant system and detoxification reaction in rice. Exposure to 1.0-50.0 µg·L-1 MC-LR resulted in significant depletion of GSH and MDA contents in rice leaves at later exposure times (15-34 days). Low MC-LR concentrations promoted nitric oxide synthase (NOS) activity, whereas high concentrations inhibited NOS activity during the later exposure times. The reduced sucrose synthase (SS) activities in rice exposed to MC-LR for 34 days indicated a decrease in the carbon accumulation ability of plants, and therefore may be directly related to the inhibition of plant growth under MC exposure. These findings indicate that the normal physiological status would be disrupted in terrestrial plants, even under exposure to low concentrations of MC-LR.
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Toxinas Marinas , Microcistinas , Oryza , Microcistinas/toxicidad , Microcistinas/metabolismo , Bioacumulación , HidroponíaRESUMEN
Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations and validation in a lowland population. Although this genocopy of relatively lower hematocrit in Andean highlanders parallels well-replicated findings in Tibetans, it likely involves distinct pathway responses based on a protein-coding versus noncoding variants, respectively. These findings illuminate how unique variants at EPAS1 contribute to the same phenotype in Tibetans and a subset of Andean highlanders despite distinct evolutionary trajectories.
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Adaptación Fisiológica , Altitud , Hematócrito , Pueblos Sudamericanos , Humanos , Adaptación Fisiológica/genética , Adaptación Fisiológica/fisiología , Pueblos del Este de Asia , Hipoxia/genética , Hipoxia/metabolismo , Mutación Missense/genética , Pueblos Sudamericanos/genéticaRESUMEN
Photoperiod is a crucial environmental cue for phenological responses, including growth cessation and winter dormancy in perennial woody plants. Two regulatory modules within the photoperiod pathway explain bud dormancy induction in poplar (Populus spp.): the circadian oscillator LATE ELONGATED HYPOCOTYL 2 (LHY2) and GIGANTEA-like genes (GIs) both regulate the key target for winter dormancy induction FLOWERING LOCUS T2 (FT2). However, modification of LHY2 and GIs cannot completely prevent growth cessation and bud set under short-day (SD) conditions, indicating that additional regulatory modules are likely involved. We identified PtoHY5a, an orthologs of the photomorphogenesis regulatory factor ELONGATED HYPOCOTYL 5 (HY5) in poplar (Populus tomentosa), that directly activates PtoFT2 expression and represses the circadian oscillation of LHY2, indirectly activating PtoFT2 expression. Thus, PtoHY5a suppresses SD-induced growth cessation and bud set. Accordingly, PtoHY5a knockout facilitates dormancy induction. PtoHY5a also inhibits bud-break in poplar by controlling gibberellic acid (GA) levels in apical buds. Additionally, PtoHY5a regulates the photoperiodic control of seasonal growth downstream of phytochrome PHYB2. Thus, PtoHY5a modulates seasonal growth in poplar by regulating the PtoPHYB2-PtoHY5a-PtoFT2 module to determine the onset of winter dormancy, and by fine-tuning GA levels to control bud-break.
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Regulación de la Expresión Génica de las Plantas , Giberelinas , Fotoperiodo , Latencia en las Plantas , Proteínas de Plantas , Populus , Populus/genética , Populus/crecimiento & desarrollo , Populus/metabolismo , Populus/fisiología , Giberelinas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Latencia en las Plantas/genética , Flores/genética , Flores/fisiología , Flores/crecimiento & desarrolloRESUMEN
Gelatin and starch are considered as promising sustainable materials for their abundant production and good biodegradability. Efforts have been made to explore their medical application. Herein, scaffolds based on gelatin and starch with a preferred microstructure and antibacterial antioxidant property were fabricated by the emulsion template method. The dialdehyde starch was firstly combined with silver nanoparticles and curcumin to carry out the efficient hybrid antibacterial agent. Then, the gelatin microsphere of appropriate size was prepared by emulsification and gathered by the above agent to obtain gelatin-based scaffolds. The prepared scaffolds showed porous microstructures with high porosity of over 74 % and the preferred pore sizes of â¼65 µm, which is conducive to skin regeneration. Moreover, the scaffolds possessed a good swelling ability of over 640 %, good degradability of over 18 days, excellent blood compatibility, and cell compatibility. The promising antibacterial and antioxidant properties came from the hybrid antibacterial agent were affirmed. As expected, the gelatin-based scaffolds fabricated by the emulsion template method with a preferred microstructure can facilitate more adhered fibroblasts. In summary, gelatin-based scaffolds functionalized by starch-based complex expanded the application of abundant sustainable materials in the biomedical field, especially as antibacterial antioxidant wound dressings.
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Gelatina , Nanopartículas del Metal , Gelatina/química , Andamios del Tejido/química , Antioxidantes/farmacología , Emulsiones , Plata/química , Antibacterianos/farmacología , Cicatrización de Heridas , Almidón/química , PorosidadRESUMEN
Drought poses a serious challenge to sustained plant growth and crop yields in the context of global climate change. Drought tolerance in poplars and their underlying mechanisms still remain largely unknown. In this article, we investigated the overexpression of PtoMYB99 - both a drought and abscisic acid (ABA) induced gene constraining drought tolerance in poplars (as compared with wild type poplars). First, we found that PtoMYB99-OE lines exhibited increased stomatal opening and conductance, higher transpiration and photosynthetic rates, as well as reduced levels of ABA and jasmonic acid (JA). Second, PtoMYB99-OE lines accumulated more reactive oxygen species (ROS), including H2O2 and O2-, as well as malonaldehyde (MDA), proline, and soluble sugar under osmotic stress; conversely, the activity of antioxidant enzymes (SOD, POD, and CAT), was weakened in the PtoMYB99-OE lines. Third, the expression of ABA biosynthetic genes, PtoNCED3.1 and PtoNCED3.2, as well as JA biosynthetic genes, PtoOPR3.1 and PtoOPR3.2, was significantly reduced in the PtoMYB99-OE lines under both normal conditions and osmotic stress. Based on our results, we conclude that the overexpression of PtoMYB99 compromises tolerance to osmotic stress in poplar. These findings contribute to the understanding of the role of the MYB genes in drought stress and the biosynthesis of ABA and JA.