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1.
Water Res ; 211: 118043, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-35026549

RESUMO

Hydrothermal treatment (HT) is effective for the deep dewatering of sewage sludge (SS); however, the effective temperature generally exceeds 180 â„ƒ, resulting in the production of refractory compounds in the sludge filtrates. To explore a new process based on HT, achieving ideal dehydration efficiency at lower temperatures, it is essential to identify the key sludge dewatering mechanism under different HT stages. In this study, the relationship between the properties of sludge polymeric substances (components and molecular structures) and the physical-chemical properties of sludge flocs during HT (120-260 â„ƒ) was investigated. The results indicated that the SS surface hydrophilicity/hydrophobicity was mainly responsible for sludge dewaterability in the solubilization (120 â„ƒ) and hydrolyzation stages (140-180 â„ƒ), while the mechanically bound water and capillary force were the main limiting factors of sludge dewaterability during the carbonization stage (200-260 â„ƒ). Moreover, in the solubilization stage (120 â„ƒ), a plenty of high-Mw (Mw > 70 kDa) polymeric substances with numerous hydrophilic functional groups and a compact structure were released from the intracellular region to the outer layer, which improved the hydrophilicity of sludge floc surface and deteriorated the sludge dewaterability. With the hydrolysis of the polymeric substances (140-180 â„ƒ, hydrolyzation stage), the destruction of proteins secondary structures and peptide chains exposed more hydrophobic groups, resulting in the release of bound water and improvement of sludge dewaterability. At HT temperatures of 200-260 â„ƒ (carbonization stage), dehydration and amine aldehyde condensation occurred, benefiting the formation of fixed carbon and smooth morphology structure of SS, reducing the capillary force-induced water-holding capacity of sludge flocs. The establishment of the three-stage influencing theory and the identification of key influencing factors are conducive to the further regulation and upgrading of HT.

2.
Nano Today ; 43: 101393, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35035515

RESUMO

There is an urgent need to develop new vaccination strategies to elevate the cross-neutralization against different SARS-CoV-2 strains. In this study, we construct the spherical amantadine-assembled nanostimulator (AAS). Amantadine as immunostimulating molecules are displayed on the outermost layer of AAS. Molecular mechanism analysis reveals that AAS can activate RIG-I-like receptor (RLR) signaling pathway to increase the expression of type I interferons in vivo. AAS-mediated activation of RLR signaling pathway further promotes the maturation and proliferation of dendritic cells (DCs) and T helper cells (Ths), finally activating B cells to produce potent antibody responses. In performance evaluation experiments, the mixture of AAS and dimeric RBD significantly enhances RBD-specific humoral responses (4-fold IgG, 3.5-fold IgG2a, 3.3-fold IgG2b, 3.8-fold IgG3 and 1.3-fold IgM), in comparison to aluminum adjuvant-assistant dimeric RBD. Importantly, AAS dramatically elevates dimeric RBD-elicited cross-neutralization against different SARS-CoV-2 strains such as Wuhan-Hu-1 (9-fold), B.1.1.7 (UK variant, 15-fold), B.1.351 (South African variant, 4-fold) and B.1.617.2 (India variant, 7-fold). Our study verifies the mechanism of AAS in activating RLR signaling pathway in host immune system and highlights the power of AAS in improving antigen-elicited cross-neutralization against different SARS-CoV-2 strains.

4.
Biochem Biophys Res Commun ; 589: 85-91, 2022 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-34896780

RESUMO

Chemotherapy is the mainstay of treatment for prostate cancer, with paclitaxel being commonly used for hormone-resistant prostate cancer. However, drug resistance often develops and leads to treatment failure in a variety of prostate cancer patients. Therefore, it is necessary to enhance the sensitivity of prostate cancer to chemotherapy. Lovastatin (LV) is a natural compound extracted from Monascus-fermented foods and is an inhibitor of HMG-CoA reductase (HMGCR), which has been approved by the FDA for hyperlipidemia treatment. We have previously found that LV could inhibit the proliferation of refractory cancer cells. Up to now, the effect of LV on chemosensitization and the mechanisms involved have not been evaluated in drug-resistant prostate cancer. In this study, we used prostate cancer cell line PC3 and its paclitaxel-resistant counterpart PC3-TxR as the cell model. Alamar Blue cell viability assay showed that LV and paclitaxel each conferred concentration-dependent inhibition of PC3-TxR cells. When paclitaxel was combined with LV, the proliferation of PC3-TxR cells was synergistically inhibited, as demonstrated by combination index <1. Moreover, colony formation decreased while apoptosis increased in paclitaxel plus LV group compared with paclitaxel alone group. Quantitative RT-PCR showed that the combination of paclitaxel and LV could significantly reduce the expression of CYP2C8, an important drug-metabolizing enzyme. Bioinformatics analysis from the TCGA database showed that CYP2C8 expression was negatively correlated with progression-free survival (PFS) in prostate cancer patients. Our results suggest that LV might increase the sensitivity of resistant prostate cancer cells to paclitaxel through inhibition of CYP2C8 and could be utilized as a chemosensitizer for paclitaxel-resistant prostate cancer cells.

5.
J Environ Sci (China) ; 111: 380-391, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34949367

RESUMO

Anaerobic digestion and incineration are widely used sewage sludge (SS) treatment and disposal approaches to recovering energy from SS, but it is difficult to select a suitable technical process from the various technologies. In this study, life-cycle assessments were adopted to compare the energy- and greenhouse gas- (GHG) emission footprints of two sludge-to-energy systems. One system uses a combination of AD with incineration (the AI system), whereas the other was simplified by direct incineration (the DI system). Comparison between three SS feedstocks (VS/TS: 57.61 -73.1 ds.%) revealed that the AI system consistently outperformed the DI system. The results of sensitivity analyses showed that the energy and GHG emission performances were mainly affected by VS content of the SS, AD conversion efficiency, and the energy consumption of sludge drying. Furthermore, the energy and GHG emission credit of the two systems increased remarkably with the increase in the VS content of the SS. For the high-organic-content sludge (VS/TS: 55%-80%), the energy and GHG emission credit of the AI system increase with the increase of AD conversion efficiency. However, for the low organic content sludge (VS/TS: 30%-55%), it has the opposite effect. In terms of energy efficiency and GHG performance, the AI system is a good choice for the treatment of high-organic-content sludge (VS/TS>55%), but DI shows superiority over AI when dealing with low organic content sludge (VS/TS<55%).


Assuntos
Gases de Efeito Estufa , Esgotos , Dessecação , Efeito Estufa , Incineração
6.
Anal Chem ; 94(2): 650-657, 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-34931818

RESUMO

The identification of metabolites in single-cell or small-volume tissue samples using single-cell mass spectrometry (MS) is challenging. In this study, hydrogen/deuterium (H/D) exchange was combined with microsampling nanospray high-resolution mass spectrometry (HRMS) to improve the efficiency and confidence level of metabolite identification in a single cell using commercial software. A nanospray ion source showed an improved reaction depth of 8% for H/D exchange compared with an electrospray ion source. In total, 273 metabolites were identified in Allium cepa L. single cells by searching commercial databases. Generally, more than one candidate is given for a precursor ion by MS or tandem MS (MS2) databases such as ChemSpider, MetDNA, MassBank, and mzCloud. With the help of the H/D exchange technique, the number of candidates decreased and reduction of the search space by a factor of 8 was achieved. In addition, two enzymolysis products of isoalliin, the transient intermediate and its isomer, were tracked at the single-cell level using the proposed method.

7.
Chemosphere ; 287(Pt 1): 132026, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34461328

RESUMO

The applications of biogenic Mn oxides (BMOs) formed by Mn-oxidizing fungus in decontaminating heavy metals have attracted increasing attention. In this study, an efficient Mn-oxidizing fungus was isolated from soil and identified as Cladosporium halotolerans strain XM01. The Mn(II) adsorption and oxidation activities of this strain were investigated, showing significantly high removal and oxidation rates of soluble Mn(II) of 99.9% and 88.2%, respectively. Dynamic analysis of the Mn(II) removal process demonstrated the oxidation process of Mn(II) to Mn(III) was the rate-limiting step in the Mn(II) metabolic process. The XRD and SAED characterization showed that more layers were orderly accumulated along the c-axis with the formation of fungal BMOs, which might lead to the decrease in its specific surface area. The adsorption of Cd(II) by the formed BMOs was investigated and compared with two typical abiotic Mn oxides, indicating that the adsorption capacity decreased with the following order: immature BMO, mature BMO, δ-MnO2, acid birnessite, while the fixation capacity decreased in the order of acid birnessite, mature BMO, δ-MnO2, immature BMO. The inverse correlation between the capacity of Cd(II) adsorption and fixation of immature and mature BMOs was probably attributed to the increase in the layer stacking of BMOs. This result indicates an interesting phenomenon of high reservation of Cd(II) resulting from sequential transformation from strong adsorption to strong fixation with the formation of BMOs. This study offers considerable insights into fungal Mn oxidation mechanisms and provides theoretical guidance for fungal BMOs in heavy metals bioremediation.


Assuntos
Compostos de Manganês , Manganês , Adsorção , Cádmio , Cladosporium , Fungos , Oxirredução , Óxidos
8.
Sci Total Environ ; 807(Pt 1): 150773, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-34619185

RESUMO

Partial ozonation of returned sludge via high and low concentration of ozone were compared to evaluate their efficiency in excess sludge production reduction. A pilot-scale system of anaerobic/anoxic/oxic (A/A/O) + ozonated sludge recycle (OSR) process was operated for 97 days, to investigate the effects of different ozone concentration (380 mg/L and 150 mg/L) on the nutrient removal capacity, sludge reduction rate, the excess sludge properties including settling, dewatering and anaerobic digestion (AD) performance. It was found that at the same total ozone dosage (13 mg/g MLSS, 25 mg/g MLVSS), the ozone of 380 mg/L achieved much higher organic matters and total excess sludge reduction (41.6% and 25.9%) than 150 mg/L applied (31.0% and 18.2%). It also laid less deterioration effect on the effluent quality and had better nutrient (COD, NH4+-N, TN) removal capacity than 150 mg/L applied. Meanwhile, little difference was found in the settling, dewatering and AD properties of excess sludge from the two A/A/O + OSR processes. Meanwhile, sludge solubilization rate, BIOLOG ECO microplate, 16S rRNA sequencing were applied comprehensively to illustrate the reasons for above advantages of the elevated ozone dosage applied. It was clarified that compared to 150 mg/L, A/A/O + OSR with ozone of 380 mg/L had higher sludge solubilization rate, less impact on bacterial community distribution and utilization capacity of carbon sources in bioreactors.


Assuntos
Ozônio , Esgotos , Reatores Biológicos , Projetos Piloto , RNA Ribossômico 16S , Eliminação de Resíduos Líquidos
9.
Am J Transl Res ; 13(11): 12988-12995, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956515

RESUMO

OBJECTIVE: To evaluate the effect of crisis intervention nursing on perioperative psychological state and self-efficacy of patients with laparoscopic radical hysterectomy. METHOD: A total of 151 cervical cancer patients that underwent laparoscopic radical surgery during January 2018 to March 2020 in our hospital were selected as the research objects. The patients were divided into control group (n=73) and observation group (n=78) according to treatment regimen. The control group received conventional nursing measures, and the observation group was treated with crisis intervention nursing in addition to the traditional measures. The changes of psychological state, self-efficacy, psychological crisis, hope degree before and after intervention, and the satisfaction of the two groups with nursing care were compared. RESULTS: The scores of HAMA, HAMD, self-efficacy, psychological crisis and hope degree in the two groups were remarkably improved after intervention compared with before intervention (all P<0.05), and the improvement of each index in observation group was obviously superior to that in control group (P<0.05). After intervention, the satisfaction to nursing care in observation group was dramatically higher than that in control group (P<0.05). CONCLUSION: The application of crisis intervention nursing on patients with laparoscopic radical hysterectomy is conductive to alleviating the adverse emotions such as anxiety and depression, reducing their sense of psychological crisis, improving the self-efficacy and hope degree of curing disease, as well as the satisfaction rate with the nursing care, which is worthy of clinical application.

10.
Front Microbiol ; 12: 744897, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34745045

RESUMO

Drought is a major threat to crop productivity and causes decreased plant growth, poor yields, and crop failure. Nevertheless, the frequency of droughts is expected to increase in the coming decades. The microbial communities associated with crop plants can influence how plants respond to various stresses; hence, microbiome manipulation is fast becoming an effective strategy for improving the stress tolerance of plants. The effect of drought stress on the root microbiome of perennial woody plants is currently poorly understood. Using Populus trees as a model ecosystem, we found that the diversity of the root microbial community decreased during drought treatment and that compositional shifts in microbes during drought stress were driven by the relative abundances of a large number of dominant phyla, including Actinobacteria, Firmicutes, and Proteobacteria. A subset of microbes, including Streptomyces rochei, Bacillus arbutinivorans, B. endophyticus, B. megaterium, Aspergillus terreus, Penicillium raperi, Trichoderma ghanense, Gongronella butleri, and Rhizopus stolonifer, was isolated from the drought-treated poplar rhizosphere soils, which have potentially beneficial to plant fitness. Further controlled inoculation experiments showed that the isolated bacterial and fungal isolates positively impacted plant growth and drought tolerance. Collectively, our results demonstrate the impact of drought on root microbiome structure and provide a novel example of manipulating root microbiomes to improve plant tolerance.

11.
Front Oncol ; 11: 733680, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722278

RESUMO

Hepatocellular carcinoma (HCC) is a common malignancy worldwide. Alpha-fetoprotein (AFP) is still the only serum biomarker widely used in clinical settings. However, approximately 40% of HCC patients exhibit normal AFP levels, including very early HCC and AFP-negative HCC; for these patients, serum AFP is not applicable as a biomarker of early detection. Thus, there is an urgent need to identify novel biomarkers for patients for whom disease cannot be diagnosed early. In this study, we screened and identified novel proteins in AFP-negative HCC and evaluated the feasibility of using autoantibodies to those protein to predict hepatocarcinogenesis. First, we screened and identified differentially expressed proteins between AFP-negative HCC tissue and adjacent non-tumor liver tissue using SWATH-MS proteome technology. In total, 2,506 proteins were identified with a global false discovery rate of 1%, of which 592 proteins were expressed differentially with 175 upregulated and 417 downregulated (adjusted p-value <0.05, fold-change FC ≥1.5 or ≤0.67) between the tumor and matched benign samples, including 14-3-3 zeta protein. For further serological verification, autoantibodies against 14-3-3 zeta in serum were evaluated using enzyme-linked immunosorbent, Western blotting, and indirect immunofluorescence assays. Five serial serum samples from one patient with AFP-negative HCC showed anti-14-3-3 zeta autoantibody in sera 9 months before the diagnosis of HCC, which gradually increased with an increase in the size of the nodule. Based on these findings, we detected the prevalence of serum anti-14-3-3 zeta autoantibody in liver cirrhosis (LC) patients, which is commonly considered a premalignant liver disease of HCC. We found that the prevalence of autoantibodies against 14-3-3 zeta protein was 16.1% (15/93) in LC patient sera, which was significantly higher than that in patients with chronic hepatitis (0/75, p = 0.000) and normal human sera (1/60, 1.7%, p = 0.01). Therefore, we suggest that anti-14-3-3 zeta autoantibody might be a biomarker for predicting hepatocarcinogenesis. Further follow-up and research of patients with positive autoantibodies will be continued to confirm the relationship between anti-14-3-3 zeta autoantibody and hepatocarcinogenesis.

12.
Pediatr Pulmonol ; 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34783192

RESUMO

OBJECTIVE: To address the effectiveness and safety of early airway combined utilization of budesonide and surfactant for bronchopulmonary dysplasia (BPD) prevention in premature infants with respiratory distress syndrome (RDS). METHODS: Literature retrieval was carried out in the PubMed, Web of Science, EMBASE, Cochrane Library, Wanfang, CQ VIP, and China National Knowledge Infrastructure databases, searching from the inception to September 2021. Stata 16.0 software was used for statistical analysis. RESULTS: This meta-analysis suggested that early combined utilization of budesonide and surfactant by airway have a superiority on BPD incidence (risk ratio [RR] = 0.62; 95% confidence interval [CI]: 0.54-0.71, p < 0.001], mortality (RR = 0.64; 95%CI: 0.45-0.92, p = 0.016), the composite outcome of BPD or mortality (RR = 0.58; 95%CI: 0.50-0.68, p < 0.001), the additional doses of surfactant (RR = 0.53; 95%CI: 0.44-0.63, p < 0.001), the duration of assisted ventilation (standard mean difference [SMD] = -1.14; 95%CI: -1.58 to -0.70, p < 0.001), duration of invasive ventilation(SMD = -1.77; 95% CI: -2.61 to -0.93, p < 0.001), and hospital stays (SMD = -1.11; 95% CI: -1.73 to -0.49, p = 0.001) in preterm infants with RDS. And these benefits were not associated with increased adverse outcomes. Furthermore, a decreased incidence of patent ducts arterious (PDA) (RR = 0.79; 95% CI: 0.65 to 0.97, p = 0.028) was found in premature infants treated with budesonide and surfactant. Subgroup analysis based on budesonide delivery methods (inhalation or intratracheal instillation) indicated that the decrease of mortality (RR = 0.63; 95% CI: 0.43-0.93, p = 0.019), duration of assisted ventilation (SMD = -0.95; 95% CI: -1.30 to -0.61, p < 0.001), hospital stays (SMD = -1.23; 95% CI: -2.05 to -0.41, p = 0.003) and PDA incidence (RR = 0.80; 95% CI: 0.65 to 0.99, p = 0.044) were mainly in budesonide intratracheal instillation subgroup, rather than in budesonide inhalation subgroup. CONCLUSIONS: This meta-analysis suggested that early combined utilization of budesonide and surfactant by airway might be an effective and safe clinical practice for BPD prevention in premature infants with RDS, especially when budesonide was delivered by intratracheal instillation. However, many of the included studies were small and were from Asian origin. More well-designed randomized controlled trials with larger sample sizes and longer follow-up from all over the world ought to be conducted in the future.

13.
PeerJ ; 9: e12429, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34820183

RESUMO

Background: Walnut is an important economic tree species with prominent economic value and ecological functions. However, in recent years, walnuts have become susceptible to drought stress, resulting in a decline in comprehensive benefits. Therefore, it is necessary to identify the regulatory molecular mechanism associated with walnut response to drought. In many plants, ethylene responsive factor (ERF) gene family plays important roles in response to biotic and abiotic stress, especial drought. Therefore, the identification and characterisation of walnut ERF genes will benefit walnut with regard to the clarification of drought response mechanism as well as the management, production, and quality of plantations. Methods: 'ERF' was compared against the walnut transcriptome, and the JrERFs with a complete open reading frame (ORF) were identified by ORF Finder. The molecular weights, amino acid residues, and theoretical isoelectric point (pI) were predicted by ExPASy. The distribution of JrERFs in chromosome locations was determined based on walnut genome data from NCBI. The intron-exon structures and conserved domains were analysed using Gene Structure Display Server 2.0 and CD-Search, accordingly. Multi-sequence alignment and a phylogenetic tree were constructed by ClustalX2.1 and MEGA7, respectively. The conserved motifs were acquired using MEME. Total RNA was isolated using the cetyltrimethylammonium ammonium bromide (CTAB) method (Yang et al., 2018). Gene expression was determined by using real-time quantitative polymerase chain reaction (qRT-PCR) analysis and calculated according to the 2-ΔΔCT method (Livak & Schmittgen, 2001). Results: A total of 44 JrERFs were identified from the walnut transcriptome, whose ORFs were 450-1,239 bp in length. The molecular weights of the JrERF proteins (consisting 149-412 amino acids) were 16.81-43.71 kDa, with pI ranging from 4.8 (JrERF11) to 9.89 (JrERF03). The JrERFs can be divided into six groups (B1-B6), and among the groups, B6 contained the most number of members. Each JrERF contained 1-6 motifs and each motif comprised 9-50 amino acids. Among the motifs, motif1, motif2, and motif3 were the most abundant. More than 40% of JrERFs were up-regulated continuously when subjected to ethephon (ETH), PEG6000, and PEG6000+ETH treatments. Of all the JrERFs, JrERF11 showed the highest expression. Therefore, we conclude that walnut ERF genes are highly conserved and involved in the regulation of drought response in the presence of ETH. JrERFs are possibly important candidate genes for molecular breeding; hence, the findings of this study provides the theoretical basis for further investigation of ERF genes in walnut and other species.

14.
Nat Commun ; 12(1): 6930, 2021 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-34836973

RESUMO

Chloranthales remain the last major mesangiosperm lineage without a nuclear genome assembly. We therefore assemble a high-quality chromosome-level genome of Chloranthus spicatus to resolve enigmatic evolutionary relationships, as well as explore patterns of genome evolution among the major lineages of mesangiosperms (eudicots, monocots, magnoliids, Chloranthales, and Ceratophyllales). We find that synteny is highly conserved between genomic regions of Amborella, Vitis, and Chloranthus. We identify an ancient single whole-genome duplication (WGD) (κ) prior to the divergence of extant Chloranthales. Phylogenetic inference shows Chloranthales as sister to magnoliids. Furthermore, our analyses indicate that ancient hybridization may account for the incongruent phylogenetic placement of Chloranthales + magnoliids relative to monocots and eudicots in nuclear and chloroplast trees. Long genes and long introns are found to be prevalent in both Chloranthales and magnoliids compared to other angiosperms. Overall, our findings provide an improved context for understanding mesangiosperm relationships and evolution and contribute a valuable genomic resource for future investigations.

15.
Dent Mater J ; 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34759126

RESUMO

This study aims to look for the best concentration of nanohydroxyapatite (NHA) and polyhexamethylene biguanide (PHMB) incorporated into glass ionomer cement (GIC) in accordance with ISO:9917-1 and evaluate its mechanical, antibacterial, biocompatible and microleakages properties. NHA was incorporated into Fuji Ⅱ GIC powder at 0-8.00 wt% concentration and specimens were prepared; the best concentration was sifted out according to ISO9917-1. Based on best NHA proportion, 0-0.80% PHMB was dispersed into powder and samples were respectively prepared. Mechanical properties include net setting time (ST), compressive strength (CS), microhardness (VNH), solubility and scanning electron microscopy (SEM) observation. Those met ISO standard were qualified to continue microleakage observation, antibacterial activity, and biocompatibility test. The results suggested that GIC/6%NHA/0.2% PHMB and GIC/6%NHA/0.4%PHMB showed great performances in mechanical, antibacterial, and microleakage improvements, and the cytotoxicity of modified GIC showed no statistical difference with pure GIC.

16.
Front Immunol ; 12: 730825, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34759919

RESUMO

Engineered variants of recombinant adeno-associated viruses (rAAVs) are being developed rapidly to meet the need for gene-therapy delivery vehicles with particular cell-type and tissue tropisms. While high-throughput AAV engineering and selection methods have generated numerous variants, subsequent tropism and response characterization have remained low throughput and lack resolution across the many relevant cell and tissue types. To fully leverage the output of these large screening paradigms across multiple targets, we have developed an experimental and computational single-cell RNA sequencing (scRNA-seq) pipeline for in vivo characterization of barcoded rAAV pools at high resolution. Using this platform, we have both corroborated previously reported viral tropisms and discovered unidentified AAV capsid targeting biases. As expected, we observed that the tropism profile of AAV.CAP-B10 in mice was shifted toward neurons and away from astrocytes when compared with AAV-PHP.eB. Transcriptomic analysis revealed that this neuronal bias is due mainly to increased targeting efficiency for glutamatergic neurons, which we confirmed by RNA fluorescence in situ hybridization. We further uncovered cell subtype tropisms of AAV variants in vascular and glial cells, such as low transduction of pericytes and Myoc+ astrocytes. Additionally, we have observed cell-type-specific transitory responses to systemic AAV-PHP.eB administration, such as upregulation of genes involved in p53 signaling in endothelial cells three days post-injection, which return to control levels by day twenty-five. The presented experimental and computational approaches for parallel characterization of AAV tropism will facilitate the advancement of safe and precise gene delivery vehicles, and showcase the power of understanding responses to gene therapies at the single-cell level.

17.
iScience ; 24(11): 103177, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34712915

RESUMO

The mammalian target of rapamycin (mTOR) is a serine-threonine kinase involved in cellular innate immunity, metabolism, and senescence. FK506-binding protein 12 (FKBP12) inhibits mTOR kinase activity via direct association. The FKBP12-mTOR association can be strengthened by the immunosuppressant rapamycin, but the underlying mechanism remains elusive. We show here that the FKBP12-mTOR association is tightly regulated by an acetylation-deacetylation cycle. FKBP12 is acetylated on the lysine cluster (K45/K48/K53) by CREB-binding protein (CBP) in mammalian cells in response to nutrient treatment. Acetyl-FKBP12 associates with CBP acetylated Rheb. Rapamycin recruits SIRT2 with a high affinity for FKBP12 association and deacetylation. SIRT2-deacetylated FKBP12 then switches its association from Rheb to mTOR. Nutrient-activated mTOR phosphorylates IRF3S386 for the antiviral response. In contrast, rapamycin strengthening FKBP12-mTOR association blocks mTOR antiviral activity by recruiting SIRT2 to deacetylate FKBP12. Hence, on/off mTOR activity in response to environmental nutrients relies on FKBP12 acetylation and deacetylation status in mammalian cells.

18.
J Exp Clin Cancer Res ; 40(1): 318, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645486

RESUMO

BACKGROUND: SETD1A, a member of SET1/MLL family H3K4 methyltransferases, is involved in the tumorigenesis of numerous cancers. However, the biological role and mechanism of SETD1A in non-small cell lung cancer (NSCLC) remain to be elucidated. METHODS: The expression of SETD1A, NEAT1, EZH2, and ß-catenin in NSCLC tissues and cell lines was detected by qRT-PCR, immunohistochemistry and western blotting. The regulatory mechanisms were validated by chromatin immunoprecipitation, co-immunoprepitation and luciferase reporter assay. The self-renewal, cisplatin sensitivity and tumorigenesis of NSCLC cells were analyzed using sphere formation, CCK-8, colony formation assays and xenograft tumor models. RESULTS: SETD1A expression was significantly increased in NSCLC and its overexpression predicted a poor prognosis of patients with NSCLC. Functional experiments showed that SETD1A positively regulated cancer stem cell property and negatively regulated cisplatin sensitivity in NSCLC cells via the Wnt/ß-catenin pathway. Next, we found that SETD1A positively regulated the Wnt/ß-catenin pathway via interacting with and stabilizing ß-catenin. The SET domain is dispensable for the interaction between SETD1A and ß-catenin. Furthermore, we identified that SETD1A bound to the promoters of NEAT1 and EZH2 to activate gene transcription by inducing H3K4me3 enrichment. Rescue experiments showed that SETD1A promoted the Wnt/ß-catenin pathway and exerted its oncogenic functions in NSCLC, at least, partly through NEAT1 and EZH2 upregulation. In addition, SETD1A was proven to be a direct target of the Wnt/ß-catenin pathway, thus forming a positive feedback loop in NSCLC cells. CONCLUSION: SETD1A and Wnt/ß-catenin pathway form a positive feedback loop and coordinately contribute to NSCLC progression.

19.
Nat Commun ; 12(1): 5550, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34548496

RESUMO

Understanding human development is of fundamental biological and clinical importance. Despite its significance, mechanisms behind human embryogenesis remain largely unknown. Here, we attempt to model human early embryo development with expanded pluripotent stem cells (EPSCs) in 3-dimensions. We define a protocol that allows us to generate self-organizing cystic structures from human EPSCs that display some hallmarks of human early embryogenesis. These structures mimic polarization and cavitation characteristic of pre-implantation development leading to blastocyst morphology formation and the transition to post-implantation-like organization upon extended culture. Single-cell RNA sequencing of these structures reveals subsets of cells bearing some resemblance to epiblast, hypoblast and trophectoderm lineages. Nevertheless, significant divergences from natural blastocysts persist in some key markers, and signalling pathways point towards ways in which morphology and transcriptional-level cell identities may diverge in stem cell models of the embryo. Thus, this stem cell platform provides insights into the design of stem cell models of embryogenesis.


Assuntos
Blastocisto/citologia , Técnicas de Cultura de Células , Embrião de Mamíferos/citologia , Desenvolvimento Embrionário/genética , Modelos Biológicos , Células-Tronco Pluripotentes/citologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores/metabolismo , Blastocisto/metabolismo , Linhagem da Célula/genética , Embrião de Mamíferos/anatomia & histologia , Embrião de Mamíferos/metabolismo , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Expressão Gênica , Humanos , Fosfolipase C beta/genética , Fosfolipase C beta/metabolismo , Células-Tronco Pluripotentes/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição SOXF/genética , Fatores de Transcrição SOXF/metabolismo , Análise de Sequência de RNA , Análise de Célula Única
20.
Front Pharmacol ; 12: 621300, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489689

RESUMO

Systemic lupus erythematosus (SLE) is a multisystem autoimmune inflammatory condition that affects multiple organs and provokes extensive and severe clinical manifestations. Lupus nephritis (LN) is one of the main clinical manifestations of SLE. It refers to the deposition of immune complexes in the glomeruli, which cause kidney inflammation. Although LN seriously affects prognosis and represents a key factor of disability and death in SLE patients, its mechanism remains unclear. The NACHT, leucine-rich repeat (LRR), and pyrin (PYD) domains-containing protein 3 (NLRP3) inflammasome regulates IL-1ß and IL-18 secretion and gasdermin D-mediated pyroptosis and plays a key role in innate immunity. There is increasing evidence that aberrant activation of the NLRP3 inflammasome and downstream inflammatory pathways play an important part in the pathogenesis of multiple autoimmune diseases, including LN. This review summarizes research progress on the elucidation of NLRP3 activation, regulation, and recent clinical trials and experimental studies implicating the NLRP3 inflammasome in the pathophysiology of LN. Current treatments fail to provide durable remission and provoke several sides effects, mainly due to their broad immunosuppressive effects. Therefore, the identification of a safe and effective therapeutic approach for LN is of great significance. Phytochemicals are found in many herbs, fruits, and vegetables and are secondary metabolites of plants. Evidence suggests that phytochemicals have broad biological activities and have good prospects in a variety of diseases, including LN. Therefore, this review reports on current research evaluating phytochemicals for targeting NLRP3 inflammasome pathways in LN therapy.

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