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1.
Sci Rep ; 12(1): 9258, 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35660780

RESUMO

Pervious concrete (PC) pavement has been widely accepted as a green infrastructure but is prone to clogging. This study comparatively investigated sand and clay clogging mechanisms of PC and vertical sediment distributions of sand-clogged and clay-clogged PCs. Clay and three sizes of sand were used to clog PC under two exposure methods (no drying and drying). X-ray computed tomography (CT) was used to scan the clogged samples before and after 30 pressure washing cycles. The clogged permeability and permeability after each washing cycle were measured. The clogging patterns of sand depend mainly on sand particle sizes relative to PC pore sizes. The applied fine sand, coarse sand, and medium sand cause easy-passing clogging, surface clogging, and full-depth clogging, respectively. After clay clogging, more than 77% of the total retained clay occurs within the vertical region 24-72 mm below the sample surface; the most clogging (the lowest-permeability layer) occurs at a depth of approximately 48 mm. The dried clay retained within the region 40-120 mm below the surface (especially within the lowest-permeability layer) is hard to wash away because the drying process increases the cohesion of internal clay particles and clay adhesion to the rough, tortuous pore wall of PC. The clogged normalized permeability of 0.154 and permeability recovery ratio of 4.91% in dried clay-clogged samples are lowest among all the samples. However, pressure washing readily washes away the retained undried clay. Accordingly, it is recommended that pressure washing is used to eliminate the clogging effect of dried clay before hot, sunny exposure conditions dry the retained clay. This study provides evidence for developing effective pavement maintenance strategies.

2.
Brain Imaging Behav ; 2022 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-35665464

RESUMO

Stroke induced by basal ganglia infarction often impair cognitive function. The exploration of topological patterns in structural and functional networks associated cognitive impairment after stroke may contribute to understand the pathological mechanism of cognitive impairment caused by stroke. In this paper, graph theory analysis was applied to diffusion-weighted imaging (DWI) data and resting-state functional MRI (fMRI) data from 23 post-stroke patients with cognitive impairment (PSCI), 17 post-stroke patients without cognitive impairment (NPSCI), and 29 healthy controls (HC). Structural and functional connectivity between 90 cortical and subcortical brain regions was estimated and set threshold to construct a set of undirected graphs. Network-based statistics (NBS) was used to characterize altered connectivity patterns among the three groups. Compared to HC, the PSCI group demonstrated substantial reductions in all three types of connections-rich club, feeder, and local-in structural and functional networks. Specifically, in structural network analysis, reduced connections were observed within basal ganglia and basal ganglia-frontal networks, whereas in the functional network analysis, reduced connections were observed in fronto-parietal network (FPN) and cingulo-opercular networks (CON). Meanwhile, compared to HC, the NPSCI group demonstrated reductions in both feeder and local connections only within occipital area and occipital-temporal structural networks. The findings of reduced structural connectivity in regions stemming from a basal ganglia core and reduced functional connectivity in FPN and CON may indicate a bottom-up cognitive impairment induced by stroke. Graph analysis and connectomics may aid clinical diagnosis and serve as potential imaging biomarkers for post-stroke patients with cognitive impairment.

3.
Chem Commun (Camb) ; 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35666182

RESUMO

A heterostructured covalent organic framework (COF) membrane is synthesized via in situ linker exchange. Narrowed pores can be formed at the interface between two types of COFs by adjusting the linker exchange duration. The resultant COF membrane demonstrates a high rejection rate toward Na2SO4 of up to 97%.

5.
Chem Sci ; 13(20): 5999-6007, 2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35685785

RESUMO

Beyond the AIE (aggregation-induced emission) phenomenon in small molecules, supramolecules with AIE properties have evolved in the AIE family and accelerated the growth of supramolecular application diversity. Inspired by its mechanism, particularly the RIV (restriction of intramolecular vibrations) process, a feasible strategy of constructing an AIE-supramolecular cage based on the oxidation of sulfur atoms and coordination of metals is presented. In contrast to previous strategies that used molecular stacking to limit molecular vibrations, we achieved the desired goal using the synergistic effects of coordination-driven self-assembly and oxidation. Upon assembling with zinc ions, S1 was endowed with a distinct AIE property compared with its ligand L1, while S2 exhibited a remarkable fluorescence enhancement compared to L2. Also, the single cage-sized nanowire structure of supramolecules was obtained via directional electrostatic interactions with multiple anions and rigid-shaped cationic cages. Moreover, the adducts of zinc porphyrin and supramolecules were investigated and characterized by 2D DOSY, ESI-MS, TWIM-MS, UV-vis, and fluorescence spectroscopy. The protocol described here enriches the ongoing research on tunable fluorescence materials and paves the way towards constructing stimuli-responsive luminescent supramolecular cages.

6.
Front Oncol ; 12: 843325, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35686102

RESUMO

Carboxypeptidase N2 (CPN2) is a plasma metallo-protease that cleaves basic amino acids from the C-terminal of peptides and proteins. Emerging evidence showed that carboxypeptidases perform many diverse functions in the body and play key roles in tumorigenesis. However, the clinical significance and biological functions of CPN2 in lung adenocarcinoma remain unclear. Our study aimed to explore the potential role and functions of CPN2 in lung adenocarcinoma. The results showed that the transcription level of CPN2 was significantly increased in the tumor tissues of lung adenocarcinoma patients compared to the adjacent normal tissues in The Cancer Genome Atlas cohort (P < 0.05). The survival plots showed that the overall survival of patients with a high expression of CPN2 was significantly lower than that of patients with a low expression of CPN2, both in the Kaplan-Meier database and the clinical sample cohort (P < 0.05). The tissue microarray analysis found that CPN2 protein expression was significantly positively correlated with node status and tumor stage as well as tumor malignancy (P < 0.05). Further univariate and multivariate Cox regression analyses showed that CPN2 may act as an independent prognostic factor in patients with lung adenocarcinoma (P < 0.05). In addition, the analysis of co-expression genes from LinkedOmics showed that CPN2 was positively associated with many genes of fibrillar collagen family members and the PI3K-Akt pathway. The gene set enrichment analysis showed that a higher expression of CPN2 may participate in mTOR, TGF-BETA, NOTCH, TOLL-like-receptor, WNT, and MAPK signaling pathway in lung adenocarcinoma. Notably, the knockdown of CPN2 significantly inhibited the ability of cell proliferation, clone formation, invasion, and migration. Our findings suggested that the upregulation of CPN2 is associated with a worse clinical outcome in lung adenocarcinoma and cancer-related pathways, which laid the foundation for further research on CPN2 during carcinogenesis.

7.
Org Lett ; 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35687371

RESUMO

Herein, we describe the copper-catalyzed arylalkylation of activated alkenes via hydrogen-atom transfer and aryl migration strategy. The reaction was carried out through a radical-mediated continuous migration pathway using N-fluorosulfonamides as the alkyl source. The primary, secondary, and tertiary alkyl radicals formed by intramolecular hydrogen-atom transfer proceeded smoothly. This methodology is an efficient approach for the synthesis of various amide derivatives possessing a quaternary carbon center with good yields and high regioselectivity.

8.
Artigo em Inglês | MEDLINE | ID: mdl-35696613

RESUMO

Inspired by nature's ability to shape soft biological materials to exhibit a range of optical functionalities, we report femtosecond (fs) laser-induced densification as a new method to generate volume or subsurface diffractive gratings within ordinary hydrogel materials. We characterize the processing range in terms of fs laser power, speed, and penetration depths for achieving densification within poly(ethylene glycol) diacrylate (PEGDA) hydrogel and characterize the associated change in local refractive index (RI). The RI change facilitates the fabrication of custom volume gratings (parallel line, grid, square, and ring gratings) within PEGDA. To demonstrate this method's broad applicability, fs laser densification was used to generate line gratings within the phenylboronic acid (PBA) hydrogel, which is known to be responsive to changes in pH. In the future, this technique can be used to convert ordinary hydrogels into multicomponent biophotonic systems.

9.
Accid Anal Prev ; 173: 106721, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35659647

RESUMO

Understanding the relationship between social vulnerability and traffic crashes is a cornerstone for promoting social justice in transportation planning and policymaking. However, few studies have examined the disparities in traffic crashes by systemically considering the influence of social vulnerability via spatial analysis approaches. This study puts forward a new approach to assess the inequity in transportation safety by spatially examining the relationships between crash risks and the social vulnerability index (SVI) established by the Centers for Disease Control and Prevention (CDC). We performed spatial autocorrelation analyses to identify the clusters of high-risk and high-vulnerable census tracts in Texas. Meanwhile, we innovatively applied the Multiscale Geographically Weighted Regression model (MGWR) to assess the impacts of CDC SVI on crash risks spatially and statistically. The results demonstrate that the crash rate and the social vulnerability are significantly correlated in the highly urbanized regions as well as the southern border along the Rio Grande in Texas. The MGWR results indicate the minority status of census tracts is strongly correlated with overall crashes in north-central and northeastern Texas, and the socioeconomic status is tightly correlated with fatal crashes across Texas. The outcomes from this study have significant implications for transportation planning and policymaking.


Assuntos
Acidentes de Trânsito , Vulnerabilidade Social , Humanos , Análise Espacial , Regressão Espacial , Texas/epidemiologia
10.
JAMA Netw Open ; 5(6): e2215589, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35666500

RESUMO

Importance: Consolidative durvalumab after definitive chemoradiation for unresectable locally advanced non-small cell lung cancer (NSCLC) can significantly improve progression-free survival (PFS) and overall survival (OS), as shown in the PACIFIC trial. However, whether patients with driver variations derive equal benefit from this regimen remains unclear. Objectives: To compare outcomes of patients with locally advanced NSCLC with and without driver variations treated with the PACIFIC regimen. Design, Setting, and Participants: This cohort study examined 104 patients with unresectable locally advanced NSCLC with mutational profiling treated at a tertiary cancer center with definitive chemoradiation and consolidative durvalumab from June 2017 through May 2020. Patients with recurrent disease or those receiving postoperative therapy were excluded. Outcomes were analyzed with Kaplan-Meier and multivariate regression analyses. Exposures: Patients were grouped according to the presence of non-KRAS driver variations (EGFR exon 19 deletion, EGFR exon 20 insertion, EGFR exon 21 mutation [L858R], ERBB2 exon 20 insertion, EML4-ALK fusion, MET exon 14 skipping, NTRK2 fusion), KRAS driver variations, or no driver variations. Main Outcomes and Measures: The primary outcomes were PFS, OS, and second progression-free survival (PFS2) times. Results: The 104 patients had a median (IQR) age of 65.1 (9.8) years, with 55 females (53%) and 85 former or current smokers (88%). There were 43 patients (41%) with driver variations with a median PFS time of 8.4 months vs 40.1 months for patients without driver variations (hazard ratio [HR], 2.75; 95% CI, 1.64-4.62; log-rank P < .001). Both patients with non-KRAS and KRAS driver variations had worse PFS. No difference in OS was found between patients with and without driver variations (log rank P = .24). Among the 63 patients who developed progressive disease, those with non-KRAS driver variations had a median PFS2 time of 13.7 months vs 4.4 months for all other patients (HR, 0.37; 95% CI, 0.21-0.64; log-rank P = .001). Rates of overall grade 2 toxic effects or higher did not differ by driver mutation status. Conclusions and Relevance: In this cohort study, driver variations in patients with unresectable locally advanced NSCLC were associated with significantly shorter PFS time after definitive chemoradiation and consolidative durvalumab. These findings suggest the need to consider additional or alternative treatment options to the PACIFIC regimen for patients with driver variations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Anticorpos Monoclonais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Estudos de Coortes , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Oncogenes , Proteínas Proto-Oncogênicas p21(ras)/genética
11.
Cell Metab ; 34(6): 888-901.e5, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35675799

RESUMO

Homeostatic thermogenesis is an essential protective feature of endotherms. However, the specific neuronal types involved in cold-induced thermogenesis remain largely unknown. Using functional magnetic resonance imaging and in situ hybridization, we screened for cold-sensitive neurons and found preprodynorphin (PDYN)-expressing cells in the dorsal medial region of the ventromedial hypothalamus (dmVMH) to be a candidate. Subsequent in vivo calcium recording showed that cold temperature activates dmVMHPdyn neurons, whereas hot temperature suppresses them. In addition, optogenetic activation of dmVMHPdyn neurons increases the brown adipose tissue and core body temperature, heart rate, and blood pressure, whereas optogenetic inhibition shows opposite effects, supporting their role in homeostatic thermogenesis. Furthermore, we found that dmVMHPdyn neurons are linked to known thermoregulatory circuits. Importantly, dmVMHPdyn neurons also show activation during mouse social interaction, and optogenetic inhibition suppresses social interaction and associated hyperthermia. Together, our study describes dual functions of dmVMHPdyn neurons that allow coordinated regulation of body temperature and social behaviors.


Assuntos
Hipertermia Induzida , Interação Social , Tecido Adiposo Marrom , Animais , Temperatura Baixa , Hipotálamo , Camundongos , Neurônios/fisiologia , Termogênese/fisiologia
12.
Sci Total Environ ; 839: 156274, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35644391

RESUMO

China is facing dual challenges of air pollution and climate change. By using city-level data, we comprehensively assessed air quality and CO2 emission changes from 2015 to 2019 for 335 Chinese cities. We selected important regions for air pollution control and categorized all cities into different classes according to their development levels. Our novel approach revealed new insights on different patterns of changes of PM2.5, O3, and CO2 by region and city class. We found that PM2.5 concentrations decreased remarkably due to mandatory city-level reduction targets, especially in the Beijing-Tianjin-Hebei (-27%) region. Nonetheless, O3 concentrations and CO2 emissions increased in 91% and 69% of Chinese cities, respectively. Observed CO2 emission reductions in more developed cities were mainly due to prominent energy intensity reduction and energy structure improvement. Our study indicates a lack of synergy in air pollution control and CO2 mitigation under current policies in China. To address both challenges holistically, we suggest setting mandatory city-level CO2 emission reduction targets and reinforcing clean energy and energy efficiency measures.

13.
Phytomedicine ; 103: 154222, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35675750

RESUMO

BACKGROUND: Dioscin, a steroidal saponin natural product, has various pharmacological activities, such as anti-inflammatory, antioxidant, lipid-lowering. However, little is known about its effects on myocardial infarction (MI) injury. Thus, the study aimed to investigate the protective effects and possible mechanisms of dioscin. METHODS: We evaluated protective effects of Dioscin on HL-1 cells after hypoxia based on MTT and ROS in vitro. In vivo, we ligated left anterior descending (LAD) of C57BL/6 mice to establish MI model and assess serum levels of LDH, CK-MB, cTnI, SOD, MDA and CAT treated by dioscin. In addition, myocardial damages were reflected by H&E, masson and ultrastructural examination and Electrocardiograph (ECG) was detected in MI mice. And the BMP4/NOX1 pathway was measured by western blotting, immunofluorescence assay and Real-time PCR. Furthermore, to investigate cardio-protective effects of dioscin via targeting BMP4, we transfected siBMP4 into HL-1 cells in vitro and injected BMP4 siRNA though tail veins in vivo. RESULTS: In vitro, dioscin significantly increased the viability of HL-1 cells and inhibited ROS level under hypoxia. In vivo, dioscin markedly reduced the elevation of ST segment and alleviated myocardial infarct area in mice. In terms of serology, dioscin evidently decreased LDH, CK-MB, cTnI, MDA levels, and increased SOD level. In addition, dioscin improved the pathological status of myocardial tissue and restrained the production of collagen fibers. Mechanism study proved that dioscin notablely regulated the levels of Nrf2, Keap1, HO-1, p-NF-κB, nNF-κB, TNF-α, IL-1ß and IL-6 by down-regulating the protein levels of BMP4 and NOX1 against oxidative stress and inflammation. Further investigation showed that siBMP4 transfection diminished hypoxia and MI-induced oxidative and inflammation injury. The transfection decreased LDH, CK-MB and cTnI levels, improved ischemia T-wave inversion and reduced striated muscle necrosis, nucleus dissolution, collagen fibrosis and mitochondrial swelling in mice. In addition, siBMP4 decreased ROS and MDA levels, increased SOD and CAT levels and down-regulated mRNA levels of TNF-α, IL-1ß and IL-6. Moreover, BMP4, NOX1 and nNF-κB protein levels were decreased and Nrf2 levels were increased by siBMP4. CONCLUSION: Our study confirmed that dioscin showed an outstanding anti-myocardial infarction effect via regulating BMP4/NOX1-mediated oxidative stress and inflammation, which has a promising application value and development prospect against MI injury in the future.

14.
EBioMedicine ; 81: 104097, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35687958

RESUMO

BACKGROUND: Most malignant brain gliomas (MBGs) are associated with dismal outcomes, mainly due to their late diagnosis. Current diagnostic methods for MBGs are based on imaging and histological examination, which limits their early detection. Here, we aimed to identify reliable plasma lipid biomarkers for non-invasive diagnosis for MBGs. METHODS: Untargeted lipidomic analysis was firstly performed using a discovery cohort (n=107). The data were processed by a support vector machine (SVM)-based discriminating model to retrieve a panel of candidate biomarkers. Then, a targeted quantification method was developed, and the SVM-based diagnostic model was constructed using a training cohort (n=750) and tested using a test cohort (n=225). Finally, the performance of the diagnostic model was further evaluated in an independent validation cohort (n=920) enrolled from multiple medical centers. FINDINGS: A panel of 11 plasma lipids was identified as candidate biomarkers with an accuracy of 0.999. The diagnostic model developed achieved a high performance in distinguishing MBGs patients from normal controls with an area under the receiver-operating characteristic curve (AUC) of 0.9877 and 0.9869 in the training and test cohorts, respectively. In the validation cohort, the 11 lipid panel still achieved an accuracy of 0.9641 and an AUC of 0.9866. INTERPRETATION: The present study demonstrates the applicability and robustness of utilizing a machine learning algorithm to analyze lipidomic data for efficient and reliable biomarker screening. The 11 lipid biomarkers show great potential for the non-invasive diagnosis of MBGs with high throughput. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgments section.

16.
Phys Rev E ; 105(5): L053203, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35706321

RESUMO

Higher implosion efficiency is of great significance in direct-drive fusion research. We demonstrated the critical role played by the intensity gradient of the main drive laser pulse in improving efficiency of direct-drive implosions, using a double-gradient nanosecond pulse. Compared with a square pulse, the burn-through depth was increased by over 200%, and the shell velocity was increased by ∼2.1 times with an optimized double-gradient pulse. As the result, the implosion efficiency was enhanced by ∼ six times. It was found that by limiting the intensity gradient of the main drive pulse to no more than ∼2.5×10^{15}W/(cm^{2}ns), heat flux inhibition by nonlocal electron thermal transport effects could be eliminated, and ultimately an efficient mass ablation process was achieved. These results have relevance for pulse designs in ignition-scale direct-drive implosions.

17.
Cell Cycle ; : 1-20, 2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35708677

RESUMO

circFCHO2 has been revealed to be overexpressed in gastric cancer (GC) patients. This article identified the function of circFCHO2 on GC progression. The expression of circFCHO2, miR-194-5p and JAK1 in 30 GC patients and cells was monitored by quantitative reverse transcription-polymerase chain reaction. circFCHO2 localization in GC cells was monitored by RNA fluorescence in situ hybridization. Cell counting kit-8 assay, 5-ethynyl-2-deoxyuridine staining, transwell experiment, tube formation and sphere formation experiments were applied to detect GC cell proliferation, invasion, angiogenesis and cancer stem cell characteristics. Dual-luciferase reporter gene assay, RNA pull down assay and RNA immunoprecipitation experiment were utilized to research the binding between two genes. In vivo tumorigenesis and lung metastasis were studied using nude mice. Immunohistochemistry and hematoxylin-eosin staining were conducted. Protein expression was assessed by Western blot. Serum exosomes of GC patients and healthy participants were isolated. circFCHO2 up-modulation in GC patients was related to poor outcome. circFCHO2 was located in the cytoplasm of GC cells. circFCHO2 silencing weakened the proliferation, invasion, angiogenesis and stem cell characteristics of GC cells. miR-194-5p knockdown counteracted this effect. circFCHO2 activated the JAK1/STAT3 pathway by sponging miR-194-5p. miR-194-5p overexpression attenuated the malignant phenotypes of GC cells. JAK1 overexpression abrogated this effect. circFCHO2 silencing weakened GC cells growth and lung metastasis in vivo. circFCHO2 was up-modulated in serum exosomes of GC patients. circFCHO2 was an oncogene in GC by activating the JAK1/STAT3 pathway via sponging miR-194-5p. circFCHO2 might be a novel target and diagnostic marker for GC.

18.
Dalton Trans ; 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35713013

RESUMO

Y-SBA-15 was synthesized by doping yttrium (Y) into SBA-15 using a solvent-free solid-state grinding method, and 1-butyl-3-methylimidazolium phosphomolybdic salt ([Bmim]3PMo12O40, abbreviated as [Bmim]PMoO) was also synthesized. [Bmim]PMoO/Y-SBA-15 was prepared and used for oxidative desulfurization (ODS). The physicochemical characteristics of the catalyst have been characterized by FT-IR, XRD, N2 adsorption-desorption, FESEM, TEM, XPS, contact angle testing, EPR, etc. A lipophilic surface is beneficial for making the catalyst well disperse in an oil phase, and a hydrophilic core can help to store aqueous oxidants. Therefore, the amphiphilic catalyst 25[Bmim]PMoO/10Y-SBA-15 exhibited high catalytic activity in dibenzothiophene (DBT) ODS, and sulfur compounds can be removed completely within 40 min under the following conditions: VOil = 10 mL, mcatalyst = 0.1 g, m[Bmim]PMoO : m[Bmim]PMoO/10Y-SBA-15 = 25%, and O/S = 4 (molar ratio). In addition, the concentration of aromatics exerted little effect on the DBT ODS. Sulfur compounds in real diesel might be reduced to 8 µg g-1. The hydroxyl radical ˙OH and superoxide radical ˙O2- play crucial roles in the ODS reaction, and the ODS reaction mechanism was also proposed.

19.
Neural Plast ; 2022: 1483101, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35574247

RESUMO

A mounting body of evidence suggests that prenatal inflammation may enhance the rate of age-associated cognitive decline and may involve aberrant amounts of synaptic proteins in the hippocampus, including synaptotagmin-1 (Syt1) and activity-regulated cytoskeleton-associated protein (Arc). However, little is known about the specific impact of adolescent environmental enrichment (EE) on age-associated cognitive decline and the changes in synaptic proteins caused by prenatal inflammation. In this study, CD-1 mice in late pregnancy were given intraperitoneal doses of lipopolysaccharide (LPS, 50 µg/kg) or normal saline. Offspring arising from LPS dams were divided into a LPS group and a LPS plus EE (LPS-E) group. The LPS-E mice were exposed to EE from 2 months of age until the end of the experiment (3 or 15 months old). The Morris water maze (MWM) was used to assess the spatial learning and memory capacities of experimental mice, while western blotting and RNA-scope were used to determine the expression levels of Arc and Syt1 in the hippocampus at the protein and mRNA levels, respectively. Analysis revealed that at 15 months of age, the control mice experienced a reduction in cognitive ability and elevated expression levels of Arc and Syt1 genes when compared to control mice at 3 months of age. The LPS-E group exhibited better cognition and lower protein and mRNA levels of Arc and Syt1 than mice in the LPS group of the same age. However, the enriched environment mitigated but did not counteract, the effects of prenatal inflammation on cognitive and synaptic proteins when tested at either 3 or 15 months of age. Our findings revealed that long-term environmental enrichment improved the expression levels of synaptic proteins in CD-1 mice and that this effect was linked to the dysfunctional cognition caused by prenatal inflammation; this process may also be involved in the reduction of hippocampal Arc and Syt1 gene expression.


Assuntos
Lipopolissacarídeos , Aprendizagem Espacial , Animais , Cognição , Feminino , Hipocampo/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Aprendizagem em Labirinto , Camundongos , Gravidez , RNA Mensageiro/metabolismo
20.
Signal Transduct Target Ther ; 7(1): 157, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35551173

RESUMO

Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics, and currently used drugs cannot reverse the disease progress. Worse still, there are still challenges to be addressed to fully decipher the intricated pathogenesis. Thus, specifying the essential mechanisms and targets in silicosis progression then exploring anti-silicosis pharmacuticals are desperately needed. In this work, multi-omics atlas was constructed to depict the pivotal abnormalities of silicosis and develop targeted agents. By utilizing an unbiased and time-resolved analysis of the transcriptome, proteome and phosphoproteome of a silicosis mouse model, we have verified the significant differences in transcript, protein, kinase activity and signaling pathway level during silicosis progression, in which the importance of essential biological processes such as macrophage activation, chemotaxis, immune cell recruitment and chronic inflammation were emphasized. Notably, the phosphorylation of EGFR (p-EGFR) and SYK (p-SYK) were identified as potential therapeutic targets in the progression of silicosis. To inhibit and validate these targets, we tested fostamatinib (targeting SYK) and Gefitinib (targeting EGFR), and both drugs effectively ameliorated pulmonary dysfunction and inhibited the progression of inflammation and fibrosis. Overall, our drug discovery with multi-omics approach provides novel and viable therapeutic strategies for the treatment of silicosis.


Assuntos
Fibrose Pulmonar , Silicose , Aminopiridinas , Animais , Receptores ErbB , Gefitinibe/farmacologia , Inflamação , Camundongos , Morfolinas , Fibrose Pulmonar/patologia , Piridinas/uso terapêutico , Pirimidinas , Silicose/tratamento farmacológico , Silicose/genética , Silicose/metabolismo
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