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COP9 signalosome catalytic subunit CSN5 plays a key role in tumorigenesis and tumor immunity, showing potential as an anticancer target. Currently, only a few CSN5 inhibitors have been reported, at least partially, due to the challenges in establishing assays for CSN5 deubiquitinase activity. Here, we present the establishment and validation of a simple and reliable non-catalytic activity assay platform for identifying CSN5 inhibitors utilizing a new fluorescent probe, CFP-1, that exhibits enhanced fluorescence and fluorescence polarization features upon binding to CSN5. By using this platform, we identified 2-aminothiazole-4-carboxylic acids as new CSN5 inhibitors, which inhibited CSN5 but slightly downregulated PD-L1 in cancer cells. Furthermore, through the integration of deep learning-enabled virtual screening, we discovered that shikonins are nanomolar CSN5 inhibitors, which can upregulate PD-L1 in HCT116 cells. The binding modes of these structurally distinct inhibitors with CSN5 were explored by using microsecond-scale molecular dynamics simulations and tryptophan quenching assays.
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Complexo do Signalossomo COP9 , Humanos , Complexo do Signalossomo COP9/metabolismo , Complexo do Signalossomo COP9/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Simulação de Dinâmica Molecular , Corantes Fluorescentes/química , Células HCT116 , Antineoplásicos/farmacologia , Antineoplásicos/química , Descoberta de Drogas/métodos , Relação Estrutura-Atividade , Peptídeo Hidrolases , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
Chemical denitrification by redox-active Fe(II) species is pivotal in the coupled iron and nitrogen cycles. The reductive dissolution of ferric minerals by ligand can generate Fe(II)-ligand complexes, but their reducing capability for electrophilic pollutants like nitrate and nitrite remains uncertain. Here, biogenic secondary iron minerals (SIM) after dissimilatory iron reduction were reductively dissolved by oxalate and the siderophore desferrioxamine B, and subsequently the partially-dissolved SIM (SIMD) effectively removed NO2- from groundwater via reduction, while exhibiting much lower reactivity towards NO3-. The dissolution and removal processes were well-fitted with the Kabai model and the pseudo-second-order adsorption model, respectively. The equilibrium NO2- removal capacity (qe) of SIMD reached 0.146-0.223 mmol/g, accompanied with the rate constants as 0.433-0.810 g/(mmol·h). The emission of N2O and NO verified the occurrence of chemical denitrification during NO2- removal by SIMD. From the perspective of Fe(II) reactivity, SIMD exhibited higher densities of surface Fe(II) and more negative Eh values than SIM, and these two indicators showed linear correlations with the removal rates. Combined with microscopic, electrochemical and spectral analysis, our results indicated the redox reaction of adsorbed Fe(II)-complexes with NO2- on SIMD surface. The concurrent substance biochar was also considered, as it indirectly influenced dissolution and pollutant removal by shifting the iron mineral phase in SIM from magnetite to goethite. These findings highlight the significant role of reductive dissolution of iron mineral in N transformation, expand the electron pool available to support chemical denitrification, and have implications for Fe and N cycling coupling with pollutant reduction.
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An increasing number of studies have demonstrated the presence of per and polyfluoroalkyl substances (PFAS) in the vapor phase. It is therefore important to consider the potential for vapor-phase transport of PFAS in soil and the vadose zone and to investigate the processes impacting the retention and transport of volatile PFAS in soil. It is also critically important to evaluate existing models and develop new models as needed for their application to PFAS vapor-phase transport. The objectives of the present work were to provide an overview of vapor-phase transport processes and modeling, with a specific focus on their relevance for PFAS, and to discuss implications for mass discharge to groundwater, vapor intrusion, and soil vapor extraction. Decades of research have been devoted to the retention and transport of legacy volatile organic contaminants in the vadose zone. This work provides an abundant source of information concerning the many factors and processes of relevance, and insights into the development and application of mathematical modeling. However, given the unique properties of PFAS, there is a need to conduct research to investigate vapor-phase transport of PFAS and to develop PFAS-specific models. We highlight with illustrative examples that vapor-phase transport can be significantly more rapid than aqueous-phase advective transport, which can result in enhanced mass discharge to groundwater.
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By incorporating polar fibers into the design of electrorheological (ER) fluids, a 130% performance improvement can be achieved with the addition of only 0.8 vol% of polar long fibers. We quantitatively analyzed the impact of relatively long fibers on improving ER performance by measuring the yield stress, shear stress, and current density after adding fibers. Both optical microscopy and transmission electron microscopy were used to observe and analyze the interaction between ER particles and polar fibers. The results indicate that, under the influence of an electric field, the fibers transform the one-dimensional chain-like structure into a two-dimensional mesh structure, greatly improving the ER performance. The transformation of structure induced by the polar fibers in the ER fluids amplifies the ER effect. However, the inclusion of non-polar fibers does not contribute to this enhancement, as a point of comparison. Moreover, to ensure the universality of this method, we used two different types of ER fluids in experiments. The utilization of this method offers a straightforward, environmentally friendly, and highly effective approach. Furthermore, this study provides a novel technical solution aimed at enhancing the performance of ER fluids.
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BACKGROUND AND AIMS: Physical activity has proven effective in preventing atherosclerotic cardiovascular disease, but its role in preventing degenerative valvular heart disease (VHD) remains uncertain. This study aimed to explore the dose-response association between moderate to vigorous physical activity (MVPA) volume and the risk of degenerative VHD among middle-aged adults. METHODS: A full week of accelerometer-derived MVPA data from 87 248 UK Biobank participants (median age 63.3, female: 56.9%) between 2013 and 2015 were used for primary analysis. Questionnaire-derived MVPA data from 361 681 UK Biobank participants (median age 57.7, female: 52.7%) between 2006 and 2010 were used for secondary analysis. The primary outcome was the diagnosis of incident degenerative VHD, including aortic valve stenosis (AS), aortic valve regurgitation (AR), and mitral valve regurgitation (MR). The secondary outcome was VHD-related intervention or mortality. RESULTS: In the accelerometer-derived MVPA cohort, 555 incident AS, 201 incident AR, and 655 incident MR occurred during a median follow-up of 8.11 years. Increased MVPA volume showed a steady decline in AS risk and subsequent AS-related intervention or mortality risk, levelling off beyond approximately 300 min/week. In contrast, its association with AR or MR incidence was less apparent. The adjusted rates of AS incidence (95% confidence interval) across MVPA quartiles (Q1-Q4) were 11.60 (10.20, 13.20), 7.82 (6.63, 9.23), 5.74 (4.67, 7.08), and 5.91 (4.73, 7.39) per 10 000 person-years. The corresponding adjusted rates of AS-related intervention or mortality were 4.37 (3.52, 5.43), 2.81 (2.13, 3.71), 1.93 (1.36, 2.75), and 2.14 (1.50, 3.06) per 10 000 person-years, respectively. Aortic valve stenosis risk reduction was also observed with questionnaire-based MVPA data [adjusted absolute difference Q4 vs. Q1: AS incidence, -1.41 (-.67, -2.14) per 10 000 person-years; AS-related intervention or mortality, -.38 (-.04, -.88) per 10 000 person-years]. The beneficial association remained consistent in high-risk populations for AS, including patients with hypertension, obesity, dyslipidaemia, and chronic kidney disease. CONCLUSIONS: Higher MVPA volume was associated with a lower risk of developing AS and subsequent AS-related intervention or mortality. Future research needs to validate these findings in diverse populations with longer durations and repeated periods of activity monitoring.
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Objective: The identification of depression primarily relies on the clinical symptoms and psychiatric evaluation of the patient, in the absence of objective and quantifiable biomarkers within clinical settings. This study aimed to explore potential serum biomarkers associated with depression. Methods: Serum samples from a training group comprising 48 depression patients and 48 healthy controls underwent proteomic analysis. Magnetic bead-based weak cation exchange (MB-WCX) and MALDI-TOF-MS were used in combination. To screen the differential peaks, ClinProTools software was employed. The proteins were identified using LC-MS/MS. ELISA was employed to confirm the expression of entire protein in the serum of the verification cohort, which encompassed 48 individuals who had been diagnosed with Depression and 48 healthy controls who were collected prospectively. Subsequently, logistic regression analysis was conducted to determine the diagnostic efficacy of the aforementioned predictors. Results: Five potential biomarker peaks indicating depression were identified in serum samples (peak 1, m/z: 1868.21; peak 2, m/z: 1062.35; peak 3, m/z: 1452.12; peak 4, m/z: 1208.72; peak 5, m/z: 1619.58). All of these peaks had higher expression in the pre-therapy group and were confirmed to be Tubulin beta chain (TUBB), Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), Complement component 3 (C3), and Complement C4A precursor (C4A) by ELISA validation. Multivariate logistic regression analysis revealed that serum levels of TUBB, ITIH4, C3, and C4A were significant independent risk factors for the development of depression. Conclusion: Depression is a prevalent psychiatric condition. Timely detection is challenging, resulting in poor prognoses for patients. Our study on plasma proteomics for depression demonstrated that TUBB, ITIH4, C3, and C4A differentiate between depression patients and healthy controls. The proteins that were identified could potentially function as biomarkers for the diagnosis of depression. Pinpointing these biomarkers could enable early identification of depression, which would advance precise treatment.
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To elucidate the molecular genetic mechanisms underpinning feather color in Muscovy ducks. A cohort of 100 Muscovy ducks was meticulously selected for this research. Follicular tissues from ducks exhibiting black and white plumage served as the experimental samples. From these tissues, RNA and proteins were extracted for further analysis. The RNA underwent reverse transcription polymerase chain reaction amplification, followed by validation through western blot assays. The data revealed a significant upregulation in the expression of FN domain-containing protein 1 (FNDC1) and ADAMTS12 genes in Muscovy ducks with white plumage traits as opposed to those with black plumage traits. Specifically, individuals with pure white plumage demonstrated a markedly elevated expression of the FNDC1 gene in comparison to their pure black counterparts. Conversely, expression levels of the ADAMTS12 gene were found to be reduced in ducks with pure black plumage relative to those with pure white plumage. Notably, the expression patterns of FNDC1 and ADAMTS12 genes exhibited inconsistencies between mRNA and protein levels. This study offers significant insights into the molecular genetic mechanisms underlying feather color variation in Muscovy ducks. FNDC1 and ADAMTS12 could be considered potential targets for genetic manipulation or selective breeding strategies aimed at achieving specific feather color phenotypes in Muscovy ducks.
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Background and objective: Acute ischemic stroke (AIS) is a leading cause of mortality, severe neurological and long-term disability world-wide. Blood-based indicators may provide valuable information on identified prognostic factors. However, currently, there is still a lack of peripheral blood indicators for the prognosis of AIS. We aimed to identify the most promising prognostic indicators and establish prognostic models for AIS. Methods: 484 subjects enrolled from four centers were analyzed immunophenotypic indicators of peripheral blood by flow cytometry. Least absolute shrinkage and selection operator (LASSO) regression was applied to minimize the potential collinearity and over-fitting of variables measured from the same subject and over-fitting of variables. Univariate and multivariable Cox survival analysis of differences between and within cohorts was performed by log-rank test. The areas under the receiving operating characteristic (ROC) curves were used to evaluate the selection accuracy of immunophenotypic indicators in identifying AIS subjects with survival risk. The prognostic model was constructed using a multivariate Cox model, consisting of 402 subjects as a training cohort and 82 subjects as a testing cohort. Results: In the prospective study, 7 immunophenotypic indicators of distinct significance were screened out of 72 peripheral blood immunophenotypic indicators by LASSO. In multivariate cox regression, CTL (%) [HR: 1.18, 95% CI: 1.03-1.33], monocytes/µl [HR: 1.13, 95% CI: 1.05-1.21], non-classical monocytes/µl [HR: 1.09, 95% CI: 1.02-1.16] and CD56high NK cells/µl [HR: 1.13, 95% CI: 1.05-1.21] were detected to decrease the survival probability of AIS, while Tregs/µl [HR:0.97, 95% CI: 0.95-0.99, p=0.004], BM/µl [HR:0.90, 95% CI: 0.85-0.95, p=0.023] and CD16+NK cells/µl [HR:0.93, 95% CI: 0.88-0.98, p=0.034] may have the protective effect. As for indicators' discriminative ability, the AUC for CD56highNK cells/µl attained the highest of 0.912. In stratification analysis, the survival probability for AIS subjects with a higher level of Tregs/µl, BM/µl, CD16+NK cells/µl, or lower levels of CD56highNK cells/µl, CTL (%), non-classical monocytes/µl, Monocytes/µl were more likely to survive after AIS. The multivariate Cox model showed an area under the curve (AUC) of 0.805, 0.781 and 0.819 and 0.961, 0.924 and 0.982 in the training and testing cohort, respectively. Conclusion: Our study identified 7 immunophenotypic indicators in peripheral blood may have great clinical significance in monitoring the prognosis of AIS and provide a convenient and valuable predictive model for AIS.
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Citometria de Fluxo , Imunofenotipagem , AVC Isquêmico , Humanos , Feminino , Masculino , AVC Isquêmico/sangue , AVC Isquêmico/mortalidade , AVC Isquêmico/diagnóstico , AVC Isquêmico/imunologia , Citometria de Fluxo/métodos , Prognóstico , Idoso , Pessoa de Meia-Idade , Estudos Prospectivos , Biomarcadores/sangue , Idoso de 80 Anos ou maisRESUMO
Haseman-Elston regression (HE-reg) has been known as a classic tool for detecting an additive genetic variance component. However, in this study we find that HE-reg can capture GxE under certain conditions, so we derive and reinterpret the analytical solution of HE-reg. In the presence of GxE, it leads to a natural discrepancy between linkage and association results, the latter of which is not able to capture GxE if the environment is unknown. Considering linkage and association as symmetric designs, we investigate how the symmetry can and cannot hold in the absence and presence of GxE, and consequently we propose a pair of statistical tests, Symmetry Test I and Symmetry Test II, both of which can be tested using summary statistics. Test statistics, and their statistical power issues are also investigated for Symmetry Tests I and II. Increasing the number of sib pairs is important to improve statistical power for detecting GxE.
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Interação Gene-Ambiente , Genótipo , Modelos Genéticos , Humanos , Ligação Genética , Análise de Regressão , Simulação por Computador , Modelos EstatísticosRESUMO
Using biodegradable films as a substitute for conventional polyolefin films has emerged as a crucial technology to combat agricultural white pollution. To address the shortcomings in the tensile strength, water vapor barrier properties, and degradation period of PBAT-based biodegradable films, this investigation aimed to create a composite film that could improve the diverse properties of PBAT films. To achieve this, a PBAT/PLA-PPC-PTLA ternary blend system was introduced in the study. The system effectively fused PBAT with PLA and PPC, as evidenced by electron microscopy tests showing no apparent defects on the surface and cross-section of the blended film. The developed ternary blend system resulted in a 58.62% improvement in tensile strength, a 70.33% enhancement in water vapor barrier properties, and a 30-day extension of the functional period compared to pure PBAT biodegradable films. Field experiments on corn crops demonstrated that the modified biodegradable film is more suitable for agricultural production, as it improved thermal insulation and moisture retention, leading to a 5.45% increase in corn yield, approaching the yield of traditional polyolefin films.
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The long-term leaching of polyfluoroalkyl substances (PFAS) within the vadose zone of an AFFF application site for which the depth to groundwater is approximately 100 m was investigated by characterizing the vertical distribution of PFAS in a high spatial resolution. The great majority (99%) of PFAS mass resides in the upper 3 m of the vadose zone. The depths to which each PFAS migrated, quantified by moment analysis, is an inverse function of molar volume, demonstrating chromatographic separation. The PFAS were operationally categorized into three chain-length groups based on the three general patterns of retention observed. The longest-chain (>â¼335 cm3/mol molar volume) PFAS remained within the uppermost section of the core, exhibiting minimal leaching. Conversely, the shortest-chain (<â¼220 cm3/mol) PFAS accumulated at the bottom of the interval, which coincides with the onset of a calcic horizon. PFAS with intermediate-chain lengths were distributed along the length of the core, exhibiting differential magnitudes of leaching. The minimal or differential leaching observed for the longest- and intermediate-chain-length PFAS, respectively, demonstrates that retention processes significantly impacted migration. The accumulation of shorter-chain PFAS at the bottom of the core is hypothesized to result from limited deep infiltration and potential-enhanced retention associated with the calcic horizon.
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Fluorocarbonos , Água Subterrânea , Poluentes Químicos da Água , Água Subterrânea/química , Monitoramento AmbientalRESUMO
The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer's disease. We report an X-ray crystal structure of sQC complexed with PQ912, revealing that the benzimidazole makes "anchor" interactions with the active site zinc ion and catalytic triad. Structure-guided design and optimization led to a series of new benzimidazole derivatives exhibiting nanomolar inhibition for both sQC and gQC. In a MPTP-induced Parkinson's disease (PD) mouse model, BI-43 manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, α-synuclein, and CCL2. This study not only offers structural basis and new leads for drug discovery targeting sQC/gQC but also provides evidence supporting sQC/gQC as potential targets for PD treatment.
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Aminoaciltransferases , Benzimidazóis , Inibidores Enzimáticos , Animais , Aminoaciltransferases/antagonistas & inibidores , Aminoaciltransferases/metabolismo , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/síntese química , Cristalografia por Raios X , Camundongos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Relação Estrutura-Atividade , Modelos Animais de Doenças , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Descoberta de Drogas , Masculino , Modelos MolecularesRESUMO
Approximation biases of value functions are considered a key problem in reinforcement learning (RL). In particular, existing RL algorithms are hindered by overestimation and underestimation biases, i.e., value mismatching between RL's actual returns and action-value approximations limits the performance of RL algorithms. In this article, we first develop a new synthesis loss function for RL's action-value estimation integrating a regularization term and a modified "clipped double Q-learning" structure for solving overestimation and underestimation biases. To minimize the differences between action-value estimations and actual returns in RL, we develop a new discrepancy function to determine the type and magnitude of approximation biases. Then, two coefficients embedded in the synthesis loss are automatically tuned by minimizing the discrepancy function during training to minimize approximation biases. We further design a new actor-critic (AC) algorithm, named AC with synthesis loss (ACSL), by integrating the synthesis loss function and an error-controlled mechanism. Experimental results on continuous control tasks illustrate that the proposed ACSL algorithm outperforms other cutting-edge RL methods in many tasks and that the proposed synthesis loss function is easily implemented into other algorithms and significantly reduces approximation biases while improving performance. The proposed method can successfully handle many complex continuous control tasks and can greatly outperform other state-of-the-art algorithms on most tasks.
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Hyperuricemia (HUA) is caused by increased synthesis and/or insufficient excretion of uric acid (UA). Long-lasting HUA may lead to a number of diseases including gout and kidney injury. Harpagoside (Harp) is a bioactive compound with potent anti-inflammatory activity from the roots of Scrophularia ningpoensis. Nevertheless, its potential effect on HUA was not reported. The anti-HUA and nephroprotective effects of Harp on HUA mice were assessed by biochemical and histological analysis. The proteins responsible for UA production and transportation were investigated to figure out its anti-HUA mechanism, while proteins related to NF-κB/NLRP3 pathway were evaluated to reveal its nephroprotective mechanism. The safety was evaluated by testing its effect on body weight and organ coefficients. The results showed that Harp significantly reduced the SUA level and protected the kidney against HUA-induced injury but had no negative effect on safety. Mechanistically, Harp significantly reduced UA production by acting as inhibitors of xanthine oxidase (XOD) and adenosine deaminase (ADA) and decreased UA excretion by acting as activators of ABCG2, OAT1 and inhibitors of GLUT9 and URAT1. Moreover, Harp markedly reduced infiltration of inflammatory cells and down-regulated expressions of TNF-α, NF-κB, NLRP3 and IL-1ß in the kidney. Harp was a promising anti-HUA agent.
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Glicosídeos , Hiperuricemia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piranos , Ácido Úrico , Animais , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Ácido Úrico/sangue , Masculino , Glicosídeos/farmacologia , Glicosídeos/uso terapêutico , Piranos/farmacologia , Piranos/uso terapêutico , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , NF-kappa B/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Two new withanolides named physaminilides L (1) and M (2), together with four known ones (3-6) were isolated from the Physalis minima L. The structures were established by analysis of the HR ESIMS, IR and NMR spectroscopic data. The absolute configurations were determined through NOESY and ECD spectra. For compounds 1-5 assayed at 20 µM and compound 6 at 10 µM, inhibition rates of hepatic fibrosis were 22.19%, 15.29%, 37.07%, 9.27%, 12.45%, and 37.03%, respectively.
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Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. Euphorbia kansui yielded 13-oxyingenol-dodecanoate (13OD), an ingenane-type diterpenoid, which had a strong cytotoxic effect on NSCLC cells. The underlying mechanism and potential target, however, remained unknown. The study found that 13OD effectively inhibited the cell proliferation and colony formation of NSCLC cells (A549 and H460 cells), with less toxicity in normal human lung epithelial BEAS-2B cells. Moreover, 13OD can cause mitochondrial dysfunction, and apoptosis in NSCLC cells. Mechanistically, the transcriptomics results showed that differential genes were mainly enriched in the mTOR and AMPK signaling pathways, which are closely related to cellular autophagy, the related indicators were subsequently validated. Additionally, bafilomycin A1 (Baf A1), an autophagy inhibitor, reversed the mitochondrial damage caused by 13OD. Furthermore, the Omics and Text-based Target Enrichment and Ranking (OTTER) method predicted ULK1 as a potential target of 13OD against NSCLC cells. This hypothesis was further confirmed using molecular docking, the cellular thermal shift assay (CETSA), and Western blot analysis. Remarkably, ULK1 siRNA inhibited 13OD's toxic activity in NSCLC cells. In line with these findings, 13OD was potent and non-toxic in the tumor xenograft model. Our findings suggested a possible mechanism for 13OD's role as a tumor suppressor and laid the groundwork for identifying targets for ingenane-type diterpenoids.
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Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Relação Estrutura-Atividade , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/antagonistas & inibidores , Estrutura Molecular , Diterpenos/farmacologia , Diterpenos/química , Apoptose/efeitos dos fármacos , Animais , Camundongos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese químicaRESUMO
Neonatal spinal cord tissues exhibit remarkable regenerative capabilities as compared to adult spinal cord tissues after injury, but the role of extracellular matrix (ECM) in this process has remained elusive. Here, we found that early developmental spinal cord had higher levels of ECM proteins associated with neural development and axon growth, but fewer inhibitory proteoglycans, compared to those of adult spinal cord. Decellularized spinal cord ECM from neonatal (DNSCM) and adult (DASCM) rabbits preserved these differences. DNSCM promoted proliferation, migration, and neuronal differentiation of neural progenitor cells (NPCs) and facilitated axonal outgrowth and regeneration of spinal cord organoids more effectively than DASCM. Pleiotrophin (PTN) and Tenascin (TNC) in DNSCM were identified as contributors to these abilities. Furthermore, DNSCM demonstrated superior performance as a delivery vehicle for NPCs and organoids in spinal cord injury (SCI) models. This suggests that ECM cues from early development stages might significantly contribute to the prominent regeneration ability in spinal cord.
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Proteínas de Transporte , Citocinas , Matriz Extracelular , Organoides , Traumatismos da Medula Espinal , Medula Espinal , Animais , Organoides/metabolismo , Organoides/citologia , Medula Espinal/metabolismo , Matriz Extracelular/metabolismo , Traumatismos da Medula Espinal/terapia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Coelhos , Diferenciação Celular , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Tenascina/metabolismo , Proliferação de Células , Animais Recém-Nascidos , Regeneração Nervosa/fisiologiaRESUMO
Plumage color, a pivotal attribute delineating diverse Muscovy duck strains, assumes considerable significance within the field of Muscovy duck breeding research. This study extends the existing research by delving into the hereditary aspects of genes associated with plumage coloration in Muscovy ducks. The principal objective is to discern marker genes conducive to targeted breeding strategies based on plumage color, thereby furnishing indispensable technical foundations for the development of novel Muscovy duck varieties. Our investigation focused on scrutinizing the impact of MYOT and MB genes on the genetic expression of plumage color at both the RNA and protein levels in Muscovy ducks. The results elucidate that black Muscovy ducks manifest markedly elevated mRNA and protein expression levels of MYOT and MB genes in comparison to their white counterparts, indicating that both genes may play a constructive regulatory role in the context of plumage coloration in Muscovy ducks. The outcomes of this study delineate a discernible correlation between MYOT and MB genes and the plumage coloration in Muscovy ducks. Employing gene expression analysis, we successfully identified candidate genes that may be intricately linked to the determination of plumage color in these ducks.