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Marek's disease (MD), caused by the Marek's disease virus (MDV), is a common infectious tumor disease in chickens and was the first neoplastic disease preventable by vaccination. However, the vaccine cannot completely prevent virulent MDV infections, allowing both the vaccine and virulent MDV to coexist in the same chicken for extended periods. This study aims to investigate the changes in viral load of the very virulent strain Md5 and the rHVT-IBD vaccine in different chicken tissues using a real-time PCR assay. The results showed that the rHVT-IBD vaccine significantly reduced the viral load of MDV-Md5 in different organs, while the load of rHVT-IBD was significantly increased when co-infected with Md5. Additionally, co-infection with Md5 and rHVT-IBD in chickens not only changed the original viral load of both viruses but also affected the positive rate of Md5 at 14 days post-vaccination. The positive rate decreased from 100% to 14.29% (feather tips), 0% (skin), 33.33% (liver), 16.67% (spleen), 28.57% (thymus), 33.33% (bursa), and 66.67% (PBL), respectively. This study enhances our understanding of the interactions between HVT vector vaccines and very virulent MDV in chickens and provides valuable insights for the future development of MD vaccines.
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Pollos , Coinfección , Vacunas contra la Enfermedad de Marek , Enfermedad de Marek , Enfermedades de las Aves de Corral , Carga Viral , Animales , Enfermedad de Marek/virología , Enfermedad de Marek/prevención & control , Enfermedad de Marek/inmunología , Pollos/virología , Coinfección/virología , Coinfección/veterinaria , Enfermedades de las Aves de Corral/virología , Enfermedades de las Aves de Corral/prevención & control , Vacunas contra la Enfermedad de Marek/inmunología , Vacunas contra la Enfermedad de Marek/genética , Virulencia , Herpesvirus Meleágrido 1/inmunología , Herpesvirus Meleágrido 1/genética , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/genética , Herpesvirus Gallináceo 2/genética , Herpesvirus Gallináceo 2/inmunología , Herpesvirus Gallináceo 2/patogenicidad , Vacunación , Vectores Genéticos/genéticaRESUMEN
Inhibition of T cell infiltration dampens antitumor immunity and causes resistance to immune checkpoint blockade (ICB) therapy. By in vivo CRISPR screening in B16F10 melanoma in female mice, here we report that loss of melanocortin-1 receptor (MC1R) in melanoma cells activates antitumor T cell response and overcomes resistance to ICB. Depletion of MC1R from another melanocytic melanoma model HCmel1274 also enhances ICB efficacy. By activating the GNAS-PKA axis, MC1R inhibits interferon-gamma induced CXCL9/10/11 transcription, thus impairing T cell infiltration into the tumor microenvironment. In human melanomas, high MC1R expression correlates with reduced CXCL9/10/11 expression, impaired T cell infiltration, and poor patient prognosis. Whereas MC1R activation is restricted to melanoma, GNAS activation by hotspot mutations is observed across diverse cancer types and is associated with reduced CXCL9/10/11 expression. Our study implicates MC1R as a melanoma immunotherapy target and suggests GNAS-PKA signaling as a pan-cancer oncogenic pathway inhibiting antitumor T cell response.
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Melanoma , Receptor de Melanocortina Tipo 1 , Animales , Femenino , Humanos , Ratones , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Melanoma/genética , Receptor de Melanocortina Tipo 1/genética , Transducción de Señal , Linfocitos T , Microambiente TumoralRESUMEN
This study aims to reveal short-run and long-run asymmetries among human capital, educational inequality, and income inequality in China over the period 1975-2020 using a nonlinear autoregressive distributed lag (NARDL) model. The estimated long-run asymmetry parameters reflect that positive shocks to secondary education (SSE) and higher education (HE) are negatively correlated with income Gini coefficient. The adverse shocks of secondary education (SSE) and higher education (HE) stimulate the Gini coefficient of income, but the effect of secondary education (SSE) on the Gini coefficient of income is not significant, while that of higher education (HE) is significant. The results also highlight that, in the long run, there is a significant asymptotic effect of the education Gini coefficient (educational inequality) and economic growth on the income Gini coefficient (income inequality). However, physical capital stock has a significant adverse effect on income inequality in the long run. Higher education significantly promotes educational inequality, while the square of higher education significantly reduces educational inequality, thus verifying the inverted U-shaped Kuznets curve hypothesis between higher education and educational inequality. Strategically, this study suggests higher education as a powerful tool for mitigating income inequality by emphasizing educational equity.
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Desarrollo Económico , Renta , Humanos , Factores Socioeconómicos , Escolaridad , ChinaRESUMEN
BACKGROUND: This study aimed to evaluate the efficacy and safety of KN046, a novel recombinant humanised antibody targeting PD-L1 and CTLA-4 in advanced non-small cell lung cancer (NSCLC) patients after failure or intolerance to platinum-based chemotherapy. METHODS: In this multi-centre, open-label phase II clinical trial, patients were enroled after failure or intolerance to platinum-based chemotherapy. KN046 at 3 mg/kg or 5 mg/kg was administered intravenously every 2weeks. The primary end-point was objective response rate (ORR) evaluated by a blinded independent review committee (BIRC). RESULTS: A total of 30 and 34 patients were included in the 3 mg/kg (cohort A) and 5 mg/kg (cohort B) cohorts. On 31st August 2021, the median follow-up duration was 24.08 months (interquartile [IQR], 22.28, 24.84) and 19.35months (IQR, 17.25, 20.90) in the 3 mg/kg and 5 mg/kg cohorts, respectively. BIRC-assessed ORRs were 13.3% and 14.7% in the 3 mg/kg and 5 mg/kg cohorts, respectively. Median progression-free survival was 3.68 (95% confidence interval [CI] 3.22-7.29) and 3.68 (95%CI 1.81-7.39) months, while overall survival was 19.70 (95.5%CI 15.44-not estimated [NE]) and 13.04 (95.5%CI 9.86-NE) months, respectively. The most common treatment-related adverse events (TRAEs) were anaemia (28.1%), hyperglycaemia (26.7%), and infusion-related reactions (26.7%). The incidence rates of grade ≥ 3 TRAEs and TRAEs leading to treatment discontinuation were 42.2% and 14.1%, respectively. CONCLUSIONS: Both 3 mg/kg and 5 mg/kg KN046 showed promising efficacy and favourable safety profile for advanced NSCLC after failure or intolerance to previous platinum-based chemotherapy. TRIAL REGISTRATION NUMBER: NCT03838848.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Antígeno B7-H1 , Antígeno CTLA-4 , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Portulaca oleracea (PO) is a commonly known medicinal crop that is an important ingredient for traditional Chinese medicine (TCM) due to its use as a vegetable in the diet. PO has been recorded to be frequently adulterated by other related species in the market of herbal plants, distorting the PO plant identity. Thus, identification of the botanical origin of PO is a crucial step before pharmaceutical or functional food application. In this research, a quick assay named "loop-mediated isothermal amplification (LAMP)" was built for the specific and sensitive authentication of PO DNA. On the basis of the divergences in the internal transcribed spacer 2 (ITS2) sequence between PO and its adulterant species, the LAMP primers were designed and verified their specificity, sensitivity, and application for the PO DNA authentication. The detection limit of the LAMP assay for PO DNA identification specifically was 100 fg under isothermal conditions at 63 °C for 30 min. In addition, different heat-processed PO samples can be applied for use in PO authentication in the LAMP assay. These samples of PO were more susceptible to the effect of steaming in authentication by PCR than boiling and drying treatment. Furthermore, commercial PO samples pursued from herbal markets were used to display their applicability of the developed LAMP analysis for PO postharvest authentication, and the investigation found that approximately 68.4% of PO specimens in the marketplace of herbal remedies were adulterated. In summary, the specific, sensitive, and rapid LAMP assay for PO authentication was first successfully developed herein, and its practical application for the inspection of adulteration in PO samples from the herbal market was shown. This LAMP assay created in this study will be useful to authenticate the botanical origin of PO and its commercial products.
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Plantas Medicinales , Portulaca , Portulaca/genética , Plantas Medicinales/genética , Técnicas de Amplificación de Ácido Nucleico , Reacción en Cadena de la Polimerasa , Cartilla de ADN/genética , ADN , Sensibilidad y EspecificidadRESUMEN
Adulteration by Bacopa monnieri (BM) in Portulaca oleracea (PO) plants frequently occurs; it decreases the efficacy of traditional Chinese medicine (TCM) and leads to fraud in the herbal marketplace. In this study, a diagnostic PCR assay was established for the rapid authentication of PO and BM in the herbal market. The sequence divergences in internal transcribed spacer 2 (ITS2) between PO and its adulterant species were used to design diagnostic PCR primers. The specific designed primer sets were evaluated and show that the diagnostic PCR assay can be used to verify the authenticity of PO and BM. The detection limits of the primer set for PO and BM identification were 10 pg and 1 pg, respectively. The reactivity of diagnostic PCR was 0.1% PO genomic DNA and 0.01% BM genomic DNA in the test sample during DNA amplification. In addition, multiplex PCR (mPCR) for PO and BM identification was also established. The samples were more susceptible to the effect of steaming in authentication by singleplex PCR and mPCR than boiling and drying treatment. Furthermore, commercial samples from the market were used to demonstrate the applicability of the developed diagnostic PCR for PO authentication and diagnose BM adulteration, and the investigation found that approximately 72.2% (13/18) of PO plants in the herbal market were adulterated. In conclusion, the diagnostic PCR assay was successfully developed and its specificity, sensitivity and reactivity for PO and BM authentication were proven. These developed PCR-based molecular methods can be applied as an identification tool for PO authenticity and can be practically applied for inspection of BM adulteration in the herbal market in the future.
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Plantas Medicinales , Portulaca , Plantas Medicinales/genética , Portulaca/genética , Reacción en Cadena de la Polimerasa Multiplex , ADN Espaciador Ribosómico/genética , ADN de Plantas/análisis , ADN de Plantas/genéticaRESUMEN
CRISPR/Cas9 has been adapted to disrupt endogenous genes in adoptive T-lymphocyte therapy to prevent graft-versus-host disease. However, genome editing also generates prevalent deleterious structural variations (SVs), including chromosomal translocations and large deletions, raising safety concerns about reinfused T cells. Here, we dynamically monitored the progression of SVs in a mouse model of T-cell receptor (TCR)-transgenic T-cell adoptive transfer, mimicking TCR T therapeutics. Remarkably, CRISPR/Cas9-induced SVs persist and undergo clonal expansion in vivo after three weeks or even two months, evidenced by high enrichment and low junctional diversity of identified SVs post infusion. Specifically, we detected 128 expanded translocations, with 20 615 as the highest number of amplicons. The identified SVs are stochastically selected among different individuals and show an inconspicuous locus preference. Similar to SVs, viral DNA integrations are routinely detected in edited T cells and also undergo clonal expansion. The persistent SVs and viral DNA integrations in the infused T cells may constantly threaten genome integrity, drawing immediate attention to the safety of CRISPR/Cas9-engineered T cells mediated immunotherapy.
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Edición Génica , Linfocitos T , Animales , Ratones , Sistemas CRISPR-Cas/genética , ADN Viral , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment1,2. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn's disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacter species induce T regulatory (Treg) and T follicular helper (TFH) cells under homeostatic conditions, but induce inflammatory T helper 17 (TH17) cells when induced Treg (iTreg) cells are compromised3,4. How Helicobacter and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iTreg cell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of Treg cells. These RORγt+ cells-probably type 3 innate lymphoid cells and/or Janus cells5-require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFß activator αv integrin. In the absence of any of these factors, there was expansion of pathogenic TH17 cells instead of iTreg cells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.
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Diferenciación Celular , Microbioma Gastrointestinal , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Linfocitos T Reguladores , Células Dendríticas/inmunología , Microbioma Gastrointestinal/inmunología , Homeostasis , Inmunidad Innata , Integrina alfaV/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Receptores CCR7/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Presentación de Antígeno/inmunología , Células Presentadoras de Antígenos/citología , Células Presentadoras de Antígenos/inmunologíaRESUMEN
This paper makes a new attempt to identify the effectiveness of innovation factor allocation with a random forest method. This method avoids the evaluation bias of the relative effectiveness caused by the noneffective selection of production frontier in the nonparametric DEA method. It does not refer to other optimal subjects but shifts the focus to the judgment of its own effectiveness. In addition, it also gets rid of the constraints of the model and variables in the parameter SFA method, ensuring the reliability of the measurement results by resampling thousands of times. The data is collected from 30 provinces in China from 2009 to 2018. The findings show the innovation factor allocation in more than half of the provinces is not fully effective. It indicates that how to make use of innovation factor inputs to achieve the actual innovation output higher than own optimal levels is currently still in a period of exploration in China. To further improve innovation factor allocation efficiency, it deeply analyzes the impacts of innovation factor inputs and finds out the important innovation factor inputs. Furthermore, this study presents the nonlinear characteristics and optimal combination of important innovation factor inputs. According to this, it offers the detailed suggestions about how to adjust current important innovation factor inputs for each province in order to greatly enhance the effectiveness of innovation factor allocation in the future.
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Asignación de Recursos , China , Humanos , Reproducibilidad de los ResultadosRESUMEN
Kidney renal clear cell carcinoma (KIRC) is one of the most common malignancies, and there is still a lack of effective biomarkers for early detection and prognostic prediction. In here, we compared the characteristics of RNA sequencing data sets of KIRC samples based on the tumor suppressor gene phosphatase and tensin homolog (PTEN). The 1016 long noncoding RNAs, 48 microRNAs (miRNAs), and 2104 messenger RNAs associated with PTEN were identified and these genes were differentially expressed between tumor and paracancerous tissues. The most relevant pathway was found to be WDFY3-AS2 - miR-21-5p/miR-221-3p/miR-222-3p - TIMP3 according to the rules of competing endogenous RNA (ceRNA) regulation. WDFY3-AS2 and TIMP3 expression were positively correlated and reduced in KIRC samples, while miR-21-5p, miR-221-3p, and miR-222-3p were relatively highly expressed. The relatively low expression of WDFY3-AS2 and TIMP3 in KIRC were associated with poor prognosis in KIRC patients, while higher expression of miR-21-5p, miR-221-3p, and miR-222-3p predicted reduced survival (p < 0.05). Univariate and multivariate Cox regression analysis showed that lower expression of WDFY3-AS2 and TIMP3 was significantly related to tumor grade, tumor size, lymph node metastasis, distant metastasis, and TNM stage. The expression of TIMP3 in KIRC tissues was also verified by immunohistochemistry, and the results were consistent with our analytical data. In summary, this study constructed a new model with clinical predictive value and identified the WDFY3-AS2/TIMP3 pathway that was closely associated with the prognosis of KIRC, which could serve as a promising biomarker for the diagnosis and treatment of KIRC.
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Carcinoma de Células Renales , Neoplasias Renales , MicroARNs , ARN Largo no Codificante , Proteínas Adaptadoras Transductoras de Señales , Proteínas Relacionadas con la Autofagia/genética , Biomarcadores , Carcinogénesis/genética , Carcinoma de Células Renales/patología , Transformación Celular Neoplásica/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Riñón/metabolismo , Neoplasias Renales/patología , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Inhibidor Tisular de Metaloproteinasa-3/genética , Inhibidor Tisular de Metaloproteinasa-3/metabolismoRESUMEN
OBJECTIVE: To develop a machine learning (ML)-based classifier for discriminating between low-grade (ISUP I-II) and high-grade (ISUP III-IV) clear cell renal cell carcinomas (ccRCCs) using MRI textures. MATERIALS AND METHODS: We retrospectively evaluated a total of 99 patients (with 61 low-grade and 38 high-grade ccRCCs), who were randomly divided into a training set (n = 70) and a validation set (n = 29). Regions of interest (ROIs) of all tumors were manually drawn three times by a radiologist at the maximum lesion level of the cross-sectional CMP sequence images. The quantitative texture analysis software, MaZda, was used to extract texture features, including histograms, co-occurrence matrixes, run-length matrixes, gradient models, and autoregressive models. Reproducibility of the texture features was assessed with the intra-class correlation coefficient (ICC). Features were chosen based on their importance coefficients in a random forest model, while the multi-layer perceptron algorithm was used to build a classifier on the training set, which was later evaluated with the validation set. RESULTS: The ICCs of 257 texture features were equal to or higher than 0.80 (0.828-0.998. Six features, namely Kurtosis, 135dr_RLNonUni, Horzl_GLevNonU, 135dr_GLevNonU, S(4,4)Entropy, and S(0,5)SumEntrp, were chosen to develop the multi-layer perceptron classifier. A three-layer perceptron model, which has 229 nodes in the hidden layer, was trained on the training set. The accuracy of the model was 95.7% with the training set and 86.2% with the validation set. The areas under the receiver operating curves were 0.997 and 0.758 for the training and validation sets, respectively. CONCLUSIONS: A machine learning-based grading model was developed that can aid in the clinical diagnosis of clear cell renal cell carcinoma using MRI images.
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Clear cell renal cell carcinoma (ccRCC) is a prevalent urological carcinoma with high metastatic risk. Circular RNAs (circRNAs) have been identified as effective diagnostic and therapeutic biomarkers for ccRCC. This research aims to disclose the effect and regulatory mechanism of circRNA ribosomal protein L23a (circ_RPL23A) in ccRCC. We performed quantitative real-time polymerase chain reaction (qRT-PCR) to examine circ_RPL23A, microRNA-1233 (miR-1233) and acetyl-coenzyme A acetyltransferase 2 (ACAT2). Cell cycle progression, apoptosis, cell viability, invasion and migration, which were respectively conducted by using flow cytometry, 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT), transwell assays. The levels of ACAT2 protein and cell cycle proteins, proliferation-associated protein, and epithelial-mesenchymal transition (EMT) associated proteins were measured by western blot. Target relationship was analyzed via dual-luciferase reporter assay and RNA pull down assay. The animal model was used to study how circ_RPL23A affects in vivo. Circ_RPL23A was lower expressed in ccRCC tissues and cells. The elevated circ_RPL23A suppressed cell cycle progression, proliferation, migration and invasion but promoted apoptosis in ccRCC cells. MiR-1233 was a target of circ_RPL23A and direct targeted to ACAT2. Besides, circ_RPL23A exerted its anti-tumor effect by sponging miR-1233, and then relieved the inhibition effect of miR-1233 on ACAT2. Overexpression of circ_RPL23A also curbed ccRCC tumor growth in vivo. Circ_RPL23A inhibited ccRCC progression by upregulating ACAT2 expression by competitively binding miR-1233, which might provide an in-depth cognition for ccRCC pathogenesis and circ_RPL23A might be a promising biomarker in ccRCC diagnosis and treatment.
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Carcinoma de Células Renales/metabolismo , Neoplasias Renales/metabolismo , MicroARNs/metabolismo , Esterol O-Aciltransferasa/metabolismo , Animales , Apoptosis/fisiología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Proliferación Celular/fisiología , Progresión de la Enfermedad , Xenoinjertos , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Transfección , Esterol O-Aciltransferasa 2RESUMEN
Loss of nigrostriatal dopamine (DA) in Parkinson's disease results in over-activation/bursting of the subthalamic nucleus (STN). The STN projects to the substantia nigra (SN) pars compacta (SNpc) and pars reticulata (SNpr). The vesicular glutamate transporter 2 (Vglut2) is localized within at least STN terminals synapsing within the SN, but it is not known if there are differential changes in the Vglut2+ input to the SNpc versus SNpr following DA loss. The goal/rationale of this current study was to determine whether there were differential changes in the density/levels of glutamate immuno-gold labeling within Vglut2+ nerve terminals synapsing in the SNpc/SNpr and in the proportion of Vglut2+ terminals contacting tyrosine hydroxylase (TH) positively(+) or negatively(-) labeled dendrites following DA loss. Within the SNpc, there was a significant increase (51.3%) in the density of nerve terminal glutamate immuno-gold labeling within Vglut2+ terminals synapsing on TH(-) dendrites following MPTP versus the vehicle (VEH) group. There was a significant decrease (16%) in the percentage of Vglut2+ terminals contacting TH(+) labeled dendrites in the MPTP- versus VEH-treated group within the SNpc. Within the SNpr, there was a significant decrease in the density of glutamate immuno-gold labeling in Vglut2+ terminals contacting TH(+) (71.5%) and TH(-) (55.5%) labeled dendrites, suggesting an increase in glutamate release. There was no change in the percentage of Vglut2+ terminals contacting TH(+) or TH(-) dendrites in the SNpr. We conclude that there is a differential effect following DA loss on the glutamate input from Vglut2+ terminals synapsing within the SNpr versus SNpc.
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Enfermedad de Parkinson , Porción Reticular de la Sustancia Negra , Animales , Dopamina , Ratones , Porción Compacta de la Sustancia Negra , Sustancia NegraRESUMEN
The antigen-binding variable regions of the B cell receptor (BCR) and of antibodies are encoded by exons that are assembled in developing B cells by V(D)J recombination1. The BCR repertoires of primary B cells are vast owing to mechanisms that create diversity at the junctions of V(D)J gene segments that contribute to complementarity-determining region 3 (CDR3), the region that binds antigen1. Primary B cells undergo antigen-driven BCR affinity maturation through somatic hypermutation and cellular selection in germinal centres (GCs)2,3. Although most GCs are transient3, those in intestinal Peyer's patches (PPs)-which depend on the gut microbiota-are chronic4, and little is known about their BCR repertoires or patterns of somatic hypermutation. Here, using a high-throughput assay that analyses both V(D)J segment usage and somatic hypermutation profiles, we elucidate physiological BCR repertoires in mouse PP GCs. PP GCs from different mice expand public BCR clonotypes (clonotypes that are shared between many mice) that often have canonical CDR3s in the immunoglobulin heavy chain that, owing to junctional biases during V(D)J recombination, appear much more frequently than predicted in naive B cell repertoires. Some public clonotypes are dependent on the gut microbiota and encode antibodies that are reactive to bacterial glycans, whereas others are independent of gut bacteria. Transfer of faeces from specific-pathogen-free mice to germ-free mice restored germ-dependent clonotypes, directly implicating BCR selection. We identified somatic hypermutations that were recurrently selected in such public clonotypes, indicating that affinity maturation occurs in mouse PP GCs under homeostatic conditions. Thus, persistent gut antigens select recurrent BCR clonotypes to seed chronic PP GC responses.
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Afinidad de Anticuerpos/genética , Centro Germinal/citología , Centro Germinal/inmunología , Ganglios Linfáticos Agregados/citología , Ganglios Linfáticos Agregados/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Animales , Heces/microbiología , Microbioma Gastrointestinal/inmunología , Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Vida Libre de Gérmenes , Homeostasis , Humanos , Región Variable de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/inmunología , Ratones , Selección Genética , Hipermutación Somática de Inmunoglobulina/genética , Recombinación V(D)J/genéticaRESUMEN
Nitrogen contamination of groundwater has become a global issue and has aroused considerable concern among authorities. However, it is difficult to trace nitrogen sources in settings where a municipal solid waste (MSW) landfill site co-exists with intensive agriculture and other human activities. Therefore, a field investigation that combined a statistical analysis (factor analysis: FA) and hydrochemical analysis was designed and undertaken to identify nitrogen-pollutant sources in the shallow groundwater beneath an MSW landfill near to an agricultural area and human settlement. The results of the case study showed that nitrate was the specific pollutant produced by agricultural non-point-sources (Pbi = 15.5) and domestic pollution sources (Pbi = 41.0). The total phosphorus (Pbi = 37.2) and organic matter (Pbi = 16.6) were the specific pollutants released by the aquaculture and animal husbandry point-sources, and chloride (Pbi = 75.4) and organic matter (Pbi = 16.1) were the specific pollutants produced by the landfill. In the investigated area, the domestic pollution sources and agricultural non-point-sources were the most likely sources of nitrate contamination in the shallow aquifer. However, the landfill source and the aquaculture and animal husbandry point sources were the most likely sources of ammonium contamination. The combined method used in this study could successfully identify the nitrogen pollution sources in the shallow groundwater beneath an MSW landfill located in the vicinity of multiple pollutant sources. The method could be used to improve the control of nitrogen contamination and the management of groundwater quality.
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Contaminantes Ambientales , Agua Subterránea , Contaminantes Químicos del Agua , Animales , Monitoreo del Ambiente , Humanos , Nitrógeno , Residuos Sólidos , Instalaciones de Eliminación de ResiduosRESUMEN
PURPOSE: The aim of this study was to investigate the effects of gain-of-function (GOF) E76K-mutant Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) on the biological behaviors of glioblastoma (GBM) cells, and explore the molecular mechanisms of GBM progression. METHODS: Firstly, a negative control vector and vectors overexpressing SHP2 and E76K-mutant SHP2 were transduced into GBM cells (U87 and A172) using a lentivirus. The effect of GOF-mutant SHP2 on proliferation was measured using the MTT assay, flow cytometry, colony formation assay, and soft agar assay. Moreover, the migration and invasion of GBM cells were determined through the transwell assay. Related proteins of the extracellular signal-regulated kinase/cAMP response element binding protein (ERK/CREB) pathway were detected by Western blotting analysis. A xenograft model was established to confirm the tumor-promoting effect of GOF-mutant SHP2 in vivo. Finally, ERK was inhibited using a mitogen-activated protein kinase/ERK kinase inhibitor (U0126) to further explore the molecular mechanism of GOF-mutant SHP2 affecting GBM cells. RESULTS: After transduction, the expression of SHP2 in the SHP2-mutant and SHP2-overexpression groups was higher than that observed in the control and normal groups. Our data indicated that GOF-mutant SHP2 enhanced the abilities of GBM cells for proliferation, migration, and invasion in vitro, and promoted tumor growth in vivo. Mechanistically, the ERK/CREB pathway was activated, and the levels of relevant proteins were increased in the SHP2-mutant group. Furthermore, following inhibition of ERK in the GOF-SHP2 mutant group, the activation of CREB was also depressed, and the malignant biological behaviors were weakened accordingly. CONCLUSION: The GOF-mutant SHP2 promoted GBM cell proliferation, metastasis, and tumor growth through the ERK/CREB pathway, providing a promising target for the treatment of GBM.
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Sleep complaints are an early clinical symptom of neurodegenerative disorders. Patients with Parkinson's disease (PD) experience sleep disruption (SD). The objective of this study was to determine if preexisting, chronic SD leads to a greater loss of tyrosine hydroxylase (TH) within the striatum and the substantia nigra following chronic/progressive exposure with the neurotoxin, 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Male mice underwent chronic SD for 4 weeks, then injected with vehicle (VEH) or increasing doses of MPTP for 4 weeks. There was a significant decrease in the plasma corticosterone levels in the MPTP group, an increase in the SD group, and a return to the VEH levels in the SD+MPTP group. Protein expression levels for TH in the striatum (terminals) and substantia nigra pars compacta (dopamine [DA] cell counts) revealed up to a 78% and 38% decrease, respectively, in the MPTP and SD+MPTP groups compared to their relevant VEH and SD groups. DA transporter protein expression increased in the striatum in the MPTP versus VEH group and in the SN/midbrain between the SD+MPTP and the VEH group. There was a main effect of MPTP on various gait measures (e.g., braking) relative to the SD or VEH groups. In the SD+MPTP group, there were no differences compared to the VEH group. Thus, SD, prior to administration of MPTP, has effects on serum corticosterone and gait but more importantly does not potentiate greater loss of TH within the nigrostriatal pathway compared to the MPTP group, suggesting that in PD patients with SD, there is no exacerbation of the DA cell loss.
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Cuerpo Estriado/enzimología , Trastornos Neurológicos de la Marcha/etiología , Trastornos Parkinsonianos/complicaciones , Trastornos Intrínsecos del Sueño/etiología , Estrés Fisiológico , Sustancia Negra/enzimología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Cuerpo Estriado/patología , Corticosterona/sangre , Modelos Animales de Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/análisis , Trastornos Neurológicos de la Marcha/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/análisis , Oxidopamina/toxicidad , Trastornos Parkinsonianos/metabolismo , Método Simple Ciego , Trastornos Intrínsecos del Sueño/sangre , Trastornos Intrínsecos del Sueño/fisiopatología , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/análisis , Proteínas de Transporte Vesicular de Monoaminas/análisisRESUMEN
The reliable prediction of transport and attenuation of dissolved-phase contamination in the unsaturated zone is a complex and multi-process problem. Based on the adsorption properties of soil samples to solutes, the soil column test and laboratory analysis were carried out in this study. The effects of the loam inter-layer on the migration and breakthrough of the characteristic pollutant benzene and non-absorbent Br- were studied. The results showed that the relatively high clay content of the inter-layer significantly changed the BTC (breakthrough curve). It not only delayed the migration time of benzene into the aquifer but also to some extent produced an attenuation effect, effectively reducing the content of the characteristic pollutants through the unsaturated zone. The dispersion coefficient was obtained through the measured Br-. The theoretical values were calculated and compared with the experimental data by using a one-dimensional unsaturated solute transport equation. The result was basically consistent, which proved the validity and reliability of the model. Through the BTC of benzene, the retardation factor was obtained and used to describe the influence of the loam inter-layer on the migration and breakthrough, which could provide the basis for the accurate modeling of groundwater remediation projects.
Asunto(s)
Benceno/química , Agua Subterránea , Modelos Químicos , Contaminantes del Suelo/química , Modelos Teóricos , Reproducibilidad de los Resultados , SueloRESUMEN
In this Letter, the 'Competing interests' statement should have stated: 'D.R.L. consults for and has equity in Vedanta Biosciences.' The original Letter has not been corrected.