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Although tumor-intrinsic fatty acid ß-oxidation (FAO) is implicated in multiple aspects of tumorigenesis and progression, the impact of this metabolic pathway on cancer cell susceptibility to immunotherapy remains unknown. Here, we report that cytotoxicity of killer T cells induces activation of FAO and upregulation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO in cancer cells. The repression of CPT1A activity or expression renders cancer cells more susceptible to destruction by cytotoxic T lymphocytes. Our mechanistic studies reveal that FAO deficiency abrogates the prosurvival signaling in cancer cells under immune cytolytic stress. Furthermore, we identify T cell-derived IFN-γ as a major factor responsible for induction of CPT1A and FAO in an AMPK-dependent manner, indicating a dynamic interplay between immune effector cells and tumor targets. While cancer growth in the absence of CPT1A remains largely unaffected, established tumors upon FAO inhibition become significantly more responsive to cellular immunotherapies including chimeric antigen receptor-engineered human T cells. Together, these findings uncover a mode of cancer resistance and immune editing that can facilitate immune escape and limit the benefits of immunotherapies.
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Carnitina O-Palmitoiltransferasa , Neoplasias , Humanos , Carnitina O-Palmitoiltransferasa/genética , Citotoxicidad Inmunológica , Ácidos Grasos , Metabolismo de los Lípidos , Neoplasias/terapia , Linfocitos T CitotóxicosRESUMEN
BACKGROUND AND AIM: Drug-induced liver injury occurs frequently and can be life threatening. Although drug-induced liver injury is mainly caused by the direct drug cytotoxicity, increasing evidence suggests that the interplay between hepatocytes and immune cells can define this pathogenic process. Here, we interrogate the role of the pattern recognition scavenger receptor A (SRA) for regulating hepatic inflammation and drug-induced liver injury. APPROACH AND RESULTS: Using acetaminophen (APAP) or halothane-induced liver injury models, we showed that SRA loss renders mice highly susceptible to drug hepatotoxicity, indicated by the increased mortality and liver pathology. Mechanistic studies revealed that APAP-induced liver injury exaggerated in the absence of SRA was associated with the decreased anti-inflammatory and prosurvival cytokine IL-10 concomitant with excessive hepatic inflammation. The similar correlation between SRA and IL-10 expression was also seen in human following APAP uptake. Bone marrow reconstitution and liposomal clodronate depletion studies established that the hepatoprotective activity of SRA mostly resized in the immune sentinel KCs. Furthermore, SRA-facilitated IL-10 production by KCs in response to injured hepatocytes mitigated activation of the Jun N-terminal kinase-mediated signaling pathway in hepatocytes. In addition, supplemental use of IL-10 with N -acetylcysteine, only approved treatment of APAP overdose, conferred mice improved protection from APAP-induced liver injury. CONCLUSION: We identify a novel hepatocyte-extrinsic pathway governed by the immune receptor SRA that maintains liver homeostasis upon drug insult. Giving that drug (ie, APAP) overdose is the leading cause of acute liver failure, targeting this hepatoprotective SRA-IL-10 axis may provide new opportunities to optimize the current management of drug-induced liver injury.
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Acetaminofén , Enfermedad Hepática Inducida por Sustancias y Drogas , Halotano , Hepatocitos , Receptores Depuradores , Receptores Depuradores/metabolismo , Animales , Ratones , Acetaminofén/toxicidad , Halotano/toxicidad , Hígado/efectos de los fármacos , Inflamación , Hepatocitos/metabolismo , HomeostasisRESUMEN
Accumulating data support the key roles of the NLRP3 inflammasome, an essential component of the innate immune system, in human pathophysiology. As an emerging drug target and a potential biomarker for human diseases, small molecule inhibitors of the NLRP3 inflammasome have been actively pursued. Our recent studies identified a small molecule, MS-II-124, as a potent NLRP3 inhibitor and potential imaging probe. In this report, MS-II-124 was further characterized by an unbiased and comprehensive analysis through Eurofins BioMAP Diversity PLUS panel that contains 12 human primary cell-based systems. The analysis revealed promising activities of MS-II-124 on inflammation and immune functions, further supporting the roles of the NLRP3 inflammasome in these model systems. Further studies of MS-II-124 in mouse model of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and NLRP3 knockout mice demonstrated its target engagement, efficacy to suppress inflammatory cytokines and infiltration of immune cells in the lung tissues. In summary, the results support the therapeutic potential of MS-II-124 as a NLRP3 inhibitor and warrant future studies of this compound and its analogs to develop therapeutics for ALI/ARDS.
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Lesión Pulmonar Aguda , Inflamasomas , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Bibliotecas de Moléculas Pequeñas , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Ratones , Humanos , Inflamasomas/antagonistas & inhibidores , Inflamasomas/metabolismo , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Ratones Endogámicos C57BL , Relación Estructura-Actividad , Relación Dosis-Respuesta a DrogaRESUMEN
OBJECTIVES: To study the effect of gut microbiota on hematopoiesis in a neonatal rat model of necrotizing enterocolitis (NEC). METHODS: Neonatal Sprague-Dawley rats were randomly divided into a control group and a model group (NEC group), with 6 rats in each group. Formula milk combined with hypoxia and cold stimulation was used to establish a neonatal rat model of NEC. Hematoxylin and eosin staining was used to observe the pathological changes of intestinal tissue and hematopoiesis-related organs. Routine blood tests were conducted for each group. Immunohistochemistry was used to observe the changes in specific cells in hematopoiesis-related organs. Flow cytometry was used to measure the changes in specific cells in bone marrow. 16S rDNA sequencing was used to observe the composition and abundance of gut microbiota. RESULTS: Compared with the control group, the NEC group had intestinal congestion and necrosis, damage, atrophy, and shedding of intestinal villi, and a significant increase in NEC histological score. Compared with the control group, the NEC group had significantly lower numbers of peripheral blood leukocytes and lymphocytes (P<0.05), nucleated cells in the spleen, thymus, and bone marrow, and small cell aggregates with basophilic nuclei in the liver (P<0.05). The NEC group had significant reductions in CD71+ erythroid progenitor cells in the liver, CD45+ lymphocytes in the spleen and bone marrow, CD3+ T lymphocytes in thymus, and the proportion of CD45+CD3-CD43+SSChi neutrophils in bone marrow (P<0.05). There was a significant difference in the composition of gut microbiota between the NEC and control groups, and the NEC group had a significant reduction in the abundance of Ligilactobacillus and a significant increase in the abundance of Escherichia-Shigella (P<0.05), which replaced Ligilactobacillus and became the dominant flora. CONCLUSIONS: Multi-lineage hematopoietic disorder may be observed in a neonatal rat model of NEC, which may be associated with gut microbiota dysbiosis and abnormal multiplication of the pathogenic bacteria Escherichia-Shigella.
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Enterocolitis Necrotizante , Microbioma Gastrointestinal , Enfermedades del Recién Nacido , Ratas , Animales , Enterocolitis Necrotizante/etiología , Ratas Sprague-Dawley , Animales Recién NacidosRESUMEN
Aroma is a key grain quality trait that directly influences the market price of rice globally. Loss of function of betaine aldehyde dehydrogenase 2 (OsBADH2) affects the biosynthesis of 2-acetyl-1-pyrroline (2-AP), which is responsible for aroma in fragrant rice. The current study was aimed at creating new alleles of BADH2 using CRISPR/Cas9 gene editing technology under the genetic background of the japonica Ningjing 1 (NJ1) and indica Huang Huazhan (HHZ) varieties. Sensory evaluation and analysis using headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) showed that the grains of the four homozygous T1 lines with new alleles of BADH2 (nj1-crâBADH2 -1, nj1-crâBADH2 -2, hhz-crâBADH2 -1 and hhz-crâBADH2 -2) produced moderate fragrance and had significantly increased 2-AP content compared with wild-types. Moreover, there were no significant differences in the amylose content and gelatinization temperature among the four lines with new alleles of BADH2 to the wild-types. Thereafter, we crossed the HHZ background new alleles of BADH2 with CMS line Taonong 1A (TN1A) to produce a three-line hybrid variety B-Tao-You-Xiangzhan (BTYXZ) with increased grain aroma. The 2-AP content in grains of the improved BTYXZ-1 and BTYXZ-2 reached at 26.16 and 18.74 µg/kg, and the gel consistency of BTYXZ-1 and BTYXZ-2 increased significantly by 9.1% and 6.5%, respectively, compared with the wild-type Tao-You-Xiangzhan (TYXZ). However, the γ-aminobutyric acid (GABA) content in the improved three-line hybrid rice BTYXZ-1 (5.6 mg/100 g) and BTYXZ-2 (10.7 mg/100 g) was significantly lower than that of the TYXZ. These results demonstrated that CRISPR/Cas9 gene editing technology could be successfully utilized in improving aroma in non-fragrant japonica and indica varieties. In addition, the newly developed BADH2 alleles provided important genetic resources for grain aroma improvement in three-line hybrid rice.
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Oryza , Alelos , Betaína Aldehído Deshidrogenasa/genética , Grano Comestible/genética , Odorantes , Oryza/genética , FenotipoRESUMEN
Mitogen-inducible gene 6 (Mig6) is a tumor suppressor, and the disruption of Mig6 expression is associated with cancer development. Mig6 directly interacts with epidermal growth factor receptor (EGFR) to suppress the activation and downstream signaling of EGFR. Therefore, loss of Mig6 enhances EGFR-mediated signaling and promotes EGFR-dependent carcinogenesis. The molecular mechanism modulating Mig6 expression in cancer remains unclear. Here we demonstrate that type I γ phosphatidylinositol phosphate 5-kinase i5 (PIPKIγi5), an enzyme producing phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), stabilizes Mig6 expression. Knockdown of PIPKIγi5 leads to the loss of Mig6 expression, which dramatically enhances and prolongs EGFR-mediated cell signaling. Loss of PIPKIγi5 significantly promotes Mig6 protein degradation via proteasomes, but it does not affect the Mig6 mRNA level. PIPKIγi5 directly interacts with the E3 ubiquitin ligase neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1). The C-terminal domain of PIPKIγi5 and the WW1 and WW2 domains of NEDD4-1 are required for their interaction. The C2 domain of NEDD4-1 is required for its interaction with PtdIns(4,5)P2 By binding with NEDD4-1 and producing PtdIns(4,5)P2, PIPKIγi5 perturbs NEDD4-1-mediated Mig6 ubiquitination and the subsequent proteasomal degradation. Thus, loss of NEDD4-1 can rescue Mig6 expression in PIPKIγi5 knockdown cells. In this way, PIPKIγi5, NEDD4-1, and Mig6 form a novel molecular nexus that controls EGFR activation and downstream signaling.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Receptores ErbB/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Proteolisis , Transducción de Señal/fisiología , Proteínas Supresoras de Tumor/metabolismo , Ubiquitinación/fisiología , Proteínas Adaptadoras Transductoras de Señales/genética , Línea Celular Tumoral , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Receptores ErbB/genética , Femenino , Humanos , Ubiquitina-Proteína Ligasas Nedd4 , Fosfatidilinositol 4,5-Difosfato/genética , Fosfatidilinositol 4,5-Difosfato/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Dominios Proteicos , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide. The majority of HNSCCs overexpress Epidermal Growth Factor Receptor (EGFR), an essential receptor tyrosine kinase (RTK) that promotes HNSCC growth and metastasis. Therefore, EGFR has been used as an important therapeutic target to treat HNSCC. Inhibition of EGFR stimulates autophagy in cancer cells. However, the role of autophagy in EGFR inhibitor-induced cancer suppression is still in a debate. Here, we reveal that the first- and the second-generation EGFR tyrosine kinase inhibitors (TKIs) differentially affect HNSCC autophagy. The second-generation EGFR TKIs have much stronger effects on autophagy than the first-generation TKIs. The second-generation EGFR TKIs not only promote autophagy initiation signaling but also block autophagic flux by disturbing the lysosomes function, indicating a novel mechanism by which EGFR TKIs modulate cancer cell autophagy. Blocking the initiation of autophagy does not affect the second-generation EGFR TKI-induced HNSCC growth suppression. This suggests that the anti-growth effect of the second-generation EGFR TKIs on HNSCC is not dependent on autophagy.
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Autofagia/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Proliferación Celular/efectos de los fármacos , Factor de Crecimiento Epidérmico/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Carcinoma de Células Escamosas/patología , Relación Dosis-Respuesta a Droga , Neoplasias de Cabeza y Cuello/patología , Humanos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Carcinoma de Células Escamosas de Cabeza y Cuello , Resultado del TratamientoRESUMEN
B-cell acute lymphoblastic leukemia is the most common type of pediatric leukemia. Despite improved remission rates, current treatment regimens for pediatric B-cell acute lymphoblastic leukemia are often associated with adverse effects and central nervous system relapse, necessitating more effective and safer agents. Bafilomycin A1 is an inhibitor of vacuolar H(+)-ATPase that is frequently used at high concentration to block late-phase autophagy. Here, we show that bafilomycin A1 at a low concentration (1 nM) effectively and specifically inhibited and killed pediatric B-cell acute lymphoblastic leukemia cells. It targeted both early and late stages of the autophagy pathway by activating mammalian target of rapamycin signaling and by disassociating the Beclin 1-Vps34 complex, as well as by inhibiting the formation of autolysosomes, all of which attenuated functional autophagy. Bafilomycin A1 also targeted mitochondria and induced caspase-independent apoptosis by inducing the translocation of apoptosis-inducing factor from mitochondria to the nucleus. Moreover, bafilomycin A1 induced the binding of Beclin 1 to Bcl-2, which further inhibited autophagy and promoted apoptotic cell death. In primary cells from pediatric patients with B-cell acute lymphoblastic leukemia and a xenograft model, bafilomycin A1 specifically targeted leukemia cells while sparing normal cells. An in vivo mouse toxicity assay confirmed that bafilomycin A1 is safe. Our data thus suggest that bafilomycin A1 is a promising candidate drug for the treatment of pediatric B-cell acute lymphoblastic leukemia.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Macrólidos/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/inmunología , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos B/patología , Beclina-1 , Núcleo Celular/efectos de los fármacos , Núcleo Celular/inmunología , Núcleo Celular/patología , Niño , Fosfatidilinositol 3-Quinasas Clase III/genética , Fosfatidilinositol 3-Quinasas Clase III/inmunología , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/inmunología , Mitocondrias/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Previously, we found that two isoforms of the ZNF268 gene (ZNF268a and ZNF268b2, with and without the KRAB domain, respectively) might play distinct roles in normal epithelia and in cervical cancer. Here we further investigated that KRAB domain defined the function disparity in part by reinforcing nuclear localization of ZNF268a. We found that the A-box of KRAB alone retained major specific nuclear localization activity. In contrast, the B-box alone did not have nuclear localization activity but enhanced it significantly. Consistent with the critical function of the A-box, each mutation of six conserved residues (V9, V11, F13, E16, E17 and W18) in the A-box dramatically impaired nuclear localization activity. Furthermore, the unique nuclear localization activity of KRAB was verified in seven additional KRAB-containing zinc finger proteins (KRAB-ZFPs), suggesting that it is a universal feature of KRAB-ZFPs. Finally, KRAB exerted its unique nuclear localization activity by interacting with the RBCC domain of its corepressor KAP1. Our results have revealed a novel mechanism by which the KRAB domain reinforces nuclear localization of KRAB-ZFPs by interacting with KAP1. Our study also suggests that loss of the KRAB domain in KRAB-ZFPs due to aberrant alternative splicing might contribute to carcinogenesis.
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Núcleo Celular/metabolismo , Proteínas Represoras/metabolismo , Transporte Activo de Núcleo Celular , Empalme Alternativo , Secuencia de Aminoácidos , Animales , Células COS , Núcleo Celular/genética , Chlorocebus aethiops , Secuencia Conservada , Elementos de Facilitación Genéticos , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Ratones , Datos de Secuencia Molecular , Mutación , Dominios y Motivos de Interacción de Proteínas , Mapeo de Interacción de Proteínas , Proteínas Represoras/genética , Transcripción Genética , Proteína 28 que Contiene Motivos TripartitoRESUMEN
Diabetes is a common disease that seriously endangers human health. Continuous glucose monitoring (CGM) is important for the prevention and treatment of diabetes. Glucose-sensing photonic nanochains (PNCs) have the advantages of naked-eye colorimetric readouts, short response time and noninvasive detection of diabetes, showing immense potential in CGM systems. However, the developed PNCs cannot disperse in physiological environment at the pH of 7.4 because of their poor hydrophilicity. In this study, we report a new kind of PNCs that can continuously and reversibly detect the concentration of glucose (Cg) in physiological environment at the pH of 7.4. Polyacrylic acid (PAA) added to the preparation of PNCs forms hydrogen bonds with polyvinylpyrrolidone (PVP) in Fe3O4@PVP colloidal nanoparticles and the hydrophilic monomer N-2-hydroxyethyl acrylamide (HEAAm), which increases the content of PHEAAm in the polymer shell of prepared PNCs. Moreover, 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AFPBA), with a relatively low pKa value, is used as the glucose-sensing monomer to further improve the hydrophilicity and glucose-sensing performances of PNCs. The obtained Fe3O4@(PVP-PAA)@poly(AFPBA-co-HEAAm) PNCs disperse in artificial serum and change color from yellow-green to red when Cg increases from 3.9 mM to 11.4 mM, showing application potential for straightforward CGM.
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Cervical cancer is one of the most common tumors affecting women's health worldwide. Although human papillomavirus can be detected in nearly all cases, the mechanism of cervical carcinogenesis remains to be further addressed. Here, we demonstrated that ZNF268, a Krüppel-associated box-containing zinc finger protein, might contribute to the development of cervical cancer. We found that ZNF268b2, an isoform of ZNF268, was overexpressed in human squamous cervical cancer specimens. Knockdown of ZNF268 in cervical cancer cells caused cell cycle arrest at the G(0)/G(1) phase, reduced colony formation, and increased sensitivity to TNFα-induced apoptosis. In addition, HeLa cell growth in xenograft nude mice was suppressed by ZNF268 knockdown, with increased apoptosis. Furthermore, ZNF268b2 was shown to increase NF-κB signaling in vitro and in vivo. Reconstitution of NF-κB activity restored proliferation in ZNF268 knockdown HeLa cells. Of note, we observed a high frequency of NF-κB activation in ZNF268-overexpressing cervical cancer tissues, suggesting a pathological coincidence of ZNF268b2 overexpression and NF-κB activation. Taken together, our results reveal a novel role of ZNF268b2 that contributes to cervical carcinogenesis in part through enhancing NF-κB signaling.
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Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , FN-kappa B/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Cicloheximida/farmacología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Femenino , Técnicas de Silenciamiento del Gen , Células HeLa , Humanos , Proteínas I-kappa B/metabolismo , Inmunohistoquímica , Ratones , Ratones Desnudos , Inhibidor NF-kappaB alfa , Transducción de Señal/efectos de los fármacos , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Mouse has served as an excellent model for studying human development and diseases due to its similarity to human. Advances in transgenic and knockout studies in mouse have dramatically strengthened the use of this model and significantly improved our understanding of gene function during development in the past few decades. More recently, global gene expression analyses have revealed novel features in early embryogenesis up to gastrulation stages and have indeed provided molecular evidence supporting the conservation in early development in human and mouse. On the other hand, little information is known about the gene regulatory networks governing the subsequent organogenesis. Importantly, mouse and human development diverges during organogenesis. For instance, the mouse embryo is born around the end of organogenesis while in human the subsequent fetal period of ongoing growth and maturation of most organs spans more than 2/3 of human embryogenesis. While two recent studies reported the gene expression profiles during human organogenesis, no global gene expression analysis had been done for mouse organogenesis. RESULTS: Here we report a detailed analysis of the global gene expression profiles from egg to the end of organogenesis in mouse. Our studies have revealed distinct temporal regulation patterns for genes belonging to different functional (Gene Ontology or GO) categories that support their roles during organogenesis. More importantly, comparative analyses identify both conserved and divergent gene regulation programs in mouse and human organogenesis, with the latter likely responsible for the developmental divergence between the two species, and further suggest a novel developmental strategy during vertebrate evolution. CONCLUSIONS: We have reported here the first genome-wide gene expression analysis of the entire mouse embryogenesis and compared the transcriptome atlas during mouse and human embryogenesis. Given our earlier observation that genes function in a given process tends to be developmentally co-regulated during organogenesis, our microarray data here should help to identify genes associated with mouse development and/or infer the developmental functions of unknown genes. In addition, our study might be useful for invesgtigating the molecular basis of vertebrate evolution.
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Desarrollo Embrionario/genética , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Animales , Análisis por Conglomerados , Femenino , Redes Reguladoras de Genes , Variación Genética , Humanos , Masculino , Ratones , Anotación de Secuencia Molecular , Organogénesis/genética , TranscriptomaRESUMEN
As an environmentally friendly means of transport, the high-speed rail (HSR) is conducive to promoting corporate performance. An innovative approach extends the impact of HSR networks on pollution emissions from the regional level to the micro-enterprise level. Based on the quasi-natural experiment of the opening of HSR, a difference-in-difference model is used to investigate the impact of HSR on enterprise pollution emission levels and its action mechanism by using the matched data from the Chinese Enterprise Pollution Emission Database, the Chinese Industrial Enterprise Database, and the Chinese City Statistical Yearbook from 2000 to 2010. The results show that opening HSR significantly reduces the enterprises' pollution emission level, while reducing the number of polluting enterprises and transportation costs as well as improving the innovation capacity of enterprises are the corresponding action mechanisms. The impact of HSR on the enterprises' pollution emission varies with industry intensity, population size, and regional economic development level. The conclusions not only provide important insights to increase the ecological quality of China's environment through transportation infrastructure upgrades but also bring some guidance to more developing countries to improve their air environment.
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Pueblo Asiatico , Desarrollo Económico , Humanos , China , Bases de Datos Factuales , Contaminación AmbientalRESUMEN
Erb-b2 receptor tyrosine kinase 2 (ErbB2) is an oncogene that frequently overexpressed in a subset of cancers. Anti-ErbB2 therapies have been developed to treat these types of cancers. However, less is known about how anti-ErbB2 drugs affect the trafficking and degradation of ErbB2. We demonstrate that the reversible and irreversible tyrosine kinase inhibitors (TKIs) differentially modulate the subcellular trafficking and downregulation of ErbB2. Only the irreversible TKIs can induce the loss of ErbB2 expression, which is not dependent on proteasome or lysosome. The irreversible TKIs promote ErbB2 endocytosis from plasma membrane and enhance the ErbB2 accumulation at endosomes. The endocytosis of ErbB2 is mediated by a dynamin-dependent but clathrin-independent mechanism. Blocking of ErbB2 endocytosis can impair the TKI-induced ErbB2 downregulation.
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The reduction of carbon emissions has become an important climate issue worldwide. However, the diversity of carbon trading systems and the differentiation policy may generate incomparable carbon abatement costs across regions and countries. Based on the nonparametric model, this paper investigates the shadow price of carbon emissions and energy structure in 38 Asian countries from 1991 to 2019. The main findings of this paper are as follows: (1) The annual average shadow price of carbon emissions experienced a fluctuating decline for Asian countries during the period 1991-2000, followed by a continuous rise and then a fluctuating decline. (2) Industrialization may lead to a decline in carbon shadow price, while urbanization may lead to a rise in the opportunity cost of carbon reduction. (3) The carbon shadow price in countries of Asia-Pacific Economic Cooperation (APEC) is lower than that in non-APEC countries. (4) The structure of energy consumption is negatively related to marginal abatement costs, while on the contrary, the coefficients of the level of human resources are significantly positive. We also derive corresponding policy measures to promote intra-regional emission reduction.
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Dióxido de Carbono , Carbono , Humanos , Carbono/análisis , Dióxido de Carbono/análisis , Asia , Desarrollo Económico , PolíticasRESUMEN
Gestational diabetes mellitus (GDM) is currently the most common metabolic complication during pregnancy, with an increasing prevalence worldwide. Maternal immune dysregulation might be partly responsible for the pathophysiology of GDM. Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of cells, emerging as a new immune regulator with potent immunosuppressive capacity. Although the fate and function of these cells were primarily described in pathological conditions such as cancer and infection, accumulating evidences have spotlighted their beneficial roles in homeostasis and physiological conditions. Recently, several studies have explored the roles of MDSCs in the diabetic microenvironment. However, the fate and function of these cells in GDM are still unknown. The current review summarized the existing knowledges about MDSCs and their potential roles in diabetes during pregnancy in an attempt to highlight our current understanding of GDM-related immune dysregulation and identify areas where further study is required.
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Diabetes Gestacional , Células Supresoras de Origen Mieloide , Neoplasias , Embarazo , Femenino , Humanos , Diabetes Gestacional/metabolismo , Homeostasis , Microambiente TumoralRESUMEN
We have previously demonstrated that scavenger receptor A (SRA) acts as an immunosuppressive regulator of dendritic cell (DC) function in activating antitumor T cells. Here we investigate the potential of inhibiting SRA activity to enhance DC-targeted chaperone vaccines including one that was recently evaluated in melanoma patients. We show that short hairpin RNA-mediated SRA silencing significantly enhances the immunogenicity of DCs that have captured chaperone vaccines designed to target melanoma (i.e., hsp110-gp100) and breast cancer (i.e., hsp110-HER/Neu-ICD). SRA downregulation results in heightened activation of antigen-specific T cells and increased CD8+ T cell-dependent tumor inhibition. Additionally, small interfering RNA (siRNA) complexed with the biodegradable, biocompatible chitosan as a carrier can efficiently reduce SRA expression on CD11c+ DCs in vitro and in vivo. Our proof-of-concept study shows that direct administration of the chitosan-siRNA complex to mice promotes chaperone vaccine-elicited cytotoxic T lymphocyte (CTL) response, culminating in improved eradication of experimental melanoma metastases. Targeting SRA with this chitosan-siRNA regimen combined with the chaperone vaccine also leads to reprogramming of the tumor environment, indicated by elevation of the cytokine genes (i.e., ifng, il12) known to skew Th1-like cellular immunity and increased tumor infiltration by IFN-γ+CD8+ CTLs as well as IL-12+CD11c+ DCs. Given the promising antitumor activity and safety profile of chaperone vaccine in cancer patients, further optimization of the chitosan-siRNA formulation to potentially broaden the immunotherapeutic benefits of chaperone vaccine is warranted.
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Vacunas contra el Cáncer , Quitosano , Melanoma Experimental , Ratones , Animales , Células Dendríticas , Quitosano/metabolismo , Antígenos/metabolismo , Chaperonas Moleculares , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Receptores Depuradores/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismoRESUMEN
BACKGROUND: Drug (e.g., acetaminophen, APAP)-associated hepatotoxicity is the major cause of acute liver failure. Emerging evidence shows that initial tissue damage caused by APAP triggers molecular and cellular immune responses, which can modulate the severity of hepatoxicity. The pro-inflammatory and cytotoxic cytokine interferon (IFN)-γ has been reported as a key molecule contributing to APAP-induced liver injury (AILI). However, its cellular source remains undetermined. RESULTS: In the current study, we show that elevation of serum IFN-γ in patients with drug hepatotoxicity correlates with disease severity. Neutralization of IFN-γ in a mouse model of AILI effectively reduces hepatotoxicity. Strikingly, we reveal that IFN-γ is expressed primarily by hepatic neutrophils, not by conventional immune cells with known IFN-γ-producing capability, e.g., CD8+ T cells, CD4+ T cells, natural killer cells, or natural killer T cells. Upon encountering APAP-injured hepatocytes, neutrophils secrete cytotoxic IFN-γ further causing cell stress and damage, which can be abrogated in the presence of blocking antibodies for IFN-γ or IFN-γreceptor. Furthermore, removal of neutrophils in vivo substantially decreases hepatic IFN-γ levels concomitantly with reduced APAP hepatotoxicity, whereas adoptive transfer of IFN-γ-producing neutrophils confers IFN-γ-/- mice susceptibility to APAP administration. CONCLUSIONS: Our findings uncover a novel mechanism of neutrophil action in promoting AILI and provide new insights into immune modulation of the disease pathogenesis.
Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Enfermedad Hepática Inducida por Sustancias y Drogas , Humanos , Animales , Ratones , Acetaminofén/toxicidad , Interferón gamma/farmacología , Neutrófilos , Linfocitos T CD8-positivos , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hígado/patología , Ratones Endogámicos C57BLRESUMEN
This study investigates economic convergence and sustainable development in Africa. By introducing an aggregate production technology and directional distance function, it examines the productivity growth of 28 African economies from 1990 to 2019. The proposed approach considers all decision-making units (countries) as a whole, and the productivity gains are then estimated under a nonparametric framework. In the empirical analysis, the carbon emissions are included in the Luenberger productivity measurement, called green productivity. The results show that the annual average growth rate of green productivity is 1.51% in African, and different types of club convergence for green productivity indicator and its decomposition are observed during the sample period. The decomposition of the Luenberger indicator shows that green African growth is mainly driven by technological progress, not efficiency change. Furthermore, the overall inefficiency is decomposed into technical and structural effects. The latter measure the potential improvement in terms of resource reallocation. Structural inefficiency is larger than technical inefficiency, suggesting that African countries could improve their economic and environmental performances by optimizing input/output mixes.
Asunto(s)
Eficiencia , Desarrollo Sostenible , África , Carbono , China , Desarrollo Económico , TecnologíaRESUMEN
Glucose-sensing photonic crystals are promising for the significant advance of continuous glucose monitoring systems due to the naked-eye colorimetric readouts and noninvasive detection of diabetes, but the long response time hampers their practical applications. Here, for the first time probes of photonic nanochains (PNCs) are demonstrated that are capable of continuously and reversibly sensing glucose concentration ([glucose]) variation within seconds by color change without power consumption, much faster by 2-3 orders of magnitude than previous ones. They are comprised of 1D equidistant arrays of magnetic nanoparticles enveloped by tens-of-nanometer-thick phenylboronic acid-functionalized hydrogels, and fabricated by developing selective concentration polymerization of monomers in binary microheterogeneous solvents of dimethyl sulfoxide (DMSO) and H2 O. In this process, both 3-acrylamido phenylboronic acid (AAPBA) and N-2-hydroxyethyl acrylamide (HEAAm) are preferentially dissolved in the small volume of free DMSO concentrated in the vicinity of poly vinylpyrrolidone coated Fe3 O4 colloidal nanoparticles (Fe3 O4 @PVP), yielding Fe3 O4 @PVP@poly(AAPBA-co-HEAAm) PNCs after UV irradiation under magnetic field. The PNCs in phosphate buffered solution have a wavelength-shift range up to 130 nm when [glucose] changes from 0 to 20 × 10-3 m. The results can facilitate real-time glucose monitoring and provide an alternative to produce functional organic-inorganic nanostructures.