RESUMEN
Benefiting from low cost and simple synthesis, polythiophene (PT) derivatives are one of the most popular donor materials for organic solar cells (OSCs). However, polythiophene-based OSCs still suffer from inferior power conversion efficiency (PCE) than those based on donor-acceptor (D-A)-type conjugated polymers. Herein, a fluorinated polythiophene derivative, namely P4T2F-HD, is introduced to modulate the miscibility and morphology of the bulk heterojunction (BHJ)-active layer, leading to a significant improvement of the OSC performance. The Flory-Huggins interaction parameters calculated from the surface energy and differential scanning calorimetry results suggest that P4T2F-HD shows moderate miscibility with the popular nonfullerene acceptor Y6-BO (2,2'-((2Z,2'Z)-((12,13-bis(2-butyloctyl)-3,9-diundecyl-12,13-dihydro-[1,2,5]thiadiazolo[3,4-e]thieno[2',3':4',5']thieno[2',3':4,5]pyrrolo[3,2-g]thieno[2',3':4,5]thieno[3,2-b]indole-2,10-diyl)bis(methanylylidene))bis(5,6-difluoro-3-oxo-2,3-dihydro-1H-indene-2,1-diylidene))dimalononitrile), while poly(3-hexylthiophene) (P3HT) is very miscible with Y6-BO. As a result, the P4T2F-HD case forms desired nanoscale phase separation in the BHJ film while the P3HT case forms a completely mixed BHJ film, as revealed by transmission electron microscopy (TEM) and grazing-incidence wide-angle X-ray scattering (GIWAXS). By optimizing the cathode interface and the morphology of the P4T2F-HD:Y6-BO films processed from nonhalogenated solvents, a new record PCE of 13.65% for polythiophene-based OSCs is demonstrated. This work highlights the importance of controlling D/A interactions for achieving desired morphology and also demonstrates a promising OSC system for potential cost-effective organic photovoltaics.
RESUMEN
In this work, a star-shaped planar acceptor named FTr-3PDI was synthesized via ring-fusion between truxene core and three bay-linked perylene diimide (PDI) branches. Compared to the unfused non-planar acceptor Tr-3PDI, FTr-3PDI exhibits better structural rigidity and planarity, as well as more effective conjugation between truxene core and PDI branches. As a result, FTr-3PDI shows up-shifted energy levels, enhanced light absorption coefficient, increased electron mobility, and more favorable phase separation morphology in bulk-heterojunction (BHJ) blend films as compared to Tr-3PDI. Consequently, FTr-3PDI afforded higher power conversion efficiency (PCE) in BHJ solar cells when blended with a polymer donor PTB7-Th. This work demonstrates that ring-fusion is a promising molecular design strategy to combine the merits of truxene and PDI for non-fullerene acceptors used in organic solar cells.
RESUMEN
The histone demethylase Jmjd3 plays a critical role in cell lineage specification and differentiation at various stages of development. However, its function during normal myeloid development remains poorly understood. Here, we carried out a systematic in vivo screen of epigenetic factors for their function in hematopoiesis and identified Jmjd3 as a new epigenetic factor that regulates myelopoiesis in zebrafish. We demonstrated that jmjd3 was essential for zebrafish primitive and definitive myelopoiesis, knockdown of jmjd3 suppressed the myeloid commitment and enhanced the erythroid commitment. Only overexpression of spi1 but not the other myeloid regulators rescued the myeloid development in jmjd3 morphants. Furthermore, preliminary mechanistic studies demonstrated that Jmjd3 could directly bind to the spi1 regulatory region to alleviate the repressive H3K27me3 modification and activate spi1 expression. Thus, our studies highlight that Jmjd3 is indispensable for early zebrafish myeloid development by promoting spi1 expression.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Histona Demetilasas con Dominio de Jumonji/genética , Células Mieloides/metabolismo , Mielopoyesis/genética , Proteínas Proto-Oncogénicas/genética , Transactivadores/genética , Proteínas de Pez Cebra/genética , Animales , Animales Modificados Genéticamente , Diferenciación Celular/genética , Embrión no Mamífero/embriología , Embrión no Mamífero/metabolismo , Técnicas de Silenciamiento del Gen , Histonas/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Lisina/metabolismo , Metilación , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismo , Pez Cebra/embriología , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismoRESUMEN
Dysregulation of ribosome biogenesis causes human diseases, such as Diamond-Blackfan anemia, del (5q-) syndrome and bone marrow failure. However, the mechanisms of blood disorders in these diseases remain elusive. Through genetic mapping, molecular cloning and mechanism characterization of the zebrafish mutant cas002, we reveal a novel connection between ribosomal dysfunction and excessive autophagy in the regulation of hematopoietic stem/progenitor cells (HSPCs). cas002 carries a recessive lethal mutation in kri1l gene that encodes an essential component of rRNA small subunit processome. We show that Kri1l is required for normal ribosome biogenesis, expansion of definitive HSPCs and subsequent lineage differentiation. Through live imaging and biochemical studies, we find that loss of Kri1l causes the accumulation of misfolded proteins and excessive PERK activation-dependent autophagy in HSPCs. Blocking autophagy but not inhibiting apoptosis by Bcl2 overexpression can fully rescue hematopoietic defects, but not the lethality of kri1l(cas002) embryos. Treatment with autophagy inhibitors (3-MA and Baf A1) or PERK inhibitor (GSK2656157), or knockdown of beclin1 or perk can markedly restore HSPC proliferation and definitive hematopoietic cell differentiation. These results may provide leads for effective therapeutics that benefit patients with anemia or bone marrow failure caused by ribosome disorders.
Asunto(s)
Autofagia , Hematopoyesis , Células Madre Hematopoyéticas , Proteínas de Pez Cebra/genética , eIF-2 Quinasa/metabolismo , Adenina/análogos & derivados , Adenina/farmacología , Animales , Autofagia/genética , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Indoles/farmacología , Mutación , Biogénesis de Organelos , Inhibidores de Proteínas Quinasas/farmacología , Ribosomas/metabolismo , Pez Cebra , eIF-2 Quinasa/antagonistas & inhibidoresRESUMEN
The interrelationship between genetic susceptibility and carcinogenic exposure is important in cancer development. Polymorphisms in detoxification enzymes of the glutathione-S-transferases (GST) family are associated with an increased incidence of lymphoma. Here we investigated the molecular connection of the genetic polymorphism of GSTT1 to the response of lymphocytes to polycyclic aromatic hydrocarbons (PAH). In neoplastic situation, GSTT1 deletions were more frequently observed in lymphoma patients (54.9%) than in normal controls (42.0%, P = 0.009), resulting in an increased risk for lymphoma in individuals with GSTT1-null genotype (Odds ratio = 1.698, 95% confidence interval = 1.145-2.518). GSTT1 gene and protein expression were accordingly decreased in GSTT1-deleting patients, consistent with activated profile of cell cycle regulation genes. Mimicking environmental exposure using long-term repeat culture with low-dose PAH metabolite Hydroquinone, malignant B- and T-lymphocytes presented increased DNA damage, pCHK1/MYC expression and cell proliferation, which were counteracted by ectopic expression of GSTT1. Moreover, GSTT1 expression retarded xenograft tumor formation of Hydroquinone-treated lymphoma cells in nude mice. In non-neoplastic situation, when zebrafish was exposed to PAH Benzo(a)pyrene, molecular silencing of gstt1 enhanced the proliferation of normal lymphocytes and upregulated myca expression. Collectively, these findings suggested that GSTT1 deletion is related to genetic predisposition to lymphoma, particularly interacting with environmental pollutants containing PAH.
Asunto(s)
Daño del ADN/efectos de los fármacos , Glutatión Transferasa/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células T/patología , Hidrocarburos Policíclicos Aromáticos/toxicidad , Polimorfismo Genético/genética , Eliminación de Secuencia/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Proliferación Celular/efectos de los fármacos , Aductos de ADN , Variaciones en el Número de Copia de ADN/genética , Daño del ADN/genética , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Genoma Humano , Genotipo , Humanos , Técnicas para Inmunoenzimas , Hibridación in Situ , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/etiología , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/etiología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto Joven , Pez Cebra/genética , Pez Cebra/crecimiento & desarrolloRESUMEN
BACKGROUND: The aberrant activation of Ras signaling is associated with human diseases including hematological malignancies and vascular disorders. So far the pathological roles of activated Ras signaling in hematopoiesis and vasculogenesis are largely unknown. METHODS: A conditional Cre/loxP transgenic strategy was used to mediate the specific expression of a constitutively active form of human N-Ras in zebrafish endothelial and hematopoietic cells driven by the zebrafish lmo2 promoter. The expression of hematopoietic and endothelial marker genes was analyzed both via whole mount in situ hybridization (WISH) assay and real-time quantitative PCR (qPCR). The embryonic vascular morphogenesis was characterized both by living imaging and immunofluorescence on the sections with a confocal microscopy, and the number of endothelial cells in the embryos was quantified by flow cytometry. The functional analyses of the blood circulation were carried out by fluorescence microangiography assay and morpholino injection. RESULTS: In the activated N-Ras transgenic embryos, the primitive hematopoiesis appeared normal, however, the definitive hematopoiesis of these embryos was completely absent. Further analysis of endothelial cell markers confirmed that transcription of arterial marker ephrinB2 was significantly decreased and expression of venous marker flt4 excessively increased, indicating the activated N-Ras signaling promotes the venous development at the expense of arteriogenesis during zebrafish embryogenesis. The activated N-Ras-expressing embryos showed atrophic axial arteries and expansive axial veins, leading to no definitive hematopoietic stem cell formation, the blood circulation failure and subsequently embryonic lethality. CONCLUSIONS: Our studies revealed for the first time that activated N-Ras signaling during the endothelial differentiation in vertebrates can disrupt the balance of arterial-venous specification, thus providing new insights into the pathogenesis of the congenital human vascular disease and tumorigenic angiogenesis.
Asunto(s)
Proteínas de Pez Cebra/fisiología , Pez Cebra/fisiología , Proteínas ras/fisiología , Animales , Animales Modificados Genéticamente , Arterias/fisiología , Diferenciación Celular/genética , Genes ras , Hematopoyesis/genética , Hematopoyesis/fisiología , Humanos , Transducción de Señal , Venas/fisiología , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
BACKGROUND: The role of cannabinoid receptor type 2 (Cnr2) in regulating immune function had been widely investigated, but the mechanism is not fully understood. RESULTS: Cnr2 activation down-regulates 5-lipoxygenase (Alox5) expression by suppressing the JNK/c-Jun activation. CONCLUSION: The Cnr2-JNK-Alox5 axis modulates leukocyte inflammatory migration. SIGNIFICANCE: Linking two important regulators in leukocyte inflammatory migration and providing a potential therapeutic strategy for treating human inflammation-associated diseases. Inflammatory migration of immune cells is involved in many human diseases. Identification of molecular pathways and modulators controlling inflammatory migration could lead to therapeutic strategies for treating human inflammation-associated diseases. The role of cannabinoid receptor type 2 (Cnr2) in regulating immune function had been widely investigated, but the mechanism is not fully understood. Through a chemical genetic screen using a zebrafish model for leukocyte migration, we found that both an agonist of the Cnr2 and inhibitor of the 5-lipoxygenase (Alox5, encoded by alox5) inhibit leukocyte migration in response to acute injury. These agents have a similar effect on migration of human myeloid cells. Consistent with these results, we found that inactivation of Cnr2 by zinc finger nuclease-mediated mutagenesis enhances leukocyte migration, while inactivation of Alox5 blocks leukocyte migration. Further investigation indicates that there is a signaling link between Cnr2 and Alox5 and that alox5 is a target of c-Jun. Cnr2 activation down-regulates alox5 expression by suppressing the JNK/c-Jun activation. These studies demonstrate that Cnr2, JNK, and Alox5 constitute a pathway regulating leukocyte migration. The cooperative effect between the Cnr2 agonist and Alox5 inhibitor also provides a potential therapeutic strategy for treating human inflammation-associated diseases.
Asunto(s)
Araquidonato 5-Lipooxigenasa/metabolismo , Movimiento Celular/efectos de los fármacos , Leucocitos/fisiología , Sistema de Señalización de MAP Quinasas , Receptor Cannabinoide CB2/metabolismo , Proteínas de Pez Cebra/metabolismo , Animales , Animales Modificados Genéticamente , Araquidonato 5-Lipooxigenasa/genética , Secuencia de Bases , Agonistas de Receptores de Cannabinoides/farmacología , Regulación Enzimológica de la Expresión Génica , Técnicas de Inactivación de Genes , Indoles/farmacología , Leucocitos/efectos de los fármacos , Datos de Secuencia Molecular , Unión Proteica , Proteínas Proto-Oncogénicas c-jun/metabolismo , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/genética , Cola (estructura animal) , Imagen de Lapso de Tiempo , Pez Cebra , Proteínas de Pez Cebra/genéticaRESUMEN
The regulation of hematopoiesis is generally evolutionarily conserved from zebrafish to mammals, including hematopoietic stem cell formation and blood cell lineage differentiation. In zebrafish, primitive granulocytes originate at two distinct regions, the anterior lateral plate mesoderm (A-LPM) and the intermediate cell mass (ICM). Few studies in the zebrafish have examined genes specifically required for the granulocytic lineage. In this study, we identified the responsible gene for a zebrafish mutant that has relatively normal hematopoiesis, except decreased expression of the granulocyte-specific gene mpx. Positional cloning revealed that phospholipase C gamma-1 (plcg1) was mutated. Deficiency of plcg1 function specifically affected development of granulocytes, especially the maturation process. These results suggested that plcg1 functioned specifically in zebrafish ICM granulopoiesis for the first time. Our studies suggest that specific pathways regulate the differentiation of the hematopoietic lineages.