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Glycogen is a form of energy storage for glucose in different tissues such as liver and skeletal muscle. It remains incompletely understood how glycogen impacts on adipose tissue functionality. Cold exposure elevated the expression of Gys1 that encodes glycogen synthase 1 in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT). The in vivo function of Gys1 was analyzed using a mouse model in which Gys1 was deleted specifically in adipose tissues. Under normal chow conditions, Gys1 deletion caused little changes to body weight and glucose metabolism. Deletion of Gys1 abrogated upregulation of UCP1 and other thermogenesis-related genes in iWAT upon prolonged cold exposure or treatment with ß3-adrenergic receptor agonist CL-316,243. Stimulation of UCP1 by CL-316,243 in adipose-derived stromal cells (stromal vascular fractions, SVFs) was also reduced by Gys1 deletion. Both the basal glycogen content and CL-316,243-stimulated glycogen accumulation in adipose tissues were reduced by Gys1 deletion. High-fat diet-induced obesity and insulin resistance were aggravated in Gys1-deleted mice. The loss of body weight upon CL-316,243 treatment was also abrogated by the loss of Gys1. In conclusion, our results underscore the pivotal role of glycogen synthesis in adaptive thermogenesis in beige adipose tissue and its impact on diet-induced obesity in mice.NEW & NOTEWORTHY Glycogen is one of major types of fuel reserve in the body and its classical function is to maintain blood glucose level. This study uncovers that glycogen synthesis is required for beige fat tissue to generate heat upon cold exposure. Such a function of glycogen is linked to development of high-fat diet-induced obesity, thus extending our understanding about the physiological functions of glycogen.
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Tecido Adiposo Bege , Dieta Hiperlipídica , Glicogênio , Obesidade , Termogênese , Animais , Termogênese/genética , Termogênese/fisiologia , Camundongos , Obesidade/metabolismo , Obesidade/genética , Tecido Adiposo Bege/metabolismo , Glicogênio/metabolismo , Glicogênio/biossíntese , Masculino , Camundongos Knockout , Camundongos Endogâmicos C57BL , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Glicogênio Sintase/metabolismo , Glicogênio Sintase/genética , Temperatura Baixa , Adaptação Fisiológica , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genéticaRESUMO
Glomerella leaf spot (GLS), caused by Colletotrichum fructicola, is a severe disease worldwide on apple, causing defoliation, leaf and fruit spot, and substantial yield loss. However, little is known about its molecular mechanisms of pathogenesis. Previous transcriptome analysis revealed that a transcription factor, CfMcm1, was induced during leaf infection. In the present work, expression pattern analysis verified that the CfMcm1 gene was strongly expressed in conidia and early infection. Phenotypic analysis revealed that the gene deletion mutant ΔCfMcm1 lost pathogenicity to apple leaves by inhibiting conidial germination and appressorium formation. In addition to appressorium-mediated pathogenicity, ΔCfMcm1 colonization and hyphal extension in wounded apple fruit was also reduced, and conidial germination mode and conidial color were altered. ΔCfMcm1 displayed impairment of cell wall integrity and response to stress caused by oxidation, osmosis, and an acid environment. Furthermore, the deletion mutant produced fewer and smaller perithecia and no ascospores. In contrast, melanin deposition in mycelia of ΔCfMcm1 was strengthened. Further comparative transcriptome and quantitative PCR analysis revealed that CfMcm1 modulated expression of genes related to conidial development (CfERG5A, CfERG5B, CfHik5, and CfAbaA), appressorium formation (CfCBP1 and CfCHS7), pectin degradation (CfPelA and CfPelB), sexual development (CfMYB, CfFork, CfHMG, and CfMAT1-2-1), and melanin biosynthesis (CfCmr1, CfPKS1, CfT4HR1, CfTHR1, and CfSCD1). Our results demonstrated that CfMcm1 is a pivotal regulator possessing multiple functions in pathogenicity, asexual and sexual reproduction, and melanin biosynthesis.
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Colletotrichum , Malus , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Germinação , Melaninas/metabolismo , Pectinas/metabolismo , Doenças das Plantas , Desenvolvimento Sexual , Esporos Fúngicos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Virulência/genéticaRESUMO
BACKGROUND: Hydatidiform moles exhibit a distinctive gross appearance of multiple vesicles in the placenta. The advances in cytogenetic technologies have helped uncover novel entities of hydatidiform moles and enabled elaborate diagnoses. However, management of a vesicular placenta with a coexistent live fetus poses a bigger challenge beyond hydatidiform moles. CASE PRESENTATION: A 33-year-old woman was referred to our department for suspected hydatidiform mole coexistent with a live fetus at 24 weeks' gestation. The patient had conceived through double embryo transplantation, and first-trimester ultrasonography displayed a single sac. Mid-trimester imaging findings of normal placenta parenchyma admixed with multiple vesicles and a single amniotic cavity with a fetus led to suspicion of a singleton partial molar pregnancy. After confirmation of a normal diploid by amniocentesis and close surveillance, the patient delivered a healthy neonate. Preliminary microscopic examination of the placenta failed to clarify the diagnosis until fluorescence in situ hybridization showed a majority of XXY sex chromosomes. The patient developed suspected choriocarcinoma and achieved remission for 5 months after chemotherapy, but relapsed with suspected intermediate trophoblastic tumor. CONCLUSION: We report a rare case of twin pregnancy comprising a partial mole and a normal fetus that resembled a singleton partial molar pregnancy. Individualized care is important in conditions where a vesicular placenta coexists with a fetus. We strongly recommend ancillary examinations in addition to traditional morphologic assessment in such cases.
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Mola Hidatiforme/diagnóstico , Placenta/patologia , Gravidez de Gêmeos , Neoplasias Uterinas/diagnóstico , Adulto , Feminino , Feto , Idade Gestacional , Humanos , Hibridização in Situ Fluorescente , Nascido Vivo , Gravidez , Primeiro Trimestre da Gravidez , Ultrassonografia Pré-NatalRESUMO
Rice (Oryza sativa L.), a major staple crop worldwide, has limited levels of the essential amino acid lysine. We previously produced engineered rice with increased lysine content by expressing bacterial aspartate kinase and dihydrodipicolinate synthase and inhibiting rice lysine ketoglutarate reductase/saccharopine dehydrogenase activity. However, the grain quality, field performance, and integration patterns of the transgenes in these lysine-enriched lines remain unclear. In the present study, we selected several elite transgenic lines with endosperm-specific or constitutive regulation of the above key enzymes but lacking the selectable marker gene. All target transgenes were integrated into the intragenic region in the rice genome. Two pyramid transgenic lines (High Free Lysine; HFL1 and HFL2) with free lysine levels in seeds up to 25-fold that of wild type were obtained via a combination of the above two transgenic events. We observed a dramatic increase in total free amino acids and a slight increase in total protein content in both pyramid lines. Moreover, the general physicochemical properties were improved in pyramid transgenic rice, but the starch composition was not affected. Field trials indicated that the growth of HFL transgenic rice was normal, except for a slight difference in plant height and grain colour. Taken together, these findings will be useful for the potential commercialization of high-lysine transgenic rice.
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Biofortificação/métodos , Lisina/metabolismo , Oryza/metabolismo , Aminoácidos/análise , Aminoácidos/metabolismo , Southern Blotting , Lisina/análise , Valor Nutritivo , Oryza/genética , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Reação em Cadeia da Polimerase , Característica Quantitativa Herdável , Sementes/química , Sementes/metabolismoRESUMO
Molecular interactions between terpenoid mosquito repellents and three typical human-secreted attractants, ammonia, 1-octen-3-ol, and formic acid were studied. Relative energies, bond distances, and bond angles of the molecular interactions were obtained at HF level to evaluate the interaction intensity and types. The effects of molecular interactions on repellency were investigated by the subsequent quantitative structure-activity relationship (QSAR) study. The results of this study suggest that attractant-repellent interaction should not be ignored and could be helpful for future research on the repelling mechanism of mosquito repellents.
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Amônia/química , Formiatos/química , Repelentes de Insetos/química , Octanóis/química , Terpenos/química , Animais , Complexos de Coordenação/química , Humanos , Estrutura Molecular , Controle de Mosquitos , Relação Quantitativa Estrutura-AtividadeRESUMO
A new water-soluble ruthenium hydride complex [Ru(H)(bpy)2(PTA)]PF6 (bpy = 2,2'-bipyridine, PTA = 1,3,5-triaza-7-phosphaadamantane) (1a) was prepared. 1a reacted with CO2 and CS2 to give the corresponding formate and dithioformate complexes, respectively. Both the insertions of CO2 and CS2 into the Ru-H bond of 1a followed second-order kinetics. The second-order rate constant (k2) of CO2 insertion reaction varied from (9.40 ± 0.41) × 10(-4) M(-1) s(-1) in acetone to (1.13 ± 0.08) × 10(-1) M(-1) s(-1) in methanol; moreover, the ln(k2) is in good linear relationship with the acceptor number (AN) of the solvent used. Although, the k2 of CS2 insertion reaction ranged from (3.43 ± 0.10) M(-1) s(-1) in methanol to (24.0 ± 0.5) M(-1) s(-1) in N,N-dimethylformamide, which is 1000 times faster than CO2 insertion. Generally, the k2 of CS2 insertion increased with the static dielectric constant (D(s)) of the reaction medium investigated. For comparison purposes, we further investigated the reactivity of [Ru(H)(bpy)2(PPh3)]PF6 (PPh3 = triphenylphosphine) (1b) with CO2 and CS2. 1b reacted with CO2 slowly in the methanol with a k2 of (1.46 ± 0.09) × 10(-3) M(-1) s(-1), yielding a formate complex [Ru(η(1)-OC(H)âO)(bpy)2(PPh3)]PF6 (2b). The reaction of 1b with CS2 is 1000 times faster than that of CO2. The structures of 1a, 1b, and 2b were determined by X-ray crystallographic analysis.
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Cancer is a complex disease resulting from abnormal cell growth that is induced by a number of genetic and environmental factors. The tumor microenvironment (TME), which involves extracellular matrix, cancer-associated fibroblasts (CAF), tumor-infiltrating immune cells and angiogenesis, plays a critical role in tumor progression. Cyclic adenosine monophosphate (cAMP) is a second messenger that has pleiotropic effects on the TME. The downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), exchange protein activated by cAMP (EPAC) and ion channels. While cAMP can activate PKA or EPAC and promote cancer cell growth, it can also inhibit cell proliferation and survival in context- and cancer type-dependent manner. Tumor-associated stromal cells, such as CAF and immune cells, can release cytokines and growth factors that either stimulate or inhibit cAMP production within the TME. Recent studies have shown that targeting cAMP signaling in the TME has therapeutic benefits in cancer. Small-molecule agents that inhibit adenylate cyclase and PKA have been shown to inhibit tumor growth. In addition, cAMP-elevating agents, such as forskolin, can not only induce cancer cell death, but also directly inhibit cell proliferation in some cancer types. In this review, we summarize current understanding of cAMP signaling in cancer biology and immunology and discuss the basis for its context-dependent dual role in oncogenesis. Understanding the precise mechanisms by which cAMP and the TME interact in cancer will be critical for the development of effective therapies. Future studies aimed at investigating the cAMP-cancer axis and its regulation in the TME may provide new insights into the underlying mechanisms of tumorigenesis and lead to the development of novel therapeutic strategies.
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Fatores de Troca do Nucleotídeo Guanina , Neoplasias , Humanos , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Microambiente Tumoral , Transdução de Sinais , AMP Cíclico/metabolismo , AMP Cíclico/farmacologiaRESUMO
Host-derived reactive oxygen species (ROS) are an important defense means to protect against pathogens. Although mitochondria are the main intracellular targets of ROS, how pathogens regulate mitochondrial physiology in response to oxidative stress remains elusive. Prohibitin 2 (PHB2) is an inner mitochondrial membrane (IMM) protein, recognized as a mitophagy receptor in animals and fungi. Here, we find that an ANK and FYVE domain-containing protein PsAF5, is an adapter of PsPHB2, interacting with PsATG8 under ROS stress. Unlike animal PHB2 that can recruit ATG8 directly to mitochondria, PsPHB2 in Phytophthora sojae cannot recruit PsATG8 to stressed mitochondria without PsAF5. PsAF5 deletion impairs mitophagy under ROS stress and increases the pathogen's sensitivity to H2O2, resulting in the attenuation of P. sojae virulence. This discovery of a PsPHB2-PsATG8 adapter (PsAF5) in plant-pathogenic oomycetes reveals that mitophagy induction by IMM proteins is conserved in eukaryotes, but with differences in the details of ATG8 recruitment.
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Phytophthora , Animais , Peróxido de Hidrogênio , Mitofagia , Espécies Reativas de Oxigênio , Mitocôndrias , Proteínas de Membrana , OligonucleotídeosRESUMO
An estimated 240 fungicides are presently in use, but the direct targets for the majority remain elusive, constraining fungicide development and efficient resistance monitoring. In this study, we found that Pcα-actinin knockout did not influence the sensitivity of Phytophthora capsici to fluopicolide, which is a notable oomycete inhibitor. Using a combination of Bulk Segregant Analysis Sequencing and Drug Affinity Responsive Target Stability (DARTS) assays, the vacuolar H+-ATPase subunit a (PcVHA-a) was pinpointed as the target protein of fluopicolide. We also confirmed four distinct point mutations in PcVHA-a responsible for fluopicolide resistance in P. capsici through site-directed mutagenesis. Molecular docking, ATPase activity assays, and a DARTS assay suggested a fluopicolide-PcVHA-a interaction. Sequence analysis and further molecular docking validated the specificity of fluopicolide for oomycetes or fish. These findings support the claim that PcVHA-a is the target of fluopicolide, proposing vacuolar H+-ATPase as a promising target for novel fungicide development.
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Fungicidas Industriais , Phytophthora , Fungicidas Industriais/farmacologia , Simulação de Acoplamento Molecular , Benzamidas/metabolismo , Phytophthora/genética , ATPases Translocadoras de Prótons/metabolismo , Doenças das PlantasRESUMO
Interactions between low-toxicity terpenoid mosquito repellents and lactic acid are studied at the HF and B3LYP level. The subsequent QSAR study shows that not only the structure of repellents but also the repellent-lactic acid complexes may play an important role. It suggests that further study on interactions between repellents and characteristic compounds from human host may be required in order to understand the repelling mechanism.
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Repelentes de Insetos/química , Terpenos/química , Animais , DEET/química , Humanos , Ácido Láctico/química , Relação Quantitativa Estrutura-AtividadeRESUMO
Histone deacetylases (HDACs) regulate gene expression by inducing conformational changes in chromatin. Ever since the discovery of a naturally occurring HDAC inhibitor, trichostatin A (TSA) stimulated the recent development of suberoylanilide (SAHA, Zolinza®), HDAC has become an important molecular target for drug development. This has created the need to develop specific in vivo radioligands to study epigenetic regulation and HDAC engagement for drug development for diseases including cancer and psychiatric disorders. 6-([(18)F]Fluoroacetamido)-1-hexanoicanilide ([(18)F]FAHA) was recently developed as a HDAC substrate and shows moderate blood-brain barrier (BBB) permeability and specific signal (by metabolic trapping/or deacetylation) but rapid metabolism. Here, we report the radiosynthesis of two carbon-11 labeled candidate radiotracers (substrate- and inhibitor-based radioligand) for HDAC and their evaluation in non-human primate brain. PET studies showed very low brain uptake and rapid metabolism of both labeled compounds but revealed a surprising enhancement of brain penetration by F for H substitution when comparing one of these to [(18)F]FAHA. Further structural refinement is needed for the development of brain-penetrant, metabolically stable HDAC radiotracers and to understand the role of fluorine substitution on brain penetration.
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Encéfalo/diagnóstico por imagem , Encéfalo/enzimologia , Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Compostos Radiofarmacêuticos/química , Anilidas/química , Animais , Barreira Hematoencefálica/metabolismo , Radioisótopos de Carbono/química , Radioisótopos de Flúor/química , Fluoracetatos/química , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/metabolismo , Permeabilidade/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Primatas , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologiaRESUMO
RIG-I-like receptors (RLRs) are intracellular pattern recognition receptors that detect viral or bacterial infection and induce host innate immune responses. The RLRs family comprises retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) that have distinctive features. These receptors not only recognize RNA intermediates from viruses and bacteria, but also interact with endogenous RNA such as the mislocalized mitochondrial RNA, the aberrantly reactivated repetitive or transposable elements in the human genome. Evasion of RLRs-mediated immune response may lead to sustained infection, defective host immunity and carcinogenesis. Therapeutic targeting RLRs may not only provoke anti-infection effects, but also induce anticancer immunity or sensitize "immune-cold" tumors to immune checkpoint blockade. In this review, we summarize the current knowledge of RLRs signaling and discuss the rationale for therapeutic targeting RLRs in cancer. We describe how RLRs can be activated by synthetic RNA, oncolytic viruses, viral mimicry and radio-chemotherapy, and how the RNA agonists of RLRs can be systemically delivered in vivo. The integration of RLRs agonism with RNA interference or CAR-T cells provides new dimensions that complement cancer immunotherapy. Moreover, we update the progress of recent clinical trials for cancer therapy involving RLRs activation and immune modulation. Further studies of the mechanisms underlying RLRs signaling will shed new light on the development of cancer therapeutics. Manipulation of RLRs signaling represents an opportunity for clinically relevant cancer therapy. Addressing the challenges in this field will help develop future generations of cancer immunotherapy.
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Imunidade Inata , Neoplasias , Humanos , Transdução de Sinais , Neoplasias/terapia , RNA , ImunoterapiaRESUMO
Progesterone and adipoQ receptor 9 (PAQR9) is an endoplasmic reticulum (ER)-localized membrane protein that is involved in protein quality control of ER by interacting with BAG6. One of the physiological functions of PAQR9 is regulation of fasting-induced ketogenesis and fatty acid oxidation in the liver via modulating protein degradation of PPARα. However, it is currently unknown whether or not PAQR9 impacts glucose homeostasis. We addressed this question using a Paqr9-deleted mouse model in which type 1 diabetes was induced by streptozotocin injection and type 2 diabetes was induced by high-fat diet (HFD) with streptozotocin injection. Paqr9 deletion improved hyperglycemia and glucose tolerance in both of the diabetic mouse models. In the pancreatic islets, Paqr9 deletion reduced apoptosis of ß cells in type 2 diabetic mice. Paqr9 deletion also reduced HFD-induced hepatic steatosis and adiposity of white adipose tissue. In Min6 cells, overexpression of DUF3538 domain of BAG6 to block the interaction of PAQR9 with BAG6 was able to enhance glucose-stimulated insulin secretion upon treatment with inflammatory factors or thapsigargin, an ER stress inducer. Thapsigargin-induced ER stress markers were also reduced by overexpression of DUF3538 domain. Collectively, these results indicate that PAQR9 has a modulatory role in glucose homeostasis, associated with regulation on insulin secretion of ß cells in vitro under stress conditions.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Camundongos , Animais , Secreção de Insulina , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Estreptozocina , Tapsigargina/metabolismo , Células Secretoras de Insulina/metabolismo , Glucose/metabolismo , Modelos Animais de Doenças , Dieta Hiperlipídica , Homeostase , Estresse do Retículo EndoplasmáticoRESUMO
Ferroptosis induced by iron-dependent accumulation of lipid peroxides (LPOs) has received increasing attention in cancer therapy, especially chemodynamic therapy (CDT). However, the quick annihilation of hydroxyl radicals (ËOH) severely restricts the ËOH/LPO conversion efficiency, which has become one of the key factors that influences the therapeutic efficacy of ferroptosis-based CDT. Herein, we designed a ËOH/LPO nano-converter with a high LPO generation efficiency via loading ferrocene (Fc), a green Fenton catalyst, in the phospholipid bilayer of liposome-PEG (Fc-Lp-PEG). Under catalysis with Fc, the over-expressed H2O2 in tumors can be decomposed to ËOH. The generated ËOH in situ reacts with unsaturated lipids on the liposome, and is converted into LPOs, which spread the lipid peroxidation chain reaction to the remote membranes of cells and organelles, triggering efficient cancer cell ferroptosis. Systematic in vitro and in vivo therapeutic outcomes showed the high tumor inhibition ratio (74.0%) and the low side effects of Fc-Lp-PEG on 4T1 tumor-bearing mice. This novel strategy for improving the ËOH/LPO conversion efficiency might provide new insights for the clinical development of ferroptosis-based CDT.
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Ferroptose , Neoplasias , Animais , Camundongos , Lipossomos , Peróxidos Lipídicos , Peróxido de Hidrogênio , Metalocenos , Fosfolipídeos , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Iron-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation play key roles in ferroptosis, which has been an attractive strategy to kill tumor cells. However, the rapid annihilation of hydroxyl radicals (ËOH) produced from the Fenton reaction has become a major obstacle in inducing lipid peroxidation in cells. In this study, we develop a nano-delivery system of unsaturated phospholipid (Lip) and polyacrylic acid (PAA) functionalized FeOCl nanosheets (FeOCl@PAA-Lip). In this system, the ËOH radicals produced from the Fenton reaction between FeOCl nanosheets and endogenous H2O2 of tumor cells attack Lip on the nanosheets in situ to initiate the lipid peroxidation chain reaction, which not only realizes free radical conversion but also leads to the amplification of ROS and lipid peroxides, thus enhancing tumor ferroptosis. The in vitro and in vivo results confirmed that FeOCl@PAA-Lip nanosheets exhibited specific tumor cell-killing effects, good biocompatibility, long circulation time, low side effects, high tumor targeting and an excellent tumor inhibition rate (73%). The Lip functionalization strategy offers a paradigm of enhancing ferroptosis treatment by conversion of ËOH/phospholipid radicals/lipid peroxyl radicals and strengthening lipid peroxidation.
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Ferroptose , Espécies Reativas de Oxigênio , Fosfolipídeos , Peróxido de Hidrogênio/farmacologia , Peroxidação de LipídeosRESUMO
TiO2 films with a three-dimensional web-like porous structure were prepared using the photo polymerization-induced phase separation method integrated with the pulling coating process. By adjusting the ratio of the substance in the precursor sol and the coating times, the relationships between the sol ratio, the coating times, the film structure, and the performance of the DSC were studied. The optimal film structure was found and a detailed description is given. The performance of the DSC was further improved by introducing the barrier layer and the surface-modified layer of the TiO2 coating. This promoted the short-circuit current density and the photoelectric conversion efficiency of the DSC, the mechanism of which was also investigated. Ultimately, the photoelectric conversion efficiency of the DSC based on the TiO2 anode films with a three-dimensional web-like structure was stabilized at a higher level as a result of the structural improvement.
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Co nanoparticles (NPs) encapsulated in N-doped carbon nanotubes (Co@NC900 ) are systematically investigated as a potential alternative to precious Pt-group catalysts for hydrogenative heterocyclization reactions. Co@NC900 can efficiently catalyze hydrogenative coupling of 2-nitroaniline to benzaldehyde for synthesis of 2-phenyl-1H-benzo[d]imidazole with >99 % yield at ambient temperature in one step. The robust Co@NC900 catalyst can be easily recovered by an external magnetic field after the reaction and readily recycled for at least six times without any evident decrease in activity. Kinetic experiments indicate that Co@NC900 -promoted hydrogenation is the rate-determining step with a total apparent activation energy of 41±1â kJ mol-1 . Theoretical investigations further reveal that Co@NC900 can activate both H2 and the nitro group of 2-nitroaniline. The observed energy barrier for H2 dissociation is only 2.70â eV in the rate-determining step, owing to the presence of confined Co NPs in Co@NC900 . Potential industrial application of the earth-abundant and non-noble transition metal catalysts is also explored for green and efficient synthesis of heterocyclic compounds.
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Nitrile (C≡N bond) activation for direct organic synthesis has been less explored so far due to a high redox potential of nitrile and its low dissociation energy of C-CN bond. Herein, we demonstrate a direct reductive coupling of nitriles and 1,2-phenylenediamines to yield various benzimidazoles in excellent yields (95%-99%) by using rhodium phosphide (Rh2P) catalyst supported on lignin-derived carbon (LC) using H2 (or hydrazine hydrate) as a hydrogen source. The high catalytic performance of Rh2P/LC is attributed to enhanced charge transfer to Rh and strong P-Rh interactions. Our isotope trace experiment confirms the presence of H/D exchange between H2 and the inert -CD3 group of CD3CN via an intramolecular D-shift. Reusability of Rh2P/LC is further demonstrated by a seven-time recycling without evident loss of activity. This research thus highlights a great potential in organic transformation with nitrile as a synthetic building block.
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Leukemias driven by chromosomal translocation of the mixed-lineage leukemia (MLL) gene are highly prevalent in hematological malignancy. The poor survival rate and lack of effective targeted therapy for patients with MLL-rearranged (MLL-r) leukemias emphasize an urgent need for improved knowledge and novel therapeutic approaches for these malignancies. The present study aimed to investigate the potential effectiveness and mechanism of Anlotinib, a novel receptor tyrosine kinase inhibitor, in MLL-r acute myeloid leukemia (AML). The findings revealed that Anlotinib significantly inhibited the growth of MLL-r AML cells in both in vivo and a murine xenograft model. RNA sequencing identified that multiple genes involved in DNA damage response were responsible for Anlotinib activity. To further elucidate the correlation between the DNA damage response induced by Anlotinib and MLL fusion, Gene Expression Profiling Interactive Analysis (GEPIA) was conducted. It revealed that Anlotinib impaired DNA damage response via inhibiting SETD1A and AKT. In conclusion, Anlotinib exerts anti-leukemia function by inhibiting SETD1A/AKT-mediated DNA damage response and highlights a novel mechanism underlying Anlotinib in the treatment of MLL-r AML.
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In this work, functionalized alkyl imidazolium hexafluorophosphate ILs were synthesized and characterized; then, they were applied in the conversion of xylose to furfural under the microwave method. The results showed that when CnMF was used as a catalyst, an acidic environment was provided to promote the formation of furfural. In addition, the heating method, the solvent, and the different structures of cations in the ionic liquid influenced their catalytic activity. In an aqueous solution, the yield of furfural obtained using the microwave method was better than that of the conventional heating method, and the catalytic activity of diimidazole hexafluorophosphate was better than that of monoimidazole. Meanwhile, for the diimidazole hexafluorophosphate, the change of the carbon chain length between the imidazole rings also slightly influenced the yield. Finally, the optimal yield of 49.76% was obtained at 205°C for 8 min using 3,3'-methylenebis(1-methyl-1H-imidazol-3-ium), C1MF, as a catalyst. Mechanistic studies suggested that the catalytic activity of C1MF was mainly due to the combined effect of POFn (OH)3-n and imidazole ring. Without a doubt, the catalytic activity of C1MF was still available after five cycles, which not only showed its excellent catalytic activity in catalyzing the xylose to prepare the biomass platform compound furfural but also could promote the application of functionalized ionic liquids.