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Protein S-acylation catalyzed by protein S-acyl transferases (PATs) is a reversible lipid modification regulating protein targeting, stability, and interaction profiles. PATs are encoded by large gene families in plants, and many proteins including receptor-like cytoplasmic kinases (RLCKs) and receptor-like kinases (RLKs) are subject to S-acylation. However, few PATs have been assigned substrates, and few S-acylated proteins have known upstream enzymes. We report that Arabidopsis (Arabidopsis thaliana) class A PATs redundantly mediate pollen tube guidance and participate in the S-acylation of POLLEN RECEPTOR KINASE1 (PRK1) and LOST IN POLLEN TUBE GUIDANCE1 (LIP1), a critical RLK or RLCK for pollen tube guidance, respectively. PAT1, PAT2, PAT3, PAT4, and PAT8, collectively named PENTAPAT for simplicity, are enriched in pollen and show similar subcellular distribution. Functional loss of PENTAPAT reduces seed set due to male gametophytic defects. Specifically, pentapat pollen tubes are compromised in directional growth. We determine that PRK1 and LIP1 interact with PENTAPAT, and their S-acylation is reduced in pentapat pollen. The plasma membrane (PM) association of LIP1 is reduced in pentapat pollen, whereas point mutations reducing PRK1 S-acylation affect its affinity with its interacting proteins. Our results suggest a key role of S-acylation in pollen tube guidance through modulating PM receptor complexes.
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Enzymatic catalysis presents an eco-friendly, energy-efficient method for lignin degradation. However, challenges arise due to the inherent incompatibility between enzymes and native lignin. In this work, we introduce a supramolecular catalyst composed of fluorenyl-modified amino acids and Cu2+, designed based on the aromatic stacking of the fluorenyl group, which can operate in ionic liquid environments suitable for the dissolution of native lignin. Amino acids and halide anions of ionic liquids shape the copper site's coordination sphere, showcasing remarkable catechol oxidase-mimetic activity. The catalyst exhibits thermophilic property, and maintains oxidative activity up to 75 °C, which allows the catalyzed degradation of the as-dissolved native lignin with high efficiency even without assistance of the electron mediator. In contrast, at this condition, the native copper-dependent oxidase completely lost its activity. This catalyst with superior stability and activity offer promise for sustainable lignin valorization through biocatalytic routes compatible with ionic liquid pretreatment, addressing limitations in native enzymes for industrially relevant conditions.
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Líquidos Iônicos , Líquidos Iônicos/química , Lignina/química , Cobre , Oxirredutases , Catálise , AminoácidosRESUMO
In mammals, odour information within the olfactory bulb (OB) is processed by complex neural circuits before being ultimately represented in the action potential activity of mitral/tufted cells (M/Ts). Cholecystokinin-expressing (CCK+) superficial tufted cells (sTCs) are a subset of tufted cells that potentially contribute to olfactory processing in the OB by orchestrating M/T activity. However, the exact role of CCK+ sTCs in modulating odour processing and olfactory function in vivo is largely unknown. Here, we demonstrate that manipulating CCK+ sTCs can generate perception and induce place avoidance. Optogenetic activation/inactivation of CCK+ sTCs exerted strong but differing effects on spontaneous and odour-evoked M/T firing. Furthermore, inactivation of CCK+ sTCs disrupted M/T odour encoding and impaired olfactory detection and odour discrimination. These results establish the role of CCK+ sTCs in odour representation and olfactory behaviours. KEY POINTS: Mice could perceive the activity of CCK+ sTCs and show place avoidance to CCK+ sTC inactivation. Optical activation of CCK+ sTCs increased the percentage of cells with odour response but reduced the odour-evoked response in M/Ts in awake mice. Optical inactivation of CCK+ sTCs greatly decreased spontaneous firing and odour-evoked response in M/Ts. Inactivation of CCK+ sTCs impairs the odour decoding performance of M/Ts and disrupts odour detection and discrimination behaviours in mice. These results indicate that CCK+ sTCs participate in modulating the odour representation and maintaining normal olfactory-related behaviours.
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Colecistocinina , Bulbo Olfatório , Animais , Feminino , Masculino , Camundongos , Colecistocinina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/fisiologia , Odorantes , Bulbo Olfatório/fisiologia , Percepção Olfatória/fisiologia , Optogenética , Olfato/fisiologiaRESUMO
BACKGROUND: Small nucleolar RNAs (snoRNAs) play key roles in ribosome biosynthesis. However, the mechanism by which snoRNAs regulate cancer stemness remains to be fully elucidated. METHODS: SNORA68 expression was evaluated in breast cancer tissues by in situ hybridization and qRTâPCR. Proliferation, migration, apoptosis and stemness analyses were used to determine the role of SNORA68 in carcinogenesis and stemness maintenance. Mechanistically, RNA pull-down, RNA immunoprecipitation (RIP), cell fractionation and coimmunoprecipitation assays were conducted. RESULTS: SNORA68 exhibited high expression in triple-negative breast cancer (TNBC) and was significantly correlated with tumor size (P = 0.048), ki-67 level (P = 0.037), and TNM stage (P = 0.015). The plasma SNORA68 concentration was significantly lower in patients who achieved clinical benefit. The SNORA68-high patients had significantly shorter disease-free survival (DFS) (P = 0.036). Functionally, SNORA68 was found to promote the cell stemness and carcinogenesis of TNBC in vitro and in vivo. Furthermore, elevated SNORA68 expression led to increased nucleolar RPL23 expression and retained RPL23 in the nucleolus by binding U2AF2. RPL23 in the nucleolus subsequently upregulated c-Myc expression. This pathway was validated using a xenograft model. CONCLUSION: U2AF2-SNORA68 promotes TNBC stemness by retaining RPL23 in the nucleolus and increasing c-Myc expression, which provides new insight into the regulatory mechanism of stemness.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , RNA , Núcleo Celular , Regulação Neoplásica da Expressão Gênica , Carcinogênese/genética , Proliferação de Células/genética , Fator de Processamento U2AF/genéticaRESUMO
BACKGROUND: The role of circRNAs in hepatocellular carcinoma (HCC) progression remains unclear. CircPIAS1 (circBase ID: hsa_circ_0007088) was identified as overexpressed in HCC cases through bioinformatics analysis. This study aimed to investigate the oncogenic properties and mechanisms of circPIAS1 in HCC development. METHODS: Functional analyses were conducted to assess circPIAS1's impact on HCC cell proliferation, migration, and ferroptosis. Xenograft mouse models were employed to evaluate circPIAS1's effects on tumor growth and pulmonary metastasis in vivo. Bioinformatics analysis, RNA immunoprecipitation, and luciferase reporter assays were utilized to elucidate the molecular pathways influenced by circPIAS1. Additional techniques, including RNA pulldown, fluorescence in situ hybridization (FISH), chromatin immunoprecipitation (ChIP), qPCR, and western blotting, were used to further explore the underlying mechanisms. RESULTS: CircPIAS1 expression was elevated in HCC tissues and cells. Silencing circPIAS1 suppressed HCC cell proliferation and migration both in vitro and in vivo. Mechanically, circPIAS1 overexpression inhibited ferroptosis by competitively binding to miR-455-3p, leading to upregulation of Nuclear Protein 1 (NUPR1). Furthermore, NUPR1 promoted FTH1 transcription, enhancing iron storage in HCC cells and conferring resistance to ferroptosis. Treatment with ZZW-115, an NUPR1 inhibitor, reversed the tumor-promoting effects of circPIAS1 and sensitized HCC cells to lenvatinib. CONCLUSION: This study highlights the critical role of circPIAS1 in HCC progression through modulation of ferroptosis. Targeting the circPIAS1/miR-455-3p/NUPR1/FTH1 regulatory axis may represent a promising therapeutic strategy for HCC.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos , Carcinoma Hepatocelular , Proliferação de Células , Ferroptose , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , MicroRNAs , Proteínas de Neoplasias , RNA Circular , Animais , Feminino , Humanos , Masculino , Camundongos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Ferroptose/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Circular/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.
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Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina , Cetuximab , Neoplasias Colorretais , Fluoruracila , Leucovorina , Neoplasias Hepáticas , Compostos Organoplatínicos , Proteínas Proto-Oncogênicas B-raf , Humanos , Cetuximab/administração & dosagem , Cetuximab/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Feminino , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Leucovorina/uso terapêutico , Leucovorina/administração & dosagem , Fluoruracila/uso terapêutico , Fluoruracila/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Adulto , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Camptotecina/administração & dosagem , Resultado do Tratamento , Proteínas ras/genéticaRESUMO
Breast cancer stem cells (BCSCs) are key players in carcinogenesis and development. Small nucleolar RNAs (snoRNAs) seem to have a crucial influence on regulating stem cell-like properties in various cancers, but the underlying mechanism in breast cancer has not been determined. In this study, we first found that the expression of SNORA51 might be strongly and positively related to BCSCs-like properties. SNORA51 expression was assessed in breast cancer tissues (n = 158 patients) by in situ hybridization. Colony formation, cell counting kit-8, and sphere formation assays were used to detect cell proliferation and self-renewal, respectively. Wound healing and transwell assays were used to detect cell migration. Coimmunoprecipitation and molecular docking were used to determine the underlying mechanism through which SNORA51 regulates BCSCs-like properties. High SNORA51 expression was associated with a worse prognosis, overall survival, and disease-free survival, in 158 breast cancer patients and was also closely related to lymph node status, ER status, the Ki-67 index, histological grade, and TNM stage. Further analysis proved that SNORA51 could enhance and maintain stem cell-like properties, including cell proliferation, self-renewal, and migration, in breast cancer. Moreover, high SNORA51 expression could reduce nucleolar RPL3 expression, induce changes in the expression of NPM1 in the nucleolus and nucleoplasm, and ultimately increase c-MYC expression. Taken together, our findings demonstrated that SNORA51 could enhance BCSCs-like properties via the RPL3/NPM1/c-MYC pathway both in vitro and in vivo. Therefore, SNORA51 might be a significant biomarker and potential therapeutic target and might even provide a new viewpoint on the regulatory mechanism of snoRNAs in breast cancer or other malignant tumors.
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Neoplasias da Mama , Proliferação de Células , Células-Tronco Neoplásicas , Nucleofosmina , Proteínas Proto-Oncogênicas c-myc , RNA Nucleolar Pequeno , Proteína Ribossômica L3 , Animais , Feminino , Humanos , Camundongos , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , RNA Nucleolar Pequeno/genética , RNA Nucleolar Pequeno/metabolismo , Transdução de Sinais , Proteína Ribossômica L3/genética , Proteína Ribossômica L3/metabolismoRESUMO
Strengthening future food security through the application of unsustainable levels of inorganic nitrogen (N) fertilizers to crop fields may exacerbate environmental damage. Coordination of N-use efficiency (NUE) and plant growth is, therefore, crucial for sustainable agriculture. Auxin plays pivotal roles in developmental and signaling responses that affect NUE. Hence, a better understanding of these processes provides great potential to improve crop NUE. This review summarizes the effects of auxin on N-related and root developmental processes that either directly or indirectly affect NUE in the model plant Arabidopsis and major crop species to highlight the potential of fostering sustainable agricultural development in the future through modulating auxin-related processes.
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Carrier screening is important to people have a higher prevalence of severe recessive or X-linked genetic conditions. This study is aimed that the frequency and uncertain nature of genetic variants was identified in Taiwanese population, providing individuals with information at risk of inherited diseases and their heritability to newborns. A total of 480 subjects receiving genetic counseling with no family history of inherited disorders were recruited into a cohort from 2018 to 2022. Next-generation sequencing (NGS) panel for autosomal dominant (AD), autosomal recessive (AR) and X-linked diseases was sequenced to assess disease prevalence and carrier frequency for the targeted diseases. Publicly available NGS datasets were analyzed following a tier-based system and ACMG recommendation. 5.3% of subjects showed the presence of variants for genetic disorder, and 2.3% of them were determined with AD. 14 of subjects with pathogenic variants were carriers for AR. The inherited genes were LDLR for AD disorders and AR disorders included GAA and ATP7B. 21.6% of subjects had highest carrier frequency of GJB2 gene. 0.5% of subjects had highest frequency of GJB6 for AR condition. In conclusions, the variants in LDLR, GAA and ATP7B genes were identified in Taiwanese population, indicating individuals had higher risk of Pompe disease, Wilson's disease and familial hypercholesterolemia. Taiwanese individuals carrying GJB2 and GJB6 had the considerable risk of hearing loss passing to their offspring.
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Degeneração Hepatolenticular , Recém-Nascido , Humanos , Prevalência , Degeneração Hepatolenticular/genética , Aconselhamento Genético , Genes Recessivos , MutaçãoRESUMO
Hepatitis B virus (HBV) infection is a serious global health problem. After the viruses infect the human body, the host can respond to the virus infection by coordinating various cellular responses, in which mitochondria play an important role. Evidence has shown that mitochondrial proteins are involved in host antiviral responses. In this study, we found that the overexpression of TIM22 and TIM29, the members of the inner membrane translocase TIM22 complex, significantly reduced the level of intracellular HBV DNA and RNA and secreted HBV surface antigens and E antigen. The effects of TIM22 and TIM29 on HBV replication and transcription is attributed to the reduction of core promoter activity mediated by the increased expression of SRSF1 which acts as a suppressor of HBV replication. This study provides new evidence for the critical role of mitochondria in the resistance of HBV infection and new targets for the development of treatment against HBV infection.
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Vírus da Hepatite B , Hepatite B , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Fatores de Processamento de Serina-Arginina , Humanos , Antígenos E da Hepatite B/genética , Antígenos E da Hepatite B/metabolismo , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/fisiologia , Fatores de Processamento de Serina-Arginina/metabolismo , Replicação Viral , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/metabolismoRESUMO
BACKGROUND: Although triglyceride-glucose (TyG) index is a reliable indicator of insulin resistance and cardiometabolic disease, its effectiveness in predicting mortality risk has not been adequately validated. We aimed to investigate the association between the TyG-related indices and all-cause and cause-specific mortality in the general population. METHODS: A total of 27,642 individuals were included from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. Three indicators were constructed, including the TyG index, TyG combined with waist-to-height ratio (TyG-WHtR), and TyG combined with waist circumference (TyG-WC). Mortality data was acquired through the linkage of NHANES data with National Death Index records. Weighted Cox proportional hazards models were used to estimate the independent association between the TyG-related indices and mortality. Nonlinear associations were explored using restricted cubic splines. RESULTS: Multivariable adjusted models showed a progressive increase in all-cause and cause-specific mortality across quartiles of the TyG-related indices. Compared with the lowest quartile of the TyG index, the highest quartile had adjusted hazard ratios of 1.26 (95% CI 1.04-1.52) for all-cause mortality, 1.38 (1.04-1.74) for cardiovascular mortality, and 1.23 (1.01-1.50) for non-cardiovascular mortality, respectively. For the TyG-WHtR index, the corresponding hazard ratios were 1.60 (1.25-2.05), 1.86 (1.26-2.50), and 1.48 (1.10-1.99), respectively. For the TyG-WC index, the corresponding hazard ratios were 1.42 (1.11-1.75), 1.48 (1.04-1.96), and 1.38 (1.05-1.72), respectively. The associations between the three TyG-related indices and all-cause, cardiovascular and non-cardiovascular mortality were J-shaped. Interaction tests revealed significant effect modification by age, low-density lipoprotein cholesterol (LDL-C) level, and statin use (all P values < 0.05). CONCLUSIONS: The TyG-related indices were independent predictors of all-cause and cause-specific mortality in the general population. Young individuals should be particularly vigilant, whereas low LDL-C levels and statin use are potentially protective.
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Biomarcadores , Glicemia , Causas de Morte , Inquéritos Nutricionais , Triglicerídeos , Humanos , Masculino , Feminino , Triglicerídeos/sangue , Pessoa de Meia-Idade , Glicemia/metabolismo , Medição de Risco , Biomarcadores/sangue , Adulto , Idoso , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Valor Preditivo dos Testes , Circunferência da Cintura , Prognóstico , Razão Cintura-Estatura , Fatores de Tempo , Fatores de Risco , Estados Unidos/epidemiologia , Fatores de Risco CardiometabólicoRESUMO
Background: Post-stroke cognitive impairment (PSCI) represents a serious post-stroke complication with poor cognitive consequences. A vascular consequence after a stroke is that the occurrence and progression of PSCI may be closely related to blood pressure (BP). Thus, we systematically reviewed and performed a meta-analysis of the literature to examine the correlations between BP and PSCI. Methods: We systematically queried databases, including PubMed, the Cochrane Library, Embase, and Scopus, and conducted meta-analyses on studies reporting odds ratios (ORs) related to the association between BP and PSCI. Two authors autonomously assessed all titles, abstracts, and full texts and extracted data following the Meta-Analysis of Observational Studies in Epidemiology guidelines. The quality of the studies was evaluated using the modified Newcastle-Ottawa scale. Results: Meta-analyses incorporated 12 articles comprising a cumulative participant cohort of 21,732 individuals. The quality assessment indicated good in five studies, fair in one study, and poor in six. Through meta-analyses, we found that hypertension, systolic or diastolic BP (SBP or DBP) was significantly associated with PSCI (OR 1.53, 95% confidence interval (CI), 1.18-1.99; p = 0.001, I 2 = 66%; OR 1.13, 95% CI, 1.05-1.23; p = 0.002, I 2 = 52%; OR 1.38, 95% CI, 1.11-1.72; p = 0.004, I 2 = 90%, respectively). In the subgroup analysis, SBP < 120 mmHg, 120-139 mmHg, 140-159 mmHg, 160-179 mmHg, and DBP ≥ 100 mmHg highly predicted the occurrence of PSCI (OR 1.15, p = 0.0003; OR 1.26, p = 0.010; OR 1.15, p = 0.05; OR 1.02, p = 0.009; OR 1.96, p < 0.00001, respectively). However, the predictive effect of BP for PSCI declines when SBP ≥ 180 mmHg and DBP ≤ 99 mmHg (p > 0.05). Statistical heterogeneity was moderate to high, and publication bias was detected in SBP for PSCI. Conclusions: Considering the multifactorial etiology of PSCI, it is difficult to conclude that BP is an independent risk factor for PSCI. Given the restricted inclusion of studies, caution is advised when interpreting the findings from this meta-analysis. Subsequent investigations with substantial sample sizes are essential to exploring BP as a prospective target for addressing PSCI. Trial Registration Number: CRD42023437783 from PROSPERO.
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A yet-outstanding supramolecular chemistry challenge is isolation of novel varieties of stacked complexes with finely-tuned donor-acceptor bonding and optoelectronic properties, as herein reported for binary adducts comprising two different cyclic trinuclear complexes (CTC@CTC'). Most previous attempts focused only on 1-2 factors among metal/ligand/substituent combinations, resulting in heterobimetallic complexes. Instead, here we show that, when all 3 factors are carefully considered, a broadened variety of CTC@CTC' stacked pairs with intuitively-enhanced intertrimer coordinate-covalent bonding strength and ligand-ligand/metal-ligand dispersion are attained (dM-M' 2.868(2) Å; ΔE>50â kcal/mol, an order of magnitude higher than aurophilic/metallophilic interactions). Significantly, CTC@CTC' pairs remain intact/strongly-bound even in solution (Keq 4.67×105â L/mol via NMR/UV-vis titrations), and the gas phase (mass spectrometry revealing molecular peaks for the entire CTC@CTC' units in sublimed samples), rather than simple co-crystal formation. Photo-/electro-luminescence studies unravel metal-centered phosphorescence useful for novel all metal-organic light-emitting diodes (MOLEDs) optoelectronic device concepts. This work manifests systematic design of supramolecular bonding and multi-faceted spectral properties of pure metal-organic macrometallacyclic donor/acceptor (inorganic/inorganic) stacks with remarkably-rich optoelectronic properties akin to well-established organic/organic and organic/inorganic analogues.
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Herein we have pioneered an innovative synthetic strategy for the efficient assembly of various heteroarene-condensed benzofuran derivatives, utilizing benzofuran-derived azadienes (BDAs) and quinolines as the starting materials. This method functions with transition-metal catalysis and uses cost-effective formic acid as the reducing agent. Mechanistic investigations indicate that this transformation would involve a [4 + 2] annulation cascade process. This approach demonstrates a high tolerance to various functional groups and yields excellent results.
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Interfacial strain engineering can induce structural transformation and introduce new physical properties into materials, which is an effective method to prepare new multifunctional materials. However, interfacial strain has a limited spatial impact size. For example, in 2D thin films, the critical thickness of biaxial strain is typically less than 20 nm, which is not conducive to the maintenance of a strained structure and properties in thick film materials. The construction of a 3D interface can solve this problem. The large lattice mismatch between the BaZrO3 thin film and the substrate can induce the out-of-phase boundary (OPB) structure, which can extend along the thickness direction with the stacking of atoms. The lattice distortion at the OPB structure can provide a clamping effect for each layer of atoms, thus expanding the spatial influence range of biaxial strain. As a result, the uniform in-plane strain distribution and strain-induced ferroelectricity (Pr = 13 µC/cm2) are maintained along the thickness direction in BaZrO3 films.
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EpsteinâBarr virus (EBV) is a double-stranded DNA virus belonging to the family Orthoherpesviridae that is associated with the development of various tumors, such as lymphoma, nasopharyngeal carcinoma, and gastric cancer. There are no uniformly effective treatments for human EBV infection, and vaccines and immunotherapies are currently the main research directions. The glycoproteins gB and gH/gL are surface glycoproteins that are common to all herpesviruses, with subtle differences in structure and function between different viruses. The core membrane fusion machinery constituted by EBV gB and gH/gL is an important target of neutralizing antibodies in epithelial EBV infection due to its essential role in the fusion of viral and target cell membranes. In this article, we review the main modes of EBV infection, the structure and function of the core fusion machinery gB and gH/gL, and the development of neutralizing antibodies and prophylactic vaccines based on this target.
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Anticorpos Neutralizantes , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Proteínas do Envelope Viral , Humanos , Infecções por Vírus Epstein-Barr/prevenção & controle , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Anticorpos Neutralizantes/imunologia , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/genética , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/genética , Anticorpos Antivirais/imunologia , Internalização do Vírus , Animais , Vacinas Virais/imunologia , Proteínas Virais/imunologia , Proteínas Virais/genética , Glicoproteínas de Membrana , Chaperonas MolecularesRESUMO
A thiosuccinimide enabled S-N cross-coupling strategy has been established for the intermolecular N-sulfenylation of clinically approved sulfa drugs under additive-free conditions. This approach features simple operation, high chemoselectivity for sulfenylating the phenylamino group of sulfonamides, wide substrate scope, and easy scale production, affording N-sulfenylated products in moderate to excellent yields (up to 90%). In addition, we also found that this transformation can be realized in a one-pot manner by employing readily available thiols as starting materials, and the obtained sulfonamide derivatives are capable of various late-stage functionalizations, including oxidation, arylation, benzylation, and methylation.
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In the present work, a series of organometallic thioates bearing a 5,6,7,12-tetrahydrodibenzo[c,f][1,5]azastibocine or -azabismocine framework were synthesized through the cross-coupling reactions of the corresponding halide precursors with thiols and disulfides at room temperature. The former transformation can be achieved under additive-free conditions, and mild dithiothreitol (DTT) is the only additive in the latter. Both methods feature simple operation, a broad substrate scope, and good reaction yields. Antifungal assays showed that the synthesized organobismuth(III) thioates possess significantly higher antibiotic activity against Candida albicans than clinical fluconazole, while the inhibitory effects of Sb-sulfenylated products are low to negligible. Furthermore, the antibiofilm potential of such Bi-S bond-containing compounds was discovered as well.
RESUMO
The oxygen reduction process generating H2O2 in the photoelectrochemical (PEC) system is milder and environmentally friendly compared with the traditional anthraquinone process but still lacks the efficient electron-oxygen-proton coupling interfaces to improve H2O2 production efficiency. Here, we propose an integrated active site strategy, that is, designing a hydrophobic C-B-N interface to refine the dearth of electron, oxygen, and proton balance. Computational calculation results show a lower energy barrier for H2O2 production due to synergistic and coupling effects of boron sites for O2 adsorption, nitrogen sites for H+ binding, and the carbon structure for electron transfer, demonstrating theoretically the feasibility of the strategy. Furthermore, we construct a hydrophobic boron- and nitrogen-doped carbon black gas diffusion cathode (BN-CB-PTFE) with graphite carbon dots decorated on a BiVO4 photoanode (BVO/g-CDs) for H2O2 production. Remarkably, this approach achieves a record H2O2 production rate (9.24 µmol min-1 cm-2) at the PEC cathode. The BN-CB-PTFE cathode exhibits an outstanding Faraday efficiency for H2O2 production of â¼100%. The newly formed h-BN integrative active site can not only adsorb more O2 but also significantly improve the electron and proton transfer. Unexpectedly, coupling BVO/g-CDs with the BN-CB-PTFE gas diffusion cathode also achieves a record H2O2 production rate (6.60 µmol min-1 cm-2) at the PEC photoanode. This study opens new insight into integrative active sites for electron-O2-proton coupling in a PEC H2O2 production system that may be meaningful for environment and energy applications.
Assuntos
Eletrodos , Elétrons , Peróxido de Hidrogênio , Oxigênio , Prótons , Oxigênio/química , Peróxido de Hidrogênio/química , Técnicas EletroquímicasRESUMO
Cyclin-dependent kinase 2 (CDK2) is a member of CDK family of kinases (CDKs) that regulate the cell cycle. Its inopportune or over-activation leads to uncontrolled cell cycle progression and drives numerous types of cancers, especially ovarian, uterine, gastric cancer, as well as those associated with amplified CCNE1 gene. However, developing selective lead compound as CDK2 inhibitors remains challenging owing to similarities in the ATP pockets among different CDKs. Herein, we described the optimization of compound 1, a novel macrocyclic inhibitor targeting CDK2/5/7/9, aiming to discover more selective and metabolically stable lead compound as CDK2 inhibitor. Molecular dynamic (MD) simulations were performed for compound 1 and 9 to gain insights into the improved selectivity against CDK5. Further optimization efforts led to compound 22, exhibiting excellent CDK2 inhibitory activity, good selectivity over other CDKs and potent cellular effects. Based on these characterizations, we propose that compound 22 holds great promise as a potential lead candidate for drug development.