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Mitochondrial biogenesis is the process of generating new mitochondria to maintain cellular homeostasis. Here, we report that viruses exploit mitochondrial biogenesis to antagonize innate antiviral immunity. We found that nuclear respiratory factor-1 (NRF1), a vital transcriptional factor involved in nuclear-mitochondrial interactions, is essential for RNA (VSV) or DNA (HSV-1) virus-induced mitochondrial biogenesis. NRF1 deficiency resulted in enhanced innate immunity, a diminished viral load, and morbidity in mice. Mechanistically, the inhibition of NRF1-mediated mitochondrial biogenesis aggravated virus-induced mitochondrial damage, promoted the release of mitochondrial DNA (mtDNA), increased the production of mitochondrial reactive oxygen species (mtROS), and activated the innate immune response. Notably, virus-activated kinase TBK1 phosphorylated NRF1 at Ser318 and thereby triggered the inactivation of the NRF1-TFAM axis during HSV-1 infection. A knock-in (KI) strategy that mimicked TBK1-NRF1 signaling revealed that interrupting the TBK1-NRF1 connection ablated mtDNA release and thereby attenuated the HSV-1-induced innate antiviral response. Our study reveals a previously unidentified antiviral mechanism that utilizes a NRF1-mediated negative feedback loop to modulate mitochondrial biogenesis and antagonize innate immune response.
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Antivirais , Biogênese de Organelas , Animais , Camundongos , DNA Mitocondrial/genética , Imunidade Inata , Fator 1 Nuclear Respiratório/genéticaRESUMO
Phytosulfokine (PSK), a plant peptide hormone with a wide range of biological functions, is recognized by its receptor PHYTOSULFOKINE RECEPTOR 1 (PSKR1). Previous studies have reported that PSK plays important roles in plant growth, development, and stress responses. However, the involvement of PSK in fruit development and quality formation remains largely unknown. Here, using tomato (Solanum lycopersicum) as a research model, we show that exogenous application of PSK promotes the initiation of fruit ripening and quality formation, while these processes are delayed in pskr1 mutant fruits. Transcriptomic profiling revealed that molecular events and metabolic pathways associated with fruit ripening and quality formation are affected in pskr1 mutant lines and transcription factors are involved in PSKR1-mediated ripening. Yeast screening further identified that DEHYDRATION-RESPONSIVE ELEMENT BINDING PROTEIN 2F (DREB2F) interacts with PSKR1. Silencing of DREB2F delayed the initiation of fruit ripening and inhibited the promoting effect of PSK on fruit ripening. Moreover, the interaction between PSKR1 and DREB2F led to phosphorylation of DREB2F. PSK improved the efficiency of DREB2F phosphorylation by PSKR1 at the tyrosine-30 site, and the phosphorylation of this site increased the transcription level of potential target genes related to the ripening process and functioned in promoting fruit ripening and quality formation. These findings shed light on the involvement of PSK and its downstream signaling molecule DREB2F in controlling climacteric fruit ripening, offering insights into the regulatory mechanisms governing ripening processes in fleshy fruits.
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Hormônios Peptídicos , Solanum lycopersicum , Solanum lycopersicum/genética , Proteínas de Plantas/metabolismo , Frutas/metabolismo , Fosforilação , Reguladores de Crescimento de Plantas/farmacologia , Reguladores de Crescimento de Plantas/metabolismo , Hormônios Peptídicos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação da Expressão Gênica de Plantas , Etilenos/metabolismoRESUMO
Global climate change is accompanied by carbon dioxide (CO2) enrichment and high temperature (HT) stress; however, how plants adapt to the combined environments and the underlying mechanisms remain largely unclear. In this study, we show that elevated CO2 alleviated plant sensitivity to HT stress, with significantly increased apoplastic glucose (Glc) levels in tomato (Solanum lycopersicum) leaves. Exogenous Glc treatment enhanced tomato resilience to HT stress under ambient CO2 conditions. Cell-based biolayer interferometry, subcellular localization, and Split-luciferase assays revealed that Glc bound to the tomato regulator of G protein signaling 1 (RGS1) and induced RGS1 endocytosis and thereby RGS1-G protein α subunit (GPA1) dissociation in a concentration-dependent manner. Using rgs1 and gpa1 mutants, we found that RGS1 negatively regulated thermotolerance and was required for elevated CO2-Glc-induced thermotolerance. GPA1 positively regulated the elevated CO2-Glc-induced thermotolerance. A combined transcriptome and chlorophyll fluorescence parameter analysis further revealed that GPA1 integrated photosynthesis- and photoprotection-related mechanisms to regulate thermotolerance. These results demonstrate that Glc-RGS1-GPA1 signaling plays a crucial role in the elevated CO2-induced thermotolerance in tomato. This information enhances our understanding of the Glc-G protein signaling function in stress resilience in response to global climate change and will be helpful for genetic engineering approaches to improve plant resilience.
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Dióxido de Carbono , Glucose , Transdução de Sinais , Solanum lycopersicum , Solanum lycopersicum/genética , Solanum lycopersicum/fisiologia , Solanum lycopersicum/metabolismo , Dióxido de Carbono/metabolismo , Glucose/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Temperatura Alta , Regulação da Expressão Gênica de Plantas , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/genética , Fotossíntese , Folhas de Planta/metabolismo , Folhas de Planta/fisiologia , Proteínas RGS/metabolismo , Proteínas RGS/genética , Termotolerância/fisiologiaRESUMO
Hematopoietic stem cell (HSC) aging is accompanied by hematopoietic reconstitution dysfunction, including loss of regenerative and engraftment ability, myeloid differentiation bias, and elevated risks of hematopoietic malignancies. Gut microbiota, a key regulator of host health and immunity, has recently been reported to affect hematopoiesis. However, there is currently limited empirical evidence explaining the direct impact of gut microbiome on aging hematopoiesis. In this study, we performed fecal microbiota transplantation (FMT) from young mice to aged mice and observed a significant increment in lymphoid differentiation and decrease in myeloid differentiation in aged recipient mice. Furthermore, FMT from young mice rejuvenated aged HSCs with enhanced short-term and long-term hematopoietic repopulation capacity. Mechanistically, single-cell RNA sequencing deciphered that FMT from young mice mitigated inflammatory signals, upregulated the FoxO signaling pathway, and promoted lymphoid differentiation of HSCs during aging. Finally, integrated microbiome and metabolome analyses uncovered that FMT reshaped gut microbiota composition and metabolite landscape, and Lachnospiraceae and tryptophan-associated metabolites promoted the recovery of hematopoiesis and rejuvenated aged HSCs. Together, our study highlights the paramount importance of the gut microbiota in HSC aging and provides insights into therapeutic strategies for aging-related hematologic disorders.
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Transplante de Microbiota Fecal , Células-Tronco Hematopoéticas , Animais , Camundongos , Células-Tronco Hematopoéticas/metabolismo , Inflamação/terapia , Inflamação/metabolismo , Diferenciação Celular , HematopoeseRESUMO
Ectopic lipid deposition and mitochondrial dysfunction are common etiologies of obesity and metabolic disorders. Excessive dietary uptake of saturated fatty acids (SFAs) causes mitochondrial dysfunction and metabolic disorders, while unsaturated fatty acids (UFAs) counterbalance these detrimental effects. It remains elusive how SFAs and UFAs differentially signal toward mitochondria for mitochondrial performance. We report here that saturated dietary fatty acids such as palmitic acid (PA), but not unsaturated oleic acid (OA), increase lysophosphatidylinositol (LPI) production to impact on the stability of the mitophagy receptor FUNDC1 and on mitochondrial quality. Mechanistically, PA shifts FUNDC1 from dimer to monomer via enhanced production of LPI. Monomeric FUNDC1 shows increased acetylation at K104 due to dissociation of HDAC3 and increased interaction with Tip60. Acetylated FUNDC1 can be further ubiquitinated by MARCH5 for proteasomal degradation. Conversely, OA antagonizes PA-induced accumulation of LPI, and FUNDC1 monomerization and degradation. A fructose-, palmitate-, and cholesterol-enriched (FPC) diet also affects FUNDC1 dimerization and promotes its degradation in a non-alcoholic steatohepatitis (NASH) mouse model. We thus uncover a signaling pathway that orchestrates lipid metabolism with mitochondrial quality.
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Ácidos Graxos , Mitofagia , Camundongos , Animais , Ácidos Graxos/metabolismo , Dimerização , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas de Membrana/metabolismoRESUMO
Prior research on racial/ethnic disparities in COVID-19 mortality has often not considered to what extent they reflect COVID-19-specific factors, versus preexisting health differences. This study examines how racial/ethnic disparities in COVID-19 mortality vary with age, sex, and time period over April-December 2020 in the United States, using mortality from other natural causes as a proxy for underlying health. We study a novel measure, the COVID excess mortality percentage (CEMP), defined as the COVID-19 mortality rate divided by the non-COVID natural mortality rate, converted to a percentage, where the CEMP denominator controls (albeit imperfectly) for differences in population health. Disparities measured using CEMP deviate substantially from those in prior research. In particular, we find very high disparities (up to 12:1) in CEMP rates for Hispanics versus Whites, particularly for nonelderly men. Asians also have elevated CEMP rates versus Whites, which were obscured in prior work by lower overall Asian mortality. Native Americans and Blacks have significant disparities compared with White populations, but CEMP ratios to Whites are lower than ratios reported in other work. This is because the higher COVID-19 mortality for Blacks and Native Americans comes partly from higher general mortality risk and partly from COVID-specific risk.
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COVID-19 , Disparidades nos Níveis de Saúde , Humanos , COVID-19/mortalidade , COVID-19/etnologia , Masculino , Feminino , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Idoso , Adulto , Adulto Jovem , Adolescente , SARS-CoV-2 , Idoso de 80 Anos ou mais , Etnicidade/estatística & dados numéricos , Criança , Lactente , Pré-EscolarRESUMO
Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable efficacy in treating advanced B-cell malignancies by targeting CD19, but antigen-negative relapses and immune responses triggered by murine-derived antibodies remain significant challenges, necessitating the development of novel humanized multitarget CAR-T therapies. Here, we engineered a second-generation 4-1BB-CD3ζ-based CAR construct incorporating humanized CD19 single-chain variable fragments (scFvs) and BAFFR single-variable domains on heavy chains (VHHs), also known as nanobodies. The resultant CAR-T cells, with different constructs, were functionally compared both in vitro and in vivo. We found that the optimal tandem and bicistronic (BI) structures retained respective antigen-binding abilities, and both demonstrated specific activation when stimulated with target cells. At the same time, BI CAR-T cells (BI CARs) exhibited stronger tumour-killing ability and better secretion of interleukin-2 and tumour necrosis factor-alpha than single-target CAR-T cells. Additionally, BI CARs showed less exhaustion phenotype upon repeated antigen stimulation and demonstrated more potent and persistent antitumor effects in mouse xenograft models. Overall, we developed a novel humanized CD19/BAFFR bicistronic CAR (BI CAR) based on a combination of scFv and VHH, which showed potent and sustained antitumor ability both in vitro and in vivo, including against tumours with CD19 or BAFFR deficiencies.
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BACKGROUND: Abnormal N6-methyladenosine (m6A) modification has become a driving factor in tumour development and progression. The linc00659 is abnormally highly expressed in digestive tract tumours and promotes cancer progression, but there is little research on the mechanism of linc00659 and m6A. METHODS: The expression of linc00659 in colorectal cancer (CRC) tissues and cells was assessed by a quantitative real-time PCR. The proliferative capacity of CRC cells was determined by colony formation, Cell Counting Kit-8 and 5-ethynyl-2 deoxyuridine assays, and the migratory capacity of CRC was determined by wound healing and transwell assays and tube formation. In vivo, a xenograft tumour model was used to detect the effect of linc00659 on tumour growth. The Wnt/ß-catenin signalling pathway and related protein expression levels were measured by western blotting. The binding of linc00659 to insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) was assessed by RNA pull-down and an immunoprecipitation assay. The effect of IGF2BP1 on FZD6 was detected by an RNA stability assay. RESULTS: The expression of linc00659 was abnormally elevated in CRC tissues and cells compared to normal colonic tissues and cells. We confirm that linc00659 promotes the growth of CRC cells both in vivo and in vitro. Mechanistically, linc00659 binds to IGF2BP1 and specifically enhances its activity to stabilize the target gene FZD6. Therefore, linc00659 and IGF2BP1 activate the Wnt/ß-catenin signalling pathway, promoting cell proliferation in CRC. CONCLUSIONS: Our results show that linc00659 and IGF2BP1 cooperate to promote the stability of the target FZD6 mRNA, thereby facilitating CRC progression, which may represent a potential diagnostic, prognostic and therapeutic target for CRC.
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Adenina , Neoplasias Colorretais , RNA Longo não Codificante , Via de Sinalização Wnt , Animais , Humanos , Adenina/análogos & derivados , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Receptores Frizzled/genética , Receptores Frizzled/metabolismo , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA MensageiroRESUMO
Malignant proliferation and abundant angiogenesis are major causes of lung adenocarcinoma (LUAD) with high morbidity and mortality. Therefore, the exploration of the key regulatory mechanisms of malignant proliferation and angiogenesis in LUAD provides an opportunity for the development of targeted precision therapy. In this study, we found that the high expression of ATPase family AAA domain-containing protein 3A (ATAD3A) in LUAD was positively associated with the poor survival of patients, while its high expression was positively associated with the angiogenesis of LUAD. Further knockdown of ATAD3A in LUAD significantly inhibited cell proliferation and suppressed expression of vascular endothelial growth factor A, FGF-2, ANG-1, and TGF-ß. The opposite effect was observed with ATAD3A overexpression. Furthermore, ATAD3A knockdown significantly inhibited tumor growth and angiogenesis in an in vivo subcutaneous xenograft tumor model. Mechanistic studies suggest that ATAD3A may promote signal transducer and activator of transcription 3 activation, a key signal regulating lung cancer cell proliferation and transcriptional secretion of proangiogenic factors. Therefore, targeted inhibition of ATAD3A may be an effective strategy for LUAD therapy, and ATAD3A may be a potential biomarker for predicting malignant progression.
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Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Angiogênese , Adenocarcinoma de Pulmão/patologia , Proliferação de Células/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , ATPases Associadas a Diversas Atividades Celulares/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/genéticaRESUMO
Silicon oxides (SiOx) have received extensive attention as an promising anode candidate for next-generation lithium-ion batteries (LIBs). However, their commerical applications have been seriously hindered by low conductivity, large volume expansion and unstable soild-electrolyte interface (SEI) layer, which result in low intial coulombic efficiency, poor rate performance and short cycling lifepan. In this work, we demonstrate a simple way to prepare a series of SiOx materials with lithium fluoride (LiF) modified by hydrothermal method and carbothermal modification. When the mass ratio of SiOx and LiF equals 1:0.15, the long-term cycling capacity retention can be greatly improve form 30.2% to 76.7% after 200 cycles. The result is primarily because the enhancement of electrons and Li+-ions transport and the stability of SEI layer due to LiF addition. However, excess LiF addition can hinder the diffusion of Li+-ions. This study presents the great potential of LiF modified on SiOx anode materials for LIBs.
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BACKGROUND: Although there is increased demand for behavioral health services, there is limited national data on the workforce prescribing psychotropics and/or medications for opioid use disorder (MOUD), and many current estimates are based on self-reported data or clinician rosters. OBJECTIVE: To describe trends in the workforce prescribing psychotropics (i.e., antidepressants, antipsychotics, antianxiety medications, mood stabilizers) and/or MOUD from 2017 to 2021. DESIGN: Cross-sectional analysis of 2017-2021 IQVIA Xponent retail prescription claims data. PARTICIPANTS: Clinicians who prescribed more than ten total prescriptions for psychotropics and/or MOUD in a calendar year. MAIN MEASURES: We analyzed the number of prescriptions and prescribers by year, month, drug type, specialty type, payor type, and clinician county rurality. KEY RESULTS: There was a 2.7% increase in the number of prescribers between 2017 and 2021, with the highest growth among psychiatric nurse practitioners (44.7%), nurse practitioners (25.5%), and physician assistants (6.5%). Primary care physicians (PCPs) and advanced practice clinicians (APCs) made up more than half of the workforce but prescribed 3.5 times fewer prescriptions on average compared to psychiatric and addiction medicine specialists. PCPs and APCs in rural areas wrote the most prescriptions collectively for psychotropics and MOUD per month. CONCLUSIONS: Using prescription data, a proxy for being active in the workforce, goes beyond specialty designation to identify the full workforce prescribing psychotropics and MOUD, including the growing role of APCs and PCPs.
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Developing efficient catalysts to degrade pollutants in water is a very important way to alleviate water pollution. However, it is crucial but challenging to broaden the functions of conventional photocatalysts and improve their environmental adaptability. In this paper, Bi(Er3+/Yb3+)OBr/polyacrylonitrile (BOB-EY/PAN) composite fibers with a swallowed-embedded structure assembled with nanopetal-rich microflowers were designed and fabricated, integrating photocatalytic and temperature-monitoring functions simultaneously. Their unique structure brings a large specific surface area, and the doping of rare earth ions improves the separation efficiency of electron-hole pairs, which enhances the photocatalytic efficiency and endows the fibers with a temperature-monitoring function at the same time. Under simulated sunlight irradiation, the nanofibers show a maximum degradation efficiency of 99.2% for tetracycline hydrochloride (TC) with a degradation constant of K as high as 0.078 min-1. Based on the fluorescence intensity ratio (FIR), the two thermally coupled levels of Er3+ in the nanofibers, 2H11/2 and 4S3/2, provide real-time temperature feedback, displaying a maximum relative sensitivity as high as 0.0215 K-1 at 303 K. Dual-functional BOB-EY/PAN composite nanofibers show great potential for industrial wastewater disposition, providing solutions for wastewater purification in special scenarios.
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Helicobacter pylori (H. pylori) is a pathogenic microorganism that colonizes the human gastric mucosa and can lead to various gastric disorders, including gastritis, gastric ulcers, and gastric cancer. However, the increasing prevalence of antibiotic resistance in H. pylori has prompted the search for alternative treatment options. Photodynamic therapy has emerged as a potential alternative therapy, thus offering the advantage of avoiding some of the side effects associated with antibiotics and effectively targeting drug-resistant strains. In the postantibiotic era, photodynamic therapy (PDT) has shown promise as a novel treatment for H. pylori infection. This review focused on elucidating the mechanism of photodynamic therapy in the treatment of H. pylori. Additionally, we present an overview of the current research on photodynamic therapy by examining both standalone photodynamic therapy and combination therapies for H. pylori infection treatment. Furthermore, the safety profile of photodynamic therapy was also evaluated. Finally, we discuss the challenges and prospects associated with this innovative technology, with an aim to provide new insights and methodologies for the treatment of H. pylori infection.
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Gastrite , Infecções por Helicobacter , Helicobacter pylori , Fotoquimioterapia , Humanos , Infecções por Helicobacter/tratamento farmacológico , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Gastrite/tratamento farmacológicoRESUMO
Lanthanide (Ln) based mononuclear single-molecule magnets (SMMs) provide probably the finest ligand regulation model for magnetic property. Recently, the development of such SMMs has witnessed a fast transition from coordination to organometallic complexes because the latter provides a fertile, yet not fully excavated soil for the development of SMMs. Especially those SMMs with heterocyclic ligands have shown the potential to reach higher blocking temperature. In this minireview, we give an overview of the design principle of SMMs and highlight those "shining stars" of heterocyclic organolanthanide SMMs based on the ring sizes of ligands, analysing how the electronic structures of those ligands and the stiffness of subsequently formed molecules affect the dynamic magnetism of SMMs. Finally, we envisaged the future development of heterocyclic Ln-SMMs.
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Ulcerative colitis (UC) is one of the high-risk pathogenic factors for colorectal cancer (CRC). However, the shared gene and signalling mechanisms between UC and CRC remain unclear. The goal of this study was to delve more into the probable causal relationship between UC and CRC. CRC and UC datasets were downloaded from the Gene Expression Omnibus database. Using R software and Perl, differentially expressed genes (DEGs) in both UC and CRC tissues were re-annotated and screened. The biological activities and signalling pathways involved in DEGs were investigated using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The STRING database and Cytoscape software were used to construct the gene interaction network. A total of 384 DEGs were selected for further investigation, and functional analysis revealed that inflammatory and immunological responses were crucial in the development of the two diseases. Moreover, the top 15 key genes involved in the UC and CRC were screened using cytoHubba, including IL1B, CXCL10, CCL20, MMP9, ICAM1, CCL4, CXCR1, MMP3, TLR2, PTGS2, IL1RN, IL6, COL1A2, TIMP1 and CXCL1. The identification of these genes in the present study may provide a novel perspective for the prediction, prevention and personalized medicine of UC and CRC patients.
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Polyradicals, i.e., multispin organic molecules, are playing important roles in radical-based material applications for their spin-spin interaction. A dynamic covalently bonded multispin molecule may endow materials with added function such as memory and switching. However, such a species has yet to be reported. We here report the synthesis, characterization, and crystal structure of a dynamic triradical species. It is generated by the self-assembly of two molecules through a Lewis acid coupled electron transfer. The crystalline species is spin-frustrated without Jahn-Teller distortion at low temperature, while it dissociates back to diamagnetic starting material in solution at high temperature. The reversible process is tracked by variable-temperature NMR, EPR, and UV-vis-NIR spectroscopy. Isolation, property study, and dynamic bonding investigation on such a species lay the foundation for the design of functional polyradicals with potential application as memory or switching devices.
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The thermostable four-coordinate divalent lanthanide (Ln) bis-amidinate complexes [Ln(Piso)2] (Ln = Tb, Dy; Piso = {(NDipp)2CtBu}, Dipp = C6H3iPr2-2,6) were prepared by the reduction of parent five-coordinate Ln(III) precursors [Ln(Piso)2I] (Ln = Tb, Dy) with KC8; halide abstraction of [Ln(Piso)2I] with [H(SiEt3)2][B(C6F5)] gave the respective Ln(III) complexes [Ln(Piso)2][B(C6F5)]. All complexes were characterized by X-ray diffraction, ICP-MS, elemental analysis, SQUID magnetometry, UV-vis-NIR, ATR-IR, NMR, and EPR spectroscopy and ab initio CASSCF-SO calculations. These data consistently show that [Ln(Piso)2] formally exhibit Ln(II) centers with 4fn5dz21 (Ln = Tb, n = 8; Dy, n = 9) valence electron configurations. We show that simple assignments of the f-d coupling to either L-S or J-s schemes are an oversimplification, especially in the presence of significant crystal field splitting. The coordination geometry of [Ln(Piso)2] is intermediate between square planar and tetrahedral. Projecting from the quaternary carbon atoms of the CN2 ligand backbones shows near-linear C···Ln···C arrangements. This results in strong axial ligand fields to give effective energy barriers to magnetic reversal of 1920(91) K for the Tb(II) analogue and 1964(48) K for Dy(II), the highest values observed for mononuclear Ln(II) single-molecule magnets, eclipsing 1738 K for [Tb(C5iPr5)2]. We tentatively attribute the fast zero-field magnetic relaxation for these complexes at low temperatures to transverse fields, resulting in considerable mixing of mJ states.
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Cholesterol is a critical molecule whose dysregulation in certain brain regions is related to multiple neurological disorders. It is of pathological importance to map the distribution of cholesterol in brain. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has been widely used in the molecular imaging of metabolites at a high spatial resolution. However, it is challenging to analyze cholesterol by MALDI-MS due to its difficulty in ionization. Herein, we present for the first time a type of reactive matrix for MALDI-MS of cholesterol. Methylpyridinium carboxaldehydes react with cholesterol and other hydroxyl-containing sterols, which greatly enhanced both desorption and ionization and improved the limits of detection to the low µg/mL range. Compared with previous methods, our reactive matrix requires only one step of chemical derivatization and avoids time-consuming enzymatic reaction, which simplified the sample pretreatment. The reactive matrix was successfully used in mapping the distribution of cholesterol in brain tissue sections using MALDI-MS imaging. In summary, this work has provided a sensitive and simple method for the MALDI-MS analysis of cholesterol, has proposed a novel solution to visualize the distribution of sterol metabolites, and has great potential for applications in neurological and pathological studies.
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Fitosteróis , Esteróis , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Colesterol , EncéfaloRESUMO
Understanding the direct interaction of nanostructures per se with biological systems is important for biomedical applications. However, whether nanostructures regulate biological systems by targeting specific cellular proteins remains largely unknown. In the present work, self-assembling nanomicelles are constructed using small-molecule oleanolic acid (OA) as a molecular template. Unexpectedly, without modifications by functional ligands, OA nanomicelles significantly activate cellular proteasome function by directly binding to 20S proteasome subunit alpha 6 (PSMA6). Mechanism study reveals that OA nanomicelles interact with PSMA6 to dynamically modulate its N-terminal domain conformation change, thereby controlling the entry of proteins into 20S proteasome. Subsequently, OA nanomicelles accelerate the degradation of several crucial proteins, thus potently driving cancer cell pyroptosis. For translational medicine, OA nanomicelles exhibit a significant anticancer potential in tumor-bearing mouse models and stimulate immune cell infiltration. Collectively, this proof-of-concept study advances the mechanical understanding of nanostructure-guided biological effects via their inherent capacity to activate proteasome.
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Nanoestruturas , Neoplasias , Animais , Camundongos , Complexo de Endopeptidases do Proteassoma/metabolismo , Piroptose , Citoplasma/metabolismo , Micelas , Nanoestruturas/químicaRESUMO
Large aperture off-axis Fresnel lens will play an important role in the future 10 m scale aperture transmission space telescope system. Improving diffraction efficiency and wavefront image quality is always the goal of engineering applications. A 4-level off-axis fresnel lens with Ф350 mm effective aperture was fabricated through overlay etching technique by laser direct writing system. The wavefront aberration characteristics of the off-axis Fresnel lens at 632.8â nm wavelength are analyzed and discussed in detail, and the large aperture off-axis Fresnel lenses wavefront aberration measurement scheme, including a high-precision plane reflector, measured LAOFL, CGH, interferometer and laser tracker to compensate for certain low-order aberrations caused by LAOFL imperfect imaging, is proposed. Wavefront aberration of 0.020 λ(1/50 λ) RMS was achieved. This work presented the best results to our knowledge among the same field with similar aperture in open publications and provided a strong foundation for the future 10 m scale aperture transmission space telescope system.