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BACKGROUND: Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage's role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response. METHODS: In this study, we used single-cell RNA-sequencing analysis of Cd45+CD11b+F4/80+ cardiac macrophages to explore the heterogeneity of cardiac macrophages. The CCR2+ (C-C chemokine receptor 2) macrophages were specifically removed by a dual recombinase approach, and the macrophage CCR2 was deleted to investigate their functions. We also performed cleavage under target and tagmentation analysis, chromatin immunoprecipitation-polymerase chain reaction, luciferase assay, and macrophage-specific lentivirus transfection to define the impact of lysozyme C in macrophages on obesity-induced inflammation. RESULTS: We find that the Ccr2 cluster undergoes a functional transition from homeostatic maintenance to proinflammation. Our data highlight specific changes in macrophage behavior during cardiac dysfunction under metabolic challenge. Consistently, inducible ablation of CCR2+CX3CR1+ macrophages or selective deletion of macrophage CCR2 prevents obesity-induced cardiac dysfunction. At the mechanistic level, we demonstrate that the obesity-induced functional shift of CCR2-expressing macrophages is mediated by the CCR2/activating transcription factor 3/lysozyme 1/NF-κB (nuclear factor kappa B) signaling. Finally, we uncover a noncanonical role for lysozyme 1 as a transcription activator, binding to the RelA promoter, driving NF-κB signaling, and strongly promoting inflammation and cardiac dysfunction in obesity. CONCLUSIONS: Our findings suggest that lysozyme 1 may represent a potential target for the diagnosis of obesity-induced inflammation and the treatment of obesity-induced heart disease.
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Macrófagos , Muramidase , Obesidade , Receptores CCR2 , Animais , Obesidade/complicações , Obesidade/metabolismo , Macrófagos/metabolismo , Receptores CCR2/metabolismo , Receptores CCR2/genética , Camundongos , Muramidase/metabolismo , Muramidase/genética , Camundongos Endogâmicos C57BL , Masculino , Camundongos Knockout , Transdução de Sinais , Inflamação/metabolismo , Inflamação/genética , Cardiopatias/etiologia , Cardiopatias/metabolismo , Cardiopatias/genéticaRESUMO
PARP1 (poly-ADP ribose polymerase 1) is recruited and activated by DNA strand breaks, catalyzing the generation of poly-ADP-ribose (PAR) chains from NAD+. PAR relaxes chromatin and recruits other DNA repair factors, including XRCC1 and DNA Ligase 3, to maintain genomic stability. Here we show that, in contrast to the normal development of Parp1-null mice, heterozygous expression of catalytically inactive Parp1 (E988A, Parp1+/A) acts in a dominant-negative manner to disrupt murine embryogenesis. As such, all the surviving F1 Parp1+/A mice are chimeras with mixed Parp1+/AN (neoR retention) cells that act similarly to Parp1+/-. Pure F2 Parp1+/A embryos were found at Mendelian ratios at the E3.5 blastocyst stage but died before E9.5. Compared to Parp1-/- cells, genotype and expression-validated pure Parp1+/A cells retain significant ADP-ribosylation and PARylation activities but accumulate markedly higher levels of sister chromatid exchange and mitotic bridges. Despite proficiency for homologous recombination and nonhomologous end-joining measured by reporter assays and supported by normal lymphocyte and germ cell development, Parp1+/A cells are hypersensitive to base damages, radiation, and Topoisomerase I and II inhibition. The sensitivity of Parp1+/A cells to base damages and Topo inhibitors exceed Parp1-/- controls. The findings show that the enzymatically inactive PARP1 dominant negatively blocks DNA repair in selective pathways beyond wild-type PARP1 and establishes a crucial physiological difference between PARP1 inactivation vs. deletion. As a result, the expression of enzymatically inactive PARP1 from one allele is sufficient to abrogate murine embryonic development, providing a mechanism for the on-target side effect of PARP inhibitors used for cancer therapy.
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ADP-Ribosilação , Instabilidade Genômica , Feminino , Gravidez , Animais , Camundongos , Causalidade , Alelos , GenótipoRESUMO
Identifying causative gene(s) within disease-associated large genomic regions of copy-number variants (CNVs) is challenging. Here, by targeted sequencing of genes within schizophrenia (SZ)-associated CNVs in 1,779 SZ cases and 1,418 controls, we identified three rare putative loss-of-function (LoF) mutations in OTU deubiquitinase 7A (OTUD7A) within the 15q13.3 deletion in cases but none in controls. To tie OTUD7A LoF with any SZ-relevant cellular phenotypes, we modeled the OTUD7A LoF mutation, rs757148409, in human induced pluripotent stem cell (hiPSC)-derived induced excitatory neurons (iNs) by CRISPR-Cas9 engineering. The mutant iNs showed a â¼50% decrease in OTUD7A expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, density of synaptic proteins GluA1 and PSD-95, and neuronal network activity. Congruent with the neuronal phenotypes in mutant iNs, our transcriptomic analysis showed that the set of OTUD7A LoF-downregulated genes was enriched for those relating to synapse development and function and was associated with SZ and other neuropsychiatric disorders. These results suggest that OTUD7A LoF impairs synapse development and neuronal function in human neurons, providing mechanistic insight into the possible role of OTUD7A in driving neuropsychiatric phenotypes associated with the 15q13.3 deletion.
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Células-Tronco Pluripotentes Induzidas , Esquizofrenia , Variações do Número de Cópias de DNA , Humanos , Neurônios , Esquizofrenia/metabolismo , Sinapses/metabolismoRESUMO
Replication fork reversal which restrains DNA replication progression is an important protective mechanism in response to replication stress. PARP1 is recruited to stalled forks to restrain DNA replication. However, PARP1 has no helicase activity, and the mechanism through which PARP1 participates in DNA replication restraint remains unclear. Here, we found novel protein-protein interactions between PARP1 and DNA translocases, including HLTF, SHPRH, ZRANB3, and SMARCAL1, with HLTF showing the strongest interaction among these DNA translocases. Although HLTF and SHPRH share structural and functional similarity, it remains unclear whether SHPRH contains DNA translocase activity. We further identified the ability of SHPRH to restrain DNA replication upon replication stress, indicating that SHPRH itself could be a DNA translocase or a helper to facilitate DNA translocation. Although hydroxyurea (HU) and MMS induce different types of replication stress, they both induce common DNA replication restraint mechanisms independent of intra-S phase activation. Our results suggest that the PARP1 facilitates DNA translocase recruitment to damaged forks, preventing fork collapse and facilitating DNA repair.
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Proteínas de Ligação a DNA , Fatores de Transcrição , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Reparo do DNA/genética , Replicação do DNA/genética , DNA/genética , Dano ao DNA/genéticaRESUMO
BACKGROUND: With the development of single-cell technology, many cell traits can be measured. Furthermore, the multi-omics profiling technology could jointly measure two or more traits in a single cell simultaneously. In order to process the various data accumulated rapidly, computational methods for multimodal data integration are needed. RESULTS: Here, we present inClust+, a deep generative framework for the multi-omics. It's built on previous inClust that is specific for transcriptome data, and augmented with two mask modules designed for multimodal data processing: an input-mask module in front of the encoder and an output-mask module behind the decoder. InClust+ was first used to integrate scRNA-seq and MERFISH data from similar cell populations, and to impute MERFISH data based on scRNA-seq data. Then, inClust+ was shown to have the capability to integrate the multimodal data (e.g. tri-modal data with gene expression, chromatin accessibility and protein abundance) with batch effect. Finally, inClust+ was used to integrate an unlabeled monomodal scRNA-seq dataset and two labeled multimodal CITE-seq datasets, transfer labels from CITE-seq datasets to scRNA-seq dataset, and generate the missing modality of protein abundance in monomodal scRNA-seq data. In the above examples, the performance of inClust+ is better than or comparable to the most recent tools in the corresponding task. CONCLUSIONS: The inClust+ is a suitable framework for handling multimodal data. Meanwhile, the successful implementation of mask in inClust+ means that it can be applied to other deep learning methods with similar encoder-decoder architecture to broaden the application scope of these models.
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Cromatina , Transcriptoma , FenótipoRESUMO
Nitroalkanes serve as essential intermediates in the synthesis of pharmaceuticals, agrochemicals, and functional materials. To date, nitroalkanes are mainly prepared from homogeneous catalysts such as noble transition metal catalysts with poor recyclability. Herein, we propose a metal-organic framework-frustrated Lewis pair (MOF-FLP) heterogeneous catalyst for selectively reducing nitroolefins to nitroalkanes under moderate reaction conditions. MOF enrichment effect can significantly improve the catalytic efficiency compared to homogeneous FLP catalysts. Benefiting from the strong interaction between FLP and MOF, the MOF-FLP catalyst exhibits outstanding recyclability. This work not only provides a convenient route for nitroalkane synthesis but also showcases the potential of porous heterogeneous FLP catalysts, offering inspiration for future catalytic design strategies.
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The unenveloped Bluetongue virus capsid comprises several structural layers, the inner two comprising a core, which assembles before addition of the outer proteins, VP2 and VP5. Two symmetric trimers of VP5 fit like pegs into two distinct pits on the core and undergo pH conformational changes in the context of the virus, associated with cell entry. Here we show that in isolation VP5 alone undergoes essentially the same changes with pH and confirm a helical transition, indicating that VP5 is a motor during cell entry. In the absence of VP5 the two pits on the core differ from each other, presumably due to the asymmetric underlying structure of VP3, the innermost capsid protein. On insertion of VP5 these pits become closely similar and remain similar at low pH whilst VP5 is present. This natural asymmetry presumably destabilises the attachment of VP5, facilitating ejection upon low pH, membrane penetration and cell entry.
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Vírus Bluetongue , Proteínas do Capsídeo , Vírus Bluetongue/fisiologia , Vírus Bluetongue/química , Concentração de Íons de Hidrogênio , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Proteínas do Capsídeo/genética , Internalização do Vírus , Animais , Conformação ProteicaRESUMO
The advent of wearable sensors heralds a transformation in the continuous, noninvasive analysis of biomarkers critical for disease diagnosis and fitness management. Yet, their advancement is hindered by the functional challenges affiliated with their active sensing analysis layer. Predominantly due to suboptimal intrinsic material properties and inconsistent dispersion leading to aggregation, thus compromising sensor repeatability and performance. Herein, an innovative approach to the functionalization of wearable electrochemical sensors was introduced, specifically addressing these limitations. The method involves a proton-induced self-assembly technique at the organic-water (O/W) interface, facilitating the generation of biomarker-responsive films. This research offers flexible, breathable sensor capable of real-time precision tracking l-cysteine (l-Cys) precision tracking. Utilizing an activation mechanism for Prussian blue nanoparticles by hydrogen peroxide, the catalytic core exhibits a specific response to l-Cys. The implications of this study refine the fabrication of film-based analysis electrodes for wearable sensing applications and the broader utilization of two-dimensional materials in functional-specific response films. Findings illuminate the feasibility of this novel strategy for precise biomarker tracking and extend to pave the way for constructing high-performance electrocatalytic analytical interfaces.
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Cisteína , Técnicas Eletroquímicas , Ferrocianetos , Dispositivos Eletrônicos Vestíveis , Cisteína/análise , Cisteína/química , Humanos , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Ferrocianetos/química , Peróxido de Hidrogênio/análise , Peróxido de Hidrogênio/química , Eletrodos , Técnicas Biossensoriais , Biomarcadores/análise , Nanopartículas/químicaRESUMO
Melatonin, historically recognized for its primary role in regulating circadian rhythms, has expanded its influence particularly due to its wide range of biological activities. It has firmly established itself in cancer research. To highlight its versatility, we delved into how melatonin interacts with key signaling pathways, such as the Wnt/ß-Catenin, PI3K, and NF-κB pathways, which play foundational roles in tumor development and progression. Notably, melatonin can intricately modulate these pathways, potentially affecting various cellular functions such as apoptosis, metastasis, and immunity. Additionally, a comprehensive review of current clinical studies provides a dual perspective. These studies confirm melatonin's potential in cancer management but also underscore its inherent limitations, particularly its limited bioavailability, which often relegates it to a supplementary role in treatments. Despite this limitation, there is an ongoing quest for innovative solutions and current advancements include the development of melatonin derivatives and cutting-edge delivery systems. By synthesizing the past, present, and future, this review provides a detailed overview of melatonin's evolving role in oncology, positioning it as a potential cornerstone in future cancer therapeutics.
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Melatonina , Neoplasias , Humanos , Melatonina/uso terapêutico , Melatonina/metabolismo , Transdução de Sinais , Biologia , Neoplasias/tratamento farmacológicoRESUMO
About 80% of persons with chronic hepatitis B virus (HBV) infection in the United States are non-US-born. Despite improvements in infant hepatitis B vaccination globally since 2000, work remains to attain the World Health Organization's (WHO) global 2030 goal of 90% vaccination. We explore the impacts on the United States of global progress in hepatitis B vaccination since 2000 and of achieving WHO hepatitis B vaccination goals. We simulated immigrants with HBV infection arriving to the United States from 2000 to 2070 using models of the 10 countries from which the largest numbers of individuals with HBV infection were born. We estimated costs in the United States among these cohorts using a disease simulation model. We simulated three scenarios: a scenario with no progress in infant vaccination for hepatitis B since 2000 (baseline), current (2020) progress and achieving WHO 2030 goals for hepatitis B vaccination. We estimate current hepatitis B vaccination progress since the 2000 baseline in these 10 countries will lead to 468,686 fewer HBV infections, avoid 35,582 hepatitis B-related deaths and save $4.2 billion in the United States through 2070. Achieving the WHO 2030 90% hepatitis B infant vaccination targets could lead to an additional 16,762 fewer HBV infections, 989 fewer hepatitis B-related deaths and save $143 million through 2070. Global hepatitis B vaccination since 2000 reduced prevalence of HBV infection in the United States. Achieving the WHO 2030 infant vaccination goals globally could lead to over one hundred million dollars in additional savings.
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Integration of hepatitis B virus (HBV) DNA into the human genome is recognized as an oncogenic factor and a barrier to hepatitis B cure. In the study, biopsy liver tissues were collected from adolescents and young adults with acute HBV infection younger than or equal to 35 years of age and from HBV-infected infant patients younger than or equal to 6 months of age. A high-throughput sequencing method was used to detect HBV DNA integration. Totally, 12 adolescents, young adults, and 6 infants were included. Among the 12 patients with acute HBV infection, immunohistochemical staining of intrahepatic hepatitis B surface antigen for all displayed negative results, and no HBV DNA integrants in the hepatocyte DNA were confirmed. All infant patients had elevated levels of alanine aminotransferase and high levels of serum HBV DNA. Numerous gene sites of hepatocyte DNA were integrated by HBV DNA for each infant patient, ranging from 120 to 430 integration sites. The fragile histidine triad gene was the high-frequency integrated site in the intragenic region for infant patients. In conclusion, hepatocyte DNA is integrated by HBV DNA in babies with active hepatitis B but seems seldom affected among adolescents and young adults with acute HBV infection. Infantile hepatitis B should be taken seriously considering abundant HBV DNA integration events.
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Hepatite B Crônica , Hepatite B , Lactente , Adolescente , Humanos , Adulto Jovem , Vírus da Hepatite B/genética , DNA Viral/genética , Fígado/patologia , Antígenos de Superfície da Hepatite B/genética , Antígenos E da Hepatite B , GenômicaRESUMO
Vasoactive intestinal polypeptide (VIP), an anti-inflammatory neuropeptide with pleiotropic cardiovascular effects, induces differentiation of hematopoietic stem cells into regulatory dendritic cells that limit graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We have previously shown that donor plasmacytoid dendritic cells (pDCs) in bone marrow (BM) donor grafts limit the pathogenesis of GVHD. In this current study we show that murine and human pDCs express VIP, and that VIP-expressing pDCs limit T-cell activation and expansion using both in vivo and in vitro model systems. Using T cells or pDCs from transgenic luciferase+ donors in murine bone marrow transplantation (BMT), we show similar homing patterns of donor pDCs and T cells to the major sites for alloactivation of donor T cells: spleen and gut. Cotransplanting VIP-knockout (KO) pDCs with hematopoietic stem cells and T cells in major histocompatibility complex mismatched allogeneic BMT led to lower survival, higher GVHD scores, and more colon crypt cell apoptosis than transplanting wild-type pDCs. BMT recipients of VIP-KO pDCs had more T helper 1 polarized T cells, and higher plasma levels of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α than recipients of wild-type pDCs. T cells from VIP-KO pDC recipients had increasing levels of bhlhe40 transcripts during the first 2 weeks posttransplant, and higher levels of CyclophilinA/Ppia transcripts at day 15 compared with T cells from recipients of wild-type pDCs. Collectively, these data indicate paracrine VIP synthesis by donor pDCs limits pathogenic T-cell inflammation, supporting a novel mechanism by which donor immune cells regulate T-cell activation and GVHD in allogeneic BMT.
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Doença Enxerto-Hospedeiro , Animais , Transplante de Medula Óssea/efeitos adversos , Células Dendríticas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/metabolismo , Peptídeo Intestinal Vasoativo/metabolismoRESUMO
BACKGROUND: The GPNMB single-nucleotide polymorphism rs199347 and GBA1 variants both associate with Lewy body disorder (LBD) risk. GPNMB encodes glycoprotein nonmetastatic melanoma protein B (GPNMB), a biomarker for GBA1-associated Gaucher's disease. OBJECTIVE: The aim of this study was to determine whether GPNMB levels (1) differ in LBD with and without GBA1 variants and (2) associate with rs199347 genotype. METHODS: We quantified GPNMB levels in plasma and cerebrospinal fluid (CSF) from 124 individuals with LBD with one GBA1 variant (121 plasma, 14 CSF), 631 individuals with LBD without GBA1 variants (626 plasma, 41 CSF), 9 neurologically normal individuals with one GBA1 variant (plasma), and 2 individuals with two GBA1 variants (plasma). We tested for associations between GPNMB levels and rs199347 or GBA1 status. RESULTS: GPNMB levels associate with rs199347 genotype in plasma (P = 0.022) and CSF (P = 0.007), but not with GBA1 status. CONCLUSIONS: rs199347 is a protein quantitative trait locus for GPNMB. GPNMB levels are unaltered in individuals carrying one GBA1 variant. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Biomarcadores , Glucosilceramidase , Doença por Corpos de Lewy , Glicoproteínas de Membrana , Polimorfismo de Nucleotídeo Único , Humanos , Feminino , Glucosilceramidase/genética , Masculino , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/sangue , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/líquido cefalorraquidiano , Idoso , Pessoa de Meia-Idade , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Idoso de 80 Anos ou mais , Genótipo , Heterozigoto , Doença de Gaucher/genética , Doença de Gaucher/sangue , Doença de Gaucher/líquido cefalorraquidianoRESUMO
BACKGROUND: Endocrine resistance driven by sustained activation of androgen receptor (AR) signaling pathway in advanced prostate cancer (PCa) is fatal. Characterization of mechanisms underlying aberrant AR pathway activation to search for potential therapeutic strategy is particularly important. Rac GTPase-activating protein 1 (RACGAP1) is one of the specific GTPase-activating proteins. As a novel tumor proto-oncogene, overexpression of RACGAP1 was related to the occurrence of various tumors. METHODS: Bioinformatics methods were used to analyze the relationship of expression level between RACGAP1 and AR as well as AR pathway activation. qRT-PCR and western blotting assays were performed to assess the expression of AR/AR-V7 and RACGAP1 in PCa cells. Immunoprecipitation and immunofluorescence experiments were conducted to detect the interaction and co-localization between RACGAP1 and AR/AR-V7. Gain- and loss-of-function analyses were conducted to investigate the biological roles of RACGAP1 in PCa cells, using MTS and colony formation assays. In vivo experiments were conducted to evaluate the effect of RACGAP1 inhibition on the tumor growth. RESULTS: RACGAP1 was a gene activated by AR, which was markedly upregulated in PCa patients with CRPC and enzalutamide resistance. AR transcriptionally activated RACGAP1 expression by binding to its promoter region. Reciprocally, nuclear RACGAP1 bound to the N-terminal domain (NTD) of both AR and AR-V7, blocking their interaction with the E3 ubiquitin ligase MDM2. Consequently, this prevented the degradation of AR/AR-V7 in a ubiquitin-proteasome-dependent pathway. Notably, the positive feedback loop between RACGAP1 and AR/AR-V7 contributed to endocrine therapy resistance of CRPC. Combination of enzalutamide and in vivo cholesterol-conjugated RIG-I siRNA drugs targeting RACGAP1 induced potent inhibition of xenograft tumor growth of PCa. CONCLUSION: In summary, our results reveal that reciprocal regulation between RACGAP1 and AR/AR-V7 contributes to the endocrine resistance in PCa. These findings highlight the therapeutic potential of combined RACGAP1 inhibition and enzalutamide in treatment of advanced PCa.
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Resistencia a Medicamentos Antineoplásicos , Proteínas Ativadoras de GTPase , Neoplasias da Próstata , Receptores Androgênicos , Masculino , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Linhagem Celular Tumoral , Animais , Proto-Oncogene Mas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Feniltioidantoína/farmacologia , Camundongos Nus , Nitrilas/farmacologia , Camundongos , Benzamidas/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Low dimensional organic inorganic metal halide materials have shown broadband emission and large Stokes shift, making them widely used in various fields and a promising candidate material. Here, the zero-dimensional lead-free bromide single crystals (C6H14N)3Bi2Br9·H2O (1) and (C6H14N)3Sb3Br12 (2) were synthesized. They crystallized in the monoclinic crystal system with the space group of P21 and P21/n, respectively. Through ultraviolet-visible-near-infrared (UV-vis-NIR) absorption analysis, the band gaps of (C6H14N)3Bi2Br9·H2O and (C6H14N)3Sb3Br12 are found to be 2.75 and 2.83 eV, respectively. Upon photoexcitation, (C6H14N)3Bi2Br9·H2O exhibit broad-band red emission peaking at 640 nm with a large Stokes shift of 180 nm and a lifetime of 2.94 ns, and the emission spectrum of (C6H14N)3Sb3Br12 are similar to those of (C6H14N)3Bi2Br9·H2O. This exclusive red emission is ascribed to the self-trapping exciton transition caused by lattice distortion, which is confirmed through both experiments and first-principles calculations. In addition, due to the polar space group structure and the large spin-orbit coupling (SOC) associated with the heavy elements of Bi and Br of crystal 1, an obvious Rashba effect was observed. The discovery of organic inorganic metal bromide material provides a critical foundation for uncovering the connection between 0D metal halide materials' structures and properties.
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Polymer products typically present as mixtures with a range of molecular weights, which notably influence the expression of their properties. In this study, a technique is proposed to separate polyethylene glycol (PEG) mixtures of varying molecular weights using metal-organic frameworks (MOFs), thereby narrowing down their molecular weight distribution. Due to the hydrogen bond interactions between PEG and -OH groups in the pores of NU-1000, NU-1000 can selectively adsorb PEG with larger molecular weights from PEG mixture. This separation method consistently yields with narrower molecular weight distribution across multiple cycles. This is the first application of MOFs in regulating the dispersity (Ð) of polymers in solution, providing a novel approach for separating and purifying mixed molecular weight polymers.
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PURPOSE: This study evaluated the performance of multiparametric magnetic resonance imaging (MRI)-based fusion radiomics models (MMFRs) to predict telomerase reverse transcriptase (TERT) promoter mutation status and progression-free survival (PFS) in glioblastoma patients. METHODS: We retrospectively analysed 208 glioblastoma patients from two hospitals. Quantitative imaging features were extracted from each patient's T1-weighted, T1-weighted contrast-enhanced, and T2-weighted preoperative images. Using a coarse-to-fine feature selection strategy, four radiomics signature models were constructed based on the three MRI sequences and their combination for TERT promoter mutation status and PFS; model performance was subsequently evaluated. Subgroup analyses were performed by the radiomics signature of TERT promoter mutation status and PFS to distinguish patients who could benefit from prolonged temozolomide chemotherapy cycles. RESULTS: TERT promoter mutation status was best predicted by MMFR, with an area under the curve (AUC) of 0.816 and 0.812 for the training and internal validation sets, respectively. The external test set also achieved stable and optimal prediction results (AUC, 0.823). MMFR better predicted patient PFS compared with the single-sequence radiomics signature in the test set (C-index, 0.643 vs 0.561 vs 0.620 vs 0.628). Subgroup analyses showed that more than six cycles of postoperative temozolomide chemotherapy were associated with improved PFS for patients in class 2 (high TERT promoter mutation and high survival rates; HR, 0.222; 95% CI, 0.054 - 0.923; p = 0.025). CONCLUSION: MMFR is an effective method to predict TERT promoter mutations and PFS in patients with glioblastoma. Moreover, subgroup analysis could differentiate patients who may benefit from prolonged TMZ chemotherapy cycles.
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Neoplasias Encefálicas , Glioblastoma , Imageamento por Ressonância Magnética Multiparamétrica , Telomerase , Humanos , Glioblastoma/diagnóstico por imagem , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Telomerase/genética , Imageamento por Ressonância Magnética/métodos , Temozolomida/uso terapêutico , Intervalo Livre de Progressão , Estudos Retrospectivos , Radiômica , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , MutaçãoRESUMO
Phosphatase and tensin homolog (PTEN) loss tightly correlates with prostate cancer (PCa) progression and metastasis. Inactivation of PTEN leads to abnormal activation of PI3K/AKT pathway. However, results from clinical trials with AKT inhibitors in PCa have been largely disappointing. Identification of novel regulators of PTEN in PTEN-dysfunctional PCa is urgently needed. Here we demonstrated that the expression level of PTEN is inversely correlated with the signature score of unfolded protein response (UPR) in PCa. Importantly, PTEN suppresses the activity of ATF6α, via interacting to de-phosphorylate ATF6α and consequently inhibiting its nuclear translocation. Conversely, ATF6α promotes the ubiquitination and degradation of PTEN by inducing CHIP expression. Thus, ATF6α and PTEN forms a negative feedback loop during PCa progression. Combination of ATF6α inhibitor with AKT inhibitor suppresses tumor cell proliferation and xenograft growth. Importantly, this study highlighted ATF6α as a therapeutic vulnerability in PTEN dysfunctional PCa.
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Fosfatidilinositol 3-Quinases , Neoplasias da Próstata , Masculino , Humanos , Retroalimentação , Proteínas Proto-Oncogênicas c-akt , Neoplasias da Próstata/genética , Próstata , Inibidores da Angiogênese , Inibidores de Proteínas Quinases , PTEN Fosfo-Hidrolase/genéticaRESUMO
BACKGROUND: An increased acetylcholine (ACh) level in the right ventricle tissue of pulmonary hypertension (PH) was revealed, which indicated the important role of ACh in disease pathogenesis. However, the relationship between plasma ACh levels and disease conditions and patients' prognosis has not been investigated. We aimed to explore the association between plasma ACh levels and the prognosis of patients with PH. We also discussed the feasibility of plasma ACh as a biomarker, which may contribute to the management of PH patients in the future. METHODS: Patients with confirmed PH in Fuwai Hospital from April 2019 to August 2020 were enrolled. The primary clinical outcome in this study was defined as a composite outcome, including death/lung transplantation, heart failure, and worsening of symptoms. Fasting plasma was collected to detect the ACh levels. The association between ACh levels and patients' prognosis was explored. RESULTS: Finally, four hundred and eight patients with PH were enrolled and followed for a mean period of 2.5 years. Patients in the high ACh group had worse World Health Organization Functional Class (WHO-FC), lower 6-minute walk distance (6 MWD), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP). Notably, echocardiographic and hemodynamic parameters in the high metabolite group also suggested a worse disease condition compared with the low ACh group. After adjusting for confounders, compared with low ACh patients, those with high metabolite levels still have worse prognoses characterized as elevated risk of mortality, heart failure, and symptoms worsening. CONCLUSION: High circulating ACh levels were associated with severe PH conditions and poor prognosis, which might serve as a potential biomarker in PH.
Assuntos
Insuficiência Cardíaca , Hipertensão Pulmonar , Humanos , Acetilcolina , Biomarcadores , Prognóstico , Peptídeo Natriurético Encefálico , Fragmentos de PeptídeosRESUMO
BACKGROUND: Summarizing the clinical features of children with intussusception secondary to small bowel tumours and enhancing awareness of the disease. METHODS: Retrospective summary of children with intussusception admitted to our emergency department from January 2016 to January 2022, who underwent surgery and were diagnosed with small bowel tumours. Summarize the types of tumours, clinical presentation, treatment, and prognosis. RESULTS: Thirty-one patients were included in our study, 24 males and 7 females, with an age of onset ranging from 1 m to 11y 5 m. Post-operative pathology revealed 4 types of small intestinal tumour, 17 lymphomas, 10 adenomas, 4 inflammatory myofibroblastomas and 1 lipoma. The majority of tumours in the small bowel occur in the ileum (83.9%, 26/31). Abdominal pain, vomiting and bloody stools were the most common clinical signs. Operative findings indicated that the small bowel (54.8%, 17/31) and ileocolic gut were the main sites of intussusception. Two types of procedure were applied: segmental bowel resection (28 cases) and wedge resection of mass in bowel wall (3 cases). All patients recovered well postoperatively, with no surgical complications observed. However, the primary diseases leading to intussusception showed slight differences in long-term prognosis due to variations in tumor types. CONCLUSIONS: Lymphoma is the most common cause of intussusception in pediatric patients with small bowel tumours, followed by adenoma. Small bowel tumours in children tend to occur in the ileum. Therefore, the treatment of SBT patients not only requires surgeons to address symptoms through surgery and obtain tissue samples but also relies heavily on the expertise of pathologists for accurate diagnosis. This has a significant impact on the overall prognosis of these patients.