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BACKGROUND: PM2.5 can induce and aggravate the occurrence and development of cardiovascular diseases (CVDs). The objective of our study is to estimate the causal effect of PM2.5 on mortality rates associated with CVDs using the instrumental variables (IVs) method. METHODS: We extracted daily meteorological, PM2.5 and CVDs death data from 2016 to 2020 in Binzhou. Subsequently, we employed the general additive model (GAM), two-stage predictor substitution (2SPS), and control function (CFN) to analyze the association between PM2.5 and daily CVDs mortality. RESULTS: The 2SPS estimated the association between PM2.5 and daily CVDs mortality as 1.14% (95% CI: 1.04%, 1.14%) for every 10 µg/m3 increase in PM2.5. Meanwhile, the CFN estimated this association to be 1.05% (95% CI: 1.02%, 1.10%). The GAM estimated it as 0.85% (95% CI: 0.77%, 1.05%). PM2.5 also exhibited a statistically significant effect on the mortality rate of patients with ischaemic heart disease, myocardial infarction, or cerebrovascular accidents (P < 0.05). However, no significant association was observed between PM2.5 and hypertension. CONCLUSION: PM2.5 was significantly associated with daily CVDs deaths (excluding hypertension). The estimates from the IVs method were slightly higher than those from the GAM. Previous studies based on GAM may have underestimated the impact of PM2.5 on CVDs.
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Poluentes Atmosféricos , Doenças Cardiovasculares , Material Particulado , Humanos , Material Particulado/efeitos adversos , Material Particulado/análise , Doenças Cardiovasculares/mortalidade , China/epidemiologia , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Exposição Ambiental/efeitos adversos , Masculino , Feminino , Poluição do Ar/efeitos adversos , Pessoa de Meia-IdadeRESUMO
Rapid detection of plant phenotypic traits is crucial for plant breeding and cultivation. Traditional measurement methods are carried out by rich-experienced agronomists, which are time-consuming and labor-intensive. However, with the increasing demand for rapid and high-throughput testing in tea plants traits, digital breeding and smart cultivation of tea plants rely heavily on precise plant phenotypic trait measurement techniques, among which hyperspectral imaging (HSI) technology stands out for its ability to provide real-time and rich-information. In this paper, we provide a comprehensive overview of the principles of hyperspectral imaging technology, the processing methods of cubic data, and relevant algorithms in tea plant phenomics, reviewing the progress of applying hyperspectral imaging technology to obtain information on tea plant phenotypes, growth conditions, and quality indicators under environmental stress. Lastly, we discuss the challenges faced by HSI technology in the detection of tea plant phenotypic traits from different perspectives, propose possible solutions, and envision the potential development prospects of HSI technology in the digital breeding and smart cultivation of tea plants. This review aims to provide theoretical and technical support for the application of HSI technology in detecting tea plant phenotypic information, further promoting the trend of developing high quality and high yield tea leaves.
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To recycle the nutrients in spiramycin (SPM) fermentation residue (SFR) through biological methods, acid hydrothermal treatment (AHT) was employed as pretreatment to enhance SFR biodegradability. The results showed that the degradation rate of residual SPM in SFR reached 100% after 120 min at 100â and 0.30 M acid with a 30.5% and 89.7% increase in proteins and polysaccharides, respectively. The SPM degradation was faster at higher acidity and temperature. However, elevated SPM concentration and the presence of protein, humic acid, and polysaccharide inhibited SPM degradation. The disintegration of SFR was evidenced by changes in its microstructure and could be predicted through the release of dissolved organic matter. Eight major SPM intermediates were identified with lower mutagenicity and antibacterial activity testing against Staphylococcus aureus. These results demonstrate that AHT not only disintegrates SFR but also degrades the residual SPM antibiotics, which implies the possibility for practical applications.
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Antibacterianos , Fermentação , Espiramicina , Antibacterianos/farmacologia , Antibacterianos/química , Espiramicina/farmacologia , Espiramicina/química , Staphylococcus aureus/efeitos dos fármacos , Temperatura , Água/química , Concentração de Íons de Hidrogênio , Ácidos/química , Biodegradação AmbientalRESUMO
Diabetes mellitus is a common chronic metabolic disease characterized by a high incidence and disability rate. Intestinal flora refers to the microbial community that lives in the intestines and plays a crucial role in maintaining intestinal health and the human immune system. In recent years, an increasing body of research has revealed a close relationship between intestinal flora and diabetes. The pathophysiological mechanisms between them have also been constantly uncovered, and the regulation of intestinal flora has shown promising efficacy in the adjuvant treatment of diabetes. This study mainly summarized the characteristics and mechanisms of intestinal flora in patients with diabetes in recent years, as well as the methods of regulating intestinal flora to prevent and treat diabetes, and prospected the future research direction. This will offer a theoretical basis for the clinical adjuvant treatment of diabetes with intestinal flora and the development of new drugs.
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BACKGROUND: The aim of this study was to investigate the frequency dependence of electroacupuncture (EA) in alleviating chronic visceral pain in patients with irritable bowel syndrome (IBS) and the differences in the gut microbiota and metabolites as potential mechanisms to explain frequency dependence. METHODS: A visceral hyperalgesia model was established by colorectal instillation of 2,4,6-trinitrobenzene sulfonic acid in rats, and EA treatment at 2/10 Hz, 2/50 Hz and 2/100 Hz was applied at ST25. Visceral sensation was quantified by the abdominal withdrawal reflex score and the area under the curve of the rectus abdominis electromyogram in response to colorectal distension. Ultrastructural morphological damage of colonic tissue of the rats was examined by transmission electron microscopy. 16S rRNA gene sequencing and 1H-nuclear magnetic resonance spectroscopy were applied to study the differences in the gut microbiota and to perform metabonomic profiling of the colonic tissue. KEY RESULTS: EA at ST25 at different frequencies attenuated chronic visceral pain, ultrastructural morphological damage to colonic tissue and disruption of the gut microbiota in IBS rats. The frequency of 2/100 Hz has more regulatory pathways than 2/10 Hz and 2/50 Hz. In addition, IBS rats exhibited colonic metabolic disorders, and pantothenate was significantly upregulated after EA treatment at different frequencies. Very low-density lipoprotein and 2-hydroxybutyrate were significantly increased in the 2/10 Hz group, while low density lipoprotein, very low-density lipoprotein, 2-hydroxybutyrate, methylmalonate and alpha-hydroxyisobutyric acid were significantly increased in the 2/100 Hz group. CONCLUSIONS AND INFERENCES: EA at ST25 at different frequencies attenuated chronic visceral pain through different gut microbiota and metabolic pathways.
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BACKGROUND: Depression is a leading cause of disability and poor health worldwide and is expected to rank first worldwide by 2030. The aim of this study is to analyze the transition and trend of depression burden in China and various income-level countries by utilizing the Global Burden of Disease (GBD) database and the Joinpoint regression model. This analysis seeks to comprehend the variations in the burden of depression across different income regions and evaluate their developmental patterns. METHODS: Based on the GBD 2019 open dataset, this study extracted data on YLD (Years Lived with Disability), DALY (Disability-Adjusted Life Years), and incidence related to depression. The analysis focused on the period between 1990 and 2019, covering global data and distinguishing between high-income, upper-middle-income, lower-middle-income, low-income countries, and China. We utilized the Joinpoint regression model to fit the spatiotemporal trend changes among different income-level countries. Pairwise comparisons were conducted to examine the parallelism and to determine if the differences in trend changes among various regions were statistically significant. RESULTS: From 1990 to 2019, the age-standardized YLD and DALY for depression female were higher than that in male. The YLD total change rate of depression men was higher than that of women. China exhibited the largest disparity in total YLD change rates between genders, reaching 0.08. During 1990 to 2019, the incidence of depression in 2005-2019 increased among females in middle to high-income countries, low-income countries, and China as compare to that of 1990-2005. Notably, China shown the most increase the incidence rate of females (from -0.4 % to 0.84 %). China experienced the most significant change in the YLD of depression during this period (AAPC = 0.45, 95 % CI = 0.41, 0.48, P < 0.01). China's YLD/Incidence rate was higher compared to the global, HICs, UMCs, LMCs, and LICs. In China, the YLD/incidence rate of depression began to rise in 1994, peaking around 2010, and then gradually declining. Since 2010, the growth rate of depression DALYs in China has been higher than the global average, high-income countries, upper-middle-income countries, lower-middle-income countries, and low-income countries. The DALY's AAPC value for the HLCs was the highest (AAPC = 0.24, 95 % CI = 0.22, 0.25, P < 0.01). The UMCs, in comparison to other regions, incidence rate had the highest AAPC value (AAPC = 0.48, 95 % CI = 0.46, 0.50, P < 0.01). CONCLUSIONS: Given the significant variations in the burden of depression across countries with different income levels, future strategies aimed at reducing the burden of depression should adopt tailored and differentiated approaches according to each country's specific needs and developmental stages.
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Depressão , Carga Global da Doença , Humanos , China/epidemiologia , Masculino , Feminino , Depressão/epidemiologia , Incidência , Carga Global da Doença/tendências , Pessoa de Meia-Idade , Adulto , Anos de Vida Ajustados por Deficiência/tendências , Renda/estatística & dados numéricos , Países em Desenvolvimento/estatística & dados numéricos , Análise de Regressão , Bases de Dados Factuais , Pessoas com Deficiência/estatística & dados numéricos , Efeitos Psicossociais da Doença , Transtorno Depressivo/epidemiologia , Idoso , Países Desenvolvidos/estatística & dados numéricosRESUMO
Understanding the interplay between top-down and bottom-up attention in visual working memory (VWM) is crucial, although the specific challenges arising from this interaction remain ambiguous. In this study, we address this complexity by examining how cue informativeness and probe status of the salient items influence this interaction. Through three experiments, we manipulated top-down attention by varying probe frequencies using pre-cues and bottom-up attention by varying the visual salience of memory items. Experiment 1 explored cue informativeness at 100% and 50%, while Experiments 2 and 3 maintained cue informativeness at 80% and 50%. Additionally, Experiment 1 tested a few of the salient items, Experiment 2 excluded them, and Experiment 3 tested half of them in each cue condition. Across all experiments, we consistently observed cueing benefits for cue-directed items, albeit with costs to non-cued items. Furthermore, cue informativeness and the probe status of salient items emerged as critical factors influencing the interaction between top-down and bottom-up attention in VWM. These findings underscore the pivotal roles of cue informativeness and salient item relevance in shaping the dynamics of top-down and bottom-up attention within VWM.
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Atenção , Sinais (Psicologia) , Memória de Curto Prazo , Percepção Visual , Humanos , Memória de Curto Prazo/fisiologia , Atenção/fisiologia , Masculino , Feminino , Adulto Jovem , Percepção Visual/fisiologia , Adulto , Tempo de Reação/fisiologia , Estimulação Luminosa , AdolescenteRESUMO
Microbial fuel cells (MFCs) have the potential to directly convert the chemical energy in organic matter into electrical energy, making them a promising technology for achieving sustainable energy production alongside wastewater treatment. However, the low extracellular electron transfer (EET) rates and limited bacteria loading capacity of MFCs anode materials present challenges in achieving high power output. In this study, three-dimensionally heteroatom-doped carbonized grape (CG) monoliths with a macroporous structure were successfully fabricated using a facile and low-cost route and employed as independent anodes in MFCs for treating brewery wastewater. The CG obtained at 900 °C (CG-900) exhibited excellent biocompatibility. When integrated into MFCs, these units initiated electricity generation a mere 1.8 days after inoculation and swiftly reached a peak output voltage of 658 mV, demonstrating an exceptional areal power density of 3.71 W m-2. The porous structure of the CG-900 anode facilitated efficient ion transport and microbial community succession, ensuring sustained operational excellence. Remarkably, even when nutrition was interrupted for 30 days, the voltage swiftly returned to its original level. Moreover, the CG-900 anode exhibited a superior capacity for accommodating electricigens, boasting a notably higher abundance of Geobacter spp. (87.1%) compared to carbon cloth (CC, 63.0%). Most notably, when treating brewery wastewater, the CG-900 anode achieved a maximum power density of 3.52 W m-2, accompanied by remarkable treatment efficiency, with a COD removal rate of 85.5%. This study provides a facile and low-cost synthesis technique for fabricating high-performance MFC anodes for use in microbial energy harvesting.
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Fontes de Energia Bioelétrica , Eletrodos , Vitis , Águas Residuárias , Fontes de Energia Bioelétrica/microbiologia , Águas Residuárias/química , Águas Residuárias/microbiologia , Vitis/química , Purificação da Água/métodos , Porosidade , EletricidadeRESUMO
The field of nanotechnology continues to grow with the ongoing discovery and characterization of novel nanomaterials with unconventional size-dependent properties; however, the ability to apply modern manufacturing strategies for practical device design of these nanoscale structures is significantly limited by their small size. Although interconnection has been previously demonstrated between nanoscale components, such approaches often require the use of expensive oxidation-resistant noble metal materials and time-consuming or untargeted strategies for welded interconnection such as laser ablation or plasmonic resonance across randomly oriented component networks. In this work, a three-segment gold-nickel-gold nanowire structure is synthesized using templated electrodeposition and modified via monolayer-directed aqueous chemical reduction of tin solder selectively on the gold segments. This core/shell nanowire structure is capable of directed magnetic assembly tip-to-tip and along substrate pads in network orientation. Upon infrared heating in a flux vapor atmosphere, the solder payload melts and establishes robust and highly conductive wire-wire joints. The targeted solder deposition strategy has been applied to various other multi-segment gold/nickel nanowire configurations and other metallic systems to demonstrate the capability of the approach. This core/shell technique of pre-loading magnetically active nanowires with solder material simplifies the associated challenges of size-dependent component orientation in the manufacture of nanoscale electronic devices.
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BACKGROUND: It appears that tumour-infiltrating neoantigen-reactive CD8 + T (Neo T) cells are the primary driver of immune responses to gastrointestinal cancer in patients. However, the conventional method is very time-consuming and complex for identifying Neo T cells and their corresponding T cell receptors (TCRs). METHODS: By mapping neoantigen-reactive T cells from the single-cell transcriptomes of thousands of tumour-infiltrating lymphocytes, we developed a 26-gene machine learning model for the identification of neoantigen-reactive T cells. RESULTS: In both training and validation sets, the model performed admirably. We discovered that the majority of Neo T cells exhibited notable differences in the biological processes of amide-related signal pathways. The analysis of potential cell-to-cell interactions, in conjunction with spatial transcriptomic and multiplex immunohistochemistry data, has revealed that Neo T cells possess potent signalling molecules, including LTA, which can potentially engage with tumour cells within the tumour microenvironment, thereby exerting anti-tumour effects. By sequencing CD8 + T cells in tumour samples of patients undergoing neoadjuvant immunotherapy, we determined that the fraction of Neo T cells was significantly and positively linked with the clinical benefit and overall survival rate of patients. CONCLUSION: This method expedites the identification of neoantigen-reactive TCRs and the engineering of neoantigen-reactive T cells for therapy.
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Antígenos de Neoplasias , Linfócitos T CD8-Positivos , Neoplasias Gastrointestinais , Linfócitos do Interstício Tumoral , Aprendizado de Máquina , Análise de Célula Única , Humanos , Linfócitos T CD8-Positivos/imunologia , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Análise de Célula Única/métodos , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/genética , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , TranscriptomaRESUMO
At the early stages of drug development, the amount of drug materials is rather limited. In this case, viscosity measurement is often postponed to the later stages, where grams of proteins can be produced. Therefore, it is necessary to develop a viscometer capable of measuring the viscosity with high accuracy while requiring low sample volume. This study presents a novel viscosity measurement technique based on measuring the resonance frequency and motional resistance of a micropillar-enhanced acoustic wave (µPAW) device. The µPAW was developed by fabricating micropillars on the quartz crystal microbalance substrate in order to achieve ultra-high sensitivity, thanks to a unique coupling between the micropillar and the resonator. The experimental measurements demonstrated a nonlinear relationship between the density and viscosity of the fluid and the response of µPAW. A calibration correlation was developed using the response of µPAW in aqueous glycerol and sucrose solutions. The measurements were then extended using high-concentration BSA solutions as the model of protein solution. The main advantage of the µPAW device in this work over other viscometers is the ability to simultaneously measure solution viscosity and protein adsorption on the surface. This is a huge step forward in the development of sensing systems for the pharmaceutical industry, where real-time sensing of target biological proteins and measuring the viscosity of a solution is required.
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Nectin cell adhesion molecule 4 (nectin-4) is a transmembrane protein overexpressed on a variety of cancers and plays an important role in oncogenic and metastatic processes. The nectin-4-targeted antibody-drug conjugate enfortumab vedotin has been approved for treating locally advanced or metastatic urothelial cancer, but the efficacy in other types of cancer remains to be explored. The aim of this study was to evaluate the feasibility of nectin-4-targeted PET imaging with 68Ga-N188 as a noninvasive method to quantify membranous nectin-4 expression in multiple tumor types-an approach that may provide insight for patient stratification and treatment selection. Methods: Sixty-two patients with 16 types of cancer underwent head-to-head 68Ga-N188 and 18F-FDG PET/CT imaging for initial staging or detection of recurrence and metastases. Correlation between lesion SUVmax and nectin-4 expression determined by immunohistochemistry staining was analyzed in 36 of 62 patients. Results: The SUVmax of 68Ga-N188 had a positive correlation with membranous nectin-4 expression in the various tumor types tested (r = 0.458; P = 0.005), whereas no association was observed between the SUVmax and cytoplasmic nectin-4 expression. The detection rates for patient-based analysis of 68Ga-N188 and 18F-FDG PET/CT examinations were comparable (95.00% [57/60] vs. 93.33% [56/60]). In patients with pancreatic cancer, 68Ga-N188 exhibited a potential advantage for detecting residual or locally recurrent tumors; this advantage may assist in clinical decision-making. Conclusion: The correlation between nectin-4-targeted 68Ga-N188 PET imaging and membranous nectin-4 expression indicates the potential of 68Ga-N188 as an effective tool for selecting patients who may benefit from enfortumab vedotin treatment. The PET imaging results provided evidence to explore nectin-4-targeted therapy in a variety of tumors. 68Ga-N188 may improve the restaging of pancreatic cancer but requires further evaluation in a powered, prospective setting.
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Moléculas de Adesão Celular , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Moléculas de Adesão Celular/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Adulto , Anticorpos Monoclonais/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Idoso de 80 Anos ou mais , Pesquisa Translacional Biomédica , NectinasRESUMO
Tea saponins (TS), a natural biosurfactant extracted from tea trees, were co-ball milled with commercial micro zero-valent iron (mZVI) to produce TS modified mZVI (TS-BZVI) for efficient hexavalent chromium (Cr(VI)) removal. The findings demonstrated that TS-BZVI could nearly remove 100% of Cr(VI) within 2 h, which was 1.43 times higher than that by ball milled mZVI (BZVI) (70%). Kinetics analysis demonstrated a high degree of compatibility with the pseudo-second-order (PSO), revealing that TS-BZVI exhibited a 2.83 times faster Cr(VI) removal rate involved primarily chemisorption. Further, X-ray photoelectron spectroscopy (XPS) and X-ray absorption near edge structure (XANES) measurements indicated that the TS co-ball milling process improved the exposure of Fe(II) and Fe(0) on mZVI, which further promoted the Cr(VI) reduction process. Impressively, the introduction of TS increased the hydrophobicity of ZVI, effectively inhibiting the H2 evolution by 95%, thus improved electron selectivity for efficient Cr(VI) removal. Ultimately, after operating for 10 days, a simulated permeable reactive barrier (PRB) column experiment revealed that TS-BZVI had a higher Cr(VI) elimination efficiency than BZVI, indicating that TS-BZVI was promising for practical environment remediation.
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ABSTRACT: Dedifferentiated liposarcoma is an extremely rare and highly malignant tumor. We demonstrated a case of a 75-year-old man with significantly PSMA-avid and mildly FDG uptake-dedifferentiated liposarcoma in the retroperitoneal area. The double-tracer (PSMA and FDG) PET scans could further contribute to differential diagnosis and the following treatment strategy for patients who were suspected with prostate cancer metastases and other malignant tumors simultaneously.
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Fluordesoxiglucose F18 , Lipossarcoma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Próstata , Humanos , Masculino , Lipossarcoma/diagnóstico por imagem , Lipossarcoma/secundário , Idoso , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Imagem Multimodal , Metástase Neoplásica , Tomografia Computadorizada por Raios X , Antígenos de Superfície/metabolismo , Glutamato Carboxipeptidase II/metabolismoRESUMO
Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.
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Fator de Ligação a CCCTC , Diferenciação Celular , Interferon gama , Interleucina 22 , Interleucinas , Células Th1 , Animais , Fator de Ligação a CCCTC/metabolismo , Fator de Ligação a CCCTC/genética , Células Th1/imunologia , Camundongos , Diferenciação Celular/imunologia , Interferon gama/metabolismo , Sítios de Ligação , Interleucinas/metabolismo , Interleucinas/genética , Elementos Facilitadores Genéticos/genética , Camundongos Endogâmicos C57BL , Cromatina/metabolismo , Toxoplasmose/imunologia , Toxoplasmose/parasitologia , Toxoplasmose/genética , Regulação da Expressão Gênica , Toxoplasma/imunologia , Citocinas/metabolismo , Linhagem da Célula , Células Th17/imunologiaRESUMO
Immunogold, that is, gold nanoparticles (AuNPs) conjugated with biomolecules such as antibodies and peptides, have been widely used to construct sandwiched immunosensors for biodetection. Two main challenges in these immunoassays are difficulties in finding and validating a suitable antibody, and the nonspecific interaction between the substrate and immunogold, which lowers the detection sensitivity and even causes false results. To avoid these issues, we took advantage of the nonspecific interaction between AuNPs and capture antibodies and proposed a new sensing mechanism. That is, after the capture of analyte targets by the capture antibodies on the substrate, AuNPs of certain chemical functionality would preferably bind to the free capture antibodies. Consequently, the amount of deposited AuNPs will inversely depend on the concentration of the analytes. As a proof-of-concept, we designed a mass-based sensor where anti-IgG antibodies were coated on a quartz crystal microbalance substrate. After IgG was introduced, tannic acid-capped AuNPs were applied to bind with the free anti-IgG antibody molecules. A frequency change (Δf) of the quartz substrate was induced by the increased mass loading. To further amplify the loading mass, an Ag enhancer solution was added, and Ag growth was catalyzed by the bound AuNPs. The Δf response showed a concentration-dependent decrease when increasing IgG concentration with a detection limit of 2.6 ng/mL. This method relies on the nonspecific interaction between AuNPs and anti-IgG antibodies to realize sensitive detection of IgG and eliminates the use of detection antibodies. The concept is an alternative to many existing immunoassay technologies.
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Técnicas Biossensoriais , Ouro , Nanopartículas Metálicas , Ouro/química , Nanopartículas Metálicas/química , Imunoensaio/métodos , Técnicas Biossensoriais/métodos , Imunoglobulina G/imunologia , Imunoglobulina G/análise , Técnicas de Microbalança de Cristal de QuartzoRESUMO
Acute pancreatitis (AP) is among the most common hospital gastrointestinal diagnoses; understanding the mechanisms underlying the severity of AP is critical for development of new treatment options for this disease. Here, we evaluate the biological function of phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in AP pathogenesis in 2 independent genetically engineered mouse models of AP. PFKFB3 was elevated in AP and severe AP (SAP), and KO of Pfkfb3 abrogated the severity of alcoholic SAP (FAEE-SAP). Using a combination of genetic, pharmacological, and molecular studies, we defined the interaction of PFKFB3 with inositol 1,4,5-trisphosphate receptor (IP3R) as a key event mediating this phenomenon. Further analysis demonstrated that the interaction between PFKFB3 and IP3R promotes FAEE-SAP severity by altering intracellular calcium homeostasis in acinar cells. Together, our results support a PFKFB3-driven mechanism controlling AP pathobiology and define this enzyme as a therapeutic target to ameliorate the severity of this condition.
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Células Acinares , Cálcio , Receptores de Inositol 1,4,5-Trifosfato , Pancreatite , Fosfofrutoquinase-2 , Animais , Fosfofrutoquinase-2/metabolismo , Fosfofrutoquinase-2/genética , Camundongos , Pancreatite/metabolismo , Pancreatite/genética , Pancreatite/patologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Cálcio/metabolismo , Células Acinares/metabolismo , Células Acinares/patologia , Camundongos Knockout , Modelos Animais de Doenças , Índice de Gravidade de Doença , Masculino , Humanos , Sinalização do Cálcio/genéticaRESUMO
Single cell RNA sequencing (scRNA-seq), a powerful tool for studying the tumor microenvironment (TME), does not preserve/provide spatial information on tissue morphology and cellular interactions. To understand the crosstalk between diverse cellular components in proximity in the TME, we performed scRNA-seq coupled with spatial transcriptomic (ST) assay to profile 41,700 cells from three colorectal cancer (CRC) tumor-normal-blood pairs. Standalone scRNA-seq analyses revealed eight major cell populations, including B cells, T cells, Monocytes, NK cells, Epithelial cells, Fibroblasts, Mast cells, Endothelial cells. After the identification of malignant cells from epithelial cells, we observed seven subtypes of malignant cells that reflect heterogeneous status in tumor, including tumor_CAV1, tumor_ATF3_JUN | FOS, tumor_ZEB2, tumor_VIM, tumor_WSB1, tumor_LXN, and tumor_PGM1. By transferring the cellular annotations obtained by scRNA-seq to ST spots, we annotated four regions in a cryosection from CRC patients, including tumor, stroma, immune infiltration, and colon epithelium regions. Furthermore, we observed intensive intercellular interactions between stroma and tumor regions which were extremely proximal in the cryosection. In particular, one pair of ligands and receptors (C5AR1 and RPS19) was inferred to play key roles in the crosstalk of stroma and tumor regions. For the tumor region, a typical feature of TMSB4X-high expression was identified, which could be a potential marker of CRC. The stroma region was found to be characterized by VIM-high expression, suggesting it fostered a stromal niche in the TME. Collectively, single cell and spatial analysis in our study reveal the tumor heterogeneity and molecular interactions in CRC TME, which provides insights into the mechanisms underlying CRC progression and may contribute to the development of anticancer therapies targeting on non-tumor components, such as the extracellular matrix (ECM) in CRC. The typical genes we identified may facilitate to new molecular subtypes of CRC.
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Neoplasias Colorretais , Análise de Célula Única , Transcriptoma , Microambiente Tumoral , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Microambiente Tumoral/genética , Transcriptoma/genética , Regulação Neoplásica da Expressão Gênica , Heterogeneidade Genética , Perfilação da Expressão Gênica , Masculino , FemininoRESUMO
Conventional two-dimensional (2D) cell culture techniques may undergo modifications in the future, as life scientists have widely acknowledged the ability of three-dimensional (3D) in vitro culture systems to accurately simulate in vivo biology. In recent years, researchers have discovered that microgravity devices can address many challenges associated with 3D cell culture. Stem cells, being pluripotent cells, are regarded as a promising resource for regenerative medicine. Recent studies have demonstrated that 3D culture in microgravity devices can effectively guide stem cells towards differentiation and facilitate the formation of functional tissue, thereby exhibiting advantages within the field of tissue engineering and regenerative medicine. Furthermore, We delineate the impact of microgravity on the biological behavior of various types of stem cells, while elucidating the underlying mechanisms governing these alterations. These findings offer exciting prospects for diverse applications.