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The tumor microenvironment (TME) promotes metabolic reprogramming and dysfunction in immune cells. Here, we examined the impact of the TME on phospholipid metabolism in CD8+ T cells. In lung cancer, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were lower in intratumoral CD8+ T cells than in circulating CD8+ T cells. Intratumoral CD8+ T cells exhibited decreased expression of phospholipid phosphatase 1 (PLPP1), which catalyzes PE and PC synthesis. T cell-specific deletion of Plpp1 impaired antitumor immunity and promoted T cell death by ferroptosis. Unsaturated fatty acids in the TME stimulated ferroptosis of Plpp1-/- CD8+ T cells. Mechanistically, programmed death-1 (PD-1) signaling in CD8+ T cells induced GATA1 binding to the promoter region Plpp1 and thereby suppressed Plpp1 expression. PD-1 blockade increased Plpp1 expression and restored CD8+ T cell antitumor function but did not rescue dysfunction of Plpp1-/- CD8+ T cells. Thus, PD-1 signaling regulates phospholipid metabolism in CD8+ T cells, with therapeutic implications for immunotherapy.
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Linfocitos T CD8-positivos , Ferroptosis , Receptor de Muerte Celular Programada 1 , Transducción de Señal , Microambiente Tumoral , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Animales , Ratones , Transducción de Señal/inmunología , Ferroptosis/inmunología , Microambiente Tumoral/inmunología , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Monoéster Fosfórico Hidrolasas/metabolismo , Monoéster Fosfórico Hidrolasas/genética , Línea Celular TumoralRESUMEN
Ionic diodes with environmentally modulated ion-rectifying characteristics have attracted much attention and show great promise in the construction of smart devices with environmental adaptability. One immediate challenge is to integrate stimuli responsiveness and ion rectification into one single ionic diode, which requires a close cooperation of chemical principles and device technologies. Herein, an ionic diode based on a photoresponsive hydrogel with optically mediated ion-rectifying performances is introduced. Relying on the photoresponsive concentration of proton in the hydrogel, the ionic current rectification can be prominently enhanced upon ultraviolet (UV) irradiation. A maximum ionic current rectification ratio of the optically mediated ionic diode about 4 × 105 is achieved. Furthermore, the hydrogel-based diode can serve as an AND logic gate operated by UV light and voltage bias as two independent inputs. As a proof of concept, to use the optically mediated diode is achieved to modulate the feedback of a robot with logic behaviors. This work provides a novel and valuable strategy for designing functional hydrogel-based devices with the integration of stimuli-responsiveness and logic signal processing through chemical approaches.
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Mumps virus (MuV) is the etiological agent of mumps, a disease characterized by painful swelling of the parotid glands and often accompanied by severe complications. To understand the molecular mechanism of MuV infection, a functional analysis of the involved host factors is required. However, little is known about the host factors involved in MuV infection, especially those involved in the late stage of infection. Here, we identified 638 host proteins that have close proximity to MuV glycoproteins, which are a major component of the viral particles, by proximity labeling and examined comprehensive protein-protein interaction networks of the host proteins. From siRNA screening and immunoprecipitation results, we found that a SNARE subfamily protein, USE1, bound specifically to the MuV fusion (F) protein and was important for MuV propagation. In addition, USE1 plays a role in complete N-linked glycosylation and expression of the MuV F protein.
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Proteínas SNARE , Proteínas Virales de Fusión , Proteínas Virales de Fusión/genéticaRESUMEN
Newcastle disease virus (NDV) is the pathogen of a zoonosis that is primarily transmitted by poultry and has severe infectivity and a high fatality rate. Many studies have focused on the role of the NDV fusion (F) protein in the cell-cell membrane fusion process. However, little attention has been given to the heptad repeat region, HR4, which is located in the NDV F2 subunit. Here, site-directed mutants were constructed to study the function of the NDV F protein HR4 region and identify the key amino acids in this region. Nine conserved amino acids were substituted with alanine or the corresponding amino acid of other aligned paramyxoviruses. The desired mutants were examined for changes in fusogenic activity through three kinds of membrane fusion assays and expression and proteolysis through IFA, FACS and WB. The results showed that when conserved amino acids (L81, Y84, L88, L91, L92, P94, L95 and I99) were replaced with alanine, the fusogenic activity of the F protein was abolished, possibly because of failed protein expression not only on the cell surface but also inside cells. These data indicated that the conserved amino acids above in NDV F HR4 are critical for normal protein synthesis and expression, possibly for the stability of the F protein monomer, formation of trimer and conformational changes.
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Mutagénesis Sitio-Dirigida , Virus de la Enfermedad de Newcastle , Proteínas Virales de Fusión , Internalización del Virus , Virus de la Enfermedad de Newcastle/genética , Virus de la Enfermedad de Newcastle/metabolismo , Proteínas Virales de Fusión/genética , Proteínas Virales de Fusión/metabolismo , Animales , Sustitución de Aminoácidos , Línea Celular , Mutación , Proteolisis , Fusión de MembranaRESUMEN
A novel glow-type chemiluminescence (CL)-based nanosensing system was developed for sensitive and rapid point-of-care testing (POCT) of H2O2 in food. CuSe nanoparticles (CuSeNPs) have excellent peroxidase-like activity. After being modified with thiols of 4-mercaptophenylboronic acid (MBA) (CuSeNPs@MBA), luminol can be catalyzed to produce long-lasting CL in the presence of H2O2. The possible reason for the long-lasting glow-type CL behavior was explored. Under the optimized condition, H2O2 can be sensitively detected with improved repeatability. The limit of detection is as low as 0.30 µM. To meet the requirement of in situ and outside of laboratory detection, a 3D-printed portable device was designed which can eliminate the environmental interference to improve detection accuracy. The developed multifunctional platform also has the advantages of simple operation and low cost, suggesting its great potential for applications in food and agricultural fields.
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Peróxido de Hidrógeno , Límite de Detección , Mediciones Luminiscentes , Luminol , Pruebas en el Punto de Atención , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/análisis , Mediciones Luminiscentes/métodos , Mediciones Luminiscentes/instrumentación , Luminol/química , Ácidos Borónicos/química , Nanopartículas/química , Nanopartículas del Metal/química , Compuestos de SulfhidriloRESUMEN
This study explores the impact of life course socioeconomic status (SES) and childhood trauma on depressive symptoms in Chinese middle-aged and older adults, while also examining the role of chronic diseases and implications for social work practice. Using data from 9,942 participants, structural equation was established to investigate these relationships. Results reveals that low childhood SES positively affects depressive symptoms through low SES in mid-to-late life (std. ß = 0.168, p < .001), and domestic child abuse negatively impacts depressive symptoms through low SES in mid-to-late life (std. ß=-0.020, p < .001). Additionally, experiencing peer bullying is directly associated with depressive symptoms (std. ß = 0.145, p < .001). Exposure to domestic violence is directly related to depressive symptoms (std. ß = 0.078, p < .001) and indirectly leads to more severe depressive symptoms through chronic disease (std. ß = 0.023, p < .001). Social workers in healthcare settings can utilize these findings to better understand risk factors for depression and provide trauma-informed care and economic assistance across the life course. Additional training for social workers on the lasting impacts of childhood adversity is warranted. By intervening at both individual and policy levels, social work practitioners can help break cycles of poverty and poor health stemming from childhood.
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The functional state of CD8+ T cells determines the therapeutic efficacy of PD-1 blockade antibodies in tumors. Amino acids are key nutrients for maintaining T cell antitumor immunity. In this study, we used samples from lung cancer patients treated with PD-1 blockade antibodies to assay the amino acids in their serum by mass spectrometry. We found that lung cancer patients with high serum taurine levels generally responded to PD-1 blockade antibody therapy, in parallel with the secretion of high levels of cytotoxic cytokines (IFN-γ and TNF-α). CD8+ T cells cultured with exogenous taurine exhibited decreased apoptosis, enhanced proliferation, and increased secretion of cytotoxic cytokines. High SLC6A6 expression in CD8+ T cells was positively associated with an effector T cell signature. SLC6A6 knockdown limited the function and proliferation of CD8+ T cells. RNA sequencing revealed that SLC6A6 knockdown altered the calcium signaling pathway, oxidative phosphorylation, and T cell receptor signaling in CD8+ T cells. Furthermore, taurine enhanced T cell proliferation and function in vitro by stimulation of PLCγ1-mediated calcium and MAPK signaling. Taurine plus immune checkpoint blockade antibody significantly attenuated tumor growth and markedly improved the function and proliferation of CD8+ T cells in a mouse tumor model. Thus, our findings indicate that taurine is an important driver for improving CD8+ T cell immune responses and could serve as a potential therapeutic agent for cancer patients.
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Antineoplásicos , Neoplasias Pulmonares , Animales , Ratones , Linfocitos T CD8-positivos , Receptor de Muerte Celular Programada 1 , Taurina/farmacología , Taurina/metabolismo , Antineoplásicos/farmacología , Citocinas/metabolismo , Anticuerpos Monoclonales/farmacología , Modelos Animales de Enfermedad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Aminoácidos/metabolismo , Aminoácidos/farmacología , Microambiente TumoralRESUMEN
The capacity to self-detect and locate damage to underwater infrastructure in emergencies is vital, as materials and technologies that securely facilitate energy and information transmission are crucial in several fields. Herein, the development of a multifunctional supramolecular ionogel (SIG) and SIG-based devices for use in detecting and locating damage to underwater infrastructure is reported. The SIG is fabricated via the single-step photoinitiated copolymerization of hydroxy and fluorinated monomers in a fluorinated ionic liquid. Hydrogen-bond/ion-dipole-interaction synergy ensures that the SIG is highly ionically conductive and extremely mechanically strong, with underwater self-healing and adhesion properties. It can be used as an underwater ionic cable to provide reporting signals via changes in strain; furthermore, SIG-based devices can be fixed to underwater infrastructure to locate damage via resistance monitoring. The SIG can also be attached to the human body for use in underwater communication, thereby safeguarding maintenance personnel while repairing underwater infrastructure. This study provides a novel pathway for developing supramolecular materials and devices.
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Non-line-of-sight (NLOS) technology has been rapidly developed in recent years, allowing us to visualize or localize hidden objects by analyzing the returned photons, which is expected to be applied to autonomous driving, field rescue, etc. Due to the laser attenuation and multiple reflections, it is inevitable for future applications to separate the returned extremely weak signal from noise. However, current methods find signals by direct accumulation, causing noise to be accumulated simultaneously and inability of extracting weak targets. Herein, we explore two denoising methods without accumulation to detect the weak target echoes, relying on the temporal correlation feature. In one aspect, we propose a dual-detector method based on software operations to improve the detection ability for weak signals. In the other aspect, we introduce the pipeline method for NLOS target tracking in sequential histograms. Ultimately, we experimentally demonstrated these two methods and extracted the motion trajectory of the hidden object. The results may be useful for practical applications in the future.
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BACKGROUND: Coronavirus disease 2019 (COVID-19) is a rapidly developing and sometimes lethal pulmonary disease. Accurately predicting COVID-19 mortality will facilitate optimal patient treatment and medical resource deployment, but the clinical practice still needs to address it. Both complete blood counts and cytokine levels were observed to be modified by COVID-19 infection. This study aimed to use inexpensive and easily accessible complete blood counts to build an accurate COVID-19 mortality prediction model. The cytokine fluctuations reflect the inflammatory storm induced by COVID-19, but their levels are not as commonly accessible as complete blood counts. Therefore, this study explored the possibility of predicting cytokine levels based on complete blood counts. METHODS: We used complete blood counts to predict cytokine levels. The predictive model includes an autoencoder, principal component analysis, and linear regression models. We used classifiers such as support vector machine and feature selection models such as adaptive boost to predict the mortality of COVID-19 patients. RESULTS: Complete blood counts and original cytokine levels reached the COVID-19 mortality classification area under the curve (AUC) values of 0.9678 and 0.9111, respectively, and the cytokine levels predicted by the feature set alone reached the classification AUC value of 0.9844. The predicted cytokine levels were more significantly associated with COVID-19 mortality than the original values. CONCLUSIONS: Integrating the predicted cytokine levels and complete blood counts improved a COVID-19 mortality prediction model using complete blood counts only. Both the cytokine level prediction models and the COVID-19 mortality prediction models are publicly available at http://www.healthinformaticslab.org/supp/resources.php .
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COVID-19 , Humanos , Área Bajo la Curva , Citocinas , Modelos Lineales , Análisis de Componente PrincipalRESUMEN
Photothermal therapy has shown great promise for cancer treatment and second near-infrared (NIR-II) -absorbing particles could further improve its precision and applicability due to its superior penetration depth and new imaging ability. Herein, high NIR-II-absorbing polymer particles were prepared by using soluble isobutyl-substituted diammonium borates (P-IDI). The P-IDI showed stronger absorption at 1000-1100 nm, which exhibited excellent photostability, strong photoacoustic imaging ability and high photothermal conversion efficiency (34.7%). The investigations in vitro and in vivo demonstrated that the excellent photothermal effect facilitated complete tumor ablation and also triggered immunogenic cell death in activation of the immune response. The high solubility and excellent photothermal conversion ability demonstrated that polymer IDI particles were promising theranostic agents for treatment of tumors with minor side effects.
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Nanopartículas , Neoplasias , Técnicas Fotoacústicas , Humanos , Fototerapia/métodos , Línea Celular Tumoral , Terapia Fototérmica , Polímeros , Muerte Celular Inmunogénica , Neoplasias/tratamiento farmacológico , Técnicas Fotoacústicas/métodosRESUMEN
Objective: Epilepsy may cause chronic cognitive impairment by disturbing sleep plasticity. Sleep spindles play a crucial role in sleep maintenance and brain plasticity. This study explored the relationship between cognition and spindle characteristics in adult epilepsy. Methods: Participants underwent one-night sleep electroencephalogram recording and neuropsychological tests on the same day. Spindle characteristics during N2 sleep were extracted using a learning-based system for sleep staging and an automated spindle detection algorithm. We investigated the difference between cognitive subgroups in spindle characteristics. Multiple linear regressions were applied to analyze associations between cognition and spindle characteristics. Results: Compared with no/mild cognitive impairment, epilepsy patients who developed severe cognitive impairment had lower sleep spindle density, the differences mainly distributed in central, occipital, parietal, middle temporal, and posterior temporal (P < 0.05), and had relatively long spindle duration in occipital and posterior temporal (P < 0.05). Mini-Mental State Examination (MMSE) was associated with spindle density (pars triangularis of the inferior frontal gyrus (IFGtri): ß = 0.253, P = 0.015, and P.adjust = 0.074) and spindle duration (IFGtri: ß = -0.262, P = 0.004, and P.adjust = 0.030). Montreal Cognitive Assessment (MoCA) was associated with spindle duration (IFGtri: ß = -0.246, P = 0.010, and P.adjust = 0.055). Executive Index Score (MoCA-EIS) was associated with spindle density (IFGtri: ß = 0.238, P = 0.019, and P.adjust = 0.087; parietal: ß = 0.227, P = 0.017, and P.adjust = 0.082) and spindle duration (parietal: ß = -0.230, P = 0.013, and P.adjust = 0.065). Attention Index Score (MoCA-AIS) was associated with spindle duration (IFGtri: ß = -0.233, P = 0.017, and P.adjust = 0.081). Conclusions: The findings suggested that the altered spindle activity in epilepsy with severe cognitive impairment, the associations between the global cognitive status of adult epilepsy and spindle characteristics, and specific cognitive domains may relate to spindle characteristics in particular brain regions.
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Disfunción Cognitiva , Epilepsia , Humanos , Adulto , Cognición , Encéfalo , Sueño , Disfunción Cognitiva/psicología , Epilepsia/complicaciones , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: Radical nephrectomy with thrombectomy in patients with renal cell carcinoma (RCC) and level IV thrombus extending to the right atrium (RA) offers improved survival. However, this procedure is associated with significant perioperative morbidity and mortality. In this report, we describe a novel milking technique for patients with RA tumor thrombus using abdominal access, which does not require diaphragmic incision, sternotomy, right atriotomy, or cardiopulmonary bypass (CPB). METHODS: Between January 2019 and January 2022, four patients underwent resection of renal cell carcinoma extending into RA by a milking technique developed to avoid diaphragmic incision, sternotomy, or CPB. Patient characteristics, perioperative data, pathological features, and survival were evaluated. RESULTS: Complete resection was successful through pure transabdominal access without diaphragmic incision, sternotomy, or CPB in all patients. CONCLUSION: We conclude that radical nephrectomy and thrombectomy in optimized cases with renal cell carcinoma extending into RA can be safely and effectively performed without diaphragmic incision, sternotomy, or CPB, avoiding serious perioperative complications while providing acceptable oncological outcomes.
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Carcinoma de Células Renales , Neoplasias Renales , Trombosis , Humanos , Carcinoma de Células Renales/cirugía , Puente Cardiopulmonar , Esternotomía , Trombectomía , Trombosis/etiología , Trombosis/cirugía , Neoplasias Renales/cirugíaRESUMEN
The rapid identification and antibiotic susceptibility testing (AST) of bacteria would help us to accurately identify the infectious sources as well as guide the use of antibiotics, which are crucial for improving the survival rate and antimicrobial resistance. Herein, a colorimetric sensor array for bacteria fingerprinting was constructed with d-amino acid (d-AA)-modified gold nanoparticles (AuNPs) as probes (Au/d-AA). Bacteria can metabolize the d-AA, triggering the aggregation of AuNPs. Making use of different metabolic capabilities of bacteria toward different d-AA, eight kinds of bacteria including antibiotic-resistant bacteria and strains of the same bacterial species are successfully differentiated via learning the response patterns. Meanwhile, the sensor array also performs well in quantitative analysis of single bacterium and differentiation of bacteria mixtures. More interestingly, a rapid colorimetric AST approach has been developed based on the Au/d-AA nanoprobes by monitoring the d-AA metabolic activity of bacteria toward various antibiotic treatments. In this regard, the outlined work here would promote clinical practicability and facilitate antibiotic stewardship.
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Colorimetría , Nanopartículas del Metal , Aminoácidos , Antibacterianos/farmacología , Bacterias , Oro/química , Nanopartículas del Metal/química , Pruebas de Sensibilidad MicrobianaRESUMEN
Bacterial infections seriously threaten human health and also bring huge financial burden. It is critical to construct multifunctional platforms for effectively inactivating bacteria right after point-of-care testing (POCT). Chemiluminescence (CL) bioassays are considered as powerful candidates for POCT as they are free from using an excitation light source, while the flash-type emission limits their further application. Herein, a CL system with long, persistent, and intensive intensity was constructed based on the peroxidase-like property of 4-mercaptophenylboronic acid (MPBA)-functionalized CuSe nanoprobes (CuSeNPs@MPBA), which improved the detection accuracy and sensitivity. By further integrating a smartphone as an analyzer, quantitative POCT of bacteria was realized with high sensitivity. The limit of detection was as low as 1.25 and 1.01 cfu mL-1 for Staphylococcus aureus and Escherichia coli detection, respectively. Specifically, bacteria can be eliminated with high efficiency due to excellent photothermal property of CuSeNPs@MPBA. The developed multifunctional platform also has advantages of simple operation with low cost, suggesting its high potential for use in food safety, environment monitoring, and clinical applications.
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Luminiscencia , Infecciones Estafilocócicas , Humanos , Mediciones Luminiscentes , Pruebas en el Punto de Atención , Staphylococcus aureusRESUMEN
Effective identification and real-time inactivation of pathogenic microorganisms is of great importance for preventing their infection and spread in public health, especially considering the huge threat of coronavirus disease 2019 (COVID-19). Herein, a novel multifunctional colorimetric sensor array with 3,3',5,5'-tetramethylbenzidine (TMB) as a single probe has been constructed. TMB can be efficiently oxidized to generate oxidized TMB (oxTMB) by HAuCl4, which displays four characteristic absorption peaks. The presence of different bacteria could inhibit the oxidation reaction and cause diverse changes in the intensity of the four characteristic peaks. Based on linear discriminant analysis (LDA), not only are nine kinds of pathogenic bacteria successfully identified, but also drug-resistant strains are distinguished from sensitive ones. Interestingly, HAuCl4 can be employed as a germicidal agent to inactivate bacteria during the identification and avoid accessional bacterial contaminations. The developed strategy provides a new and simple avenue for bacterial identification and elimination to effectively protect the public from bacterial contamination.
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COVID-19 , Colorimetría , Bacterias , COVID-19/prevención & control , Humanos , Oxidación-ReducciónRESUMEN
Dehydrochlorination is one of the main (thus far discovered) processes for aerobic microbial transformation of hexachlorocyclohexane (HCH) which is mainly catalyzed by LinA enzymes. In order to gain a better understanding of the reaction mechanisms, multi-element compound-specific stable isotope analysis was applied for evaluating α- and γ-HCH transformations catalyzed by LinA1 and LinA2 enzymes. The isotopic fractionation (εE) values for particular elements of (+)α-HCH (εC = -10.8 ± 1.0, εCl = -4.2 ± 0.5, εH = -154 ± 16) were distinct from the values for (-)α-HCH (εC = -4.1 ± 0.7, εCl = -1.6 ± 0.2, εH = -68 ± 10), whereas the dual-isotope fractionation patterns were almost identical for both enantiomers (ΛC-Cl = 2.4 ± 0.4 and 2.5 ± 0.2, ΛH-C = 12.9 ± 2.4 and 14.9 ± 1.1). The εE of γ-HCH transformation by LinA1 and LinA2 were -7.8 ± 1.0 and -7.5 ± 0.8 (εC), -2.7 ± 0.3 and -2.5 ± 0.4 (εCl), -170 ± 25 and -150 ± 13 (εH), respectively. Similar ΛC-Cl values (2.7 ± 0.2 and 2.9 ± 0.2) were observed as well as similar ΛH-C values (20.1 ± 2.0 and 18.4 ± 1.9), indicating a similar reaction mechanism by both enzymes during γ-HCH transformation. This is the first data set on 3D isotope fractionation of α- and γ-HCH enzymatic dehydrochlorination, which gave a more precise characterization of the bond cleavages, highlighting the potential of multi-element compound-specific stable isotope analysis to characterize different transformation processes (e.g., dehydrochlorination and reductive dehalogenation).
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Hexaclorociclohexano , Isótopos , Hexaclorociclohexano/química , Isomerismo , Estereoisomerismo , Isótopos de Carbono , Biodegradación AmbientalRESUMEN
In view of the high toxicity and widespread availability, it is of great importance to develop accurate, sensitive, and convenient assays for fluoride ion (F-) detection. Herein, a ratiometric fluorescent system is established for point-of-care testing (POCT) of F- with a smartphone as analyzer. The sensing system of calcein-QDs-Eu3+ contains two fluorescent probes of calcein (green emission) and ZnCdSe/ZnS QDs (red emission). The sensing system only presents red emission in that the calcein emission is quenched due to the combination between calcein and Eu3+. When F- is introduced, the fluorescence of calcein is recovered due to the stronger interaction between F- and Eu3+, which changes the emission from red to green. The ratiometric strategy offers an obvious fluorescence color change of the system, which eliminates interference and improves the detection accuracy. Specifically, the sensing system has excellent selectivity in that Eu3+ is more inclined to bind with F- rather than other anions. The developed assay was further used to prepare a test paper and hydrogel for POCT. To further improve the detection sensitivity and realize quantitative analysis, a smartphone installed with a color scan app is integrated as signal reader and analyzer, which is used for POCT of F- in real samples, showing great application potential in environmental protection and food safety evaluation.
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Fluoruros , Teléfono Inteligente , Colorantes Fluorescentes , Flúor , Pruebas en el Punto de AtenciónRESUMEN
BACKGROUND: Different from Fe ions in Fenton reaction, Mn ions can function both as catalyst for chemodynamic therapy and immune adjuvant for antitumor immune responses. In Mn-mediated Fenton-like reaction, bicarbonate ([Formula: see text]), as the most important component to amplify therapeutic effects, must be present, however, intracellular [Formula: see text] is strictly limited because of the tight control by live cells. RESULTS: Herein, Stimuli-responsive manganese carbonate-indocyanine green complexes (MnCO3-ICG) were designed for intracellular marriage of bicarbonate and Mn ions as "immune ion reactors" to regulate intracellular redox homeostasis and antitumor immune responses. Under the tumor acidic environment, the biodegradable complex can release "ion reactors" of Mn2+ and [Formula: see text], and ICG in the cytoplasm. The suddenly increased [Formula: see text] in situ inside the cells regulate intracellular pH, and accelerate the generation of hydroxyl radicals for the oxidative stress damage of tumors cells because [Formula: see text] play a critical role to catalyze Mn-mediated Fenton-like reaction. Investigations in vitro and in vivo prove that the both CDT and phototherapy combined with Mn2+-enhanced immunotherapy effectively suppress tumor growth and realize complete tumor elimination. CONCLUSIONS: The combination therapy strategy with the help of novel immune adjuvants would produce an enhanced immune response, and be used for the treatment of deep tumors in situ.
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Bicarbonatos , Neoplasias , Bicarbonatos/uso terapéutico , Línea Celular Tumoral , Homeostasis , Humanos , Inmunidad , Neoplasias/tratamiento farmacológico , Oxidación-ReducciónRESUMEN
BACKGROUND: We explored the therapeutic effects of Adipose-derived mesenchymal stem cells (ADMSCs) and Synovial-derived mesenchymal stem cells (SDMSCs) on osteoarthritis (OA). METHODS: SDMSCs and ADMSCs were co-cultured with chondrocytes and stimulated with interleukin (IL)-1ß. An OA model was established on rats by intra-articular injection with ADMSCs and SDMSCs. After 8 weeks, the joint diameter difference was detected, and histological staining was used to observe the pathological changes in cartilage tissue. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expressions of IL-6, tumor necrosis factor (TNF)-α and IL-1ß in joint fluid. The expressions of COL2A1, Aggrecan, Matrix metalloproteinase (MMP)-13, SOX9, IL-6, TNF-α and IL-1ß were detected by qRT-PCR and Western blotting in cartilage tissue. Reactive oxygen species (ROS) content in cells and cartilage tissues was detected by ROS kit. RESULTS: SDMSCs and ADMSCs co-cultured with chondrocytes could reduce MMP-13 expression, increase the expressions of COL2A1, Aggrecan and SOX9, as well as reverse the effects of IL-1ß on promoting ROS content and inflammatory factors levels. After the OA model was established, the injection of ADMSCs and SDMSCs reduced the differences in joint diameter and tissue lesions in OA rats. The OA model led to increased levels of IL-6, TNF-α and IL-1ß in joint fluid and cartilage tissue, while the injection of ADMSCs and SDMSCs inhibited the inflammatory factor levels in OA rats, and increased the expressions of COL2A1, Aggrecan and SOX9 in OA rats. CONCLUSION: ADMSCs and SDMSCs improve osteoarthritis in rats by reducing chondrocyte ROS and inhibiting inflammatory response.