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Enabling and constraining immune activation is of fundamental importance in maintaining cellular homeostasis. Depleting BAK1 and SERK4, the co-receptors of multiple pattern recognition receptors (PRRs), abolishes pattern-triggered immunity but triggers intracellular NOD-like receptor (NLR)-mediated autoimmunity with an elusive mechanism. By deploying RNAi-based genetic screens in Arabidopsis, we identified BAK-TO-LIFE 2 (BTL2), an uncharacterized receptor kinase, sensing BAK1/SERK4 integrity. BTL2 induces autoimmunity through activating Ca2+ channel CNGC20 in a kinase-dependent manner when BAK1/SERK4 are perturbed. To compensate for BAK1 deficiency, BTL2 complexes with multiple phytocytokine receptors, leading to potent phytocytokine responses mediated by helper NLR ADR1 family immune receptors, suggesting phytocytokine signaling as a molecular link connecting PRR- and NLR-mediated immunity. Remarkably, BAK1 constrains BTL2 activation via specific phosphorylation to maintain cellular integrity. Thus, BTL2 serves as a surveillance rheostat sensing the perturbation of BAK1/SERK4 immune co-receptors in promoting NLR-mediated phytocytokine signaling to ensure plant immunity.
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Arabidopsis , Inmunidad de la Planta , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas/genética , Receptores de Reconocimiento de Patrones , Transducción de SeñalRESUMEN
Near-infrared (NIR) luminescent lanthanide materials hold great promise for bioanalysis, as they have anti-interference properties. The approach of efficient luminescence is sensitization through a reasonable chromophore to overcome the obstacle of the aqueous phase. The involvement of the surfactant motif is an innovative strategy to arrange the amphiphilic groups to be regularly distributed near the polymer to form a closed sensitized space. Herein, a lanthanide polymer (TCPP-PEI70K-FITC@Yb/SDBS) is designed in which the meso-tetra(4-carboxyphenyl)porphine (TCPP) ligand serves as both a sensitizer and photocatalytic switch. The surfactant sodium dodecyl benzenesulfonate (SDBS) wraps the photosensitive polymers to form a hydrophobic layer, which augments the light-harvesting ability and expedites its photocatalysis. TCPP-PEI70K-FITC@Yb/SDBS is subsequently applied as an amplified photocatalysis toolbox for universally regulating the generation of reactive oxygen species (ROS). Boosting 3,3',5,5'-tetramethylbenzidine (TMB) oxidation to produce blue products, a dual-mode biosensor is fabricated for improving the diagnosis of programmed death ligand-1-positive (PDL1) cancer exosomes. Exosomes were captured by Fe3O4 modified by the PDL1 aptamer, enabling replacement of alkaline phosphatase (ALP)-labeled multiple hybridized chains; then, the isolated ALP triggered a hydrolysis reaction to block the generation of oxTMB. Detection sensitivity improves by 1 order of magnitude through SDBS modulation, down to 104 particles/mL. The sensor performed well clinically in distinguishing cancer patients from healthy individuals, expanding physiological applications of near-infrared lanthanide luminescence.
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Elementos de la Serie de los Lantanoides , Luz , Polímeros , Humanos , Elementos de la Serie de los Lantanoides/química , Polímeros/química , Catálisis , Exosomas/química , Exosomas/metabolismo , Rayos Infrarrojos , Neoplasias/diagnóstico , Procesos Fotoquímicos , Técnicas Biosensibles , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Designing lanthanide luminescence lifetime sensors in the second near-infrared (NIR-II) window holds great potentials for physiological studies. However, the single lifetime signal is confined to one or two orders of magnitude of signal variation, which limits the sensitivity of lifetime probes. In this study, a lifetime cascade system, i.e., ZGO:Mn, Eu-DNA-1/TCPP-PEI70K@Yb-AptEpCAM, with a variety of signals (τm, τn, τµ, τm/τn and τm/τµ) is constructed for exosome identification using time-domain multiplexing. The sensitized ligand TCPP acts as both target-modulated switch and a bridge for connecting long lifetime ZGO:Mn, Eu-DNA-1 emitter to lanthanide Yb3+. This drives successive dual-path energy transfer and forms two D(donor)-A(acceptor) pairs. The lifetime variation is dominantly modulated by arranging TCPP as energy intermediate relay to covert milliseconds to nanoseconds to microseconds. It enables a broad lifetime range of six orders of magnitude. The presence of exosome specifically recognizes aptamers on TCPP-PEI70K@Yb-AptEpCAM to impede D-A pairs and reverse multiplexed response signals of the lifetime cascade system. The ratio lifetime signals τm/τn and τm/τµ achieve prominent exosome quantification and exosome type differentiation attributed to signal amplification. The cascade system relying on lifetime criteria can realize precise quantization and provide an effective strategy for subsequent physiological study.
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Exosomas , Elementos de la Serie de los Lantanoides , Elementos de la Serie de los Lantanoides/química , Exosomas/metabolismo , Exosomas/química , Humanos , Transferencia de Energía , Neoplasias/metabolismoRESUMEN
Previous studies did not provide substantial evidence for long-term immune persistence after the hepatitis B vaccine (HepB) in preterm birth (PTB) children. Consequently, there is ongoing controversy surrounding the booster immunization strategy for these children. Therefore, we conducted a retrospective cohort study to evaluate the disparities in immune persistence between PTB children and full-term children. A total of 1027 participants were enrolled in this study, including 505 PTB children in the exposure group and 522 full-term children in the control group. The negative rate of hepatitis B surface antibody (HBsAb) in the PTB group was significantly lower than that in the control group (47.9% vs. 41.4%, p = .035). The risk of HBsAb-negative in the exposure group was 1.5 times higher than that in the control group (adjusted odds ratio [aOR] = 1.5, 95% confidence interval [CI]: 1.1-2.0). The geometric mean concentration (GMC) of HBsAb was much lower for participants in the exposure group compared to participants in the control group (9.3 vs. 12.4 mIU/mL, p = .029). Subgroup analysis showed that the very preterm infants (gestational age <32 weeks) and the preterm low birth weight infants (birth weight <2000 g) had relatively low GMC levels of 3.2 mIU/mL (95% CI: 0.9-11.1) and 7.9 mIU/mL (95% CI: 4.2-14.8), respectively. Our findings demonstrated that PTB had a significant impact on the long-term persistence of HBsAb after HepB vaccination. The very preterm infants (gestational age <32 weeks) and the preterm low birth weight infants (birth weight <2000 g) may be special populations that should be given priority for HepB booster vaccination.
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Hepatitis B , Fenilbutiratos , Nacimiento Prematuro , Niño , Femenino , Humanos , Lactante , Recién Nacido , Peso al Nacer , Estudios de Seguimiento , Hepatitis B/epidemiología , Hepatitis B/prevención & control , Anticuerpos contra la Hepatitis B , Antígenos de Superficie de la Hepatitis B , Vacunas contra Hepatitis B , Recien Nacido Prematuro , Nacimiento Prematuro/epidemiología , Estudios Retrospectivos , VacunaciónRESUMEN
A reduced graphene oxide/molybdenum selenosulfide (rGO/MoSSe) heterojunction was synthesized, and a molecularly imprinted photoelectrochemical sensor for the detection of chlortetracycline was prepared. MoSSe was grown in situ on rGO by a hydrothermal method to form an rGO/MoSSe heterojunction, which acts as the sensitive film of the sensor. Since rGO can promote electron transfer and effectively inhibit electron-hole recombination, it effectively reduces the recombination probability of electrons and holes and improves the photoelectric efficiency, thus enhancing the detection sensitivity of the PEC sensor. The rGO/MoSSe was immobilized on an FTO electrode, and molecularly imprinted polymers (MIPs) were prepared by electropolymerization on the rGO/MoSSe-modified FTO electrode with chlortetracycline as the template molecule and o-phenylenediamine as the functional monomer, so as to construct a molecularly imprinted photoelectrochemical (MIP-PEC) sensor. The determination of chlortetracycline was realized by the strategy of a "gate-controlled effect", and the detection range of the chlortetracycline concentration was 5.0 × 10-13-5 × 10-9 mol L-1 with a detection limit of 1.57 × 10-13 mol L-1. The sensor has been applied to the determination of chlortetracycline in animal-derived food samples.
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Clortetraciclina , Grafito , Impresión Molecular , Animales , Molibdeno , Polímeros/química , Límite de Detección , Electrodos , Impresión Molecular/métodos , Técnicas Electroquímicas/métodosRESUMEN
Placental DNA methylation (DNAm) may be a potential mechanism underlying the effects of prenatal bisphenol analogues (BPs) exposure on reproductive health. Based on the Shanghai-Minhang Birth Cohort Study (S-MBCS), this study investigated associations of placental DNAm at reproduction-related genes with prenatal BPs exposure and children's digit ratios at age 4 using multiple linear regression models, and mediation analysis was further used to examine the mediating role of placental DNAm in the associations between prenatal BPs exposure and digit ratios among 345 mother-child pairs. Prenatal exposure to bisphenol A (BPA) was associated with hypermethylation at Protocadherin 8 (PCDH8), RBMX Like 2 (RBMXL2), and Sperm Acrosome Associated 1 (SPACA1), while bisphenol F (BPF) exposure was associated with higher methylation levels of Fibroblast Growth Factor 13 (FGF13). Consistent patterns were found in associations between higher DNAm at the 4 genes and increased digit ratios. Further mediation analysis showed that about 15% of the effect of BPF exposure on increased digit ratios was mediated by placental FGF13 methylation. In conclusion, the altered placental DNAm status might be a mediator underlying the feminizing effect of prenatal BPs exposure.
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Metilación de ADN , Fenoles , Placenta , Humanos , Femenino , Embarazo , Placenta/efectos de los fármacos , Placenta/metabolismo , Fenoles/toxicidad , Estudios de Cohortes , Efectos Tardíos de la Exposición Prenatal , Masculino , Compuestos de Bencidrilo , Cohorte de Nacimiento , Reproducción/efectos de los fármacos , Exposición Materna , Adulto , Dedos/anatomía & histología , PreescolarRESUMEN
China is the largest global orchard distribution area, where high fertilization rates, complex terrain, and uncertainties associated with future climate change present challenges in managing non-point source pollution (NPSP) in orchard-dominant growing areas (ODGA). Given the complex processes of climate, hydrology, and soil nutrient loss, this study utilized an enhanced Soil and Water Assessment Tool model (SWAT-CO2) to investigate the impact of future climate on NPSP in ODGA in a coastal basin of North China. Our investigation focused on climate-induced variations in hydrology, nitrogen (N), and phosphorus (P) losses in soil, considering three Coupled Model Intercomparison Project phase 6 (CMIP6) climate scenarios: SSP1-2.6, SSP2-4.5, and SSP5-8.5. Research results indicated that continuous changes in CO2 levels significantly influenced evapotranspiration (ET) and water yield in ODGA. Influenced by sandy soils, nitrate leaching through percolation was the principal pathway for N loss in the ODGA. Surface runoff was identified as the primary pathway for P loss. Compared to the reference period (1971-2000), under three future climate scenarios, the increase in precipitation of ODGA ranged from 15% to 28%, while the growth rates of P loss and surface runoff were the most significant, both exceeding 120%. Orchards in the northwest basin proved susceptible to nitrate leaching, while others were more sensitive to N and P losses via surface runoff. Implementing targeted strategies, such as augmenting organic fertilizer usage and constructing terraced fields, based on ODGA's response characteristics to future climate, could effectively improve the basin's environment.
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Cambio Climático , Contaminación Difusa , Fósforo , China , Fósforo/análisis , Contaminación Difusa/prevención & control , Contaminación Difusa/análisis , Nitrógeno/análisis , Suelo/química , Agricultura/métodos , Monitoreo del Ambiente/métodos , Modelos TeóricosRESUMEN
INTRODUCTION: This study aimed to evaluate the predictive value of the low-frequency/high-frequency (LF/HF) ratio in all causes of death and hospitalizations in maintenance hemodialysis (MHD) patients. METHODS: This is a single-center prospective study with a 48-h electrocardiograph (ECG) recording. A total of 110 patients were enrolled in the study from October 1, 2021, to September 30, 2022. ECG recordings started before initiation of the hemodialysis (HD) session and lasted for 48 h, covering the intra- as well as inter-HD period. We divided our participants into two groups based on the median value of LF/HF, one of the frequency domain parameters of heart rate variability (HRV). Patients with LF/HF <1.33 were categorized as group A and those with LF/HF ≥1.33 were group B. The endpoint of the study was a composite event of death or hospitalization. We followed all patients until the composite endpoint or the end of the study on February 28, 2023. Multivariate Cox regression was used to assess the adjusted effect of LF/HF on the composite endpoint. RESULTS: Patients in group A were older and the number of patients with diabetes was more than that of group B. With regards to the laboratory data, group A had lower serum creatinine and uric acid and higher ferritin and NT-ProBNP. In the index HD session, systolic blood pressure was higher but diastolic blood pressure was significantly lower in group A. During the median follow-up period of 8.8 (7.6-9.8) months, 27 hospitalizations and 10 deaths were documented. Increased LF/HF ratio was an independent protective factor of composite endpoint events (HR = 0.357, 95% CI: 0.162-0.790, p = 0.011). CONCLUSION: Risks of mortality and hospitalizations are higher among HD patients having decreased LF/HF ratios. LF/HF in the 48-h recording can be considered as a prognostic factor for risk stratification in HD patients.
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Frecuencia Cardíaca , Hospitalización , Diálisis Renal , Humanos , Diálisis Renal/mortalidad , Estudios Prospectivos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Electrocardiografía , Fallo Renal Crónico/terapia , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/sangre , Fallo Renal Crónico/fisiopatología , PronósticoRESUMEN
In this study, Holstein dairy cows raised in Ningxia were selected as the research object. Mammary epithelial cells (BMECs) were extracted from the milk of eight Holstein cows with significantly different milk fat expression rates and transcribed for sequencing. Bioinformatics analysis was used to analyse the correlation of fat milk percentage, and the critical miR-2285f regulating milk fat was screened out. The target gene binding sites were predicted, and 293T cells and mammary epithelial cells were used as miRNA and target gene models for functional verification in vitro. The tissue difference of miR-2285f Holstein cows was quantitatively analysed by transfecting miR-2285f mimic and inhibitor. Assay (dual luciferase reporter gene assay) and quantitative real-time PCR (quantitative real-time PCR, qRT-PCR), triglyceride (TAG) detection, oil red O detection of lipid droplets, Western Blot assay, Edu and Flow cytometry, The molecular regulatory effects of miR-2285f and target gene MAP2K2 on milk fat metabolism of Holstein dairy cows were studied. The wild-type vector and mutant vector of map2k2-3'utr were constructed, and double luciferase reporting experiments were conducted to verify that MAP2K2 was one of the target genes of miR-2285f. According to qRT-PCR and Western Blot analysis, miR-2285f mainly regulates the expression of MAP2K2 protein in BMECs at the translation level. Bta-miR-2285f can promote cell proliferation and slow cell apoptosis by regulating MAP2K2. Bta-miR-2285f can promote triglyceride (TAG) and lipid droplet accumulation in mammary epithelial cells by targeting MAP2K2. Bta-miR-2285f can regulate protein levels of fat milk marker gene PPARG by targeting MAP2K2. In conclusion, miR-2285f can target the expression of the MAP2K2 gene, promote the proliferation of dairy mammary epithelial cells, inhibit cell apoptosis and regulate the milk fat metabolism in dairy mammary epithelial cells. The results of this study revealed the function of miR-2285f in regulating the differential expression of fat milk in Holstein dairy cows at the cellular level. They provided a theoretical and experimental basis for analysing the regulation network of milk fat synthesis of Holstein dairy cows and the molecular breeding of dairy cows.
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Células Epiteliales , Glándulas Mamarias Animales , MicroARNs , Leche , Animales , Bovinos , MicroARNs/metabolismo , MicroARNs/genética , Femenino , Leche/química , Glándulas Mamarias Animales/metabolismo , Células Epiteliales/metabolismo , MAP Quinasa Quinasa Quinasa 2/metabolismo , MAP Quinasa Quinasa Quinasa 2/genética , Metabolismo de los Lípidos , Triglicéridos/metabolismo , Apoptosis , Humanos , Regulación de la Expresión Génica , Proliferación CelularRESUMEN
PURPOSE: Iatrogenic lip injury may occur during oral and maxillofacial surgical procedures. This study aimed to evaluate the effect of oral retractors on iatrogenic lip injury prevention during intraoral procedures of oral and maxillofacial surgery. METHODS: We conducted a randomized controlled trial and included patients who underwent intraoral procedures of oral and maxillofacial surgery. Patients were randomly allocated to receive oral retractor (intervention group) or traditional procedure without lip protection (control group). The incidence of lip injury was the outcome variable. Other study variables included surgical time and satisfaction of patients and surgeons with treatment experience evaluated by visual analog scale (VAS). Student t test and χ 2 test were used to compare both groups' variables and measure the relationship between the predictor variable and the outcome variable. P <0.05 was considered significant for all analyses. RESULTS: A total of 114 patients were included, with 56 allocated to intervention group and 58 to control group. The results showed that the application of an oral retractor did not significantly increase surgical time ( P =0.318). A total of 12 patients had lip injury, with 1 in the intervention group and 11 in the control group ( P =0.003). For the assessment of satisfaction with treatment experience, the intervention group had significantly higher VAS scores for doctors and patients ( P <0.05). CONCLUSIONS: We found that the oral retractor was a good tool for iatrogenic lip injury prevention in oral and maxillofacial surgical procedures and could be considered in clinical treatment.
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Enfermedad Iatrogénica , Labio , Procedimientos Quirúrgicos Orales , Satisfacción del Paciente , Humanos , Labio/lesiones , Femenino , Masculino , Adulto , Enfermedad Iatrogénica/prevención & control , Procedimientos Quirúrgicos Orales/instrumentación , Persona de Mediana Edad , Instrumentos Quirúrgicos , Tempo Operativo , Resultado del TratamientoRESUMEN
Global warming is altering the frequency of extreme rainfall events and introducing uncertainties for non-point source pollution (NPSP). This research centers on orchard-influenced planting areas (OIPA) in the Wulong River Watershed of Shandong Province, China, which are known for their heightened nitrogen (N) and phosphorus (P) pollution. Leveraging meteorological data from both historical (1989-2018) and projected future periods (2041-2100), this research identified five extreme rainfall indices (ERI): R10 (moderate rain), R20 (heavy rain), R50 (rainstorm), R95p (Daily rainfall between the 95th and 99th percentile of the rainfall), and R99p (>99th percentile). Utilizing an advanced watershed hydrological model, SWAT-CO2, this study carried out a comparison between ERI and average conditions and evaluated the effects of ERI on the hydrology and nutrient losses in this coastal watershed. The findings revealed that the growth multiples of precipitation in the OIPA for five ERI varied between 16 and 59 times for the historical period and 14 to 65 times for future climate scenarios compared to the average conditions. The most pronounced increases in surface runoff and total phosphorus (TP) loss were observed with R50, R95p, and R99p, showing growth multiples as high as 352 and 330 times, and total nitrogen (TN) growth multiples varied between 4.6 and 30.3 times. The contribution rates of R50 and R99p for surface runoff and TP loss in the OIPA during all periods exceeded 55%, however, TN exhibited the opposite trend, primarily due to the dominated NO3-N leaching in the sandy soil. This research revealed how the OIPA reacts to different ERI and pinpointed essential elements influencing water and nutrient losses.
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Long-term weightlessness in animals can cause changes in myocardial structure and function, in which mitochondria play an important role. Here, a tail suspension (TS) Kunming mouse (Mus musculus) model was used to simulate the effects of weightlessness on the heart. We investigated the effects of 2 and 4 weeks of TS (TS2 and TS4) on myocardial mitochondrial ultrastructure and oxidative respiratory function and on the molecular mechanisms of apoptosis and mitochondrial fission, autophagy and fusion-related signalling. Our study revealed significant changes in the ultrastructural features of cardiomyocytes in response to TS. The results showed: (1) mitochondrial swelling and disruption of cristae in TS2, but mitochondrial recovery and denser cristae in TS4; (2) an increase in the total number of mitochondria and number of sub-mitochondria in TS4; (3) no significant changes in the nuclear ultrastructure or DNA fragmentation among the two TS groups and the control group; (4) an increase in the bax/bcl-2 protein levels in the two TS groups, indicating increased activation of the bax-mediated apoptosis pathway; (5) no change in the phosphorylation ratio of dynamin-related protein 1 in the two TS groups; (6) an increase in the protein levels of optic atrophy 1 and mitofusin 2 in the two TS groups; and (7) in comparison to the TS2 group, an increase in the phosphorylation ratio of parkin and the ratio of LC3II to LC3I in TS4, suggesting an increase in autophagy. Taken together, these findings suggest that mitochondrial autophagy and fusion levels increased after 4 weeks of TS, leading to a restoration of the bax-mediated myocardial apoptosis pathway observed after 2 weeks of TS. NEW FINDINGS: What is the central question of this study? What are the effects of 2 and 4 weeks of tail suspension on myocardial mitochondrial ultrastructure and oxidative respiratory function and on the molecular mechanisms of apoptosis and mitochondrial fission, autophagy and fusion-related signalling? What is the main finding and its importance? Increased mitochondrial autophagy and fusion levels after 4 weeks of tail suspension help to reshape the morphology and increase the number of myocardial mitochondria.
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Suspensión Trasera , Mitocondrias Cardíacas , Ratones , Animales , Mitocondrias Cardíacas/metabolismo , Dinámicas Mitocondriales/genética , Proteína X Asociada a bcl-2/metabolismo , Apoptosis/fisiología , Autofagia , Miocitos Cardíacos/metabolismoRESUMEN
OBJECTIVE: Emerging evidence suggests that glucose depletion (GD)-induced cell death depends on system Xc- , a glutamate/cystine antiporter extensively studied in ferroptosis. However, the underlying mechanism remains debated. Our study confirmed the correlation between system Xc- and GD-induced cell death and provided a strategic treatment for oral squamous cell carcinoma (OSCC). METHODS: qPCR and Western blotting were performed to detect changes in xCT and CD98 expression after glucose withdrawal. Then, the cell viability of OSCCs under the indicated conditions was measured. To identify the GD-responsible transcriptional factors of SLC7A11, we performed a luciferase reporter assay and a ChIP assay. Further, metabolomics was conducted to identify changes in metabolites. Finally, mitochondrial function and ATP production were evaluated using the seahorse assay, and NADP+ /NADPH dynamics were measured using a NADP+ /NADPH kit. RESULTS: In OSCCs, system Xc- promoted GD-induced cell death by increasing glutamate consumption, which promoted NADPH exhaustion and TCA blockade. Moreover, GD-induced xCT upregulation was governed by the p-eIF2α/ATF4 axis. CONCLUSIONS: System Xc- overexpression compromised the metabolic flexibility of OSCC under GD conditions, and thus, glucose starvation therapy is effective for killing OSCC cells.
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Novel and portable cotton swab-based fluorometry was constructed for the first time for 3-aminosalicylic acid (3-ASA) and 5-aminosalicylic acid (5-ASA) detection. It was carried out by fluorescence enhancement on silver (Ag)-doped black phosphorus quantum dots (Ag@BPQD). Ag@BPQD were prepared from AgNO3 and bulk black phosphorus in N, N-dimethylformamide (DMF) solution by solvothermal decomposition after mechanical exfoliation. Ag@BPQD show blue fluorescence with a quantum yield (QY) of 2.43%. In the presence of Ag@BPQD, 3-ASA exhibited bright blue fluorescence (λex = 328 nm, λem = 448 nm). The fluorescence of 5-ASA was also enhanced significantly and exhibited bright green emission (λex = 328 nm, λem = 484 nm). The linear range of 3-ASA is 0-90 µM with a detection limit (LOD) of 0.10 µM, relative standard deviation (RSD) ≤ 2.04%, and a recovery range of 98.0-104.3%. The linear range of 5-ASA is 0-120 µM with a LOD of 0.12 µM, RSD ≤ 1.34%, and a recovery range of 98.0-101.3%. When 3-ASA and 5-ASA were mixed in different ratios, the fluorescence showed different colors. The possible mechanism of the interaction between 3-ASA (or 5-ASA) and Ag@BPQD may be ascribed to the generation of excited-state intramolecular proton transfer. To realize convenient detection of 3-ASA and 5-ASA, a Ag@BPQD portable sensing method using cotton swabs were built. The proposed approach provides the detection of 3-ASA and 5-ASA in environmental and biological samples with high efficiency, accuracy and portability.
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Next-generation urinary protein biomarkers have been qualified to enable monitoring for drug-induced kidney injury in toxicology studies conducted in rats. However, there is limited literature on the utility of these biomarkers in dogs. To add to the existing body of knowledge on the utility of the next-generation drug-induced kidney injury (DIKI) biomarkers, we evaluated the value of these biomarkers for the early detection of DIKI in Beagle dogs using a differentiated nephrotoxicant, Amphotericin B (AmpB). In dogs with AmpB-induced kidney injury, we monitored the response of urinary albumin, total protein, clusterin, kidney injury molecule 1, neutrophil gelatinase-associated lipocalin and N-acetyl-beta-D-glucosaminidase. We also measured blood urea nitrogen, serum creatinine and cystatin C. The results showed that urinary clusterin (up to â¼ 112x) was much more sensitive to AmpB-induced kidney injury relative to other biomarkers. Moreover, other than urinary clusterin and to a much lesser extent urinary albumin and total protein, none of the other biomarkers analyzed in this study were more sensitive than blood urea nitrogen and serum creatinine. The AmpB related tubular alterations were characterized by minimal to mild, multifocal necrosis, degeneration, regeneration, dilatation and mineralization. The mild nature of these histopathologic findings further attested to the sensitivity of urinary clusterin to AmpB-induced kidney injury in dogs. These results will help drug developers make informed decisions when selecting urinary biomarkers for monitoring DIKI in dogs for toxicology studies.
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Lesión Renal Aguda , Enfermedades Renales , Perros , Animales , Ratas , Anfotericina B/toxicidad , Clusterina/orina , Creatinina , Riñón/patología , Biomarcadores , Enfermedades Renales/inducido químicamente , Albúminas/toxicidad , Lesión Renal Aguda/inducido químicamenteRESUMEN
OBJECTIVES: At present, the doctor-patient relationship is tense. The prevalence of negative emotions, such as depression and anxiety, among healthcare workers is increasing every year. Negative attitudes of medical workers toward mental problems may aggravate the doctor-patient conflict and psychological problems of medical workers. This study aims to explore the complex network relationships between outpatient medical workers' attitudes toward mental problems, doctor-patient relationships, and their depression/anxiety levels. METHODS: A total of 578 outpatient medical staff from the Second Xiangya Hospital of Central South University (167 males, 411 females) completed questionnaires on their attitudes toward mental problems, doctor-patient relationships, and depression/anxiety symptoms. Network analysis was conducted separately to construct the "attitude towards mental problems-doctor-patient relationship network" and "depression-anxiety related network". RESULTS: The edge between "M15 (insulting words)" and "D8 (waste time)" showed the strongest strength in the "attitude towards mental problems-doctor-patient relationship network", and "M15 (insulting words)" had the highest bridge strength in the network. For the analysis of emotional variables, "P1 (anhedonia)" showed the most obvious association with "D10 (communication difficulties)" in the doctor-patient relationship and "M2 (poor quality of life)" in the psychiatric attitudes, and "P1 (anhedonia)" was the key bridge symptom in the network. CONCLUSIONS: The "insulting words" may be an intervention target for medical workers' attitudes toward mental problems. The "anhedonia" in depression is the potential symptom that needs to be treated. Intervention targeting these variables may be beneficial to improve the mental health level of medical workers and the doctor-patient relationship.
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Anhedonia , Depresión , Femenino , Masculino , Humanos , Relaciones Médico-Paciente , Calidad de Vida , Ansiedad , Personal de SaludRESUMEN
Selective detection of colliding entities, especially cells and microbes, is of great challenge in single-entity electrochemistry. Herein, based on the different cellular electron transport pathways between microbes and mediators, we report a three-mediator system [K3Fe(CN)6, K4Fe(CN)6, and menadione] to achieve redox activity analysis and selective identification of single Saccharomyces cerevisiae without the usage of antibodies. K4Fe(CN)6 in the three-mediator system will oxidize near the electrode surface and increase the local concentration of K3Fe(CN)6, which will promote the redox reaction of S. cerevisiae. The hydrophobic mediatorâmenadioneâcan selectively penetrate through the S. cerevisiae membrane and get access to its intracellular redox center and can further react with K3Fe(CN)6 in the bulk solution. In contrast, the mediator can only get access to the bacterial membranes of Escherichia coli and Staphylococcus aureus, which results in different electrochemical collision signals between the above microbes. In the three-mediator system, upward step-like collision signals were observed in S. cerevisiae suspension, which are related to their microbial redox activity. In comparison, E. coli or S. aureus only generated downward current steps because the blockage effect of mediator diffusion suppresses their redox activities. When S. cerevisiae co-existed with E. coli or S. aureus, transients generated by both blockage and redox activity were observed. The approach enables us to trace the collision behaviors of different microbes and distinguish their simultaneous collisions, which is the foundation for further application of electrochemical collision technique in the specific identification of single biological entities.
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Saccharomyces cerevisiae , Vitamina K 3 , Escherichia coli/metabolismo , Oxidación-Reducción , Saccharomyces cerevisiae/metabolismo , Staphylococcus aureus/metabolismoRESUMEN
Hypersensitive response (HR) cell death is the most effective plant immune response restricting fungal pathogen invasion. Here, we report that incompatible rice (Oryza sativa) Magnaporthe oryzae interactions induce iron- and reactive oxygen species (ROS)-dependent ferroptotic cell death in rice cells. Ferric ions and ROS (i.e., H2O2) accumulated in tissues undergoing HR cell death of rice leaf sheath tissues during avirulent M. oryzae infection. By contrast, iron did not accumulate in rice cells during virulent M. oryzae infection or treatment with the fungal elicitor chitin. Avirulent M. oryzae infection in ΔOs-nadp-me2-3 mutant rice did not trigger iron and ROS accumulation and suppressed HR cell death, suggesting that NADP-malic enzyme2 is required for ferroptotic cell death in rice. The small-molecule ferroptosis inhibitors deferoxamine, ferrostatin-1, and cytochalasin E and the NADPH oxidase inhibitor diphenyleneiodonium suppressed iron-dependent ROS accumulation and lipid peroxidation to completely attenuate HR cell death in rice sheaths during avirulent M. oryzae infection. By contrast, the small-molecule inducer erastin triggered iron-dependent ROS accumulation and glutathione depletion, which ultimately led to HR cell death in rice in response to virulent M. oryzae These combined results demonstrate that iron- and ROS-dependent signaling cascades are involved in the ferroptotic cell death pathway in rice to disrupt M. oryzae infection.
Asunto(s)
Hierro/metabolismo , Magnaporthe/patogenicidad , Oryza/metabolismo , Oryza/microbiología , Especies Reactivas de Oxígeno/metabolismo , Ciclohexilaminas/farmacología , Citocalasinas/farmacología , Deferoxamina/farmacología , Peroxidación de Lípido/efectos de los fármacos , Fenilendiaminas/farmacologíaRESUMEN
Calcium-activated chloride channels (CaCCs) are widespread chloride channels which rely on calcium activation to perform their functions. In 2008, TMEM16A (also known as anoctamin1, ANO1) was identified as the molecular basis of the CaCCs, which provided the possibility to study the physiological function of CaCCs. TMEM16A is widely expressed in various cells and controls basic physiological functions, including neuronal and cardiac excitability, nerve transduction, smooth muscle contraction, epithelial Cl- secretion and fertilization. However, the abnormal function of TMEM16A may cause a variety of diseases, including asthma, gastrointestinal motility disorder and various cancers. Therefore, TMEM16A is a putative drug target for many diseases, and it is important to determine specific and efficient modulators of TMEM16A channel. In recent years, we and others have screened several natural modulators of TMEM16A against cancers and gastrointestinal motility dysfunction. This article reviews the screening methods, efficacy of TMEM16A modulators and pharmacological effects of TMEM16A modulators on different diseases. GRAPHIC ABSTACT.
Asunto(s)
Calcio , Canales de Cloruro , Anoctamina-1/genética , Calcio/metabolismo , Canales de Cloruro/genética , Motilidad GastrointestinalRESUMEN
Transmembrane 16A (TMEM16A), also known as anoctamin 1, is the molecular basis of the calcium-activated chloride channels. TMEM16A is present in interstitial cells of Cajal, which are the pacemaker cells that control smooth muscle contraction. TMEM16A is implicated in gastrointestinal disorders. Activation of TMEM16A is believed to promote the gastrointestinal muscle contraction. Here, we report a highly efficient, nontoxic, and selective activator of TMEM16A, canthaxanthin (CX). The study using molecular docking and site-directed mutation revealed that CX-specific binging site in TMEM16A is K769. CX was also found to promote the contraction of smooth muscle cells in gastrointestinal tract through activation of TMEM16A channels, which provides an excellent basis for development of CX as a chemical tool and potential therapeutic for gastrointestinal dysfunction.