In this study, a novel sandwiched electrochemiluminescence (ECL) immunosensor for the detection of carcinoembryonic antigen (CEA) was developed. The nanocomposite of polydopamine and Ag nanoparticles ...(PDA-AgNPs) was prepared by the redox reaction between Ag+ and dopamine. This nanocomposite not only provided an effective matrix for the immobilization of primary antibody (Ab1) but also enhanced the conductivity of the electrode. Carbon quantum dots (CQDs) were immobilized on the poly(ethylenimine) functionalized graphene oxide (PEI-GO) through amido-bond. Then Au nanoparticles were decorated on the CQDs modified PEI-GO matrix, and the resulted complex AuNPs/CQDs-PEI-GO was introduced to link secondary antibody (Ab2). The CQDs can be connected to the electrode surface through the combination of CEA with Ab1 and Ab2, and then the amplified electrochemiluminescence signal of CQDs was obtained with the synergistic effect of AgNPs, polydopamine, AuNPs and PEI-GO. Under the optimal conditions, the ECL intensity was proportional to the logarithm value of CEA concentration in the linear range from 5pgmL−1 to 500ngmL−1 with a detection limit of 1.67pgmL−1 for CEA detection. The immunosensor was applied for the CEA detection in real samples with satisfactory results. The proposed ECL immunosensor showed good performance with high sensitivity, specificity, reproducibility, stability and will be potential in clinical detection.
•The nanocomposite of polydopamine and Ag nanoparticles (PDA-AgNPs) provided an effective matrix for the immobilization of primary antibody (Ab1).•Carbon quantum dots (CQDs), the electrochemiluminescence material, were immobilized on the poly(ethylenimine) functionalized graphene oxide (PEI-GO) to link secondary antibody (Ab2).•The ECL signals of CQDs were greatly amplified under the synergistic effect of AgNPs, polydopamine, AuNPs and PEI-GO.•The proposed ECL immunosensor can be used for the detection of CEA in real human serum samples.
Ratiometric electrochemiluminescence (ECL) sensors can efficiently remove environmental interference to attain precise detection. Nonetheless, two eligible luminophores or coreactants were usually ...needed, increasing the complexity and restricting their practical application. In this study, a single luminophore of luminol with a single coreactant of H2O2 was employed to construct a dual-potential ratiometric ECL sensor for the detection of carcinoembryonic antigen (CEA). The produced palladium nanoclusters (Pd NCs) employing a DNA duplex as a template could not only stimulate luminol to produce cathodic ECL (I cathodic) but also quench its anodic ECL (I anodic). During the detection process, CEA could damage the double-stranded structure and reduce the Pd NCs’ amount, triggering a significant decrease in the ratio of I cathodic to I anodic (I cathodic /I anodic) and thereby achieving sensitive CEA’s detection. Furthermore, the I cathodic /I anodic was independent of the H2O2 concentration, which avoided a prejudicial effect from H2O2 decomposition and considerably enhanced the detection’s reliability. The developed ratiometric ECL sensor demonstrated a sensitive detection toward CEA with a wide linear range from 100 ag/mL to 10 ng/mL and a detection limit of 87.1 ag/mL (S/N = 3). In conclusion, this study offers a new idea for constructing ratiometric ECL sensors based on a single luminophore and technical support for cancer’s early diagnosis.
Structural and sequential ambidexterity are proved to be two prevalent approaches in managing tension between exploration and exploitation. Dominant studies have treated the two approaches as ...mutually exclusive but have provided less insight about their combination, and the organizational configurations that advance such combination, which is a major meaningful gap explored in the current study. This study aims to explore the configurations of organization design choices to combine structural and sequential approaches from a holistic perspective. We apply fuzzy-set qualitative comparative analysis (fsQCA) to analyze the empirical data collected from 102 firms in China. The results show that firms attain high ambidexterity with both separated and blended configurations. Blended ones demonstrate that the structural and sequential approaches can be combined in a way that one approach dominates and the other subordinates. Organizational design mechanisms regarding the configurations for combining structural and sequential approaches are concluded as multielements (complements and substitutes) and multilevels (fit and interaction). These findings are also interpreted through the Chinese ‘Yin-Yang’ framework, which introduces ‘Yin-Yang balancing’ into the ambidexterity literature. 结构双元与时序双元被证明是缓解组织的探索和利用战略之间冲突关系的两种常见方法。现有的研究认为这两种方法是相互排斥的，对两者的组合以及促进这种组合的组织构型缺乏关注。本研究旨在从整体的角度探索组织设计选择的构型，以实现结构与时序双元的有机联结。本研究运用模糊集定性比较分析(fsQCA)的方法，对102家中国企业的实证数据进行了分析。结果表明，企业可以通过分离构型或混合构型取得高组织双元。其中，混合构型意味着，结构双元和时序双元以一种方法占主导地位、另一种方法为从属的方式进行组合。关于联结结构双元与时序双元构型的组织设计机制被总结为多要素(补充和替代)和多层次(匹配和交互)。最后，本研究尝试将“阴阳平衡”引入双元研究，用中国的“阴阳”框架来解释研究发现。
Outbreaks of emerging infectious diseases pose a serious threat to public health security, human health and economic development. After an outbreak, an animal model for an emerging infectious disease ...is urgently needed for studying the etiology, host immune mechanisms and pathology of the disease, evaluating the efficiency of vaccines or drugs against infection, and minimizing the time available for animal model development, which is usually hindered by the nonsusceptibility of common laboratory animals to human pathogens. Thus, we summarize the technologies and methods that induce animal susceptibility to human pathogens, which include viral receptor humanization, pathogen-targeted tissue humanization, immunodeficiency induction and screening for naturally susceptible animal species. Furthermore, the advantages and deficiencies of animal models developed using each method were analyzed, and these will guide the selection of susceptible animals and potentially reduce the time needed to develop animal models during epidemics.
The repeated measurements of heart rate variability (HRV) is more relevant than a single HRV measurement in predicting patient prognosis but is less addressed previously. This prospective study aimed ...to investigate the association between repeated measurements of HRV and long-term mortality in chronic hemodialysis patients. The 164 patients (65.0 ± 13.1 years; woman, 57.3%) were enrolled from June 1, 2010, to August 31, 2010, and received four HRV measurements (before and during the index hemodialysis session) after the enrollment. The baseline characteristic and clinical variables, including mortality, were documented. The joint modeling method and Cox regression were used for statistical analyses. After an 8-year follow-up, 79 patients expired, and 85 patients survived. We found that higher normalized high-frequency (nHF) (hazard ratio HR 1.033) as well as lower very-low-frequency (HR 0.990), Variance (HR 0.991), normalized low-frequency (HR 0.999, P = 0.006), and low-frequency/high-frequency ratio (HR 0.796) were independent predictors for cardiovascular mortality. Whereas the independent predictors for infection-associated mortality included higher nHF (HR 1.033) as well as higher age (HR 19.29) and lower serum albumin (HR 0.01, P = 0.001). (all P < 0.001 unless otherwise stated) In conclusion, HRV measurement predicts long-term mortality among hemodialysis patients.
The present work reported a simple, lable-free and sensitive electrochemical method for the detection of protein kinase A (PKA) activity. This method was based on the specific recognition of aptamer ...and the aptamer-induced hybridization chain reaction (HCR) amplification strategy. The aptasensor was constructed by immobilizing capture probe on a gold electrode via an Au–S bond. When adenosine triphosphate (ATP) aptamer was introduced, its one terminus hybridized with capture probe and the other hybridized with the complementary region of an auxiliary probe, which other region triggered HCR between two hairpin DNA (H1 and H2) to form a long DNA concatamer. At last a large number of electroactive methyle blue (MB) molecules were assembled on the dsDNA concatamer, which generated a significantly amplified electrochemical signal. In the presence of ATP, the HCR would not be performed because the aptamer specifically bond to ATP and the electrochemical response would decrease. However, when ATP and PKA coexisted, the electrochemical response would recovery because that ATP had been translated into ADP by PKA. So the activity of PKA could be effectively monitored according to the change of electrochemical signal. Based on the HCR amplification strategy, the aptasensor showed a wide linear range (4 − 4 ×105 U L−1) and a low detection limit (1.5 U L−1) for the detection of PKA. Furthermore, the method was applied to study the inhibitory effect of H-89 on PKA activity. The developed aptasensor was also used to the analysis of drug-induced PKA activity in cell lysates, indicating the potential application of the developed method in the fields of clinical diagnostics and discovery of new targeted drugs.
Pulmonary arterial hypertension (PAH) is a malignant disease with high mortality and closely involves the bone morphogenetic protein (BMP) pathway. Mutations in BMPR2 caused proliferation of ...pulmonary artery smooth muscle cells (PASMCs) leading to PAH. Isorhamnetin, one of the main naturally occurring flavonoids extracted from Hippophae rhamnoides L, shows antiinflammatory and anti‐proliferative properties. Nevertheless, the effects of isorhamnetin on PAH remain unclear. This study aimed to investigate whether isorhamnetin has protective effects against PAH and explore possible mechanisms. An in vivo model of PAH induced by monocrotaline (MCT) was employed, and sildenafil and isorhamnetin were orally administered for 21 consecutive days. An in vitro model induced by TNF‐α was employed, and cell proliferation of HPASMCs was detected. Results indicated that isorhamnetin significantly improved hemodynamic, histopathological, and echocardiographic changes in MCT‐induced PAH in rats. In vitro, isorhamnetin suppressed TNF‐α‐induced HPASMCs proliferation. Furthermore, isorhamnetin improved protein expression of BMPR2 and suppressed protein expression of TNF‐α and IL‐6 in rat lungs. Isorhamnetin improved protein expression of BMPR2 and p‐smad1/5 and mRNA expression of Id1 and Id3 in HPASMCs. Isorhamnetin ameliorated MCT‐induced PAH in rats and inhibited TNF‐α‐induced HPASMCs proliferation by a mechanism likely involving the regulation of the BMP signaling pathway.
The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13-2 (Munc13-2), which is highly expressed in the brain-predominantly in the cerebral cortex-and plays an ...essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of the UNC13B mutation in human disease is not known. In this study, we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed a favourable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database (gnomAD). Computational modelling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiological recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results indicate that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favourable outcome under anti-epileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.
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