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This review provides an overview of the latest research progress in mRNA structural optimization strategies and their delivery systems, and discusses key considerations for their future clinical use.

Here, core-shell hydrogel beads for oral insulin delivery at intestine was reported, which was a target site for insulin absorption. The core-shell hydrogel beads were prepared using naturally derived alginate and chitosan polysaccharides by simple dropping technique. In order to effectively control leakage of insulin from core-shell hydrogel beads, insulin was embedded into the layered double hydroxides (LDHs). LDH/insulin-loaded complexes were firstly coated with chitosan, and then coated with alginate to generate core-shell hydrogel beads. The biocompatibility and angiogenic response of core-shell hydrogel beads were evaluated by direct contact of the beads with chick embryo chorioallantoic membrane, which indicates safety of the core-shell beads. The beads successfully retained the insulin within the core-shell structure at pH 1.2, indicating that insulin had a good protective effect in harsh acidic environments. Interestingly, insulin release starts at the simulated intestinal fluid (pH 6.8) and continue to release for 24 h in a sustained manner.

C-terminal tensin-like (CTEN) is a tensin family protein typically localized to the cytoplasmic side of focal adhesions, and primarily contributes to cell adhesion and migration. Elevated expression and nuclear accumulation of CTEN have been reported in several types of cancers and found to be associated with malignant behaviors. However, the function of nuclear CTEN remains elusive. In this study, we report for the first time that nuclear CTEN associates with chromatin DNA and occupies the region proximal to the transcription start site in several genes. The mRNA expression level of CTEN positively correlates with that of one of its putative target genes, cell division cycle protein 27 (CDC27), in a clinical colorectal cancer dataset, suggesting that CTEN may play a role in the regulation of CDC27 gene expression. Furthermore, we demonstrated that CTEN is recruited to the promoter region of the CDC27 gene and that the mRNA expression and promoter activity of CDC27 are both reduced when CTEN is downregulated. In addition, we found that enhanced nuclear accumulation of CTEN in HCT116 cells by overexpression of CTEN fused with nuclear localization signals increases CDC27 transcript levels and promoter activity. The increased nuclear-localized CTEN also significantly promotes cell migration, and the migratory ability is suppressed when CDC27 is knocked down. These results demonstrate that nuclear CTEN regulates CDC27 expression transcriptionally and promotes cell migration through CDC27. Our findings provide new insights into CTEN moonlighting in the nucleus as a DNA-associated protein and transcriptional regulator involved in modulating cancer cell migration.

The purpose of this study was to explore the feasibility of pancreatic imaging at 5 T and evaluate the practical improvement of T2-weighted MRI and diffusion-weighted imaging (DWI) at 5 T as compared with 3 T.Eighteen healthy subjects were recruited for this pilot study. MRI examinations were performed using 3 and 5 T scanners. MRI sequences included T2-weighted fast spin-echo and DWI with reduced field-of-view. Subjective image analysis using a four-point Likert scale was performed by two experienced radiologists. The SNR, contrast ratio, and apparent diffusion coefficient (ADC) were measured in the pancreatic head, body, and tail. The coefficient of variation (CV) of the ADC was calculated. A series of paired Wilcoxon tests were used to compare the subjective image quality, mean ADC value, and CV of ADC between the 3 and 5 T measurements. p0.05 was considered statistically significant.For T2-weighted images, there were no significant differences in image quality ratings between 3 and 5 T. On DWI images (b = 0 and 800 s/mmThis initial study proved that 5 T MRI can be used to acquire pancreatic images with higher SNR and sufficient image quality compared to 3 T MRI.

Data about volumetric remodeling of the provisional extension to induce complete attachment (PETTICOAT) technique on DeBakey type IIIb aortic dissection in acute and subacute phases were scarce. The proper timing to perform this technique to promote false lumen reduction was also unknown.Patients with DeBakey type IIIb aortic dissection who underwent the PETTICOAT technique between December 2005 and March 2017 were reviewed and divided into acute (treatment occurred ≦14 days after symptom onset) and subacute (15-90 days) groups. Remodeling parameters of the true and false lumens were analyzed. Receiver operating characteristic curve was used to deduce the timing of this technique.In the 2-year follow-up, the acute group (N = 20) demonstrated significant true lumen expansion and false lumen regression in the thoracic, abdominal, and total aorta. However, the subacute group (N = 20) only showed significant shrinkage in the false lumen of the thoracic and total aorta. Using PETTICOAT technique within 36 days after the aortic event may result in better total false lumen reduction.For DeBakey type IIIb aortic dissection, more prominent true lumen expansion and false lumen reduction were noted when using the PETTICOAT technique in the acute phase. When performed within 36 days after symptoms onset, the PETTICOAT technique may potentiate better total false lumen regression.

The fall armyworm (FAW) Spodoptera frugiperda Smith (Lepidoptera: Noctuidae) invaded Myanmar and China in 2018 and greatly impacted agricultural production and ecosystem balance in these areas. FAW is a migratory insect, but its seasonal migration pattern between the two countries has been largely unknown. From 2019 to 2021, we monitored the seasonal migration of FAW in the China-Myanmar border area using a searchlight trap, assessed the reproductive development status of female migrants and traced the migratory routes by trajectory simulation.FAW moths were trapped by the searchlight trap in Lancang County (Yunnan, China) all year, with obvious seasonal differences in the number caught. There were small-scale persistent trapping peaks in spring and summer, and obvious peaks in autumn; only a small number of moths were trapped in winter. Examination of the ovaries of female moths collected in different seasons showed that most females had matured, indicating that the moths were migrating and did not take off from the local area. In the migration trajectory simulation, FAW mainly migrated from Myanmar to Southwest China in spring and summer and back to Myanmar in autumn.Our findings indicate that FAW migrates between China and Myanmar according to the monsoon circulation, which will help guide cross-border regional monitoring and management strategies against this pest. © 2022 Society of Chemical Industry.

To distinguish MR features according to different proportions of the histopathological hepatocellular carcinoma (HCC) component and to investigate whether the proportion of the HCC component can predict the prognosis of patients with cHCC-CCA.The study enrolled 106 cHCC-CCA patients confirmed by histopathology. The MR imaging features and clinicopathological findings were retrospectively evaluated and compared between two subgroups with different proportions of the HCC component. The recurrence-free survival (RFS) and overall survival (OS) were evaluated using Kaplan-Meier survival curves and compared using the log-rank test. Moreover, whether the proportion of the HCC component was a predictor of RFS and OS was investigated using Cox regression analyses.The Liver Imaging Reporting and Data System (LI-RADS) category 4/5 was more prevalent in cHCC-CCAs with an HCC component50% (odds ratio (OR) = 5.559, p = 0.018), 70% (OR = 4.031, p = 0.008), and 90% (OR = 6.282, p = 0.012) than in those with an HCC component ≤ 50%, 70%, and 90%, respectively. In addition, cHCC-CCAs with an HCC component70% (HR: 0.241, p = 0.023) had a better OS prognosis than those with an HCC component ≤ 70%.cHCC-CCAs categorized as LR-4/5 are mainly composed of HCC component, and cHCC-CCAs with an HCC component70% are associated with better OS than those with an HCC component ≤ 70%. These findings suggest that the proportion of HCC or CCA component can predict the prognosis of cHCC-CCA patients.• cHCC-CCAs categorized as LR-4/5 are mainly composed of HCC component. • cHCC-CCAs with an HCC component70% are associated with better OS than those with an HCC component ≤ 70%.

Increasing life expectancy and declining birth rate are two key drivers of population aging globally, resulting in a falling population.This study investigated the evolution of pediatric patients with vertigo/dizziness during the past two decades.From 2001 to 2010, a total of 17,123 new patients with vertigo/dizziness visited our neurotological clinic. Of them, 472 (2.8%) were children (Group A). In contrast, 260 children (1.3%) out of 20,404 new patients with vertigo/dizziness were experienced during the period 2011-2020 (Group B). All patients underwent an inner ear test battery before diagnosis.The incidence of pediatric vertigo/dizziness in relation to overall neurotological cases significantly decreased from the first decade (2.8%) to the second decade (1.3%). Approximately 80% prevalence of pediatric vertigo/dizziness cases were referred to as vestibular migraine and benign paroxysmal vertigo of childhood regardless of Group A or B. Correlation between annual birth rate (The evolution of pediatric vertigo/dizziness revealed decreased incidence from 2.8% (2001-2010) to 1.3% (2011-2020), which may be related to the declined annual birth rate from 11.7‰ (2001) to 7.0‰ (2020).

Cardiac paragangliomas are exceedingly rare. Herein, we describe a patient with a large dopaminesecreting cardiac paraganglioma who had a history of pheochromocytoma after right adrenalectomy. The cardiac surgery was uneventful and without blood pressure fluctuations.The measurement of plasma-free metanephrines or urinary fractionated metanephrines is used as an initial screening test for pheochromocytoma or paraganglioma detection. However, these results must be combined with those of a plasma 3-methoxytyramine test to accurately establish the rare dopaminergic phenotype of pheochromocytomas or paragangliomas, if suspected. F-FDOPA (6-[18F]-L-fluoro-L-3, 4-dihydroxyphenylalanine)-based positron emission tomography (PET) and PET-computed tomography are relatively sensitive and specific; therefore, these techniques are recommended for patients with pheochromocytomas or paragangliomas before operation or during postoperative follow-up.

EZH2, a member of the polycomb repressive complex 2, induces trimethylation of the downstream gene at the histone three lysine 27 (H3K27me3) position to inhibit tumor cell proliferation. Here, we showed that the apoptosis rate and apoptotic protein expression increased after EZH2 inhibition, whereas key molecules of the NF-κB signaling pathway and the downstream target genes were inhibited. Additionally, the expression of CD155, a TIGIT high-affinity ligand in multiple myeloma (MM) cells, was decreased by the mTOR signaling pathway. Furthermore, the combination of EZH2 inhibitor and TIGIT monoclonal antibody blockade enhanced the anti-tumor effect of natural killer cells. In summary, the EZH2 inhibitor not only plays an anti-tumor role as an epigenetic drug, but also enhances the anti-tumor effect of the TIGIT monoclonal antibody by affecting the TIGIT-CD155 axis between NK cells and MM cells, thus providing new ideas and theoretical basis for the treatment of MM patients.

Abstract: Chronic liver disease is a known risk factor for the development of liver cancer, and the development of microRNA (miRNA) liver therapies has been hampered by the difficulty of delivering miRNA to damaged tissues. In recent years, numerous studies have shown that hepatic stellate cell (HSC) autophagy and exosomes play an important role in maintaining liver homeostasis and ameliorating liver fibrosis. In addition, the interaction between HSC autophagy and exosomes also affects the progression of liver fibrosis. In this paper, we review the research progress of mesenchymal stem cell-derived exosomes (MSC-EVs) loaded with specific miRNA and autophagy, and their related signaling pathways in liver fibrosis, which will provide a more reliable basis for the use of MSC-EVs for therapeutic delivery of miRNAs targeting the chronic liver disease.

PurposeBuilding on resource dependence theory and the dynamic institution-based view, this paper examines the influence of government affiliations on firm product innovation in a dynamic institutional environment.Design/methodology/approachUsing unique panel data of Chinese manufacturing firms covering a period of 12 years (1998–2009) with 2,564,547 firm-year observations, this study chooses the panel Tobit model with random effects to explore the influence of government affiliations on firm product innovation, followed by an analysis to test the moderation effects of dynamic institutional environments.FindingsThe study findings suggest that Chinese firms with higher-level government affiliations have a relatively high product innovation performance. It finds that this innovation stimulating effect is contingent on the dynamic nature of the institutional environment. To be specific, a high speed of institutional transition may depress the positive innovation effects of government affiliations, while a more synchronized transition speed of institutional components may enhance the positive innovation effects of firms' government affiliations.Originality/valueThis study adds to a better understanding of the drivers of product innovation in Chinese firms that are situated in environments that are characterized by institutional change, using and contributing to resource dependence theory and the dynamic institution-based view.

As a key characteristic in audio-visual speech recognition (AVSR), relating linguistic information observed across visual and audio data has been a challenge, benefiting not only audio/visual speech recognition (ASR/VSR) but also for manipulating data within/across modalities. In this paper, we present a feature disentanglement-based framework for jointly addressing the above tasks. By advancing cross-modal mutual learning strategies, our model is able to convert visual or audio-based linguistic features into modality-agnostic representations. Such derived linguistic representations not only allow one to perform ASR, VSR, and AVSR, but also to manipulate audio and visual data output based on the desirable subject identity and linguistic content information. We perform extensive experiments on different recognition and synthesis tasks to show that our model performs favorably against state-of-the-art approaches on each individual task, while ours is a unified solution that is able to jointly tackle the aforementioned audio-visual learning tasks.

Silk fibroin, a natural macromolecular protein without physiological activity, has been widely used in different fields, such as the regeneration of bones, cartilage, nerves, and other tissues. Due to irrevocable neuronal injury, the treatment and prognosis of neurological diseases need to be investigated. Despite attempts to propel neuroprotective therapeutic approaches, numerous attempts to translate effective therapies for brain disease have been largely unsuccessful. As a good candidate for biomedical applications, hydrogels based on silk fibroin effectively amplify their advantages. The ability of nerve tissue regeneration, inflammation regulation, the slow release of drugs, antioxidative stress, regulation of cell death, and hemostasis could lead to a new approach to treating neurological disorders. In this review, we introduced the preparation of SF hydrogels and then delineated the probable mechanism of silk fibroin in the treatment of neurological diseases. Finally, we showed the application of silk fibroin in neurological diseases.

The aim of this study was to apply registration and three-dimensional (3D) display tools to assess the evolution of intraparenchymal hemorrhage (IPH) in patients with traumatic brain injury (TBI). We identified 109 TBI patients who had two computed tomography (CT) scans within 4 days retrospectively. The IPH was manually outlined. The registration was performed in 39 lesions from 29 patients with lesion volume 1.5 cm on both baseline and follow-up CT. The center of mass (COM) of each lesion was calculated, and the distance between baseline and follow-up CT was used to evaluate the registration effect. The mean distances of COM before registration in the XYZ, XY, and YZ coordinates were 20.5 ± 10.2 mm, 17.8 ± 9.4 mm, and 15.9 ± 9.4 mm, respectively, which decreased significantly (p 0.001) to 7.9 ± 4.9, 7.8 ± 5.0, and 6.1 ± 4.1 mm after registration. A 3D short video displaying the rendering view of all lesions in 34 randomly selected patients from baseline and follow-up scans were presented side-by-side for comparison. The detection rate of new IPH lesions increased in 3D videos (100%) as compared with axial CT slices (78.6-92.9%). A very high interrater agreement (k = 0.856) on perceiving IPH lesion progression upon viewing 3D video was noted, and the absolute volume increase was significantly higher (p 0.001) for progressive lesions (median 7.36 cc) over non-progressive lesions (median 0.01 cc). Compared to patients with spontaneous hemorrhagic stroke, evaluation of multiple small traumatic hemorrhages in TBI is more challenging. The applied image analysis and visualization methods may provide helpful tools for comparing changes between serial CT scans.

Missense mutations in myosin heavy chain 7 (MYH7) are a common cause of hypertrophic cardiomyopathy (HCM), but the molecular mechanisms underlying MYH7-based HCM remain unclear. In this work, we generated cardiomyocytes derived from isogenic human induced pluripotent stem cells to model the heterozygous pathogenic MYH7 missense variant, E848G, which is associated with left ventricular hypertrophy and adult-onset systolic dysfunction. MYH7E848G/+ increased cardiomyocyte size and reduced the maximum twitch forces of engineered heart tissue, consistent with the systolic dysfunction in MYH7E848G/+ HCM patients. Interestingly, MYH7E848G/+ cardiomyocytes more frequently underwent apoptosis that was associated with increased p53 activity relative to controls. However, genetic ablation of TP53 did not rescue cardiomyocyte survival or restore engineered heart tissue twitch force, indicating MYH7E848G/+ cardiomyocyte apoptosis and contractile dysfunction are p53-independent. Overall, our findings suggest that cardiomyocyte apoptosis is associated with the MYH7E848G/+ HCM phenotype in vitro and that future efforts to target p53-independent cell death pathways may be beneficial for the treatment of HCM patients with systolic dysfunction.

OBJECTIVES: Sacral insufficiency fracture (SIF) is not an uncommon osteoporosis fracture among the elderly. Aside from traditional treatments, sacroplasty and teriparatide (TPTD) injection have been introduced. This report aims to compare the effects of sacroplasty and teriparatide on clinical outcomes of SIF. METHODS: Thirty-one elderly patients with SIF were enrolled in this retrospective observational study. Four male patients were excluded. Fourteen patients who received TPTD for 6 months were classified into the TPTD group (TT), and 13 who underwent sacroplasty were classified into the sacroplasty group (SS). All patients in both groups were instructed to take calcium and vitamin D supplements daily. Their symptoms and signs, visual analog score (VAS), Oswestry disability index (ODI), and radiographic studies were retrospectively reviewed. RESULTS: The TT group showed significantly lower VAS than SS group after 3 (P

Background Appropriate preoperative identification of iCCA subtype is essential for personalized management, so the aim of this study is to investigate the role of MR imaging features in preoperatively differentiating the iCCA subtype. Methods Ninety-three patients with mass-forming intrahepatic cholangiocarcinoma (iCCA, 63 small duct type and 30 large duct type) were retrospectively enrolled according to the latest 5th WHO classification (mean age, males vs. females: 60.66 ± 10.53 vs. 61.88 ± 12.82, 50 men). Significant imaging features for differentiating large duct iCCA and small duct iCCA were identified using univariate and multivariate logistic regression analyses, and a regression-based predictive model was then generated. Furthermore, diagnostic performance parameters of single significant imaging features and the predictive model were obtained, and corresponding receiver operating characteristic (ROC) curves were subsequently presented. Results The univariate analysis showed that tumor in vein, arterial phase hypoenhancement, intrahepatic duct dilatation, lack of targetoid restriction and lack of targetoid appearance in T2 were predictors of large duct type iCCA. Arterial phase hypoenhancement, intrahepatic duct dilatation and lack of targetoid restriction were independent predictors for large duct type iCCA in multivariate analysis. The regression-based predictive model has achieved the best preoperative prediction performance in iCCA subcategorization so far. The area under the ROC curve of the regression-based predictive model was up to 0.91 (95% CI: 0.85, 0.98), and it was significantly higher than every single significant imaging feature. Conclusions Arterial phase hypoenhancement, intrahepatic duct dilatation and lack of targetoid restriction could be considered reliable MR imaging indicators of large duct type iCCA. MR imaging features can facilitate noninvasive prediction of iCCA subtype with satisfactory predictive performance.

Background Patients suffering from chronic pain often also exhibit depression symptoms. Soluble epoxide hydrolase (sEH) inhibitors can decrease blood levels of inflammatory cytokines. However, whether inhibiting sEH signaling is beneficial for the comorbidity of pain and depression is unknown. Methods According to a sucrose preference test (SPT), spared nerve injury (SNI) mice were classified into pain with or without an anhedonia phenotype. Then, sEH protein expression and inflammatory cytokines were assessed in selected tissues. Furthermore, we used sEH inhibitor TPPU to determine the role of sEH in chronic pain and depression. Importantly, agonists and antagonists of aryl hydrocarbon receptor (AHR) and translocator protein (TSPO) were used to explore the pathogenesis of sEH signaling. Results In anhedonia-susceptible mice, the tissue levels of sEH were significantly increased in the medial prefrontal cortex (mPFC), hippocampus, spinal cord, liver, kidney, and gut. Importantly, serum CYP1A1 and inflammatory cytokines, such as interleukin 1β (IL-1β) and the tumor necrosis factor α (TNF-α), were increased simultaneously. TPPU improved the scores of mechanical withdrawal threshold (MWT) and SPT, and decreased the levels of serum CYP1A1 and inflammatory cytokines. AHR antagonist relieved the anhedonia behaviors but not the algesia behaviors in anhedonia-susceptible mice, whereas an AHR agonist abolished the antidepressant-like effect of TPPU. In addition, a TSPO agonist exerted a similar therapeutic effect to that of TPPU, whereas pretreatment with a TSPO antagonist abolished the antidepressant-like and analgesic effects of TPPU. Conclusions sEH underlies the mechanisms of the comorbidity of chronic pain and depression and that TPPU exerts a beneficial effect on anhedonia behaviors in a pain model via AHR and TSPO signaling.

Modification of cysteine residues by oxidative and nitrosative stress affects structure and function of proteins, thereby contributing to the pathogenesis of cardiovascular disease. Although the major function of thioredoxin 1 (Trx1) is to reduce disulfide bonds, it can also act as either a denitrosylase or transnitrosylase in a context-dependent manner. Here we show that Trx1 transnitrosylates Atg7, an E1-like enzyme, thereby stimulating autophagy. Trx1 was S-nitrosylated at Cys73 when Cys32-35, the oxidoreductase catalytic center, was oxidized and forms a disulfide bond during ischemia. Unexpectedly, Atg7 Cys545-548 reduced the disulfide bond in Trx1 at Cys32-35 through thiol-disulfide exchange and this then allowed NO to be released from Cys73 in Trx1 and transferred to Atg7 at Cys402. Experiments conducted with Atg7 C402S knock-in mice showed that S-nitrosylation of Atg7 at Cys402 promotes autophagy by stimulating E1-like activity, thereby protecting the heart against ischemia. These results suggest that the thiol-disulfide exchange and the NO transfer are functionally coupled, allowing oxidized Trx1 to mediate a salutary effect during myocardial ischemia through transnitrosylation of Atg7 and stimulation of autophagy.

This study applied the theory of stimulus–organism–response to test the role of green animation advertising influencing green brand love and green customer citizenship behavior. We used questionnaire survey and the target are those who having the experience of seeing the Apple’s animation advertisement “Earth Day” in China. Finally there were 516 effective samples gathered for analysis. The result indicated that reliability, attractiveness and informativity are the antecedents of green brand love. Green brand love is positively related to green customer citizenship behavior. In addition, the result confirmed the significant mediating effect of green brand love between reliability, attractiveness, informativity and green customer citizenship behavior. This research was conducted only in Apple’s animation case. Hence, the results may not be generalizable to other contexts. Future research can apply the experimental methods and manipulate different forms of green advertising animation to generalize the findings in this area.

Digital polymerase chain reaction (dPCR) technology has provided a new technique for molecular diagnostics, with superior advantages, such as higher sensitivity, precision, and specificity over quantitative real-time PCRs (qPCR). Eight companies have offered commercial dPCR instruments: Fluidigm Corporation, Bio-Rad, RainDance Technologies, Life Technologies, Qiagen, JN MedSys Clarity, Optolane, and Stilla Technologies Naica. This paper discusses the working principle of each offered dPCR device and compares the associated: technical aspects, usability, costs, and current applications of each dPCR device. Lastly, up-and-coming dPCR technologies are also presented, as anticipation of how the dPCR device landscape may likely morph in the next few years.

Coercive and constraints mechanism analysis between rural ecosystem health (REH) and urbanization is required to comprehend spatio-temporal coupling coordination relationship and promote rural ecosystem health development under the pressure of urbanization, especially those with dramatic changes in Chinese countryside. This paper, taking Chongqing municipality as the case study, analyzed the temporal and spatial characteristics of the coupling coordination between urbanization and REH of 38 districts and counties from 2010 to 2018 with support of coordination coupling degree (CCD) model, entropy method, and GIS spatial methods. The main conclusions were as follows: (1) the EUS (34.84%) and RSceS (35.64%) separately made the highest share contribution to urbanization and REH, the proportion of non-agricultural population in total population and consumption of farmland chemical fertilizer intensity were the main two indicators. (2) The study has confirmed the existence of an obvious differentiated U-shaped curves between urbanization and REH, a dynamic coupling coordination-X was found to exist, which conformed to a linear continuous growth curve, and has transitioned to "high quality coupling coordination" stage from "severe disorder" stage from 2000 to 2018; (3) the spatial differentiation characteristics of coupling coordination in 2018 have shown a significant regional differences pattern, and the coupling coordination in more developed areas was generally higher than most developed areas and less developed areas, namely western Chongqing metropolitan areas northeastern Chongqing and southeastern Chongqing. This report could provide policy implications for Chinese decision makers to formulate sustainable measures to balance urbanization development and REH protection.

MicroRNAs (miRNAs) have emerged as essential regulators that could have pivotal roles in cardiac homeostasis and pathological remodeling of various cardiovascular diseases. We previously demonstrated that miRNA-122-5p overexpression exacerbated the process of vascular hypertrophy, fibrosis, and dysfunction in hypertensive rats and rat aortic adventitial fibroblasts. However, the exact roles and underlying mechanisms of miRNA-122-5p in myocardial fibroblasts remain largely unknown. In this work, neonatal rat cardiofibroblasts (CFs) were isolated and primarily cultured from the hearts of 2- to 3-d-old Sprague-Dawley rats. Stimulation of angiotensin II (Ang II) resulted in marked increases in cellular proliferation and migration and levels of collagen I, collagen III, CTGF, and TGF-β1 in cultured CFs. Furthermore, Ang II led to promoted expression of P62, Bax, and phosphorylated mTOR as well as downregulation of LC3II, beclin-1, and AMPK-phosphorylated levels, thereby contributing to imbalance of autophagy and apoptosis, and cellular injury in CFs, which were significantly ameliorated by treatment with miRNA-122-5p inhibitor. These changes were associated with decreased levels of collagen I, collagen III, CTGF, and TGF-β1. Furthermore, Ang II-induced loss of autophagy and promotion of apoptosis in CFs were prevented by the treatment with Pyr

Argonaute 2 (Ago2) is an essential component of the RNA-induced silencing complex (RISC) and it participates in diverse physiological processes, while dysregulation of Ago2 activity is closely linked to a variety of human diseases including cancers. The reported Ago2 assays often suffer from laborious procedures, complicated reaction schemes, and unsatisfactory sensitivity. Herein, we develop a new gold nanoparticle (AuNP)-based single-molecule biosensor for simple and sensitive detection of Ago2 activity. The Ago2-responsive AuNP nanoprobe is constructed through the self-assembly of multiple Cy5-labeled signal probes onto the AuNP, in which the Cy5 fluorescence is efficiently quenched by the AuNP. Target Ago2 can bind with guide RNA to form an active RISC, inducing the cyclic cleavage of the signal probes and the release of Cy5 moieties from the AuNP nanoprobe. The released Cy5 molecules can be simply quantified by single-molecule counting. This single-molecule biosensor enables detection of Ago2 activity with the involvement of only a single AuNP nanoprobe, eliminating the use of any extra antibodies and protein enzymes. This single-molecule biosensor achieves good specificity and high sensitivity with a detection limit of 9.1 pM, and it can be exploited for the screening of Ago2 inhibitors, Ago2 kinetic analysis, and the imaging of intracellular Ago2 activity in live cells, holding great promise in Ago2-related biomedical research and clinical diagnosis.

Human T-cell lymphotropic virus type I and type II (HTLV-I and HTLV-II) are the two most prevalent subtypes of HTLVs, and they usually infect individuals asymptomatically and may induce various diseases. Herein, we develop a single-molecule biosensor with an ultra-low background for the simultaneous detection of multiple retroviral DNAs. This biosensor is constructed by immobilizing two types of signal probes (

Fifteen dammarane-type triterpenoid saponins including one new compound isolated from P. notoginseng exhibited anti-inflammatory, anti-angiogenetic and antiviral activities.

Protein kinases play important roles in regulating various cellular processes and may function as potential diagnostic and therapeutic targets for various diseases including cancers. Herein, we construct a phos-tag-directed self-assembled fluorescent magnetobiosensor to simultaneously detect multiple protein kinases with good selectivity and high sensitivity. In the presence of protein kinases (

Protein kinase can catalyze the phosphorylation of peptides/proteins, and it is closely associated with various human diseases such as cancer, immune deficiencies, and Alzheimer's disease. Sensitive monitoring of protein kinase activity is significant for biochemical research and drug discovery. Herein, we develop a phos-tag-based fluorescent biosensor for sensitive detection of cAMP-dependent protein kinase (PKA) activity in cancer cells. We design a peptide-DNA conjugate and a signal probe for PKA activity assay, and employ a biotinylated phos-tag (a selective phosphate-binding agent) to recognize and capture the phosphorylated peptide-DNA substrate. The peptide-DNA conjugates as the catalytic substrates can translate the peptide signal to a nucleotide signal for the initiation of the RNase HII-driven cycling signal amplification. The magnetic nanobeads (MBs) as the carriers can separate and enrich the phosphorylated peptide in complex matrices. Meanwhile, the combination of MBs with the phos-tag-mediated phosphate group recognition can effectively eliminate the interference from the complex matrix, and the introduction of single-molecule detection endows this assay with high sensitivity. This biosensor can achieve a detection limit of 1.98 × 10

Background Although epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) have been the standard treatment for advanced EGFR‐mutant adenocarcinoma, the effects of upfront EGFR‐TKI use in unresectable stage III EGFR‐mutant adenocarcinoma remain unexplored. Here, we conducted a retrospective study to compare different treatment strategies in these patients. Methods From October 2010 to June 2019, patients with unresectable stage III adenocarcinoma who received treatment at a tertiary referral center were enrolled. Patients were classified into three groups: EGFR‐mutant adenocarcinoma treated with concurrent chemoradiotherapy (group 1) or EGFR‐TKI (group 2) and EGFR wild‐type adenocarcinoma treated with concurrent chemoradiotherapy (group 3). Progression‐free survival, progression‐free survival‐2, and overall survival were estimated and compared using Kaplan–Meier and log‐rank tests. Results A total of 92 patients were enrolled; 10, 40, and 42 patients were assigned to groups 1, 2, and 3, respectively. Patients with EGFR mutations who received upfront EGFR‐TKIs had significantly longer progression‐free and overall survival than those who received upfront concurrent chemoradiotherapy (hazard ratio 0.33 vs. 0.34, p = 0.006 vs. 0.031) according to a Cox model adjusted for possible confounders. Moreover, upfront concurrent chemoradiotherapy did not lead to higher survival rates in patients with EGFR mutations than in those with EGFR wild‐type adenocarcinoma (progression‐free survival; hazard ratio 0.37, p = 0.036; overall survival; hazard ratio 0.35, p = 0.080) by Cox regression analysis. Conclusion This current study suggests that EGFR‐TKIs is a better choice for patients with unresectable stage III EGFR‐mutant adenocarcinoma. However, further randomized studies are required to validate the results., The study regarding comparison of upfront EGFR‐TKI and upfront CCRT in unresectable stage III EGFR‐mutant adenocarcinoma remain limited. Our real‐world data suggest that upfront EGFR‐TKI monotherapy is a better treatment strategy than upfront CCRT in unresectable stage III EGFR‐mutant adenocarcinoma.

Jia-You Fang,1– 3 Wei-Ling Chou,4 Chwan-Fwu Lin,2,3,5 Calvin T Sung,6 Ahmed Alalaiwe,7 Shih-Chun Yang1,8 1Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; 2Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; 3Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan; 4Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan; 5Department of Cosmetic Science, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; 6Department of Dermatology, University of California, Irvine, CA, USA; 7Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia; 8Department of Cosmetic Science, Providence University, Taichung, TaiwanCorrespondence: Shih-Chun YangPharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, TaiwanEmail phageyang@gmail.comBackground: The biofilm produced by Cutibacterium acnes is a major infection threat for skin and implanted catheters. Nanoparticles provide a new approach to eradicate biofilms. The present study evaluated the capability of cationic liposomes loaded with DNase I (DNS) and proteinase K (PK) to remove preformed C. acnes biofilms.Methods: DNS and PK were able to target and disassemble the biofilm by degrading extracellular polymer substances (EPS). Soyaethyl morpholinium ethosulfate (SME) was used to render a positive charge and enhance the antibacterial activity of the liposomes.Results: The cationic liposomes containing enzymes yielded monodisperse nanovesicles ranging between 95 and 150 nm. The entrapment efficiency of the enzymes in the liposomes achieved a value of 67– 83%. All liposomal formulations suppressed planktonic C. acnes growth at a minimum inhibitory concentration (MIC) equal to the free SME in the solution. The enzyme in the liposomal form inhibited biofilm growth much better than that in the free form, with the dual enzyme-loaded liposomes demonstrating the greatest inhibition of 54% based on a crystal violet assay. The biofilm-related virulence genes PA380 and PA1035 were downregulated by the combined enzymes in the liposomes but not the individual DNS or PK. Scanning electron microscopy (SEM) and confocal microscopy displayed reduced C. acnes aggregates and biofilm thickness by the liposomal system. The liposomes could penetrate through about 85% of the biofilm thickness. The in vitro pig skin permeation also showed a facile delivery of liposomes into the epidermis, deeper skin strata, and hair follicles. The liposomes exhibited potent activity to eliminate C. acnes colonization in mouse skin and catheters in vivo. The colony-forming units (CFUs) in the catheter treated with the liposomes were reduced by 2 logs compared to the untreated control.Conclusion: The data suggested a safe application of the enzyme-loaded cationic liposomes as antibacterial and antibiofilm agents.Keywords: liposomes, cationic surfactant, DNase I, proteinase K, Cutibacterium acnes, biofilm

Background/purpose To quantify savings of loss-of-QALE (quality-adjusted life expectancy) and lifetime medical costs from prevention of different cancers. Methods We collected nation-wide data on 808,700 new cancer cases of 14 different organ systems and followed them from 1998 to 2014 in Taiwan. We also collected 13,005 cancer patients from a medical center and 47,320 repeated measurements of quality of life (QoL) of EQ-5D to obtain utility values and multiplied them with the corresponding survival rates to calculate QALE. With Kaplan–Meier estimation to survival function to the end of follow-up, we extrapolated to lifetime through a rolling over algorithm on the logit transform of the survival ratio between the index cohort and age-, sex, and calendar year matched referents simulated from vital statistics. Lifetime costs for each cancer were estimated by multiplying survival with average monthly costs after adjustment with annual discount rate. The loss-of-QALE was estimated by the difference in QALE between the index cancer cohort and corresponding referents. Results The dynamic changes and weighted averages of the QoL utility values of 14 different cancers ranged from 0.82 to 0.95. Successful prevention of liver, lung, esophagus, or nasopharynx cancer would save more than 10 quality-adjusted life years and more than 21,000 USD per case for both genders. Since the saving of loss-of-QALE was adjusted for different age, sex, and calendar-year distributions, it could be used in cost effectiveness evaluation. Conclusion Savings of loss-of-QALE and lifetime costs could be used for comparison of prevention, diagnosis, treatment and rehabilitation from a lifetime horizon.

Background and aims A simplified magnetic resonance index of activity (MaRIAs) was recently proposed. Our aim was to verify whether MaRIAs can accurately assess the activity degree of CD. Methods We retrospectively analyzed the MRI, ileocolonoscopy, fecal calprotectin (FC), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) data of 93 CD patients. With the SES-CD as the gold standard, MaRIAs’ accuracy, the correlation of MaRIAs and SES-CD, FC, ESR, CRP, and interevaluator reliability were assessed. Results MaRIAs ≥ 1 detected segments with active CD with 90.80% specificity and 81.37% sensitivity (area under the curve was 0.91, 95% confidence interval 0.87–0.94). MaRIAs score of 2 or more detected severe lesions with 88.89% specificity and 95.12% sensitivity (AUC was 0.96, 95% confidence interval was 0.94–0.98). The MaRIAs score showed a high correlation with the SES-CD in the terminal ileum, transverse colon, right colon, and left colon (r = 0.85, 0.91, 0.88, 0.86, P r = 0.74, P r = 0.90, P r = 0.77, r = 0.64, and r = 0.68). The intragroup correlation coefficient (ICC) of the two physicians was nice in the terminal ileum, the right colon, the transverse colon, the left colon and was moderately good in the rectum. Conclusion MaRIAs can accurately evaluate the disease activity level of CD and are highly correlated with SES-CD and biomarkers. The interrater reliability of the two physicians was moderately good to nice.

Background Immune indicators are routinely used for the detection of myelodysplastic syndrome (MDS), but these are not utilized as a reference indicator to assess prognosis in MDS-related prognostic evaluation systems, such as the World Health Organizational prognostic scoring system, the international prostate symptom score, and the revised international prostate symptom score. Methods We examined immune indicators, including cluster of differentiation (CD)3, CD4, CD8, CD56, CD19, interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-a, and interferon-γ in 155 newly diagnosed MDS patients. We also conducted a correlation analysis with clinical indices. Results IL-4 was found to be a predictor of survival in these 155 patients using the receiver operating characteristic curve, with 5.155 as the cut-off point. Patients with serum IL-4 levels ≥ 5.155 had a lower overall survival (OS) than those with IL-45.155 at diagnosis. Furthermore, multivariate analysis revealed that IL-4 levels > 5.155 were an independent predictor of OS (hazard ratio: 0.237; 95% confidence interval, 0.114–0.779; P = 0.013). In addition, serum IL-4 expression in the three different scoring systems showed significant differences in the survival of medium- to high-risk MDS patients (P = 0.014, P P Conclusions According to our study, IL-4 levels at the time of diagnosis can predict MDS prognosis in patients as a simple index reflecting host systemic immunity.

Lipoprotein modification by reactive dicarbonyls, including isolevuglandin (IsoLG), produces dysfunctional particles. Kidneys participate in lipoprotein metabolism, including tubular uptake. However, the process beyond the proximal tubule is unclear, as is the effect of kidney injury on this pathway. We found that patients and animals with proteinuric injury have increased urinary apolipoprotein AI (apoAI), IsoLG, and IsoLG adduct enrichment of the urinary apoAI fraction compared with other proteins. Proteinuric mice, induced by podocyte-specific injury, showed more tubular absorption of IsoLG-apoAI and increased expression of lipoprotein transporters in proximal tubular cells compared with uninjured animals. Renal lymph reflects composition of the interstitial compartment and showed increased apoAI and IsoLG in proteinuric animals, supporting a tubular cell-interstitium-lymph pathway for renal handling of lipoproteins. IsoLG-modified apoAI was not only a marker of renal injury but also directly damaged renal cells. IsoLG-apoAI increased inflammatory cytokines in cultured tubular epithelial cells (TECs), activated lymphatic endothelial cells (LECs), and caused greater contractility of renal lymphatic vessels than unmodified apoAI. In vivo, inhibition of IsoLG by a dicarbonyl scavenger reduced both albuminuria and urinary apoAI and decreased TEC and LEC injury, lymphangiogenesis, and interstitial fibrosis. Our results indicate that IsoLG-modified apoAI is, to our knowledge, a novel pathogenic mediator and therapeutic target in kidney disease.

Background Suicide remains the second leading cause of death among youths. Family-related factors are considered important determinants of children's suicidal ideation, whereas their short-/long-term influence is seldom quantified. Aims We aim to confirm the simultaneous/lagged effects of family-related factors on the occurrence of recent suicidal ideation from childhood to young adulthood (aged from 10 to 22 years old). Method Data were derived from a longitudinal prospective cohort study. Participants included 2065 students who were followed up for 13 years. Generalized estimating equations were used to clarify the influential effects of family-related factors on suicidal ideation during the past month. Results The peak of the rate of recent suicidal ideation arrived during junior high school years. Family interaction, family support, family involvement, and parental punishment had simultaneous effects on recent suicidal ideation. Family involvement, parental conflict, and psychological control had lagged and lasting effects on suicidal ideation. Notably, the lasting protective effects of family involvement were more obvious than simultaneous effects. Conclusions Providing parents with sustained support and education to improve their "positive parenting literacy" can help with their children's mental health development. This is especially the case during COVID-19 quarantine periods when families spend the most time together at home.

Seawater, NaOH, NaClO, NaClO2, H2O2 and KMnO4 were used as scrubbing liquids to react with SOx and NOx separately in a customized wet scrubber. The absorption of SO2 in the aqueous phase was influenced by three factors: pH, ionic concentration and oxidation potential. For NOx removal, the effectiveness of various chemical compounds can be ranked from least to most effective as follows: Seawater, NaOH, H2O2 4 2. This effectiveness was influenced by the chemical compound’s ability to oxidize NO to NO2, absorb the NO2 that was formed and retaining the nitrogen in the aqueous phase. High oxidation potential promoted the oxidation of NO to NO2 but hindered the absorption of NO2. NaClO2 was superior compared to NaClO in all three categories of oxidizing, absorption and retention. NaClO could not retain a significant amount of NO2 which it absorbed in the aqueous phase. The pH around 8 provided a good balance between oxidation versus absorption/retention and reactant utilization for the chlorine-based oxidants. KMnO4 had the lowest reactant consumption rate; only half a mole was consumed for every mole of NO removed, compared to around 2–3 moles of chlorite or 3–5 moles of hypochlorite.