A recurrence of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) is one of the major concerns reflecting the higher mortality of HCC. This study aimed to explore the ...impact of circulating exosomes on HCC development and recurrence. One‐shot transfusion of hepatoma serum to naïve rats induced liver cancer development with gradual elevation of alpha‐fetoprotein (AFP), but exosome‐free hepatoma serum failed to induce AFP elevation. The microarray analysis revealed miR‐92b as one of the highly expressing microribonucleic acids in hepatoma serum exosomes. Overexpression of miR‐92b enhanced the migration ability of liver cancer cell lines with active release of exosomal miR‐92b. The hepatoma‐derived exosomal miR‐92b transferred to natural killer (NK) cells, resulting in the downregulation of CD69 and NK cell‐mediated cytotoxicity. Furthermore, higher expression of miR‐92b in serum exosomes was confirmed in HCC patients before LDLT, and its value at 1 month after LDLT was maintained at a higher level in the patients with posttransplant HCC recurrence. In summary, we demonstrated the impact of circulating exosomes on liver cancer development, partly through the suppression of CD69 on NK cells by hepatoma‐derived exosomal miR‐92b. The value of circulating exosomal miR‐92b may predict the risk of posttransplant HCC recurrence.
This study demonstrates the impact of circulating exosomes on liver cancer development in rats, explores functional roles of exosomal miR‐92b in the tumor microenvironment, and verifies its clinical value for early prediction of posttransplant hepatocellular carcinoma recurrence.
Frailty status can be improved by intervention. Both exergaming and combined exercise have been proposed for improving physical performance in community-dwelling elderly. However, whether frailty ...status can be improved by exergaming is unclear. Moreover, whether Kinect-based exergaming training can exert a stronger effect on improving frailty status than combined exercise needs to be established. The aim of this study was to investigate the effects of Kinect-based exergaming on improving frailty status and physical performance in the prefrail and frail elderly by comparing its effects with those of combined exercise. Fifty-two prefrail and frail elderly were recruited and randomized to the Kinect-based exergaming group (EXER group) or combined exercise group (CE group), emphasizing resistance, aerobic, and balance training for 36 sessions over 12 weeks. Our results showed that both groups improved the frailty status (EXER group: p = 0.016, effect size = 2.29; and CE group: p = 0.031, effect size = 2.67). Three out of 5 physical characteristics of the frailty phenotype, namely, weakness, slow walking speed, and low activity level, were significantly reversed by both exergaming and combined exercise. However, the exergaming training also significantly reversed exhaustion. Furthermore, compared with the CE group, the EXER group showed greater improvement in dynamic balance control, as indicated by the forward reaching test (p = 0.0013, effect size = 0.40) and single leg stance test (p = 0.049, effect size = 0.42). Thus, Kinect-based exergaming exerted effects that were at least as beneficial as those of combined exercise in improving frailty status and the frailty phenotype. We recommend the use of exergaming aided by Kinect in the prefrail and frail elderly.
In a smart home linked to a smart grid (SG), demand-side management (DSM) has the potential to reduce electricity costs and carbon/chlorofluorocarbon emissions, which are associated with electricity ...used in today's modern society. To meet continuously increasing electrical energy demands requested from downstream sectors in an SG, energy management systems (EMS), developed with paradigms of artificial intelligence (AI) across Internet of things (IoT) and conducted in fields of interest, monitor, manage, and analyze industrial, commercial, and residential electrical appliances efficiently in response to demand response (DR) signals as DSM. Usually, a DSM service provided by utilities for consumers in an SG is based on cloud-centered data science analytics. However, such cloud-centered data science analytics service involved for DSM is mostly far away from on-site IoT end devices, such as DR switches/power meters/smart meters, which is usually unacceptable for latency-sensitive user-centric IoT applications in DSM. This implies that, for instance, IoT end devices deployed on-site for latency-sensitive user-centric IoT applications in DSM should be aware of immediately analytical, interpretable, and real-time actionable data insights processed on and identified by IoT end devices at IoT sources. Therefore, this work designs and implements a smart edge analytics-empowered power meter prototype considering advanced AI in DSM for smart homes. The prototype in this work works in a cloud analytics-assisted electrical EMS architecture, which is designed and implemented as edge analytics in the architecture described and developed toward a next-generation smart sensing infrastructure for smart homes. Two different types of AI deployed on-site on the prototype are conducted for DSM and compared in this work. The experimentation reported in this work shows the architecture described with the prototype in this work is feasible and workable.
Modality exclusivity norms have been developed in different languages for research on the relationship between perceptual and conceptual systems. This paper sets up the first modality exclusivity ...norms for Chinese, a Sino-Tibetan language with semantics as its orthographically relevant level. The norms are collected through two studies based on Chinese sensory words. The experimental designs take into consideration the morpho-lexical and orthographic structures of Chinese. Study 1 provides a set of norms for Mandarin Chinese single-morpheme words in mean ratings of the extent to which a word is experienced through the five sense modalities. The degrees of modality exclusivity are also provided. The collected norms are further analyzed to examine how sub-lexical orthographic representations of sense modalities in Chinese characters affect speakers' interpretation of the sensory words. In particular, we found higher modality exclusivity rating for the sense modality explicitly represented by a semantic radical component, as well as higher auditory dominant modality rating for characters with transparent phonetic symbol components. Study 2 presents the mean ratings and modality exclusivity of coordinate disyllabic compounds involving multiple sense modalities. These studies open new perspectives in the study of modality exclusivity. First, links between modality exclusivity and writing systems have been established which has strengthened previous accounts of the influence of orthography in the processing of visual information in reading. Second, a new set of modality exclusivity norms of compounds is proposed to show the competition of influence on modality exclusivity from different linguistic factors and potentially allow such norms to be linked to studies on synesthesia and semantic transparency.
The state of protein phosphorylation can be a key determinant of cellular physiology such as early-stage cancer, but the development of phosphoproteins in biofluids for disease diagnosis remains ...elusive. Here we demonstrate a strategy to isolate and identify phosphoproteins in extracellular vesicles (EVs) from human plasma as potential markers to differentiate disease from healthy states. We identified close to 10,000 unique phosphopeptides in EVs isolated from small volumes of plasma samples. Using label-free quantitative phosphoproteomics, we identified 144 phosphoproteins in plasma EVs that are significantly higher in patients diagnosed with breast cancer compared with healthy controls. Several biomarkers were validated in individual patients using paralleled reaction monitoring for targeted quantitation. This study demonstrates that the development of phosphoproteins in plasma EV as disease biomarkers is highly feasible and may transform cancer screening and monitoring.
DNA methylation is an epigenetic mechanism essential for gene regulation and vital for mammalian development. 5-hydroxymethylcytosine (5hmC) is the first oxidative product of the TET-mediated ...5-methylcytosine (5mC) demethylation pathway. Aside from being a key intermediate in cytosine demethylation, 5hmC may have potential regulatory functions with emerging importance in mammalian biology.
Here, we investigate the global 5hmC enrichment in five brain structures, including cerebellum, cerebral cortex, hippocampus, hypothalamus and thalamus, as well as liver tissues from female and male adult mice by using chemical capture-based technique coupled with next-generation sequencing. At the same time, we carried out total RNA sequencing (RNA-seq) to analyze the transcriptomes of brain regions and liver tissues.
Our results reveal preferential 5hmC enrichment in the gene bodies of expressed genes, and 5hmC levels of many protein-coding genes are positively correlated with RNA expression intensity. However, more than 75% of genes with low or no 5hmC enrichment are genes encode for mitochondrial proteins and ribosomal proteins despite being actively transcribed, implying different transcriptional regulation mechanisms of these housekeeping genes. Brain regions developed from the same embryonic structures have more similar 5hmC profiles. Also, the genic 5hmC enrichment pattern is highly tissue-specific, and 5hmC marks genes involving in tissue-specific biological processes. Sex chromosomes are mostly depleted of 5hmC, and the X inactive specific transcript (Xist) gene located on the X chromosome is the only gene to show sex-specific 5hmC enrichment.
This is the first report of the whole-genome 5hmC methylome of five major brain structures and liver tissues in mice of both sexes. This study offers a comprehensive resource for future work of mammalian cytosine methylation dynamics. Our findings offer additional evidence that suggests 5hmC is an active epigenetic mark stably maintained after the global reprogramming event during early embryonic development.
Host cell proteins (HCPs) impurities are critical quality attributes that have the potential to negatively impact the quality and safety profile of a biopharmaceutical product. Since HCPs often are ...present at low levels, developing highly sensitive analytical method for their identification and quantitation is critical for process optimization and improvement to reduce them in the final drug product. While an enzyme-linked immunosorbent assay (ELISA) can capture and quantify overall HCP levels, liquid chromatography coupled to mass spectrometry (LC-MS) is emerging as a powerful tool to monitor individual HCP levels during the purification process development. The massive dynamic range of protein species present in a therapeutic antibody is a major challenge for mass spectrometry-based methods to detect low-abundance HCP impurities. This study reports a powerful strategy to identify HCPs in antibody drug substance by applying ProteoMiner enrichment with optimized conditions followed by shotgun proteomic analysis. Using this strategy, we observed that the low abundance HCPs were enriched up to 1000-fold. In addition, by spiking in known amounts of HCPs to purified antibody drug substance with low levels of HCPs, we demonstrated that our method could detect HCP at a concentration as low as 0.05 ppm. When applying this methodology to the study of HCPs in NIST monoclonal antibody (NISTmAb), more than 500 HCPs were confidently identified, which tripled the number of identified HCPs that have been previously reported. Parallel reaction monitoring (PRM) results confirmed that the novel HCPs found using this method were enriched between 100 and 400-fold, highlighting that our method enriches and equalizes all proteins thus improving the sensitivity of HCP identification and quantification.
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•The optimized ProteoMiner protocol provides detection limit as low as 0.05 ppm of HCP in therapeutic antibody drug.•More than 500 host cell proteins were identified in NIST standard using this strategy.•High reproducibility demonstrated this strategy is highly stable and repeatable.
Background
Dyspepsia is a prevalent condition in the general population. Besides organic causes, the differential diagnosis of dyspepsia includes functional dyspepsia (FD) and gastroparesis (GP) ...which share similar pathophysiological mechanisms and clinical presentation. So far, no study investigated the prevalence of FD and GP in a primary care in Belgium.
Methods
Data were obtained from Intego, a Flemish‐Belgian general practice‐based morbidity registration network. From 586,164 patients between 2000 and 2021, we selected patients with ICD‐10 code for FD and GP. Patients with organic gastrointestinal diseases were excluded. We determined demographics and comorbidities of FD/GP. For prevalence and incidence calculation, we included those who consulted their general practitioners at least once in the given year. Pair‐wise comparison was conducted to access the impact of comorbidities on risk of FD/GP.
Key Results
Between 2011 and 2021, the prevalence of FD/GP ranged from 1.03% to 1.21%. The incidence of FD/GP ranged from 109 to 142 per 100,000 adults. In total 5242 cases of FD/GP were identified. These cases shared commonly coexisting diagnoses of gastroesophageal reflux disease (18.8%), irritable bowel syndrome (17.1%), and chronic constipation (18.7%). Patients with somatization/anxiety/depression had significantly higher risk of FD/GP, compared to the control (OR 1.38, 95% CI 1.19–1.61, p < 0.01).
Conclusions and Inferences
The prevalence (1.03%–1.21%) and incidence (109–142/100,000) of FD/GP in primary care over last decade appear to conflict with epidemiological research in the general population. The discrepancies suggest a potential lack of awareness of FD and GP among physicians and/or patients in Flemish‐Belgium.
The prevalence (1.03%–1.21%) and incidence (109–142/100,000) of functional dyspepsia/gastroparesis in primary care remained stable over the past decade in primary care and were less prevalent than in the general population. The discrepancies suggest a potential lack of awareness of two entities among physicians and/or patients in Flemish‐Belgium.
Extracellular vesicles (EVs) are increasingly being recognized as important vehicles for intercellular communication and as promising sources for biomarker discovery. Because the state of protein ...post-translational modifications (PTMs) such as phosphorylation and glycosylation can be a key determinant of cellular physiology, comprehensive characterization of protein PTMs in EVs can be particularly valuable for early-stage diagnostics and monitoring of disease status. However, the analysis of PTMs in EVs has been complicated by limited amounts of purified EVs, low-abundance PTM proteins, and interference from proteins and metabolites in biofluids. Recently, we developed an approach to isolate phosphoproteins and glycoproteins in EVs from small volumes of human plasma that enabled us to identify nearly 10,000 unique phosphopeptides and 1,500 unique N-glycopeptides. The approach demonstrated the feasibility of using these data to identify potential markers to differentiate disease from healthy states. Here we present an updated workflow to sequentially isolate phosphopeptides and N-glycopeptides, enabling multiple PTM analyses of the same clinical samples. In this updated workflow, we have improved the reproducibility and efficiency of EV isolation, protein extraction, and phosphopeptide/N-glycopeptide enrichment to achieve sensitive analyses of low-abundance PTMs in EVs isolated from 1 mL of plasma. The modularity of the workflow also allows for the characterization of phospho- or glycopeptides only and enables additional analysis of total proteomes and other PTMs of interest. After blood collection, the protocol takes 2 d, including EV isolation, PTM/peptide enrichment, mass spectrometry analysis, and data quantification.
Summary
Background
The European consensus defined gastroparesis as a condition characterised by delayed gastric emptying (GE) in the absence of mechanical obstruction, with a symptom pattern of ...predominant nausea and/or vomiting and overlapping postprandial distress syndrome (PDS). The distinction between patients with gastroparesis and those with functional dyspepsia (FD), another gastrointestinal condition characterised by predominant PDS or epigastric pain syndrome symptoms, is ongoing.
Aim
To investigate the extent that symptom patterns may differentiate gastroparesis from FD.
Methods
This retrospective study included 637 patients from Leuven University Hospital in 2006–2021 who had upper gastrointestinal symptoms, underwent a GE test, and completed the Dyspepsia Symptom Severity (DSS) questionnaire. Patients were identified as with gastroparesis‐like symptoms (GPLS; i.e., moderate to severe nausea with moderate to severe PDS) or FD symptoms (not fitting GPLS). We excluded patients aged <18 years, and those with diabetes, organic gastrointestinal disease or a history of abdominal surgeries. Demographic and clinical variables were compared.
Results
Among 545 patients, 238 reported GPLS and 307 reported FD symptoms. Those with GPLS had a significantly higher prevalence of delayed GE (half emptying time (T1/2) ≥109 min) and lower body mass index than those with FD (33.2% vs 17.6%, p < 0.01; 19.9 vs 21.2, p < 0.01, respectively). Among GPLS patients, those with delayed GE had higher DSS than those without (13.0 vs 12.0, p < 0.01).
Conclusions
In tertiary care patients who reported gastroparesis or FD symptoms, the presence of delayed GE was associated with GPLS. In patients with GPLS, delayed GE was associated with higher symptom severity.
Prevalence of delayed gastric emptying in patients with gastroparesis‐like symptoms.
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