Novel potential biomarkers for severe alcoholic liver disease

BackgroundAlcoholic liver disease (ALD) is a leading cause of advanced liver disease; however, minor clinical symptoms in the early stage frequently result in delayed diagnosis and therapy. Invasive liver biopsy, the gold standard for diagnosing ALD, is unsuitable for repetitive analysis. This study aims to identify potential serum biomarkers that could contribute to non-invasive disease screening and monitoring.MethodsLabel-free LC-MS/MS quantitative proteomics analysis was performed to identify differentially expressed proteins in the discovery cohort, followed by bioinformatics analysis based on the KEGG, GO, and String databases. Prioritized proteins were validated subsequently by quantitative assays. The area under the receiver operating characteristic curve (AUROC) was used to assess the diagnosis performance of potential biomarkers.ResultsA total of 161 differentially expressed proteins were identified in the discovery cohort, of which 123 were up-regulated and 38 were down-regulated. B2M, IGFALS, and IGFBP3 were evaluated, and all demonstrated excellent diagnosis performance with AUROCs of over 0.9 when distinguishing patients with severe ALD from healthy controls. The AUROC values of B2M, IGFBP3, and IGFALS were 0.7131, 0.8877, and 0.9896 for differentiating severe ALD from non-severe ALD to indicate disease severity. B2M could distinguish patients with non-severe ALD and HC participants with an AUROC value of 0.8985. The efficiency of multiple combinations of these biomarkers was superior to that of the existing liver fibrosis evaluation indices used to monitor disease progression, with AUROC values of over 0.9. IGFALS showed a positive correlation with ALT/AST (r=0.4648, P=0.0009) and may be developed as a therapeutic target.ConclusionThis proteomic study identified three novel candidate proteins as promising circulating biomarkers for clinical diagnosis and disease progression and also provided the proteomic atlas for ALD pathophysiological mechanisms

Multiple linear epitopes (B-cell, CTL and Th) of JEV expressed in recombinant MVA as multiple epitope vaccine induces a protective immune response

Epitope-based vaccination might play an important role in the protective immunity against Japanese encephalitis virus (JEV) infection. The purpose of the study is to evaluate the immune characteristics of recombinant MVA carrying multi-epitope gene of JEV (rMVA-mep). The synthetic gene containing critical epitopes (B-cell, CTL and Th) of JEV was cloned into the eukaryotic expression vector pGEM-K1L, and the rMVA-mep was prepared. BALB/c mice were immunized with different dosages of purified rMVA-mep and the immune responses were determined in the form of protective response against JEV, antibodies titers (IgG1 and IgG2a), spleen cell lymphocyte proliferation, and the levels of interferon-γ and interleukin-4 cytokines. The results showed that live rMVA-mep elicited strongly immune responses in dose-dependent manner, and the highest level of immune responses was observed from the groups immunized with 107 TCID50 rMVA-mep among the experimental three concentrations. There were almost no difference of cytokines and neutralizing antibody titers among 107 TCID50 rMVA-mep, recombinant ED3 and inactivated JEV vaccine. It was noteworthy that rMVA-mep vaccination potentiates the Th1 and Th2-type immune responses in dose-dependent manner, and was sufficient to protect the mice survival against lethal JEV challenge. These findings demonstrated that rMVA-mep can produce adequate humoral and cellular immune responses, and protection in mice, which suggested that rMVA-mep might be an attractive candidate vaccine for preventing JEV infection

Characterization of a porcine model of atrial arrhythmogenicity in the context of ischaemic heart failure

Atrial fibrillation (AF) is a major healthcare challenge contributing to high morbidity and mortality. Treatment options are still limited, mainly due to insufficient understanding of the underlying pathophysiology. Further research and the development of reliable animal models resembling the human disease phenotype is therefore necessary to develop novel, innovative and ideally causal therapies. Since ischaemic heart failure (IHF) is a major cause for AF in patients we investigated AF in the context of IHF in a close-tohuman porcine ischaemia-reperfusion model. Myocardial infarction (AMI) was induced in propofol/fentanyl/ midazolam-anaesthetized pigs by occluding the left anterior descending artery for 90 minutes to model ischaemia with reperfusion. After 30 days ejection fraction (EF) was significantly reduced and haemodynamic parameters (pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), left ventricular enddiastolic pressure (LVEDP)) were significantly elevated compared to age/weight matched control pigs without AMI, demonstrating an IHF phenotype. Electrophysiological properties (sinus node recovery time (SNRT), atrial/AV nodal refractory periods (AERP, AVERP)) did not differ between groups. Atrial burst pacing at 1200 bpm, however, revealed a significantly higher inducibility of atrial arrhythmia episodes including AF in IHF pigs (3/15 vs. 10/16, p = 0.029). Histological analysis showed pronounced left atrial and left ventricular fibrosis demonstrating a structural substrate underlying the increased arrhythmogenicity. Consequently, selective ventricular infarction via LAD occlusion causes haemodynamic alterations inducing structural atrial remodeling which results in increased atrial fibrosis as the arrhythmogenic atrial substrate in pigs with IHF

Feature Flow: In-network Feature Flow Estimation for Video Object Detection

Optical flow, which expresses pixel displacement, is widely used in many computer vision tasks to provide pixel-level motion information. However, with the remarkable progress of the convolutional neural network, recent state-of-the-art approaches are proposed to solve problems directly on feature-level. Since the displacement of feature vector is not consistent to the pixel displacement, a common approach is to:forward optical flow to a neural network and fine-tune this network on the task dataset. With this method,they expect the fine-tuned network to produce tensors encoding feature-level motion information. In this paper, we rethink this de facto paradigm and analyze its drawbacks in the video object detection task. To mitigate these issues, we propose a novel network (IFF-Net) with an \textbf{I}n-network \textbf{F}eature \textbf{F}low estimation module (IFF module) for video object detection. Without resorting pre-training on any additional dataset, our IFF module is able to directly produce \textbf{feature flow} which indicates the feature displacement. Our IFF module consists of a shallow module, which shares the features with the detection branches. This compact design enables our IFF-Net to accurately detect objects, while maintaining a fast inference speed. Furthermore, we propose a transformation residual loss (TRL) based on \textit{self-supervision}, which further improves the performance of our IFF-Net. Our IFF-Net outperforms existing methods and sets a state-of-the-art performance on ImageNet VID

Optimal promotional mix and pricing when faced with uncertain product value

The rapid development of digital technology has facilitated firms to adopt a variety of innovative strategies for promoting their new products. However, as different promotion strategies have different implications on market reach, consumers’ information structure, and incurred cost, figuring out how to minimize wastage on marketing expenditure with a combination of multiple promotion strategies remains a challenging task. To provide insights into the efficient adoption of a promotional mix, we develop a stylized model that considers a firm selling an innovative product to a market wherein the product value is ex ante unknown to each consumer and the firm. The firm has two promotion strategies, hype advertising campaign (HAC) and referral reward program (RRP). Specifically, HAC refers to a basic publicity that aims only on raising product awareness through an extensive market reach. In contrast, in line with the pay-for-performance nature, RRP is an incentive-based program that offers rewards to the existing customers for bringing new buyers through consumer-to-consumer (C2C) referrals. Whereas both strategies allow previously ignorant consumers to learn of a product’s existence, due to the variation on the communication intensity, only those who become aware of the product through C2C referrals will be able to make an informed purchase decision. We find that both HAC and RRP should not always be adopted simultaneously since consumer referrals may intensify the wastage on HAC expenditure. The condition under which the promotional mix yields the optimal outcome and the circumstances when the firm should abandon either HAC or RRP are investigated

The Role of Mitochondrial Quality Control in Cardiac Ischemia/Reperfusion Injury

A healthy mitochondrial network produces a large amount of ATP and biosynthetic intermediates to provide sufficient energy for myocardium and maintain normal cell metabolism. Mitochondria form a dynamic and interconnected network involved in various cellular metabolic signaling pathways. As mitochondria are damaged, controlling mitochondrial quantity and quality is activated by changing their morphology and tube network structure, mitophagy, and biogenesis to replenish a healthy mitochondrial network to preserve cell function. There is no doubt that mitochondrial dysfunction has become a key factor in many diseases. Ischemia/reperfusion (IR) injury is a pathological manifestation of various heart diseases. Cardiac ischemia causes temporary tissue and organelle damage. Although reperfusion is essential to compensate for nutrient deficiency, blood flow restoration inconsequently further kills the previously ischemic cardiomyocytes. To date, dysfunctional mitochondria and disturbed mitochondrial quality control have been identified as critical IR injury mechanisms. Many researchers have detected abnormal mitochondrial morphology and mitophagy, as well as aberrant levels and activity of mitochondrial biogenesis factors in the IR injury model. Although mitochondrial damage is well-known in myocardial IR injury, the causal relationship between abnormal mitochondrial quality control and IR injury has not been established. This review briefly describes the molecular mechanisms of mitochondrial quality control, summarizes our current understanding of the complex role of mitochondrial quality control in IR injury, and finally speculates on the possibility of targeted control of mitochondria and the methods available to mitigate IR injury

Macrocycles and Related Hosts as Supramolecular Antidotes

International audienceMacrocycles and congeners are now being used to reverse the effects of poisonous substances and to alleviate the toxicity of several medicines in vivo. Here we showcase the emergence of this class of compounds behaving as supramolecular antidotes, some of which outperform "gold standards" in the field

Semiconductor Quantum Dots Surface Modification for Potential Cancer Diagnostic and Therapeutic Applications

Semiconductor Quantum dots (QDs) have generated extensive interest for biological and clinical applications. These applications arise from their unique properties, such as high brightness, long-term stability, simultaneous detection of multiple signals, tunable emission spectra. However, high-quality QDs, whether single or core-shell QDs, are most commonly synthesized in organic solution and surface-stabilized with hydrophobic organic ligands and thus lack intrinsic aqueous solubility. For biological applications, very often it is necessary to make the QDs dispersible in water and therefore to modify the QD surfaces with various bifunctional surface ligands or caps to promote solubility in aqueous media. Well-defined methods have been developed for QD surface modification to impart biocompatibility to these systems. In this review, we summarize the recent progress and strategies of QDs surface modification for potential cancer diagnostic and therapeutic applications. In addition, the question that arose from QD surface modification, such as impact of size increase of QD bioconjugates after surface-functionalization or surface modification on photophysical properties of QDs, are also discussed