Intracellular interferons in fish : a unique means to combat viral infection

Peer reviewedPublisher PD

HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndrome

Introduction: Sjögren’s syndrome (SS) is a chronic autoimmune disorder characterized by exocrine gland dysfunction, leading to loss of salivary function. Histological analysis of salivary glands from SS patients reveals a high infiltration of immune cells, particularly activated CD4+ T cells. Thus, interventions targeting abnormal activation of CD4+ T cells may provide promising therapeutic strategies for SS. Here, we demonstrate that Hect, uba, and wwe domain containing 1 (HUWE1), a member of the eukaryotic Hect E3 ubiquitin ligase family, plays a critical role in CD4+ T-cell activation and SS pathophysiology.Methods: In the context of HUWE1 inhibition, we investigated the impact of the HUWE1 inhibitor BI8626 and sh-Huwe1 on CD4+ T cells in mice, focusing on the assessment of activation levels, proliferation capacity, and cholesterol abundance. Furthermore, we examined the therapeutic potential of BI8626 in NOD/ShiLtj mice and evaluated its efficacy as a treatment strategy.Results: Inhibition of HUWE1 reduces ABCA1 ubiquitination and promotes cholesterol efflux, decreasing intracellular cholesterol and reducing the expression of phosphorylated ZAP-70, CD25, and other activation markers, culminating in the suppressed proliferation of CD4+ T cells. Moreover, pharmacological inhibition of HUWE1 significantly reduces CD4+ T-cell infiltration in the submandibular glands and improves salivary flow rate in NOD/ShiLtj mice.Conclusion: These findings suggest that HUWE1 may regulate CD4+ T-cell activation and SS development by modulating ABCA1-mediated cholesterol efflux and presents a promising target for SS treatment

A scenario analysis-based optimal management of water resources supply and demand balance: A case study of Chengdu, China.

Water resources scarcity has threatened the coordinative development of demographics, society and economy. As a typical rapidly urbanizing area and an emerging megacity in China, Chengdu is confronting the pressure of inadequate water supply. The present study divides the macroeconomic factors that affect the water resource supply and demand balance into six major subsystems: water resources supply, water demand, water drainage, population, ecological environment and economy. The combining variable interaction description and predictive simulation models are applied to simulate the water supply and demand ratio (S:D) from 2005 to 2035. Further, this study designs different development scenarios to simulate the change of S:D ratios by altering the parameter values of driving factors. The results show that: (1) the S:D ratio will decline if the current development scenario continues, implying the serious water resources shortage and the severe water supply-demand conflict in Chengdu; (2) socio-economic water demand and wastewater/rainwater reuse are the key driving parameters of S:D ratio, especially the water consumption per ten thousand yuan of industrial value-added; (3) the S:D ratio will increase from 0.92 in the current baseline scenario to 1.06 in the integrated optimization scenario in 2025, and the long-term planning brings 2035 from 0.71 to 1.03, with the proportion of unconventional water supply rise to 38% and 61%, respectively. This study can provide a decision-making tool for policy-makers to explore plausible policy scenarios necessary for bridging the gap between the water supply and demand in megacities

Intrinsic Safety Risk Control and Early Warning Methods for Lithium-Ion Power Batteries

Since 2014, the electric vehicle industry in China has flourished and has been accompanied by rapid growth in the power battery industry led by lithium-ion battery (LIB) development. Due to a variety of factors, LIBs have been widely used, but user abuse and battery quality issues have led to explosion accidents that have caused loss of life and property. Current strategies to address battery safety concerns mainly involve enhancing the intrinsic safety of batteries and strengthening safety controls with approaches such as early warning systems to alert users before thermal runaway and ensure user safety. In this paper, we discuss the current research status and trends in two areas, intrinsic battery safety risk control and early warning methods, with the goal of promoting the development of safe LIB solutions in new energy applications

Hypothetical modes of action of trout intracellular IFNs.

<p>Hypothetical modes of action of trout intracellular IFNs.</p

Overexpression of iIFN1a and iIFN1b in RTG-2 cells enhances resistance to viral infection.

<p>(A) Fluorescent microscopic images of GFP positive cells after transfection with ptGFP1-sIFN1, ptGFP1-iIFN1a or ptGFP1-iIFN1b. (B, C) Confirmation of overexpression of IFN genes in transfected RTG-2 by real time PCR and Western blotting using an antiserum to iIFN1b. (D) The impact on Mx expression of overexpression of IFN1 variants in RTG-2 cells. (E, F) The impact of overexpression of IFN1 variants on antiviral resistance of transfected cells following infection with VHSV. Cells overexpressing the IFN1 variants were infected with serial dilutions of virus (left hand wells) and compared with cells transfected with empty vector (ptGFP1) and uninfected cells (right hand wells) as controls. The cytopathic effect was visualized after staining with crystal violet (E) and subsequent spectrophotometric analysis (F). Note: no obvious cell lysis was observed for the cells transfected with ptGFP1-iIFN1b although they were lightly stained.</p

Characterisation of intracellular IFN receptors.

<p>(A) Phylogenetic tree analysis of identified trout IFN receptors with known homologues in vertebrates, as determined by the Neighbour-Joining method. The bootstrap values of the tree nodes are indicated as percentages. (B) Schematic illustrating the modes for generation of iIFNR transcript variants. Trout membrane bound and intracellular IFNAR1 are transcribed from two distinct genes whilst membrane bound and intracellular IFNAR2 are generated by alternative splicing of an RNA transcript derived from the same gene. (C) Protein structural domains of human and trout IFNAR1 and IFNAR2 receptors. (D, E) Confirmation that intracellular IFNR proteins are produced in RTG-2 cells. RTG-2 cells were transfected with pTurbo-iIFNR1-GFP or pTurbo-iIFNR2-GFP and analysed by Western blot analysis using a polyclonal antibody against GFP.</p

Alternative splicing of rainbow trout IFN1 mRNA leads to synthesis of intracellular proteins.

<p>(A) Diagram showing the alternative splicing of IFN transcripts and corresponding protein sequences of the trout IFN1 variants. (B) Confirmation that the intracellular IFN1 (iIFN1) proteins are translated from the IFN1 transcript variants. RTG-2 cells were transfected with plasmids containing the 5′ untranslated region and the open reading frame of the iIFN1a or iIFN1b cDNA linked to GFP cDNA, and then analysed for fusion protein production by Western blotting with a polyclonal antibody against GFP.</p

Expression of IFN1 and IFNAR variants in RTG-2 cells.

<p>(A) Constitutive expression in normal cells; (B, C, D) expression modulation of genes in RTG-2 cells incubated (B) or transfected (c) with polyI∶C, or in head kidney tissue of fish (n = 4) after VHSV infection (D). Gene expression was analysed by real time PCR and normalised to EF-1α. Fold change of gene expression was calculated by comparing the normalised gene expression between the treated and untreated groups. * = P<0.05 relative to unstimulated/uninfected control samples at the same time point.</p