•Many viruses have evolved to utilize the host UPS for their own benefit.•Viruses subvert the UPS to maintain optimal level/function of viral proteins.•Viruses exploit the UPS to degrade host ...proteins which impede viral growth.•The UPS serves as an important host anti-viral defense mechanism.•The UPS is inhibited by some viruses to prevent viral clearance.
The ubiquitin–proteasome system (UPS) plays a central role in a wide range of fundamental cellular functions by ensuring protein quality control and through maintaining a critical level of important regulatory proteins. Viruses subvert or manipulate this cellular machinery to favor viral propagation and to evade host immune response. The UPS serves as a double-edged sword in viral pathogenesis: on the one hand, the UPS is utilized by many viruses to maintain proper function and level of viral proteins; while on the other hand, the UPS constitutes a host defense mechanism to eliminate viral components. To combat this host anti-viral machinery, viruses have evolved to employ the UPS to degrade or inactivate cellular proteins that limit viral growth. This review will highlight our current knowledge pertaining to the different roles for the UPS in viral pathogenesis.
Viral myocarditis remains a prominent infectious-inflammatory disease for patients throughout the lifespan. The condition presents several challenges including varied modes of clinical presentation, ...a range of timepoints when patients come to attention, a diversity of approaches to diagnosis, a spectrum of clinical courses, and unsettled perspectives on therapeutics in different patient settings and in the face of different viral pathogens. In this review, we examine current knowledge about viral heart disease and especially provide information on evolving understanding of mechanisms of disease and efforts by investigators to identify and evaluate potential therapeutic avenues for intervention.
Fault diagnosis under specific working conditions has achieved remarkable success. However, due to variations in working conditions, the assumption that training and test samples are independent and ...identically distributed is often violated, which makes the diagnostic model brittle under unseen working conditions. To this end, a generic generalization strategy, namely, regularized domain adaptive weight optimization strategy (RDAWOs), is devised for fault diagnosis of rotating machinery. We first design the architecture of a 1-D convolutional neural network. Then, the hyperparameter regularization term and an adaptive pooling layer are designed to control the complexity and improve the adaptability of the overparameterized deep model, respectively. Finally, domain adaptive weight optimization is established to identify the working condition abundant in spurious label-related information and to mine the robust fault knowledge under various working conditions. Obtained results indicate the strong generalization ability for out-of-distribution samples, as well as relatively high diagnostic accuracy of the RDAWOs-based deep model under unseen working conditions.
Host nucleases are implicated in antiviral response through the processing of pathogen-derived nucleic acids. Among many host RNases, decapping enzymes DCP1 and 2, and 5'→3' exonuclease XRN1, which ...are components of the RNA decay machinery, have been extensively studied in prokaryotes, plants, and invertebrates but less so in mammalian systems. As a result, the implication of XRN1 and DCPs in viral replication, in particular, the spatio-temporal dynamics during RNA viral infections remains elusive. Here, we highlight that XRN1 and DCPs play a critical role in limiting several groups of RNA viral infections. This antiviral activity was not obvious in wild-type cells but clearly observed in type I interferon (IFN-I)-deficient cells. Mechanistically, infection with RNA viruses induced the enrichment of XRN1 and DCPs in viral replication complexes (vRCs), hence forming distinct cytoplasmic aggregates. These aggregates served as sites for direct interaction between XRN1, DCP1/2, and viral ribonucleoprotein that contains viral RNA (vRNA). Although these XRN1-DCP1/2-vRC-containing foci resemble antiviral stress granules (SGs) or P-body (PB), they did not colocalize with known SG markers and did not correlate with critical PB functions. Furthermore, the presence of 5' mono- and 5' triphosphate structures on vRNA was not required for the formation of XRN1-DCP1/2-vRC-containing foci. On the other hand, single-, double-stranded, and higher-ordered vRNA species play a role but are not deterministic for efficient formation of XRN1-DCP1/2 foci and consequent antiviral activity in a manner proportional to RNA length. These results highlight the mechanism behind the antiviral function of XRN1-DCP1/2 in RNA viral infections independent of IFN-I response, protein kinase R and PB function.
Oncolytic viruses have emerged as a promising strategy for cancer therapy due to their dual ability to selectively infect and lyse tumor cells and to induce systemic anti-tumor immunity. Among ...various candidate viruses, coxsackievirus group B (CVBs) have attracted increasing attention in recent years. CVBs are a group of small, non-enveloped, single-stranded, positive-sense RNA viruses, belonging to species human Enterovirus B in the genus Enterovirus of the family Picornaviridae. Preclinical studies have demonstrated potent anti-tumor activities for CVBs, particularly type 3, against multiple cancer types, including lung, breast, and colorectal cancer. Various approaches have been proposed or applied to enhance the safety and specificity of CVBs towards tumor cells and to further increase their anti-tumor efficacy. This review summarizes current knowledge and strategies for developing CVBs as oncolytic viruses for cancer virotherapy. The challenges arising from these studies and future prospects are also discussed in this review.
Breast cancer continues to be the most frequently diagnosed malignancy among women, putting their life in jeopardy. Cancer immunotherapy is a novel approach with the ability to boost the host immune ...system to recognize and eradicate cancer cells with high selectivity. As a promising treatment, immunotherapy can not only eliminate the primary tumors, but also be proven to be effective in impeding metastasis and recurrence. However, the clinical application of cancer immunotherapy has faced some limitations including generating weak immune responses due to inadequate delivery of immunostimulants to the immune cells as well as uncontrolled modulation of immune system, which can give rise to autoimmunity and nonspecific inflammation. Growing evidence has suggested that nanotechnology may meet the needs of current cancer immunotherapy. Advanced biomaterials such as nanoparticles afford a unique opportunity to maximize the efficiency of immunotherapy and significantly diminish their toxic side-effects. Here we discuss recent advancements that have been made in nanoparticle-involving breast cancer immunotherapy, varying from direct activation of immune systems through the delivery of tumor antigens and adjuvants to immune cells to altering immunosuppression of tumor environment and combination with other conventional therapies.
While silver nanoparticles are widely used to endow materials with antibacterial activity, silver nanowires (AgNWs) have not attracted much attention. Herein, the composites of bacterial cellulose ...(BC) and AgNWs were prepared through a novel step-by-step in situ biosynthesis which retains the three-dimensional network of BC. The results of water vapor permeability, water uptake rate, and water retention rate showed that the BC/AgNW wound dressings could absorb wound skin exudates and maintain moisture environments. Furthermore, the BC/AgNW dressings were robust and stretchable. More importantly, the BC/AgNW dressings exhibited sustained release of Ag+. The results from animal tests indicated that the BC/AgNW dressing with 38.4 wt% AgNWs exhibited higher expression levels of cytokeratin-10 and integrin-β4, greater proliferation of keratinocytes and formation of epithelial tissues and greatly improved skin regeneration over the bare BC. We propose that the integrated nanofibrous structure and the excellent and sustained antibacterial activity of AgNWs are responsible for the excellent in vivo wound healing ability and biocompatibility. These results suggest that the BC/AgNW composites have promising application as wound dressings.
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•Silver nanowires (AgNWs) and bacterial cellulose (BC) were integrated to obtain an advanced wound dressing.•The BC/AgNW dressing exhibited sustained release of silver ions.•The BC/AgNW dressing is robust, stretchable, antibacterial, and biocompatible.•The BC/AgNW dressing showed improved in vivo skin regeneration over bare BC.
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•A novel layer-by-layer in situ culture (LBLC) method was developed.•Bacterial cellulose/graphene/polyaniline nanocomposites were made by LBLC and polymerization.•The as-prepared ...nanocomposites are mechanically strong and highly flexible.•The as-prepared nanocomposites show excellent gravimetric capacitance and cycling stability.
Rational structure, mechanical robustness, high conductivity, and favorable flexibility are important requirements for superior electrodes, which should not only possess high capacitance but also have freestanding structure without collector to improve the overall performance of supercapacitors. Herein, we demonstrate the fabrication of three-dimensional (3D) porous graphene-containing nanocomposites with highly dispersed graphene (GE) nanosheets in a 3D matrix of bacterial cellulose (BC) by a novel layer-by-layer in situ culture (LBLC) method. The BC/GE nanocomposites are then deposited with polyaniline (PANI), leading to the formation of BC/GE/PANI nanocomposites. Mechanical tests demonstrate excellent robustness and flexibility of the as-prepared BC/GE/PANI nanocomposites, which are used as electrodes directly without any nickel foam or stainless steel wire. The BC/GE/PANI electrode with an optimal GE content has a specific capacitance of 645 F g−1 at a current density of 1 A g−1, which is 2.5 times higher than that of BC/PANI and superior to most previously reported PANI-based electrodes. In addition, the symmetric supercapacitor assembled with BC/GE/PANI demonstrates a high energy density of 14.2 Wh kg−1 at a power density of 200 W kg−1. The excellent electrochemical performance of this BC/GE/PANI electrode is due to its unique 3D porous structure with the uniform distribution of GE nanosheets in the BC matrix and even PANI on BC nanofibers and GE nanosheets, which makes it very promising for diverse flexible energy storage devices. The methodology presented in this work can be extended to the preparation of other BC-based nanocomposite electrodes.
A novel facile and scalable strategy is developed to prepare freestanding carbon nanofiber/graphene nanosheet composites using a scalable membrane–liquid interface culture method followed by ...carbonization. The carbon nanofibers (CNFs) and graphene nanosheets (GNs) are uniformly dispersed in a three‐dimensional (3D) conductive architecture. Robust mechanical properties are demonstrated with fine flexibility, good structure stability, and high specific surface area. As supercapacitor electrodes, the 3D nanocomposite delivers good electrochemical performance with a high capacitance of 215 F g−1 at 1 A g−1 and extraordinary cycling stability with no capacitance degradation after 5000 cycles, which are among the best carbon electrodes in supercapacitors. The energy density is as high as 20 Wh kg−1 at a power density of 900 W kg−1, superior to other CNF‐based electrode materials. The superb electrochemical performance of the 3D nanocomposite electrode is ascribed to the unique structure: 3D conductive network, uniform dispersion of carbon nanofibers and graphene nanosheets, robust mechanical property, and large specific surface area. The combination of facile fabrication method, good performance, and robust mechanical property makes the 3D nanocomposites very promising as a new type of superior supercapacitor electrodes.
Large‐area freestanding carbon nanofiber/graphene nanosheet composite electrodes are prepared using a facile and scalable membrane–liquid interface biological culture method and demonstrate a high reversible capacity and extraordinary cycling stability with no capacitance degradation after 5000 cycles. The energy density is as high as 20 Wh kg−1 at a power density of 900 W kg−1.
There is growing evidence showing that single administration of immunotherapeutic agents has limited efficacy in a number of cancer patients mainly due to tumor heterogeneity and immunosuppressive ...tumor microenvironment. In this study, a novel nanoparticle-based strategy was applied to achieve efficient tumor-targeted therapy by combining chemotherapeutic agents, i.e., doxorubicin (Dox) and melittin (Mel), with an immune checkpoint inhibitor (PD-L1 DsiRNA). The proposed nanoparticle was prepared by the formation of a complex between Mel and PD-L1 DsiRNA (Dicer-substrate short-interfering RNA), followed by the loading of Dox. The surface of the resultant particles (DoxMel/PD-L1 DsiRNA) was then modified with hyaluronic acid (HA) to increase their stability and distribution. In addition, HA can also act as a tumor-targeting agent through binding to its receptor CD44 on the surface of cancer cells. We demonstrated that the surface engineering of DoxMel/PD-L1 DsiRNA with HA significantly enhances its specificity towards breast cancer cells. Moreover, we observed a noticeable reduction in PD-L1 expression together with a synergistic effect of Dox and Mel on killing cancer cells and inducing immunogenic cell death, leading to significantly diminished tumor growth in 4T1-breast tumor bearing Balb/c mice, improved survival rate and extensive infiltration of immune cells including cytotoxic T cells into the tumor microenvironment. Safety analysis revealed that there is no significant toxicity associated with the developed nanoparticle. All in all, the proposed targeted combination treatment strategy can be considered as a useful method to reduce cancer-associated mortality.
•A novel nanoparticle-based chemo-immunotherapy (DoxMel/PD-L1 DsiRNA@HA) for breast cancer was developed.•DoxMel/PD-L1 DsiRNA@HA significantly suppressed both primary and distant breast tumors in tumor-bearing Balb/c mice.•Induction of ICD along with suppression of PD-L1 expression by DoxMel/PD-L1 DsiRNA@HA led to a robust systemic immunity against cancer cells.•DoxMel/PD-L1 DsiRNA@HA has high potential for future clinical translation due to its high safety profile and strong anti-tumor efficacy.
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