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To design new CARs targeting hepatitis B virus (HBV), we isolated human monoclonal antibodies recognizing the HBV envelope proteins from single B cells of a patient with a resolved infection. HBV-specific memory B cells were isolated by incubating peripheral blood mononuclear cells with biotinylated hepatitis B surface antigen (HBsAg), followed by single-cell flow cytometry-based sorting of live, CD19+ IgG+ HBsAg+ cells. Amplification and sequencing of immunoglobulin genes from single memory B cells identified variable heavy and light chain sequences. Corresponding immunoglobulin chains were cloned into IgG1 expression vectors and expressed in mammalian cells. Two antibodies named 4D06 and 4D08 were found to be highly specific for HBsAg, recognized a conformational and a linear epitope, respectively, and showed broad reactivity and neutralization capacity against all major HBV genotypes. 4D06 and 4D08 variable chain fragments were cloned into a 2nd generation CAR format with CD28 and CD3zeta intracellular signaling domains. The new CAR constructs displayed a high functional avidity when expressed on primary human T cells. CAR-grafted T cells proved to be polyfunctional regarding cytokine secretion and killed HBV-positive target cells. Interestingly, background activation of the 4D08-CAR recognizing a linear instead of a conformational epitope was consistently low. In a preclinical model of chronic HBV infection, murine T cells grafted with the 4D06 and the 4D08 CAR showed on target activity indicated by a transient increase in serum transaminases, and a lower number of HBV-positive hepatocytes in the mice treated. This study demonstrates an efficient and fast approach to identifying pathogen-specific monoclonal human antibodies from small donor cell numbers for the subsequent generation of new CARs.

The exploitation and utilization of clean energy is a resource and environmental issue of common concern for global sustainable development. As a vital strategic and sustainable future energy, hot dry rock (HDR) has attracted more and more attention. In this paper some thoughts on the future research direction of HDR resources in China are provided based on a worldwide experience summary, hoping to provide a useful reference for the future exploration and engineering development of HDR. Since the concept of HDR was put forward in the 1970s, the number of worldwide HDR construction has been increasingly growing. Although a lot of theoretical and technical breakthroughs have been made, only a small fraction of projects still in operation due to the lack of sustained financial support, induced microearthquakes and other issues. At present, the global development of HDR is gradually entering a new stage of exploration, and the basic theories of HDR to tackle the key problems are strengthening around the world. Since 2012, the China Geological Survey has organized and implemented the nationwide terrestrial HDR resources survey, evaluation, exploration and development, and significant stage progress has been achieved. A series of fundamental maps have been compiled, such as terrestrial heat flow value, curie surface depth, distribution of acidic rock, and heat-controlling structure in China. The resource potential of terrestrial HDR in China has been preliminarily estimated and a sounding basis for the target site selection is provided. HDR exploration and evaluation have been carried out in typical areas of Qinghai, Shandong, Hebei, Shanxi and Jiangsu provinces, and a breakthrough has been achieved in the Gonghe Basin of Qinghai. The first HDR resources exploration and production demonstration project in China was carried out in 2019, which made a series of meaningful outcomes in deep HDR exploration, high-temperature hard rock drilling, large-scale reservoir stimulation, reservoir connectivity and flow circulation, organic Rankine cycle (ORC) power generation, etc. The large-scale reservoir stimulation was carried out in 2020, and the first power generation test was completed in 2021. In general, the global exploration and development of HDR has made great progress. Practice has proved that HDR resources are a promising green energy and are expected to become an inexhaustible energy support for the world in the future. However, there is still a large gap between the existing path of HDR development and utilization and the economics of its supporting technologies compared with commercial development expectations at present. Although the development of HDR resources in China has achieved a breakthrough from “0” to “1”, there is still a long way to go from the international level. In order to solve the problems of large-scale and economic development, it is still needed to promote disruptive technological innovation in high temperature hard rock drilling and completion, fine characterization of deep reservoirs, safe large-scale reservoir construction, efficient heat transfer and heat recovery and other aspects.

ABSTRACT Host innate immunity is an important defense line against virus infection and is precisely regulated by various factors. Studying the mechanism of virus-host interaction is essential to developing novel antivirals. Being one of the key host natural antiviral responses, host small non-coding RNAs (miRNAs) possess promising antiviral potential worthy of study. Herein, we found that miR-26a exerted broad-spectrum antiviral effect against multiple viruses, e.g., Hepatitis E virus, Vesicular Stomatitis Virus, and Sendai Virus. Mechanistically, miR-26a specifically targets 3′UTR of mRNA to inhibit USP15 expression. USP15 interacted directly with RIG-I to deubiquitinate K63-linked RIG-I, thus negatively regulating type I interferon (IFN) signaling. Consequently, miR-26a, by downregulating USP15, promotes K63 ubiquitination of RIG-I to enhance type I IFN responses, resulting in an active antiviral state against virus infection. Intriguingly, the activation of type I IFN responses could suppress miR-26a expression, serving as an intrinsic negative feedback loop to avoid dysregulated signal activation. Hence, the broad-spectrum antiviral effects of miR-26a and its mode-of-action enriched the interaction networks between miRNAs and innate immunity, providing insights for the development of broad-spectrum antivirals against viral infection. IMPORTANCE miR-26a serves as a potent positive regulator of type I interferon (IFN) responses. By inhibiting USP15 expression, miR-26a promotes RIG-I K63-ubiquitination to enhance type I IFN responses, resulting in an active antiviral state against viruses. Being an intricate regulatory network, the activation of type I IFN responses could in turn suppress miR-26a expression to avoid the disordered activation that might result in the so-called “type I interferonopathy.” The knowledge gained would be essential for the development of novel antiviral strategies against viral infection.

Background & Aims: Hepatitis D virus (HDV) is the causative agent of chronic hepatitis delta, the most severe form of viral hepatitis. HDV encodes one protein, hepatitis delta antigen (HDAg), in two isoforms: S- and L-HDAg. They are identical in sequence except that L-HDAg contains an additional 19-20 amino acids at its C-terminus, which confer regulatory roles that are distinct from those of S-HDAg. Notably, these residues are divergent between different genotypes. We aimed to elucidate the molecular determinants within the C-termini that are essential for the regulatory role of L-HDAg in HDV replication and assembly. Methods: Northern blot, reverse-transcription quantitative PCR, and a newly established HDV trans-complementary system were used in this study. Results: C-termini of L-HDAg, albeit with high sequence variation among different genotypes, are interchangeable with respect to the trans-inhibitory function of L-HDAg and HDV assembly. The C-terminus of L-HDAg features a conserved prenylation CXXQ motif and is enriched with proline and hydrophobic residues. Abolishment of the CXXQ motif attenuated the inhibitory effect of L-HDAg on HDV replication. In contrast, the enrichment of proline and hydrophobic residues per se does not modify the trans-inhibitory function of L-HDAg. Nevertheless, these residues are essential for HDV assembly. Mechanistically, prolines and hydrophobic residues contribute to HDV assembly via a mode of action independent of the prenylated CXXQ motif. Conclusions: Within the C-terminus of L-HDAg, the CXXQ motif and the enrichment of proline and hydrophobic residues are all essential determinants of L-HDAg’s regulatory roles in HDV replication and assembly. This intrinsic viral regulatory mechanism we elucidated deepens our understanding of the unique life cycle of HDV. Impact and implications: Hepatitis D virus (HDV) encodes one protein, hepatitis delta antigen (HDAg), in two isoforms: S- and L-HDAg. They are identical in sequence except that L-HDAg contains an additional 19-20 amino acids at its C-terminus. This C-terminal extension in L-HDAg confers regulatory roles in the HDV life cycle that are distinct from those of S-HDAg. Herein, we found that C-termini of L-HDAg, although with high sequence variation, are interchangeable among different HDV genotypes. Within the C-terminus of L-HDAg, the prenylation motif, and the enrichment of proline and hydrophobic residues are all essential determinants of L-HDAg’s regulatory roles in HDV replication and assembly.

Summary: Severe infections with coronaviruses are often accompanied with hyperinflammation, requiring therapeutic strategies to simultaneously tackle the virus and inflammation. By screening a safe-in-human broad-spectrum antiviral agents library, we identified that indomethacin can inhibit pan-coronavirus infection in human cell and airway organoids models. Combining indomethacin with oral antiviral drugs authorized for treating COVID-19 results in synergistic anti-coronavirus activity. Coincidentally, screening a library of FDA-approved drugs identified indomethacin as the most potent potentiator of interferon response through increasing STAT1 phosphorylation. Combining indomethacin with interferon-alpha exerted synergistic antiviral effects against multiple coronaviruses. The anti-coronavirus activity of indomethacin is associated with activating interferon response. In a co-culture system of lung epithelial cells with macrophages, indomethacin inhibited both viral replication and inflammatory response. Collectively, indomethacin is a pan-coronavirus inhibitor that can simultaneously inhibit virus-triggered inflammatory response. The therapeutic potential of indomethacin can be further augmented by combining it with oral antiviral drugs or interferon-alpha.

Chronic infection with the hepatitis B virus (HBV) and hepatitis D virus (HDV) can cause a major global health burden. Current medication regimens can repress viral replication and help to control disease progression, but a complete cure is hardly achieved due to the difficulties to eradicate viral templates (cccDNA and integrates). To develop novel curative antiviral therapies for HBV/HDV infection, it is vital to precisely understand the details of the molecular biology of both viruses and the virus-host interactions. One important prerequisite for gaining this aim is the availability of suitable in vitro models that support HBV/HDV infection, replicate both viruses via their authentic template and allow to adequately study host cell responses. The discovery of sodium taurocholate cotransporting polypeptide (NTCP) receptor as the most crucial host factor promoted HBV/HDV research to a new era. Recently, the structure of human NTCP was solved, gaining a deeper understanding of HBV recognition as the bona fide receptor. After decades of continuous efforts, new progress has been achieved in the development of cell culture models supporting HBV/HDV study. This review summarizes the cell culture models currently available, discusses the advantages and disadvantages of each model, and highlights their future applications in HBV and HDV research.

Abstract The optimal operation analysis plays an important role in estimating the expected return of investment for power systems. However, this work could be highly challenging under the context of active distribution network, where a variety of renewable energy sources and emerging active loads (such as Internet data centers) could be penetrated that introduce a high level of nonlinearity and nonconvexity characteristics into the system modeling. To overcome such challenge, this paper presents a new methodological framework based on the improvements of symbiotic organisms search (SOS) algorithm to address the optimal operation problem of active distribution systems containing renewable energy sources and datacenter resources, aiming to provide a practical tool for system analysis, particularly subject to nonconvexity nature of system components. For this purpose, a generic model for the distribution system including wind power, PV, and datacenter resources is first developed, which not only captures the uncertain nature of system components but also accounts for their spatiotemporal flexibility during operation. On this basis, in order to improve the computation efficiency of the problem, the SOS algorithm is improved by designing the selection strategy of random parameters. By using the penalty function method, the concerned problem is expressed as a nonlinear unconstrained optimization problem. The performance of the proposed model and algorithm is examined through comparative studies. It is shown that the proposed method is able to schedule the renewable energy resources and flexible demand of datacenters coordinately to reduce the operation cost of the system significantly in the case study. In addition, the proposed algorithm demonstrates a higher level of accuracy as well as better convergence efficiency compared to other conventional techniques.

The sheer ubiquity of Gioblastoma (GBM) cases would lead you to believe that there should have been many opportunities for the discovery of treatments to successfully render it into remission. Unfortunately, its persistent commonality is due in large part to the fact that it is the most treatment-resistant tumors in adults. That completely changes the treatment plan of attack. Long established and accepted treatment therapies such as surgical resection, radiation, and aggressive chemotherapy, (and any combination thereof) have only confirmed that the disease lives up to its treatment-resistant reputation. To add to the seemingly insurmountable task of finding a cure, GBM has also proven to be a very stubborn and formidable opponent to newer immunotherapies. Across the board, regardless of the therapy combination, the five-year survival rate of GBM patients is still very poor at a heartbreaking 5.6%. Obviously, the present situation cannot be tolerated or deemed acceptable. The grave situation calls for researchers to be more innovative and find more efficient strategies to discover new and successful strategies to treat GBM. Inspired by researchers worldwide attempting to control GBM, we provide in this review a comprehensive overview of the many diverse cell therapies currently being used to treat GBM. An overview of the treatments include: CAR T cells, CAR NK cells, gamma-delta T cells, NKT cells, dendritic cells, macrophages, as well stem cell-based strategies. To give you the complete picture, we will discuss the efficacy, safety, and developmental stages, the mechanisms of action and the challenges of each of these therapies and detail their potential to be the next-generation immunotherapeutic to eliminate this dreadful disease.

Exploration of hot dry rock in China has just started. In order to accurately evaluate the amount of hot dry rock geothermal resources in China, high-quality hot dry rock drilling cores are needed. However, there are few researches on coring drilling of hot dry rock under the conditions of high temperature, high hardness and high grinding, which seriously restricts the accurate evaluation of hot dry rock geothermal resources. Therefore, independent research and development of the turbodrill Φ127 mm are carried out. The HDR-1 well in Zhangzhou of Fujian and the GR1 well in Gonghe of Qinghai were drilled and the research and application of hot dry rock drilling coring were performed to verify the research and development of turbodrill and the suitability of the KT-140 coring drilling tools and the matching of turbodrill and diamond core bit. The high temperature and hard rock characteristics of turbodrill working under the well conditions are revealed, the test of high temperature of 236 ℃ at the bottom of the bore is withstood, and the application test of turbodrill parameters is obtained. Compared with the conventional coring drilling technology, the turbodrill composite coring drilling technology not only plays an important role in the performance of high rotating speed of the turbodrill, but also makes full use of the characteristics of high temperature resistance, grinding resistance, high ground stress resistance, long service life and low on-site labor intensity, which greatly improves the drilling speed of hot dry rock. The method is of high temperature deep hole hot dry rock underground rotary drill driving core bit coring drilling and is the first successful attempt for hot dry rock of turbodrill coring drilling technology. The field test and application may provide valuable construction experience. The results will also provide a new technical support for hot dry rock scientific drilling and deep geothermal resource exploration in China.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with unclear etiology, and due to the lack of effective treatment, ASD patients bring enormous economic and psychological burden to families and society. In recent years, many studies have found that children with ASD are associated with gastrointestinal diseases, and the composition of intestinal microbiota (GM) is different from that of typical developing children. Thus, many researchers believe that the gut-brain axis may play an important role in the occurrence and development of ASD. Indeed, some clinical trials and animal studies have reported changes in neurological function, behavior, and comorbid symptoms of autistic children after rebalancing the composition of the GM through the use of antibiotics, prebiotics, and probiotics or microbiota transfer therapy (MMT). In view of the emergence of new therapies based on the modulation of GM, characterizing the individual gut bacterial profile evaluating the effectiveness of intervention therapies could help provide a better quality of life for subjects with ASD. This article reviews current studies on interventions to rebalance the GM in children with ASD. The results showed that Lactobacillus plantarum may be an effective strain for the probiotic treatment of ASD. However, the greater effectiveness of MMT treatment suggests that it may be more important to pay attention to the overall balance of the patient’s GM. Based on these findings, a more thorough assessment of the GM is expected to contribute to personalized microbial intervention, which can be used as a supplementary treatment for ASD.

Cancer stem cells (CSCs) are thought to be the main drivers for disease progression and treatment resistance in liver cancer. This study identifies the LGR5+ compartment as an important CSC population, representing a viable therapeutic target for combating liver cancer.

Hepatitis E virus (HEV) infection is a major cause of acute hepatitis but also provokes chronic infection in immunocompromised patients. Although the pathogenesis and treatment outcome involve complex interplay between the virus and host, the nature of adaptive responses of HEV to the host immune system remain obscure at best. In this study, we used large-scale proteomic bioinformatics to profile characteristic mutations in human HEV isolates associated to ribavirin treatment failure, chronic hepatitis, hepatic failure or altered immunoreactivity. The prevalence of specific mutations was examined in a large number of protein sequences of ORF1 and ORF2 regions of the 3 major human-derived HEV genotypes (1, 3 and 4). By analyzing potential B, CD4+ and CD8+ T cell epitopes, we found that many of these mutations overlap with the predicted epitopes and are frequently present among the 3 HEV genotypes. These overlapping mutations mediate reduced antigenicity. Finally, by delineation of diversification and evolution of the underlying epitopes, we observe that most of these variants apparently evolved earlier in genotype 1 when compared with genotypes 3 and 4. These results indicate that HEV is under substantial evolutionary pressure to develop mutations enabling evasion of the host immune response and resistance to antiviral treatment. This indicates the existence of an ongoing evolutionary arms race between human immunity, antiviral medication and HEV.

Rotavirus infection is a major cause of severe dehydrating diarrhea in infants younger than 5 y old and in particular cases of immunocompromised patients irrespective to the age of the patients. Although vaccines have been developed, antiviral therapy is an important complement that cannot be substituted. Because of the lack of specific approved treatment, it is urgent to facilitate the cascade of further understanding of the infection biology, identification of druggable targets and the final development of effective antiviral therapies. PI3K-Akt-mTOR signaling pathway plays a vital role in regulating the infection course of many viruses. In this study, we have dissected the effects of PI3K-Akt-mTOR signaling pathway on rotavirus infection using both conventional cell culture models and a 3D model of human primary intestinal organoids. We found that PI3K-Akt-mTOR signaling is essential in sustaining rotavirus infection. Thus, blocking the key elements of this pathway, including PI3K, mTOR and 4E-BP1, has resulted in potent anti-rotavirus activity. Importantly, a clinically used mTOR inhibitor, rapamycin, potently inhibited both experimental and patient-derived rotavirus strains. This effect involves 4E-BP1 mediated induction of autophagy, which in turn exerts anti-rotavirus effects. These results revealed new insights on rotavirus-host interactions and provided new avenues for antiviral drug development.

BACKGROUND:The Pregnane X Receptor (PXR) is a principal signal transducer in mucosal responses to xenobiotic stress. It is well-recognized that inflammatory bowel disease is accompanied by xenobiotic stress, but the importance of the PXR in limiting inflammatory responses in inflammatory bowel disease remains obscure at best. METHODS:We stimulate a total of 106 colonic biopsies from 19 Crohn's disease patients with active disease, 36 colonic biopsies from 8 control patients, colonic organoids and various cell culture models (either proficient or genetically deficient with respect to PXR) in vitro with the PXR ligand rifampicin or vehicle. Effects on NF-κB activity are assessed by measuring interleukin-8 (IL-8) and interleukin-1ß (IL-1ß) mRNA levels by qPCR and in cell culture models by NF-κB reporter-driven luciferase activity and Western blot for signal transduction elements. RESULTS:We observe a strict inverse correlation between colonic epithelial PXR levels and NF-κB target gene expression in colonic biopsies from Crohn's disease patients. PXR, activated by rifampicin, is rate-limiting for mucosal NF-κB activation in IBD. The correlation between colonic epithelial PXR levels and NF-κB target gene expression was also observed in intestinal organoids system. Furthermore, in preclinical in vitro models of intestinal inflammation, including intestinal organoids, genetic inactivation of PXR unleashes NF-κB-dependent signal transduction whereas conversely NF-κB signaling reduces levels of PXR expression. CONCLUSIONS:Our data indicate that the PXR is a major and clinically relevant antagonist of NF-κB activity in the intestinal epithelial compartment during inflammatory bowel disease.

In this paper, a novel methodological framework for energy hub (EH) planning, considering the correlation between renewable energy source (RES) and demand response (DR) uncertainties, is proposed. Unlike other existing works, our study explicitly considers the potential correlation between the uncertainty of integrated energy system operations (i.e., wind speed, light intensity, and demand response). Firstly, an EH single-objective interval optimization model is established, which aims at minimizing investment and operation costs. The model fully considers the correlation between various uncertain parameters. Secondly, the correlation between uncertainties is dealt with by the interval models of multidimensional parallelism and affine coordinate transformation, which are transformed into a deterministic optimization problem by the interval order relationship and probability algorithm, and then solved by a genetic algorithm. Finally, an experimental case is analyzed, and the results show that the research method in this paper has good engineering practicability. At the same time, different correlations among uncertainties have different influences on integrated energy system planning. Correlation and influence are positively correlated.

Hepatitis E virus (HEV) infection represents an emerging global health issue, whereas the clinical outcomes vary dramatically among different populations. The host innate immune system provides a first-line defense against the infection, but dysregulation may partially contribute to severe pathogenesis. A growing body of evidence has indicated the active response of the host innate immunity to HEV infection both in experimental models and in patients. In turn, HEV has developed sophisticated strategies to counteract the host immune system. In this review, we aim to comprehensively decipher the processes of pathogen recognition, interferon, and inflammatory responses, and the involvement of innate immune cells in HEV infection. We further discuss their implications in understanding the pathogenic mechanisms and developing antiviral therapies.

Eastern equine encephalitis virus (EEEV) is a mosquito-borne virus that can cause both human and equine encephalitis with high case fatality rates. EEEV can also be widespread among birds, including pheasants, ostriches, emu, turkeys, whooping cranes and chickens. The E2 protein of EEEV and other Alphaviruses is an important immunogenic protein that elicits antibodies of diagnostic value. While many therapeutic and diagnostic applications of E2 protein-specific antibodies have been reported, the specific epitopes on E2 protein recognized by the antibody responses of different susceptible hosts, including avian species, remain poorly defined. In the present study, the avian E2-reactive polyclonal antibody (PAb) response was mapped to linear peptide epitopes using PAbs elicited in chickens and ducks following immunization with recombinant EEEV E2 protein and a series of 42 partially overlapping peptides covering the entire EEEV E2 protein. We identified 12 and 13 peptides recognized by the chicken and duck PAb response, respectively. Six of these linear peptides were commonly recognized by PAbs elicited in both avian species. Among them five epitopes recognized by both avian, the epitopes located at amino acids 211-226 and 331-352 were conserved among the EEEV antigenic complex, but not other associated alphaviruses, whereas the epitopes at amino acids 11-26, 30-45 and 151-166 were specific to EEEV subtype I. The five common peptide epitopes were not recognized by avian PAbs against Avian Influenza Virus (AIV) and Duck Plague Virus (DPV). The identification and characterization of EEEV E2 antibody epitopes may be aid the development of diagnostic tools and facilitate the design of epitope-based vaccines for EEEV. These results also offer information with which to study the structure of EEEV E2 protein.

To design new CARs targeting hepatitis B virus (HBV), we isolated human monoclonal antibodies recognizing the HBV envelope proteins from single B cells of a patient with a resolved infection. HBV-specific memory B cells were isolated by incubating peripheral blood mononuclear cells with biotinylated hepatitis B surface antigen (HBsAg), followed by single-cell flow cytometry-based sorting of live, CD19+ IgG+ HBsAg+ cells. Amplification and sequencing of immunoglobulin genes from single memory B cells identified variable heavy and light chain sequences. Corresponding immunoglobulin chains were cloned into IgG1 expression vectors and expressed in mammalian cells. Two antibodies named 4D06 and 4D08 were found to be highly specific for HBsAg, recognized a conformational and a linear epitope, respectively, and showed broad reactivity and neutralization capacity against all major HBV genotypes. 4D06 and 4D08 variable chain fragments were cloned into a 2nd generation CAR format with CD28 and CD3zeta intracellular signaling domains. The new CAR constructs displayed a high functional avidity when expressed on primary human T cells. CAR-grafted T cells proved to be polyfunctional regarding cytokine secretion and killed HBV-positive target cells. Interestingly, background activation of the 4D08-CAR recognizing a linear instead of a conformational epitope was consistently low. In a preclinical model of chronic HBV infection, murine T cells grafted with the 4D06 and the 4D08 CAR showed on target activity indicated by a transient increase in serum transaminases, and a lower number of HBV-positive hepatocytes in the mice treated. This study demonstrates an efficient and fast approach to identifying pathogen-specific monoclonal human antibodies from small donor cell numbers for the subsequent generation of new CARs. [ABSTRACT FROM AUTHOR]

Hepatitis E virus (HEV) infection can cause severe complications and high mortality, particularly in pregnant women, organ transplant recipients, individuals with pre-existing liver disease and immunosuppressed patients. However, there are still unmet needs for treating chronic HEV infections. Herein, we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds. Upon screening, we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities. Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase (DHODH) inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection. Pyrazofurin selectively targets uridine monophosphate synthetase (UMPS). Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains. Encouragingly, both drugs exhibited a sizeable therapeutic window against HEV. For instance, the IC50 value of vidofludimus calcium is 4.6-7.6-fold lower than the current therapeutic doses in patients. Mechanistically, their anti-HEV mode of action depends on the blockage of pyrimidine synthesis. Notably, two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants (Y1320H, G1634R). Their combination with IFN-a resulted in synergistic antiviral activity. In conclusion, we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections. Based on their antiviral potency, and also the favorable safety profile identified in clinical studies, our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E. [ABSTRACT FROM AUTHOR]

This document is an editorial published in Frontiers in Microbiology titled "Viral emerging and re-emerging diseases: basic understanding and future intervention strategies." The editorial discusses the recent pandemic of COVID-19 caused by the SARS-CoV-2 virus and highlights the impact of other emerging and re-emerging viruses on global health and the economy. The authors emphasize the importance of collaboration between the scientific community and public health authorities to anticipate and address future viral outbreaks. The editorial also presents recent research on various viral diseases, including influenza, monkeypox, papillomaviruses, and SARS-CoV-2, and discusses topics such as viral-host interactions, viral adaptation, and antiviral development. The authors conclude by emphasizing the need for early detection, prevention, and effective management of viral infectious diseases. [Extracted from the article]