In this task, you're given a paragraph from the research paper and your task is to generate a suitable title for the research paper based on the given paper. Under 100 words is a good title length.

Input: Consider Input: of the virus per se and cellular NF-κB activity; and (ii) to study the underling mechanisms. We found that tylophorine-based compounds target the TGEV viral RNA and effectively inhibit TGEV replication. NF-κB inhibition also leads to anti-TGEV replication. NF-κB activation induced by TGEV infection was found to be associated with two convergent pathways, IKK-2_IκBα/p65 and JAK2 mediated p65 phosphorylation, in swine testicular cells. JAK2 inhibition either by CYT387 (a JAK family inhibitor) or by silencing JAK2-expression revealed a dominant JAK2 mediated p65 phosphorylation pathway for NF-κB activation and resulted in NF-κB inhibition, which overrode the IκBα regulation via the IKK-2. Finally, tylophorine-based compounds work cooperatively with CYT387 to impart comprehensive anti-TGEV activities. The combination treatment, wherein a tylophorine compound targets TGEV and a JAK2 inhibitor blocks the alternative dominant NF-κB activation mediated by JAK2, is more effective and comprehensive than either one alone and constitutes a feasible approach for the treatment of SARS-CoV or MERS-CoV. Coronaviruses are animal viruses containing an enveloped, positive-sense, single-stranded RNA genome; and include the common cold human coronavirus (CoV)-229E & CoV-OC43, severe acute respiratory syndrome (SARS) CoV, Middle East respiratory syndrome (MERS) CoV, porcine transmissible gastroenteritis virus (TGEV), and murine hepatitis virus (MHV) etc 1-3 . Since the 2003 SARS outbreak (which had a mortality rate of ~10%), novel anti-SARS-CoV treatments have been vigorously pursued. No new cases of SARS have been reported since the 2003 outbreak, but another novel coronavirus (MERS-CoV), this time with a mortality rate of ~35%, came to light in 2012 4 . To date, neither a commercially available vaccine for human coronaviruses nor a specific treatment for SARS-CoV or MERS-CoV is available. Coronaviruses primarily infect the upper respiratory and gastrointestinal tract and induce host inflammation 5 . Nuclear factor κB (NF-κB) activation by coronaviruses is usually responsible for mediating the production of pro-inflammatory cytokines and chemokines and thus plays an important role in the pathogenesis of disease caused by coronaviruses 6, 7 . Inhibition of NF-κB-mediated inflammation induced by coronavirus in mice was reported to increase the survival rate 6 . Thus, NF-κB inhibitors constitute a promising class of antivirals in infections caused by pathogenic coronaviruses. However, targeting NF-κB is limited by intrinsic pathway complexity, cross talk with other pathways, and drug resistance 8 . In addition, many small chemical molecules targeting either viral entry or the intracellular viral life cycle were reported to impart anti-coronavirus activity 2, 9, 10 . Despite these advances, however, SARS-CoV and MERS-CoV remain untreatable diseases for which novel therapies are sought. Published: xx xx xxxx OPEN www.nature.com/scientificreports/ 2 Scientific RepoRts | 7: 4105 | Tylophorine based compounds, whether isolated from plants, e.g. Asclepiadaceae and Moraceae or chemically synthesized, exert potent anti-coronaviral activities against a variety of coronaviruses including SARS-CoV, MHV, and TGEV 11, 12 , but both the underlying mechanism(s) of this inhibitory effect and the target are unknown. NF-κB is significantly activated after infection by coronaviruses, e.g. TGEV, and MHV etc 6, 7, [13] [14] [15] . Otherwise, coronaviral nucleocapsid (N) protein plays a vital role in the regulation of viral genome replication and host gene transcription 16 . Therefore, the combination treatment for the inhibition of coronavirus per se, e.g. viral genome replication, and blocking cellular NF-κB activation by coronaviruses, is a promising approach for the development of anti-coronavirals. TGEV infected swine testicular (ST) cells constitute a surrogate system for the search and study of potential anti-coronavirus agents 11, 12, 17 . Herein, we report: (1) tylophorine-based compounds exert potent anti-TGEV replication by directly targeting the viral RNA/ribonucleoprotein (RNP) complex for viral replication/synthesis; (2) NF-κB inhibition also leads to anti-TGEV replication; (3) A combination treatment consisting of both a tylophorine compound and an NF-κB inhibitor acts additively or synergically to more effectively and comprehensively inhibit TGEV replication than either (1) or (2) alone.

Output: Targeting Coronaviral Replication and Cellular JAK2 Mediated Dominant NF-κB Activation for Comprehensive and Ultimate Inhibition of Coronaviral Activity OPEN


Input: Consider Input: Genome Detective is a web-based, user-friendly software application to quickly and accurately assemble all known virus genomes from next generation sequencing datasets. This application allows the identification of phylogenetic clusters and genotypes from assembled genomes in FASTA format. Since its release in 2019, we have produced a number of typing tools for emergent viruses that have caused large outbreaks, such as Zika and Yellow Fever Virus in Brazil. Here, we present The Genome Detective Coronavirus Typing Tool that can accurately identify the novel severe acute respiratory syndrome (SARS) related coronavirus (SARS-CoV-2) sequences isolated in China and around the world. The tool can accept up to 2,000 sequences per submission and the analysis of a new whole genome sequence will take approximately one minute. The tool has been tested and validated with hundreds of whole genomes from ten coronavirus species, and correctly classified all of the SARS-related coronavirus (SARSr-CoV) and all of the available public data for SARS-CoV-2. The tool also allows tracking of new viral mutations as the outbreak expands globally, which may help to accelerate the development of novel diagnostics, drugs and vaccines to stop the COVID-19 disease.

Output: Genome Detective Coronavirus Typing Tool for rapid identification and characterization of novel coronavirus genomes


Input: Consider Input: Defensins are an effector component of the innate immune system with broad antimicrobial activity. Humans express two types of defensins, -and -defensins, which have antiviral activity against both enveloped and non-enveloped viruses. The diversity of defensin-sensitive viral species reflects a multitude of antiviral mechanisms. These include direct defensin targeting of viral envelopes, glycoproteins, and capsids in addition to inhibition of viral fusion and post-entry neutralization. Binding and modulation of host cell surface receptors and disruption of intracellular signaling by defensins can also inhibit viral replication. In addition, defensins can function as chemokines to augment and alter adaptive immune responses, revealing an indirect antiviral mechanism. Nonetheless, many questions regarding the antiviral activities of defensins remain. Although significant mechanistic data is known for -defensins, molecular details fordefensin inhibition are mostly lacking. Importantly, the role of defensin antiviral activity in vivo has not been addressed due to the lack of a complete defensin knockout model. Overall, the antiviral activity of defensins is well established as are the variety of mechanisms by which defensins achieve this inhibition; however, additional research is needed to fully understand the role of defensins in viral pathogenesis. simplex virus 1 (HSV-1) was one of the defining criteria in the identification and purification of the -defensins human neutrophil peptide 1 (HNP1), HNP2, and HNP3 from human neutrophils 3 . In this review, we will summarize the known activities of -anddefensins against viruses, and we refer the reader to additional recent reviews on this topic for further insight 4; 5; 6; 7 . Our focus will be primarily on human defensins, and we have organized our discussion by mechanism ( Figure 1 ) to emphasize commonalities in the antiviral activities of defensins against diverse viral families. The structure, evolution, and tissue distribution of defensins have been summarized in a number of recent reviews 4; 8; 9; 10; 11; 12; 13 . Briefly, defensins are small (~29-42 amino acid) cationic, amphipathic peptides with a predominantly -sheet structure stabilized by 3 disulfide bonds. They can be broadly classified on the basis of structure and disulfide bond organization into three groups: -, -, and -defensins. As humans lack -defensins, they will not be discussed in detail; however, their antiviral properties have been recently reviewed 8; 14 . Humans express six -defensins and up to 31 -defensins 15 . The -defensins can be further subdivided into myeloid (HNP1-4) and enteric [human defensin (HD) 5 and 6] peptides on the basis of both expression patterns and genetic organization 11 . All of thedefensins have been shown to multimerize into at least dimers either in solution or in crystal structures 16; 17; 18; 19 . HNP1-4 are predominantly expressed by neutrophils but can also be found in or expressed by monocyte/macrophages, natural killer (NK) cells, some T cells, B cells, and immature dendritic cells (DCs) 11; 13 . HD5 and HD6 are expressed by specialized epithelial Paneth cells of the small intestine 20; 21 . HD5 is also expressed by epithelial cells in the male and female genitourinary tract 22; 23; 24; 25 . Human -defensins (HBDs) are more widely expressed by epithelial cells in skin and at mucosal surfaces in contact with the environment 26 . Like the -defensins, some -defensins (e.g., HBD3) exist in oligomeric forms, while others, such as HBD1 and HBD2, are monomeric 27 . They are also expressed by monocytes, macrophages, and certain DCs, and a subset of -defensins are only expressed in the male reproductive tract 26; 28 . Although there are commonalities in expression patterns of defensins in humans and other species, one important difference relevant for experimental models of infectious disease is that mice lack myeloiddefensins 29; 30 . Quantification of physiologic defensin concentrations in vivo is complex, as defensins are present at high local concentrations within specific cell types or upon release from cells into confined anatomical niches (e.g., crypts of the small intestine) but can become diluted in extracellular fluids. For the myeloid -defensins, Daher et al. estimated ~3 mM (10 mg/ml) HNPs in neutrophils, with even higher local concentrations in the azurophilic granules in which they are stored 1 . For the enteric -defensins, Ayabe et al. estimated concentrations of ≥3.5 mM (15-100 mg/ml) in the crypt lumen, the site of Paneth cell degranulation 31 . These concentrations are likely similar in the human small intestine, where HD5 expression exceeds that of HD6 by 6-fold 32 . In healthy patients, epithelial lining fluid of the lung contains 31-79 nM HNP1-3, nasal fluid contains ~2.7 M HNP1-3, saliva contains 0.3-3 M HNP1-3, and vaginal secretions contain ~1.5 M HNPs and 0.3-14 M HD5 23; 33; 34; 35; 36; 37; 38 . For the -defensins, 5-10 nM HBD2 has been measured in nasal fluid 37; 39 . However, in certain disease states defensin levels can be highly elevated. For example, 57 M to 2.4 mM concentrations of HNP1 have been found in epithelial lining fluid of cystic fibrosis patients 36 . Overall, the concentrations of defensins present in vivo are generally within the range that is needed for direct antiviral activity by -defensins and generally below the concentrations required for direct antiviral activity by -defensins. Wilson et al. 


Output: Antiviral Mechanisms of Human Defensins