Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID-19.

Confronting the challenge of the outbreak of COVID-19 should sharpen our focus on global drug access as a key issue in antiviral therapy testing. The testing and adoption of effective therapies for novel coronaviruses are hampered by the challenge of conducting controlled studies during a state of emergency. The access to direct antiviral drugs, such as ribavirin, that have an existing inventory and reliable supply chain may be a priority consideration for therapies developed for the 2019-nCoV infection outbreaks and any strain variants that may emerge. On the basis of the direct antiviral activity of ribavirin against 2019-nCoV in vitro and evidence for potency enhancement strategies developed during the prior SARS and MERS outbreaks, ribavirin may significantly impact our ability to end the lingering outbreaks in China and slow outbreaks in other countries. The apparent COVID-19 pandemic provides an opportunity to follow dosage guidelines for treatment with ribavirin, test new therapeutic concepts, and conduct controlled testing to apply the scientific rigor required to address the controversy around this mainstay of antiviral therapy.

The accessible chromatin landscape of the human genome.

DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ∼2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect ∼580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.

Codon Optimization Using a Recurrent Neural Network.

Codon optimization of a DNA sequence can significantly increase efficiency of protein expression, reducing the cost to manufacture biologic pharmaceuticals. Although directed methods based on such factors as codon usage bias and GC nucleotide content are often used to optimize protein expression, undirected optimization using machine learning could further improve the process by capitalizing on undiscovered patterns that exist within real DNA sequences. To explore this hypothesis, Chinese hamster DNA sequences were used to train a recurrent neural network (RNN) model of codon optimization. The model was used to generate optimized DNA sequence based on an input amino acid sequence for the example receptor programmed death-ligand 1 and for an example monoclonal antibody. When RNN-optimized sequences were transfected transiently or stably into Chinese hamster ovary cells, the resulting protein expression was as high or higher than that produced by DNA sequences optimized by conventional algorithms.

Mono- and Co-Doped Mn-Doped CsPbCl3 Perovskites with Enhanced Doping Efficiency and Photoluminescent Performance.

To investigate the effect of Mn and other metal dopants on the photoelectronic performance of CsPbCl3 perovskites, we conducted a series of theoretical analyses. Our findings showed that after Mn mono-doping, the CsPbCl3 lattice contracted and the bonding strength increased, resulting in a more compact structure of the metal octahedral cage. The relaxation of the metal octahedral cage, along with the Jahn-Teller effect, results in a decrease in lattice strain between the octahedra and a reduction in the energy of the entire lattice due to the deformation of the metal octahedron. These three factors work together to reduce intrinsic defects and enhance the stability and electronic properties of CsPbCl3 perovskites. The solubility of the Mn dopant is significantly increased when co-doped with Ni, Fe, and Co dopants, as it compensates for the lattice strain induced by Mn. Doping CsPbCl3 perovskites reduces the band gap due to the decreased contributions of 3d orbitals from the dopants. Our analyses have revealed that strengthening the CsPbCl3 lattice and reducing intrinsic defects can result in improved stability and PL properties. Moreover, increasing Mn solubility and decreasing the bandgap can enhance the PLQY of orange luminescence in CsPbCl3 perovskites. These findings offer valuable insights for the development of effective strategies to enhance the photoelectronic properties of these materials.

Strong, Tough, and Adhesive Polyampholyte/Natural Fiber Composite Hydrogels.

Hydrogels with high mechanical strength, good crack resistance, and good adhesion are highly desirable in various areas, such as soft electronics and wound dressing. Yet, these properties are usually mutually exclusive, so achieving such hydrogels is difficult. Herein, we fabricate a series of strong, tough, and adhesive composite hydrogels from polyampholyte (PA) gel reinforced by nonwoven cellulose-based fiber fabric (CF) via a simple composite strategy. In this strategy, CF could form a good interface with the relatively tough PA gel matrix, providing high load-bearing capability and good crack resistance for the composite gels. The relatively soft, sticky PA gel matrix could also provide a large effective contact area to achieve good adhesion. The effect of CF content on the mechanical and adhesion properties of composite gels is systematically studied. The optimized composite gel possesses 35.2 MPa of Young's modulus, 4.3 MPa of tensile strength, 8.1 kJ m-2 of tearing energy, 943 kPa of self-adhesive strength, and 1.4 kJ m-2 of self-adhesive energy, which is 22.1, 2.3, 1.8, 6.0, and 4.2 times those of the gel matrix, respectively. The samples could also form good adhesion to diverse substrates. This work opens a simple route for fabricating strong, tough, and adhesive hydrogels.

Research Progress of Transparent Electrode Materials with Sandwich Structure.

The nonrenewable nature of fossil energy has led to a gradual decrease in reserves. Meanwhile, as society becomes increasingly aware of the severe pollution caused by fossil energy, the demand for clean energy, such as solar energy, is rising. Moreover, in recent years, electronic devices with screens, such as mobile phones and computers, have had increasingly higher requirements for light transmittance. Whether in solar cells or in the display elements of electronic devices, transparent conductive films directly affect the performance of these devices as a cover layer. In this context, the development of transparent electrodes with low sheet resistance and high light transmittance has become one of the most urgent issues in related fields. At the same time, conventional electrodes can no longer meet the needs of some of the current flexible devices. Because of the high sheet resistance, poor light transmittance, and poor bending stability of the conventional tin-doped indium tin oxide conductive film and fluorine-doped tin oxide transparent conductive glass, there is a need to find alternatives with better performance. In this article, the progress of research on transparent electrode materials with sandwich structures and their advantages is reviewed according to the classification of conductive materials to provide reference for research in related fields.

Role of the cytoplasmic tail amino acid sequences of Newcastle disease virus hemagglutinin-neuraminidase protein in virion incorporation, cell fusion, and pathogenicity.

To determine the role of amino acid sequences of the hemagglutinin-neuraminidase (HN) cytoplasmic tail in Newcastle disease virus (NDV) replication and pathogenicity, we generated recombinant NDVs with a deletion or point mutation in the N-terminal cytoplasmic tail. The first 2-amino-acid deletion in the cytoplasmic tail did not affect the biological characteristics of NDV. However, a 4-amino-acid deletion and the substitution of alanine for serine at position 6 affected cell fusion, pathogenicity, and colocalization of the HN and M proteins of NDV, indicating that these residues of the HN cytoplasmic tail are critical for its specific incorporation into virions.

Role of untranslated regions of the hemagglutinin-neuraminidase gene in replication and pathogenicity of newcastle disease virus.

To determine the role of untranslated regions (UTRs) in replication and pathogenesis of Newcastle disease virus (NDV), we generated recombinant viruses with deletions in 5' and 3' UTRs of the HN mRNA. Deletion of any HN UTR did not noticeably affect in vitro replication of these viruses. However, complete deletion of the 5' UTR of the HN gene decreased the HN mRNA levels and HN protein contents in virus particles, resulting in attenuation of the virus in chickens. This indicates that the 5' UTR of HN mRNA plays an important role in replication and pathogenicity of NDV in vivo.

A Y526Q mutation in the Newcastle disease virus HN protein reduces its functional activities and attenuates virus replication and pathogenicity.

The hemagglutinin-neuraminidase (HN) protein of Newcastle disease virus (NDV) is a multifunctional protein that plays a crucial role in virus infectivity. In this study, using the mesogenic strain Beaudette C (BC), we mutated three conserved amino acids thought to be part of the binding/catalytic active site in the HN protein. We also mutated five additional residues near the proposed active site that are nonconserved between BC and the avirulent strain LaSota. The eight recovered NDV HN mutants were assessed for effects on biological activities. While most of the mutations had surprisingly little effect, mutation at conserved residue Y526 reduced the neuraminidase, receptor binding, and fusion activities and attenuated viral virulence in eggs and young birds.

The MHC class II-associated invariant chain interacts with the neonatal Fc gamma receptor and modulates its trafficking to endosomal/lysosomal compartments.

The neonatal Fc receptor for IgG (FcRn) transfers maternal IgG to the offspring and protects IgG from degradation. The FcRn resides in an acidic intracellular compartment, allowing it to bind IgG. In this study, we found the association of FcRn and invariant chain (Ii). The interaction was initiated within the endoplasmic reticulum by Ii binding to either the FcRn H chain alone or FcRn H chain-beta(2)-microglobulin complex and appeared to be maintained throughout the endocytic pathway. The CLIP in Ii was not required for FcRn-Ii association. The interaction was also detected in IFN-gamma-treated THP-1, epithelial and endothelial cells, and immature mouse DCs. A truncated FcRn without the cytoplasmic tail was unable to traffic to early endosomes; however, its location in early endosomes was restored by Ii expression. FcRn was also detected in the late endosome/lysosome only in the presence of Ii or on exposure to IFN-gamma. In immature human or mouse DCs, FcRn was barely detected in the late endosome/lysosome in the absence of Ii. Furthermore, the cytoplasmic tail of Ii conferred tailless FcRn to route to both the early endosome and late endosome/lysosome in a hybrid molecule. Because the FcRn is expressed in macrophages and DCs or epithelial and endothelial cells where Ii is induced under inflammation and infection, these results reveal the complexity of FcRn trafficking in which Ii is capable of expanding the boundary of FcRn trafficking. Taken together, the intracellular trafficking of FcRn is regulated by its intrinsic sorting information and/or an interaction with Ii chain.

Role of intergenic sequences in newcastle disease virus RNA transcription and pathogenesis.

Newcastle disease virus (NDV), a member of the family Paramyxoviridae, has a nonsegmented negative-sense RNA genome consisting of six genes (3'-NP-P-M-F-HN-L-5'). The first three 3'-end intergenic sequences (IGSs) are single nucleotides (nt), whereas the F-HN and HN-L IGSs are 31 and 47 nt, respectively. To investigate the role of IGS length in NDV transcription and pathogenesis, we recovered viable viruses containing deletions or additions in the IGSs between the F and HN and the HN and L genes. The IGS of F-HN was modified to contain an additional 96 nt or more or a deletion of 30 nt. Similarly, the IGS of HN-L was modified to contain an additional 96 nt or more or a deletion of 42 nt. The level of transcription of each mRNA species (NP, F, HN, and L) was examined by Northern blot analysis. Our results showed that NDV can tolerate an IGS length of at least 365 nt. The extended lengths of IGSs down-regulated the transcription of the downstream gene and suggested that 31 nt in the F-HN IGS and 47 nt in the HN-L IGS are required for efficient transcription of the downstream gene. The effect of IGS length on pathogenicity of mutant viruses was evaluated in embryonated chicken eggs, 1-day-old chicks, and 6-week-old chickens. Our results showed that all IGS mutants were attenuated in chickens. The level of attenuation increased as the length of the IGS increased. Interestingly, decreased IGS length also attenuated the viruses. These findings can have significant applications in NDV vaccine development.

Experimental infection of calves with Newcastle disease virus induces systemic and mucosal antibody responses.

Calves were infected intranasally and intratracheally with Newcastle disease virus (NDV), an avian paramyxovirus. Clinical signs, viral replication, and antibody production were evaluated. This study showed that NDV replicated in calves, as evidenced by development of NDV-specific humoral and mucosal antibody responses, but was attenuated in this unnatural host. These results suggest that NDV has the potential for development as a host-range-restricted, intranasal vaccine vector for cattle that lack preexisting immunity to NDV.