UAV telephotography elucidates floristic variability and beta diversity of island cliffs under grazing interventions.

Cliffs contain one of the least known plant communities, which has been overlooked in biodiversity assessments due to the inherent inaccessibility. Our study adopted the unmanned aerial vehicle (UAV) with the telephoto camera to remotely clarify floristic variability across unreachable cliffs. Studied cliffs comprised 17 coastal and 13 inland cliffs in Gageodo of South Korea, among which 9 and 5 cliffs were grazed by the introduced cliff-dwelling goats. The UAV telephotography showed 154 and 166 plant species from coastal and inland cliffs, respectively. Inland cliffs contained more vascular plant species (P < 0.001), increased proportions of fern and woody species (P < 0.05), and decreased proportion of herbaceous species (P < 0.001) than coastal cliffs. It was also found that coastal and inland cliffs differed in the species composition (P < 0.001) rather than taxonomic beta diversity (P = 0.29). Furthermore, grazed coastal cliffs featured the elevated proportions of alien and annual herb species than ungrazed coastal cliffs (P < 0.05). This suggests that coastal cliffs might not be totally immune to grazing if the introduced herbivores are able to access cliff microhabitats; therefore, such anthropogenic introduction of cliff-dwelling herbivores should be excluded to conserve the native cliff plant communities.

Effect of Secondary Phase on Passivation Layer of Super Duplex Stainless Steel UNS S 32750: Advanced Safety of Li-Ion Battery Case Materials.

Aluminum, traditionally the primary material for battery casings, is increasingly being replaced by UNS S 30400 for enhanced safety. UNS S 30400 offers superior strength and corrosion resistance compared to aluminum; however, it undergoes a phase transformation owing to stress during processing and a lower high-temperature strength. Duplex stainless steel UNS S 32750, consisting of both austenite and ferrite phases, exhibits excellent strength and corrosion resistance. However, it also precipitates secondary phases at high temperatures, which are known to form through the segregation of Cr and Mo. Various studies have investigated the corrosion resistance of UNS S 32750; however, discrepancies exist regarding the formation and thickness of the passivation layer. This study analyzed the oxygen layer on the surface of UNS S 32750 after secondary-phase precipitation. The microstructure, volume fraction, chemical composition, and depth of O after the precipitation of the secondary phases in UNS S 32750 was examined using FE-SEM, EDS, EPMA and XRD, and the surface chemical composition and passivation layer thickness were analyzed using electron probe microanalysis and glow-discharge spectroscopy. This study demonstrated the segregation of alloy elements and a reduction in the passivation-layer thickness after precipitation from 25 µm to 20 µm. The findings of the analysis aid in elucidating the impact of secondary-phase precipitation on the passivation layer.

SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 'highly transmissible respiratory pathogen, leading to severe multi-organ damage. However, knowledge regarding SARS-CoV-2-induced cellular alterations is limited. In this study, we report that SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral infection. SARS-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNA-nucleocapsid cluster, thereby abnormally promoting mitochondrial elongation and the OXPHOS process, followed by enhancing ATP production. Furthermore, SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking, contributing to abnormal OXPHOS process and viral propagation. Approved EGFR inhibitors remarkably reduce SARS-CoV-2 propagation, among which vandetanib exhibits the highest antiviral efficacy. Treatment of SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation, thereby resulting in the reduction of SARS-CoV-2 propagation. Furthermore, oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung inflammation. Vandetanib also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern, including alpha, beta, delta and omicron, in in vitro cell culture experiments. Taken together, our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation, suggesting that EGFR is an attractive host target for combating COVID-19.

Study of Precipitated Secondary Phase at 700 °C on the Electrochemical Properties of Super Duplex Stainless Steel AISI2507: Advanced High-Temperature Safety of a Lithium-Ion Battery Case.

Super duplex stainless steel (SDSS) is a suitable structural material for various engineering applications due to its outstanding strength and corrosion resistance. In particular, its high-temperature strength can enhance the safety of electronic products and cars. SDSS AISI2507, known for its excellent strength and high corrosion resistance, was analyzed for its microstructure and electrochemical behavior at the ignition temperature of Li-ion batteries, 700 °C. At 700 °C, AISI2507 exhibited secondary phase precipitation values of 1% and 8% after 5 and 10 h, respectively. Secondary phase precipitation was initiated by the expansion of austenite, forming sigma, chi, and CrN phases. The electrochemical behavior varied with the fraction of secondary phases. Secondary phase precipitation reduced the potential (From -0.25 V to -0.31 V) and increased the current density (From 8 × 10-6 A/cm2 to 3 × 10-6 A/cm2) owing to galvanic corrosion by sigma and chi. As the fraction of secondary phases increased (From 0.0% to 8.1%), the open circuit potential decreased (From -0.25 V to -0.32 V). Secondary phase precipitation is a crucial factor in reducing the corrosion resistance of SDSS AISI2507 and occurs after 1 h of exposure at 700 °C.

High-radiation-exposure tasks in Korean pressurized heavy-water reactors.

This study analysed the occupational dose in Korean pressurized heavy-water reactors (PHWRs) and identified tasks involving high radiation exposure. The average individual dose was sufficiently low to be below the annual effective dose limit for radiation workers and is even lower than the dose limit for the general public. However, some workers received relatively higher doses than others. Furthermore, most PHWR workers are exposed to radiation during planned maintenance periods. In this study, the radiation dose was normalized (radiation dose per unit time) to determine the high-radiation-exposure tasks in Korean PHWRs. Consequently, end-fitting lapping, delayed neutron tube work and fuel channel fixed-end change tasks were identified as high-radiation-exposure tasks in Korean PHWRs. If appropriate radiation protection measures are prioritized for the identified high-dose exposure tasks, optimization of radiological protection will be effectively achieved by reducing the dose that is relatively higher than the average.

Characterization of genotype V Japanese encephalitis virus isolates from Republic of Korea.

Japanese encephalitis (JE), caused by the Japanese encephalitis virus (JEV) infection, continues to pose significant public health challenges worldwide despite efficient vaccines. The virus is classified into five genotypes, among which genotype V (GV) was not detected for a long period after its initial isolation in 1952, until reports emerged from China and the Republic of Korea (ROK) since 2009. The characteristics of the virus are crucial in estimating its potential epidemiological impact. However, characterization of GV JEVs has so far been limited to two strains: Muar, the original isolate, and XZ0934, isolated in China. Two additional ROK GV JEV isolates, NCCP 43279 and NCCP 43413, are currently available, but their characteristics have not been explored. Our phylogenetic analysis revealed that GV virus sequences from the ROK segregate into two clades. NCCP 43279 and NCCP 43413 belong to different clades and exhibit distinct in vitro phenotypes. NCCP 43279 forms larger plaques but demonstrates inefficient propagation in cell culture compared to NCCP 43413. In vivo, NCCP 43279 induces higher morbidity and mortality in mice than NCCP 43413. Notably, NCCP 43279 shows more severe blood-brain barrier damage, suggesting superior brain invasion capabilities. Consistent with its higher virulence, NCCP 43279 displays more pronounced histopathological and immunopathological outcomes. In conclusion, our study confirms that the two ROK isolates are not only classified into different clades but also exhibit distinct in vitro and in vivo characteristics.

Generation of a lethal mouse model expressing human ACE2 and TMPRSS2 for SARS-CoV-2 infection and pathogenesis.

Mouse models expressing human ACE2 for coronavirus disease 2019 have been frequently used to understand its pathogenesis and develop therapeutic strategies against SARS-CoV-2. Given that human TMPRSS2 supports viral entry, replication, and pathogenesis, we established a double-transgenic mouse model expressing both human ACE2 and TMPRSS2 for SARS-CoV-2 infection. Co-overexpression of both genes increased viral infectivity in vitro and in vivo. Double-transgenic mice showed significant body weight loss, clinical disease symptoms, acute lung injury, lung inflammation, and lethality in response to viral infection, indicating that they were highly susceptible to SARS-CoV-2. Pretreatment with the TMPRSS2 inhibitor, nafamostat, effectively reduced virus-induced weight loss, viral replication, and mortality in the double-transgenic mice. Moreover, the susceptibility and differential pathogenesis of SARS-CoV-2 variants were demonstrated in this animal model. Together, our results demonstrate that double-transgenic mice could provide a highly susceptible mouse model for viral infection to understand SARS-CoV-2 pathogenesis and evaluate antiviral therapeutics against coronavirus disease 2019.

Effect of Secondary Phase on Electroless Ni Plating Behaviour of Super Duplex Stainless Steel SAF2507 for Advanced Li-Ion Battery Case.

The development of Li-ion battery cases requires superior electrical conductivity, strength, and corrosion resistance for both cathode and anode to enhance safety and performance. Among the various battery case materials, super duplex stainless steel (SDSS), which is composed of austenite and ferrite as two-phase stainless steel, exhibits outstanding strength and corrosion resistance. However, stainless steel, which is an iron-based material, tends to have lower electrical conductivity. Nevertheless, nickel-plating SDSS can achieve excellent electrical conductivity, making it suitable for Li-ion battery cases. Therefore, this study analysed the plating behaviour of SDSS plates after nickel plating to leverage their exceptional strength and corrosion resistance. Electroless Ni plating was performed to analyse the plating behaviour, and the plating behaviour was studied with reference to different plating durations. Heat treatment was conducted at 1000 °C for one hour, followed by cooling at 50 °C/s. Post-heat treatment, the analysis of phases was executed using FE-SEM, EDS, and EPMA. Electroless Ni plating was performed at 60-300 s. The plating duration after the heat treatment was up to 300 s, and the behaviour of the materials was observed using FE-SEM. The phase analysis concerning different plating durations was conducted using XRD. Post-heat treatment, the precipitated secondary phases in SAF2507 were identified as Sigma, Chi, and CrN, approximating a 13% distribution. During the electroless Ni plating, the secondary phase exhibited a plating rate equivalent to that of ferrite, entirely plating at around 180 s. Further increments in plating time displayed growth of the plating layer from the austenite direction towards the ferrite, accompanied by a reduced influence from the substrate. Despite the differences in composition, both the secondary phase and austenite demonstrated comparable plating rates, showing that electroless Ni plating on SDSS was primarily influenced by the substrate, a finding which was primarily confirmed through phase analysis.

High-Performance One-Body Electrochemical Torsional Artificial Muscles Built Using Carbon Nanotubes and Ion-Exchange Polymers.

Electrochemical torsional artificial muscles have the potential to replace electric motors in the field of miniaturization. In particular, carbon nanotubes (CNTs) are some of the best materials for electrochemical torsional artificial muscles due to their remarkable mechanical strength and high electrical conductivity. However, previous studies on CNT torsional muscle utilize only half of the whole potential range for torsional actuation because the actuations in the positive and negative voltage ranges offset each other. Here, we used an ion-exchange polymer, poly(sodium 4-styrenesulfonate) (PSS), which leads to the participation of only positive ions in the actuation of CNT muscles so that the whole potential range can be used for torsional actuation. As a result, PSS-coated CNT muscle can provide 1.9 times higher torsional actuation compared to neat CNT torsional muscle. This PSS-coated CNT muscle not only provides high performance but also facilitates a one-body system for electrochemical torsional actuation. From these advantages, we implement a one-body torsional muscle for the realization of the forward motion of a model boat. This high performance and one-body structure for electrochemical torsional muscles can be used for further applications, such as soft robotics and implantable devices.

Asymbiotic Seed Germination and In Vitro Seedling Development of the Endangered Orchid Species Cypripedium guttatum.

Cypripedium guttatum is a highly restricted terrestrial orchid that faces increasing endangerment owing to its habitat destruction and illegal collection. Compared to epiphytic orchids, terrestrial orchids such as C. guttatum have harder seed coats and more demanding in vitro germination conditions. This study aimed to develop an effective in vitro propagation system for C. guttatum to aid in its conservation. Seeds from mature capsules were subjected to various conditions, including sterilization using 1% sodium hypochlorite (NaOCl) and different light conditions, culture media, hormones, and organic supplements, to assess germination and early seedling development in vitro. Sterilization with 1% NaOCl significantly improved the germination rate, especially under dark conditions. Germination initiation occurred at 2 and 3 months in orchid seed sowing medium (OSM) and Murashige and Skoog (MS) medium, respectively. The addition of 1 mg/L naphthaleneacetic acid (NAA) further enhanced germination. However, the inclusion of organic supplements, such as apple and banana homogenates, in the culture medium led to substantial growth inhibition after 12 months. Notably, orchid maintenance medium (OMM) without organic additives proved to be the most suitable for seedling growth. The results of this study show that sterilization, appropriate light, and optimal NAA concentrations are beneficial for seed germination.

Anti-Inflammatory Effects of Tegoprazan in Lipopolysaccharide-Stimulated Bone-Marrow-Derived Macrophages.

The purpose of this study was to investigate the anti-inflammatory effect of tegoprazan (TEGO) in lipopolysaccharide (LPS)-stimulated bone-marrow-derived macrophages (BMMs). To this end, compared to methylprednisolone (MP; positive control), we evaluated whether TEGO effectively differentiates LPS-stimulated BMMs into M2-phenotype macrophages. Moreover, the expression of pro- and anti-inflammatory cytokines genes influenced by TEGO was measured using quantitative real-time polymerase chain reaction (qRT-PCR) analysis. TEGO was found to reduce nitric oxide (NO) production in BMMs significantly. In addition, TEGO significantly decreased and increased the gene expression levels of pro-inflammatory and anti-inflammatory cytokines, respectively. In addition, we evaluated the phosphorylated values of the extracellular signal-regulatory kinase (ERK) and p38 in the mitogen-activated protein (MAP) kinase signaling pathway through Western blotting. TEGO significantly reduced the phosphorylated values of the ERK and p38. In other words, TEGO suppressed the various pro-inflammatory responses in LPS-induced BMMs. These results show that TEGO has the potential to be used as an anti-inflammatory agent.

Current Status of Epidemiology, Diagnosis, Therapeutics, and Vaccines for the Re-Emerging Human Monkeypox Virus.

Monkeypox (Mpox) virus, a member of the Poxviridae family, causes a severe illness similar to smallpox, which is characterized by symptoms such as high fever, rash, and pustules. Human-to-human transmission cases have been reported but remained low since the first recorded case of human infection occurred in the Congo in 1970. Recently, Mpox has re-emerged, leading to an alarming surge in infections worldwide since 2022, originating in the United Kingdom. Consequently, the World Health Organization (WHO) officially declared the '2022-23 Mpox outbreak'. Currently, no specific therapy or vaccine is available for Mpox. Therefore, patients infected with Mpox are treated using conventional therapies developed for smallpox. However, the vaccines developed for smallpox have demonstrated only partial efficacy against Mpox, allowing viral transmission among humans. In this review, we discuss the current epidemiology of the ongoing Mpox outbreak and provide an update on the progress made in diagnosis, treatment, and development of vaccines for Mpox.

Multi-site assessment of soil nitrogen stocks across temperate forests under different thinning intensities, recovery times, and site conditions.

Increasing research interests have been paid to understand the factors controlling soil nitrogen (N) stocks under diverse environmental conditions and forest thinning regimes. This study investigated soil N stocks across 13 temperate forests, each of which received three thinning intensities (unthinned control, 15-30 %, and 30-50 % basal area removals) under varying pre-treatment conditions (altitude, slope, soil pH, soil moisture, stand age, stand density, diameter at breast height, and tree height). The total N stored in the forest floor (L, F, and H layers) and mineral soils (0-10, 10-20, and 20-30 cm) was determined 1, 4, and 7 years after thinning. Given the various site conditions and thinning regimes, a standardized effect size was used to analyze the influences of thinning on N stocks. The N stocks (Mg N ha-1) of the forest floor and at 0-10, 10-20, and 20-30 cm mineral soil depths were 0.02-0.46, 0.32-3.21, 0.29-3.03, and 0.25-2.54 across all studied forests, respectively. The averaged effect sizes indicated decrease in forest floor N stocks and increase in mineral soil N stocks under thinning due to the reduced litterfall and eventual input of thinning residues. Thinning intensity negatively affected the effect sizes for the N stocks (P < 0.05), suggesting that excessively heavy thinning may be inappropriate for retaining forest soil N. However, multimodel inference showed that soil pH (relative importance = 1.00) and stand age (relative importance = 0.42) had the largest influence on the effect sizes for forest floor and mineral soil N stocks. This pattern suggests that the effects of thinning on soil N stocks might vary with pre-treatment conditions, even more than thinning intensities and recovery time; therefore, thinning to manage forest soil N should consider pre-treatment environmental conditions in addition to thinning regime.

Sparsier2Sparse: Self-supervised convolutional neural network-based streak artifacts reduction in sparse-view CT images.

BACKGROUND: Sparse-view computed tomography (CT) has attracted a lot of attention for reducing both scanning time and radiation dose. However, sparsely-sampled projection data generate severe streak artifacts in the reconstructed images. In recent decades, many sparse-view CT reconstruction techniques based on fully-supervised learning have been proposed and have shown promising results. However, it is not feasible to acquire pairs of full-view and sparse-view CT images in real clinical practice. PURPOSE: In this study, we propose a novel self-supervised convolutional neural network (CNN) method to reduce streak artifacts in sparse-view CT images. METHODS: We generate the training dataset using only sparse-view CT data and train CNN based on self-supervised learning. Since the streak artifacts can be estimated using prior images under the same CT geometry system, we acquire prior images by iteratively applying the trained network to given sparse-view CT images. We then subtract the estimated steak artifacts from given sparse-view CT images to produce the final results. RESULTS: We validated the imaging performance of the proposed method using extended cardiac-torso (XCAT) and the 2016 AAPM Low-Dose CT Grand Challenge dataset from Mayo Clinic. From the results of visual inspection and modulation transfer function (MTF), the proposed method preserved the anatomical structures effectively and showed higher image resolution compared to the various streak artifacts reduction methods for all projection views. CONCLUSIONS: We propose a new framework for streak artifacts reduction when only the sparse-view CT data are given. Although we do not use any information of full-view CT data for CNN training, the proposed method achieved the highest performance in preserving fine details. By overcoming the limitation of dataset requirements on fully-supervised-based methods, we expect that our framework can be utilized in the medical imaging field.

Protein Ligation-Assisted Reconstitution of Split HRP Fragments for Facile Production of HRP Fusion Proteins in E.†coli.

Horseradish peroxidase (HRP) is a pivotal biocatalyst for biosensor development and fine chemical synthesis. HRP proteins are mostly extracted and purified from the roots of horseradish because the solubility and productivity of recombinant HRP in bacteria are significantly low. In this study, we investigate the reconstitution system of split HRP fragments to improve its soluble expression levels in E. coli allowing the cost-effective production of bioactive HRPs. To promote the effective association between two HRP fragments (HRPn and HRPc), we exploit SpyTag-SpyCatcher chemistry, a versatile protein coupling method with high affinity and selectivity. Each HRP fragment was genetically fused with SpyTag and SpyCatcher, respectively, exhibiting soluble expression in the E. coli cytoplasm. The engineered split HRPs were effectively and irreversibly reconstituted into a biologically active and stable assembly that can catalyze intrinsic enzymatic reactions. Compared to the chaperone co-expression system, our approach shows that the production yield of soluble HRP is comparable, but the purity of the final product is relatively high. Therefore, our results can be applied to the high-yield production of recombinant HRP variants and other difficult-to-express proteins in bacteria without complex downstream processes.

Generation of telomeric repeat binding factor 1 (TRF1)-knockout human embryonic stem cell lines, KRIBBe010-A-95, KRIBBe010-A-96, and KRIBBe010-A-97, using CRISPR/Cas9 technology.

Telomeric repeat binding factor 1 (TRF1) plays an essential role in maintaining telomere length. Here, we established TRF1-knockout human pluripotent stem cells (hPSCs; hTRF1-KO) using the CRISPR/Cas9 technology. The hTRF1-KO cell lines expressed pluripotency markers and demonstrated a normal karyotype (46, XX) and DNA profile. In addition, hTRF1-KOcells spontaneously differentiated into all three germ layers in vitro. Thus, these cell lines could be useful models in various research fields.

Real-Time Visualizing Nucleation and Growth of Electrodes for Post-Lithium-Ion Batteries.

ConspectusUntil recently, most studies on nucleation and growth mechanisms have employed electrochemical transient measurements, and numerous models have been established on various metal electrode elements. Contrary to the conventional tip-induced nucleation and growth model, a base-induced nucleation and growth mode was discovered not so long ago, which highlighted the importance of direct real-time observations such as visualization. As analysis techniques developed, diverse in situ/operando imaging methods have spurred the fundamental understanding of complex and dynamic battery electrochemistry. Experimental observations of alkali Li and Na metals are limited and difficult because their high reactivity makes not only the fabrication but also the analysis itself challenging. Na metal has high reactivity to electrolytes. Accordingly, it is difficult to visualize the Na deposition in real-time due to gas evolution and resolution limitation. Only a few studies have examined the Na deposition and dissolution reactions in operando. It is generally believed that the Mg anode is free from the dendrite growth of Mg metal, and Mg deposition preferentially occurs along the surface direction. However, whether the Mg anode always follows the dendrite-free growth has currently become a controversial topic and is being discussed and redefined based on real-time imaging analyses. In addition, a variety of morphological evolutions in the metal anodes are required to be systematically distinguished by key parameters. Real-time imaging analysis can directly confirm the solid-liquid-solid multiphase conversion reactions of S and Se cathodes. S and Se elements belong to the same chalcogen group, but their crystal structures and morphological changes significantly differ in each electrode during deposition and dissolution reactions. Therefore, it is necessitated to discuss the nucleation and growth behaviors by examining intrinsic properties of each element in chalcogen cathodes. Considering that a mechanistic understanding of the Se cathode is in its infancy, its nucleation and growth behaviors must be further explored through fundamental studies. In this Account, we aim to discuss the nucleation and growth behaviors of metal (Li, Na, and Mg) anodes and chalcogen (S and Se) cathodes. To elucidate their nucleation and growth mechanisms, we overview the morphological evolutions on the electrode surface and interface by in situ/operando visualizations. Our recent studies covering Li, Na, Mg, S, and Se electrodes verified by operando X-ray imaging are used as critical resources in understanding their nucleation and growth behaviors. Overall, with validation of the complex and dynamic nucleation and growth behaviors of metal and chalcogen electrodes by in situ/operando visualization methods, we hope that this Account can contribute to supporting the fundamental knowledge for the development of high-energy-density metal and chalcogen electrodes.

Cognitive Refined Augmentation for Video Anomaly Detection in Weak Supervision.

Weakly supervised video anomaly detection is a methodology that assesses anomaly levels in individual frames based on labeled video data. Anomaly scores are computed by evaluating the deviation of distances derived from frames in an unbiased state. Weakly supervised video anomaly detection encounters the formidable challenge of false alarms, stemming from various sources, with a major contributor being the inadequate reflection of frame labels during the learning process. Multiple instance learning has been a pivotal solution to this issue in previous studies, necessitating the identification of discernible features between abnormal and normal segments. Simultaneously, it is imperative to identify shared biases within the feature space and cultivate a representative model. In this study, we introduce a novel multiple instance learning framework anchored on a memory unit, which augments features based on memory and effectively bridges the gap between normal and abnormal instances. This augmentation is facilitated through the integration of an multi-head attention feature augmentation module and loss function with a KL divergence and a Gaussian distribution estimation-based approach. The method identifies distinguishable features and secures the inter-instance distance, thus fortifying the distance metrics between abnormal and normal instances approximated by distribution. The contribution of this research involves proposing a novel framework based on MIL for performing WSVAD and presenting an efficient integration strategy during the augmentation process. Extensive experiments were conducted on benchmark datasets XD-Violence and UCF-Crime to substantiate the effectiveness of the proposed model.

Ocular tropism of SARS-CoV-2 in animal models with retinal inflammation via neuronal invasion following intranasal inoculation.

Although ocular manifestations are reported in patients with COVID-19, consensus on ocular tropism of SARS-CoV-2 is lacking. Here, we infect K18-hACE2 transgenic mice with SARS-CoV-2 using various routes. We observe ocular manifestation and retinal inflammation with production of pro-inflammatory cytokines in the eyes of intranasally (IN)-infected mice. Intratracheal (IT) infection results in dissemination of the virus from the lungs to the brain and eyes via trigeminal and optic nerves. Ocular and neuronal invasions are confirmed using intracerebral (IC) infection. Notably, the eye-dropped (ED) virus does not cause lung infection and becomes undetectable with time. Ocular and neurotropic distribution of the virus in vivo is evident in fluorescence imaging with an infectious clone of SARS-CoV-2-mCherry. The ocular tropic and neuroinvasive characteristics of SARS-CoV-2 are confirmed in wild-type Syrian hamsters. Our data can improve the understanding regarding viral transmission and clinical characteristics of SARS-CoV-2 and help in improving COVID-19 control procedures.

PLK1-ELAVL1/HuR-miR-122 signaling facilitates hepatitis C virus proliferation.

The liver-specific microRNA, miR-122, plays an essential role in the propagation of hepatitis C virus (HCV) by binding directly to the 5'-end of its genomic RNA. Despite its significance for HCV proliferation, the host factors responsible for regulating miR-122 remain largely unknown. In this study, we identified the cellular RNA-binding protein, ELAVL1/HuR (embryonic lethal-abnormal vision-like 1/human antigen R), as critically contributing to miR-122 biogenesis by strong binding to the 3'-end of miR-122. The availability of ELAVL1/HuR was highly correlated with HCV proliferation in replicon, infectious, and chronically infected patient conditions. Furthermore, by screening a kinase inhibitor library, we identified rigosertib, an anticancer agent under clinical trials, as having both miR-122-modulating and anti-HCV activities that were mediated by its ability to target polo-like kinase 1 (PLK1) and subsequently modulate ELAVL1/HuR-miR-122 signaling. The expression of PLK1 was also highly correlated with HCV proliferation and the HCV positivity of HCC patients. ELAVL1/HuR-miR-122 signaling and its mediation of PLK1-dependent HCV proliferation were demonstrated by performing various rescue experiments and utilizing an HCV mutant with low dependency on miR-122. In addition, the HCV-inhibitory effectiveness of rigosertib was validated in various HCV-relevant conditions, including replicons, infected cells, and replicon-harboring mice. Rigosertib was highly effective in inhibiting the proliferation of not only wild-type HCVs, but also sofosbuvir resistance-associated substitution-bearing HCVs. Our study identifies PLK1-ELAVL1/HuR-miR-122 signaling as a regulatory axis that is critical for HCV proliferation, and suggests that a therapeutic approach targeting this host cell signaling pathway could be useful for treating HCV and HCV-associated diseases.