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In this study, a deep eutectic solvent (DES) pretreatment using choline chloride (ChCl)/lactic acid (LA), betaine (BE)/LA, and potassium carbonate (PC)/glycerol (GLY) was used to prepare lignocellulose nanofibrils (LCNF). An increase in the reaction temperature (100, 120, and 130 °C) and time (6, 12, and 24 h) caused a decrease in the content of lignin and hemicellulose in lignocellulose (Pinus densiflora S. et Z.). Lignocellulose nanofibrils (LCNFs) were prepared from the DES-treated products using a high-pressure homogenizer. As the lignin content of the DES-treated products decreased, the defibrillation efficiency of the LCNFs improved, resulting in a smaller diameter, longer filtration time, larger specific surface area, higher water retention value, and higher viscosity. DES pretreatment using ChCl/LA was more effective for delignification and improvement of defibrillation efficiency than pretreatment using BE/LA and PC/GLY. A decrease in the lignin content caused an increase in the crystallinity index and crystallite size. The significant delignification due to the ChCl/LA treatment can be attributed to the improved tensile properties of the LCNF nanosheets. [ABSTRACT FROM AUTHOR]

Background: Despite high vaccination coverage, measles outbreaks have been reported in measles elimination countries, especially among healthcare workers in their 20 and 30 s. This study was designed to identify measles-susceptible individuals and to evaluate whether primary or secondary vaccine failure occurred during measles outbreak response immunization (ORI) activities.Methods: The study population was divided into three groups as follows: natural immunity group (Group 1), vaccine-induced immunity group (Group 2), and vaccine failure group (Group 3). We evaluated the immunogenicity of measles among healthcare workers using three methods-enzyme-linked immunoassays, plaque reduction neutralization tests, and avidity assays. The results were assessed at baseline, 4 weeks after, and 6 months after the completion of measles-mumps-rubella (MMR) vaccination.Results: In total, 120 subjects were enrolled, with 40 subjects in each group. The median age of Group 3 was 29 years, which was significantly lower than that of the other groups. The baseline negative measles virus (MeV) IgG in Group 3 increased to a median value of 165 AU/mL at 4 weeks after ORI and was lower than that in Groups 1 and 2. The median neutralizing antibody titer was highest in Group 1, and this was significantly different from that in Group 2 or Group 3 at 4 weeks (944 vs. 405 vs. 482 mIU/mL, P = 0.001) and 6 months (826 vs. 401 vs. 470, P = 0.011) after ORI. The rates of high MeV avidity IgG were highest in Group 2, and these were significantly different from those in Groups 1 or 3 at 4 weeks (77.5 vs. 90% vs. 88.6%, P = 0.03) and 6 months (81 vs. 94.8 vs. 82.1%, P = 0.01) after ORI.Conclusions: Considering the MeV-neutralizing antibodies and IgG avidity after MMR vaccination in measles-susceptible group, vaccine failure is inferred as secondary vaccine failure, and further data regarding the maintenance of immunogenicity are needed based on long-term data. The MeV-neutralizing antibody levels were highest in the natural immunity group, and the primary vaccine-induced immunity group showed the highest rates of high MeV IgG avidity. [ABSTRACT FROM AUTHOR]

Avian influenza viruses (AIVs) are carried by wild migratory waterfowl across migratory flyways. To determine the strains of circulating AIVs that may pose a risk to poultry and humans, regular surveillance studies must be performed. Here, we report the surveillance of circulating AIVs in South Korea during the winter seasons of 2009–2013. A total of 126 AIVs were isolated from 7942 fecal samples from wild migratory birds, with a total isolation rate of 1.59%. H1‒H7 and H9‒H11 hemagglutinin (HA) subtypes, and N1‒N3, N5, and N7‒N9 neuraminidase (NA) subtypes were successfully isolated, with H6 and N2 as the most predominant HA and NA subtypes, respectively. Sequence identity search showed that the HA and NA genes of the isolates were highly similar to those of low-pathogenicity influenza strains from the East Asian-Australasian flyway. No match was found for the HA genes of high-pathogenicity influenza strains. Thus, the AIV strains circulating in wild migratory birds from 2009 to 2013 in South Korea likely had low pathogenicity. Continuous surveillance studies such as this one must be performed to identify potential precursors of influenza viruses that may threaten animal and human health. [ABSTRACT FROM AUTHOR]

Influenza viruses cause significant morbidity and mortality worldwide. Long-term or frequent use of approved anti-influenza agents has resulted in drug-resistant strains, thereby necessitating the discovery of new drugs. In this study, we found aprotinin, a serine protease inhibitor, as an anti-influenza candidate through screening of compound libraries. Aprotinin has been previously reported to show inhibitory effects on a few influenza A virus (IAV) subtypes (e.g., seasonal H1N1 and H3N2). However, because there were no reports of its inhibitory effects on the other types of influenza viruses, we investigated the inhibitory effects of aprotinin in vitro on a wide range of influenza viruses, including avian and oseltamivir-resistant influenza virus strains. Our cell-based assay showed that aprotinin had inhibitory effects on seasonal human IAVs (H1N1 and H3N2 subtypes), avian IAVs (H5N2, H6N5, and H9N2 subtypes), an oseltamivir-resistant IAV, and a currently circulating influenza B virus. We have also confirmed its activity in mice infected with a lethal dose of influenza virus, showing a significant increase in survival rate. Our findings suggest that aprotinin has the capacity to inhibit a wide range of influenza virus subtypes and should be considered for development as a therapeutic agent against influenza. [ABSTRACT FROM AUTHOR]

Paucity of the survival motor neuron (SMN) protein triggers the oft-fatal infantile-onset motor neuron disorder, spinal muscular atrophy (SMA). Augmenting the protein is one means of treating SMA and recently led to FDA approval of an intrathecally delivered SMN-enhancing oligonucleotide currently in use. Notwithstanding the advent of this and other therapies for SMA, it is unclear whether the paralysis associated with the disease derives solely from dysfunctional motor neurons that may be efficiently targeted by restricted delivery of SMN-enhancing agents to the nervous system, or stems from broader defects of the motor unit, arguing for systemic SMN repletion. We investigated the disease-contributing effects of low SMN in one relevant peripheral organ - skeletal muscle - by selectively depleting the protein in only this tissue. We found that muscle deprived of SMN was profoundly damaged. Although a disease phenotype was not immediately obvious, persistent low levels of the protein eventually resulted in muscle fiber defects, neuromuscular junction abnormalities, compromised motor performance, and premature death. Importantly, restoring SMN after the onset of muscle pathology reversed disease. Our results provide the most compelling evidence yet for a direct contributing role of muscle in SMA and argue that an optimal therapy for the disease must be designed to treat this aspect of the dysfunctional motor unit. [ABSTRACT FROM AUTHOR]

Recently, transparent wood (TW) has been considered for many applications, such as windows, energy storage, and electronic devices. This study presents the fabrication of eco-friendly TW using waste lignin as a resource to enhance the TW's performance by providing UV-shielding functionality. Three different pretreatment methods were explored for TW fabrication, including solar-assisted bleaching, steam bleaching, and NaOH delignification. The average size of the lignin nanoparticles (LNs) characterized using a scanning electron microscope and nanoparticle analyzer and was found to be around 100 nm. The LNs had zeta potentials of − 44.2 mV to − 34.9 mV for the first and sixth months, respectively. The transmittance of TW ranged from 20% to 80%, depending on the pretreatment and additional LNs content. By incorporating just 1% of LN, the TW composites were found to effectively block all UV-C, UV-B, and UV-A radiation while maintaining adequate visible light transmittance. The thermal stability, crystallinity index, and mechanical properties of wood and TW were investigated and compared. The NaOH delignification TW (Na-TW) has shown the highest transmittance, tensile strength, UV-shielding functionality, and comparable thermal stability with solar transparent wood (SL-TW) and steam transparent wood (ST-TW) methods. These findings indicate that TW LNs nanocomposite is a promising candidate for UV-shielding window applications. [Display omitted] • Transparent wood was fabricated by infiltrating lignin nanoparticles (LNs). • Transparent wood offered good transparency, UV-shielding, mechanical properties. • 1% LNs contained wood shows good transparence and UV-shielding. • Eco-friendly transparent wood was fabricated using waste lignin. [ABSTRACT FROM AUTHOR]

Influenza A viruses must undergo adaptation to acquire virulence in new host species. In mouse models, host adaptation for virulence is generally performed through 5 to 20 lung-to-lung passages. However, highly pathogenic avian influenza viruses (e.g., H5N1 and H7N7 subtypes) have been observed to acquire virulence in mice after only a few in vivo passages. In this study, a low-pathogenic avian influenza H5N2 virus, A/Aquatic Bird/Korea/CN2/2009, which was a prevalent subtype in South Korea in 2009, was serially passaged in mice to evaluate its potential to become highly pathogenic. Unexpectedly, the virus became highly pathogenic in mice after a single lung-to-lung passage, resulting in 100% lethality with a mean death time (MDT) of 6.1 days postinfection (DPI). Moreover, the pathogenicity gradually increased after subsequent in vivo passages with an MDT of 5.2 and 4.2 DPI after the second and third passage, respectively. Our molecular analysis revealed that two amino acid changes in the polymerase complex (a glutamate-to-lysine substitution at position 627 of PB2 and a threonine-to-isoleucine substitution at position 97 of PA) were associated with the increased pathogenicity; the PB2 E627K mutation was responsible for the initial virulence conversion (0 to 100% lethality), while the PA T97I mutation acted as an accessory for the increased virulence. [ABSTRACT FROM AUTHOR]

An outbreak of a canine influenza virus (CIV) H3N2 reassortant derived from pandemic (pdm) H1N1 and CIV H3N2 in companion animals has underscored the urgent need to monitor CIV infections for potential zoonotic transmission of influenza viruses to humans. In this study, we assessed the virulence of a novel CIV H3N2 reassortant, VC378, which was obtained from a dog that was coinfected with pdm H1N1 and CIV H3N2, in ferrets, dogs, and mice. Significantly enhanced virulence of VC378 was demonstrated in mice, although the transmissibility and pathogenicity of VC378 were similar to those of classical H3N2 in ferrets and dogs. This is notable because mice inoculated with an equivalent dose of classical CIV H3N2 showed no clinical signs and no lethality. We found that the PA and NS gene segments of VC378 were introduced from pdmH1N1, and these genes included the amino acid substitutions PA-P224S and NS-I123V, which were previously found to be associated with increased virulence in mice. Thus, we speculate that the natural reassortment between pdm H1N1 and CIV H3N2 can confer virulence and that continuous surveillance is needed to monitor the evolution of CIV in companion animals. [ABSTRACT FROM AUTHOR]

Background The emergence of zoonotic viruses in domestic animals is a significant public health concern. Canine influenza virus (CIV) H3N2 is a virus that can infect companion animals and is, therefore, a potential public health concern. Objective This study investigated the inter- and intraspecies transmission of CIV among dogs, cats, and ferrets, under laboratory conditions, to determine whether transmission of the virus was possible between as well as within these domestic animal species. Method The transmission routes for inter- and intraspecies transmission were airborne and direct contact, respectively. Transmission was conducted through intranasal infection of dogs followed by exposure to either cats or ferrets and by comingling infected and naïve animals of the same species. Results The interspecies transmission of CIV H3N2 via airborne was only observed from dogs to cats and not from dogs to ferrets. However, direct intranasal infection of either cats or ferrets with CIV could induce influenza-like clinical signs, viral shedding, and serological responses. Additionally, naïve cats and ferrets could be infected by CIV via direct contact with infected animals of the same species. Conclusion Cats appear to be another susceptible host of CIV H3N2, whereas ferrets are not likely natural hosts. The molecular-based mechanism of interspecies and intraspecies transmission of CIV H3N2 should be further studied. [ABSTRACT FROM AUTHOR]

Abstract: The continued spread of a highly pathogenic avian influenza (HPAI) H5N1 virus among wild birds and poultry has posed a potential threat to human public health. In the present study, we report the isolation of HPAI H5N1 viruses (A/Md/Korea/W401/11 and A/Md/Korea/W404/11) from fecal samples of migratory birds. Genetic and phlyogenetic analyses demonstrated that these viruses are genetically identical possessing gene segments from avian virus origin and showing highest sequence similarities (as high as 99.8%) to A/Ws/Hokkaido/4/11 and 2009–2010 Mongolian-like clade 2.3.2 isolates rather than previous Korean H5N1 viruses. Both viruses possess the polybasic motif (QRERRRK/R) in HA but other genes did not bear additional virulence markers. Pathogenicity of A/Md/Korea/W401/11 was assessed and compared with a 2006 clade 2.2 HPAI H5N1 migratory bird isolate (A/EM/Korea/W149/06) in chickens, ducks, mice and ferrets. Experimental infection in these hosts showed that both viruses have high pathogenic potential in chickens (2.3–3.0LD50s) and mice (3.3–3.9LD50s), but A/Md/Korea/W401/11 was less pathogenic in duck and ferret models. Despite recovery of both infection viruses in the upper respiratory tract, efficient ferret-to-ferret transmission was not observed. These data suggest that the 2011 Korean HPAI wild bird H5N1 virus could replicate in mammalian hosts without pre-adaptation but could not sustain subsequent infection. This study highlights the role of migratory birds in the perpetuation and spread of HPAI H5N1 viruses in Far-East Asia. With the changing pathobiology caused by H5N1 viruses among wild and poultry birds, continued surveillance of influenza viruses among migratory bird species remains crucial for effective monitoring of high-pathogenicity or pandemic influenza viruses. [Copyright &y& Elsevier]

Background: The transcriptional cofactor, Hairless (HR), acts as one of the key regulators of hair follicle cycling; the loss of function mutations is the cause of the expression of the hairless phenotype in humans and mice. Recently, we reported a new Hr mutant mouse called 'Hairpoor' (HrHp). These mutants harbor a gain of the function mutation, T403A, in the Hr gene. This confers the overexpression of HR and HrHp is an animal model of Marie Unna hereditary hypotrichosis in humans. In the present study, the expression profile of HrHp/HrHp skin was investigated using microarray analysis to identify genes whose expression was affected by the overexpression of HR. Results: From 45,282 mouse probes, differential expressions in 43 (>2-fold), 306 (>1.5-fold), and 1861 genes (>1.2-fold) in skin from HrHp/HrHp mice were discovered and compared with skin from wild-type mice. Among the 1861 genes with a > 1.2-fold increase in expression, further analysis showed that the expression of eight genes known to have a close relationship with hair follicle development, ascertained by conducting real-time PCR on skin RNA produced during hair follicle morphogenesis (P0-P14), indicated that four genes, Wif1, Casp14, Krt71, and Sfrp1, showed a consistent expression pattern with respect to HR overexpression in vivo. Conclusion: Wif1 and Casp14 were found to be upregulated, whereas Krt71 and Sfrp1 were downregulated in cells overexpressing HR in transient transfection experiments on keratinocytes, suggesting that HR may transcriptionally regulate these genes. Further studies are required to understand the mechanism of this regulation by the HR cofactor. [ABSTRACT FROM AUTHOR]

Given that local cell-mediated immunity (CMI) against the human papillomavirus type 16 E6 (HPV16 E6) protein is important for eradication of HPV16 E6-expressing cancer cells in the cervical mucosa, the HPV16 E6 protein may be a target for the mucosal immunotherapy of cervical cancer. Here, we expressed the HPV16 E6 antigen on Lactobacillus casei ( L. casei) and investigated E6-specific CMI following oral administration of the L. casei-PgsA-E6 to mice. Surface expression of HPV16 E6 antigens was confirmed and mice were orally inoculated with the L. casei-PgsA or the L. casei-PgsA-E6. Compared to the L. casei-PgsA-treated mice, significantly higher levels of serum IgG and mucosal IgA were observed in L. casei-PgsA-E6-immunized mice; these differences were significantly enhanced after boost. Consistent with this, systemic and local CMI were significantly increased after the boost, as shown by increased counts of IFN-γ-secreting cells in splenocytes, mesenteric lymph nodes (MLN), and vaginal samples. Furthermore, in the TC-1 tumor model, animals receiving the orally administered L. casei-PgsA-E6 showed reduced tumor size and increased survival rate versus mice receiving control ( L. casei-PgsA) immunization. We also found that L. casei-PgsA-E6-induced antitumor effect was decreased by in vivo depletion of CD4 or CD8 T cells. Collectively, these results indicate that the oral administration of lactobacilli bearing the surface-displayed E6 protein induces T cell-mediated cellular immunity and antitumor effects in mice. [ABSTRACT FROM AUTHOR]

Abstract: The rapid evolution, genetic diversity, broad host range, and increasing human infection with avian influenza A (H5N1) viruses highlight the need for an efficacious cross-clade vaccine. Using the ferret model, we compared induction of cross-reactive immunity and protective efficacy of three single-clade H5N1 vaccines and a novel multiple-clade H5N1 vaccine, with and without MF59 adjuvant. Reverse genetics (rg) was used to generate vaccine viruses containing the hemagglutinin (HA) and neuraminidase genes of wild-type H5N1 viruses. Ferrets received two doses of inactivated whole-virus vaccine separated by 3 weeks. Single-clade vaccines (7.5μg HA per dose) included rg-A/Vietnam/1203/04 (clade 1), rg-A/Hong Kong/213/03 (clade 1), and rg-A/Japanese White Eye/Hong Kong/1038/06 (clade 2.3). The multiple-clade vaccine contained 3.75μg HA per dose of each single-clade vaccine and of rg-A/Whooper Swan/Mongolia/244/05 (clade 2.2). Two doses of vaccine were required to substantially increase anti-HA and virus neutralizing antibody titers to H5N1 viruses. MF59 adjuvant enhanced induction of clade-specific and cross-clade serum antibody responses, reduced frequency of infection (as determined by upper respiratory tract virus shedding and seroconversion data), and eliminated disease signs. The rg-A/Hong Kong/213/03 vaccine induced the highest antibody titers to homologous and heterologous H5N1 viruses, while rg-A/Japanese White Eye/Hong Kong/1038/06 vaccine induced the lowest. The multiple-clade vaccine was broadly immunogenic against clade 1 and 2 viruses. The rg-A/Vietnam/1203/04 vaccine (the currently stockpiled H5N1 vaccine) most effectively reduced upper respiratory tract virus shedding after challenge with clade 1 and 2 viruses. Importantly, all vaccines protected against lethal challenge with A/Vietnam/1203/04 virus and provided cross-clade protection. [Copyright &y& Elsevier]

This study reports the preparation of a polybutylene succinate (PBS) film reinforced with pure cellulose nanofibril (PCNF) and lignocellulose nanofibril (LCNF) by a two-step process that consists of solvent dispersion and twin-screw extrusion. Compared to the conventional one-step process, this method offered improved mechanical properties. The addition of 5% CNF increased the tensile properties up to 18.8%. Further, the effect of the lignin content was also studied by using LCNF as a reinforcement. The LCNF was prepared with and without a deep eutectic solvent (DES) pretreatment to gain LCNF with a lignin content that varied between 5, 19, and 30%. The mechanical properties results show that a 5% addition of LCNF to the PBS matrix increased its tensile strength and elastic modulus. Further, the morphological and thermal properties of the composites were also studied in detail. [ABSTRACT FROM AUTHOR]

Lignocellulose nanofibrils (LCNFs) with different lignin contents were prepared using choline chloride (ChCl)/lactic acid (LA), deep eutectic solvent (DES) pretreatment, and subsequent mechanical defibrillation. The LCNFs had a diameter of 15.3–18.2 nm, which was similar to the diameter of commercial pure cellulose nanofibrils (PCNFs). The LCNFs and PCNFs were wet-spun in CaCl2 solution for filament fabrication. The addition of sodium alginate (AL) significantly improved the wet-spinnability of the LCNFs. As the AL content increased, the average diameter of the composite filaments increased, and the orientation index decreased. The increase in AL content improved the wet-spinnability of CNFs but deteriorated the tensile properties. The increase in the spinning rate resulted in an increase in the orientation index, which improved the tensile strength and elastic modulus. [ABSTRACT FROM AUTHOR]

In this study, cellulose acetate (CA)/cellulose nanofibril (CNF) film was prepared via solvent casting. CNF was used as reinforcement to increase tensile properties of CA film. CNF ratio was varied into 3, 5, and 10 phr (parts per hundred rubbers). Triacetin (TA) and triethyl citrate (TC) were used as two different eco-friendly plasticizers. Two different types of solvent, which are acetone and N-methyl-2-pyrrolidone (NMP), were also used. CA/CNF film was prepared by mixing CA and CNF in acetone or NMP with 10% concentration and stirred for 24 h. Then, the solution was cast in a polytetrafluoroethylene (PTFE) dish followed by solvent evaporation for 12 h at room temperature for acetone and 24 h at 80 °C in an oven dryer for NMP. The effect of solvent type, plasticizers type, and CNF amount on film properties was studied. Good dispersion in NMP was evident from the morphological study of fractured surface and visible light transmittance. The results showed that CNF has a better dispersion in NMP which leads to a significant increase in tensile strength and elastic modulus up to 38% and 65%, respectively, compared with those of neat CA. CNF addition up to 5 phr loading increased the mechanical properties of the film composites. [ABSTRACT FROM AUTHOR]

In this study, the effect of lignin esterification with fatty acid chloride on the properties of lignin and lignin/poly(lactic acid) (PLA) composites was investigated. Lignocellulose (Pinus densiflora S. et Z.) was treated using a deep eutectic solvent (DES) with choline chloride (ChCl)/lactic acid (LA). From the DES-soluble fraction, DES-lignin (DL) was isolated by a regeneration process. Lignin esterification was conducted with palmitoyl chloride (PC). As the PC loading increased for DL esterification, the Mw of esterified DL (EDL) was increased, and the glass transition temperature (Tg) was decreased. In DL or EDL/PLA composite films, it was observed that EDL/PLA had cleaner and smoother morphological characteristics than DL/PLA. The addition of DL or EDL in a PLA matrix resulted in a deterioration of tensile properties as compared with neat PLA. The EDL/PLA composite film had a higher tensile strength and elastic modulus than the DL/PLA composite film. DL esterification decreased water absorption with lower water diffusion coefficients. The effect of lignin esterification on improving the compatibility of lignin and PLA was demonstrated. These results are expected to contribute to the development of high-strength lignin composites. [ABSTRACT FROM AUTHOR]

We aimed to improve the mechanical properties of alginate fibers by reinforcing with various cellulose nanofibrils (CNFs). Pure cellulose nanofibril (PCNF), lignocellulose nanofibril (LCNF) obtained via deep eutectic solvent (DES) pretreatment, and TEMPO-oxidized lignocellulose nanofibril (TOLCNF) were employed. Sodium alginate (AL) was mixed with PCNF, LCNF, and TOLCNF with a CNF content of 5–30%. To fabricate microcomposite filaments, the suspensions were wet-spun in calcium chloride (CaCl2) solution through a microfluidic channel. Average diameters of the microcomposite filaments were in the range of 40.2–73.7 μm, which increased with increasing CNF content and spinning rate. The tensile strength and elastic modulus improved as the CNF content increased to 10%, but the addition of 30% CNF deteriorated the tensile properties. The tensile strength and elastic modulus were in the order of LCNF/AL > PCNF/AL > TOLCNF/AL > AL. An increase in the spinning rate improved the tensile properties. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) is a mosquito-borne member of the Flaviviridae family. ZIKV infection has been associated with neurological complications such as microcephaly in newborns and Guillain-Barré syndrome in adults; thus, therapeutic agents are urgently needed. Statins are clinically approved for lowering cholesterol levels to prevent cardiovascular disease but have shown potential as antiviral drugs. In this study, we explored the possibility of utilizing statins as anti-ZIKV drugs. We found that, generally, lipophilic statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, and simvastatin) could reduce ZIKV production in vitro and result in smaller foci of infection. Time-of-drug-addition assay revealed that early treatment with statins is more beneficial than late treatment; however, statins could not completely inhibit the entry stage of ZIKV infection. Furthermore, individual lipophilic statins differed in anti-ZIKV capacity, with fluvastatin being the most efficient at low concentrations. Taken together, this study shows that statins or their derivatives have the potential to be used as anti-ZIKV therapeutic agents. [ABSTRACT FROM AUTHOR]

Background: Avian-origin H3N2 canine influenza virus (CIV) has been the most common subtype in Korea and China since 2007. Here, we compared the pathogenicity and transmissibility of three H3N2 CIV strains [Chinese CIV (JS/10), Korean CIV (KR/07), and Korean recombinant CIV between the classic H3N2 CIV and the pandemic H1N1 virus (MV/12)] in BALB/c mouse and guinea pig models. The pandemic H1N1 (CA/09) strain served as the control. Results: BALB/c mice infected with H1N1 had high mortality and obvious body weight loss, whereas no overt disease symptoms were observed in mice inoculated with H3N2 CIV strains. The viral titers were higher in the group MV/12 than those in groups JS/10 and KR/07, while the mice infected with JS/10 showed higher viral titers in all tissues (except for the lung) than the mice infected with KR/07. The data obtained in guinea pigs also demonstrated that group MV/12 presented the highest loads in most of the tissues, followed by group JS/10 and KR/07. Also, direct contact transmissions of all the three CIV strains could be observed in guinea pigs, and for the inoculated and the contact groups, the viral titer of group MV/12 and KR/07 was higher than that of group JS/10 in nasal swabs. These findings indicated that the matrix (M) gene obtained from the pandemic H1N1 may enhance viral replication of classic H3N2 CIV; JS/10 has stronger viral replication ability in tissues as compared to KR/07, whereas KR/07 infected guinea pigs have more viral shedding than JS/10 infected guinea pigs. Conclusions: There exists a discrepancy in pathobiology among CIV isolates. Reverse genetics regarding the genomes of CIV isolates will be helpful to further explain the virus characteristics. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8 G470R in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it., Competing Interests: Declaration of competing interest The authors have declared that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The influenza virus poses a global health burden. Currently, an annual vaccine is used to reduce influenza virus-associated morbidity and mortality. Most influenza vaccines have been developed to elicit neutralizing Abs against influenza virus. These Abs primarily target immunodominant epitopes derived from hemagglutinin (HA) or neuraminidase (NA) of the influenza virus incorporated in vaccines. However, HA and NA are highly variable proteins that are prone to antigenic changes, which can reduce vaccine efficacy. Therefore, it is essential to develop universal vaccines that target immunodominant epitopes derived from conserved regions of the influenza virus, enabling cross-protection among different virus variants. The internal proteins of the influenza virus serve as ideal targets for universal vaccines. These internal proteins are presented by MHC class I molecules on Ag-presenting cells, such as dendritic cells, and recognized by CD8 T cells, which elicit CD8 T cell responses, reducing the likelihood of disease and influenza viral spread by inducing virus-infected cell apoptosis. In this review, we highlight the importance of CD8 T cell-mediated immunity against influenza viruses and that of viral epitopes for developing CD8 T cell-based influenza vaccines., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2024. The Korean Association of Immunologists.)

Purpose: Globally, chronic kidney disease (CKD) is common and has been associated with an increased risk of colorectal cancer (CRC). There is a dearth of literature on the real-world morbidity and mortality associated with CKD comorbid with CRC. This study was performed to evaluate real-world survival outcomes of colorectal malignancy in Korean CKD patients., Methods: The National Health Insurance Service of Korea provided data on patients who underwent surgical resection among patients diagnosed with CRC from 2002 to 2019., Results: A total of 219,550 patients were included: 6,181 patients with underlying CKD and 213,369 patients without it. Each morbidity was significantly higher in the CKD-CRC group, and the postoperative mortality rates for the 30-day (3.11% vs. 1.78%, P < 0.001), 60-day (5.95% vs. 3.83%, P < 0.001), and 90-day mortality rate (8.12% vs. 5.32%, P < 0.001) were significantly higher in the CKD group. The median survival time (MST, year) was significantly lower in the CKD-CRC group (5.63; interquartile range [IQR], 5.26-5.91) than in the non-CKD-CRC group (8.71; IQR, 8.37-8.93). MST was significantly lower among CKD patients who received chemotherapy after adjustment by multivariate analysis (adjusted hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.37-1.49; P < 0.001]). Subgroup analysis showed that in the CKD-CRC group, MST was lower in patients who received dialysis than in those who did not, even after multivariate analysis (adjusted HR, 2.38; 95% CI, 2.20-2.58; P < 0.001)., Conclusion: Prevention of CKD-to-end-stage renal disease progression should be adopted as a strategy to increase postoperative survival, along with active surveillance and cancer treatment., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2023, the Korean Surgical Society.)

Spinal muscular atrophy (SMA) is a pediatric-onset neuromuscular disorder caused by insufficient survival motor neuron (SMN) protein. SMN restorative therapies are now approved for the treatment of SMA; however, they are not curative, likely due to a combination of imperfect treatment timing, inadequate SMN augmentation, and failure to optimally target relevant organs. Here, we consider the implications of imperfect treatment administration, focusing specifically on outcomes for skeletal muscle. We examine the evidence that muscle plays a contributing role in driving neuromuscular dysfunction in SMA. Next, we discuss how SMN might regulate the health of myofibers and their progenitors. Finally, we speculate on therapeutic outcomes of failing to raise muscle SMN to healthful levels and present strategies to restore function to this tissue to ensure better treatment results.

Surveillance of influenza A viruses (IAVs) among migratory waterfowl is a first step in understanding the ecology, biology, and pathogenicity of IAVs. As part of the nationwide surveillance effort for IAVs in fowl in South Korea, we collected environmental fecal samples in different migratory bird stopover sites in South Korea during the winter seasons within November 2014 through January 2018. We collected a total of 6758 fecal samples, 75 of which were positive for IAV (1.11% positivity). Prevalence of IAVs varied per site and per year. Based on sequencing, the most prevalent hemagglutinin (HA) subtypes were H1, H6, and H5, and the most prevalent neuraminidase (NA) subtypes were N1, N3, and N2. Phylogenetic analyses showed that the genes we isolated clustered with reported isolates collected from other locations along the East Asian-Australasian Flyway. All the H5 and H7 isolates collected in this study were of low pathogenicity. None of the N1 and N2 genes carried amino acid markers of resistance against NA inhibitors. The winter 2016-2017 subset were primarily borne by migratory geese (Anser spp.). These results suggest that majority of the IAVs circulating among migratory wild fowl in South Korea in 2014-2018 were of low pathogenicity., (© 2023. The Author(s).)

Reduced survival motor neuron (SMN) protein triggers the motor neuron disease, spinal muscular atrophy (SMA). Restoring SMN prevents disease, but it is not known how neuromuscular function is preserved. We used model mice to map and identify an Hspa8 G470R synaptic chaperone variant, which suppressed SMA. Expression of the variant in the severely affected mutant mice increased lifespan >10-fold, improved motor performance, and mitigated neuromuscular pathology. Mechanistically, Hspa8 G470R altered SMN2 splicing and simultaneously stimulated formation of a tripartite chaperone complex, critical for synaptic homeostasis, by augmenting its interaction with other complex members. Concomitantly, synaptic vesicular SNARE complex formation, which relies on chaperone activity for sustained neuromuscular synaptic transmission, was found perturbed in SMA mice and patient-derived motor neurons and was restored in modified mutants. Identification of the Hspa8 G470R SMA modifier implicates SMN in SNARE complex assembly and casts new light on how deficiency of the ubiquitous protein causes motor neuron disease., Competing Interests: Declaration of interests J.-K.K. and U.R.M. are inventors on a provisional patent application filed by Columbia University on the use of Hspa8 as a means of treating neurodegenerative disease., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic is one of the most consequential global health crises in over a century. Since its discovery in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to mutate into different variants and sublineages, rendering previously potent treatments and vaccines ineffective. With significant strides in clinical and pharmaceutical research, different therapeutic strategies continue to be developed. The currently available treatments can be broadly classified based on their potential targets and molecular mechanisms. Antiviral agents function by disrupting different stages of SARS-CoV-2 infection, while immune-based treatments mainly act on the human inflammatory response responsible for disease severity. In this review, we discuss some of the current treatments for COVID-19, their mode of actions, and their efficacy against variants of concern. This review highlights the need to constantly evaluate COVID-19 treatment strategies to protect high risk populations and fill in the gaps left by vaccination., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2023. The Korean Association of Immunologists.)

The Zika virus (ZIKV) remains a global health concern. Thus far, no antiviral or vaccine has been approved to prevent or treat ZIKV infection. In a previous study, we found that lipophilic statins can inhibit ZIKV production in Vero cells. These statins appear to have different potencies against ZIKV infection. Here, we determined whether combinations of statins would have synergistic effects to maximize the efficacy of the statins and to reduce potential side effects. Specifically, we used a modified fixed-ratio assay for the combinations of atorvastatin (ATO) or fluvastatin (FLU) with mevastatin (MEV) or simvastatin (SIM). All combinations with MEV tended towards synergy, especially with higher fractions of MEV in the combinations. The ATO + SIM combination tended towards additivity. The FLU + SIM combination also tended towards additivity except for one combination which had the highest fraction of FLU over SIM among the tested combinations. Overall, certain combinations of ATO or FLU with SIM or MEV may be synergistic. More exhaustive combinatorial assays in vitro and in vivo could help define whether combining lipophilic statins would be beneficial and safe for treating ZIKV infections.

Alternatively activated or M2 macrophages, as opposed to the well characterized pro-inflammatory or M1 macrophages, vitally regulate anti-inflammation, wound healing, and tissue repair to maintain tissue homeostasis. Although ubiquitous presence of macrophages in diverse tissues, exposed to different physical environments, infers distinct immune responses of M2 macrophages with high phenotypic heterogeneity, the underlying mechanism of how the varying extracellular mechanical conditions alter their immunological activation remains unclear. Here, we demonstrate that M2 activation requires a threshold mechanical cue from the extracellular microenvironment, and matrix rigidity-dependent macrophage spreading is mediated by the F-actin formation that is essential to regulate mechanosensitive M2 activation of macrophages. We identified a new mechanosensing function of STAT6 (signal transducer and activator of transcription 6), a key transcription factor for M2 activation, whose intranuclear transportation is promoted by the rigid matrix that facilitates the F-actin formation. Our findings further highlight the critical role of mechanosensitive M2 activation of macrophages in long-term adaptation to the extracellular microenvironment by bridging nuclear mechanosensation and immune responses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Vaccination with tumor peptide epitopes associated with MHC class I molecules is an attractive approach directed at inducing tumor-specific CTLs. However, challenges remain in improving the therapeutic efficacy of peptide epitope vaccines, including the low immunogenicity of peptide epitopes and insufficient stimulation of innate immune components in vivo . To overcome this, we aimed to develop and test an innovative strategy that elicits potent CTL responses against tumor epitopes. The essential feature of this strategy is vaccination using tumor epitope-loaded nanoparticles (NPs) in combination with polyinosinic-polycytidylic acid (poly-IC) and anti-PD1 mAb. Carboxylated NPs were prepared using poly(lactic-co-glycolic acid) and poly(ethylene/maleic anhydride), covalently conjugated with anti-H-2K b mAbs, and then attached to H-2K b molecules isolated from the tumor mass (H-2 b ). Native peptides associated with the H-2K b molecules of H-2K b -attached NPs were exchanged with tumor peptide epitopes. Tumor peptide epitope-loaded NPs efficiently induced tumor-specific CTLs when used to immunize tumor-bearing mice as well as normal mice. This activity of the NPs significantly was increased when co-administered with poly-IC. Accordingly, the NPs exerted significant anti-tumor effects in mice implanted with EG7-OVA thymoma or B16-F10 melanoma, and the anti-tumor activity of the NPs was significantly increased when applied in combination with poly-IC. The most potent anti-tumor activity was observed when the NPs were co-administered with both poly-IC and anti-PD1 mAb. Immunization with tumor epitope-loaded NPs in combination with poly-IC and anti-PD1 mAb in tumor-bearing mice can be a powerful means to induce tumor-specific CTLs with therapeutic anti-tumor activity., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2022. The Korean Association of Immunologists.)

Background: Tumor budding is associated with lymph node (LN) metastasis in submucosal colorectal cancer (CRC). However, the rate of LN metastasis associated with the number of tumor buds is unknown. Here, we determined the optimal tumor budding cut-off number and developed a composite scoring system (CSS) for estimating LN metastasis of submucosal CRC., Methods: In total, 395 patients with histologically confirmed T1N0-2M0 CRC were evaluated. The clinicopathological characteristics were subjected to univariate and multivariate analyses. The Akaike information criterion (AIC) values of the multivariate models were evaluated to identify the optimal cut-off number. A CSS for LN metastasis was developed using independent risk factors., Results: The prevalence of LN metastasis was 13.2%. Histological differentiation, lymphatic or venous invasion, and tumor budding were associated with LN metastasis in univariate analyses. In multivariate models adjusted for histological differentiation and lymphatic or venous invasion, the AIC value was lowest for five tumor buds. Unfavorable differentiation (odds ratio [OR], 8.16; 95% confidence interval [CI], 1.80-36.89), lymphatic or venous invasion (OR, 5.91; 95% CI, 2.91-11.97), and five or more tumor buds (OR, 3.01; 95% CI, 1.21-7.69) were independent risk factors. In a CSS using these three risk factors, the rates of LN metastasis were 5.6%, 15.5%, 31.0%, and 52.4% for total composite scores of 0, 1, 2, and ≥ 3, respectively., Conclusions: For the estimation of LN metastasis in submucosal CRC, the optimal tumor budding cut-off number was five. Our CSS can be utilized to estimate LN metastasis., (© 2022. The Author(s).)

Plants contain underutilized resources of compounds that can be employed to combat viral diseases. Aloe vera (L.) Burm. f. (syn. Aloe barbadensis Mill.) has a long history of use in traditional medicine, and A. vera extracts have been reported to possess a huge breadth of pharmacological activities. Here, we discuss the potential of A. vera compounds as antivirals and immunomodulators for the treatment of viral diseases. In particular, we highlight the use of aloe emodin and acemannan as lead compounds that should be considered for further development in the management and prevention of viral diseases. Given the immunomodulatory capacity of A. vera compounds, especially those found in Aloe gel, we also put forward the idea that these compounds should be considered as adjuvants for viral vaccines. Lastly, we present some of the current limitations to the clinical applications of compounds from Aloe , especially from A. vera .

Background: Anorectal condyloma is the representative venereal disease caused by human papilloma virus (HPV), which has more 180 subtypes. Although there are various known risk factors for recurrence, few studies have investigated the influence of HPV subtypes., Objective: We aimed to investigate the correlation between the recurrence of anorectal condyloma and HPV subtypes., Methods: We analyzed the clinical and histopathological information of 143 patients who underwent surgery for anorectal condyloma at the National Medical Center between March 2016 and September 2020. PCR analyses were performed to confirm the HPV subtype in 24 patients., Results: Recurrence was confirmed in 63 patients through outpatient follow-up over a median of 31.7 months (range: 0-56.2) after surgery. Recurrence was significantly associated with anorectal condyloma severity (p < 0.001), but there were no differences between the primary and recurrent groups, CD4-positive cell counts, or human immunodeficiency virus loads. The high-risk HPV subtype was associated with a high recurrence rate. Furthermore, the overall recurrence rate in anorectal condyloma patients was 44.1%., Conclusion: These results suggest that recurrence of anorectal condyloma has a significant association with high-risk HPV subtypes. Therefore, it is necessary to check for recurrences during follow-up after surgery., (© 2022. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Tumor peptides associated with MHC class I molecules or their synthetic variants have attracted great attention for their potential use as vaccines to induce tumor-specific CTLs. However, the outcome of clinical trials of peptide-based tumor vaccines has been disappointing. There are various reasons for this lack of success, such as difficulties in delivering the peptides specifically to professional Ag-presenting cells, short peptide half-life in vivo , and limited peptide immunogenicity. We report here a novel peptide vaccination strategy that efficiently induces peptide-specific CTLs. Nanoparticles (NPs) were fabricated from a biodegradable polymer, poly(D,L-lactic-co-glycolic acid), attached to H-2K b molecules, and then the natural peptide epitopes associated with the H-2K b molecules were exchanged with a model tumor peptide, SIINFEKL (OVA 257-268 ). These NPs were efficiently phagocytosed by immature dendritic cells (DCs), inducing DC maturation and activation. In addition, the DCs that phagocytosed SIINFEKL-pulsed NPs potently activated SIINFEKL-H-2K b complex-specific CD8 + T cells via cross-presentation of SIINFEKL. In vivo studies showed that intravenous administration of SIINFEKL-pulsed NPs effectively generated SIINFEKL-specific CD8 + T cells in both normal and tumor-bearing mice. Furthermore, intravenous administration of SIINFEKL-pulsed NPs into EG7.OVA tumor-bearing mice almost completely inhibited the tumor growth. These results demonstrate that vaccination with polymeric NPs coated with tumor peptide-MHC-I complexes is a novel strategy for efficient induction of tumor-specific CTLs., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2021. The Korean Association of Immunologists.)

The coronavirus disease 2019 (COVID-19) pandemic has underscored the lack of approved drugs against acute viral diseases. Plants are considered inexhaustible sources of drugs for several diseases and clinical conditions, but plant-derived compounds have seen little success in the field of antivirals. Here, we present the case for the use of compounds from vascular plants, including alkaloids, flavonoids, polyphenols, and tannins, as antivirals, particularly for the treatment of COVID-19. We review current evidence for the use of these phytochemicals against SARS-CoV-2 infection and present their potential targets in the SARS-CoV-2 replication cycle., (© 2021. The Microbiological Society of Korea.)

Infantile-onset spinal muscular atrophy is the quintessential example of a disorder characterized by a predominantly neurodegenerative phenotype that nevertheless stems from perturbations in a housekeeping protein. Resulting from low levels of the Survival of Motor Neuron (SMN) protein, spinal muscular atrophy manifests mainly as a lower motor neuron disease. Why this is so and whether other cell types contribute to the classic spinal muscular atrophy phenotype continue to be the subject of intense investigation and are only now gaining appreciation. Yet, what is emerging is sometimes as puzzling as it is instructive, arguing for a careful re-examination of recent study outcomes, raising questions about established dogma in the field and making the case for a greater focus on milder spinal muscular atrophy models as tools to identify key mechanisms driving selective neuromuscular dysfunction in the disease. This review examines the evidence for novel molecular and cellular mechanisms that have recently been implicated in spinal muscular atrophy, highlights breakthroughs, points out caveats and poses questions that ought to serve as the basis of new investigations to better understand and treat this and other more common neurodegenerative disorders., Competing Interests: None

Background: Aloe vera is a functional food with various pharmacological functions, including an immune-modulating effect. Until now, A. vera has never been studied as an adjuvant in influenza vaccine, and its effects on upper respiratory tract infection (URI) are unknown., Purpose: The objective of our study was to investigate the effect of processed A. vera gel (PAG) on immunogenicity of quadrivalent inactivated influenza vaccine and URI in healthy adults., Study Design: A randomized, double-blind, placebo-controlled clinical trial was performed., Methods: This study was conducted in 100 healthy adults at a single center from September 2017 to May 2018. Subjects were randomly divided into a PAG group (n = 50) and a placebo group (n = 50). The enrolled subjects were instructed to ingest the study drug for 8 weeks. The participants received a single dose of quadrivalent inactivated influenza vaccine after taking the study drug for the first 4 weeks of the study. The primary endpoint was seroprotection rate against at least one viral strain at 4 weeks post-vaccination. Other outcomes were seroprotection rate at 24 weeks post-vaccination, seroconversion rate, geometric mean fold increase (GMFI) at 4 and 24 weeks post-vaccination, seroprotection rate ratio and geometric mean titer ratio (GMTR) at 4 weeks post-vaccination between PAG and placebo groups, and incidence, severity, and duration of URI., Results: The European Committee for proprietary medicinal products (CPMP) evaluation criteria were met at least one in the PAG and placebo groups for all strains. However, there was no significant difference in the seroprotection rate at 4 weeks post-vaccination against all strains in both PAG and placebo groups. Among secondary endpoints, the GMFI at 4 weeks post-vaccination for the A/H3N2 was significantly higher in the PAG than in placebo group. The GMTR as adjuvant effect was 1.382 (95% CI, 1.014-1.1883). Kaplan-Meier curve analysis showed a reduction in incidence of URI (p = 0.035), and a generalized estimating equation model identified a decrease in repeated URI events (odds ratio 0.57; 95% CI, 0.39-0.83; p = 0.003) in the PAG group., Conclusions: Oral intake of PAG did not show a significant increase in seroprotection rate from an immunogenicity perspective. However, it reduced the number of URI episodes. A well-designed further study is needed on the effect of PAG's antibody response against A/H3N2 in the future., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Abstract: To investigate the feasibility, safety, and outcomes of three-dimensional (3D) laparoscopic vaginoplasty with a rectosigmoid colon flap for vaginal reconstruction.Following appropriate preoperative patient counseling, 17 consecutive patients underwent vaginoplasty using a 3D laparoscopic system. Perioperative and postoperative outcomes were retrospectively evaluated.Between September 2016 and February 2020, 17 patients underwent 3D laparoscopic vaginoplasty with a rectosigmoid colon flap. Of them, 15 (88%) were transgender female patients, and 2 (12%) were cisgender female patients with congenital deformities. Among the 15 transgender patients, 12 (80%) underwent de novo surgeries and 3 (20%) underwent re-do surgeries. The mean age at the time of operation was 33.0 years, and the mean total operation time was 529 ± 128 minutes. The initial intraoperative mean vaginal depth was 15.2 ± 1.3 cm, and the 30-day readmission rate was 5.9% (1/17 cases). The mean follow-up duration was 24.8 months.Perioperative and postoperative outcomes suggest that 3D laparoscopic rectosigmoid colon vaginoplasty is a potentially acceptable, effective, and safe method for vaginal reconstruction., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 has severely impacted global health and economy. There is currently no effective approved treatment for COVID-19; although vaccines have been granted emergency use authorization in several countries, they are currently only administered to high-risk individuals, thereby leaving a gap in virus control measures. The scientific and clinical communities and drug manufacturers have collaborated to speed up the discovery of potential therapies for COVID-19 by taking advantage of currently approved drugs as well as investigatory agents in clinical trials. In this review, we stratified some of these candidates based on their potential targets in the progression of COVID-19 and discuss some of the results of ongoing clinical evaluations., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2021. The Korean Association of Immunologists.)

Recent findings about cell fate change induced by physical stimuli have expedited the discovery of underlying regulatory mechanisms that determine stem cell differentiation. Progress with regards to micro-/nanofabrication technology have led to the development of advanced materials that can mimic biophysical features of in vivo related circumstances of the human body. Since the cellular microenvironment directly defines cellular structure and function, diverse material properties including stiffness, topology, and surface chemistry are investigated to regulate multiple signaling cascades involved in stem cell differentiation for the development of innovative tools that can be widely utilized in various fields ranging from basic research to medical applications. This progress report addresses essential biophysical regulation and alteration of material properties applied to control stem cell differentiation. It also presents novel strategies to regulate stem cell differentiation based on relationships between recently discovered mechanotransduction pathways and cell differentiation signaling. A new perspective on stem cell physiology will further provide a framework of biomedical applications such as regenerative medicine and stem cell therapy., (© The Authors. Published by Wiley-VCH GmbH.)

Aging is a progressive functional decline in organs and tissues over time and typically represents the accumulation of psychological and social changes in a human being. Diverse diseases, such as cardiovascular, musculoskeletal, and neurodegenerative disorders, are now understood to be caused by aging. While biological assessment of aging mainly focuses on the gradual changes that occur either on the molecular scale, for example, alteration of gene expression and epigenetic modification, or on larger scales, for example, changes in muscle strength and cardiac function, the mechanics that regulates the behavior of individual cells and interactions between the internal elements of cells, are largely missing. In this study, we show that the dynamic features of migrating cells across different human ages could help to establish the underlying mechanism of biological age-dependent cellular functional decline. To determine the relationship between cellular dynamics and human age, we identify the characteristic relationship between cell migration and nuclear motion which is tightly regulated by nucleus-bound cytoskeletal organization. This analysis demonstrates that actomyosin contractility-dependent nuclear motion plays a key role in cell migration. We anticipate this study to provide noble biophysical insights on biological aging in order to precisely diagnose age-related chronic diseases.

The effectiveness of current influenza vaccines is considered suboptimal, and 1 way to improve the vaccines is using adjuvants. However, the current pool of adjuvants used in influenza vaccination is limited due to safety concerns. Aloe vera , or aloe, has been shown to have immunomodulatory functions and to be safe for oral intake. In this study, we explored the potential of orally administered processed Aloe vera gel (PAG) as an adjuvant for influenza vaccines in C57BL/6 mice. We first evaluated its adjuvanticity with a split-type pandemic H1N1 (pH1N1) Ag by subjecting the mice to lethal homologous influenza challenge. Oral PAG administration with the pH1N1 Ag increased survival rates in mice to levels similar to those of alum and MF59, which are currently used as adjuvants in influenza vaccine formulations. Similarly, oral PAG administration improved the survival of mice immunized with a commercial trivalent influenza vaccine against lethal homologous and heterologous virus challenge. PAG also increased hemagglutination inhibition and virus neutralization Ab titers against homologous and heterologous influenza strains following immunization with the split-type pH1N1 Ag or the commercial trivalent vaccine. Therefore, this study demonstrates that PAG may potentially be used as an adjuvant for influenza vaccines., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2020. The Korean Association of Immunologists.)

Paucity of the survival motor neuron (SMN) protein triggers the oft-fatal infantile-onset motor neuron disorder, spinal muscular atrophy (SMA). Augmenting the protein is one means of treating SMA and recently led to FDA approval of an intrathecally delivered SMN-enhancing oligonucleotide currently in use. Notwithstanding the advent of this and other therapies for SMA, it is unclear whether the paralysis associated with the disease derives solely from dysfunctional motor neurons that may be efficiently targeted by restricted delivery of SMN-enhancing agents to the nervous system, or stems from broader defects of the motor unit, arguing for systemic SMN repletion. We investigated the disease-contributing effects of low SMN in one relevant peripheral organ - skeletal muscle - by selectively depleting the protein in only this tissue. We found that muscle deprived of SMN was profoundly damaged. Although a disease phenotype was not immediately obvious, persistent low levels of the protein eventually resulted in muscle fiber defects, neuromuscular junction abnormalities, compromised motor performance, and premature death. Importantly, restoring SMN after the onset of muscle pathology reversed disease. Our results provide the most compelling evidence yet for a direct contributing role of muscle in SMA and argue that an optimal therapy for the disease must be designed to treat this aspect of the dysfunctional motor unit.

Spinal muscular atrophy (SMA) is a common and oft-fatal pediatric neuromuscular disorder caused by insufficient SMN protein. Now, two clinical trials (Mendell et al., 2017; Finkel et al., 2017) demonstrate that restoring the protein is therapeutic, offering new treatment options and renewed hope to SMA patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Homozygous mutations in the aromatic l-amino acid decarboxylase (AADC) gene result in a severe depletion of its namesake protein, triggering a debilitating and often fatal form of infantile Parkinsonism known as AADC deficiency. AADC deficient patients fail to produce normal levels of the monoamine neurotransmitters dopamine and serotonin, and suffer a multi-systemic disorder characterized by movement abnormalities, developmental delay and autonomic dysfunction; an absolute loss of dopamine is generally considered incompatible with life. There is no optimal treatment for AADC deficiency and few truly good models in which to investigate disease mechanisms or develop and refine therapeutic strategies. In this study, we introduced a relatively frequently reported but mildly pathogenic S250F missense mutation into the murine Aadc gene. We show that mutants homozygous for the mutation are viable and express a stable but minimally active form of the AADC protein. Although the low enzymatic activity of the protein resulted in only modestly reduced concentrations of brain dopamine, serotonin levels were markedly diminished, and this perturbed behavior as well as autonomic function in mutant mice. Still, we found no evidence of morphologic abnormalities of the dopaminergic cells in mutant brains. The striatum as well as substantia nigra appeared normal and no loss of dopamine expressing cells in the latter was detected. We conclude that even minute levels of active AADC are sufficient to allow for substantial amounts of dopamine to be produced in model mice harboring the S250F mutation. Such mutants represent a novel, mild model of human AADC deficiency., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A novel avian-origin H3N2 canine influenza A virus (CIV) that showed high sequence similarities in hemagglutinin and neuraminidase genes with those of non-pathogenic avian influenza viruses was isolated in our routine surveillance program in South Korea. We previously reported that the pathogenicity of this strain could be reproduced in dogs and cats. In the present study, the host tropism of H3N2 CIV was examined by experimental inoculation into several host species, including chickens, pigs, mice, guinea pigs, and ferrets. The CIV infection resulted in no overt symptoms of disease in these host species. However, sero-conversion, virus shedding, and gross and histopathologic lung lesions were observed in guinea pig and ferrets but not in pigs, or mice. Based on the genetic similarity of our H3N2 CIV with currently circulating avian influenza viruses and the presence of α-2,3-linked rather than α-2,6-linked sialic acid receptors in the respiratory tract of dogs, we believed that this strain of CIV would have avian virus-like receptor specificity, but that seems to be contrary to our findings in the present study. Further studies are needed to determine the co-receptors of hemagglutinin or post-attachment factors related to virus internalization or pathogenesis in other animals., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Spinal muscular atrophy (SMA) is a frequently fatal neuromuscular disorder and the most common inherited cause of infant mortality. SMA results from reduced levels of the survival of motor neuron (SMN) protein. Although the disease was first described more than a century ago, a precise understanding of its genetics was not obtained until the SMA genes were cloned in 1995. This was followed in rapid succession by experiments that assigned a role to the SMN protein in the proper splicing of genes, novel animal models of the disease, and the eventual use of the models in the pre clinical development of rational therapies for SMA. These successes have led the scientific and clinical communities to the cusp of what are expected to be the first truly promising treatments for the human disorder. Yet, important questions remain, not the least of which is how SMN paucity triggers a predominantly neuromuscular phenotype. Here we review how our understanding of the disease has evolved since the SMA genes were identified. We begin with a brief description of the genetics of SMA and the proposed roles of the SMN protein. We follow with an examination of how the genetics of the disease was exploited to develop genetically faithful animal models, and highlight the insights gained from their analysis. We end with a discussion of ongoing debates, future challenges, and the most promising treatments to have emerged from our current knowledge of the disease.

Sublingual (SL) administration of influenza vaccine would be non-invasive and effective way to give human populations protective immunity against the virus, especially when pandemic influenza outbreaks. In this study, the efficacy of pandemic influenza virus-based subunit vaccines was tested after sublingual (SL) adjuvant administration in pigs. Eight specific pathogen-free Yucatan pigs were divided into 4 groups: nonvaccinated but challenged (A) and vaccinated and challenged (B, C, and D). The vaccinated groups were subdivided by vaccine type and inoculation route: SL subunit vaccine (hemagglutinin antigen 1 [HA1] + wild-type cholera toxin [wtCT], B); IM subunit vaccine (HA1 + aluminum hydroxide, C); and IM inactivated vaccine (+ aluminum hydroxide, D). The vaccines were administered twice at a 2-week interval. All pigs were challenged with pandemic influenza virus (A/swine/GCVP-KS01/2009 [H1N1]) and monitored for clinical signs, serology, viral shedding, and histopathology. After vaccination, hemagglutination inhibition titre was higher in group D (320) than in the other vaccinated groups (40-80) at the time of challenge. The mobility and feed intake were reduced in group C. Both viral shedding and histopathological lesions were reduced in groups B and D. Although this study has limitation due to the limited number of pigs (2 pigs per a group), the preliminary data in this study provided the protective potential of SL administration of bacteria-expressed pandemic H1N1 influenza vaccine in pigs. There should be additional animal studies about effective adjuvant system and vaccine types for the use of SL influenza vaccination.

An avian-origin Korean H3N2 canine influenza virus (CIV) strain, designated A/canine/Korea/01/2007 (H3N2), was isolated from nasal swabs of pet dogs exhibiting severe respiratory syndrome in 2007. In the present study, we report the first complete genome sequence containing 3' and 5' noncoding regions (NCRs) of H3N2 CIV, which will provide important insights into the molecular basis of pathogenesis, transmission, and evolution of CIV.