Publications by authors named "Jung-Eun Park"

264 Publications

Effect of -Derived Extracellular Protease vEP-45 on the Blood Complement System.

Biology (Basel) 2021 Aug 18;10(8). Epub 2021 Aug 18.

Department of Biomedical Science, College of Natural Sciences and Public Health and Safety, Chosun University, Gwangju 61452, Korea.

is a pathogenic bacterium that can causes wound infections and fetal septicemia. We have reported that ATCC29307 produces an extracellular zinc-metalloprotease (named vEP-45). Our previous results showed that vEP-45 can convert prothrombin to active thrombin and also activate the plasma kallikrein/kinin system. In this study, the effect of vEP-45 on the activation of the complement system was examined. We found that vEP-45 could proteolytically convert the key complement precursor molecules, including C3, C4, and C5, to their corresponding active forms (e.g., C3a, C3b, C4a, C4b, and C5a) in vitro cleavage assays. C5b production from C5 cleavage mediated by vEP-45 was not observed, whereas the level of C5a was increased in a dose-dependent manner compared to that of the non-treated control. The cleavage of the complement proteins in human plasma by vEP-45 was also confirmed via Western blotting. Furthermore, vEP-45 could convert C3 and C5 to active C3a and C5a as a proinflammatory mediator, while no cleavage of C4 was observed. These results suggest that vEP-45 can activate the complement system involved in innate immunity through an alternative pathway.
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http://dx.doi.org/10.3390/biology10080798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389632PMC
August 2021

CGFS-type glutaredoxin mutations reduce tolerance to multiple abiotic stresses in tomato.

Physiol Plant 2021 Aug 15. Epub 2021 Aug 15.

Department of Horticulture and Natural Resources, Kansas State University, Manhattan, Kansas, USA.

Sessile organisms such as plants have adopted diverse reactive oxygen species (ROS) scavenging mechanisms to mitigate damage under abiotic stress conditions. Though CGFS-type glutaredoxin (GRX) genes are important regulators of ROS homeostasis, each of their functions in crop plants have not yet been well understood. We performed a targeted mutagenesis analysis of four CGFS-type GRXs (SlGRXS14, SlGRXS15, SlGRXS16, and SlGRXS17) in tomato plants (Solanum lycopersicum) using a multiplex clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system and found that Slgrxs mutants were more sensitive to various abiotic stresses compared with the wild-type tomatoes. Slgrxs15 mutants were embryonic lethal. Single, double, and triple combinations of Slgrxs14, 16, and 17 mutants were examined under heat, chilling, drought, heavy metal toxicity, nutrient deficiency, and short photoperiod stresses. Slgrxs14 and 17 mutants showed hypersensitivity to almost all stresses while Slgrxs16 mutants were affected by chilling stress and showed milder sensitivity to other stresses. Additionally, Slgrxs14 and 17 mutants showed delayed flowering time. Our results indicate that the CGFS-type SlGRXs have specific roles against abiotic stresses, providing valuable resources to develop tomato and, possibly, other crop species that are tolerant to multiple abiotic stresses by genetic engineering.
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http://dx.doi.org/10.1111/ppl.13522DOI Listing
August 2021

Characteristics of Biodegradable Gelatin Methacrylate Hydrogel Designed to Improve Osteoinduction and Effect of Additional Binding of Tannic Acid on Hydrogel.

Polymers (Basel) 2021 Jul 31;13(15). Epub 2021 Jul 31.

Department of Dental Biomaterials, Institute of Biodegradable Materials, School of Dentistry, Jeonbuk National University, Jeonju-si 54896, Jeollabuk-do, Korea.

In this study, a hydrogel using single and double crosslinking was prepared using GelMA, a natural polymer, and the effect was evaluated when the double crosslinked hydrogel and tannic acid were treated. The resulting hydrogel was subjected to physicochemical property evaluation, biocompatibility evaluation, and animal testing. The free radicals generated through APS/TEMED have a scaffold form with a porous structure in the hydrogel, and have a more stable structure through photo crosslinking. The double crosslinked hydrogel had improved mechanical strength and better results in cell compatibility tests than the single crosslinked group. Moreover, in the hydrogel transplanted into the femur of a rat, the double crosslinked group showed an osteoinductive response due to the attachment of bone minerals after 4 and 8 weeks, but the single crosslinked group did not show an osteoinductive response due to rapid degradation. Treatment with a high concentration of tannic acid showed significantly improved mechanical strength through H-bonding. However, cell adhesion and proliferation were limited compared to the untreated group due to the limitation of water absorption capacity, and no osteoinduction reaction was observed. As a result, it was confirmed that the treatment of high-concentration tannic acid significantly improved mechanical strength, but it was not a suitable method for improving bone induction due to the limitation of water absorption.
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http://dx.doi.org/10.3390/polym13152535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347985PMC
July 2021

Translational GTPase BipA Is Involved in the Maturation of a Large Subunit of Bacterial Ribosome at Suboptimal Temperature.

Front Microbiol 2021 13;12:686049. Epub 2021 Jul 13.

School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.

BPI-inducible protein A (BipA), a highly conserved paralog of the well-known translational GTPases LepA and EF-G, has been implicated in bacterial motility, cold shock, stress response, biofilm formation, and virulence. BipA binds to the aminoacyl-(A) site of the bacterial ribosome and establishes contacts with the functionally important regions of both subunits, implying a specific role relevant to the ribosome, such as functioning in ribosome biogenesis and/or conditional protein translation. When cultured at suboptimal temperatures, the genomic deletion strain (Δ) exhibits defects in growth, swimming motility, and ribosome assembly, which can be complemented by a plasmid-borne supplementation or suppressed by the genomic deletion. Based on the growth curve, soft agar swimming assay, and sucrose gradient sedimentation analysis, mutation of the catalytic residue His78 rendered plasmid-borne unable to complement its deletion phenotypes. Interestingly, truncation of the C-terminal loop of BipA exacerbates the aforementioned phenotypes, demonstrating the involvement of BipA in ribosome assembly or its function. Furthermore, tandem mass tag-mass spectrometry analysis of the Δ strain proteome revealed upregulations of a number of proteins (e.g., DeaD, RNase R, CspA, RpoS, and ObgE) implicated in ribosome biogenesis and RNA metabolism, and these proteins were restored to wild-type levels by plasmid-borne supplementation or the genomic deletion, implying BipA involvement in RNA metabolism and ribosome biogenesis. We have also determined that BipA interacts with ribosome 50S precursor (pre-50S), suggesting its role in 50S maturation and ribosome biogenesis. Taken together, BipA demonstrates the characteristics of a 50S assembly factor in ribosome biogenesis.
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http://dx.doi.org/10.3389/fmicb.2021.686049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313970PMC
July 2021

Differential Diagnosis for Highly Pathogenic Avian Influenza Virus Using Nanoparticles Expressing Chemiluminescence.

Viruses 2021 06 30;13(7). Epub 2021 Jun 30.

Laboratory of Veterinary Public Health, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

Highly pathogenic avian influenza (HPAI) virus is a causative agent of systemic disease in poultry, characterized by high mortality. Rapid diagnosis is crucial for the control of HPAI. In this study, we aimed to develop a differential diagnostic method that can distinguish HPAI from low pathogenic avian influenza (LPAI) viruses using dual split proteins (DSPs). DSPs are chimeras of an enzymatic split, Renilla luciferase (RL), and a non-enzymatic split green fluorescent protein (GFP). Nanoparticles expressing DSPs, sialic acid, and/or transmembrane serine protease 2 (TMPRSS2) were generated, and RL activity was determined in the presence of HPAI or LPAI pseudotyped viruses. The RL activity of nanoparticles containing both DSPs was approximately 2 × 10 RLU, indicating that DSPs can be successfully incorporated into nanoparticles. The RL activity of nanoparticles containing half of the DSPs was around 5 × 10 RLU. When nanoparticles containing half of the DSPs were incubated with HPAI pseudotyped viruses at low pH, RL activity was increased up to 1 × 10 RLU. However, LPAI pseudotyped viruses produced RL activity only in the presence of proteases (trypsin or TMPRSS2), and the average RL activity was around 7 × 10 RLU. We confirmed that nanoparticle fusion assay also diagnoses authentic viruses with specificity of 100% and sensitivity of 91.67%. The data indicated that the developed method distinguished HPAI and LPAI, and suggested that the diagnosis using DSPs could be used for the development of differential diagnostic kits for HPAI after further optimization.
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http://dx.doi.org/10.3390/v13071274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310176PMC
June 2021

Subclinical Infection and Transmission of Clade 2.3.4.4 H5N6 Highly Pathogenic Avian Influenza Virus in Mandarin Duck () and Domestic Pigeon ().

Viruses 2021 06 4;13(6). Epub 2021 Jun 4.

Avian Disease Laboratory, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea.

Since 2014, H5Nx clade 2.3.4.4 highly pathogenic avian influenza viruses (HPAIV) have caused outbreaks in wild birds and poultry in multiple continents, including Asia, Europe, Africa, and North America. Wild birds were suspected to be the sources of the local and global spreads of HPAIV. This study evaluated the infectivity, pathogenicity, and transmissibility of clade 2.3.4.4 H5N6 HPAIV in mandarin ducks ) and domestic pigeons (). None of the birds used in this study, 20 mandarin ducks or 8 pigeons, showed clinical signs or mortality due to H5N6 HPAI infection. Two genotypes of H5N6 HPAIV showed replication and transmission by direct and indirect contact between mandarin ducks. H5N6 HPAIV replicated and transmitted by direct contact between pigeons, although the viral shedding titer and duration were relatively lower and shorter than those in mandarin ducks. Influenza virus antigen was detected in various internal organs of infected mandarin ducks and pigeons, indicating systemic infection. Therefore, our results indicate mandarin ducks and pigeons can be subclinically infected with clade 2.3.4.4 H5N6 HPAIV and transfer the virus to adjacent birds. The role of mandarin ducks and pigeons in the spread and prevalence of clade 2.3.4.4 H5N6 viruses should be carefully monitored.
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http://dx.doi.org/10.3390/v13061069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227613PMC
June 2021

Assay System for Simultaneous Detection of SARS-CoV-2 and Other Respiratory Viruses.

Diagnostics (Basel) 2021 Jun 13;11(6). Epub 2021 Jun 13.

Department of Molecular Diagnostics, Seegene Medical Foundation, Seoul 04805, Korea.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggers disease with nonspecific symptoms that overlap those of infections caused by other seasonal respiratory viruses (RVs), such as the influenza virus (Flu) or respiratory syncytial virus (RSV). A molecular assay for accurate and rapid detection of RV and SARS-CoV-2 is crucial to manage these infections. Here, we compared the analytical performance and clinical reliability of Allplex™ SARS-CoV-2/FluA/FluB/RSV (SC2FabR; Seegene Inc., Seoul, South Korea) kit with those of four commercially available RV detection kits. Upon testing five target viral strains (SARS-CoV-2, FluA, FluB, RSV A, and RSV B), the analytical performance of SC2FabR was similar to that of the other kits, with no significant difference ( ≥ 0.78) in z-scores. The efficiency of SC2FabR (E-value, 81-104%) enabled reliable SARS-CoV-2 and seasonal RV detection in 888 nasopharyngeal swab specimens processed using a fully automated nucleic acid extraction platform. Bland-Altman analyses revealed an agreement value of 95.4% (SD ± 1.96) for the kits, indicating statistically similar results for all five. In conclusion, SC2FabR is a rapid and accurate diagnostic tool for both SARS-CoV-2 and seasonal RV detection, allowing for high-throughput RV analysis with efficiency comparable to that of commercially available kits. This can be used to help manage respiratory infections in patients during and after the coronavirus disease 2019 pandemic.
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http://dx.doi.org/10.3390/diagnostics11061084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231941PMC
June 2021

Immunogenicity of replication-deficient vesicular stomatitis virus based rabies vaccine in mice.

Vet Q 2021 Dec;41(1):202-209

Research Institute of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea.

Background: Rabies is a viral disease that causes severe neurological manifestations both in humans and various mammals. Although inactivated and/or attenuated vaccines have been developed and widely used around the world, there are still concerns with regard to their safety, efficacy, and costs.

Objective: As demand has grown for a new rabies vaccine, we have developed a new vesicular stomatitis viruses (VSVs) based rabies vaccine that replaces glycoproteins with rabies virus (RABV) glycoprotein (GP), or so-called VSV/RABV-GP.

Methods: VSV/RABV-GP production was measured by sandwich ELISA. The generation of VSV/RABV-GP was evaluated with GP-specific antibodies and reduced transduction with GP-specific neutralizing antibodies. Virus entry was quantified by measuring the luciferase levels at 18-h post-transduction. BALB/c mice (three groups of six mice each) were intraperitoneally immunized with PBS, RABA, or VSV/RABV-GP at 0 and 14 days. At 28 days post-immunization serology was performed. Statistical significance was calculated using the Holm-Sidak multiple Student's test.

Results: Mice immunized with VSV/RABV-GP produced IgM and IgG antibodies, whereas IgM titers were significantly higher in mice immunized with VSV/RABV-GP compared to inactivated RABV. The secretion profiles of IgG1 and IgG2a production suggested that VSV/RAVB-GP induces the T helper cell type-2 immune bias. In addition, the average (±SD;  = 3) serum neutralization titers of the inactivated RABV and VSV/RABV-GP groups were 241 ± 40 and 103 ± 54 IU/mL, respectively.

Conclusion: Our results confirm that VSV/RABV-GP could be a new potential vaccination platform for RABV.
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http://dx.doi.org/10.1080/01652176.2021.1930277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172215PMC
December 2021

Reliability of scapular upward rotation and anterior-posterior tilt measurements using a modified digital inclinometer in patients with subacromial impingement syndrome.

J Back Musculoskelet Rehabil 2021 ;34(5):837-843

Department of Physical Therapy, Pusan National Yangsan Hospital, Yangsan, Gyeongsangnam-do, Korea.

Backgroud: Reliable scapular upward rotation and anterior-posterior tilt data are required for patients with subacromial impingement syndrome (SIS). Only a few studies have explored the reliability of such measurements derived using a modified inclinometer.

Objectives: To determine the relative and absolute reliability of scapular upward rotation and anterior-posterior tilt measurements derived using a modified digital inclinometer in patients with SIS.

Method: Seventeen SIS patients were assessed twice within 1 week. We determined the relative and absolute measurement reliability by calculating the intraclass correlation coefficient (ICC), standard error of measurement (SEM), and minimal clinically important difference (MCID). Both intra- and interrater reliability were determined.

Results: The intra-rater reliability (both measurements) was high (0.72-0.88), and the interrater ICC was high to excellent (0.72-0.98). Clinically acceptable SEM and MCID values were obtained for scapular upward rotation (SEM: 4.28-9.33∘, MCID: 5.1-11.3∘) and anterior-posterior tilt (SEM: 3.72-7.55∘, MCID: 2.5-10.8∘).

Conclusions: Measurements of scapular upward rotation and anterior-posterior tilt using a modified digital inclinometer reliably reveal scapular position and kinematics in patients with SIS.
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http://dx.doi.org/10.3233/BMR-200080DOI Listing
September 2021

Construction of Porcine Epidemic Diarrhea Virus-Like Particles and Its Immunogenicity in Mice.

Vaccines (Basel) 2021 Apr 11;9(4). Epub 2021 Apr 11.

Laboratory of Veterinary Public Health, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

Porcine epidemic diarrhea (PED), a highly contagious and lethal enteric disease in piglets, is characterized by diarrhea, vomiting, and dehydration, with high mortality in neonatal piglets. Despite the nationwide use of attenuated and inactivated vaccines, the outbreak of PED is still a major problem in the swine industry. Virus-like particles (VLPs) are artificial nanoparticles similar to viruses that are devoid of genetic material and are unable to replicate. VLPs have good safety profiles and elicit robust cellular and humoral immune responses. Here, we generated PED VLPs in eukaryotic cells and examined their immune responses in mice. We found that the M protein is essential for the formation of PED VLPs. Interestingly, PED VLP formation was decreased in the presence of E proteins and increased in the presence of N proteins. Both IgG and IgA antibodies were induced in mice immunized with PED VLPs. Moreover, these antibodies protected against PED virus infection in Vero cells. PED VLPs immunization induced Th2-dominant immune responses in mice. Our results indicate that PED VLPs induce strong immune responses in mice, suggesting that the VLP-based vaccine is a promising vaccine candidate.
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http://dx.doi.org/10.3390/vaccines9040370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069460PMC
April 2021

Urinary Metabolomic Profiling after Administration of Corydalis Tuber and Pharbitis Seed Extract in Healthy Korean Volunteers.

Pharmaceutics 2021 Apr 9;13(4). Epub 2021 Apr 9.

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea.

Pharmacometabolomics is a useful tool to identify biomarkers that can assess and predict response after drug administration. The primary purpose of pharmacometabolomics is to better understand the mechanisms and pathways of a drug by searching endogenous metabolites that have significantly changed after drug administration. DA-9701, a prokinetic agent, consists of Pharbitis seed and Corydalis tube extract and it is known to improve the gastrointestinal motility. Although the overall mechanism of action of DA-9701 remains unclear, its active ingredients, corydaline and chlorogenic acid, act as a 5-HT3 and D2 receptor antagonist and 5-HT4 receptor agonist. To determine the significant metabolites after the administration of DA-9701, a qualitative analysis was carried out using ultra-high performance liquid chromatography coupled with orbitrap mass spectrometer followed by a multivariate analysis. Seven candidates were selected and a statistical analysis of fold change was performed over time. Our study concluded that all the seven selected metabolites were commonly involved in lipid metabolism and purine metabolism.
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http://dx.doi.org/10.3390/pharmaceutics13040522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069993PMC
April 2021

Papaverine Exerts Neuroprotective Effect by Inhibiting NLRP3 Inflammasome Activation in an MPTP-Induced Microglial Priming Mouse Model Challenged with LPS.

Biomol Ther (Seoul) 2021 May;29(3):295-302

Department of Molecular Medicine and the Ewha Medical Research Institute, School of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea.

Microglial priming is the process of microglial proliferation and activation in response to neurodegeneration and abnormal protein accumulation. Priming makes microglia susceptible to secondary inflammatory stimuli and causes exaggerated inflammatory responses. In the present study, we established a microglial priming model in mice by administering a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg). MPTP induced microglial activation without dopaminergic degeneration; however, subsequent treatment with a sub-toxic dose of lipopolysaccharides (LPS) induced an amplified inflammatory response and caused nigrostriatal dopaminergic degeneration. These pathological and inflammatory changes, including microglial activation and dopaminergic cell loss in the substantia nigra (SN) area were reversed by papaverine (PAP) administration. In addition, MPTP/LPS enhanced interleukin-1β (IL-1β) expression and processing via nod-like receptor protein 3 (NLRP3) inflammasome activation in the SN region of mice. However, PAP treatment suppressed inflammasome activation and subsequent IL-1β maturation. Moreover, PAP inhibited nuclear factor-κB (NF-κB) and enhanced cAMP-response element binding protein (CREB) activity in the SN of MPTP/LPS mice. These results suggest that PAP inhibits the activation of NLRP3 inflammasome by modulating NF-κB and CREB signaling pathways, which results in reduced microglial activation and neuronal cell death. Thus, PAP may be a potential candidate for the treatment of Parkinsons's disease, which is aggravated by systemic inflammation.
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http://dx.doi.org/10.4062/biomolther.2021.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094076PMC
May 2021

Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis.

Atherosclerosis 2021 05 25;324:58-68. Epub 2021 Mar 25.

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551. Electronic address:

Background And Aims: Aging is the primary risk factor for cardiovascular disease (CVD), but the mechanisms underlying age-linked atherosclerosis remain unclear. We previously observed that long-lived vascular matrix proteins can acquire 'gain-of-function' isoDGR motifs that might play a role in atherosclerotic pathology.

Methods: IsoDGR-specific mAb were generated and used for ELISA-based measurement of motif levels in plasma samples from patients with coronary artery diseases (CAD) and non-CAD controls. Functional consequences of isoDGR accumulation in age-damaged fibronectin were determined by bioassay for capacity to activate monocytes, macrophages, and endothelial cells (signalling activity, pro-inflammatory cytokine expression, and recruitment/adhesion potential). Mice deficient in the isoDGR repair enzyme PCMT1 were used to assess motif distribution and macrophage localisation in vivo.

Results: IsoDGR-modified fibronectin and fibrinogen levels in patient plasma were significantly enhanced in CAD and further associated with smoking status. Functional assays demonstrated that isoDGR-modified fibronectin activated both monocytes and macrophages via integrin receptor 'outside in' signalling, triggering an ERK:AP-1 cascade and expression of pro-inflammatory cytokines MCP-1 and TNFα to drive additional recruitment of circulating leukocytes. IsoDGR-modified fibronectin also induced endothelial cell expression of integrin β1 to further enhance cellular adhesion and matrix deposition. Analysis of murine aortic tissues confirmed accumulation of isoDGR-modified proteins co-localised with CD68 macrophages in vivo.

Conclusions: Age-damaged fibronectin features isoDGR motifs that increase binding to integrins on the surface of monocytes, macrophages, and endothelial cells. Subsequent activation of 'outside-in' signalling elicits a range of potent cytokines and chemokines that drive additional leukocyte recruitment to the developing atherosclerotic matrix.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.020DOI Listing
May 2021

Fabrication and Characterization of Biodegradable Gelatin Methacrylate/Biphasic Calcium Phosphate Composite Hydrogel for Bone Tissue Engineering.

Nanomaterials (Basel) 2021 Mar 2;11(3). Epub 2021 Mar 2.

Department of Dental Biomaterials, Institute of Biodegradable Materials, School of Dentistry, Jeonbuk National University, Jeonju-si 54896, Jeollabuk-do, Korea.

In the field of bone tissue, maintaining adequate mechanical strength and tissue volume is an important part. Recently, biphasic calcium phosphate (BCP) was fabricated to solve the shortcomings of hydroxyapatite (HA) and beta-tricalcium phosphate (β-TCP), and it is widely studied in the field of bone-tissue engineering. In this study, a composite hydrogel was fabricated by applying BCP to gelatin methacrylate (GelMA). It was tested by using a mechanical tester, to characterize the mechanical properties of the prepared composite hydrogel. The fabricated BCP was analyzed through FTIR and XRD. As a result, a different characteristic pattern from hydroxyapatite (HA) and beta-tricalcium phosphate (β-TCP) was observed, and it was confirmed that it was successfully bound to the hydrogel. Then, the proliferation and differentiation of preosteoblasts were checked to evaluate cell viability. The analysis results showed high cell viability and relatively high bone differentiation ability in the composite hydrogel to which BCP was applied. These features have been shown to be beneficial for bone regeneration by maintaining the volume and shape of the hydrogel. In addition, hydrogels can be advantageous for clinical use, as they can shape the structure of the material for custom applications.
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http://dx.doi.org/10.3390/nano11030617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999599PMC
March 2021

Assisted Reproductive Techniques and Genetic Manipulation in the Common Marmoset.

ILAR J 2021 Mar 8. Epub 2021 Mar 8.

Department of Marmoset Biology and Medicine, Central Institute for Experimental Animals in Kawasaki, Kanagawa, Japan.

Genetic modification of nonhuman primate (NHP) zygotes is a useful method for the development of NHP models of human diseases. This review summarizes the recent advances in the development of assisted reproductive and genetic manipulation techniques in NHP, providing the basis for the generation of genetically modified NHP disease models. In this study, we review assisted reproductive techniques, including ovarian stimulation, in vitro maturation of oocytes, in vitro fertilization, embryo culture, embryo transfer, and intracytoplasmic sperm injection protocols in marmosets. Furthermore, we review genetic manipulation techniques, including transgenic strategies, target gene knock-out and knock-in using gene editing protocols, and newly developed gene-editing approaches that may potentially impact the production of genetically manipulated NHP models. We further discuss the progress of assisted reproductive and genetic manipulation techniques in NHP; future prospects on genetically modified NHP models for biomedical research are also highlighted.
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http://dx.doi.org/10.1093/ilar/ilab002DOI Listing
March 2021

Effect of 7-Methylsulfinylheptyl Isothiocyanate on the Inhibition of Melanogenesis in B16-F1 Cells.

Life (Basel) 2021 Feb 20;11(2). Epub 2021 Feb 20.

Department of Biomedical Science, College of Natural Sciences, Chosun University, Gwangju 61452, Korea.

Skin aging, characterized by hyperpigmentation, inflammation, wrinkles, and skin cancer, is influenced by intrinsic and extrinsic factors with synergistic effects. Autophagy maintains the homeostatic balance between the degradation, synthesis, and recycling of cellular proteins and organelles, and plays important roles in several cellular and biological processes, including aging. The compound 7-methylsulfinylheptyl isothiocyanate (7-MSI) is a sulfur-containing phytochemical produced by various plants, particularly cruciferous vegetables, with reported anti-inflammatory properties and a role in pathogen defense; however, its effects on skin whitening have not been studied in detail. The purpose of this study was to observe the effects of 7-MSI on skin whitening and autophagy in cultured murine melanoma (B16-F1) cells. Western blotting was used to evaluate the impact of 7-MSI on melanogenesis-, tyrosinase-, and autophagy-associated proteins. The levels of the melanogenesis-associated protein's microphthalmia-associated transcription factor (MITF) and tyrosinase and tyrosinase-related protein-1 were decreased by treatment with 7-MSI under melanogenesis induction. Melanin synthesis also decreased by approximately 63% after treatment with 7-MSI for 73 h, compared with that non-treated controls. In addition, autophagosome formation and the expression levels of the autophagy-related proteins mTOR, p-mTOR, Beclin-1, Atg12, and LC3 were higher in 7-MSI-treated B16-F1 cells than in non-treated cells. These results indicate that 7-MSI can inhibit melanin synthesis in B16-F1 cells by suppressing melanogenesis and autophagy activation and thus can potentially be used as a novel multifunctional cosmetic agent.
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http://dx.doi.org/10.3390/life11020162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923422PMC
February 2021

Programmable C:G to G:C genome editing with CRISPR-Cas9-directed base excision repair proteins.

Nat Commun 2021 03 2;12(1):1384. Epub 2021 Mar 2.

Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore.

Many genetic diseases are caused by single-nucleotide polymorphisms. Base editors can correct these mutations at single-nucleotide resolution, but until recently, only allowed for transition edits, addressing four out of twelve possible DNA base substitutions. Here, we develop a class of C:G to G:C Base Editors to create single-base genomic transversions in human cells. Our C:G to G:C Base Editors consist of a nickase-Cas9 fused to a cytidine deaminase and base excision repair proteins. Characterization of >30 base editor candidates reveal that they predominantly perform C:G to G:C editing (up to 90% purity), with rAPOBEC-nCas9-rXRCC1 being the most efficient (mean 15.4% and up to 37% without selection). C:G to G:C Base Editors target cytidine in WCW, ACC or GCT sequence contexts and within a precise three-nucleotide window of the target protospacer. We further target genes linked to dyslipidemia, hypertrophic cardiomyopathy, and deafness, showing the therapeutic potential of these base editors in interrogating and correcting human genetic diseases.
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http://dx.doi.org/10.1038/s41467-021-21559-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925527PMC
March 2021

Removal of Radioactive Iodine Using Silver/Iron Oxide Composite Nanoadsorbents.

Nanomaterials (Basel) 2021 Feb 26;11(3). Epub 2021 Feb 26.

Department of Nuclear Engineering, Pakistan Institute of Engineering and Applied Sciences, P. O. Nilore, Islamabad 45650, Pakistan.

Efficient and cost-effective removal of radioactive iodine (radioiodine) from radioactive contaminated water has become a crucial task, following nuclear power plant disasters. Several materials for removing radioiodine have been reported in the literature. However, most of these materials exhibit some limitations, such as high production cost, slow adsorption kinetics, and poor adsorption capacity. Herein, we present silver/iron oxide nanocomposites (Ag/FeO) for the efficient and specific removal of iodine anions from contaminated water. The Ag/FeO were synthesized using a modified method and characterized via scanning electron microscopy, transmission electron microscopy, and X-ray diffraction analyses. This adsorbent showed a high adsorption capacity for iodine anions (847 mg/g of the adsorbent) in pure water. Next, Ag/FeO was applied to the removal of radioiodine, and high removal efficiencies were observed in water. In addition, its desalination capacity was retained in the presence of competitive ions and varied pH. After the adsorption process, Ag/FeO was easily removed from the water by applying an external magnetic field. Moreover, the same operation can be repeated several times without a significant decrease in the performance of Ag/FeO. Therefore, it is expected that the findings presented in this study will offer a new method for desalinating radioiodine in various aqueous media.
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http://dx.doi.org/10.3390/nano11030588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996965PMC
February 2021

NQO1 mediates the anti-inflammatory effects of nootkatone in lipopolysaccharide-induced neuroinflammation by modulating the AMPK signaling pathway.

Free Radic Biol Med 2021 02 15;164:354-368. Epub 2021 Jan 15.

Department of Molecular Medicine and the Ewha Medical Research Institute, School of Medicine, Ewha Womans University, Seoul, South Korea; Department of Brain & Cognitive Sciences, Ewha Womans University, Seoul, South Korea. Electronic address:

Neuroinflammation and oxidative stress play key roles in the progression of neurodegenerative diseases. Thus, the use of potent anti-inflammatory/antioxidant agents has been suggested as a promising therapeutic strategy for neurodegenerative diseases. In the present study, we investigated the anti-inflammatory and antioxidant effects of nootkatone (NKT), a sesquiterpenoid compound isolated from grapefruit, in in vitro and in vivo models of neuroinflammation. In lipopolysaccharide (LPS)-stimulated BV2 microglial cells, NKT inhibited the expression of iNOS, COX-2, and pro-inflammatory cytokines, and increased the expression of the anti-inflammatory cytokine, IL-10. In addition, NKT inhibited reactive oxygen species (ROS) production and upregulated the expression of antioxidant enzymes, such as NQO1 and HO-1. Molecular mechanistic studies showed that NKT inhibited Akt, p38 MAPK, and NF-κB activities, while increasing AMPK, PKA/CREB, and Nrf2/ARE signaling in LPS-stimulated BV2 cells. Since NKT dramatically increased NQO1 expression, we investigated the role of this enzyme using pharmacological inhibition or knockdown experiments. Treatment of BV2 cells with the NQO1-specific inhibitor, dicoumarol, or with NQO1 siRNA significantly blocked NKT-mediated inhibition of NO, ROS, TNF-α, IL-1β, and upregulation of IL-10. Furthermore, NQO1 inhibition reversed the effects of NKT on pro- and anti-inflammatory signaling molecules. Intriguingly, we found that the AMPK inhibitor, compound C, mimicked the effects of dicoumarol, suggesting the presence of a crosstalk between NQO1 and AMPK. Finally, we demonstrated that NKT inhibited microglial activation, lipid peroxidation, and the expression of pro-inflammatory markers in the brains of LPS-injected mice, which was also reversed by dicoumarol. These data collectively suggest that NQO1 plays a critical role in mediating the anti-inflammatory and antioxidant effects of NKT in LPS-induced neuroinflammation by modulating AMPK and its downstream signaling pathways.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.01.015DOI Listing
February 2021

Inhibitory Neural Network's Impairments at Hippocampal CA1 LTP in an Aged Transgenic Mouse Model of Alzheimer's Disease.

Int J Mol Sci 2021 Jan 12;22(2). Epub 2021 Jan 12.

Department of Biomedical Sciences, Graduate School, Chonnam National University, 61186 Gwangju, Korea.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a rapid accumulation of amyloid β (Aβ) protein in the hippocampus, which impairs synaptic structures and neuronal signal transmission, induces neuronal loss, and diminishes memory and cognitive functions. The present study investigated the impact of neuregulin 1 (NRG1)-ErbB4 signaling on the impairment of neural networks underlying hippocampal long-term potentiation (LTP) in 5xFAD mice, a model of AD with greater symptom severity than that of TG2576 mice. Specifically, we observed parvalbumin (PV)-containing hippocampal interneurons, the effect of NRG1 on hippocampal LTP, and the functioning of learning and memory. We found a significant decrease in the number of PV interneurons in 11-month-old 5xFAD mice. Moreover, synaptic transmission in the 5xFAD mice decreased at 6 months of age. The 11-month-old transgenic AD mice showed fewer inhibitory PV neurons and impaired NRG1-ErbB4 signaling than did wild-type mice, indicating that the former exhibit the impairment of neuronal networks underlying LTP in the hippocampal Schaffer-collateral pathway. In conclusion, this study confirmed the impaired LTP in 5xFAD mice and its association with aberrant NRG1-ErbB signaling in the neuronal network.
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http://dx.doi.org/10.3390/ijms22020698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828160PMC
January 2021

Plasma contact factors as novel biomarkers for diagnosing Alzheimer's disease.

Biomark Res 2021 Jan 9;9(1). Epub 2021 Jan 9.

Department of Biomedical Science, College of Natural Sciences, Chosun University, 309 Pilmun-Daero, Gwangju, 61452, Republic of Korea.

Background: Alzheimer's disease (AD) is the most common cause of dementia and most of AD patients suffer from vascular abnormalities and neuroinflammation. There is an urgent need to develop novel blood biomarkers capable of diagnosing Alzheimer's disease (AD) at very early stage. This study was performed to find out new accurate plasma diagnostic biomarkers for AD by investigating a direct relationship between plasma contact system and AD.

Methods: A total 101 of human CSF and plasma samples from normal and AD patients were analyzed. The contact factor activities in plasma were measured with the corresponding specific peptide substrates.

Results: The activities of contact factors (FXIIa, FXIa, plasma kallikrein) and FXa clearly increased and statistically correlated as AD progresses. We present here, for the first time, the FXIIa cut-off scores to as: > 26.3 U/ml for prodromal AD [area under the curve (AUC) = 0.783, p < 0.001] and > 27.2 U/ml for AD dementia (AUC = 0.906, p < 0.001). We also describe the cut-off scores from the ratios of CSF Aβ versus the contact factors. Of these, the representative ratio cut-off scores of Aβ/FXIIa were to be: < 33.8 for prodromal AD (AUC = 0.965, p < 0.001) and < 27.44 for AD dementia (AUC = 1.0, p < 0.001).

Conclusion: The activation of plasma contact system is closely associated with clinical stage of AD, and FXIIa activity as well as the cut-off scores of CSF Aβ/FXIIa can be used as novel accurate diagnostic AD biomarkers.
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http://dx.doi.org/10.1186/s40364-020-00258-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796542PMC
January 2021

Application of Polarization Sensitive-Optical Coherence Tomography to the Assessment of Phase Retardation in Subpleural Cancer in Rabbits.

Tissue Eng Regen Med 2021 02 7;18(1):61-69. Epub 2021 Jan 7.

Kosin Innovative Smart Healthcare Research Center, Kosin University Gospel Hospital, Busan, 49267, Korea.

Background: Polarization sensitive-optical coherence tomography (PS-OCT) provides the unique advantage of being able to measure the optical characteristics of tissues by using polarized light. Although the well-organized fibers of healthy muscle can change the polarization states of passing light, damaged tissue has different behaviors. There are studies on optical imaging methods applied to the respiratory organs; however, they are restricted to structural imaging. In particular, the intercostal muscle situated under the pleura is very challenging to visualize due to the difficulty of access.

Method: In this study, PS-OCT was used to identify subpleural cancer in male New Zealand white rabbits (3.2-3.4 kg) and to assess the phase retardation changes in normal and cancerous chest walls. VX2 cell suspension was injected between the intercostal muscle and parietal pleura and a tented area was observed by thoracic scope. A group of rabbits (n = 3) were sacrificed at day 7 after injection and another group (n = 3) at day 14.

Results: In the PS-OCT images, pleura thickness changes and muscle damage were criteria to understand the stages of the disease. The results of image and phase retardation analysis matched well with the pathologic examinations.

Conclusion: We were able to visualize and analyze subpleural cancer by PS-OCT, which provided structural and functional information. The measured phase retardation could help to identify the margin of the tumor. For further studies, various approaches into other diseases using polarization light are expected to have positive results.
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http://dx.doi.org/10.1007/s13770-020-00318-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862481PMC
February 2021

Autophosphorylation-induced self-assembly and STIL-dependent reinforcement underlie Plk4's ring-to-dot localization conversion around a human centriole.

Cell Cycle 2020 12 15;19(24):3419-3436. Epub 2020 Dec 15.

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA.

Polo-like kinase 4 (Plk4) is a key regulator of centriole biogenesis. Studies have shown that Plk4 undergoes dynamic relocalization from a ring-like pattern around a centriole to a dot-like morphology at the procentriole assembly site and this event is central for inducing centriole biogenesis. However, the detailed mechanisms underlying Plk4's capacity to drive its symmetry-breaking ring-to-dot relocalization remain largely unknown. Here, we showed that Plk4 self-initiates this process in an autophosphorylation-dependent manner and that STIL, its downstream target, is not required for this event. Time-dependent analyses with mEOS-fused photoconvertible Plk4 revealed that a portion of ring-state Plk4 acquires a capacity, presumably through autophosphorylation, to linger around a centriole, ultimately generating a dot-state morphology. Interestingly, Plk4 WT, but not its catalytically inactive mutant, showed the ability to form a nanoscale spherical assembly in the cytosol of human cells or heterologous , demonstrating its autophosphorylation-dependent self-organizing capacity. At the biochemical level, Plk4 - unlike its N-terminal βTrCP degron motif - robustly autophosphorylated the PC3 SSTT motif within its C-terminal cryptic polo-box, an event critical for inducing its physical clustering. Additional experiments showed that although STIL was not required for Plk4's initial ring-to-dot conversion, coexpressed STIL greatly enhanced Plk4's ability to generate a spherical condensate and recruit Sas6, a major component of the centriolar cartwheel structure. We propose that Plk4's autophosphorylation-induced clustering is sufficient to induce its ring-to-dot localization conversion and that subsequently recruited STIL potentiates this process to generate a procentriole assembly body critical for Plk4-dependent centriole biogenesis.
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http://dx.doi.org/10.1080/15384101.2020.1843772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781628PMC
December 2020

Embryonic Stem Cell Differentiation Is Regulated by SET through Interactions with p53 and β-Catenin.

Stem Cell Reports 2020 12;15(6):1260-1274

Department of Genetics, The Institute of Life Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel; The Edmond and Lily Safra Center for Brain Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address:

The multifunctional histone chaperone, SET, is essential for embryonic development in the mouse. Previously, we identified SET as a factor that is rapidly downregulated during embryonic stem cell (ESC) differentiation, suggesting a possible role in the maintenance of pluripotency. Here, we explore SET's function in early differentiation. Using immunoprecipitation coupled with protein quantitation by LC-MS/MS, we uncover factors and complexes, including P53 and β-catenin, by which SET regulates lineage specification. Knockdown for P53 in SET-knockout (KO) ESCs partially rescues lineage marker misregulation during differentiation. Paradoxically, SET-KO ESCs show increased expression of several Wnt target genes despite reduced levels of active β-catenin. Further analysis of RNA sequencing datasets hints at a co-regulatory relationship between SET and TCF proteins, terminal effectors of Wnt signaling. Overall, we discover a role for both P53 and β-catenin in SET-regulated early differentiation and raise a hypothesis for SET function at the β-catenin-TCF regulatory axis.
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http://dx.doi.org/10.1016/j.stemcr.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724474PMC
December 2020

Highly Pathogenic Avian Influenza Clade 2.3.4.4b Subtype H5N8 Virus Isolated from Mandarin Duck in South Korea, 2020.

Viruses 2020 12 4;12(12). Epub 2020 Dec 4.

Avian Diseases Laboratory, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea.

In October 2020, a highly pathogenic avian influenza (HPAI) subtype H5N8 virus was identified from a fecal sample of a wild mandarin duck () in South Korea. We sequenced all eight genome segments of the virus, designated as A/Mandarin duck/Korea/K20-551-4/2020(H5N8), and conducted genetic characterization and comparative phylogenetic analysis to track its origin. Genome sequencing and phylogenetic analysis show that the hemagglutinin gene belongs to H5 clade 2.3.4.4 subgroup B. All genes share high levels of nucleotide identity with H5N8 HPAI viruses identified from Europe during early 2020. Enhanced active surveillance in wild and domestic birds is needed to monitor the introduction and spread of HPAI via wild birds and to inform the design of improved prevention and control strategies.
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http://dx.doi.org/10.3390/v12121389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761861PMC
December 2020

Psychometric Evaluation of the Korean Version of the Student Evidence-Based Practice Questionnaire (S-EBPQ).

Asian Nurs Res (Korean Soc Nurs Sci) 2021 Feb 20;15(1):47-52. Epub 2020 Nov 20.

College of Nursing Science, Kyung Hee University, Seoul, Republic of Korea. Electronic address:

Purpose: Evidence-based practice (EBP) is a key competency that undergraduate nursing students need to learn, as EBP competence is essential for the effective implementation of EBP. However, few studies have comprehensively assessed the aspects of EBP competence using a reliable and valid measure specific to Korean nursing students. This study aimed to translate the Student Evidence-Based Practice Questionnaire (S-EBPQ) into Korean and evaluate its psychometric properties.

Methods: The original S-EBPQ was translated into Korean. After a pilot test, a convenience sample of 249 college students with more than four weeks of clinical training experience was selected from three universities in September 2017. Reliability and construct validity were evaluated using exploratory and confirmatory factor analyses. Concurrent validity was evaluated by correlating the measure with informatics competency.

Results: The exploratory factor analysis revealed four factors that explained 66.3 of the variance. The confirmatory factor analysis yielded a 4-factor structure (χ/df = 1.52, p < .001, standardized root-mean-square residual = .07, root-mean-square error of approximation = .07, goodness of fit index = .84, comparative fit index = .91). The Cronbach's α was .81 for the total scale. The scale's correlation with informatics competency was r = .55.

Conclusions: The Korean S-EBPQ is a reliable and valid tool that has utility for assessing EBP competence in Korean nursing students and for making comparisons of the EBP competence of nursing students from other countries.
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http://dx.doi.org/10.1016/j.anr.2020.10.003DOI Listing
February 2021

Phase separation of the Cep63•Cep152 complex underlies the formation of dynamic supramolecular self-assemblies at human centrosomes.

Cell Cycle 2020 12 18;19(24):3437-3457. Epub 2020 Nov 18.

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA.

The centrosome is a unique membraneless organelle that plays a pivotal role in the orderly progression of the cell cycle in animal cells. It has been shown that two pericentriolar scaffold proteins, Cep63 and Cep152, generate a heterotetrameric complex to self-assemble into a higher-order cylindrical architecture around a centriole. However, the mechanisms underlying how they reach their threshold concentrations in the vast intracellular space and generate a self-assembled architecture remain mysterious. Here we demonstrate that, like liquid-like assemblies, Cep63 and Cep152 cooperatively generate amorphous aggregates capable of undergoing dynamic turnover and inter-aggregate fusion and a significant level of internal rearrangemefnt within a condensate . Consistently, 1,6-hexanediol, a liquid-liquid phase separation disruptor, greatly diminished the ability of endogenous Cep63 and Cep152 to localize to centrosomes. Interestingly, a purified Cep63•Cep152 complex generated either a cylindrical structure or a vesicle-like hollow sphere in a spatially controlled manner. It also formed condensate-like solid spheres in the presence of a macromolecular crowder. At the molecular level, two hydrophobic motifs, one each from Cep63 and Cep152, were required for generating phase-separating condensates and a high molecular-weight assembly. Thus, we propose that the self-assembly of the Cep63•Cep152 complex is triggered by an intrinsic property of the complex undergoing density transition through the hydrophobic-motif-mediated phase separation. PCM, pericentriolar material; LLPS, liquid-liquid phase separation; MW, molecular-weight; CLEM, correlative light and electron microscopy; WT, wild-type; CMV, cytomegalovirus; FRAP, fluorescence recovery after photobleaching; FITC, fluorescein isothiocyanate; PCR, polymerase chain reaction; 3D-SIM, three-dimensional structured illumination microscopy; DMEM, Dulbecco's Modified Eagle Medium; PEI Max, Polyethylenimine Max; PBS, phosphate-buffered saline; RT, room temperature; DAPI, 4', 6-diamidino-2-phenylindole; AOTF, acousto-optic tunable filter; LB, Luria broth; OD, optical density; IPTG, isopropyl β-D-1-thiogalactopyranoside; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
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http://dx.doi.org/10.1080/15384101.2020.1843777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781590PMC
December 2020

Vimentin protects differentiating stem cells from stress.

Sci Rep 2020 11 11;10(1):19525. Epub 2020 Nov 11.

Department of Experimental Neurodegeneration, University Medical Center Göttingen, Waldweg 33, 37073, Göttingen, Germany.

Vimentin is one of the first cytoplasmic intermediate filaments to be expressed in mammalian cells during embryogenesis, but its role in cellular fitness has long been a mystery. Vimentin is acknowledged to play a role in cell stiffness, cell motility, and cytoplasmic organization, yet it is widely considered to be dispensable for cellular function and organismal development. Here, we show that Vimentin plays a role in cellular stress response in differentiating cells, by recruiting aggregates, stress granules, and RNA-binding proteins, directing their elimination and asymmetric partitioning. In the absence of Vimentin, pluripotent embryonic stem cells fail to differentiate properly, with a pronounced deficiency in neuronal differentiation. Our results uncover a novel function for Vimentin, with important implications for development, tissue homeostasis, and in particular, stress response.
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http://dx.doi.org/10.1038/s41598-020-76076-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658978PMC
November 2020

Constructing PCM with architecturally distinct higher-order assemblies.

Curr Opin Struct Biol 2021 02 8;66:66-73. Epub 2020 Nov 8.

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Pericentriolar material (PCM) present around a pair of centrioles functions as a platform for various cellular processes, including microtubule (MT) assembly. While PCM is known to be an electron-dense proteinaceous matrix made of long coiled-coil proteins and their client molecules, the molecular mechanism underlying PCM organization remains largely elusive. A growing body of evidence suggests that PCM is constructed in part by an interphase cylindrical self-assembly and the mitotic mesh-like architectures surrounding it. In this review, we will discuss how these higher-order structures are constructed to achieve the functional proficiency of the centrosome.
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http://dx.doi.org/10.1016/j.sbi.2020.09.013DOI Listing
February 2021

Identification of a New Heterocyclic Scaffold for Inhibitors of the Polo-Box Domain of Polo-like Kinase 1.

J Med Chem 2020 11 11;63(22):14087-14117. Epub 2020 Nov 11.

Chemistry Section, Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.

As a mitotic-specific target widely deregulated in various human cancers, polo-like kinase 1 (Plk1) has been extensively explored for anticancer activity and drug discovery. Although multiple catalytic domain inhibitors were tested in preclinical and clinical studies, their efficacies are limited by dose-limiting cytotoxicity, mainly from off-target cross reactivity. The C-terminal noncatalytic polo-box domain (PBD) of Plk1 has emerged as an attractive target for generating new protein-protein interaction inhibitors. Here, we identified a 1-thioxo-2,4-dihydro-[1,2,4]triazolo[4,3-]quinazolin-5(1)-one scaffold that efficiently inhibits Plk1 PBD but not its related Plk2 and Plk3 PBDs. Structure-activity relationship studies led to multiple inhibitors having ≥10-fold higher inhibitory activity than the previously characterized Plk1 PBD-specific phosphopeptide, PLHSpT ( ∼ 450 nM). In addition, -methyl prodrugs effectively inhibited mitotic progression and cell proliferation and their metabolic stability was determined. These data describe a novel class of small-molecule inhibitors that offer a promising avenue for future drug discovery against Plk1-addicted cancers.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769008PMC
November 2020
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