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Abstract The tripartite ATP-independent periplasmic (TRAP) transporters use an extra cytoplasmic substrate binding protein (SBP) to transport a wide variety of substrates in bacteria and archaea. The SBP can adopt an open- or closed state depending on the presence of substrate. The two transmembrane domains of TRAP transporters form a monomeric elevator whose function is strictly dependent on the presence of a sodium ion gradient. Insights from experimental structures, structural predictions and molecular modeling have suggested a conformational coupling between the membrane elevator and the substrate binding protein. Here, we use a disulfide engineering approach to lock the TRAP transporter HiSiaPQM from Haemophilus influenzae in different conformational states. The SBP, HiSiaP, is locked in its substrate-bound form and the transmembrane elevator, HiSiaQM, is locked in either its assumed inward- or outward-facing states. We characterize the disulfide-locked constructs and use single-molecule total internal reflection fluorescence (TIRF) microscopy to study their interactions. Our experiments demonstrate that the SBP and the transmembrane elevator are indeed conformationally coupled, meaning that the open and closed state of the SBP recognize specific conformational states of the transporter and vice versa.

Objectives This study aimed to examine the correlations between the regional characteristics of counties in Gangwon Province, Republic of Korea and the ratio of intracounty to extracounty sources of coronavirus disease 2019 (COVID-19) infection. Methods The region of the infectious contact was analysed for each COVID-19 case reported in Gangwon Province between February 22, 2020 and February 7, 2022. The population, population density, area, the proportion of urban residents, the proportion of older adults (>65 years), financial independence, and the number of adjacent counties were assessed for each of the 18 counties in Gangwon Province. Correlation coefficients between regional characteristics and the ratio of intracounty to extracounty infections were calculated. Results In total, 19,645 cases were included in this study. The population, population density, proportion of older adults, and proportion of urban residents were significantly correlated with the ratio of intracounty to extracounty infections. A stratified analysis with an age cut-point of 65 years showed that the proportion of older adults had a significant negative correlation with the ratio of intracounty to extracounty infections. In other words, the proportions of extracounty infections were higher in counties with higher proportions of older adults. Conclusion Regions with ageing populations should carefully observe trends in infectious disease outbreaks in other regions to prevent possible transmission.

Background: The brain–gut axis has emerged as a potential target in neurodegenerative diseases, including dementia, as individuals with dementia exhibit distinct gut microbiota compositions. Fecal microbiota transplantation (FMT), the transfer of fecal solution from a healthy donor to a patient, has shown promise in restoring homeostasis and cognitive enhancement. Objective: This study aimed to explore the effects of FMT on specific cognitive performance measures in Alzheimer’s dementia (AD) patients and investigate the relationship between cognition and the gut microbiota by evaluating changes in gene expression following FMT. Methods: Five AD patients underwent FMT, and their cognitive function [Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB)] was assessed before and after FMT. The patients’ fecal samples were analyzed with 16S rRNA to compare the composition of their gut microbiota. We also assessed modifications in the serum mRNA expression of patients’ genes related to lipid metabolism using serum RNA sequencing and quantitative real-time polymerase chain reaction. Results: Significant improvements in cognitive function, as measured by the MMSE (pre- and post-FMT was 13.00 and 18.00) and MoCA were seen. The MoCA scores at 3 months post-FMT (21.0) were the highest (12.0). The CDR-SOB scores at pre- and post-FMT were 10.00 and 5.50, respectively. Analysis of the gut microbiome composition revealed changes via 16S rRNA sequencing with an increase in Bacteroidaceae and a decrease in Enterococcaceae. Gene expression analysis identified alterations in lipid metabolism-related genes after FMT. Conclusion: These findings suggest a link between alterations in the gut microbiome, gene expression related to lipid metabolism, and cognitive function. The study highlights the importance of gut microbiota in cognitive function and provides insights into potential biomarkers for cognitive decline progression. FMT could complement existing therapies and show potential as a therapeutic intervention to mitigate cognitive decline in AD.

IntroductionIdentification of Alzheimer's Disease (AD)-related transcriptomic signatures from blood is important for early diagnosis of the disease. Deep learning techniques are potent classifiers for AD diagnosis, but most have been unable to identify biomarkers because of their lack of interpretability.MethodsTo address these challenges, we propose a pathway information-based neural network (PINNet) to predict AD patients and analyze blood and brain transcriptomic signatures using an interpretable deep learning model. PINNet is a deep neural network (DNN) model with pathway prior knowledge from either the Gene Ontology or Kyoto Encyclopedia of Genes and Genomes databases. Then, a backpropagation-based model interpretation method was applied to reveal essential pathways and genes for predicting AD.ResultsThe performance of PINNet was compared with a DNN model without a pathway. Performances of PINNet outperformed or were similar to those of DNN without a pathway using blood and brain gene expressions, respectively. Moreover, PINNet considers more AD-related genes as essential features than DNN without a pathway in the learning process. Pathway analysis of protein-protein interaction modules of highly contributed genes showed that AD-related genes in blood were enriched with cell migration, PI3K-Akt, MAPK signaling, and apoptosis in blood. The pathways enriched in the brain module included cell migration, PI3K-Akt, MAPK signaling, apoptosis, protein ubiquitination, and t-cell activation.DiscussionBy integrating prior knowledge about pathways, PINNet can reveal essential pathways related to AD. The source codes are available at https://github.com/DMCB-GIST/PINNet.

Abstract Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Recent studies have shown that histone demethylases are implicated in osteoblastogenesis; however, little is known about the role of histone demethylases in osteoclast formation. Here, we identified KDM4B as an epigenetic regulator of osteoclast differentiation. Knockdown of KDM4B significantly blocked the formation of tartrate-resistant acid phosphatase-positive multinucleated cells. Mice with myeloid-specific conditional knockout of KDM4B showed an osteopetrotic phenotype due to osteoclast deficiency. Biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and MED1 in a complex. Using genome-wide chromatin immunoprecipitation (ChIP)-sequencing, we revealed that the KDM4B–CCAR1–MED1 complex is localized to the promoters of several osteoclast-related genes upon receptor activator of NF-κB ligand stimulation. We demonstrated that the KDM4B–CCAR1–MED1 signaling axis induces changes in chromatin structure (euchromatinization) near the promoters of osteoclast-related genes through H3K9 demethylation, leading to NF-κB p65 recruitment via a direct interaction between KDM4B and p65. Finally, small molecule inhibition of KDM4B activity impeded bone loss in an ovariectomized mouse model. Taken together, our findings establish KDM4B as a critical regulator of osteoclastogenesis, providing a potential therapeutic target for osteoporosis.

Zinc plays a pivotal role in the function of cells and can induce apoptosis in various cancer cells, including Raji B lymphoma. However, the metabolic mechanism of Zn-induced apoptosis in Raji cells has not been explored. In this study, we performed global metabolic profiling using UPLC−Orbitrap−MS to assess the apoptosis of Raji cells induced by Zn ions released from ZnO nanorods. Multivariate analysis and database searches identified altered metabolites. Furthermore, the differences in the phosphorylation of 1380 proteins were also evaluated by Full Moon kinase array to discover the protein associated Zn−induced apoptosis. From the results, a prominent increase in glycerophosphocholine and fatty acids was observed after Zn ion treatment, but only arachidonic acid was shown to induce apoptosis. The kinase array revealed that the phosphorylation of p53, GTPase activation protein, CaMK2a, PPAR−γ, and PLA−2 was changed. From the pathway analysis, metabolic changes showed earlier onset than protein signaling, which were related to choline metabolism. LC−MS analysis was used to quantify the intracellular choline concentration, which decreased after Zn treatment, which may be related to the choline consumption required to produce choline-containing metabolites. Overall, we found that choline metabolism plays an important role in Zn-induced Raji cell apoptosis.

We investigated the protective effect and mechanisms of apigenin against cognitive impairments in a scopolamine-injected mouse model. Our results showed that intraperitoneal (i.p.) injection of scopolamine leads to learning and memory dysfunction, whereas the administration of apigenin (synthetic compound, 100 and 200 mg/kg/day) improved cognitive ability, which was confirmed by behavioral tests such as the T-maze test, novel objective recognition test, and Morris water maze test in mice. In addition, scopolamine-induced lipid peroxidation in the brain was attenuated by administration of apigenin. To further evaluate the protective mechanisms of apigenin on cognitive and memory function, Western blot analysis was carried out. Administration of apigenin decreased the B-cell lymphoma 2-associated X/B-cell lymphoma 2 (Bax/Bcl-2) ratio and suppressed caspase-3 and poly ADP ribose polymerase cleavage. Furthermore, apigenin down-regulated the β-site amyloid precursor protein-cleaving enzyme, along with presenilin 1 (PS1) and PS2 protein levels. Apigenin-administered mice showed lower protein levels of a receptor for advanced glycation end-products, whereas insulin-degrading enzyme, brain-derived neurotrophic factor (BDNF), and tropomyosin receptor kinase B (TrkB) expression were promoted by treatment with apigenin. Therefore, this study demonstrated that apigenin is an active substance that can improve cognitive and memory functions by regulating apoptosis, amyloidogenesis, and BDNF/TrkB signaling pathways.

Cultural diversity is a topic that has been taught across disciplines, but the pandemic has made it more difficult for universities and colleges to teach and discuss it when active interaction is limited in the classroom setting. The difficulties and challenges observed in communication courses, including advertising and public relations, brought this interdisciplinary talk with three professors. In the reflective essay, the faculties discuss the importance of teaching and discussing cultural diversity in the disciplines and how to incorporate the topic into the curriculum while acknowledging the challenges during the pandemic. Finally, the observations from teaching the courses last two years and analysis of theories and literature offered some guidelines and recommendations to help students and faculties move forward in the post-pandemic.

Abeliophyllum distichum Nakai is known as a monotypic genus endemic to South Korea. Currently, several pharmacological studies have revealed that A. distichum extract exhibits diverse biological functions, including anti-cancer, anti-diabetic, anti-hypertensive, and anti-inflammatory activities. In this study, we present the anti-osteoporotic activity of A. distichum extract by inhibiting osteoclast formation. First, we show that the methanolic extract of the leaves of A. distichum, but not extracts of the branches or fruits, significantly inhibits receptor activator of the NF-κB ligand (RANKL)-induced osteoclast differentiation. Second, our transcriptome analysis revealed that the leaf extract (LE) blocks sets of RANKL-mediated osteoclast-related genes. Third, the LE attenuates the phosphorylation of extracellular signal-related kinase. Finally, treatment with the LE effectively prevents postmenopausal bone loss in ovariectomized mice and glucocorticoid-induced osteoporosis in zebrafish. Our findings show that the extract of A. distichum efficiently suppressed osteoclastogenesis by regulating osteoclast-related genes, thus offering a novel therapeutic strategy for osteoporosis.

The number of wind-generating resources has increased considerably, owing to concerns over the environmental impact of fossil-fuel combustion. Therefore, wind power forecasting is becoming an important issue for large-scale wind power grid integration. Ensemble forecasting, which combines several forecasting techniques, is considered a viable alternative to conventional single-model-based forecasting for improving the forecasting accuracy. In this work, we propose the day-ahead ensemble forecasting of wind power using statistical methods. The ensemble forecasting model consists of three single forecasting approaches: autoregressive integrated moving average with exogenous variable (ARIMAX), support vector regression (SVR), and the Monte Carlo simulation-based power curve model. To apply the methodology, we conducted forecasting using the historical data of wind farms located on Jeju Island, Korea. The results were compared between a single model and an ensemble model to demonstrate the validity of the proposed method.

Osteoporosis is a common disorder of bone remodeling, caused by the imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Recently, we reported that matrix metalloproteinase-9 (MMP-9)-dependent histone H3 proteolysis is a key event for proficient osteoclast formation. Although it has been reported that several MMP-9 inhibitors, such as tetracycline and its derivatives, show an inhibitory effect on osteoclastogenesis, the molecular mechanisms for this are not fully understood. Here we show that tetracycline analogs, especially tigecycline and minocycline, inhibit osteoclast formation by blocking MMP-9-mediated histone H3 tail cleavage. Our molecular docking approach found that tigecycline and minocycline are the most potent inhibitors of MMP-9. We also observed that both inhibitors significantly inhibited H3 tail cleavage by MMP-9 in vitro. These compounds inhibited receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast formation by blocking the NFATc1 signaling pathway. Furthermore, MMP-9-mediated H3 tail cleavage during osteoclast differentiation was selectively blocked by these compounds. Treatment with both tigecycline and minocycline rescued the osteoporotic phenotype induced by prednisolone in a zebrafish osteoporosis model. Our findings demonstrate that the tetracycline analogs suppress osteoclastogenesis via MMP-9-mediated H3 tail cleavage, and suggest that MMP-9 inhibition could offer a new strategy for the treatment of glucocorticoid-induced osteoporosis.

The bone tissue is a dynamic complex that constitutes of several interdependent systems and is continuously remodeled through the concerted actions of bone cells. Osteoblasts are mononucleated cells, derived from mesenchymal stem cells, responsible for bone formation. Osteoclasts are large multinucleated cells that differentiate from hematopoietic progenitors of the myeloid lineage and are responsible for bone resorption. The lineage-specific differentiation of bone cells requires an epigenetic regulation of gene expressions involving chromatin dynamics. The key step for understanding gene regulatory networks during bone cell development lies in characterizing the chromatin modifying enzymes responsible for reorganizing and potentiating particular chromatin structure. This review covers the histone-modifying enzymes involved in bone development, discusses the impact of enzymes on gene expression, and provides future directions and clinical significance in this area.

There are few studies on the severity and prognosis of patients infected with the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) omicron variant. From January 11, 2022 to January 25, 2022, 181 patients were infected with the SARS-CoV-2 omicron variant in a single hospital in Korea. The initial clinical characteristics were investigated through the COVID-19 basic investigation form. Outcomes were reviewed using medical records. The median age of the patients was 57 years (range 1--90), and 95 patients (52.5%) were male. None were re-infected with SARS-CoV-2, and 127 (70.2%) were fully vaccinated (boosted or within 6 months after second vaccination). Forty-two patients (23.2%) were asymptomatic. Among symptomatic patients, the frequency of symptoms was as follows: cough (37.0%), sore throat (33.7%), and fever (30.4%). In terms of disease severity, 168 (92.8%) patients did not require supplemental oxygen, 6 (3.3%) required low-flow oxygen, 5 (2.8%) required high-flow oxygen, and 2 (1.1%) died. Four of the five individuals who required high-flow oxygen and the two who died were not vaccinated. Most of the patients who contracted the SARS-CoV-2 omicron variant exhibited mild clinical features; however, severe clinical features including mortality were encountered among individuals who were not vaccinated. [ABSTRACT FROM AUTHOR]