Comparative analysis of the efficacy of vaccines using structural protein subunits of the severe fever with thrombocytopenia syndrome virus.

The severe fever with thrombocytopenia syndrome virus (SFTSV) represents a significant emerging health threat as a tick-borne pathogen that causes SFTS, with mortality rates ranging between 10 and 30%. Despite the considerable risk presented by SFTSV, an effective vaccine has yet to be developed. Our study assessed the efficacy of recombinant protein vaccines, focusing on the purified nucleocapsid protein (NP) and surface glycoproteins (Gn and Gc), against SFTSV in both singular and combined formulations. Individual vaccinations with NP or Gn subunits yielded partial protection in type I interferon receptor-knockout (IFNAR-KO) mice, with survival rates of 66.7 and 16.7%, respectively, whereas Gc vaccination did not confer significant protection, resulting in 100% mortality similar to that of the unvaccinated control group. Notably, NP vaccination substantially enhanced antigen-specific T cell responses, and Gc vaccination exhibited strong neutralizing activity against SFTSV. Among the combined recombinant protein formulations (Gn + NP, Gc + NP, and Gn + Gc + NP) tested, the Gc + NP combination provided the highest survival rate (85.7%) following challenge with a lethal dose of SFTSV, highlighting its potential as a vaccine candidate. Longitudinal studies showed that antibody levels in both wild type C57BL/6 and IFNAR-KO mice peaked between 2 and 3 months post-vaccination and declined over time. A notable decrease in NP-specific CD8+ T cell responses was observed 6 months post-vaccination in C57BL/6 mice, while NP-specific CD4+ T cell responses persisted up to 12 months. By 12 months post-vaccination, all IFNAR-KO mice vaccinated with single subunit antigens succumbed to the virus, suggesting that effective protection against SFTS may rely on antibody responses to subunit antigens and/or CD8+ T cell activity. These findings underscore the necessity of an optimized SFTS vaccine that combines protective antigens with an adjuvant system to ensure durable humoral and cellular immunity.

Vaccine Development for Severe Fever with Thrombocytopenia Syndrome Virus in Dogs.

Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening viral zoonosis. The causative agent of this disease is the Dabie bandavirus, which is usually known as the SFTS virus (SFTSV). Although the role of vertebrates in SFTSV transmission to humans remains uncertain, some reports have suggested that dogs could potentially transmit SFTSV to humans. Consequently, preventive measures against SFTSV in dogs are urgently needed. In the present study, dogs were immunized three times at two-week intervals with formaldehyde-inactivated SFTSV with two types of adjuvants. SFTSV (KCD46) was injected into all dogs two weeks after the final immunization. Control dogs showed viremia from 2 to 4 days post infection (dpi), and displayed white pulp atrophy in the spleen, along with a high level of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay (TUNEL) positive area. However, the inactivated SFTSV vaccine groups exhibited rare pathological changes and significantly reduced TUNEL positive areas in the spleen. Furthermore, SFTSV viral loads were not detected at any of the tested dpi. Our results indicate that both adjuvants can be safely used in combination with an inactivated SFTSV formulation to induce strong neutralizing antibodies. Inactivated SFTSV vaccines effectively prevent pathogenicity and viremia in dogs infected with SFTSV. In conclusion, our study highlighted the potential of inactivated SFTSV vaccination for SFTSV control in dogs.

Assessment of acetylcholinesterase activity in CD9-positive exosomes from patients with Parkinson's disease.

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic dysfunction and associated with abnormalities in the cholinergic system. However, the relationship between PD and cholinergic dysfunction, particularly in exosomes, is not fully understood. Methods: We enrolled 37 patients with PD and 44 healthy controls (HC) to investigate acetylcholinesterase (AChE) activity in CD9-positive and L1CAM-positive exosomes. Exosomes were isolated from plasma using antibody-coupled magnetic beads, and their sizes and concentrations were assessed using transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Subsequently, the AChE activity in these exosomes was analyzed in relation to various clinical parameters. Results: A significant decrease in AChE activity was observed in CD9-positive exosomes derived from patients with PD, whereas no significant differences were found in L1CAM-positive exosomes. Further analysis with a larger sample size confirmed a substantial reduction in AChE activity in CD9-positive exosomes from the PD plasma, with moderate diagnostic accuracy. The decrease in AChE activity of CD9-positive exosomes did not show an association with cognitive impairment but displayed a trend toward correlation with PD progression. Discussion: The reduction in AChE activity in CD9-positive exosomes suggests potential peripheral cholinergic dysfunction in PD, independent of the central cholinergic system. The observed alterations in AChE activity provide valuable insights into the association between cholinergic dysfunction and the pathogenesis of PD.

Structural Identification of Ginsenoside Based on UPLC-QTOF-MS of Black Ginseng (Panax Ginseng C.A. Mayer).

Black ginseng (BG) is processed ginseng traditionally made in Korea via the steaming and drying of ginseng root through three or more cycles, leading to changes in its appearance due to the Maillard reaction on its surface, resulting in a dark coloration. In this study, we explored markers for differentiating processed ginseng by analyzing the chemical characteristics of BG. We elucidated a new method for the structural identification of ginsenoside metabolites and described the features of processed ginseng using UPLC-QTOF-MS in the positive ion mode. We confirmed that maltose, glucose, and fructose, along with L-arginine, L-histidine, and L-lysine, were the key compounds responsible for the changes in the external quality of BG. These compounds can serve as important metabolic markers for distinguishing BG from conventionally processed ginseng. The major characteristics of white ginseng, red ginseng, and BG can be distinguished based on their high-polarity and low-polarity ginsenosides, and a precise method for the structural elucidation of ginsenosides in the positive ion mode is presented.

Crystal structure of Bak bound to the BH3 domain of Bnip5, a noncanonical BH3 domain-containing protein.

The activation or inactivation of B-cell lymphoma-2 (Bcl-2) antagonist/killer (Bak) is critical for controlling mitochondrial outer membrane permeabilization-dependent apoptosis. Its pro-apoptotic activity is controlled by intermolecular interactions with the Bcl-2 homology 3 (BH3) domain, which is accommodated in the hydrophobic pocket of Bak. Bcl-2-interacting protein 5 (Bnip5) is a noncanonical BH3 domain-containing protein that interacts with Bak. Bnip5 is characterized by its controversial effects on the regulation of the pro-apoptotic activity of Bak. In the present study, we determined the crystal structure of Bak bound to Bnip5 BH3. The intermolecular association appeared to be typical at first glance, but we found that it is maintained by tight hydrophobic interactions together with hydrogen/ionic bonds, which accounts for their high binding affinity with a dissociation constant of 775 nM. Structural analysis of the complex showed that Bnip5 interacts with Bak in a manner similar to that of the Bak-activating pro-apoptotic factor peroxisomal testis-enriched protein 1, particularly in the destabilization of the intramolecular electrostatic network of Bak. Our structure is considered to reflect the initial point of drastic and consecutive conformational and stoichiometric changes in Bak induced by Bnip5 BH3, which helps in explaining the effects of Bnip5 in regulating Bak-mediated apoptosis.

Association of plasma amyloid-ß oligomerization with theta/beta ratio in older adults.

Background: Oligomeric Aß (OAß) is a promising candidate marker for Alzheimer's disease (AD) diagnosis. Electroencephalography (EEG) is a potential tool for early detection of AD. Still, whether EEG power ratios, particularly the theta/alpha ratio (TAR) and theta/beta ratio (TBR), reflect Aß burden-a primary mechanism underlying cognitive impairment and AD. This study investigated the association of TAR and TBR with amyloid burden in older adults based on MDS-OAß levels. Methods: 529 individuals (aged ≥60 years) were recruited. All participants underwent EEG (MINDD SCAN, Ybrain Inc., South Korea) and AlzOn™ test (PeopleBio Inc., Gyeonggi-do, Republic of Korea) for quantifying MDS-OAß values in the plasma. EEG variables were log-transformed to normalize the data distribution. Using the MDS-OAß cutoff value (0.78 ng/mL), all participants were classified into two groups: high MDS-OAß and low MDS-OAß. Results: Participants with high MDS-OAß levels had significantly higher TARs and TBRs than those with low MDS-OAß levels. The log-transformed TBRs in the central lobe (ß = 0.161, p = 0.0026), frontal lobe (ß = 0.145, p = 0.0044), parietal lobe (ß = 0.166, p = 0.0028), occipital lobe (ß = 0.158, p = 0.0058), and temporal lobe (beta = 0.162, p = 0.0042) were significantly and positively associated with increases in MDS-OAß levels. After adjusting for the Bonferroni correction, the TBRs in all lobe regions, except the occipital lobe, were significantly associated with increased MDS-OAß levels. Conclusion: We found a significant association of MDS-OAß with TBR in older adults. This finding indicates that an increase in amyloid burden may be associated with an increase in the low-frequency band and a decrease in the relatively high-frequency band.

Insights into the recognition mechanism in the UBR box of UBR4 for its specific substrates.

The N-end rule pathway is a proteolytic system involving the destabilization of N-terminal amino acids, known as N-degrons, which are recognized by N-recognins. Dysregulation of the N-end rule pathway results in the accumulation of undesired proteins, causing various diseases. The E3 ligases of the UBR subfamily recognize and degrade N-degrons through the ubiquitin-proteasome system. Herein, we investigated UBR4, which has a distinct mechanism for recognizing type-2 N-degrons. Structural analysis revealed that the UBR box of UBR4 differs from other UBR boxes in the N-degron binding sites. It recognizes type-2 N-terminal amino acids containing an aromatic ring and type-1 N-terminal arginine through two phenylalanines on its hydrophobic surface. We also characterized the binding mechanism for the second ligand residue. This is the report on the structural basis underlying the recognition of type-2 N-degrons by the UBR box with implications for understanding the N-end rule pathway.

Cellular toxicity profile of a new ophthalmic sponge.

Introduction: Ophthalmic sponges are used for cleaning the eye surface and absorbing fluids during ophthalmic procedures. This study compared the biological safety and stability of a new ophthalmic sponge, Occucell® (OccuTech Inc, Seongnam, Korea), on the human conjunctival epithelial cells with those of preexisting products to evaluate its clinical application.Materials and Methods: The cytotoxicity of four products, Occucell, a new product, Ultracell®, Eyetec-1, and Eyetec-2, on conjunctival epithelial cells, was evaluated using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) analysis. Additionally, human conjunctival epithelial cells were stained with a Live & Dead marker and observed using a fluorescence microscope. To evaluate the effect of the ophthalmic sponges on the secretion of IL-1ß and TNF-α, cultured conjunctival epithelial cells were treated with 0.5% DMSO eluates of the ophthalmic sponges, and IL-1ß and TNF-α mRNA levels were estimated using real-time polymerase chain reaction assays.Results: Cells treated with Occucell showed comparable viability to those treated with other preexisting products. Conjunctival epithelial cells showed more than 90% viability when treated with the ophthalmic sponge extracts, as determined by the MTT assay. No significant differences in the number of live & dead cells were observed between the control and treatment groups. Cells treated with all four ophthalmic sponge eluates showed similar IL-1ß and TNF-α mRNA levels.Discussion: Occucell, an eye sponge used during ophthalmic surgery in clinical practice, did not affect the viability of conjunctival epithelial cells, and more than 90% of the cells were viable after the treatment. Further, Occucell showed similar effects on IL-1ß and TNF-α secretion as that of other ophthalmic sponges used in the clinic. This suggested that Occucell is a safe product comparable to the preexisting products.

A natural variation in the RNA polymerase of severe fever with thrombocytopenia syndrome virus enhances viral replication and in vivo virulence.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with high mortality in Eastern Asia. The disease is caused by the SFTS virus (SFTSV), also known as Dabie bandavirus, which has a segmented RNA genome consisting of L, M, and S segments. Previous studies have suggested differential viral virulence depending on the genotypes of SFTSV; however, the critical viral factor involved in the differential viral virulence is unknown. Here, we found a significant difference in viral replication in vitro and virulence in vivo between two Korean isolates belonging to the F and B genotypes, respectively. By generating viral reassortants using the two viral strains, we demonstrated that the L segment, which encodes viral RNA-dependent RNA polymerase (RdRp), is responsible for the enhanced viral replication and virulence. Comparison of amino acid sequences and viral replication rates revealed a point variation, E251K, on the surface of RdRp to be the most significant determinant for the enhanced viral replication rate and in vivo virulence. The effect of the variation was further confirmed using recombinant SFTSV generated by reverse genetic engineering. Therefore, our results indicate that natural variations affecting the viral replicase activity could significantly contribute to the viral virulence of SFTSV.

Association Between the Loss of Gait Harmony and Cognitive Impairment: Cross-Sectional Study.

BACKGROUND: Functional limitations and disabilities have been associated with a decrease in cognitive function due to increasing age. Gait performance and cognitive function have been associated with gait variability in executive function, the phase domain in memory, and gait abnormalities in cognitive decline. OBJECTIVE: Our study aimed to investigate whether gait harmony was associated with cognitive function in the older adult population. Moreover, we aimed to investigate whether gait harmony was associated with cognitive function and explore each cognitive function in a specific harmonic state. METHODS: The study population included 510 adults aged ≥60 years who visited the Department of Neurology at the Veterans Health Service Medical Center, Seoul, South Korea. Gait data were collected using a 3D motion capture device with a wireless inertial measurement unit system. For cognitive function assessments, we used the Seoul Neuropsychological Screening Battery-Core test, which evaluates the level of cognitive function or impairment in 5 cognitive domains. RESULTS: In general, the association between the Seoul Neuropsychological Screening Battery-Core tests and the stance-to-swing ratio in the >1.63 ratio group yielded lower ß coefficients than those in the 1.50-1.63 ratio group. After adjustment for confounders, the odds ratio (OR) for the Digit Symbol Coding test (adjusted OR 0.42, 95% CI 0.20-0.88) and the Korean version of the Color Word Stroop Test: 60 seconds (adjusted OR 0.51, 95% CI 0.29-0.89) for frontal and executive function were significantly lower for the >1.63 ratio group than the reference group. CONCLUSIONS: Our findings suggest that the gait phase ratio is a valuable indicator of walking deficits and may also be associated with cognitive impairment in older adults.

Brain-derived neurotrophic factor levels and macular ganglion cell-inner plexiform layer thickness in macular telangiectasia type 2.

PURPOSE: To determine brain-derived neurotrophic factor (BDNF) levels in the serum and aqueous humor (AH) and assess the relationship between BDNF levels and the thickness of the macular ganglion cell-inner plexiform layer (GCIPL) in macular telangiectasia type 2 (MacTel). METHODS: This study included 25 patients with MacTel (MacTel group) and 25 control subjects (control group). The levels of BDNF in the serum and AH were tested using an enzyme-binding immunosorbent assay. GCIPL thickness was measured by segmentation analysis using optical coherence tomography (OCT). RESULTS: There was no significant difference in the mean serum BDNF levels between the MacTel and control groups (p = 0.145). The average BDNF level in the AH was significantly lower than that in the control group (p = 0.026). OCT segmentation analyses revealed that the minimum GCIPL thickness was significantly lower in the MacTel group than in the control group (p = 0.039). In the correlation analysis of BDNF levels with GCIPL thickness, significant correlations existed between the BDNF level of the AH and minimum GCIPL thickness in the MacTel group. CONCLUSION: The concentration of BDNF in the AH was decreased in the MacTel group, and this reduction was related to the minimum GCIPL thickness. The low BDNF levels detected in the MacTel group may have resulted in thinning of the GCIPL due to the loss of retinal ganglion cells.

Bacillus integrative plasmid system combining a synthetic gene circuit for efficient genetic modifications of undomesticated Bacillus strains.

BACKGROUND: Owing to CRISPR-Cas9 and derivative technologies, genetic studies on microorganisms have dramatically increased. However, the CRISPR-Cas9 system is still difficult to utilize in many wild-type Bacillus strains owing to Cas9 toxicity. Moreover, less toxic systems, such as cytosine base editors, generate unwanted off-target mutations that can interfere with the genetic studies of wild-type strains. Therefore, a convenient alternative system is required for genetic studies and genome engineering of wild-type Bacillus strains. Because wild-type Bacillus strains have poor transformation efficiencies, the new system should be based on broad-host-range plasmid-delivery systems. RESULTS: Here, we developed a Bacillus integrative plasmid system in which plasmids without the replication initiator protein gene (rep) of Bacillus are replicated in a donor Bacillus strain by Rep proteins provided in trans but not in Bacillus recipients. The plasmids were transferred to recipients through a modified integrative and conjugative element, which is a wide host range plasmid-delivery system. Genetic mutations were generated in recipients through homologous recombination between the transferred plasmid and the genome. The system was improved by adding a synthetic gene circuit for efficient screening of the desired mutations by double crossover recombination in recipient strains. The improved system exhibited a mutation efficiency of the target gene of approximately 100% in the tested wild-type Bacillus strains. CONCLUSION: The Bacillus integrative plasmid system developed in this study can generate target mutations with high efficiency when combined with a synthetic gene circuit in wild-type Bacillus strains. The system is free of toxicity and unwanted off-target mutations as it generates the desired mutations by traditional double crossover recombination. Therefore, our system could be a powerful tool for genetic studies and genome editing of Cas9-sensitive wild-type Bacillus strains.

High-throughput analysis of amniotic fluid proteins associated with histological chorioamnionitis in preterm premature rupture of membranes using an antibody-based microarray.

PROBLEM: To identify potential proteins in the amniotic fluid (AF) that may be associated with histologic chorioamnionitis (HCA) in patients with preterm premature rupture of membranes (PPROM) using antibody-based microarray analysis. METHOD OF STUDY: This was a retrospective cohort study involving 100 singleton pregnant women with PPROM at 24-34 weeks who underwent amniocentesis and delivered within 120 h of amniocentesis. First, the AF proteomes of 15 patients with PPROM and HCA were compared with those of 15 gestational age-matched patients without HCA using a protein microarray. Next, 12 candidate proteins associated with HCA were further validated in 100 consecutive patients with PPROM by ELISA. RESULTS: Of 507 proteins assessed in the microarray analysis, 46 showed significant intergroup differences. Further quantification confirmed that the levels of EN-RAGE, IL-6, MMP-9, TNFR2, SPARC, TSP2, and uPA were higher in the AF of PPROM patients with HCA than in those without. Multivariate analyses also showed that elevated AF EN-RAGE, IL-6, MMP-9, and TNFR2 levels were independently associated with HCA when adjusted for baseline variables. The frequency of the highest quartile of the aforementioned proteins significantly increased as the total grade of HCA increased; the risk of HCA significantly increased with increasing AF levels of each protein (P for trend < .001). CONCLUSIONS: Using protein-antibody microarray technology, we discovered several potential AF proteins (EN-RAGE, IL-6, MMP-9, and TNFR2) independently associated with HCA in patients with PPROM. Furthermore, we demonstrated a direct correlation between the gradation of the intra-amniotic inflammatory response and HCA severity.

Recapitulated Crosstalk between Cerebral Metastatic Lung Cancer Cells and Brain Perivascular Tumor Microenvironment in a Microfluidic Co-Culture Chip.

Non-small cell lung carcinoma (NSCLC), which affects the brain, is fatal and resistant to anti-cancer therapies. Despite innate, distinct characteristics of the brain from other organs, the underlying delicate crosstalk between brain metastatic NSCLC (BM-NSCLC) cells and brain tumor microenvironment (bTME) associated with tumor evolution remains elusive. Here, a novel 3D microfluidic tri-culture platform is proposed for recapitulating positive feedback from BM-NSCLC and astrocytes and brain-specific endothelial cells, two major players in bTME. Advanced imaging and quantitative functional assessment of the 3D tri-culture model enable real-time live imaging of cell viability and separate analyses of genomic/molecular/secretome from each subset. Susceptibility of multiple patient-derived BM-NSCLCs to representative targeted agents is altered and secretion of serpin E1, interleukin-8, and secreted phosphoprotein 1, which are associated with tumor aggressiveness and poor clinical outcome, is increased in tri-culture. Notably, multiple signaling pathways involved in inflammatory responses, nuclear factor kappa-light-chain-enhancer of activated B cells, and cancer metastasis are activated in BM-NSCLC through interaction with two bTME cell types. This novel platform offers a tool to elucidate potential molecular targets and for effective anti-cancer therapy targeting the crosstalk between metastatic cancer cells and adjacent components of bTME.

Cell Factory Engineering of Undomesticated Bacillus Strains Using a Modified Integrative and Conjugative Element for Efficient Plasmid Delivery.

A large number of Bacillus strains have been isolated from various environments and many of them have great potential as cell factories. However, they have been rarely developed as cell factories due to their poor transformation efficiency. In this study, we developed a highly efficient plasmid delivery system for undomesticated Bacillus strains using a modified integrative and conjugative element (MICE), which was designed to be activated by an inducer, prevent self-transfer, and deliver desired plasmids to the recipient cells. The MICE system was demonstrated to successfully introduce a gfp-containing plasmid into all 41 undomesticated Bacillus subtilis strains tested and eight other Bacillus species. The MICE was used to deliver a cytosine base editor (CBE)-based multiplex genome-editing tool for the cell factory engineering of the Bacillus species. The introduced CBE enabled one-step inactivation of the major extracellular protease genes of the tested strains. The engineered strains were used as hosts for heterologous expression of nattokinase, which resulted in various enzyme expression levels. The results suggested that the MICE and CBE systems can be powerful tools for genetic engineering of undomesticated Bacillus strains, and greatly contribute to the expansion of the Bacillus cell factory.

The association between maternal pre-pregnancy body mass index and pregnancy outcomes of preeclampsia.

OBJECTIVE: To evaluate the effects of pre-pregnancy maternal body mass index (BMI) to pregnancy outcomes in patients diagnosed as preeclampsia. MATERIALS AND METHODS: This was a retrospectively study on women who had been diagnosed as preeclampsia and delivered at Seoul National University Bundang Hospital between June 2017 and March 2020. Multifetal gestation, major fetal anomaly, and fetal death in utero were excluded. A total of 150 singleton pregnancies were included and divided into four groups according to the pre-pregnancy BMI classification: underweight (<18.5 kg/m2, n = 6), normal (18.5-22.9 kg/m2, n = 66), overweight (23.0-24.9 kg/m2, n = 26), and obese (≥25.0 kg/m2, n = 52). Pregnancy outcomes including gestational age at delivery, birthweight, and delivery modes were reviewed. RESULTS: The rates of preterm birth before 34 weeks of gestation were 67%, 49%, 35%, and 27% for underweight group, normal BMI group, overweight group, and obese group, respectively (p-trend = 0.006). The birthweight of newborn increased significantly as pre-pregnancy BMI increased (p-trend<0.001). The proportions of small for gestational age (SGA) were highest in underweight group and decreased as pre-pregnancy BMI increased (67%, 41%, 42%, and 10% for each group, respectively, p-trend<0.001). CONCLUSION: The rates of preterm birth before 34 weeks and SGA increased as pre-pregnancy BMI decreased in patients with preeclampsia. IMPLICATIONS FOR PRACTICE: Women with underweight before pregnancy are at the highest risk for preterm birth and SGA, therefore they need to be monitored more intensively when diagnosed as preeclampsia.

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer's Disease.

Early-onset Alzheimer's disease (EOAD) is characterized by the presence of neurological symptoms in patients with Alzheimer's disease (AD) before 65 years of age. Mutations in pathological genes, including amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), were associated with EOAD. Seventy-six mutations in PSEN2 have been found around the world, which could affect the activity of γ-secretase in amyloid beta processing. Here, a heterozygous PSEN2 point mutation from G to A nucleotide change at position 166 (codon 56; c.166G>A, Gly56Ser) was identified in a 64-year-old Korean female with AD with progressive cognitive memory impairment for the 4 years prior to the hospital visit. Hippocampal atrophy was observed from magnetic resonance imaging-based neuroimaging analyses. Temporal and parietal cortex hypometabolisms were identified using fluorodeoxyglucose positron emission tomography. This mutation was at the N-terminal portion of the presenilin 2 protein on the cytosolic side. Therefore, the serine substitution may have promoted AD pathogenesis by perturbing to the mutation region through altered phosphorylation of presenilin. In silico analysis revealed that the mutation altered protein bulkiness with increased hydrophilicity and reduced flexibility of the mutated region of the protein. Structural changes were likely caused by intramolecular interactions between serine and other residues, which may have affected APP processing. The functional study will clarify the pathogenicity of the mutation in the future.

Chronic Status of Serum Albumin and Cognitive Function: A Retrospective Cohort Study.

Previous studies have found an association between serum albumin levels and cognitive function. However, the results of this association are inconsistent, and the effect of Apolipoprotein E (APOE) on the association is less clear. Using retrospective cohort data (2008-2020), we investigated whether chronic serum albumin was associated with cognitive performance in older adults. We further assessed how the APOE genotype modifies its relevance. A total of 2396 Korean veterans and their families who were aged 65 years or older in 2008 and who had both data of serum albumin and cognitive performance (assessed by the Mini-Mental State Examination, MMSE) were included for the current study. The serum albumin levels were divided into four groups by quartiles: Group 1 (<4.0 g/dL), Group 2 (4.0-4.19 g/dL), Group 3 (4.2-4.49 g/dL), and Group 4 (≥4.5 g/dL). APOE ε4 carriers were defined as the presence of at least one ε4 allele (ε2/4, ε3/4, ε4/4). After adjusting for age, sex, and medical conditions, serum albumin levels (assessed by the median serum albumin levels during the study period) were significantly associated with increases in the median MMSE scores (beta = 3.30, p < 0.0001). Compared with the lowest median albumin category (Group 1), the beta coefficients for the median MMSE score were significantly and gradually increased in Group 2 (beta = 2.80, p < 0.0001), Group 3 (beta = 3.71, p < 0.0001), and Group 4 (beta = 4.01, p < 0.0001), respectively. In the analysis of repeated albumin measures, similar patterns were observed in cognitive function. All regression coefficients were greater in ε4 carriers than in non-carriers. Our findings suggested that sustained lower serum albumin levels were associated with lower MMSE scores. This observation may be modified by APOE polymorphisms.

Use of continuous infusion of nicardipine to control persistent postpartum hypertension: A retrospective study.

To evaluate the effect of continuous infusion of nicardipine on the management of uncontrolled blood pressure (BP) during postpartum period. This retrospective study included 209 women diagnosed in hospital with hypertensive disorders during pregnancy and had uncontrolled BP after delivery between January 2018 to December 2020 Uncontrolled BP was defined as persistent elevation of systolic BP ≥ 160 mm Hg or diastolic BP ≥ 110 mm Hg. Patients were divided into 2 groups: nicardipine (N = 53; continuous nicardipine infusion and additional bolus of labetalol or hydralazine) and control (N = 156; consecutive bolus of labetalol or hydralazine). BP data were analyzed using the Mann-Whitney U and χ2 tests by dividing the time interval of 4 hours by the delivery time. The highest BP trends showed that the mean values of both systolic and diastolic BP immediately before delivery were higher in the nicardipine group than in the control. After 8 to 12 hours following delivery, both systolic and diastolic BP were lower in the nicardipine group than in the control. Subsequently, 16 to 20 hours after delivery, both systolic and diastolic BP were significantly lower in the nicardipine group than in the control (137/80 vs 141/84 mm Hg). Initially, the proportions of uncontrolled BP in the nicardipine group were higher than those in the control; however, it then became lower at all time intervals 8 hours after delivery. The proportions of patients who received additional antihypertensive agents and the median cumulative dosages were lower in the nicardipine group than in the control. Continuous infusion of nicardipine can help manage uncontrolled BP during the postpartum period.

Bioactivity-Guided Extract Optimization of Osmanthus fragrans var. aurantiacus Leaves and Anti-Inflammatory Activities of Phillyrin.

The aim of this study was to identify the optimal extraction conditions for leaves of Osmanthus fragrans var. aurantiacus. Inhibitory effects of various extracts on NO production were compared. Antioxidant evaluations for total phenol and flavonoid contents were carried out using various extracts of O. fragrans var. aurantiacus leaves obtained under optimal extraction conditions that showed the greatest effect on NO production. The optimal method for extracting O. fragrans var. aurantiacus leaves resulted in an extract named OP OFLE. OP OFLE showed DPPH and ABTS radical scavenging activities in a concentration-dependent manner. Phillyrin (PH) was isolated as a major compound from OP OFLE by HPLC/DAD analysis. OP OFLE and PH reduced inducible nitric oxide (iNOS) and cyclooxygenase (COX)-2 protein expression and downregulated proinflammatory cytokines such as interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor (TNF)-α in LPS-stimulated RAW 264.7 and HT-29 cells. To determine the signal pathway involved in the inhibition of NO production, a Western blot analysis was performed. Results showed that OP OFLE decreased phosphorylation of extracellular regulated kinase (pERK) 1/2 and the expression of nuclear factor-kappa B (NF-κB). Our results suggest that extracts of O. fragrans var. aurantiacus leaves and its major components have biological activities such as antioxidative and anti-inflammatory properties.