Effects of sub-inhibitory concentrations of nafcillin, vancomycin, ciprofloxacin, and rifampin on biofilm formation of clinical methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are often difficult to treat because of their biofilm-forming ability and antimicrobial resistance. We investigated the effects of sub-minimal inhibitory concentrations (MICs) of antibiotics on MRSA biofilm formation. Clinical MRSA isolates were grown with sub-MICs (1/256-1/2 × MICs) of nafcillin, vancomycin, ciprofloxacin, and rifampin. The biofilm biomass was measured using crystal violet staining. Of the 107 MRSA isolates tested, 63 (58.9%) belonged to sequence type 5 (ST5), and 44 (41.1%) belonged to ST72. The MIC50/MIC90 values of nafcillin, vancomycin, ciprofloxacin, and rifampin were 256/512, 1/2, 64/512, and 0.008/0.03 mg/L, respectively. The sub-MICs of nafcillin, vancomycin, ciprofloxacin, and rifampin promoted biofilm formation in 75 (70.1%), 49 (45.8%), 89 (83.2%), and 89 (83.2%) isolates, respectively. At sub-MICs of nafcillin, the factors associated with strong biofilm induction were the ST5 strain (P = 0.001) and agr dysfunction (P = 0.005). For the sub-MICs of ciprofloxacin, the associated factors were the ST5 strain (P = 0.002), staphylococcal protein A type t002 strain (P < 0.001), and ciprofloxacin resistance (P < 0.001). Among the sub-MICs of rifampin, only ST5 was associated with strong biofilm induction (P = 0.006). Because the sub-MICs of rifampin were much lower than clinically relevant concentrations, we further tested the capability of biofilm induction in 0.03[Formula: see text]32 mg/L of rifampin. At these concentrations, rifampin-induced biofilm formation was rare in rifampin-susceptible MRSA [1.0% (1 of 100)] but common in rifampin-resistant MRSA [71.4% (5 of 7), P < 0.001]. Induction of biofilm biomass at sub-MICs of antibiotics is common in clinical MRSA isolates and is differentially affected by the MRSA strain and antibiotic class. IMPORTANCE: Bacteria can be exposed to sub-MICs of antibiotics at the beginning and end of a dosing regimen, between doses, or during low-dose therapies. Growing evidence suggests that sub-MICs of antimicrobials can stimulate MRSA biofilm formation and alter the composition of the biofilm matrix. Pevious studies have found that sub-MICs of oxacillin, methicillin, and amoxicillin promote biofilm formation in some community-acquired MRSA (CA-MRSA). We evaluated biofilm induction by sub-MICs of four different classes of antibiotics in 44 CA-MRSA and 63 healthcare-associated MRSA (HA-MRSA) strains. Our study indicated that sub-MICs of nafcillin, vancomycin, ciprofloxacin, and rifampin frequently promote biofilm induction in clinical MRSA isolates. Strong biofilm induction in sub-MICs of nafcillin, ciprofloxacin, and rifampin was more frequent in HA-MRSA than in CA-MRSA. Antibiotic-induced biofilm formation depends on the antibiotic class, MRSA strain, and antibiotic resistance. Our results emphasize the importance of maintaining effective bactericidal concentrations of antibiotics to treat biofilm-related infections.

Air pollution mixture associated with oxidative stress exacerbation and symptoms deterioration in allergic rhinitis patients: Evidence from a panel study.

With allergic rhinitis (AR) on the rise globally, there has been a growing focus on the role of environmental pollutants in the onset of AR. However, the potential mechanisms by how and which these pollutants exacerbate AR conditions remain unknown. This panel study of 49 patients diagnosed with AR over one year aimed to assess the individual and combined effects of short-term exposure to multiple ambient pollutants on oxidative stress, symptoms, and quality of life among patients with AR. All participants underwent four repeated assessments of health conditions and personal environmental exposures (PM2.5, O3, SO2, and NO2) over warm and cold seasons during 2017-2018. We evaluated two oxidative stress biomarkers (malondialdehyde [MDA], and superoxide dismutase [SOD]) via nasal lavage. We collected information on self-reported symptoms and quality of life using the Rhinitis Symptom Scale (SRS), the Visual Analog Scale (VAS), and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) through in-person interviews. Bayesian kernel machine regression (BKMR) was used to evaluate the joint effects of pollutant mixture and identify key contributors. The results revealed a significant association of the pollutant mixture when all four pollutants were at or above their median levels, with increased oxidative stress. This was evidenced by elevated MDA and reduced SOD. We found a joint detrimental effect of the pollutant mixture on AR symptoms with a strong association with increased SRS scores, but a non-significant positive association with VAS and RQLQ scores. PM2.5, O3, and SO2 presented as the potentially primary contributors to the adverse health effects associated with the pollutant mixture in Taiyuan city. Patients with AR exposed to short-term air pollutant mixture are more likely to have greater nasal symptoms and worse quality of life from increased oxidative stress and reduced antioxidant capacity. Further research is warranted to better elucidate the underlying mechanisms.

Low-Intensity Statin Plus Ezetimibe Versus Moderate-Intensity Statin for Primary Prevention: A Population-Based Retrospective Cohort Study in Asian Population.

BACKGROUND: While moderate-intensity statin therapy is recommended for primary prevention, statins may not be utilized at a recommended intensity due to dose-dependent adverse events, especially in an Asian population. However, evidence supporting the use of low-intensity statins in primary prevention is limited. OBJECTIVE: We sought to compare clinical outcomes between a low-intensity statin plus ezetimibe and a moderate-intensity statin for primary prevention. METHODS: This population-based retrospective cohort study used the Korean nationwide claims database (2002-2019). We included adults without atherosclerotic cardiovascular diseases who received moderate-intensity statins or low-intensity statins plus ezetimibe. The primary outcome was a composite of all-cause mortality, myocardial infarction, and ischemic stroke. The safety outcomes were liver and muscle injuries and new-onset diabetes mellitus (DM). We used standardized inverse probability of treatment weighting (sIPTW) and propensity score matching (PSM). RESULTS: In the sIPTW model, 1717 and 36 683 patients used a low-intensity statin plus ezetimibe and a moderate-intensity statin, respectively. In the PSM model, each group included 1687 patients. Compared with moderate-intensity statin use, low-intensity statin plus ezetimibe use showed similar risks of the primary outcome (hazard ratio [HR] = 0.92, 95% CI = 0.81-1.12 in sIPTW and HR = 1.16, 95% CI = 0.87-1.56 in PSM model). Low-intensity statin plus ezetimibe use was associated with decreased risks of liver and muscle injuries (subHR [sHR] = 0.84, 95% CI = 0.74-0.96 and sHR = 0.87, 95% CI = 0.77-0.97 in sIPTW; sHR = 0.84, 95% CI = 0.72, 0.96 and sHR = 0.82, 95% CI = 0.72-0.94 in PSM model, respectively). For new-onset DM and hospitalization of liver and muscle injuries, no difference was observed. CONCLUSION AND RELEVANCE: Low-intensity statin plus ezetimibe may be an alternative to moderate-intensity statin for primary prevention. Our findings provide evidence on safety and efficacy of statin therapy in Asian population.

On-Site Formation of Functional Dopaminergic Presynaptic Terminals on Neuroligin-2-Modified Gold-Coated Microspheres.

Advancements in neural interface technologies have enabled the direct connection of neurons and electronics, facilitating chemical communication between neural systems and external devices. One promising approach is a synaptogenesis-involving method, which offers an opportunity for synaptic signaling between these systems. Janus synapses, one type of synaptic interface utilizing synaptic cell adhesion molecules for interface construction, possess unique features that enable the determination of location, direction of signal flow, and types of neurotransmitters involved, promoting directional and multifaceted communication. This study presents the first successful establishment of a Janus synapse between dopaminergic (DA) neurons and abiotic substrates by using a neuroligin-2 (NLG2)-mediated synapse-inducing method. NLG2 immobilized on gold-coated microspheres can induce synaptogenesis upon contact with spatially isolated DA axons. The induced DA Janus synapses exhibit stable synaptic activities comparable to that of native synapses over time, suggesting their suitability for application in neural interfaces. By calling for DA presynaptic organizations, the NLG2-immobilized abiotic substrate is a promising tool for the on-site detection of synaptic dopamine release.

Dextran sodium sulfate (DSS)-induced colitis is alleviated in mice after administration of flavone-derived NRF2-activating molecules.

Inflammatory Bowel Disease (IBD) is a chronic and relapsing inflammatory condition characterized by severe symptoms such as diarrhea, fatigue, and weight loss. Growing evidence underscores the direct involvement of the nuclear factor-erythroid 2-related factor 2 (NRF2) in the development and progression of IBD, along with its associated complications, including colorectal cancer. The NRF2 pathway plays a crucial role in cellular responses to oxidative stress, and dysregulation of this pathway has been implicated in IBD. Flavones, a significant subclass of flavonoids, have shown pharmacological impacts in various diseases including IBD, through the NRF2 signaling pathway. In this study, we conducted a screening of compounds with a flavone structure and identified NJK15003 as a promising NRF2 activator. NJK15003 demonstrated potent NRF2 activation, as evidenced by the upregulation of downstream proteins, promoter activation, and NRF2 nuclear translocation in IBD cellular models. Treatment with NJK15003 effectively restored the protein levels of tight junctions in cells treated with dextran sodium sulfate (DSS) and in DSS-treated mice, suggesting its potential to protect cells from barrier integrity disruption in IBD. In DSS-treated mice, the administration of NJK15003 resulted in the prevention of body weight loss, a reduction in colon length shortening, and a decrease in the disease activity index. Furthermore, NJK15003 treatment substantially alleviated inflammatory responses and apoptotic cell death in the colon of DSS-treated mice. Taken together, this study proposes the potential utility of NRF2-activating flavone compounds, exemplified by NJK15003, for the treatment of IBD.

Inhibition of microfold cells ameliorates early pathological phenotypes by modulating microglial functions in Alzheimer's disease mouse model.

BACKGROUND: The gut microbiota has recently attracted attention as a pathogenic factor in Alzheimer's disease (AD). Microfold (M) cells, which play a crucial role in the gut immune response against external antigens, are also exploited for the entry of pathogenic bacteria and proteins into the body. However, whether changes in M cells can affect the gut environments and consequently change brain pathologies in AD remains unknown. METHODS: Five familial AD (5xFAD) and 5xFAD-derived fecal microbiota transplanted (5xFAD-FMT) naïve mice were used to investigate the changes of M cells in the AD environment. Next, to establish the effect of M cell depletion on AD environments, 5xFAD mice and Spib knockout mice were bred, and behavioral and histological analyses were performed when M cell-depleted 5xFAD mice were six or nine months of age. RESULTS: In this study, we found that M cell numbers were increased in the colons of 5xFAD and 5xFAD-FMT mice compared to those of wild-type (WT) and WT-FMT mice. Moreover, the level of total bacteria infiltrating the colons increased in the AD-mimicked mice. The levels of M cell-related genes and that of infiltrating bacteria showed a significant correlation. The genetic inhibition of M cells (Spib knockout) in 5xFAD mice changed the composition of the gut microbiota, along with decreasing proinflammatory cytokine levels in the colons. M cell depletion ameliorated AD symptoms including amyloid-ß accumulation, microglial dysfunction, neuroinflammation, and memory impairment. Similarly, 5xFAD-FMT did not induce AD-like pathologies, such as memory impairment and excessive neuroinflammation in Spib-/- mice. CONCLUSION: Therefore, our findings provide evidence that the inhibiting M cells can prevent AD progression, with therapeutic implications.

Development of a semi-quantitative food frequency questionnaire for dietary intake of elementary school children: data from the Seventh Korea National Health and Nutrition Examination Survey.

BACKGROUND/OBJECTIVES: In Korea, studies of diet in elementary school children are hindered by the need for a comprehensive dietary assessment tool. Thus, the aim of this study was to develop a semi-quantitative food frequency questionnaire (FFQ) for Korean elementary school children. SUBJECTS/METHODS: The 24-h recall data for 1,624 subjects aged 6-11 yrs from the seventh Korea National Health and Nutrition Examination Survey were used to extract the items included in the questionnaire. The FFQ items were developed by selecting major dishes based on the results of nutritional contribution and between-person variability for energy and 14 nutrients (carbohydrate, protein, fat, crude fiber, calcium, phosphorous, iron, sodium, potassium, vitamin A, thiamin, riboflavin, niacin, and vitamin C). We selected the major dishes with over 90% of the total contribution to each nutrient and with over 90% of the accumulated R2 for each nutrient. Among the 452 dishes, we selected 248 dishes contributing more than 1% of the total consumption. RESULTS: Finally, the FFQ included 107 items combined from 248 dishes based on nutrient profile and recipe. The FFQ items accounted for an average of 88.6% of the energy, 14 nutrient intakes, and 91.4% of the between-person variability. Quantities of dietary intake were assessed by 9 categories of frequency and 3 categories of portion size. Percentages of coverage for energy, protein, fat, carbohydrate, and calcium were 90.2%, 87.8%, 89.9%, 90.8%, and 88.7%, respectively. CONCLUSIONS: We developed a dish-based, semi-quantitative FFQ comprising 107 items for Korean elementary school children aged 6 to 11. Further studies are needed to evaluate the reproducibility and validity of this FFQ for elementary school children.

Are We Truly Safe? Unfolding the Final Chapters of COVID-19 Walk-Through Booths.

This research proposes a safety strategy for coronavirus disease 2019 (COVID-19) walk-through booths to optimize pandemic preparedness. These booths, designed for respiratory sample collection during the COVID-19 pandemic, effectively reduce infection risk and personal protective equipment-related fatigue among healthcare workers. However, inadequate disinfection and glove management could escalate infection transmission. Using computational fluid dynamics simulations, we analyzed droplet dispersion on booth surfaces and gloves under various wind conditions. Our findings suggest that when setting up COVID-19 walk-through booths, their location should be strategically chosen to minimize the effects of wind. All surfaces of booth gloves must be thoroughly disinfected with a certified disinfectant after nasopharyngeal swab collection. It is also recommended to wear disposable gloves over booth gloves when changing between patient examinations. In wind-affected areas, individuals nearby should not solely rely on the 2-meter distancing rule due to potential droplet spread from walk-through booths. We strongly recommend consistent and proper mask use for effective droplet blocking. Adherence to these guidelines can significantly enhance the safety and efficiency of walk-through booths, particularly in potential future pandemics.

Clinical pharmacokinetic study of tacrolimus in continuous intravenous administration for lung transplantation.

Tacrolimus is a cornerstone of immunosuppression after lung transplantation. However, there are no clear guidelines on how to administer the drug and the duration to achieve the required therapeutic range in the early phase of lung transplantation. This is a single-center cohort study of adult patients who had lung transplantation. Tacrolimus was administered beginning with a low dose of 0.01 mg/kg/day immediately after transplantation. In addition, the designated clinical pharmacist conducted a daily intervention with trough concentrations to achieve the target of 10-15 ng/mL. Time in the therapeutic range (TTRin, %), time to the therapeutic range (TTRto, days), and coefficient of variation (CoV) of tacrolimus were evaluated for the 2-week post-transplant period. A total of 67 adult patients who had received first-time lung transplantation were included in the analysis. The median percentage of tacrolimus TTRin was 35.7% (21.4-42.9%) for the 2-week postoperative period. The median day of TTRto was 7 days (5-9 days), and the median tacrolimus trough concentration was 10.02 ng/mL (7.87-12.26 ng/mL) for the 2-week postoperative period. The median CoV of tacrolimus was 49.7% (40.8-61.6%). Acute kidney injury following tacrolimus infusion occurred in 23 (34.3%) patients, but there was no neurotoxicity or acute cellular rejection within 1 month of the postoperative period. In conclusion, continuous intravenous administration with the daily measure and dose titration of tacrolimus trough concentrations allowed the therapeutic range of tacrolimus to be reached within 1 week without significant adverse events, although the pharmacokinetic parameters were highly variable over time.

Eugenol relieves the pathological manifestations of Alzheimer's disease in 5×FAD mice.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid-ß (Aß) and excessive neuroinflammation, resulting in neuronal cell death and cognitive impairments. Eugenol, a phenylpropene, is the main component of Syzygium aromaticum L. (Myrtaceae) and has multiple therapeutic effects, including neuroprotective and anti-inflammatory effects, through multimodal mechanisms. PURPOSE: We aimed to investigate the effect of eugenol on AD pathologies using a 5× familiar AD (5×FAD) mouse model. METHODS: Eight-month-old 5×FAD and wild-type mice were administered with eugenol (10 or 30 mg/kg/day, p.o) for 2 months. Y-maze and Morris water maze tests were performed to assess the cognitive function of mice. After the behavioral test, molecular analysis was conducted to investigate the therapeutic mechanism of eugenol. RESULTS: Our findings indicate that eugenol treatment effectively mitigated cognitive impairments in 5×FAD mice. This beneficial effect was associated with a decrease in AD pathologies, including neuronal cell loss and Aß deposition. Specifically, eugenol inhibited necroptosis activation and increased microglial phagocytosis, which were the underlying mechanisms for the observed reductions in neuronal cell loss and Aß deposition, respectively. CONCLUSION: Overall, our data suggest that eugenol would be a potential therapeutic candidate for AD.

A comparison of methods for the measurement of adherence to antihypertensive multidrug therapy and the clinical consequences: a retrospective cohort study using the Korean nationwide claims database.

OBJECTIVES: In observational studies, the methods used to measure medication adherence may affect assessments of the clinical outcomes of drug therapy. This study estimated medication adherence to multidrug therapy in patients with hypertension using different measurement methods and compared their impacts on clinical outcomes. METHODS: This was a retrospective cohort study using the Korean National Health Insurance Service-National Sample Cohort database (2006-2015). Adults diagnosed with hypertension who initiated multidrug antihypertensive therapy in the index year 2007 were included. Adherence was defined as over 80% compliance. Adherence to multidrug antihypertensive therapy was measured in 3 ways using the proportion of days covered (PDC) with 2 approaches to the end-date of the study observations: PDC with at least one drug (PDCwith≥1), PDC with a duration weighted mean (PDCwm), and the daily polypharmacy possession ratio (DPPR). The primary clinical outcome was a composite of cardiovascular and cerebrovascular disease-specific hospitalizations or all-cause mortality. RESULTS: In total, 4,226 patients who initiated multidrug therapy for hypertension were identified. The mean adherence according to the predefined measurements varied from 72.7% to 79.8%. Non-adherence was associated with an increased risk of a primary outcome. The hazard ratios (95% confidence intervals, CIs) primary outcomes varied from 1.38 (95% CI, 1.19 to 1.59) to 1.44 (95% CI, 1.25 to 1.67). CONCLUSIONS: Non-adherence to multidrug antihypertensive therapy was significantly associated with an increased risk of a primary clinical outcome. Across the varying estimates based on different methods, medication adherence levels were similar. These findings may provide evidence to support decision-making when assessing medication adherence.

On-site applicable diagnostic fluorescent probe for fire blight bacteria.

Fire blight is a representative plant infection that contaminates edible plants and causes socio-economic problems in agricultural and livestock industries globally. It is caused by the pathogen Erwinia amylovora (E. amylovora) creates lethal plant necrosis and spreads rapidly across plant organs. We newly disclose the fluorogenic probe B-1 for real-time on-site detection of fire blight bacteria for the first time. B-1 exhibited no emission signals but manifested bright emission properties in the presence of fire blight bacteria. Based on these features, fluorescence imaging of the fire blight bacteria and its real-time detection from the infected host plant tissues were conducted. The detection limit against E. amylovora was 102 CFU/mL, which had excellent sensitivity. The fluorogenic probe-based on-site diagnostic technology was supplemented by introducing a new portable UV device. This work holds enormous potential to be a new advanced tool for detecting fire blight in agricultural and livestock industries.

Clinical outcomes and predictors of a gap in direct-acting oral anticoagulant therapy in the elderly: A time-varying analysis of a nationwide cohort study.

INTRODUCTION: As direct-acting oral anticoagulants (DOACs) have short half-lives of around 12 h, even a short gap in DOAC therapy may diminish anticoagulation effects, increasing risks of adverse clinical outcomes. We aimed to evaluate clinical consequences of a gap in DOAC therapy with atrial fibrillation (AF) and to identify its potential predictors. MATERIALS AND METHODS: In this retrospective cohort study, we included DOAC users aged over 65 years with AF from the 2018 Korean nationwide claims database. We defined a gap in DOAC therapy as no claim for a DOAC one or more days after the due date of a refill prescription. We used a time-varying-analysis method. The primary outcome was a composite of death and thrombotic events including ischemic stroke/transient ischemic attack or systemic embolism. Potential predictors of a gap included sociodemographic and clinical factors. RESULTS AND CONCLUSIONS: Among 11,042 DOAC users, 4857 (44.0 %) patients had at least one gap. Standard national health insurance, non-metropolitan locations of medical institutions, history of liver disease, chronic obstructive pulmonary disease, cancer, or dementia, and use of diuretics or non-oral agents were associated with increased risks of a gap. In contrast, history of hypertension, ischemic heart disease, or dyslipidemia were associated with a decreased risk of a gap. A short gap in DOAC therapy was significantly associated with a higher risk of the primary outcome compared to no gap (hazard ratio 4.04, 95 % confidence interval 2.95-5.52). The predictors could be utilized to identify at-risk patients to provide additional support to prevent a gap.

Porous zeolitic imidazolate frameworks assembled with highly-flattened tetrahedral copper(II) centres and 2-nitroimidazolates.

Cu(II)-based zeolitic imidazolates (Cu-ZIFs), Cu-ZIF-gis and -rho, formulated as Cu(nIm)2 (nIm = 2-nitroimidazolate) have highly-flattened tetrahedral coordination geometry. Cu-ZIF-gis has 2.4 Å cylindrical pores that can adsorb H2 gas, and Cu-ZIF-rho has 19.8 Å cages with a BET surface area of 1320 m2 g-1.

A Double-Blind, Randomized, Placebo-Controlled, Phase II Clinical Study To Evaluate the Efficacy and Safety of Camostat Mesylate (DWJ1248) in Adult Patients with Mild to Moderate COVID-19.

Although several antiviral agents have become available for coronavirus disease 2019 (COVID-19) treatment, oral drugs are still limited. Camostat mesylate, an orally bioavailable serine protease inhibitor, has been used to treat chronic pancreatitis in South Korea, and it has an in vitro inhibitory potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study was a double-blind, randomized, placebo-controlled, multicenter, phase 2 clinical trial in mild to moderate COVID-19 patients. We randomly assigned patients to receive either camostat mesylate (DWJ1248) or placebo orally for 14 days. The primary endpoint was time to clinical improvement of subject symptoms within 14 days, measured using a subjective 4-point Likert scale. Three hundred forty-two patients were randomized. The primary endpoint was nonsignificant, where the median times to clinical improvement were 7 and 8 days in the camostat mesylate group and the placebo group, respectively (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 0.84 to 1.43; P = 0.50). A post hoc analysis showed that the difference was greatest at day 7, without reaching significance. In the high-risk group, the proportions of patients with clinical improvement up to 7 days were 45.8% (50/109) in the camostat group and 38.4% (40/104) in the placebo group (odds ratio [OR] = 1.33; 95% CI, 0.77 to 2.31; P = 0.31); the ordinal scale score at day 7 improved in 20.0% (18/90) of the camostat group and 13.3% (12/90) of the placebo group (OR = 1.68; 95% CI, 0.75 to 3.78; P = 0.21). Adverse events were similar in the two groups. Camostat mesylate was safe in the treatment of COVID-19. Although this study did not show clinical benefit in patients with mild to moderate COVID-19, further clinical studies for high-risk patients are needed. (This trial was registered with ClinicalTrials.gov under registration no. NCT04521296).

Hesperidin Improves Memory Function by Enhancing Neurogenesis in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by memory and cognitive impairments. Neurogenesis, which is related to memory and cognitive function, is reduced in the brains of patients with AD. Therefore, enhancing neurogenesis is a potential therapeutic strategy for neurodegenerative diseases, including AD. Hesperidin (HSP), a bioflavonoid found primarily in citrus plants, has anti-inflammatory, antioxidant, and neuroprotective effects. The objective of this study was to determine the effects of HSP on neurogenesis in neural stem cells (NSCs) isolated from the brain of mouse embryos and five familial AD (5xFAD) mice. In NSCs, HSP significantly increased the proliferation of NSCs by activating adenosine monophosphate (AMP)-activated protein kinase (AMPK)/cAMP-response element-binding protein (CREB) signaling, but did not affect NSC differentiation into neurons and astrocytes. HSP administration restored neurogenesis in the hippocampus of 5xFAD mice via AMPK/brain-derived neurotrophic factor/tropomyosin receptor kinase B/CREB signaling, thereby decreasing amyloid-beta accumulation and ameliorating memory dysfunction. Collectively, these preclinical findings suggest that HSP is a promising candidate for the prevention and treatment of AD.

Thermodynamic Separation of Hydrogen Isotopes Using Hofmann-Type Metal-Organic Frameworks with High-Density Open Metal Sites.

Hydrogen isotope separation with nanoporous materials is a very challenging yet promising approach. To overcome the limitation of the conventional isotope separation strategy, quantum sieving-based separation using nanoporous materials has been investigated recently. In this study, to see the thermodynamic deuterium separation phenomena attributed to the chemical affinity quantum sieving effect, we examine Hofmann-type metal-organic frameworks (MOFs), Co(pyz)[M(CN)4] (pyz = pyrazine, M = Pd2+, Pt2+, and Ni2+), which have microporosity (4.0 × 3.9 Å2) and an extraordinarily high density of open metal sites (∼9 mmol/cm3). Owing to the preferential adsorption of D2 over H2 at strongly binding open metal sites, the Hofmann-type MOF, Co(pyz)[Pd(CN)4] exhibited a high selectivity (SD2/H2) of 21.7 as well as a large D2 uptake of 10 mmol/g at 25 K. This is the first study of Hofmann-type MOFs to report high selectivity and capacity, both of which are important parameters for the practical application of porous materials toward isotope separation.

Systematic multi-omics reveals the overactivation of T cell receptor signaling in immune system following bisphenol A exposure.

Bisphenol A (BPA) is pervasive in the environment, and exposure to BPA may increase the incidence of noncommunicable diseases like autoimmune diseases and cancer. Although BPA causes immunological problems at the cellular level, no system-level research has been conducted on this. Hence, in this study, we aimed to gain a better understanding of the biological response to BPA exposure and its association with immunological disorders. For that, we explored the transcriptome and the proteomic modifications at the systems and cellular levels following BPA exposure. Our integrated multi-omics data showed the alteration of the T cell receptor (TCR) signaling pathway at both levels. The proportion of enlarged T cells increased with upregulation of CD69, a surface marker of early T cell activation, even though the number of T cells reduced after BPA exposure. Additionally, on BPA exposure, the levels of pLCK and pSRC increased in T cells, while that of pLAT decreased. Following BPA exposure, we investigated cytokine profiles and discovered that chitinase 3 Like 1 and matrix metalloproteinase 9 were enriched in T cells. These results indicated that T cells were hyperactivated by CD69 stimulation, and phosphorylation of SRC accelerated on BPA exposure. Hence, alteration in the TCR signaling pathway during development and differentiation due to BPA exposure could lead to insufficient and hasty activation of TCR signaling in T cells, which could modify cytokine profiles, leading to increased environmental susceptibility to chronic inflammation or diseases, increasing the chance of autoimmune diseases and cancer. This study enhances our understanding of the effects of environmental perturbations on immunosuppression at molecular, cellular, and systematic levels following pubertal BPA exposure, and may help develop better predictive, preventative, and therapeutic techniques.

Design and evaluation of in vivo bioavailability in beagle dogs of bilayer tablet consisting of immediate release nanosuspension and sustained release layers of rebamipide.

The purpose of this study was to develop a once-daily, bilayer matrix tablet with immediate (IR) and sustained release (SR) layers of poorly water-soluble and absorption site dependent rebamipide (RBM) to substitute three times a day IR tablet. Owing to the pH-dependent poor water solubility of RBM in low pH condition, salt-caged nanosuspensions (NSPs) consisting of RBM and poloxamer 407 (POX 407) or poloxamer 188 (POX 188) were prepared using an acid-base neutralization method to increase the dissolution rate, which was subsequently applied to the immediate-release (IR) layer. Polyethylene oxide (PEO) with different molecular weights (PEO 100,000 and PEO 5,000,000) and hydroxypropyl methylcellulose 4000 (HPMC 4000) were then investigated as SR agents to incorporate into the SR layer with pure RBM via wet granulation method. The dissolution profile of the optimized bilayer tablet having 50% IR and 50% SR layer of 300 mg RBM showed that the IR layer could rapidly disintegrate in pH 1.2 buffer solution within 2 h, reaching 50% of drug release from the tablet, followed by an extended drug release from the SR layer in pH 6.8 buffer over 24 h. An in vivo pharmacokinetic study was carried out in beagle dogs to compare the optimal formulation (300 mg RBM bilayer tablet) and the commercial tablet (Mucosta® 100 mg) as a reference. Unexpectedly, despite enhanced dissolution rate in a controlled manner, a designed bilayer tablet had no dose- and dosage form dependent in vivo bioavailability in beagle dogs as compared with IR 100 mg RBM reference tablet. It was evident that solubility in low pH condition, gastric residence time and absorption site of RBM should be carefully considered for designing specific SR or gastroretentive dosage form to improve therapeutic outcomes.

Analysis of Infection Transmission Routes through Exhaled Breath and Cough Particle Dispersion in a General Hospital.

Identifying infection transmission routes in hospitals may prevent the spread of respiratory viruses and mass infections. Most previous related research focused on the air movement of passive tracers, which typically represent breathing. In this study, particle evaporation and dispersions with various particle sizes were applied to evaluate particle movement because of breathing and coughing using computational fluid dynamics (CFD) simulations. Pyeongtaek St. Mary Hospital, where a Middle East respiratory syndrome (MERS) index patient infected several patients on the same floor, was used for a case study. We compared the dispersion characteristics of various particle sizes and validated results by comparing infection rates in different ward. Results indicated that droplets spread across the corridor and dispersed to wards that were more than 17 m apart from the index patient by natural ventilation. Droplets from exhaled breath under steady-state simulation showed a wider range of dispersion than cough droplets under transient simulation, but cough droplet dispersion was more consistent with the actual infection rate in each ward. Cough droplets sized under 75 µm evaporated to 26% of the initial size and started to disperse into the corridor within one minute; in nine minutes, droplets dispersed throughout every ward. This study may increase awareness on the dispersion characteristics of infectious particles.