Once upon a Time, There Was a Piece of Wood: Present Knowledge and Future Perspectives in Fungal Deterioration of Wooden Cultural Heritage in Terrestrial Ecosystems and Diagnostic Tools.

Wooden Cultural Heritage (WCH) represents a significant portion of the world's historical and artistic heritage, consisting of immovable and movable artefacts. Despite the expertise developed since ancient times to enhance its durability, wooden artefacts are inevitably prone to degradation. Fungi play a pivotal role in the deterioration of WCH in terrestrial ecosystems, accelerating its decay and leading to alterations in color and strength. Reviewing the literature of the last 25 years, we aimed to provide a comprehensive overview of fungal diversity affecting WCH, the biochemical processes involved in wood decay, and the diagnostic tools available for fungal identification and damage evaluation. Climatic conditions influence the occurrence of fungal species in threatened WCH, characterized by a prevalence of wood-rot fungi (e.g., Serpula lacrymans, Coniophora puteana) in architectural heritage in temperate and continental climates and Ascomycota in indoor and harsh environments. More efforts are needed to address the knowledge fragmentation concerning biodiversity, the biology of the fungi involved, and succession in the degradative process, which is frequently centered solely on the main actors. Multidisciplinary collaboration among engineers, restorers, and life sciences scientists is vital for tackling the challenges posed by climate change with increased awareness. Traditional microbiology and culture collections are fundamental in laying solid foundations for a more comprehensive interpretation of big data.

L-DOPA regulates neuroinflammation and Aß pathology through NEP and ADAM17 in a mouse model of AD.

Dopamine plays important roles in cognitive function and inflammation and therefore is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Drugs that increase or maintain dopamine levels in the brain could be a therapeutic strategy for AD. However, the effects of dopamine and its precursor levodopa (L-DOPA) on Aß/tau pathology in vivo and the underlying molecular mechanisms have not been studied in detail. Here, we investigated whether L-DOPA treatment alters neuroinflammation, Aß pathology, and tau phosphorylation in 5xFAD mice, a model of AD. We found that L-DOPA administration significantly reduced microgliosis and astrogliosis in 5xFAD mice. In addition, L-DOPA treatment significantly decreased Aß plaque number by upregulating NEP and ADAM17 levels in 5xFAD mice. However, L-DOPA-treated 5xFAD mice did not exhibit changes in tau hyperphosphorylation or tau kinase levels. These data suggest that L-DOPA alleviates neuroinflammatory responses and Aß pathology but not tau pathology in this mouse model of AD.

Defining mesenchymal stem/stromal cell-induced myeloid-derived suppressor cells using single-cell transcriptomics.

Mesenchymal stem/stromal cells (MSCs) modulate the immune response through interactions with innate immune cells. We previously demonstrated that MSCs alleviate ocular autoimmune inflammation by directing bone marrow cell differentiation from pro-inflammatory CD11bhiLy6ChiLy6Glo cells into immunosuppressive CD11bmidLy6CmidLy6Glo cells. Herein, we analyzed MSC-induced CD11bmidLy6Cmid cells using single-cell RNA sequencing and compared them with CD11bhiLy6Chi cells. Our investigation revealed seven distinct immune cell types including myeloid-derived suppressor cells (MDSCs) in the CD11bmidLy6Cmid cells, while CD11bhiLy6Chi cells included mostly monocytes/macrophages with a small cluster of neutrophils. These MSC-induced MDSCs highly expressed Retnlg, Cxcl3, Cxcl2, Mmp8, Cd14, and Csf1r as well as Arg1. Comparative analyses of CSF-1RhiCD11bmidLy6Cmid and CSF-1RloCD11bmidLy6Cmid cells demonstrated that the former had a homogeneous monocyte morphology and produced elevated levels of interleukin-10. Functionally, these CSF-1RhiCD11bmidLy6Cmid cells, compared with the CSF-1RloCD11bmidLy6Cmid cells, inhibited CD4+ T cell proliferation and promoted CD4+CD25+Foxp3+ Treg expansion in culture and in a mouse model of experimental autoimmune uveoretinitis. Resistin-like molecule (RELM)-γ encoded by Retnlg, one of the highly upregulated genes in MSC-induced MDSCs, had no direct effects on T cell proliferation, Treg expansion, or splenocyte activation. Together, our study revealed a distinct transcriptional profile of MSC-induced MDSCs and identified CSF-1R as a key cell-surface marker for detection and therapeutic enrichment of MDSCs.

Developing theragnostics for Alzheimer's disease: Insights from cancer treatment.

The prevalence of Alzheimer's disease (AD) and its associated economic and societal burdens are on the rise, but there are no curative treatments for AD. Interestingly, this neurodegenerative disease shares several biological and pathophysiological features with cancer, including cell-cycle dysregulation, angiogenesis, mitochondrial dysfunction, protein misfolding, and DNA damage. However, the genetic factors contributing to the overlap in biological processes between cancer and AD have not been actively studied. In this review, we discuss the shared biological features of cancer and AD, the molecular targets of anticancer drugs, and therapeutic approaches. First, we outline the common biological features of cancer and AD. Second, we describe several anticancer drugs, their molecular targets, and their effects on AD pathology. Finally, we discuss how protein-protein interactions (PPIs), receptor inhibition, immunotherapy, and gene therapy can be exploited for the cure and management of both cancer and AD. Collectively, this review provides insights for the development of AD theragnostics based on cancer drugs and molecular targets.

Predicting 2-year neurodevelopmental outcomes in preterm infants using multimodal structural brain magnetic resonance imaging with local connectivity.

The neurodevelopmental outcomes of preterm infants can be stratified based on the level of prematurity. We explored brain structural networks in extremely preterm (EP; < 28 weeks of gestation) and very-to-late (V-LP; ≥ 28 and < 37 weeks of gestation) preterm infants at term-equivalent age to predict 2-year neurodevelopmental outcomes. Using MRI and diffusion MRI on 62 EP and 131 V-LP infants, we built a multimodal feature set for volumetric and structural network analysis. We employed linear and nonlinear machine learning models to predict the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) scores, assessing predictive accuracy and feature importance. Our findings revealed that models incorporating local connectivity features demonstrated high predictive performance for BSID-III subsets in preterm infants. Specifically, for cognitive scores in preterm (variance explained, 17%) and V-LP infants (variance explained, 17%), and for motor scores in EP infants (variance explained, 15%), models with local connectivity features outperformed others. Additionally, a model using only local connectivity features effectively predicted language scores in preterm infants (variance explained, 15%). This study underscores the value of multimodal feature sets, particularly local connectivity, in predicting neurodevelopmental outcomes, highlighting the utility of machine learning in understanding microstructural changes and their implications for early intervention.

Glycerol-derived organic carbonates: environmentally friendly plasticizers for PLA.

Polylactic acid (PLA) stands as a promising material, sourced from renewables and exhibiting biodegradability-albeit under stringent industrial composting settings. A primary challenge impeding PLA's broad applications is its inherent brittleness, as it fractures with minimal elongation despite its commendable tensile strength. A well-established remedy involves blending PLA with plasticizers. In this study, a range of organic carbonates-namely, 4-ethoxycarbonyloximethyl-[1,3]dioxolan-2-one (1), 4-methoxycarbonyloximethyl-[1,3]dioxolan-2-one (2), glycerol carbonate (3), and glycerol 1-acetate 2,3-carbonate (4)-were synthesized on a preparative scale (∼100 g), using renewable glycerol and CO2-derived diethyl carbonate (DEC) or dimethyl carbonate (DMC). Significantly, 1-4 exhibited biodegradability under ambient conditions within a week, ascertained through soil exposure at 25 °C-outpacing the degradation of comparative cellulose. Further investigations revealed 1's efficacy as a PLA plasticizer. Compatibility with PLA, up to 30 phr (parts per hundred resin), was verified using an array of techniques, including DSC, DMA, SEM, and rotational rheometry. The resulting blends showcased enhanced ductility, evident from tensile property measurements. Notably, the novel plasticizer 1 displayed an advantage over conventional acetyltributylcitrate (ATBC) in terms of morphological stability. Slow crystallization, observed in PLA/ATBC blends over time at room temperature, was absent in PLA/1 blends, preserving amorphous domain dimensions and mitigating plasticizer migration-confirmed through DMA assessments of aged and unaged specimens. Nevertheless, biodegradation assessments of the blends revealed that the biodegradable organic carbonate plasticizers did not augment PLA's biodegradation. The PLA in the blends remained mostly unchanged under ambient soil conditions of 25 °C over a 6 month period. This work underscores the potential of organic carbonates as both eco-friendly plasticizers for PLA and as biodegradable compounds, contributing to the development of environmentally conscious polymer systems.

Serum Extracellular Vesicle Protein Profiling for Prediction of Corneal Transplant Rejection.

BACKGROUND: Corneal transplantation is the most common transplant procedure worldwide. Despite immune and angiogenic privilege of the cornea, 50% to 70% of corneal transplants fail in high-risk recipients, primarily because of immune rejection. Therefore, it is crucial to identify predictive biomarkers of rejection to improve transplant survival. METHODS: In search for predictive biomarkers, we performed proteomics analysis of serum extracellular vesicles (EVs) in a fully major histocompatibility complex-mismatched (C57BL/6-to-BALB/c) murine corneal transplantation model, wherein 50% of transplants undergo rejection by day 28 following transplantation. RESULTS: Our time course study revealed a decrease in the number of serum EVs on day 1, followed by a gradual increase by day 7. A comparative analysis of proteomics profiles of EVs from transplant recipients with rejection (rejectors) and without rejection (nonrejectors) found a distinct enrichment of histocompatibility 2, Q region locus 2, which is a part of major histocompatibility complex-class I of donor C57BL/6 mice, in day 7 EVs of rejectors, compared with nonrejectors, syngeneic controls, or naïve mice. In contrast, serum amyloid A2, a protein induced in response to injury, was increased in day 7 EVs of nonrejectors. CONCLUSIONS: Our findings offer noninvasive EV-based potential biomarkers for predicting corneal allograft rejection or tolerance.

Mesenchymal Stem/Stromal Cells Induce Myeloid-Derived Suppressor Cells in the Bone Marrow via the Activation of the c-Jun N-Terminal Kinase Signaling Pathway.

Our previous study demonstrated that mesenchymal stem/stromal cells (MSCs) induce the differentiation of myeloid-derived suppressor cells (MDSCs) in the bone marrow (BM) under inflammatory conditions. In this study, we aimed to investigate the signaling pathway involved. RNA-seq revealed that the mitogen-activated protein kinase (MAPK) pathway exhibited the highest number of upregulated genes in MSC-induced MDSCs. Western blot analysis confirmed the strong phosphorylation of c-Jun N-terminal kinase (JNK) in BM cells cocultured with MSCs under granulocyte-macrophage colony-stimulating factor stimulation, whereas p38 kinase activation remained unchanged in MSC-cocultured BM cells. JNK inhibition by SP600125 abolished the expression of Arg1 and Nos2, hallmark genes of MDSCs, as well as Hif1a, a molecule mediating monocyte functional reprogramming toward a suppressive phenotype, in MSC-cocultured BM cells. JNK inhibition also abrogated the effects of MSCs on the production of TGF-ß1, TGF-ß2 and IL-10 in BM cells. Furthermore, JNK inhibition increased Tnfa expression, while suppressing IL-10 production, in MSC-cocultured BM cells in response to lipopolysaccharides. Collectively, our results suggest that MSCs induce MDSC differentiation and promote immunoregulatory cytokine production in BM cells during inflammation, at least in part, through the activation of the JNK-MAPK signaling pathway.

Antioxidant and Anti-Inflammatory Activities of Lindera glauca Extracts.

INTRODUCTION: The current study investigated the antioxidant and anti-inflammatory effects of ethanol extracts from Lindera glauca twig (LGT) and leaf/stem (LGLS). METHODS: The antioxidant activities were measured by total content of polyphenol and flavonoid, DPPH radical scavenging, and ABTS+ radical scavenging activity. To evaluate the anti-inflammatory effect in the LPS-induced RAW 264.7 cells, protein and mRNA expression of major inflammatory factors were analyzed using Western blot analysis and RT-PCR. RESULTS: The total polyphenol content of LGT and LGLS was 88.45 ± 11.74 and 115.75 ± 7.87 GA mg/g, respectively. The total flavonoid content was 66 ± 2.89 and 74.33 ± 2.89 QE mg/g. Both LGT and LGLS showed high DPPH and ABTS+ radical scavenging activities. Neither LGT nor LGLS was cytotoxic to RAW 264.7 cells. The anti-inflammatory activities were measured by LPS-induced RAW 264.7 cells. LGT and LGLS showed inhibition of the LPS-induced production of nitric oxide (NO), inducible NO synthase, cyclooxygenase-2 at the protein and mRNA levels, as determined by Western blotting and RT-PCR, respectively. In addition, the release of tumor necrosis factor-α and interleukin-6 mRNA expression levels of these cytokines was reduced by LGT and LGLS. CONCLUSION: These results suggest that LGT and LGLS extracts have potential for use as a functional antioxidant and anti-inflammatory ingredient in cosmetic industry.

Association between placental oxygen transport and fetal brain cortical development: a study in monochorionic diamniotic twins.

Normal cortical growth and the resulting folding patterns are crucial for normal brain function. Although cortical development is largely influenced by genetic factors, environmental factors in fetal life can modify the gene expression associated with brain development. As the placenta plays a vital role in shaping the fetal environment, affecting fetal growth through the exchange of oxygen and nutrients, placental oxygen transport might be one of the environmental factors that also affect early human cortical growth. In this study, we aimed to assess the placental oxygen transport during maternal hyperoxia and its impact on fetal brain development using MRI in identical twins to control for genetic and maternal factors. We enrolled 9 pregnant subjects with monochorionic diamniotic twins (30.03 ± 2.39 gestational weeks [mean ± SD]). We observed that the fetuses with slower placental oxygen delivery had reduced volumetric and surface growth of the cerebral cortex. Moreover, when the difference between placenta oxygen delivery increased between the twin pairs, sulcal folding patterns were more divergent. Thus, there is a significant relationship between placental oxygen transport and fetal brain cortical growth and folding in monochorionic twins.

Aptamer Based SPREETA Sensor for the Detection of Porphyromonas gingivalis G-Protein.

We have developed an aptamer that specifically binds to Porphyromonas gingivalis to reduce the cellular damage caused by P. gingivalis infection and applied it as a biosensor. P. gingivalis is one of the major pathogens causing destructive periodontal disease among the periodontal microorganisms constituting complex biofilms. Porphyromonas gingivalis G-protein (PGP) known to play an important role in the transmission of germs was used as a target protein for the screening of aptamer. The aptamer that has binds to the G-protein of P. gingivalis, was screened and developed through the Systemic Evolution of Ligands by Exponential Energy (SELEX) method. Modified-Western blot analysis was performed with the aptamer which consisted of 38 single-stranded DNA to confirm the selectivity. ELONA (enzyme linked oligonucleotide assay) used to confirm that the aptamer was sensitive to PGP even at low concentration of 1 µg/ml. For the rapid detection of P. gingivalis, we constructed a surface plasmon resonance biosensor with SPREETA using the PGP aptamer. It was confirmed that PGP could be detected as low concentration as at 0.1 pM, which is the minimum concentration of aptamer sensor within 5 min. Based on these results, we have constructed a SPREETA biosensor based on aptamer that can bind to P. gingivalis G-protein. It can be used as an infection diagnosis system to rapidly diagnose and analyze oral diseases caused by P. gingivalis.

Brain age predicted using graph convolutional neural network explains neurodevelopmental trajectory in preterm neonates.

OBJECTIVES: Dramatic brain morphological changes occur throughout the third trimester of gestation. In this study, we investigated whether the predicted brain age (PBA) derived from graph convolutional network (GCN) that accounts for cortical morphometrics in third trimester is associated with postnatal abnormalities and neurodevelopmental outcome. METHODS: In total, 577 T1 MRI scans of preterm neonates from two different datasets were analyzed; the NEOCIVET pipeline generated cortical surfaces and morphological features, which were then fed to the GCN to predict brain age. The brain age index (BAI; PBA minus chronological age) was used to determine the relationships among preterm birth (i.e., birthweight and birth age), perinatal brain injuries, postnatal events/clinical conditions, BAI at postnatal scan, and neurodevelopmental scores at 30 months. RESULTS: Brain morphology and GCN-based age prediction of preterm neonates without brain lesions (mean absolute error [MAE]: 0.96 weeks) outperformed conventional machine learning methods using no topological information. Structural equation models (SEM) showed that BAI mediated the influence of preterm birth and postnatal clinical factors, but not perinatal brain injuries, on neurodevelopmental outcome at 30 months of age. CONCLUSIONS: Brain morphology may be clinically meaningful in measuring brain age, as it relates to postnatal factors, and predicting neurodevelopmental outcome. CLINICAL RELEVANCE STATEMENT: Understanding the neurodevelopmental trajectory of preterm neonates through the prediction of brain age using a graph convolutional neural network may allow for earlier detection of potential developmental abnormalities and improved interventions, consequently enhancing the prognosis and quality of life in this vulnerable population. KEY POINTS: •Brain age in preterm neonates predicted using a graph convolutional network with brain morphological changes mediates the pre-scan risk factors and post-scan neurodevelopmental outcomes. •Predicted brain age oriented from conventional deep learning approaches, which indicates the neurodevelopmental status in neonates, shows a lack of sensitivity to perinatal risk factors and predicting neurodevelopmental outcomes. •The new brain age index based on brain morphology and graph convolutional network enhances the accuracy and clinical interpretation of predicted brain age for neonates.

Maternal pre-pregnancy obesity affects the uncinate fasciculus white matter tract in preterm infants.

Background: A growing body of evidence suggests an association between a higher maternal pre-pregnancy body mass index (BMI) and adverse long-term neurodevelopmental outcomes for their offspring. Despite recent attention to the effects of maternal obesity on fetal and neonatal brain development, changes in the brain microstructure of preterm infants born to mothers with pre-pregnancy obesity are still not well understood. This study aimed to detect the changes in the brain microstructure of obese mothers in pre-pregnancy and their offspring born as preterm infants using diffusion tensor imaging (DTI). Methods: A total of 32 preterm infants (born to 16 mothers with normal BMI and 16 mothers with a high BMI) at <32 weeks of gestation without brain injury underwent brain magnetic resonance imaging at term-equivalent age (TEA). The BMI of all pregnant women was measured within approximately 12 weeks before pregnancy or the first 2 weeks of gestation. We analyzed the brain volume using a morphologically adaptive neonatal tissue segmentation toolbox and calculated the major white matter (WM) tracts using probabilistic maps of the Johns Hopkins University neonatal atlas. We investigated the differences in brain volume and WM microstructure between preterm infants of mothers with normal and high BMI. The DTI parameters were compared among groups using analysis of covariance adjusted for postmenstrual age at scan and multiple comparisons. Results: Preterm infants born to mothers with a high BMI showed significantly increased cortical gray matter volume (p = 0.001) and decreased WM volume (p = 0.003) after controlling for postmenstrual age and multiple comparisons. We found a significantly lower axial diffusivity in the uncinate fasciculus (UNC) in mothers with high BMI than that in mothers with normal BMI (1.690 ± 0.066 vs. 1.762 ± 0.101, respectively; p = 0.005). Conclusion: Our study is the first to demonstrate that maternal obesity impacts perinatal brain development patterns in preterm infants at TEA, even in the absence of apparent brain injury. These findings provide evidence for the detrimental effects of maternal obesity on brain developmental trajectories in offspring and suggest potential neurodevelopmental outcomes based on an altered UNC WM microstructure, which is known to be critical for language and social-emotional functions.

In planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation.

In humans, aggregation of polyglutamine repeat (polyQ) proteins causes disorders such as Huntington's disease. Although plants express hundreds of polyQ-containing proteins, no pathologies arising from polyQ aggregation have been reported. To investigate this phenomenon, we expressed an aggregation-prone fragment of human huntingtin (HTT) with an expanded polyQ stretch (Q69) in Arabidopsis thaliana plants. In contrast to animal models, we find that Arabidopsis sp. suppresses Q69 aggregation through chloroplast proteostasis. Inhibition of chloroplast proteostasis diminishes the capacity of plants to prevent cytosolic Q69 aggregation. Moreover, endogenous polyQ-containing proteins also aggregate on chloroplast dysfunction. We find that Q69 interacts with the chloroplast stromal processing peptidase (SPP). Synthetic Arabidopsis SPP prevents polyQ-expanded HTT aggregation in human cells. Likewise, ectopic SPP expression in Caenorhabditis elegans reduces neuronal Q67 aggregation and subsequent neurotoxicity. Our findings suggest that synthetic plant proteins, such as SPP, hold therapeutic potential for polyQ disorders and other age-related diseases involving protein aggregation.

Rhythm-based assessment and training for children with attention deficit hyperactivity disorder (ADHD): a feasibility study protocol.

Background: The timing-related deficits in individuals with attention deficit hyperactivity disorder (ADHD) contribute to the symptom-related difficulties and cognitive impairments. Current assessment and training measurement only target specific aspects of the timing ability, highlighting the need for more advanced tools to address timing deficits in ADHD. The aim of this study is to develop and validate a rhythm-based assessment and training (RAT) program, which intends to provide a comprehensive understanding of and enhancement to the time-related abilities of children with ADHD, thereby demonstrating its clinical efficacy. Methods: We will use randomized crossover trials in this study, with participants being randomly assigned to either start with the RAT and then proceed to cognitive training or start with cognitive training and then proceed to the RAT. Both groups will undergo pre- and post- evaluations. The evaluation will be administered immediately before and after the 4-week training period using diagnostic questionnaires, cognitive evaluation tools, and resting electroencephalography (EEG) measurements. Notably, EEG measurements will be conducted concurrently with the RAT evaluations. Discussion: This study develops and evaluates the feasibility and effectiveness of a RAT while using EEG measurements to elucidate the underlying therapeutic mechanism of auditory rhythm at varying levels of complexity. The study will investigate the potential of RAT as a supplementary or alternative approach for managing ADHD. The multifaceted data collected will yield valuable insights to customize training agendas based on individual developmental stages and prognoses.

Profiling tyrosine kinase inhibitors as AD therapeutics in a mouse model of AD.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by Aß deposition, tauopathy, neuroinflammation, and impaired cognition. The recent identification of associations between protein kinases and AD pathology has spurred interest in tyrosine kinase inhibitors (TKIs) as potential strategic therapeutic agents for AD. In the present study, we investigated whether the TKIs ibrutinib, PD180970, and cabozantinib, which have different on-targets, selectively regulate AD pathology in 3.5- to 4-month-old 5xFAD mice (a model of the early phase of AD). Ibrutinib (10 mg/kg, i.p.) effectively reduced amyloid-ß (Aß) plaque number, tau hyperphosphorylation and neuroinflammation in 5xFAD mice. Surprisingly, PD180970 (10 mg/kg, i.p.) did not alter Aß plaque number or neuroinflammatory responses and exacerbated tau hyperphosphorylation in 5xFAD mice. Cabozantinib (10 mg/kg, i.p.) had no effect on amyloidopathy but partially relieved tau hyperphosphorylation and astrogliosis. Taken together, our results suggest that not all TKIs have therapeutic effects on AD pathology in a mouse model of AD. Consequently, optimization of drug dosage, injection periods and administration routes should be considered when repurposing TKIs as novel AD therapeutics.

Risk Factors for Sudden Death Within 2 Days After Diagnosis of COVID-19 in Korea.

BACKGROUND: We aimed to analyze the risk factors for sudden death after diagnosis of coronavirus disease 2019 (COVID-19) in South Korea and to provide evidence for informing prevention and control interventions for patients at risk of sudden death. METHODS: We included 30,302 COVID-19 related deaths registered in the patient management information system (Central Disease Control Headquarters) between January 1, 2021, and December 15, 2022. We collected their epidemiological data recorded by the reporting city, province, or country. We performed multivariate logistic regression analysis to identify risk factors for sudden death after diagnosis of COVID-19. RESULTS: Among the 30,302 deaths, there were 7,258 (24.0%) and 23,044 (76.0%) sudden and non-sudden deaths, respectively. Sudden death means a person who died within 2 days of diagnosis and who did not receive inpatient treatment. Underlying condition, vaccination status, and place of death were significantly associated with the survival period in all age groups. Moreover, region, sex, and prescription were significantly associated with the survival period only in certain age groups. However, reinfection was not significantly associated with the survival period in any age group. CONCLUSION: To our knowledge, this is the first study on the risk factors for sudden death after a diagnosis of COVID-19, which included age, underlying condition, vaccination status, and place of death. Additionally, individuals aged < 60 years without an underlying condition were at high risk for sudden death. However, this group has relatively low interest in health, as can be seen from the high non-vaccination rate (16.1% of the general population vs. 61.6% of the corresponding group). Therefore, there is a possibility for the presence of an uncontrolled underlying disease in this population. In addition, many sudden deaths occurred due to delayed hospital visits to continue economic activities even after the onset of COVID-19 symptoms (7 days overall vs. 10 days average for the group). In conclusion, 'continued interest in health' is a key factor in avoiding sudden death in the economically active group (under 60 years of age).

Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/ß.

Introduction: Lomerizine is a calcium channel blocker that crosses the blood-brain barrier and is used clinically in the treatment of migraines. However, whether lomerizine is beneficial in modulating neuroinflammatory responses has not been tested yet. Methods: To assess the potential of lomerizine for repurposing as a treatment for neuroinflammation, we investigated the effects of lomerizine on LPS-induced proinflammatory responses in BV2 microglial cells, Alzheimer's disease (AD) excitatory neurons differentiated from induced pluripotent stem cells (iPSCs), and in LPS-treated wild type mice. Results: In BV2 microglial cells, lomerizine pretreatment significantly reduced LPS-evoked proinflammatory cytokine and NLRP3 mRNA levels. Similarly, lomerizine pretreatment significantly suppressed the increases in Iba-1, GFAP, proinflammatory cytokine and NLRP3 expression induced by LPS in wild-type mice. In addition, lomerizine posttreatment significantly decreased LPS-stimulated proinflammatory cytokine and SOD2 mRNA levels in BV2 microglial cells and/or wild-type mice. In LPS-treated wild-type mice and AD excitatory neurons differentiated from iPSCs, lomerizine pretreatment ameliorated tau hyperphosphorylation. Finally, lomerizine abolished the LPS-mediated activation of GSK3α/ß and upregulation of DYRK1A, which is responsible for tau hyperphosphorylation, in wild-type mice. Discussion: These data suggest that lomerizine attenuates LPS-mediated neuroinflammatory responses and tau hyperphosphorylation and is a potential drug for neuroinflammation- or tauopathy-associated diseases.

Risk factors for deaths associated with COVID-19 according to the cause of death classification in Republic of Korea.

OBJECTIVES: This study aimed to classify coronavirus disease 2019 (COVID-19)-related deaths according to whether COVID-19 was listed as the cause of death, and to investigate the differences in demographic characteristics and risk factors for COVID-19 death classifications. METHODS: A total of 5,625 deaths in South Korea among patients with confirmed COVID-19 from January 20, 2020 to December 31, 2021 were selected. Excluding false reports and unnatural deaths, 5,597 deaths were analyzed. Based on death report data, deaths were classified according to whether the cause of death was listed as COVID-19 (CD) or not (NCD). The epidemiological characteristics and causes of deaths were investigated using descriptive, univariate, and multivariate statistical analyses. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to analyze the risk factors. RESULTS: The case fatality ratio was 0.89% and increased with age. Additionally, 96.4% of the subjects had an underlying disease, and 53.4% died in winter. The proportion of NCDs was 9.3%, of whom 19.1% died at home and 39.0% were confirmed to have COVID-19 after death. Malignant neoplasms (102/416 vs. 637/4,442; OR, 1.71; 95% CI, 1.36-2.16; p<0.001) were significantly associated with NCD. CONCLUSION: This is the first study to analyze risk factors by cause of death using COVID-19 death report data in South Korea. These results are expected to be used as evidence for establishing a death monitoring system that can collect timely information in a new infectious disease pandemic.