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Author(s): C H Song [1]; W S Choi [1]; H J Oh [2]; K S Kim [1] Introduction Several lines of evidence suggest that low dietary intake of calcium or [...]

Hepatic endoplasmic reticulum (ER) stress is implicated in the development of steatosis and its progression to nonalcoholic steatohepatitis (NASH). The ER in the liver can sustain metabolic function by activating defense mechanisms that delay or prevent the progression of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanisms by which the ER stress response protects against NAFLD remain largely unknown. Recently, activin E has been linked to metabolic diseases such as insulin resistance and NAFLD. However, the physiological conditions and regulatory mechanisms driving hepatic Inhbe expression (which encodes activin E) as well as the metabolic role of activin E in NAFLD require further investigation. Here we found that hepatic Inhbe expression increased under prolonged fasting and ER stress conditions, which was mediated by ATF4, as determined by promoter analysis in a mouse model. Consistently, a positive correlation between INHBE and ATF4 expression levels in relation to NAFLD status was confirmed using public human NAFLD datasets. To investigate the role of activin E in hepatic steatosis, we assessed the fluxes of the lipid metabolism in an Inhbe-knockout mouse model. These mice displayed a lean phenotype but developed severe hepatic steatosis under a high-fat diet. The deficiency of Inhbe resulted in increased lipolysis in adipose tissue, leading to increased fatty acid influx into the liver. Conversely, hepatic overexpression of Inhbe ameliorated hepatic steatosis by suppressing lipolysis in adipose tissue through ALK7-Smad signaling. In conclusion, activin E serves as a regulatory hepatokine that prevents fatty acid influx into the liver, thereby protecting against NAFLD., Competing Interests: Competing interests: I.-Y.K. and S.P. are shareholders in Myocare, Inc. The other authors have no conflicts of interest to report., (© 2025. The Author(s).)

Gastric carcinoma with lymphoid stroma (GCLS) is characterized by dense intra-and peritumoral lymphocytic infiltration and a high rate of Epstein Barr Virus (EBV) infection, suggesting being a promising candidate for immunotherapy. We investigated correlations between PD-L1 expression and clinicopathologic factors, including EBV positivity and microsatellite instability (MSI) status in GCLSs. The study included resected 214 GCLSs and 300 gastric adenocarcinomas (GACs) for control. Epstein Barr Virus encoding region in situ hybridization (EBER ISH), immunohistochemistry for PD-L1 and HER2, dual-colored in situ hybridization for HER2, and MSI analysis were performed. EBV positivity was found in 181 (85%) of 214 GCLSs. MSI analysis demonstrated that 0.6% of EBV + GCLSs and 54.5% of EBV-GCLSs were MSI-high compared to 7% of EBV-GACs. Approximately 3% and 3.9% of HER2 amplifications were found in EBV- and EBV + GCLSs compared to 13% of EBV-GACs. PD-L1 expression with ≥ 1, ≥ 5, and ≥ 10 combined positive scores (CPS) were observed in 81.8%, 70.2%, and 55.3% of EBV + GCLSs. PD-L1 expression with ≥ 10 CPS was observed in 21.2% of EBV-GCLSs, predominantly in MSI-H tumors (85.7%). EBV positivity and MSI are associated with PD-L1 positivity rates in patients with GCLS who may respond better to PD-1/PD-L1 inhibitors but not anti-HER2 inhibitors., Competing Interests: Declarations. Ethical approval and consent to participate: This study was conducted in accordance with the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Jeju National University Hospital (IRB File No. JEJUNUH 2022-01-016). The informed written consent was also obtained from the subjects involved in this study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

This study aimed to investigate the effects of crown seating speed, crown seating force, quantity of cement used, and type of implant cement on the amount of remnant cement in the subgingival region (RCS) after cementation. Cement-retained implant crowns were cemented to titanium abutments using the following methods: four types of implant cement (TBN: TEMP BOND NE, NR: NEXUS RMGI, ME: MAXCEM ELITE, and U200: RELYX U200), three quantities of cement (0.02 ml, 0.04 ml, and 0.06 ml), three crown seating speeds (5 mm/s, 10 mm/s, and 15 mm/s), and two crown seating forces (25 N, 50 N). The surface area and length of the RCS were measured using a 3D intraoral scanner. The total RCS weight was measured using an analytical balance. The RCS increased significantly as the seating speed increased, the seating force increased, and the quantity of cement increased (p < 0.05). The RCS values were the highest for TBN, followed by U200, NR, and ME (p < 0.05). The lower seating speed, smaller quantity of cement used, and smaller seating force applied in cement-retained implant restorations minimized the RCS in cement-retained prostheses. The type of cement is a factor that determines the aspects of the RCS., (© 2024. The Author(s).)

HER2 amplification-associated molecular alterations and clinicopathologic features in colorectal cancers (CRCs) have not been well established. In this study, we assessed the prevalence of HER2 amplification and microsatellite instability (MSI) status of 992 patients with primary CRC. In addition, molecular alterations of HER2 amplified and unamplified CRCs were examined and compared by next-generation sequencing. HER2 amplifications were found in 41 (4.1%) of 992 primary CRCs. HER2 amplification was identified in 1.0% of the right colonic tumors, 5.1% of the left colonic tumors, and 4.8% of the rectal tumors. Approximately 95% of HER2 amplification was observed in the left colon and rectum. Seven (87.5%) of eight metastatic tumors showed HER2 amplification. Most clinicopathologic features were unrelated to HER2 amplification except tumor size and MSI status. All 41 HER2 amplified CRCs were microsatellite stable. In a molecular analysis of frequently identified somatic mutations in CRCs, HER2 amplified CRCs showed a lower rate of KRAS mutations (24.4%) but a higher rate of TP53 mutations (83%) than unamplified CRCs. No BRAF and NRAS mutations were identified in HER2 amplified CRCs. Our study suggests that HER2 amplified CRCs are mutually exclusive of MSI and harbor less frequent KRAS/NRAS/BRAF mutations but frequent T53 mutations., (© 2024. The Author(s).)

Fairness has become a critical value online, and the latest studies consider it in many problems. In recommender systems, fairness is important since the visibility of items is controlled by systems. Previous fairness-aware recommender systems assume that sufficient relationship data between users and items are available. However, it is common that new users and items are frequently introduced, and they have no relationship data yet. In this paper, we study recommendation methods to enhance fairness in a cold-start state. Fairness is more significant when the preference of a user or the popularity of an item is unknown. We propose a meta-learning-based cold-start recommendation framework called FaRM to alleviate the unfairness of recommendations. The proposed framework consists of three steps. We first propose a fairness-aware meta-path generation method to eliminate bias in sensitive attributes. In addition, we construct fairness-aware user representations through the meta-path aggregation approach. Then, we propose a novel fairness objective function and introduce a joint learning method to minimize the trade-off between relevancy and fairness. In extensive experiments with various cold-start scenarios, it is shown that FaRM is significantly superior in fairness performance while preserving relevance accuracy over previous work., (© 2024. The Author(s).)

Iontronic devices, recognized for user-friendly soft electronics, establish an electrical double layer (EDL) at the interface between ion gels and electrodes, significantly influencing device performance. Despite extensive research on ion gels and diverse electrode materials, achieving a stable interfacial formation remains a persistent challenge. In this work, we report a solution to address this challenge by employing CO 2 irradiation as a bottom-up methodology to directly fabricate highly conductive, conformable laser-induced graphene (LIG) electrodes on a polyimide (PI)-based ion gel. The PI ion gel exhibits exceptional EDL formation at the electrode interface, primarily attributable to efficient ion migration. Particularly, ionic laser-induced graphene (i-LIG) electrodes, derived from the PI ion gel as a precursor, yield high-quality graphene with enhanced crystallinity and an expanded porous structure in the upward direction. This outcome is achieved through a pronounced thermal transfer effect and intercalation phenomenon between graphene layers, facilitated by the presence of ionic liquids (ILs) within the PI ion gel. Ultimately, in comparison to alternative soft electrode-based vertical capacitors, the utilization of i-LIGs and PI ion gels in the vertical capacitor demonstrates reduced interfacial resistance and increased EDL capacitance, emphasizing the extensive potential of iontronic devices. These results not only highlight these features but also introduce a new perspective for advancing next-generation iontronic devices., (© 2024. The Author(s).)

There have been growing trends using deep learning-based approaches for photo retouching which aims to enhance unattractive images and make them visually appealing. However, the existing methods only considered the RGB color space, which limited the available color information for editing. To address this issue, we propose a dual-color space network that extracts color representations from multiple color spaces to provide more robust color information. Our approach is based on the observation that converting an image to a different color space generates a new image that can be further processed by a neural network. Hence, we utilize two separate networks: a transitional network and a base network, each operating in a different color space. Specifically, the input RGB image is converted to another color space (e.g., YCbCr) using color space converter (CSC). The resulting image is then passed through the transitional network to extract color representations from the corresponding color space using color prediction module (CPM). The output of the transitional network is converted back to the RGB space and fed into the base network, which operates in RGB space. By utilizing global priors from each representation in different color spaces, we guide the retouching process to produce natural and realistic results. Experimental results demonstrate that our proposed method outperforms state-of-the-art methods on the MIT-Adobe FiveK dataset, and an in-depth analysis and ablation study highlight the advantages of our approach., (© 2023. The Author(s).)

Dense, longitudinal sampling represents the ideal for studying biological growth. However, longitudinal samples are not typically possible, due to limits of time, prohibitive cost, or health concerns of repeat radiologic imaging. In contrast, cross-sectional samples have few such drawbacks, but it is not known how well estimates of growth milestones can be obtained from cross-sectional samples. The Craniofacial Growth Consortium Study (CGCS) contains longitudinal growth data for approximately 2000 individuals. Single samples from the CGCS for individuals representing cross-sectional data were used to test the ability to predict growth parameters in linear trait measurements separately by sex. Testing across a range of cross-sectional sample sizes from 5 to the full sample, we found that means from repeated samples were able to approximate growth rates determined from the full longitudinal CGCS sample, with mean absolute differences below 1 mm at cross-sectional sample sizes greater than ~ 200 individuals. Our results show that growth parameters and milestones can be accurately estimated from cross-sectional data compared to population-level estimates from complete longitudinal data, underscoring the utility of such datasets in growth modeling. This method can be applied to other forms of growth (e.g., stature) and to cases in which repeated radiographs are not feasible (e.g., cone-beam CT)., (© 2023. The Author(s).)

Mucosal tissues serve as the first defense line and their commensal microbiota play a role in sustaining of host health. This study aimed to isolate and evaluate a putative probiotic strain on various mucosal regions. Lactobacillus sakei HEM 224 was isolated from traditional Korean kimchi and identified. In the safety assessment L. sakei HEM 224 showed negative results for hemolysis, biogenic amine production and transferable antibiotic resistance. The probiotic potential of strain HEM 224 in diverse mucosal areas was shown in two different models, viz. a murine model with colitis induced by dextran sulfate sodium (DSS) and an allergic airway inflammation model induced by ovalbumin (OVA). In the colitis model, oral administration of L. sakei HEM 224 improved colitis physiology with immunomodulation, enhancing barrier components and gut microbiota alteration. In the allergic airway inflammation model, the intranasal administration of the strain decreased type 2 inflammation and enhanced epithelial barrier integrity from the airways. These results demonstrate that L. sakei HEM 224 can ameliorate inflammatory conditions in both the gastrointestinal and respiratory tracts through the reinforcement of the epithelial barrier and immunomodulation., (© 2023. Springer Nature Limited.)

Severe fever with thrombocytopenia syndrome virus was first discovered in 2009 as the causative agent of severe fever with thrombocytopenia syndrome. Despite its potential threat to public health, no prophylactic vaccine is yet available. This study developed a heterologous prime-boost strategy comprising priming with recombinant replication-deficient human adenovirus type 5 (rAd5) expressing the surface glycoprotein, Gn, and boosting with Gn protein. This vaccination regimen induced balanced Th1/Th2 immune responses and resulted in potent humoral and T cell-mediated responses in mice. It elicited high neutralizing antibody titers in both mice and non-human primates. Transcriptome analysis revealed that rAd5 and Gn proteins induced adaptive and innate immune pathways, respectively. This study provides immunological and mechanistic insight into this heterologous regimen and paves the way for future strategies against emerging infectious diseases., (© 2023. The Author(s).)

We developed a novel prediction model for recurrence and survival in patients with localized renal cell carcinoma (RCC) after surgery and a novel statistical method of machine learning (ML) to improve accuracy in predicting outcomes using a large Asian nationwide dataset, updated KOrean Renal Cell Carcinoma (KORCC) database that covered data for a total of 10,068 patients who had received surgery for RCC. After data pre-processing, feature selection was performed with an elastic net. Nine variables for recurrence and 13 variables for survival were extracted from 206 variables. Synthetic minority oversampling technique (SMOTE) was used for the training data set to solve the imbalance problem. We applied the most of existing ML algorithms introduced so far to evaluate the performance. We also performed subgroup analysis according to the histologic type. Diagnostic performances of all prediction models achieved high accuracy (range, 0.77-0.94) and F1-score (range, 0.77-0.97) in all tested metrics. In an external validation set, high accuracy and F1-score were well maintained in both recurrence and survival. In subgroup analysis of both clear and non-clear cell type RCC group, we also found a good prediction performance., (© 2023. The Author(s).)

Volume loading of feedstock using trimodal iron (Fe) powders was investigated for the application of extrusion-based additive manufacturing (AM). Fe trimodal powder composed of nano, sub-nano, and micro particles was manufactured via the powder metallurgy process where small particles behave as rolling bearings among large particles, and thereby improving the flow characteristics of feedstock by minimizing friction among the particles. The flow behavior and microstructures of the monomodal feedstock were compared with those of the trimodal feedstock. We have confirmed that the critical powder loading of monomodal powder was measured to be 70 vol.% while trimodal powder showed up to 74 vol.%. Furthermore, trimodal feedstocks of 60, 65, 70, 75, and 80 vol.% Fe powder were prepared to determine the optimal powder content for sintering. As a result, the feedstock with powder content of 70 vol.% gave the highest sintered density of 92.32%, the highest Vickers hardness of 80.67 HV, with the smallest dimensional variation in shrinkage, proposing 70 vol.% of trimodal feedstock to be the suitable powder content for AM. Finally, its microstructural and mechanical comparison with 70 vol.% sintered part using monomodal Fe powder, showed that the sintered part using trimodal feedstock displayed higher hardness, uniform shrinkage as well as smaller grain size, confirming trimodal feedstock to be favorable for the application of extrusion-based AM., (© 2023. The Author(s).)

This study aimed to evaluate the alteration of PAP compliance after nasal surgery and to determine the optimal indications of nasal surgery in obstructive sleep apnea (OSA) subjects. Among OSA subjects using PAP devices, 29 subjects who underwent septoturbinoplasty due to nasal obstruction were included and their pre- and postoperative medical and PAP records were reviewed retrospectively. Postoperative autoPAP usage data was further assessed by grouping the compliance (the percentage of days with usage ≥ 4 h) data (group 1: the good compliance group; group 2: the poor compliance group). The data showed that 56% of subjects in group 1 complained of nasal obstruction as the only barrier to using a PAP device and about 89% reported experiencing the efficacy of PAP usage. Both the mean and peak average PAP pressures were significantly reduced in group 1 following nasal surgery. Group 2 had multiple subjective problems that interfered with wearing a PAP device and reported a lack of experiencing the efficacy of PAP usage. Preoperative nasal cavity volume values were smaller and absolute blood eosinophil counts were significantly lower in group 1. The current data demonstrate that nasal surgery might increase the compliance of PAP device wear in OSA subjects who complained of only nasal obstruction as a barrier to wearing PAP and who had small nasal cavity volumes combined with allergic inflammation., (© 2023. The Author(s).)

Although 2020 was the fourth warmest year on record in northern Asia, the cold condition in April 2020 caused severe damage to the agricultural and marine ecosystems in northeastern Asia. Previous studies have indicated that the dipole atmospheric circulation over Siberia and the East Sea (Japan Sea) produced this cold environment with strong northwesterly wind. However, the potential causes of the dipole circulation over northeastern Asia remain unclear. In this study, we found that the East Atlantic/Western Russia (EAWR) pattern and blocking combined to produce the atmospheric structure. The wave train originated from the vorticity forcing of northwestern/central Russia and propagated from Western Europe to the East Sea via the background westerly and northerly winds. In addition, the Siberian blocking days increased eleven times in April 2020 relative to the climatological average, and an easterly (westerly) anomaly was observed over Mongolia-northeastern China (northern Russia). The strong blocking and EAWR pattern led to the robust atmospheric dipole structure with a prevailing northerly flow in April 2020, thereby causing the extreme cold condition over northeastern Asia. Our results provide novel insights into the cause of extreme cold condition in April over northeastern Asia., (© 2023. The Author(s).)

Submacular hemorrhage (SMH) can lead to devastating visual loss in patients with age-related macular degeneration. We retrospectively evaluated the surgical outcomes of vitrectomy with subretinal injection of tissue plasminogen activator, bevacizumab, and air in 13 cases. Visual prognosis, anatomical results obtained with optical coherence tomography (OCT), and their correlations were investigated. We analyzed OCT parameters including SMH height, pigment epithelial detachment (PED) height and width, and status of ellipsoid zone (EZ) line. Complete displacement of SMH was achieved in 12 eyes. At 3 months post-surgery, best-corrected visual acuity (BCVA) and SMH height exhibited significant improvements (P < 0.01). In eyes with preoperative SMH height < 300 µm and a detectable EZ line, BCVA was significantly improved at as early as 1 month, whereas the remaining eyes exhibited visual improvements only at 3 months. Postoperative BCVA positively correlated with preoperative BCVA (r = 0.86, P < 0.005), and negatively correlated with SMH size (r = 0.69, P < 0.01) and PED height (r = 0.58, P < 0.05) and width (r = 0.67, P < 0.05). Multivariate analyses confirmed preoperative BCVA as the predominant factor associated with postoperative BCVA (β = 1.093, P < 0.05). In conclusion, significant improvements in BCVA and anatomical findings can be achieved with our reported surgical technique. Preoperative OCT findings may influence the duration required for visual improvements., (© 2022. The Author(s).)

The coronavirus (COVID-19) pandemic has led to substantial daily life changes for people worldwide. We investigated the association between daily life restrictions and depression during the COVID-19 pandemic based on the Korea Community Health Survey. Daily life restrictions were evaluated using a questionnaire to population into three restriction categories: no/slightly, moderately, and severely. Depression was assessed by the Korean version of the Patient Health Questionnaire-9 (PHQ-9). Chi-square tests and Fisher's exact tests were used to compare the demographic characteristics of individuals with and without depression. Logistic regression was used to assess the association between the severity of daily life restrictions and the prevalence of depression. The prevalence of depression was 2.4% in the total population: 5.7% in the severely restricted group and 2.7% in the moderately restricted group. After adjusting for age, sex, educational level, income, marital status, and employment status, the severely restricted group was more likely to have depression than was the no change/slightly restricted group (OR = 2.40, 95% CI 2.16-2.67, p < 0.001). Employers with severely restricted daily life exhibited a higher OR for depression compared to the no/slightly restricted group (OR = 3.24, 95% CI 2.37-4.45, p < 0.001). It is necessary to consider the mental health of vulnerable affected by the COVID-19 pandemic., (© 2022. The Author(s).)

There is a small body of evidence suggesting that unclean cooking fuel use may be associated with cognitive decline. However, to date, no study has investigated the association between unclean cooking fuel and mild cognitive impairment (MCI). Thus, we investigated the association between cooking fuel type or ventilation type and MCI among adults aged ≥ 65 years using nationally representative datasets from six low- and middle-income countries. Cross-sectional, community-based data from the World Health Organization (WHO) Study on global Ageing and adult health (SAGE) were analyzed. MCI was defined using the National Institute on Aging-Alzheimer's Association criteria. Unclean cooking fuel referred to kerosene/paraffin, coal/charcoal, wood, agriculture/crop, animal dung, and shrubs/grass. Multivariable logistic regression analysis was conducted to assess associations. Data on 13,623 individuals were analyzed [mean (SD) age 72.8 (11.0) years; 45.5% males]. Unclean cooking fuel (vs. clean cooking fuel) was associated with a significant 1.48 (95% CI = 1.08-2.03) times higher odds for MCI. Having no chimney or hood for cooking ventilation was also associated with significantly higher odds for MCI (OR = 1.88; 95% CI = 1.25-2.84). Unclean cooking fuel use and lack of chimney or hood for cooking ventilation were associated with higher odds for MCI. Findings support the implementation of the United Nations Sustainable Goal 7, which advocates affordable, reliable, sustainable, and modern energy for all, as this may also help reduce MCI and ultimately dementia., (© 2022. The Author(s).)

The gold standard for diagnosing bullous pemphigoid (BP) is the detection of linear deposition of IgG and/or C3 at the dermoepidermal junction using direct immunofluorescence (DIF). Because DIF has several disadvantages, primarily the requirement for frozen specimens, we assessed the diagnostic value of immunohistochemical (IHC) staining for BP detection. Eighty-eight patients with bullous lesions were included in this study. IHC staining for C3d, C4d, and IgG was performed on 88 samples, which included specimens from patients with DIF-confirmed BP (n = 43), clinicopathologically suspected BP with negative DIF results (n = 9), and other bullous diseases (n = 36). Diagnosis based on positive results for C3d, C4d, or IgG in IHC staining detected 86% of DIF-confirmed BP cases. The sensitivity of IHC staining for the detection of DIF-confirmed BP cases and clinicopathologically suspected BP cases was similar to that of DIF (80.8% vs. 84.3%), but the specificity was higher (83.3% vs. 75.0%). Five of the nine clinicopathologically suspected BP cases were diagnosed using IHC staining. Thus, IHC staining of routine biopsy material could be an alternative method for diagnosing BP. IHC staining has considerable diagnostic potential, especially in cases with a high suspicion of BP, but negative or suboptimal DIF results.Please check and confirm the author names and initials are correct. Author 2: Given name: [Chul Hwan] Family name: [Kim], Author 3: Given name: [Yoo Jin] Family name: [Lee].Checked it., (© 2022. The Author(s).)

Objectives: To assess the association between far vision impairment (objective and subjective) and perceived stress among older adults from six low- and middle-income countries (LMICs, i.e., China, Ghana, India, Mexico, Russia, and South Africa)., Methods: Data from the WHO Study on global AGEing and adult health were analyzed. Objective visual acuity was measured using the tumbling E LogMAR chart and was used as a four-category variable (no, mild, moderate, and severe visual impairment). Subjective visual impairment referred to difficulty in seeing and recognizing an object or a person across the road. Using two questions from the Perceived Stress Scale, a perceived stress variable was computed, and ranged from 0 (lowest stress) to 100 (highest stress). Multivariable linear regression with perceived stress as the outcome was conducted., Results: Data on 14,585 adults aged ≥65 years [mean (SD) age 72.6 (11.5) years; 55.0% females] were analyzed. Only severe objective visual impairment (versus no visual impairment) was significantly associated with higher levels of stress (b = 6.91; 95% CI = 0.94-12.89). In terms of subjective visual impairment, compared with no visual impairment, mild (b = 2.67; 95% CI = 0.56-4.78), moderate (b = 8.18; 95% CI = 5.84-10.52), and severe (b = 11.86; 95% CI = 9.11-14.61) visual impairment were associated with significantly higher levels of perceived stress., Conclusions: This large study showed that far vision impairment was associated with increased perceived stress levels among older adults in LMICs. Increased availability of eye care services may reduce stress among those with visual impairment in LMICs, while more research is needed to better characterize the directionality of the far vision impairment-perceived stress relationship., (© 2021. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Little is known about socioeconomic differences in epilepsy mortality. This study examined educational inequalities in epilepsy mortality in the general population in the Baltic countries and Finland in 2000-2015. Education-specific mortality estimates for individuals aged 30-74 in Estonia, Latvia and Lithuania were obtained from census-linked mortality datasets while data for Finland came from the register-based population and death data file of Statistics Finland. Trends and educational inequalities in epilepsy mortality were assessed using age-standardised mortality rates (ASMRs) per 100,000 person years and age-adjusted mortality rate ratios (RRs) calculated using Poisson regression. ASMRs were higher in men than women in all countries. ASMRs reduced in 2000-2015 among all men and women except for Finnish women. Among men, an inverse educational gradient in epilepsy mortality in 2000-2007 widened in 2008-2015 with ASMRs falling among high and mid educated men in all countries but increasing among low educated men in three countries. An inverse educational gradient in female mortality remained in all countries throughout 2000-2015. Although epilepsy mortality fell in the Baltic countries and Finland (men only) in 2000-2015, this masked a clear inverse educational gradient in mortality that became steeper across the period., (© 2022. The Author(s).)

The pandemic of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a public health emergency, and research on the development of various types of vaccines is rapidly progressing at an unprecedented development speed internationally. Some vaccines have already been approved for emergency use and are being supplied to people around the world, but there are still many ongoing efforts to create new vaccines. Virus-like particles (VLPs) enable the construction of promising platforms in the field of vaccine development. Here, we demonstrate that non-infectious SARS-CoV-2 VLPs can be successfully assembled by co-expressing three important viral proteins membrane (M), envelop (E) and nucleocapsid (N) in plants. Plant-derived VLPs were purified by sedimentation through a sucrose cushion. The shape and size of plant-derived VLPs are similar to native SARS-CoV-2 VLPs without spike. Although the assembled VLPs do not have S protein spikes, they could be developed as formulations that can improve the immunogenicity of vaccines including S antigens, and further could be used as platforms that can carry S antigens of concern for various mutations., (© 2022. The Author(s).)

Reduced brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid (GABA) neurotransmission co-occur in brain conditions (depression, schizophrenia and age-related disorders) and are associated with symptomatology. Rodent studies show they are causally linked, suggesting the presence of biological pathways mediating this link. Here we first show that reduced BDNF and GABA also co-occur with attenuated autophagy in human depression. Using mice, we then show that reducing Bdnf levels (Bdnf +/- ) leads to upregulated sequestosome-1/p62, a key autophagy-associated adaptor protein, whose levels are inversely correlated with autophagic activity. Reduced Bdnf levels also caused reduced surface presentation of α5 subunit-containing GABA A receptor (α5-GABA A R) in prefrontal cortex (PFC) pyramidal neurons. Reducing p62 gene dosage restored α5-GABA A R surface expression and rescued PFC-relevant behavioral deficits of Bdnf +/- mice, including cognitive inflexibility and reduced sensorimotor gating. Increasing p62 levels was sufficient to recreate the molecular and behavioral profiles of Bdnf +/- mice. Collectively, the data reveal a novel mechanism by which deficient BDNF leads to targeted reduced GABAergic signaling through autophagic dysregulation of p62, potentially underlying cognitive impairment across brain conditions., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Impedance-based protein detection sensors for point-of-care diagnostics require quantitative specificity, as well as rapid or real-time operation. Furthermore, microfabrication of these sensors can lead to the formation of factors suitable for in vivo operation. Herein, we present microfabricated needle-shaped microwell impedance sensors for rapid-sample-to-answer, label-free detection of cytokines, and other biomarkers. The microneedle form factor allows sensors to be utilized in transcutaneous or transvascular sensing applications. In vitro, experimental characterization confirmed sensor specificity and sensitivity to multiple proteins of interest. Mechanical characterization demonstrated sufficient microneedle robustness for transcutaneous insertion, as well as preserved sensor function postinsertion. We further utilized these sensors to carry out real-time in vivo quantification of human interleukin 8 (hIL8) concentration levels in the blood of transgenic mice that endogenously express hIL8. To assess sensor functionality, hIL8 concentration levels in serum samples from the same mice were quantified by ELISA. Excellent agreement between real-time in vivo sensor readings in blood and subsequent ELISA serum assays was observed over multiple transgenic mice expressing hIL8 concentrations from 62 pg/mL to 539 ng/mL., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2021.)

Gemigliptin is one of the latest dipeptidyl peptidase-4 inhibitors developed by LG Life Sciences. Since the early 2000s, several randomized controlled trials (RCTs) of gemigliptin have been conducted. However, no study has directly compared its antidiabetic effects through a systematic review and meta-analysis. Therefore, in this study, we performed a systematic review and meta-analysis on RCTs. In particular, a subsequent meta-analysis was performed using Bayesian inference, and an updated quality management system model was integrated throughout our study. The mean differences and 95% confidence intervals for glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), homeostatic model assessment beta cell function (HOMA-β), and low-density lipoprotein (LDL) were evaluated for the efficacy outcomes of gemigliptin as compared to those of placebo and other oral antidiabetic drugs (OADs). In conclusion, we found that gemigliptin was superior to placebo and comparable to other OADs in terms of the effect on HbA1c, FPG, HOMA-β, and LDL. Further, gemigliptin was more effective than other OADs in HbA1c and HOMA-β in Bayesian inference analysis and statistically significant to other OADs in HbA1c and HOMA-β in sensitivity analysis excluding metformin. However, to confirm the results, more studies need to be analysed and the minimum clinically important difference must be applied., (© 2021. The Author(s).)

Glycyrrhizin (GL) is a direct inhibitor of HMGB1 which acts as an alarmin when excreted into the extracellular space. High-dose radiation in radiotherapy induces collateral damage to the normal tissue, which can be mitigated by GL inhibiting HMGB1. The purpose of this study was to assess changes in HMGB1 and pro-inflammatory cytokines and to evaluate the protective effect of GL after low-dose radiation exposure. BALB/c mice were irradiated with 0.1 Gy (n = 10) and 1 Gy (n = 10) with GL being administered to half of the mice (n = 5, respectively) before irradiation. Blood and spleen samples were harvested and assessed for oxidative stress, HMGB1, pro-inflammatory cytokines, and cell viability. HMGB1 and pro-inflammatory cytokines increased and cell viability decreased after irradiation in a dose-dependent manner. Oxidative stress also increased after irradiation, but did not differ between 0.1 Gy and 1 Gy. With the pretreatment of GL, oxidative stress, HMGB1, and all of the pro-inflammatory cytokines decreased while cell viability was preserved. Our findings indicate that even low-dose radiation can induce sterile inflammation by increasing serum HMGB1 and pro-inflammatory cytokines and that GL can ameliorate the sterile inflammatory process by inhibiting HMGB1 to preserve cell viability., (© 2021. The Author(s).)

Post contrast-acute kidney injury (PC-AKI) is defined as the deterioration of renal function after administration of iodinated contrast media. HMGB1 is known to play an important role in the development of acute kidney injury. The purpose of this study was to investigate the association between HMGB1 and PC-AKI and the protective effect of glycyrrhizin, a direct inhibitor of HMGB1, in rats. Rats were divided into three groups: control, PC-AKI and PC-AKI with glycyrrhizin. Oxidative stress was measured with MDA levels and H 2 DCFDA fluorescence intensity. The mRNA expressions of pro-inflammatory cytokines (IL-1α, IL-1β, IL-6 and TNF-α) and kidney injury markers (KIM-1, NGAL and IL-18) were assessed using RT-PCR and ELISA in kidney tissue. In addition, the serum and intracellular protein levels of HMGB1were analyzed with the enzyme-linked immunosorbent assay (ELISA) and western blotting. Histologic changes were assessed with H&E staining using the transmission electron microscope (TEM). Moreover, serum creatinine (SCr), blood urea nitrogen (BUN) and lactate dehydrogenase (LDH) levels were assessed. Oxidative stress, pro-inflammatory cytokines, kidney injury markers and LDH were significantly higher in PC-AKI compared to the controls, but were lower in PC-AKI with glycyrrhizin. Intracellular and serum HMGB1 levels significantly increased after contrast media exposure, whereas they markedly decreased after glycyrrhizin pretreatment. SCr and BUN also decreased in PC-AKI with glycyrrhizin compared to PC-AKI. In PC-AKI, we could frequently observe tubular dilatation with H&E staining and cytoplasmic vacuoles on TEM, whereas these findings were attenuated in PC-AKI with glycyrrhizin. Our findings indicate that HMGB1 plays an important role in the development of PC-AKI and that glycyrrhizin has a protective effect against renal injury and dysfunction by inhibiting HMGB1 and reducing oxidative stress., (© 2021. The Author(s).)

The prevalence of cardiovascular diseases (CVDs) in Korea tends to be increasing. It has worsened during the COVID-19 pandemic. Increasing evidence shows heavy metals are associated with increased CVD risk. We aimed to determine the association between the serum heavy metal levels and 10-year risk of CVDs and to predict risks of CVDs based on marginal effects. Heavy metals were measured by a graphite furnace atomic absorption spectrometry and direct mercury analyzer. The results show a significant relationship between the increase in cadmium, lead, mercury, hs-CRP levels and the 10-year risk of CVD after adjustment for serum cotinine, age group, sex, body mass index, a family history of CVDs, diabetes or hyperlipidemia, high-risk drinking, physical activity, and diabetes. A doubling of serum cadmium, lead, mercury, and hs-CRP was associated with the increase in the 10-year risk of CVD by 0.14%, 0.10%, 0.11% and 0.22%, respectively. Therefore, a special concern should be given to the harmful impacts of heavy metals on the 10-year risk of CVD. It is important to develop a prevention strategy targeting the high-risk population to slow down this progression to risk factors related to heavy metals and reduce prevalence. Remarkedly, hs-CRP is the most validated and widely used inflammatory marker, and could be a potential clinical value in predicting and monitoring CVDs., (© 2021. The Author(s).)

Previous studies suggested that genetic, environmental factors and their interactions could affect body fat mass (BFM). However, studies describing these effects were performed at a single time point in a population. In this study, we investigated the interaction between genetic and environmental factors in affecting BFM and implicate the healthcare utilization of lifestyle modifications from a personalized and genomic perspective. We examined how nutritional intake or physical activity changes in the individuals affect BFM concerning the genetic composition. We conducted an observational study including 259 adult participants with single nucleotide polymorphism (SNP) genotyping and longitudinal lifestyle monitoring, including food consumption and physical activities, by following lifestyle modification guidance. The participants' lifelog data on exercise and diet were collected through a wearable device for 3 months. Moreover, we measured anthropometric and serologic markers to monitor their potential changes through lifestyle modification. We examined the influence of genetic composition on body fat reduction induced by lifestyle changes using genetic risk scores (GRSs) of three phenotypes: GRS-carbohydrate (GRS-C), GRS-fat (GRS-F), and GRS-exercise (GRS-E). Our results showed that lifestyle modifications affected BFM more significantly in the high GRS class compared to the low GRS class, indicating the role of genetic factors affecting the efficiency of the lifestyle modification-induced BFM changes. Interestingly, the influence of exercise modification in the low GRS class with active lifestyle change was lower than that in the high GRS class with inactive lifestyle change (P = 0.022), suggesting the implication of genetic factors for efficient body fat control.

The land snail Ellobium chinense (L. Pfeiffer, 1855) (Eupulmonata, Ellobiida, Ellobiidae), which inhabits the salt marshes along the coastal areas of northwestern Pacific, is an endangered species on the IUCN Red List. Over recent decades, the population size of E. chinense has consistently decreased due to environmental interference caused by natural disasters and human activities. Here, we provide the first assessment of the genetic diversity and population genetic structures of northwestern Pacific E. chinense. The results analyzed with COI and microsatellites revealed that E. chinense population exhibit metapopulation characteristics, retaining under the influence of the Kuroshio warm currents through expansion of the Late-Middle and Late Pleistocene. We also found four phylogenetic groups, regardless of geographical distributions, which were easily distinguishable by four unidirectional and stepwise adenine-to-guanine transitions in COI (sites 207-282-354-420: A-A-A-A, A-A-G-A, G-A-G-A, and G-G-G-G). Additionally, the four COI hotspots were robustly connected with a high degree of covariance between them. We discuss the role of these covariate guanines which link to form four consecutive G-quadruplexes, and their possible beneficial effects under positive selection pressure.

The classification of Alzheimer's disease (AD) using deep learning methods has shown promising results, but successful application in clinical settings requires a combination of high accuracy, short processing time, and generalizability to various populations. In this study, we developed a convolutional neural network (CNN)-based AD classification algorithm using magnetic resonance imaging (MRI) scans from AD patients and age/gender-matched cognitively normal controls from two populations that differ in ethnicity and education level. These populations come from the Seoul National University Bundang Hospital (SNUBH) and Alzheimer's Disease Neuroimaging Initiative (ADNI). For each population, we trained CNNs on five subsets using coronal slices of T1-weighted images that cover the medial temporal lobe. We evaluated the models on validation subsets from both the same population (within-dataset validation) and other population (between-dataset validation). Our models achieved average areas under the curves of 0.91-0.94 for within-dataset validation and 0.88-0.89 for between-dataset validation. The mean processing time per person was 23-24 s. The within-dataset and between-dataset performances were comparable between the ADNI-derived and SNUBH-derived models. These results demonstrate the generalizability of our models to different patients with different ethnicities and education levels, as well as their potential for deployment as fast and accurate diagnostic support tools for AD.

We report flexible and monolithically integrated multicolor light-emitting diode (LED) arrays using morphology-controlled growth of GaN microstructures on chemical-vapor-deposited (CVD) graphene films. As the morphology-controlled growth template of GaN microstructures, we used position-controlled ZnO nanostructure arrays with different spacings grown on graphene substrates. In particular, we investigated the effect of the growth parameters, including micropattern spacings and growth time and temperature, on the morphology of the GaN microstructures when they were coated on ZnO nanostructures on graphene substrates. By optimizing the growth parameters, both GaN microrods and micropyramids formed simultaneously on the graphene substrates. Subsequent depositions of InGaN/GaN quantum well and p-GaN layers and n- and p-type metallization yielded monolithic integration of microstructural LED arrays on the same substrate, which enabled multicolor emission depending on the shape of the microstructures. Furthermore, the CVD graphene substrates beneath the microstructure LEDs facilitated transfer of the LED arrays onto any foreign substrate. In this study, Cu foil was used for flexible LEDs. The flexible devices exhibited stable electroluminescence, even under severe bending conditions. Cyclic bending tests demonstrated the excellent mechanical stability and reliability of the devices.

Efficiently detecting and characterizing individual spins in solid-state hosts is an essential step to expand the fields of quantum sensing and quantum information processing. While selective detection and control of a few 13 C nuclear spins in diamond have been demonstrated using the electron spin of nitrogen-vacancy (NV) centers, a reliable, efficient, and automatic characterization method is desired. Here, we develop an automated algorithmic method for decomposing spectral data to identify and characterize multiple nuclear spins in diamond. We demonstrate efficient nuclear spin identification and accurate reproduction of hyperfine interaction components for both virtual and experimental nuclear spectroscopy data. We conduct a systematic analysis of this methodology and discuss the range of hyperfine interaction components of each nuclear spin that the method can efficiently detect. The result demonstrates a systematic approach that automatically detects nuclear spins with the aid of computational methods, facilitating the future scalability of devices.

E6 oncoprotein derived from high-risk human papillomavirus (HPV) drives the development of cervical cancer through p53 degradation. Because cervical cancer therapies to inactivate HPV or E6 protein are not available, alternative strategies are required. Here, we show that HPV-mediated nuclear export of human heterochromatin protein 1γ (HP1γ) reduces the stability of p53 through UBE2L3-mediated p53 polyubiquitination during cervical cancer progression. In general, HP1 plays a key role in heterochromatin formation and transcription in the nucleus. However, our immunostaining data showed that the majority of HP1γ is localized in the cytoplasm in HPV-mediated cervical cancer. We found that HPV E6 protein drives unusual nuclear export of HP1γ through the interaction between the NES sequence of HP1γ and exportin-1. The mutation of the NES sequence in HP1γ led to nuclear retention of HP1γ and reduced cervical cancer cell growth and tumor generation. We further discovered that HP1γ directly suppresses the expression of UBE2L3 which drives E6-mediated proteasomal degradation of p53 in cervical cancer. Downregulation of UBE2L3 by overexpression of HP1γ suppressed UBE2L3-dependent p53 degradation-promoting apoptosis of cervical cancer cells. Our findings propose a useful strategy to overcome p53 degradation in cervical cancer through the blockage of nuclear export of HP1γ.

Individual lifestyle risk factors have been associated with an increased risk of mortality. However, limited evidence is available on the combined association of lifestyle risk factors with mortality in non-Western populations. The analysis included 37,472 participants (aged ≥19 years) in the Korea National Health and Nutrition Examination Surveys (2007-2014) for whom the data were linked to death certificates/medical records through December 2016. A lifestyle risk score was created using five unhealthy behaviors: current smoking, high-risk alcohol drinking, unhealthy weight, physical inactivity, and insufficient/prolonged sleep. Cox proportional hazards models were used to estimate hazard ratio (HR) and 95% confidence interval (CI). During up to 9 years of follow-up, we documented 1,057 total deaths. Compared to individuals with zero lifestyle risk factor, those with 4-5 lifestyle risk factors had 2.01 times (HR = 2.01, 95% CI = 1.43-2.82) and 2.59 times (HR = 2.59, 95% CI = 1.24-5.40) higher risk of all-cause and cardiovascular mortality, respectively. However, higher lifestyle risk score was not significantly associated with cancer mortality (p-trend >0.05). In stratified analyses, the positive associations tended to be stronger in adults aged <65 years, unemployed, and those with lower levels of education. In conclusion, combined unhealthy lifestyle behaviors were associated with substantially increased risk of total and cardiovascular mortality in Korean adults.

Lateral pharyngeal wall appears to be a critical culprit of obstructive sleep apnea (OSA) subjects and relocation pharyngoplasty has been expected to be a promising surgical option to correct retropalatal circumferential narrowing in OSA patients. The purpose of our study is to evaluate the therapeutic outcomes of relocation pharyngoplasty and its clinical effectiveness in OSA patients with retropalatal circumferential narrowing. We performed relocation pharyngoplasty combined with nasal surgery in 133 OSA patients with the following characteristics: apnea-hypopnea index (AHI) over 10, retropalatal circumferential narrowing greater than grade I when awake, and redundant soft tissue around the lateral pharyngeal wall. The analysis of surgical success rate was performed with the data of 68 subjects who underwent pre and postoperative polysomnography. The objective success rate of relocation pharyngoplasty was 52.9%, and significant reduction of mean AHI with improvement of lowest SpO2 was seen in 69% of patients 3 months after the surgery. The median AHI was decreased from preoperative 37.3 to postoperative 21.4. Median lowest SpO2 changed from 78.4 to 84.1%. Total sleep time, daytime sleepiness, and visual analogue scale for snoring showed improvement as well. Postoperative complications including pain or bleeding were minimal in 133 subjects and a few patients complained of subtle taste loss. Our data demonstrate that relocation pharyngoplasty can be a favorable surgical option fighting against retropalatal circumferential narrowing.

Spreading rumors on the Internet has become increasingly pervasive due to the proliferation of online social media. This paper investigates how rumors are amplified by a group of users who share similar interests or views, dubbed as an echo chamber. To this end, we identify and analyze 'rumor' echo chambers, each of which is a group of users who have participated in propagating common rumors. By collecting and analyzing 125 recent rumors from six popular fact-checking sites, and their associated 289,202 tweets/retweets generated by 176,362 users, we find that the rumors that are spread by rumor echo chamber members tend to be more viral and quickly propagated than those that are not spread by echo chamber members. We propose the notion of an echo chamber network that represents relations among rumor echo chambers. By identifying the hub rumor echo chambers (in terms of connectivity to other rumor echo chambers) in the echo chamber network, we show that the top 10% of hub rumor echo chambers contribute to propagation of 24% rumors by eliciting more than 36% of retweets, implying that core rumor echo chambers significantly contribute to rumor spreads.

Chemical investigation of the marine-derived fungal isolate Penicillium sp. SF-5497 resulted in the isolation of two new preaustinoid-related meroterpenoids, named preaustinoid A6 (1) and preaustinoid A7 (2), along with three known metabolites (3-5). Their structures were elucidated by extensive spectroscopic analyses, such as 1D and 2D NMR and MS data. Among these, compounds 1 and 3 inhibited PTP1B activity in a dose-dependent manner, with IC 50 values of 17.6 and 58.4 µM, respectively. Furthermore, kinetic analyses indicated that compound 1 inhibited PTP1B in a noncompetitive manner, with the K i value of 17.0 µM.

During ligand-mediated receptor endocytosis, the small GTPase Rab5 functions in vesicle fusion and trafficking. Rab5 activation is known to require interactions with its guanine nucleotide-exchange factors (GEFs); however, the mechanism regulating Rab5 interactions with GEFs remains unclear. Here, we show that the SH3-adapter protein SPIN90 participates in the activation of Rab5 through the recruitment of both Rab5 and its GEF, Gapex5, to endosomal membranes during epidermal growth factor (EGF)-mediated endocytosis. SPIN90 strongly interacts with the inactive Rab5/GDI2 complex through its C-terminus. In response to EGF signaling, extracellular signal-regulated kinase (ERK)-mediated phosphorylation of SPIN90 at Thr-242 enables SPIN90 to bind Gapex5 through its N-terminal SH3 domain. Gapex5 is a determinant of Rab5 membrane targeting, while SPIN90 mediates the interaction between Gapex5 and Rab5 in a phosphorylation-dependent manner. Collectively, our findings suggest that SPIN90, as an adaptor protein, simultaneously binds inactive Rab5 and Gapex5, thereby altering their spatial proximity and facilitating Rab5 activation.

Dengue fever is one of the most important mosquito-borne viral infections in large parts of tropical and subtropical countries and is a significant public health concern and socioeconomic burden. There is an urgent need to develop antivirals that can effectively reduce dengue virus (DENV) replication and decrease viral load. Niclosamide, an antiparasitic drug approved for human use, has been recently identified as an effective antiviral agent against a number of pH-dependent viruses, including flaviviruses. Here, we reveal that neutralization of low-pH intracellular compartments by niclosamide affects multiple steps of the DENV infectious cycle. Specifically, niclosamide-induced endosomal neutralization not only prevents viral RNA replication but also affects the maturation of DENV particles, rendering them non-infectious. We found that niclosamide-induced endosomal neutralization prevented E glycoprotein conformational changes on the virion surface of flaviviruses, resulting in the release of non-infectious immature virus particles with uncleaved pr peptide from host cells. Collectively, our findings support the potential application of niclosamide as an antiviral agent against flavivirus infection and highlight a previously uncharacterized mechanism of action of the drug.

The role of angiopoietin-like 3 (ANGPTL3) in blood lipid levels, cardiovascular disease risk, and glucose metabolism has received wide attention. This study aimed to examine whether rs11207997 in ANGPTL3 is associated with a 10-year risk of diabetes mellitus (DM) and if the association is modified by the consumption of certain food groups or nutrients. A prospective cohort study was designed using the Ansan-Ansung data of the Korean Genome and Epidemiology Study (n = 7,358; age ≥40 years at baseline). Participants with the T allele of rs11207997, particularly TT homozygotes, had lower triglyceride (TG) and total cholesterol levels than those with CC. There was no association with fasting blood glucose or other biochemical parameters. ANGPTL3 mRNA was positively associated with circulating TG levels and blood pressure (all p < 0.05). Cox proportional hazard models showed that the rs11207997 T allele is associated with a lower risk of DM after adjusting for covariates (hazard ratio: 0.90, 95% confidence interval: 0.812-0.998, p = 0.046). Furthermore, the association between rs11207997 and the risk of DM was modified by dietary factors. These associations were no longer statistically significant when additionally adjusted for baseline TG, a potential mediator. Our data suggest that genetic variation of rs11207997 in the ANGPTL3 gene is associated with risk of DM, possibly through contributing to a lifelong set point of TG.

Advancements in the fabrication of upconversion nanoparticles (UCNPs) for synthetic control can enable a broad range of applications in biomedical systems. Herein, we experimentally verified the role of the hydrothermal reaction (HR) time in the synthesis of NaYF 4 :20%Yb 3+ /3%Er 3+ UCNPs on their morphological evolution and phase transformation at different temperatures. Characterizations of the as-prepared UCNPs were conducted using X-ray diffraction (XRD), electron microscopy and spectroscopy, and thermogravimetric and upconversion (UC) luminescence analysis. We demonstrated that determining the optimal HR time, also referred to here as the threshold time, can produce particles with good homogeneity, hexagonal phase, and UC luminescence efficiency. Subsequently, the polymer coated UCNPs maintained their original particle size distribution and luminescence properties, and showed improved dispersibility in a variety of solvents, cellular nontoxicity, in vitro bioimaging, and biocompatibility as compared to the bare UCNP. Besides this, polyacrylic acid conjugated UCNPs (UCNP@PAA) also revealed the strong anticancer effect by conjugating with doxorubicin (DOX) as compared to the free DOX. Based on these findings, we suggest that these particles will be useful in drug-delivery systems and as in vivo bioimaging agents synchronously.

The histone methyltransferase multiple myeloma SET domain protein (MMSET/WHSC1) is highly expressed in diverse tumor types, and its expression appears to be involved in cell proliferation. In this study, we report that MMSET interacts with and methylates Aurora kinase A (AURKA). We show that MMSET-mediated methylation of AURKA induces interaction with p53 as well as enhanced kinase activity of AURKA, which results in the proteasomal degradation of p53. MMSET-mediated p53 degradation increases cell proliferation and results in oncogenic activity. Furthermore, knockdown of MMSET potently inhibits tumorigenic cells and renders them sensitive to growth inhibition by the therapeutic drug, alisertib (AURKA inhibitor). Taken together, our results suggest that MMSET is a regulator of p53 stability via methylation of AURKA in proliferating cells and might be a potential therapeutic target in solid tumors.

Five new secondary metabolites, modiolides D-G (1-4) and 1-(2,5-dihydroxyphenyl)-3-methoxy-butan-1-one (8), one new natural product, 1-(2,5-dihydroxyphenyl)-3-hydroxybutan-1-one (7), along with three known compounds, modiolides A (5) and B (6), and 1-(2,5-dihydroxyphenyl)-2-buten-1-one (9) were isolated from a fermentation culture of the marine endophytic fungus Paraconiothyrium sp. VK-13. Their chemical structures were elucidated by the NMR and MS spectroscopic analysis as well as the modified Mosher's method. Compounds 7 and 9 inhibited the overproduction of proinflammatory mediators NO and PGE 2 in LPS-stimulated RAW264.7 cells, with IC 50 values ranging from 3.9 to 12.5 µM. The inhibitory effects of 7 and 9 on the release of NO and PGE 2 were correlated with their significant suppression of iNOS and COX-2 protein expression, respectively. Furthermore, both compounds 7 and 9 inhibited the mRNA expression of proinflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-12, with IC 50 values in a range of 2.4-12.5 µM.

Four new compounds, phomalichenones A-D (1-4), and seven known compounds (5-11) were isolated from the cultures of an endolichenic fungus Phoma sp. EL002650. Their structures were determined by the analysis of their spectroscopic data (NMR and MS). Compounds 1 and 6 inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. In addition, compound 1 diminished the protein expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and decreased the mRNA expression levels of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin(IL)-1β, and IL-6.

Two new meroterpenoid-type fungal metabolites, furanoaustinol (1) and 7-acetoxydehydroaustinol (2), were isolated from the ethyl acetate extract of a marine-derived fungal strain Penicillium sp. SF-5497, along with eight (3-10) known meroterpenoids. Their structures were elucidated mainly based on the analysis of their NMR (1D and 2D) and MS data. Particularly, the novel meroterpenoid, furanoaustinol (1), belonging to the austin group, was identified to possess an unprecedented hexacyclic ring system. Biological evaluation of these compounds revealed that furanoaustinol (1) weakly inhibited the activity of protein tyrosine phosphatase 1B in a dose-dependent manner with an IC 50 value of 77.2 μM. In addition, 7-acetoxydehydroaustinol (2) and four other known meroterpenoids (5, 7, 9, and 10) weakly suppressed the overproduction of nitric oxide in lipopolysaccharide-challenged BV2 microglial cells with IC 50 values of 61.0, 30.1, 58.3, 37.6, and 40.2 μM, respectively.

E-cadherin (CDH1) is a putative tumor suppressor gene implicated in breast carcinogenesis. Yet, whether risk factors or survival differ by E-cadherin tumor expression is unclear. We evaluated E-cadherin tumor immunohistochemistry expression using tissue microarrays of 5,933 female invasive breast cancers from 12 studies from the Breast Cancer Consortium. H-scores were calculated and case-case odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression. Survival analyses were performed using Cox regression models. All analyses were stratified by estrogen receptor (ER) status and histologic subtype. E-cadherin low cases (N = 1191, 20%) were more frequently of lobular histology, low grade, >2 cm, and HER2-negative. Loss of E-cadherin expression (score < 100) was associated with menopausal hormone use among ER-positive tumors (ever compared to never users, OR = 1.24, 95% CI = 0.97-1.59), which was stronger when we evaluated complete loss of E-cadherin (i.e. H-score = 0), OR = 1.57, 95% CI = 1.06-2.33. Breast cancer specific mortality was unrelated to E-cadherin expression in multivariable models. E-cadherin low expression is associated with lobular histology, tumor characteristics and menopausal hormone use, with no evidence of an association with breast cancer specific survival. These data support loss of E-cadherin expression as an important marker of tumor subtypes.

The East Asian Summer Monsoon driven by temperature and moisture gradients between the Asian continent and the Pacific Ocean, leads to approximately 50% of the annual rainfall in the region across 20-40°N. Due to its increasing scientific and social importance, there have been several previous studies on identification of moisture sources for summer monsoon rainfall over East Asia mainly using Lagrangian or Eulerian atmospheric water vapor models. The major source regions for EASM previously proposed include the North Indian Ocean, South China Sea and North western Pacific. Based on high-precision and high-frequency 6-year measurement records of hydrofluorocarbons (HFCs), here we report a direct evidence of rapid intrusion of warm and moist tropical air mass from the Southern Hemisphere (SH) reaching within a couple of days up to 33°N into East Asia. We further suggest that the combination of direct chemical tracer record and a back-trajectory model with physical meteorological variables helps pave the way to identify moisture sources for monsoon rainfall. A case study for Gosan station (33.25°N, 126.19°E) indicates that the meridional transport of precipitable water from the SH accompanying the southerly/southwesterly flow contributes most significantly to its summer rainfall.