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The simplified molecular-input line-entry system (SMILES) has been utilized in a variety of artificial intelligence analyses owing to its capability of representing chemical structures using line notation. However, its ease of representation is limited, which has led to the proposal of BigSMILES as an alternative method suitable for the representation of macromolecules. Nevertheless, research on BigSMILES remains limited due to its preprocessing requirements. Thus, this study proposes a conversion workflow of BigSMILES, focusing on its automated generation from SMILES representations of homopolymers. BigSMILES representations for 4,927,181 records are provided, thereby enabling its immediate use for various research and development applications. Our study presents detailed descriptions on a validation process to ensure the accuracy, interchangeability, and robustness of the conversion. Additionally, a systematic overview of utilized codes and functions that emphasizes their relevance in the context of BigSMILES generation are produced. This advancement is anticipated to significantly aid researchers and facilitate further studies in BigSMILES representation, including potential applications in deep learning and further extension to complex structures such as copolymers., (© 2024. The Author(s).)

Sterol regulatory element-binding protein (SREBP)-1c is involved in cellular lipid homeostasis and cholesterol biosynthesis and is highly increased in nonalcoholic steatohepatitis (NASH). However, the molecular mechanism by which SREBP-1c regulates hepatic stellate cells (HSCs) activation in NASH animal models and patients have not been fully elucidated. In this study, we examined the role of SREBP-1c in NASH and the regulation of LCN2 gene expression. Wild-type and SREBP-1c knockout (1cKO) mice were fed a high-fat/high-sucrose diet, treated with carbon tetrachloride (CCl 4 ), and subjected to lipocalin-2 (LCN2) overexpression. The role of LCN2 in NASH progression was assessed using mouse primary hepatocytes, Kupffer cells, and HSCs. LCN2 expression was examined in samples from normal patients and those with NASH. LCN2 gene expression and secretion increased in CCl 4 -induced liver fibrosis mice model, and SREBP-1c regulated LCN2 gene transcription. Moreover, treatment with holo-LCN2 stimulated intracellular iron accumulation and fibrosis-related gene expression in mouse primary HSCs, but these effects were not observed in 1cKO HSCs, indicating that SREBP-1c-induced LCN2 expression and secretion could stimulate HSCs activation through iron accumulation. Furthermore, LCN2 expression was strongly correlated with inflammation and fibrosis in patients with NASH. Our findings indicate that SREBP-1c regulates Lcn2 gene expression, contributing to diet-induced NASH. Reduced Lcn2 expression in 1cKO mice protects against NASH development. Therefore, the activation of Lcn2 by SREBP-1c establishes a new connection between iron and lipid metabolism, affecting inflammation and HSCs activation. These findings may lead to new therapeutic strategies for NASH., (© 2024. The Author(s).)

Tumor expression of prostate-specific membrane antigen (PSMA) is lost in 15-20% of men with castration-resistant prostate cancer (CRPC), yet the underlying mechanisms remain poorly defined. In androgen receptor (AR)-positive CRPC, we observed lower PSMA expression in liver lesions versus other sites, suggesting a role of the microenvironment in modulating PSMA. PSMA suppression was associated with promoter histone 3 lysine 27 methylation and higher levels of neutral amino acid transporters, correlating with 18 F-fluciclovine uptake on positron emission tomography imaging. While PSMA is regulated by AR, we identified a subset of AR-negative CRPC with high PSMA. HOXB13 and AR co-occupancy at the PSMA enhancer and knockout models point to HOXB13 as an upstream regulator of PSMA in AR-positive and AR-negative prostate cancer. These data demonstrate how PSMA expression is differentially regulated across metastatic lesions and in the context of the AR, which may inform selection for PSMA-targeted therapies and development of complementary biomarkers., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Axl is a tyrosine kinase receptor, a negative regulator for innate immune responses and inflammatory bowel disease (IBD). The gut microbiota regulates intestinal immune homeostasis, but the role of Axl in the pathogenesis of IBD through the regulation of gut microbiota composition remains unresolved. In this study, mice with DSS-induced colitis showed increased Axl expression, which was almost entirely suppressed by depleting the gut microbiota with antibiotics. Axl -/- mice without DSS administration exhibited increased bacterial loads, especially the Proteobacteria abundant in patients with IBD, significantly consistent with DSS-induced colitis mice. Axl -/- mice also had an inflammatory intestinal microenvironment with reduced antimicrobial peptides and overexpression of inflammatory cytokines. The onset of DSS-induced colitis occurred faster with an abnormal expansion of Proteobacteria in Axl -/- mice than in WT mice. These findings suggest that a lack of Axl signaling exacerbates colitis by inducing aberrant compositions of the gut microbiota in conjunction with an inflammatory gut microenvironment. In conclusion, the data demonstrated that Axl signaling could ameliorate the pathogenesis of colitis by preventing dysbiosis of gut microbiota. Therefore, Axl may act as a potential novel biomarker for IBD and can be a potential candidate for the prophylactic or therapeutic target of diverse microbiota dysbiosis-related diseases., (© 2023. The Author(s).)

Human sterile α motif and HD domain-containing protein 1 (SAMHD1) has deoxyribonucleoside triphosphohydrolase (dNTPase) activity that allows it to defend against human immunodeficiency virus type I (HIV-1) infections and regulate the cell cycle. Although SAMHD1 mutations have been identified in various cancer types, their role in cancer is unclear. Here, we aimed to investigate the oncogenic role of SAMHD1 in human clear cell renal cell carcinoma (ccRCC), particularly as a core molecule promoting cancer cell migration. We found that SAMHD1 participated in endocytosis and lamellipodia formation. Mechanistically, SAMHD1 contributed to the formation of the endosomal complex by binding to cortactin. Thereafter, SAMHD1-stimulated endosomal focal adhesion kinase (FAK) signaling activated Rac1, which promoted lamellipodia formation on the plasma membrane and enhanced the motility of ccRCC cells. Finally, we observed a strong correlation between SAMHD1 expression and the activation of FAK and cortactin in tumor tissues obtained from patients with ccRCC. In brief, these findings reveal that SAMHD1 is an oncogene that plays a pivotal role in ccRCC cell migration through the endosomal FAK-Rac1 signaling pathway., (© 2023. The Author(s).)

We aimed to determine the metabolomic profile of kidney cells under high glucose conditions and following sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment. Targeted metabolomics using the Absolute IDQ-p180 kit was applied to quantify metabolites in kidney cells stimulated with high glucose (25 and 50 mM) and treated with SGLT2 inhibitor, dapagliflozin (2 µM). Primary cultured human tubular epithelial cells and podocytes were used to identify the metabolomic profile in high glucose conditions following dapagliflozin treatment. The levels of asparagine, PC ae C34:1, and PC ae C36:2 were elevated in tubular epithelial cells stimulated with 50 mM glucose and were significantly decreased after 2 µM dapagliflozin treatment. The level of PC aa C32:0 was significantly decreased after 50 mM glucose treatment compared with the control, and its level was significantly increased after dapagliflozin treatment in podocytes. The metabolism of glutathione, asparagine and proline was significantly changed in tubular epithelial cells under high-glucose stimulation. And the pathway analysis showed that aminoacyl-tRNA biosynthesis, arginine and proline metabolism, glutathione metabolism, valine, leucine and isoleucine biosynthesis, phenylalanine, tyrosine, and tryptophan biosynthesis, beta-alanine metabolism, phenylalanine metabolism, arginine biosynthesis, alanine, aspartate and glutamate metabolism, glycine, serine and threonine metabolism were altered in tubular epithelial cells after dapagliflozin treatment following 50 mM glucose compared to those treated with 50 mM glucose., (© 2023. The Author(s).)

Despite recent advances, there remains a significant unmet need for the development of new targeted therapies for triple-negative breast cancer (TNBC). Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction of the heat shock response (HSR) and off-target effects leading to toxicity. SL-145 is a novel, rationally-designed C-terminal HSP90 inhibitor that induces apoptosis in TNBC cells via the suppression of oncogenic AKT, MEK/ERK, and JAK2/STAT3 signaling and does not trigger the HSR, in contrast to other inhibitors. In an orthotopic allograft model incorporating breast cancer stem cell-enriched TNBC tumors, SL-145 potently suppressed tumor growth, angiogenesis, and metastases concomitant with dysregulation of the JAK2/STAT3 signaling pathway. Our findings highlight the potential of SL-145 in suppressing metastatic TNBC independent of the HSR., (© 2022. The Author(s).)

Interspecific somatic hybridization has been performed in potato breeding experiments to increase plant resistance against biotic and abiotic stress conditions. We analyzed the mitochondrial and plastid genomes and 45S nuclear ribosomal DNA (45S rDNA) for the cultivated potato (S. tuberosum, St), wild potato (S. commersonii, Sc), and their somatic hybrid (StSc). Complex genome components and structure, such as the hybrid form of 45S rDNA in StSc, unique plastome in Sc, and recombinant mitogenome were identified. However, the mitogenome exhibited dynamic multipartite structures in both species as well as in the somatic hybrid. In St, the mitogenome is 756,058 bp and is composed of five subgenomes ranging from 297,014 to 49,171 bp. In Sc, it is 552,103 bp long and is composed of two sub-genomes of 338,427 and 213,676 bp length. StSc has 447,645 bp long mitogenome with two subgenomes of length 398,439 and 49,206 bp. The mitogenome structure exhibited dynamic recombination mediated by tandem repeats; however, it contained highly conserved genes in the three species. Among the 35 protein-coding genes of the StSc mitogenome, 21 were identical for all the three species, and 12 and 2 were unique in Sc and St, respectively. The recombinant mitogenome might be derived from homologous recombination between both species during somatic hybrid development., (© 2022. The Author(s).)

The autonomic nervous system (ANS) plays an important role in the initiation and maintenance of atrial fibrillation (AF). However, the meaning of higher heart rate variability (HRV) in predicting AF remains unclear. Among 2100 patients in the Holter registry, a total of 782 hypertensive patients were included in this study. Baseline HRV was measured by time domain and frequency domain methods using 24-h Holter monitoring. The primary outcome was the development of AF. During an average follow-up of 1.1 years, 44 patients developed AF. Higher HRV parameters including high-frequency (P < 0.001), the square root of the mean squared differences of successive NN intervals (P < 0.001), and the percentage of NN intervals that are more than 50 ms different from the previous interval (P < 0.001) were associated with the occurrence of AF in univariate analysis. Premature atrial contractions burden, lower baseline heart rate, age, hemodialysis, coronary artery disease, and chronic heart failure were also associated with AF. In Cox regression analysis, higher HRV (representing excessive autonomic fluctuation) was an independent risk factor for AF. Excessive autonomic fluctuation represented by higher HRV in patients with hypertension was associated with an increased risk of AF., (© 2022. The Author(s).)

Sarcopenia is an age-related disorder characterised by a progressive decrease in skeletal muscle mass. As the genetic biomarkers for sarcopenia are not yet well characterised, this study aimed to investigate the genetic variations related to sarcopenia in a relatively aged cohort, using genome-wide association study (GWAS) meta-analyses of lean body mass (LBM) in 6961 subjects. Two Korean cohorts were analysed, and subgroup GWAS was conducted for appendicular skeletal muscle mass (ASM) and skeletal muscle index. The effects of significant single nucleotide polymorphisms (SNPs) on gene expression were also investigated using multiple expression quantitative trait loci datasets, differentially expressed gene analysis, and gene ontology analyses. Novel genetic biomarkers were identified for LBM (rs1187118; rs3768582) and ASM (rs6772958). Their related genes, including RPS10, NUDT3, NCF2, SMG7, and ARPC5, were differently expressed in skeletal muscle tissue, while GPD1L was not. Furthermore, the 'mRNA destabilisation' biological process was enriched for sarcopenia. Our study identified RPS10, NUDT3, and GPD1L as significant genetic biomarkers for sarcopenia. These genetic loci were related to lipid and energy metabolism, suggesting that genes involved in metabolic dysregulation may lead to the pathogenesis of age-related sarcopenia., (© 2022. The Author(s).)

Interleukin-7 (IL-7) is a cytokine known for its importance in T cell development and survival. How IL-7 shapes CD8 T cell responses during an acute viral infection is less understood. We had previously shown that IL-7 signaling deficient mice have reduced accumulation of influenza-specific CD8 T cells following influenza infection. We sought to determine whether IL-7 affects early CD8 T cell expansion in the mediastinal lymph node and effector function in the lungs. Using IL-7Rα signaling deficient mice, we show that IL-7 is required for a normal sized mediastinal lymph node and the early clonal expansion of influenza-specific CD8 T cells therein. We show that IL-7 plays a cell-intrinsic role in the accumulation of NP 366-374 and PA 224-233 -specific CD8 T cells in the lymph node. We also found that IL-7 shapes terminal differentiation, degranulation and cytokine production to a greater extent in PA 224-233 -specific than NP 366-374 -specific CD8 T cells. We further demonstrate that IL-7 is induced in the lung tissue by viral infection and we characterize multiple cellular sources that contribute to IL-7 production. Our findings on IL-7 and its effects on lower respiratory diseases will be important for expanding the utility of therapeutics that are currently available., (© 2022. The Author(s).)

Cathepsin K is highly expressed in various types of cancers. However, the effect of cathepsin K inhibition in cancer cells is not well characterized. Here, cathepsin K inhibitor (odanacatib; ODN) and knockdown of cathepsin K (siRNA) enhanced oxaliplatin-induced apoptosis in multiple cancer cells through Bax upregulation. Bax knockdown significantly inhibited the combined ODN and oxaliplatin treatment-induced apoptotic cell death. Stabilization of p53 by ODN played a critical role in upregulating Bax expression at the transcriptional level. Casein kinase 2 (CK2)-dependent phosphorylation of OTUB1 at Ser16 played a critical role in ODN- and cathepsin K siRNA-mediated p53 stabilization. Interestingly, ODN-induced p53 and Bax upregulation were modulated by the production of mitochondrial reactive oxygen species (ROS). Mitochondrial ROS scavengers prevented OTUB1-mediated p53 stabilization and Bax upregulation by ODN. These in vitro results were confirmed by in mouse xenograft model, combined treatment with ODN and oxaliplatin significantly reduced tumor size and induced Bax upregulation. Furthermore, human renal clear carcinoma (RCC) tissues revealed a strong correlation between phosphorylation of OTUB1(Ser16) and p53/Bax expression. Our results demonstrate that cathepsin K inhibition enhances oxaliplatin-induced apoptosis by increasing OTUB1 phosphorylation via CK2 activation, thereby promoting p53 stabilization, and hence upregulating Bax., (© 2021. The Author(s).)

N-terminal HSP90 inhibitors in development have had issues arising from heat shock response (HSR) induction and off-target effects. We sought to investigate the capacity of NCT-58, a rationally-synthesized C-terminal HSP90 inhibitor, to kill trastuzumab-resistant HER2-positive breast cancer stem-like cells. NCT-58 does not induce the HSR due to its targeting of the C-terminal region and elicits anti-tumor activity via the simultaneous downregulation of HER family members as well as inhibition of Akt phosphorylation. NCT-58 kills the rapidly proliferating bulk tumor cells as well as the breast cancer stem-like population, coinciding with significant reductions in stem/progenitor markers and pluripotent transcription factors. NCT-58 treatment suppressed growth and angiogenesis in a trastuzumab-resistant xenograft model, concomitant with downregulation of ICD-HER2 and HSF-1/HSP70/HSP90. These findings warrant further investigation of NCT-58 to address trastuzumab resistance in heterogeneous HER2-positive cancers., (© 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.

Purpose: To evaluate the symptoms and signs of ocular surface disease (OSD) and tear-film matrix metalloproteinase-9 (MMP-9) overexpression using point-of-care testing (InflammaDry test) in patients with primary open-angle glaucoma (POAG)., Methods: This prospective, case-control study included 67 patients diagnosed with POAG and 47 healthy control subjects. The OSD assessment included Schirmer-I test, the Oxford corneal stain scale, tear breakup time (TBUT), and the five-item dry eye questionnaire (DEQ-5). Measurement of extracellular MMP-9 level was performed using the InflammaDry test. The OSD parameters and MMP-9 expression levels were compared between the POAG group and the control group. Additional subgroup analysis in POAG group was performed according to number of topical glaucoma medications (Bottle 1, 2, or 3 medications)., Results: There were significant differences between the control and POAG groups for all OSD parameters. MMP-9 overexpression was observed in 71.6% of POAG group, whereas only 31.9% of control group showed MMP-9 overexpression. The subgroup analysis revealed that DEQ-5, Oxford stain score, Schirmer-I, and MMP-9 overexpression demonstrated no significant difference among the three groups. Abnormal TBUT (≤5 s) was observed in 37.5%, 59.1%, and 76.2% for each subgroup according to number of bottles (1, 2, and 3), and strong MMP-9 overexpression were also detected in 25.0%, 40.9%, and 61.9%, respectively (P = 0.032, P = 0.043)., Conclusions: The use of preservative-containing medications may affect the ocular surface in patients with POAG. Graded measurement of tear-film MMP-9 could provide more information on OSD and might be a more useful marker for inflammation than then conventional results obtained by using an MMP-9 kit.

Sirt6 is involved in multiple biological processes, including aging, metabolism, and tumor suppression. Sirt1, another member of the sirtuin family, functionally overlaps with Sirt6, but its role in tumorigenesis is controversial. In this study, we focused on cell death in association with Sirt6/Sirt1 and reactive oxygen species (ROS) in head and neck squamous cell carcinomas (HNSCCs). Sirt6 induced cell death, as widely reported, but Sirt1 contributed to cell death only when it was suppressed by Sirt6 via regulation of MDM2. Sirt6 and Sirt6-mediated suppression of Sirt1 upregulated ROS, which further led to HNSCC cell death. These results provide insight into the molecular roles of Sirt6 and Sirt1 in tumorigenesis and could therefore contribute to the development of novel strategies to treat HNSCC.

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses, and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that is enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several Activator Protein-1 (AP-1) transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors., Competing Interests: Competing Interests Statement S.G. is the recipient of research funding from Eli Lilly and Co which has been used to support a part of this work. S.G. has served as a paid advisory board member for Eli Lilly and Co, G1 Therapeutics, Pfizer, and Novartis. S.G. also conducts laboratory research sponsored by G1 Therapeutics and clinical research sponsored by Eli Lilly and Co and by Novartis. J.J.Z. is founder and board director of Crimson Biotech and Geode Therapeutics. J.M. is a consultant for Oncoheroes Biosciences and Vivid Biosciences. M.B. receives sponsored research support from Novartis. M.B. is a consultant to H3 Biomedicine and serves on the SAB of Kronos Bio and GV20 Therapeutics. C.M. is a consultant for Pfizer, Novartis, Seattle Genetics and Eli Lilly and Co and receives institutional research funding from Pfizer and Puma. I.K. receives institutional research funding and grants from Genentech/Roche and Pfizer. I.K. is an advisory board participant, consultant, and has received honoraria from Daiichi/Sankyo, Macrogenics, and Genentech/Roche. I.K. is an advisory board participant and has received honoraria from Context Therapeutics, Taiho Oncology, and Seattle Genetics. I.K. is a data monitoring board member at Novartis. E.W. is a consultant at and has received honoraria from Carrick Therapeutics, DragonFly, Genentech/Roche, Genomic Health, GSK, Jounce, Eli Lilly and Co, Seattle Genetics, and Merck. E.W. is a scientific advisory board member and has received honoraria from Leap. M.E. has patents and receives royalties from prosigna/Nanostring. O. M.-F. receives institutional research funding from AbbVie, Genentech, Roche, and Pfizer, and has received honoraria from Roche. M.A.D. has been a member of the advisory boards for CTX CRC, Storm Therapeutics, Celgene and Cambridge Epigenetix. The Dawson lab receives research funding from CTX CRC. All other authors declare no conflicts of interest.

Very few population-based studies have examined the epidemiology of Wilson's disease (WD). We investigated the epidemiology of WD using the National Health Insurance Service (NHIS) database in South Korea. We analyzed not only the statistical variables of WD, but also those of WD-related diseases. WD patients were identified with the relevant International Classification of Diseases-10 code out of 50.5 million people. We used the NHIS database from 2009 to 2016 and analyzed the incidence rate, prevalence, and clinical symptoms of WD. A total of 1,333 patients were identified. The average annual incidence rate was 3.8 per million person-years. The prevalence was 38.7 per million people. The mean diagnostic age was 26.1 ± 17.2 with earlier diagnosis in men (P = 0.0003). Among the patients, 988 (74.1%) had hepatic symptoms, 510 (38.3%) had neurologic symptoms, and 601 (45.1%) had psychiatric symptoms. Before the diagnosis of WD, 350 (26.3%) had neurologic symptoms, and 427 (32%) had psychiatric symptoms. The annual mortality rate was 0.7%. Age, liver cirrhosis, and liver failure correlated with a fatal prognosis (P < 0.05). Many patients showed neurologic and psychiatric symptoms before they were diagnosed with WD. Prognosis correlated with age, liver cirrhosis, and liver failure.

Mitochondria behave as functional and structural hubs for innate defense against intracellular infection. While the mitochondrial membrane serves as a platform for the assembly of signaling complexes activated by intracellular infection, various danger molecules derived from impaired mitochondria activate innate signaling pathways. Using methionyl-tRNA formyl transferase (MTFMT)-deficient cells, which exhibit impaired mitochondrial activity, we examined the role of mitochondrial integrity in regulating innate defense against infection. Since MTFMT functions at the early steps of mitochondrial translation, its loss was expected to cause defects in mitochondrial activity. Under transient MTFMT gene silencing conditions, we observed shortened mitochondria along with reduced activity. MTFMT-silenced cells were more susceptible to intracellular infection, as examined by infection with RNA viruses and the intracellular bacterium Shigella flexneri. In support of this observation, MTFMT-silenced cells possessed lowered basal NF-κB activity, which remained low after S. flexneri infection. In addition, the mitochondrial accumulation of evolutionarily conserved signaling intermediate in Toll pathway (ECSIT), an adaptor protein for NF-κB activation, was significantly decreased in MTFMT-silenced cells, explaining the reduced NF-κB activity observed in these cells. Since impaired mitochondria likely release mitochondrial molecules, we evaluated the contribution of mitochondrial N-formyl peptides to the regulation of bacterial infection. Transient transfection of mitochondrial-derived N-formyl peptides favored S. flexneri infection, which was accompanied by enhanced bacterial survival, but did not affect host cell viability. However, transient transfection of mitochondrial-derived N-formyl peptides did not affect basal NF-κB activity. Altogether, these data suggest that the integrity of mitochondria is essential to their proper function in protecting against infection, as intact mitochondria not only block the release of danger molecules but also serve as signaling hubs for the downstream NF-κB pathway.

Several studies have reported an association between hypertension and upper aerodigestive tract cancer, but no large-scale, population-based studies have been conducted to confirm this.The aim of this study was to explore the association between hypertension and risk of upper aerodigestive tract cancer in Koreans. Participants who underwent a national health screening examination from January 1 to December 31, 2009 (n = 9,746,606) were enrolled. We assessed the development of oral, laryngeal, or esophageal cancer until 2016 using records from the Korean Health Insurance claims database during the study period. During the seven-year follow-up period, 6,062, 2,658, and 4,752 subjects were newly diagnosed with oral, laryngeal, and esophageal cancer, respectively. Participants with metabolic syndrome had the highest risk of developing oral cancer (hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.03-1.16), laryngeal cancer (HR 1.27, 95% CI 1.17-1.38), and esophageal cancer (HR 1.11, 95% CI 1.04-1.19). Hypertension was a remarkable risk factor for each cancer (HR 1.11, 95% CI 1.04-1.17 for oral cancer; HR 1.23, 95% CI 1.13-1.33 for laryngeal cancer; HR 1.25, 95% CI 1.18-1.33 for esophageal cancer) after adjusting for age and other variables including gender, smoking status, alcohol intake, exercise, body mass index, and diabetes. Patients with untreated hypertension were at highest risk of developing oral cancer (HR 1.15; 95% CI 1.05-1.26), laryngeal cancer (HR 1.25; 95% CI 1.09-1.44), and esophageal cancer (HR 1.47; 95% CI 1.33-1.63) after adjusting for confounders. Hypertension was associated with the risk of oral, laryngeal, and esophageal cancer, despite of the lack of detailed biochemical information including the cancer cell types (squamous cell carcinoma or adenocarcinoma), cancer stage, physical findings and other medical history. Further studies are warranted to determine the reasons for this association and to establish effective interventions in this vulnerable population.

Although carbohydrate antigen 19-9 (CA 19-9) may be elevated in benign diseases, elevated CA 19-9 may cause a fear of cancer and unnecessary follow-up studies. Research on how to approach systematically in this case is very limited. The purpose of this study was to analyze the clinical features and the causes of CA 19-9 elevation without evidence of malignant or pancreatobiliary diseases. We retrospectively reviewed the medical records of patients who had CA 19-9 elevation (≥80 U/mL) and were found to be unrelated to cancer after follow-up. After exclusion, 192 patients were included in this study. The median level of CA 19-9 was 136.5 U/mL. The causes of CA 19-9 elevation were determined in 147 (76.6%) patients, and that was unknown in 45 (23.4%). The estimated causative diseases were hepatic diseases in 63 patients, pulmonary diseases in 32, gynecologic diseases in 38, endocrine diseases in 13, and spleen disease in 1. Of 45 patients with unknown cause, 35 had normalization of CA 19-9 and 10 had persistently elevated CA 19-9. In conclusion, CA 19-9 elevation without malignancies or pancreatobiliary diseases should be systematically evaluated and followed up. We suggest an algorithm to investigate the causes and follow up these patients.

Tumor mitochondria have heightened protein folding quality control, but the regulators of this process and how they impact cancer traits are not completely understood. Here we show that the ATP-directed mitochondrial protease, LonP1 is upregulated by stress conditions, including hypoxia, in tumor, but not normal cells. In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity. Interference with this pathway induces accumulation of misfolded subunits of electron transport chain complex II and complex V, resulting in impaired oxidative bioenergetics and heightened ROS production. Functionally, this suppresses mitochondrial trafficking to the cortical cytoskeleton, shuts off tumor cell migration and invasion, and inhibits primary and metastatic tumor growth, in vivo. These data identify LonP1 as a key effector of mitochondrial reprogramming in cancer and potential therapeutic target.

Although rapamycin is a well-known conformational inhibitor of mTORC1, it is now widely used for treating arterial restenosis. Various rapamycin analogues (rapalogue) have been made for applying to drug-eluting stents. Here we show that two major rapalogues, everolimus and biolimus, exert a differential effect on the mTORC1-mediated signaling pathways in vascular smooth muscle cells. In balloon-injured carotid arteries, both rapalogues strongly inhibit neointimal hyperplasia. Signaling pathway analyses reveal that everolimus exert cytotoxicity by increasing cellular reactive oxygen species and consequently reduce energy metabolism. By contrast, biolimus confers a preferential induction of autophagy by more strongly activating major autophagy regulator, ULK1, in vascular smooth muscle cells than everolimus does. As a consequence, the implantation of biolimus-eluting stent reduces endothelial loss, which in turn reduces inflammation, in porcine coronary arteries. Thus, this study reveals that a chemical derivatization can cause a change among mTORC1-dependent signaling pathways in vascular smooth muscle cells, thereby enabling to elicit a differential efficacy on arterial restenosis.

Post-translational modifications (PTMs) are chemical alterations that occur in proteins that play critical roles in various cellular functions. Lysine acetylation is an important PTM in eukaryotes, and it is catalyzed by lysine acetyltransferases (KATs). KATs transfer acetyl-coenzyme A to the internal lysine residue of substrate proteins. Arrest defective 1 (ARD1) is a member of the KAT family. Since the identification of its KAT activity 15 years ago, many studies have revealed that diverse cellular proteins are acetylated by ARD1. ARD1-mediated lysine acetylation is a key switch that regulates the enzymatic activities and biological functions of proteins and influences cell biology from development to pathology. In this review, we summarize protein lysine acetylation mediated by ARD1 and describe the biological meanings of this modification.

Hepatocellular carcinoma (HCC), a representative example of a malignancy with a poor prognosis, is characterized by high mortality because it is typically in an advanced stage at diagnosis and leaves very little hepatic functional reserve. Despite advances in medical and surgical techniques, there is no omnipotent tool that can diagnose HCC early and then cure it medically or surgically. Several recent studies have shown that a variety of pathways are involved in the development, growth, and even metastasis of HCC. Among a variety of cytokines or molecules, some investigators have suggested that arrest-defective 1 (ARD1), an acetyltransferase, plays a key role in the development of malignancies. Although ARD1 is thought to be centrally involved in the cell cycle, cell migration, apoptosis, differentiation, and proliferation, the role of ARD1 and its potential mechanistic involvement in HCC remain unclear. Here, we review the present literature on ARD1. First, we provide an overview of the essential structure, functions, and molecular mechanisms or pathways of ARD1 in HCC. Next, we discuss potential clinical implications and perspectives. We hope that, by providing new insights into ARD1, this review will help to guide the next steps in the development of markers for the early detection and prognosis of HCC.

Baeyer-Villiger monooxygenases (BVMOs) can be used for the biosynthesis of lactones and esters from ketones. However, the BVMO-based biocatalysts are not so stable under process conditions. Thereby, this study focused on enhancing stability of the BVMO-based biocatalysts. The biotransformation of ricinoleic acid into (Z)-11-(heptanoyloxy)undec-9-enoic acid by the recombinant Escherichia coli expressing the BVMO from Pseudomonas putida and an alcohol dehydrogenase from Micrococcus luteus was used as a model system. After thorough investigation of the key factors to influence stability of the BVMO, Cys302 was identified as an engineering target. The substitution of Cys302 to Leu enabled the engineered enzyme (i.e., E6BVMO C302L ) to become more stable toward oxidative and thermal stresses. The catalytic activity of E6BVMO C302L -based E. coli biocatalysts was also greater than the E6BVMO-based biocatalysts. Another factor to influence biocatalytic performance of the BVMO-based whole-cell biocatalysts was availability of carbon and energy source during biotransformations. Glucose feeding into the reaction medium led to a marked increase of final product concentrations. Overall, the bioprocess engineering to improve metabolic stability of host cells in addition to the BVMO engineering allowed us to produce (Z)-11-(heptanoyloxy)undec-9-enoic acid to a concentration of 132 mM (41 g/L) from 150 mM ricinoleic acid within 8 h.

Because healthcare workers (HCWs) are at high risk for tuberculosis (TB) infection, it is essential to research the prevalence of latent TB infection (LTBI) and to implement health interventions including early treatment of LTBI and TB infection control measures. The purpose of the study was to determine the prevalence and risk factors for LTBI using interferon-γ release assay (IGRA) among HCWs in South Korea. The cross-sectional study was carried in the National Health Insurance Service Ilsan Hospital, which is a 740-bed general hospital, South Korea. HCWs who participated in this survey were required to complete a questionnaire and IGRA was performed. Of the 1,655 HCWs, 271 results were positive and the prevalence of LTBI was 16% (95% CI; 15-18%). In the multivariate analysis, age (OR; 2.201, 95% CI; 1.911-2.536, P < 0.001), male sex (OR; 1.523, 95% CI; 1.133-2.046, P = 0.005), contact active TB patients (OR; 1.461, 95% CI; 1.061-2.010, P = 0.02) and diabetes (OR; 2.837, 95% CI; 1.001-8.044, P = 0.05) were significant risk factors for LTBI. LTBI among HCWs in Korea, although prevalent, might not exceed the background level of the general population. Because contact with active TB patients has been identified as a risk factor for LTBI, more effective TB infection control measures are essential in healthcare facilities and congregate settings.

Mito-TEMPO is a well-known mitochondria-specific superoxide scavenger. However, the effect of Mito-TEMPO on porcine embryo development, to our knowledge, has not been studied yet. In the present study, porcine embryos were classified into two groups (G1 and G2) based on the cytoplasm lipid contents at the zygote stage. The development of blastocysts derived from G2 zygotes was reduced (G2:16.2 ± 7.9% vs G1: 26.5 ± 5.9%; 1.6-fold, p < 0.05) compared to those from G1 zygotes. In G2 embryos, the proportion of TUNEL-positive cells was also higher than that of G1 embryos. Superoxide in G2 embryos was significantly increased compared to that in G1 embryos. Mitochondrial membrane potential and ATP production were lower in G2 embryos than in G1 embryos. Phosphorylation of Drp1 at Ser 616 increased in G1 embryos during the cleavage stages compared to that in the zygote but was not significantly different in G2 embryos. Then, the effects of Mito-TEMPO were investigated in G2 embryos. Blastocyst formation rate (G2: 19.1 ± 5.1% vs G2 + Mito-TEMPO: 28.8 ± 4.0%; 1.5-fold, p < 0.05) and mitochondrial aggregation were recovered after superoxide reduction by Mito-TEMPO treatment. Thus, we showed that Mito-TEMPO improves blastocyst development by superoxide reduction in porcine embryos in vitro.

Liver fibrosis can be reversed by removing its causative injuries; however, the molecular mechanisms mediating the resolution of liver fibrogenesis are poorly understood. We investigate the role of a scaffold protein, A-Kinase Anchoring Protein 12 (AKAP12), during liver fibrosis onset, and resolution. Biliary fibrogenesis and fibrosis resolution was induced in wild-type (WT) or AKAP12-deficient C57BL/6 mice through different feeding regimens with 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing chow. AKAP12 expression in portal fibroblasts (PFs) and liver sinusoidal endothelial cells (LSECs) gradually decreased as fibrosis progressed but was restored after cessation of the fibrotic challenge. Histological analysis of human liver specimens with varying degrees of fibrosis of different etiologies revealed that AKAP12 expression diminishes in hepatic fibrosis from its early stages onward. AKAP12 KO mice displayed reduced fibrosis resolution in a DDC-induced biliary fibrosis model, which was accompanied by impaired normalization of myofibroblasts and capillarized sinusoids. RNA sequencing of the liver transcriptome revealed that genes related to ECM accumulation and vascular remodeling were mostly elevated in AKAP12 KO samples. Gene ontology (GO) and bioinformatic pathway analyses identified that the differentially expressed genes were significantly enriched in GO categories and pathways, such as the adenosine 3',5'-cyclic monophosphate (cAMP) pathway. Knockdown of the AKAP12 gene in cultured primary PFs revealed that AKAP12 inhibited PF activation in association with the adenosine 3',5'-cyclic monophosphate (cAMP) pathway. Moreover, AKAP12 knockdown in LSECs led to enhanced angiogenesis, endothelin-1 expression and alterations in laminin composition. Collectively, this study demonstrates that AKAP12-mediated regulation of PFs and LSECs has a central role in resolving hepatic fibrosis.

Embryonic stem cells (ESCs) are metabolically distinct from their differentiated counterparts. ESC mitochondria are less complex and fewer in number than their differentiated progeny. However, few studies have examined the proteins responsible for differences in mitochondrial structure and function between ESCs and somatic cells. Therefore, in this study, we aimed to investigate the differences between mitochondrial proteins in these two cell types. We demonstrate that HSP60 is more abundant in mouse ESC mitochondria than in mouse embryonic fibroblasts. Depletion of HSP60 inhibited mouse ESC proliferation and self-renewal, characterized by decreased OCT4 expression. HSP60 depletion also enhanced apoptosis during mouse ESC differentiation into embryoid bodies. Our results suggest that HSP60 expression has an essential role in ESC self-renewal and survival of differentiated cells from ESCs.

The topotactic phase transition in SrCoO x (x = 2.5-3.0) makes it possible to reversibly transit between the two distinct phases, i.e. the brownmillerite SrCoO 2.5 that is a room-temperature antiferromagnetic insulator (AFM-I) and the perovskite SrCoO 3 that is a ferromagnetic metal (FM-M), owing to their multiple valence states. For the intermediate x values, the two distinct phases are expected to strongly compete with each other. With oxidation of SrCoO 2.5 , however, it has been conjectured that the magnetic transition is decoupled to the electronic phase transition, i.e., the AFM-to-FM transition occurs before the insulator-to-metal transition (IMT), which is still controversial. Here, we bridge the gap between the two-phase transitions by density-functional theory calculations combined with optical spectroscopy. We confirm that the IMT actually occurs concomitantly with the FM transition near the oxygen content x = 2.75. Strong charge-spin coupling drives the concurrent IMT and AFM-to-FM transition, which fosters the near room-T magnetic transition characteristic. Ultimately, our study demonstrates that SrCoO x is an intriguingly rare candidate for inducing coupled magnetic and electronic transition via fast and reversible redox reactions.

We report on infrared spectroscopy experiments on the electronic response in (Sr 1-x La x ) 2 IrO 4 (x = 0, 0.021, and 0.067). Our data show that electron doping induced by La substitution leads to an insulator-to-metal transition. The evolution of the electronic structure across the transition reveals the robustness of the strong electronic correlations against the electron doping. The conductivity data of the metallic compound show the signature of the pseudogap that bears close similarity to the analogous studies of the pseudogap in the underdoped cuprates. While the low energy conductivity of the metallic compound is barely frequency dependent, the formation of the pseudogap is revealed by the gradual suppression of the featureless conductivity below a threshold frequency of about 17 meV. The threshold structure develops below about 100 K which is in the vicinity of the onset of the short-range antiferromagnetic order. Our results demonstrate that the electronic correlations play a crucial role in the anomalous charge dynamics in the (Sr 1-x La x ) 2 IrO 4 system.

Macrophages exhibit phenotypic plasticity, as they have the ability to switch their functional phenotypes during inflammation and recovery. Simultaneously, the mechanical environment actively changes. However, how these dynamic alterations affect the macrophage phenotype is unknown. Here, we observed that the extracellular matrix (ECM) constructed by AKAP12+ colon mesenchymal cells (CMCs) generated M2 macrophages by regulating their shape during recovery. Notably, rounded macrophages were present in the linear and loose ECM of inflamed colons and polarized to the M1 phenotype. In contrast, ramified macrophages emerged in the contracted ECM of recovering colons and mainly expressed M2 macrophage markers. These contracted structures were not observed in the inflamed colons of AKAP12 knockout (KO) mice. Consequently, the proportion of M2 macrophages in inflamed colons was lower in AKAP12 KO mice than in WT mice. In addition, clinical symptoms and histological damage were more severe in AKAP12 KO mice than in WT mice. In experimentally remodeled collagen gels, WT CMCs drove the formation of a more compacted structure than AKAP12 KO CMCs, which promoted the polarization of macrophages toward an M2 phenotype. These results demonstrated that tissue contraction during recovery provides macrophages with the physical cues that drive M2 polarization.

We report the preparation of Cu 2 S, In 2 S 3 , CuInS 2 and Cu(In,Ga)S 2 semiconducting films via the spin coating and annealing of soluble tertiary-alkyl thiolate complexes. The thiolate compounds are readily prepared via the reaction of metal bases and tertiary-alkyl thiols. The thiolate complexes are soluble in common organic solvents and can be solution processed by spin coating to yield thin films. Upon thermal annealing in the range of 200-400 °C, the tertiary-alkyl thiolates decompose cleanly to yield volatile dialkyl sulfides and metal sulfide films which are free of organic residue. Analysis of the reaction byproducts strongly suggests that the decomposition proceeds via an SN 1 mechanism. The composition of the films can be controlled by adjusting the amount of each metal thiolate used in the precursor solution yielding bandgaps in the range of 1.2 to 3.3 eV. The films form functioning p-n junctions when deposited in contact with CdS films prepared by the same method. Functioning solar cells are observed when such p-n junctions are prepared on transparent conducting substrates and finished by depositing electrodes with appropriate work functions. This method enables the fabrication of metal chalcogenide films on a large scale via a simple and chemically clear process.

Epidermal electronic systems feature physical properties that approximate those of the skin, to enable intimate, long-lived skin interfaces for physiological measurements, human-machine interfaces and other applications that cannot be addressed by wearable hardware that is commercially available today. A primary challenge is power supply; the physical bulk, large mass and high mechanical modulus associated with conventional battery technologies can hinder efforts to achieve epidermal characteristics, and near-field power transfer schemes offer only a limited operating distance. Here we introduce an epidermal, far-field radio frequency (RF) power harvester built using a modularized collection of ultrathin antennas, rectifiers and voltage doublers. These components, separately fabricated and tested, can be integrated together via methods involving soft contact lamination. Systematic studies of the individual components and the overall performance in various dielectric environments highlight the key operational features of these systems and strategies for their optimization. The results suggest robust capabilities for battery-free RF power, with relevance to many emerging epidermal technologies., Competing Interests: The authors declare no conflict of interest.

Baeyer-Villiger monooxygenases (BVMOs) are able to catalyze regiospecific Baeyer-Villiger oxygenation of a variety of cyclic and linear ketones to generate the corresponding lactones and esters, respectively. However, the enzymes are usually difficult to express in a functional form in microbial cells and are rather unstable under process conditions hindering their large-scale applications. Thereby, we investigated engineering of the BVMO from Pseudomonas putida KT2440 and the gene expression system to improve its activity and stability for large-scale biotransformation of ricinoleic acid (1) into the ester (i.e., (Z)-11-(heptanoyloxy)undec-9-enoic acid) (3), which can be hydrolyzed into 11-hydroxyundec-9-enoic acid (5) (i.e., a precursor of polyamide-11) and n-heptanoic acid (4). The polyionic tag-based fusion engineering of the BVMO and the use of a synthetic promoter for constitutive enzyme expression allowed the recombinant Escherichia coli expressing the BVMO and the secondary alcohol dehydrogenase of Micrococcus luteus to produce the ester (3) to 85 mM (26.6 g/L) within 5 h. The 5 L scale biotransformation process was then successfully scaled up to a 70 L bioreactor; 3 was produced to over 70 mM (21.9 g/L) in the culture medium 6 h after biotransformation. This study demonstrated that the BVMO-based whole-cell reactions can be applied for large-scale biotransformations.

The simplification of fabrication processes that can define very fine patterns for large-area flexible radio-frequency (RF) applications is very desirable because it is generally very challenging to realize submicron scale patterns on flexible substrates. Conventional nanoscale patterning methods, such as e-beam lithography, cannot be easily applied to such applications. On the other hand, recent advances in nanoimprinting lithography (NIL) may enable the fabrication of large-area nanoelectronics, especially flexible RF electronics with finely defined patterns, thereby significantly broadening RF applications. Here we report a generic strategy for fabricating high-performance flexible Si nanomembrane (NM)-based RF thin-film transistors (TFTs), capable of over 100 GHz operation in theory, with NIL patterned deep-submicron-scale channel lengths. A unique 3-dimensional etched-trench-channel configuration was used to allow for TFT fabrication compatible with flexible substrates. Optimal device parameters were obtained through device simulation to understand the underlying device physics and to enhance device controllability. Experimentally, a record-breaking 38 GHz maximum oscillation frequency fmax value has been successfully demonstrated from TFTs with a 2 μm gate length built with flexible Si NM on plastic substrates.

This article presents a novel technique to estimate the mechanical properties of the aluminum composite layer on silicon solar cells by using a hybrid 3-dimensional laser scanning force measurement (3-D LSFM) system. The 3-D LSFM system measures the material properties of sub-layers constituting a solar cell. This measurement is critical for realizing high-efficient ultra-thin solar cells. The screen-printed aluminum layer, which significantly affects the bowing phenomenon, is separated from the complete solar cell by removing the silicon (Si) layer with deep reactive ion etching. An elastic modulus of ~15.1 GPa and a yield strength of ~35.0 MPa for the aluminum (Al) composite layer were obtained by the 3-D LSFM system. In experiments performed for 6-inch Si solar cells, the bowing distances decreased from 12.02 to 1.18 mm while the Si layer thicknesses increased from 90 to 190 μm. These results are in excellent agreement with the theoretical predictions for ultra-thin Si thickness (90 μm) based on the obtained Al composite layer properties.

Blood-brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases.

Idiopathic infantile nystagmus (IIN) is the involuntary oscillation of the eyes with onset in the first few months of life. The most common form of inheritance is X-linked, and mutations in FRMD7 gene are a major cause. To identify the FRMD7 gene mutations associated with X-linked IIN, we performed PCR-based DNA direct sequencing in 4 affected subjects from 2 Korean families. We also assessed structural abnormalities of retina and optic nerve head using optical coherence tomography (OCT). Genetic analysis revealed a A>G transversion at nucleotide c.1, the first base of the start codon. This mutation leads to the loss of the primary start codon ATG for methionine, which is replaced by a triplet GTG for valine. The alternative in-frame start codon is not present around a mutation. OCT revealed the morphological changes within the optic nerve head, including shallow cup depth and small cup-to-disc ratio. In summary, we identified a novel start codon mutation within the FRMD7 gene of 2 Korean families. Our data expands the mutation spectrum of FRMD7 causing IIN. We also demonstrated abnormal developments of afferent system in patients with FRMD7 mutations using OCT, which may help to understand the etiological factor in development of nystagmus.

Herein, we report a two-step deglycosylation mediated by the oxidation of glycoside which is different from traditional glycoside hydrolase (GH) mechanism. Previously, we reported a novel flavin adenine dinucleotide (FAD)-dependent glycoside oxidoreductase (FAD-GO) having deglycosylation activity. Various features of the reaction of FAD-GO such as including mechanism and catalytic residue and substrate specificity were studied. In addition, classification of novel FAD-GO subfamily was attempted. Deglycosylation of glycoside was performed spontaneously via oxidation of 3-OH of glycone moiety by FAD-GO mediated oxidation reaction. His493 residue was identified as a catalytic residue for the oxidation step. Interestingly, this enzyme has broad glycone and aglycon specificities. For the classification of FAD-GO enzyme subfamily, putative FAD-GOs were screened based on the FAD-GO from Rhizobium sp. GIN611 (gi 365822256) using BLAST search. The homologs of R. sp. GIN611 included the putative FAD-GOs from Stenotrophomonas strains, Sphingobacterium strains, Agrobacterium tumefaciens str. C58, and etc. All the cloned FAD-GOs from the three strains catalyzed the deglycosylation via enzymatic oxidation. Based on their substrate specificities, deglycosylation and oxidation activities to various ginsenosides, the FAD-GO subfamily members can be utilized as novel biocatalysts for the production of various aglycones.

Fast flexible electronics operating at radio frequencies (>1 GHz) are more attractive than traditional flexible electronics because of their versatile capabilities, dramatic power savings when operating at reduced speed and broader spectrum of applications. Transferrable single-crystalline Si nanomembranes (SiNMs) are preferred to other materials for flexible electronics owing to their unique advantages. Further improvement of Si-based device speed implies significant technical and economic advantages. While the mobility of bulk Si can be enhanced using strain techniques, implementing these techniques into transferrable single-crystalline SiNMs has been challenging and not demonstrated. The past approach presents severe challenges to achieve effective doping and desired material topology. Here we demonstrate the combination of strained- NM-compatible doping techniques with self-sustained-strain sharing by applying a strain-sharing scheme between Si and SiGe multiple epitaxial layers, to create strained print-transferrable SiNMs. We demonstrate a new speed record of Si-based flexible electronics without using aggressively scaled critical device dimensions.

The intracellular delivery of enzymes is an essential methodology to extend their therapeutic application. Herein, we have developed dissociable supermolecule-enzyme polyelectrolyte complexes based on reduction-cleavable cationic polyrotaxanes (PRXs) for the reactivation of delivered enzymes. These PRXs are characterized by their supramolecular frameworks of a polymeric chain threading into cyclic molecules, which can form polyelectrolyte complexes with anionic enzymes while retaining their three dimensional structure, although their enzymatic activity is reduced. Upon the addition of a reductant, the PRXs dissociate into their constituent molecules and release the enzymes, resulting in a complete recovery of enzymatic activity. Under the intracellular environment, the PRX-based enzyme complexes showed the highest intracellular enzymatic activity and efficient activation of anticancer prodrugs to induce cytotoxic effects in comparison with the non-dissociable complexes and the commercial cell-penetrating peptide-based reagents. Thus, the intracellularly dissociable supermolecules are an attractive system for delivering therapeutic enzymes into living cells.

Clusterin is a secretory glycoprotein, which is highly up-regulated in a variety of normal and injury tissues undergoing apoptosis including infarct region of the myocardium. Here, we report that clusterin protects H9c2 cardiomyocytes from H2O2-induced apoptosis by triggering the activation of Akt and GSK-3β. Treatment with H2O2 induces apoptosis of H9c2 cells by promoting caspase cleavage and cytochrome c release from mitochondria. However, co-treatment with clusterin reverses the induction of apoptotic signaling by H2O2, thereby recovers cell viability. The protective effect of clusterin on H2O2-induced apoptosis is impaired by PI3K inhibitor LY294002, which effectively suppresses clusterin-induced activation of Akt and GSK-3β. In addition, the protective effect of clusterin is independent on its receptor megalin, because inhibition of megalin has no effect on clusterin-mediated Akt/GSK-3β phosphoylation and H9c2 cell viability. Collectively, these results suggest that clusterin has a role protecting cardiomyocytes from oxidative stress and the Akt/GSK-3β signaling mediates anti-apoptotic effect of clusterin.

Tumor progression is a multiple step process in which, in addition to oncogenic mutation, other supporting factors can contribute to transformation. The role these factors have in cancer is an open question. Using the Emicro-myc model of B-cell transformation, we evaluated the contribution of the cytokine interleukin-7 (IL-7) in supporting lymphomagenesis. We have previously shown that disruption of the Y449xxM motif of the IL-7 receptor alpha (IL-7Ralpha) in a knock-in mouse model (IL-7Ralpha(449F)) has minor effects on lymphocyte production, but interferes with the activation of survival effectors. To address the hypothesis that targeted signal ablation would selectively affect lymphocyte transformation, IL-7Ralpha(449F) mice were crossed with two lymphomagenesis models, transgenic (Tg) IL-7 and Emicro-myc mice. We found that the loss of IL-7Ralpha Y449 signaling prevented Tg IL-7-mediated T- and B-lymphocyte transformation and decreased the development of Emicro-myc-induced B-cell tumors. We showed that the IL-7Ralpha(449F) mutation prevented increased survival of Tg IL-7 CD8 T cells, and decreased viability of bone marrow progenitor B cells, as well as Emicro-myc-induced proliferation. This study shows that IL-7Ralpha Y449 is important for lymphocyte transformation, and that unlike deficiencies in pre-B cell receptor signaling, Myc overexpression cannot compensate for the loss of IL-7Ralpha signals in early B-cell development.

Purpose: To compare retinal nerve fibre layer (RNFL) thickness changes between mitochondrial DNA (mtDNA) mutations at nucleotides 11778 and 14484 in Leber's hereditary optic neuropathy (LHON) using optical coherence tomography (OCT)., Methods: Thirty LHON patients with mtDNA mutations at nucleotides 11778 or 14484 underwent full ophthalmologic examinations including Stratus OCT. Patients were divided into four groups according to disease duration (early 6 months) and mtDNA mutation type (11778 and 14484), and their RNFL thicknesses were compared., Results: Average RNFL thickness in the early 11778 group was significantly greater than that in the early 14484 group (P=0.04). Average RNFL thickness in the late 11778 group was significantly less than that in the late 14484 group (P=0.02). Quadrant analysis of the superior, nasal, and inferior quadrant RNFL thickness in the late 11778 group showed more severe RNFL atrophy than in the late 14484 group (P=0.023, 0.015, 0.003, respectively)., Conclusions: RNFL thickness was significantly increased in the early stage and decreased in the late stage in the 11778 group than in the 14484 group.

Increased expression of a number of proinflammatory genes, including IL-8, is associated with inflammatory conditions such as asthma. Glucocorticoid receptor (GR)beta, one of the GR isoforms, has been suggested to be upregulated in asthma associated with glucocorticoid insensitivity and to work as a dominant negative inhibitor of wild type GRalpha. However, recent data suggest that GRbeta is not a dominant negative inhibitor of GRalpha in the transrepressive process and has its own functional role. We investigated the functional role of GRbeta expression in the suppressive effect of glucocorticoids on tumor necrosis factor (TNF)-alpha-induced IL-8 release in an airway epithelial cell line. GRbeta expression was induced by treatment of epithelial cells with either dexamethasone or TNF-alpha. GRbeta was able to inhibit glucocorticoid-induced transcriptional activation mediated by binding to glucocorticoid response elements (GREs). The suppressive effect of dexamethasone on TNF-alpha-induced IL-8 transcription was not affected by GRbeta overexpression, rather GRbeta had its own weak suppressive activity on TNF-alpha-induced IL-8 expression. Overall histone deacetylase activity and histone acetyltransferase activity were not changed by GRbeta overexpression, but TNF-alpha-induced histone H4 acetylation at the IL-8 promoter was decreased with GRbeta overexpression. This study suggests that GRbeta overexpression does not affect glucocorticoid-induced suppression of IL-8 expression in airway epithelial cells and GRbeta induces its own histone deacetylase activity around IL-8 promoter site.

Lysophosphatidic acid (LPA) is a bioactive phospholipids and involves in various cellular events, including tumor cell migration. In the present study, we investigated LPA receptor and its transactivation to EGFR for cyclooxygenase-2 (COX-2) expression and cell migration in CAOV-3 ovarian cancer cells. LPA induced COX-2 expression in a dose-dependent manner, and pretreatment of the cells with pharmacological inhibitors of Gi (pertussis toxin), Src (PP2), EGF receptor (EGFR) (AG1478), ERK (PD98059) significantly inhibited LPA- induced COX-2 expression. Consistent to these results, transfection of the cells with selective Src siRNA attenuated COX-2 expression by LPA. LPA stimulated CAOV-3 cell migration that was abrogated by pharmacological inhibitors and antibody of EP2. Higher expression of LPA2 mRNA was observed in CAOV-3 cells, and transfection of the cells with a selective LPA2 siRNA significantly inhibited LPA-induced activation of EGFR and ERK, as well as COX-2 expression. Importantly, LPA2 siRNA also blocked LPA-induced ovarian cancer cell migration. Collectively, our results clearly show the significance of LPA2 and Gi/Src pathway for LPA-induced COX-2 expression and cell migration that could be a promising drug target for ovarian cancer cell metastasis.