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Since around the year 2000, hundreds of people in Korea have developed humidifier disinfectant-associated lung injury (HDLI). We collected all HD exposure-related information from the field investigations into the locations in which the 1199 registered patients had used HD. Among the people who registered, 38% (1st round = 214, 2nd = 73, 3rd = 166) were confirmed as HDLI patients. Children aged under eight years old made up the highest proportion of HDLI cases (N = 279, 62%), followed by pregnant women (N = 31, 7%). One hundred thirty-three (29%) of the confirmed HDLI patients died. Fifty-seven percent of HDLI patients (N = 259) developed HDLI after <1 year of HD use. The number of HDLI patients who used only the Oxy Saksak HD brand was found to be 176 (39%), followed by the brands Cefu (N = 27, 6%) and Aekyung (N = 22, 5%). HD products containing only polyhexamethylene guanidine phosphate (PHMG-P) were the most frequently used among HDLI patients (N = 234, 52%), followed by oligo (2-(2-ethoxy)ethoxyethyl) guanidinium (PGH) (N = 27, 6%) and a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) (N = 26, 6%). The average PHMG-P inhalation level estimated from the patient group classified as suffering lung injury definitely associated with HD use was 145.1 μg/m 3 (N = 91, SD = 395.1 μg/m 3 ), higher than levels estimated from both the probable and possible HDLI patient groups. In conclusion, HD exposure-related variables, including type of HD brand and estimated inhalation HD level, were associated with the risk of HDLI., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The morphology of a Suzuki coupling-based microporous organic polymer (SUM) was controlled by the use of a Sonogashira coupling-based microporous organic polymer (SOM). The template synthesis resulted in water compatible and hollow SOM@SUM materials bearing tetraphenylethylene moieties (H-SOM@SUM-T), which showed aggregation-induced emission and promising sensing performance towards nitrophenols in water.

Objective: We investigated the impact of depressed mood (dysphoria) and loss of interest or pleasure (anhedonia)on the risk of dementia in cognitively-normal elderly individuals., Methods: This study included 2,685 cognitively-normal elderly individuals who completed the baseline and 4-year follow-up assessments of the Korean Longitudinal Study on Cognitive Aging and Dementia. We ascertained the presence of dysphoria and anhedonia using the Mini International Neuropsychiatric Inventory. We defined subjective cognitive decline as the presence of subjective cognitive complaints without objective cognitive impairments. We analyzed the association of dysphoria and anhedonia with the risk of cognitive disorders using multinomial logistic regression analysis adjusted for age, sex, education, Cumulative Illness Rating Scale score, Apolipoprotein E genotype, and neuropsychological test performance., Results: During the 4-year follow-up period, anhedonia was associated with an approximately twofold higher risk of mild cognitive impairment (OR=2.09, 95% CI=1.20-3.64, p=0.008) and fivefold higher risk of dementia (OR=5.07, 95% CI=1.44-17.92, p=0.012) but was not associated with the risk of subjective cognitive decline. In contrast, dysphoria was associated with an approximately twofold higher risk of subjective cognitive decline (OR=2.06, 95% CI=1.33-3.19, p=0.001) and 1.7-fold higher risk of mild cognitive impairment (OR=1.75, 95% CI=1.00-3.05, p=0.048) but was not associated with the risk of dementia., Conclusion: Anhedonia, but not dysphoria, is a risk factor of dementia in cognitively-normal elderly individuals.

Red Liriope platyphylla (RLP) is a known herbal medicine used in the treatment of some chronic diseases including constipation, neurodegenerative disorders, diabetes and obesity. To determine and characterize putative biomarkers that predict the laxative effects induced by RLP treatment, alteration of endogenous metabolites was measured in the serum of loperamide (Lop)-induced constipation rats after administration of RLP extract (EtRLP) using 1 H nuclear magnetic resonance ( 1 H NMR) spectral data. The urine volume and amounts, and weights and water contents of stools were significantly recovered in the Lop + EtRLP treated group as compared to the No group, whereas body weight and food intake maintained constant levels. Also, significant recoveries in the thickness of mucosa and muscle were detected in the colon of the Lop + EtRLP treated group. Furthermore, pattern recognition showed absolutely different clustering of the serum analysis parameters when comparing the Lop treated group and Lop + EtRLP treated group. Of the 33 endogenous metabolites, 7 amino acids (alanine, arginine, glutamate, glutamine, glycine, threonine and valine) and 8 endogenous metabolites (betaine, creatine, glucose, taurine, ethanol, lactate, glycerol and succinate) were dramatically increased in the Lop + EtRLP treated SD rats. These results provide the first evidence pertaining to metabolic changes in the constipation rats treated with Lop + EtRLP. Additionally, these findings correlate with changes observed in 15 metabolites during the laxative effects of EtRLP., Competing Interests: Competing interestsThe authors declare that there is no financial conflict of interests to publish these results., (© The Author(s) 2019.)

Objective: A defense mechanism is an automatic psychological process necessary for successful adaptation. It reflects adaptive capacity. The purpose of this study is to explore the relationship between the adaptation ability of individuals who face mandatory military service and the pattern of defense mechanisms., Methods: The subjects were 69 men (21.4±2.2 years) who expressed psychological difficulties in three military service situations. Control group was 36 men (24.0±1.4 years) who had successfully completed military service. We examined psychiatric history, the pattern of defense mechanisms, and depression and anxiety levels. Defense mechanisms were compared between two groups., Results: The maladjusted group used immature defenses more frequently than the control group did. There were no differences in the defense patterns according to diagnosis. The control group used more identification and rationalization, classified as immature defenses. The temporarily maladjusted group used more somatization, regression, and avoidance., Conclusion: Using mature defense mechanisms helped young adults to adapt to a particular situation. The maturity of the defense is more valuable than the psychiatric diagnosis. Some immature defenses are also helpful to adapt. We cautiously assume that some defenses can be protective or risk factors in adapting to stressful situations by young adults.

Objective: This study aimed to examine the association between normal-but-low folate levels and cognitive function in the elderly population using a prospective cohort study., Methods: We analyzed 3,910 participants whose serum folate levels were within the normal reference range (1.5-16.9 ng/mL) at baseline evaluation in the population-based prospective cohort study named the "Korean Longitudinal Study on Cognitive Aging and Dementia." The association between baseline folate quartile categories and baseline cognitive disorders [mild cognitive impairment (MCI) or dementia] was examined using binary logistic regression analysis adjusting for confounding variables. The risks of incident MCI and dementia associated with the decline of serum folate level during a 4-year follow-up period were examined using multinomial logistic regression analysis., Results: The lowest quartile group of serum folate (≥1.5, ≤5.9 ng/mL) showed a higher risk of cognitive disorders than did the highest quartile group at baseline evaluation (odds ratio 1.314, p=0.012). Over the 4 years of follow-up, the risk of incident dementia was 2.364 times higher among subjects whose serum folate levels declined from the 2nd-4th quartile group to the 1st quartile than among those for whom it did not (p=0.031)., Conclusion: Normal-but-low serum folate levels were associated with the risk of cognitive disorders in the elderly population, and a decline to normal-but-low serum folate levels was associated with incident dementia. Maintaining serum folate concentration above 5.9 ng/mL may be beneficial for cognitive status.

Background: In this study, we used phenotypic and genetic analysis to investigate Double haploid (DH) lines derived from normal corn parents (HF1 and 11S6169). DH technology offers an array of advantages in maize genetics and breeding as follows: first, it significantly shortens the breeding cycle by development of completely homozygous lines in two or three generations; and second, it simplifies logistics, including requiring less time, labor, and financial resources for developing new DH lines compared with the conventional RIL population development process., Objectives: In our study, we constructed a maize genetic linkage map using SSR markers and a DH population derived from a cross of normal corn (HF1) and normal corn (11S6169)., Methods: The DH population used in this study was developed by the following methods: we crossed normal corn (HF1) and normal corn (11S6169), which are parent lines of a normal corn cultivar, in 2014; and the next year, the F 1 hybrids were crossed with a tropicalized haploid inducer line (TAIL), which is homozygous for the dominant marker gene R1-nj (Nanda and Chase in Crop Sci 6:213-215, 1966), and we harvested seeds of the haploid lines., Results: A total of 200 SSR markers were assigned to 10 linkage groups that spanned 1145.4 cM with an average genetic distance between markers of 5.7 cM. 68 SSR markers showed Mendelian segregation ratios in the DH population at a 5% significance threshold. A total of 15 quantitative trait loci (QTLs) for plant height (PH), ear height (EH), ear height ratio (ER), leaf length (LL), ear length (EL), set ear length (SEL), set ear ratio (SER), ear width (EW), 100 kernel weight (100 KW), and cob color (CC) were found in the 121 lines in the DH population., Conclusion: The results of this study may help to improve the detection and characterization of agronomic traits and provide great opportunities for maize breeders and researchers using a DH population in maize breeding programs.

The inositol pyrophosphate, diphosphoinositol pentakisphosphate (IP 7 ), is thought to negatively regulate the critical insulin signaling protein Akt/PKB. Knockdown of the IP 7 -generating inositol hexakisphosphate kinase 1 (IP6K1) results in a concomitant increase in signaling through Akt/PKB in most cell types so far examined. Total in vivo knockout of IP6K1 is associated with a phenotype resistant to high-fat diet, due to enhanced Akt/PKB signaling in classic insulin regulated tissues, counteracting insulin resistance. In contrast, we have shown an important positive role for IP6K1 in insulin exocytosis in the pancreatic β-cell. These cells also possess functional insulin receptors and the feedback loop following insulin secretion is a key aspect of their normal function. Thus we examined the effect of silencing IP6K1 on the activation of Akt/PKB in β-cells. Silencing reduced the glucose-stimulated increase in Akt/PKB phosphorylation on T308 and S473. These effects were reproduced with the selective pan-IP6K inhibitor TNP. The likely explanation for IP 7 reduction decreasing rather than increasing Akt/PKB phosphorylation is that IP 7 is responsible for generating the insulin signal, which is the main source of Akt/PKB activation. In agreement, insulin receptor activation was compromised in TNP treated cells. To test whether the mechanism of IP 7 inhibition of Akt/PKB still exists in β-cells, we treated them at basal glucose with an insulin concentration equivalent to that reached during glucose stimulation. TNP potentiated the Akt/PKB phosphorylation of T308 induced by exogenous insulin. Thus, the IP 7 regulation of β-cell Akt/PKB is determined by two opposing forces, direct inhibition of Akt/PKB versus indirect stimulation via secreted insulin. The latter mechanism is dominant, masking the inhibitory effect. Consequently, pharmacological strategies to knock down IP6K activity might not have the same positive output in the β-cell as in other insulin regulated tissues., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Invasive aspergillosis (IA) is an opportunistic fungal infection that mostly occurs in immunocompromised patients, such as those having hematologic malignancy or receiving hematopoietic stem cell transplantation. Inhalation of Aspergillus spores is the main transmission route of IA in immunocompromised patients. Construction work in hospitals is a risk factor for environmental fungal contamination. We measured airborne fungal contamination and the incidence of IA among immunocompromised patients, and evaluated their correlation with different types of construction works., Methods: Our tertiary hospital in Seoul, Korea underwent facility construction from September 2017 to February 2018. We divided the entire construction period into period 1 (heavier works: demolition and excavation) and period 2 (lighter works: framing, interior designing, plumbing, and finishing). We conducted monthly air sampling for environmental spore surveillance in three hematologic wards. We evaluated the incidence of IA among all immunocompromised patients hospitalized in the three hematologic wards (2 adult wards and 1 pediatric ward) during this period. IA was categorized into proven, probable, and possible aspergillosis based on the revised European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria., Results: A total of 15 patients was diagnosed with proven (1 case), probable (8 cases), or possible (6 cases) hospital-acquired IA during period 1. In period 2, 14 patients were diagnosed with either proven (1 case), probable (10 cases), or possible (3 cases) hospital-acquired IA. Total mold and Aspergillus spp. spore levels in the air tended to be higher in period 1 ( p  = 0.06 and 0.48, respectively). The incidence rate of all IA by the EORTC/MSG criteria was significantly higher in period 1 than in period 2 (1.891 vs. 0.930 per 1000 person-days, p  = 0.05)., Conclusions: Airborne fungal spore levels tended to be higher during the period with heavier construction works involving demolition and excavation, during which the incidence of IA was significantly higher as well. We recommend monitoring airborne fungal spore levels during construction periods in hospitals with immunocompromised patients. Subsequently, the effect of airborne fungal spore level monitoring in reducing hospital-acquired IA should be evaluated., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

To this date, the criteria to distinguish peritoneal macrophages and dendritic cells (DCs) are not clear. Here we delineate the subsets of myeloid mononuclear cells in the mouse peritoneal cavity. Considering phenotypical, functional, and ontogenic features, peritoneal myeloid mononuclear cells are divided into 5 subsets: large peritoneal macrophages (LPMs), small peritoneal macrophages (SPMs), DCs, and 2 MHCII + CD11c + CD115 + subpopulations (i.e., MHCII + CD11c + CD115 + CD14 - CD206 - and MHCII + CD11c + CD115 + CD14 + CD206 + ). Among them, 2 subsets of competent Ag presenting cells are demonstrated with distinct functional characteristics, one being DCs and the other being MHCII + CD11c + CD115 + CD14 - CD206 - cells. DCs are able to promote fully activated T cells and superior in expanding cytokine producing inflammatory T cells, whereas MHCII + CD11c + CD115 + CD14 - CD206 - cells generate partially activated T cells and possess a greater ability to induce Treg under TGF-β and retinoic acid conditions. While the development of DCs and MHCII + CD11c + CD115 + CD14 - CD206 - cells are responsive to the treatment of FLT3 ligand and GM-CSF, the number of LPMs, SPMs, and MHCII + CD11c + CD115 + CD14 + CD206 + cells are only influenced by the injection of GM-CSF. In addition, the analysis of gene expression profiles among MHCII + peritoneal myeloid mononuclear cells reveals that MHCII + CD11c + CD115 + CD14 + CD206 + cells share high similarity with SPMs, whereas MHCII + CD11c + CD115 + CD14 - CD206 - cells are related to peritoneal DC2s. Collectively, our study identifies 2 distinct subpopulations of MHCII + CD11c + CD115 + cells, 1) MHCII + CD11c + CD115 + CD14 - CD206 - cells closely related to peritoneal DC2s and 2) MHCII + CD11c + CD115 + CD14 + CD206 + cells to SPMs., Competing Interests: Conflicts of Interest: The authors declare no potential conflicts of interest.

We examined the role of phospholipase D2 (PLD2) on acetaminophen (APAP)-induced acute liver injury using a PLD2 inhibitor (CAY10594). 500 mg/kg of APAP challenge caused acute liver damage. CAY10594 administration markedly blocked the acute liver injury in a dose-dependent manner, showing almost complete inhibition with 8 mg/kg of CAY10594. During the pathological progress of acute liver injury, GSH levels are decreased, and this is significantly recovered upon the administration of CAY10594 at 6 hours post APAP challenge. GSK-3β (Serine 9)/JNK phosphorylation is mainly involved in APAP-induced liver injury. CAY10594 administration strongly blocked GSK-3β (Serine 9)/JNK phosphorylation in the APAP-induced acute liver injury model. Consistently, sustained JNK activation in the cytosol and mitochondria from hepatocytes were also decreased in CAY10594-treated mice. Many types of immune cells are also implicated in APAP-induced liver injury. However, neutrophil and monocyte populations were not different between vehicle- and CAY10594-administered mice which are challenged with APAP. Therapeutic administration of CAY10594 also significantly attenuated liver damage caused by the APAP challenge, eliciting an enhanced survival rate. Taken together, these results indicate that PLD2 is involved in the intrinsic response pathway of hepatocytes driving the pathogenesis of APAP-induced acute liver injury, and PLD2 may therefore represent an important therapeutic target for patients with drug-induced liver injury.

Background: Metamemory is the process of monitoring and controlling one's memory. Improving metamemory may reduce the memory problem in old age. We hypothesized that metamemory training (MMT) would improve cognition in older adults with subjective memory complaints and change the brain region related to metacognition., Method: We recruited and randomized older adults to the multi-strategic memory training of 10 weekly 90-min sessions, based on the metamemory concept or usual care. Cognitive tests including the Elderly Verbal Learning Test, Simple Rey Figure Test, Digit Span, Spatial Span, Categorical Fluency, and the Boston Naming Test were done in 201 participants, together with magnetic resonance imaging (MRI) in 49 participants before and after training., Results: A total of 112 in the training group and 89 in the control group participated. The training group had a significant increase in long-term delayed free recall, categorical fluency, and the Boston Naming test. In MRI, the mean diffusivity of the bundles of axon tracts passing from the frontal lobe to the posterior end of the lateral sulcus decreased in the training group., Conclusion: These results indicate that the MMT program has a positive impact on enhancing older people' cognitive performance. Improved white matter integrity in the anterior and posterior cerebrum and increased cortical thickness of prefrontal regions, which related to metacognition, possibly suggest that the effects of the MMT would be induced via the enhancement of cognitive control., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Background: Recently, the use of common marmoset ( Callithrix jacchus ) has increased in biomedical research as an animal model. This study aimed to test fecal samples to monitor bacterial and parasite infections in common marmoset at the Laboratory Animal Center of Osong Medical Innovation Foundation in Korea., Methods: To monitor bacteria and parasites in common marmoset, we tested 43 fecal samples of 43 common marmosets by culture and parasitological test in 2014. Infection by Chilomastix mesnili was determined by PCR method., Results: We identified nonpathogenic bacteria such as Proteus mirabilis and Escherichia coli in feces of normal common marmosets. Interestingly, C. mesnili was isolated from a healthy common marmoset by fecal centrifugation concentration and PCR. The monkey infected with C. mesnili was treated with metronidazole. After the treatment, C. mesnili were not found in feces using fecal centrifugation concentration and PCR., Conclusion: This is the first case report of C. mesnili infection in common marmoset. Treatment with metronidazole is found to be highly effective in eradicating C. mesnili infection in common marmoset., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest.

Ambipolar organic semiconductors are considered promising for organic electronics because of their interesting electric properties. Many hurdles remain yet to be overcome before they can be used for practical applications, especially because their orientation is hard to control. We demonstrate a method to control the orientation of columnar structures based on a hydrogen (H)-bonded donor-acceptor complex between a star-shaped tris(triazolyl)triazine and triphenylene-containing benzoic acid, using physicochemical nanoconfinement. The molecular configuration and supramolecular columnar assemblies in a one-dimensional porous anodic aluminium oxide (AAO) film were dramatically modulated by controlling the pore-size and by chemical modification of the inner surface of the porous AAO film. In situ experiments using grazing-incidence X-ray diffraction (GIXRD) were carried out to investigate the structural evolution produced at the nanometer scale by varying physicochemical conditions. The resulting highly ordered nanostructures may open a new pathway to effectively control the alignment of liquid crystal ambipolar semiconductors., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In the event of a mass casualty radiation scenario, biodosimetry has the potential to quantify individual exposures for triaging and providing dose-appropriate medical intervention. Structural maintenance of chromosomes 1 (SMC1) is phosphorylated in response to ionizing radiation. The goal of this study was to develop a new biodosimetry method using SMC1 phosphorylation as a measure of exposure to radiation. In the initial experiments, two normal human cell lines (WI-38VA-13 and HaCaT) and four lymphoblastoid cell lines were irradiated, and the levels of SMC1 phosphorylation at Ser-360 and Ser-957 were assessed using Western blotting. Subsequently, similar experiments were performed using peripheral blood mononuclear cells (PBMCs) obtained from 20 healthy adults. Phosphorylation of SMC1 at Ser-957 and Ser-360 was increased by exposure in a dose-dependent manner, peaked at 1-3 h postirradiation and then decreased gradually. Ser-360 was identified as a new phosphorylation site and was more sensitive to radiation than Ser-957, especially at doses below 1 Gy. Our results demonstrate a robust ex vivo response of phospho-SMC1-(Ser-360) to ionizing radiation in human PBMCs. Detection of phosphorylation at Ser-360 in SMC1 could be used as a marker of radiation exposure. Our findings suggest that it is feasible to measure blood cell-based changes in the phosphorylation level of a protein as an ex vivo radiation exposure detection method, even after low-dose exposure.

Microsatellite markers from a fresh water yellow catfish, Pseudobagrus fulvidraco , were developed by whole-genome sequencing in the Ion S5 system. Of the 40 chosen sets of microsatellite markers, with tetra-repeat and penta-repeat motifs, from a total 19,743 sequence, only 13 markers were successfully applied in 78 individual fish sampled to detect genomic variability from four natural populations of Korea. On an average, the number of alleles per marker was 6.7. The observed heterozygosity varied from 0.048 to 0.810. Twelve microsatellite markers conformed to Hardy-Weinberg equilibrium and none exhibited significant linkage disequilibrium. In yellow catfish, genetic differentiation among four natural populations was further supported by F ST ( P < 0.05) and STRUCTURE analysis. The microsatellite markers identified could facilitate genetic diversity and population structure studies and thus aid in conservation of the yellow catfish.

Selective filtration of near-infrared (NIR) regions is of primary importance to energy saving via thermal shielding. However, uniform coating of highly effective nanomaterials on flexible substrates remains very challenging. Here, we introduce new material processing and fabrication methodologies that manufacture electrospun copper sulfide/polyvinylpyrrolidone (CuS/PVP) nanowires for enhanced thermal shielding efficiency. Electrospinning offers well-dispersed CuS nanoparticles in a thermal shielding film, which is not achievable in typical solution coating processes. Directly deposited CuS/PVP nanowires on a flexible polymer membrane are enabled by a fluorination treatment that decreases the interfacial electrostatic repulsion. Monitoring of in situ temperature change of a box-shielded, CuS/PVP nanowire film demonstrates excellent NIR shielding efficiency (87.15%). Direct integration of the film with a model car and exposure to direct sunlight demonstrates about twice-higher shielding efficiency than commercial tungsten oxide films. Overall, the comprehensive study of nanomaterial preparation, surface treatment, and integration techniques allows the fabrication of highly flexible and reliable thermal shielding films.

IL-17 produced by Th17 cells has been implicated in the pathogenesis of rheumatoid arthritis (RA). It is important to prevent the differentiation of Th17 cells in RA. Homodimeric soluble γc (sγc) impairs IL-2 signaling and enhances Th17 differentiation. Thus, we aimed to block the functions of sγc by inhibiting the formation of homodimeric sγc. The homodimeric form of sγc was strikingly disturbed by sγc-binding DNA aptamer. Moreover, the aptamer effectively inhibited Th17 cell differentiation and restored IL-2 and IL-15 signaling impaired by sγc with evidences of increased survival of T cells. sγc was highly expressed in SF of RA patients and increased in established CIA mice. The therapeutic effect of PEG-aptamer was tested in CIA model and its treatment alleviated arthritis pathogenesis with impaired differentiation of pathogenic Th17, NKT1, and NKT17 cells in inflamed joint. Homodimeric sγc has pathogenic roles to exacerbate RA progression with differentiation of local Th17, NKT1, and NKT17 cells. Therefore, sγc is suggested as target of a therapeutic strategy for RA.

Objective: To find out whether levels of fibrin degradation products (FDP) and D-dimer are increased in breast cancer-related lymphedema (BCRL) as in many vascular diseases. FDP and D-dimer have been used in blood tests to help differentiate deep vein thrombosis in the diagnosis of lymphedema. Levels of FDP and D-dimer are often elevated in patients with BCRL., Methods: Patients with BCRL (group I), non-lymphedema after breast cancer treatment (group II), and deep venous thrombosis (group III) from January 2012 to December 2016 were enrolled. Levels of FDP and D-dimer were measured in all groups and compared among groups., Results: Mean values of FDP and D-dimer of group I were 5.614±12.387 and 1.179±2.408 μg/μL, respectively. These were significantly higher than their upper normal limits set in our institution. Levels of FDP or D-dimer were not significantly different between group I and group II. However, values of FDP and D-dimer in group III were significantly higher than those in group I., Conclusion: Values of FDP and D-dimer were much higher in patients with thrombotic disease than those in patients with lymphedema. Thus, FDP and D-dimer can be used to differentiate between DVT and lymphedema. However, elevated levels of FDP or D-dimer cannot indicate the occurrence of lymphedema.

Pleurotus eryngii var. ferulae (PEF) is traditionally used in the prevention and treatment of lifestyle-related diseases. In this study, we investigated the ability of PEF extract to prevent obesity and metabolic diseases and explored the underlying mechanism. Mice were fed a high-fat diet (HFD) containing PEF extract for 12 weeks, and their body weight, adipose tissue and liver weights, and lipid profiles and blood glucose levels, were monitored. Fecal triglyceride (TG) levels were also measured and olive oil-loading tests were performed. Furthermore, the effect of PEF extract on pancreatic lipase (PL) activity was examined in vitro. Treatment with PEF extract for 12 weeks resulted in a significant decrease in the HFD-induced increases in body weight, white adipose tissue weight, liver weights, and lipid profiles, and improved glucose tolerance and insulin sensitivity. To assess the mechanism underlying the effect of PEF extract on obesity and diabetes, we investigated its role in inhibiting lipid absorption. Consumption of an HFD containing PEF extract significantly increased the TG level in feces compared with the controls, suggesting inhibition of TG absorption in the digestive tract. Furthermore, PEF extract suppressed the increase in serum TG levels resulting from oral administration of a lipid emulsion to mice, confirming inhibition of TG absorption. Moreover, PEF extract inhibited PL activity in vitro. Our combined results indicate that the anti-obesity and antidiabetic effect of PEF extract in mice fed an HFD may be caused by inhibition of lipid absorption as a result of reduced PL activity.

Dementia increases the risk of mortality (ROM) in the elderly and estimates of hazard ratio (HR) of dementia for mortality have ranged from 1.7 to 6.3. However, previous studies may have underestimated ROM of dementia due to length bias, which occurs when failing to include the persons with rapidly progressive diseases, who died before they could be included in the study. This population-based prospective cohort study conducted on 6,752 randomly sampled Koreans, aged 60 years or older (the Korean Longitudinal Study on Cognitive Aging and Dementia). Cognitive disorders were evaluated at baseline and 2-year follow-up using the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD-K), and prevalent and incident cases of dementia were identified. The participants' deaths were confirmed through the National Mortality Database of Statistics Korea. We compared the ROM between prevalent and incident dementia, and estimated HR of dementia for mortality using Cox proportional hazards model. Of the 5,097 responders to the 2-year follow-up assessment, 150 participants had dementia from the baseline (prevalent dementia), and 95 participants developed dementia during the 2-year follow-up period (incident dementia). The ROM of participants with incident dementia was about 3 times higher than the ROM of those with prevalent dementia (HR = 3.04, 95% confidence interval [CI] = 1.34-6.91). Compared to cognitively normal participants at both the baseline and 2-year follow-up assessments, the ROM of those with incident dementia approximately 8 times higher (HR = 8.37, 95 % CI = 4.23-16.54). In conclusion, the ROM of dementia using prevalent cases was underestimated due to length bias, and dementia may be much more fatal than previously estimated. In clinical settings, the ROM of dementia warrants the attention of physicians, particularly in recently incident dementia cases.

Cisplatin (CP) is an anti-cancer drug used for treatment of solid tumors, but the major adverse effect is drug-induced nephrotoxicity. The current study aimed to determine biomarkers that might predict nephrotoxicity induced by CP using serum or urinary proton nuclear magnetic resonance ( 1 H NMR) spectral data in male Sprague-Dawley (S-D) rats. CP (0, 0.5 or 5 mg/kg) was intraperitoneally (i.p.) administered for single dose. Animals were sacrificed 2 days (D2) or 8 days (D8) after administration of CP in order to perform analysis of serum biochemistries and histopathologic examination. Urine samples were collected every 24 hr from pre-treatment to sacrifice. Serum and urinary 1 H NMR spectral data revealed apparent differential clustering between control and CP-treated groups as evidenced by principal component analysis (PCA) and orthogonal projections to latent structures-discriminant analysis (OPLS-DA) in global and targeted profiling. The concentrations of endogenous serum metabolites, alanine, betaine, glucose, glutamine, lactate, and leucine were significantly increased on D2. Urinary concentrations of alanine, glucose, glycine, guanidinoacetate, acetate, and lactate were significantly elevated on D2 or D8, whereas concentrations of urinary metabolites, citrate and hippurate were significantly decreased on D2 or D8. The correlation of serum and urinary 1 H NMR OPLS-DA with serum biochemistry and renal histopathologic changes suggests that 1 H NMR urinalysis may be used to reliably predict or screen CP-induced nephrotoxicity. Data suggest that these altered endogenous metabolites might serve as specific biomarkers for CP-induced nephrotoxicity.

Prospective studies concerning sleep architecture and cognitive function have focused on individual sleep measures per se, without considering the complementary role of non-REM (NREM) and REM sleep. We explored the association between NREM/REM cycle-related sleep architecture and cognitive decline. Community-dwelling elderly people in Korea from the Korean Longitudinal Study on Cognitive Aging and Dementia were enrolled. They were cognitively normal and underwent overnight polysomnography at baseline. A NREM/REM cycle is a sequence of NREM and REM sleep, uninterrupted by a waking period of >2 min. After 4 years, the development of mild cognitive impairment (MCI) or dementia was related to the measures of sleep architecture, including NREM/REM cycle parameters by logistic regression analyses. Of 235 participants (mean [SD] age 68 [5] years; 60% female) at baseline, 14 (5.9%) developed MCI/dementia at follow-up. A short average cycle length (OR, 0.97 [95% CI, 0.94-0.99]; p = 0.02) was significantly associated with cognitive decline. When its substructure and NREM and REM sleep outside of cycles were considered simultaneously, the average REM sleep duration per cycle (OR, 0.87 [95% CI, 0.76-0.98]; p = 0.03) was significantly related to the outcome. In conclusion, short average duration of NREM/REM cycles, especially average REM sleep duration in each cycle, in cognitively normal elderly might be used as an early marker of cognitive decline.

Interactions between membrane proteins are poorly understood despite their importance in cell signaling and drug development. Here, we present a co-immunoimmobilization assay (Co-II) enabling the direct observation of membrane protein interactions in single living cells that overcomes the limitations of currently prevalent proximity-based indirect methods. Using Co-II, we investigated the transient homodimerizations of epidermal growth factor receptor (EGFR) and beta-2 adrenergic receptor (β2-AR) in living cells, revealing the differential regulation of these receptors' dimerizations by molecular conformations and microenvironment in a plasma membrane. Co-II should provide a simple, rapid, and robust platform for visualizing both weak and strong protein interactions in the plasma membrane of living cells., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The development of NIRF cathepsin activity probes offered the ability to visualize tumor associated tumor reaction and act as a surrogate marker to delineate the dysplastic lesions. One major type is a NIRF substrate of cathepsins (SBP), which is involved in catalytic way to produce high levels of fluorescence emission. The other major type (ABP) reacts with active cathepsins in stoichiometric manner since they bind covalently with their active center. Little is known about the sensitivity and the specificity of the NIRF probes to detect autochthonous developed dysplastic lesions. Dual laser NIRF endoscope provides a good tool to determine the efficiency of various NIRF probes in vivo in the same lesions., Experimental Design: In the current study, we validated both types of NIRF probes by using the dual laser NIRF endoscope to detect lesions colon cancer mouse model (TS4Cre/cAPC +/lox)., Results: The dual laser NIRF endoscope is emitting equal power with both lasers. It can detect with the same efficiency in 680 mode, as well as, 750 mode when NIFR probes of the same scaffold in vivo. When SBP and ABP were used, our results showed both probes are efficient enough to detect large polyps but small dysplastic lesions could not efficiently imaged with the ABP., Conclusions: The dual laser NIRF endoscope is a powerful tool to validate probes. The probes that react catalytically with the active center of cathepsins are more efficient than the ones that react stoichiometrically in detecting small lesions., Competing Interests: The authors have declared that no competing interests exist.

AKAP12 belongs to A-kinase anchoring protein (AKAP) family of scaffold proteins and is known as a tumor suppressor in several human cancer types. Its role as a tumor suppressor in hepatocellular carcinoma (HCC) was proposed due to its downregulation and epigenetic modification in human HCC; however, the effect of its deficiency on liver injuries, such as liver fibrosis and cancer has been poorly studied. By analyzing tumor and non-tumor tissues of 15 patients with HCC, it was confirmed that AKAP12 expression was downregulated in human HCC as compared with adjacent non-tumor tissues. Immunohistochemical staining of mouse liver tissue for AKAP12 revealed that its sinusoidal expression was diminished in capillarized endothelium after 8 weeks of thioacetamide (TAA) administration. AKAP12 deficiency resulted in the promotion of ductular response of biliary epithelial cells, whereas overall fibrosis and myofibroblast activation were comparable between genotypes after short-term TAA treatment. The mRNA expressions of some fibrosis-related genes such as those encoding epithelial cell adhesion molecule, collagen type 1 α1 and elastin were upregulated in liver tissues of AKAP12-knockout mice. Long-term administration of TAA for 26 weeks led to the development of liver tumors; the incidence of tumor development was higher in AKAP12-deficient mice than in wild-type littermates. Together, these results suggest that AKAP12 functions as a tumor suppressor in liver cancer and is associated with the regulation of hepatic non-parenchymal cells.

Regulation of tyrosine phosphorylation on insulin receptor substrate-1 (IRS-1) is essential for insulin signaling. The protein tyrosine phosphatase (PTP) C1-Ten/Tensin2 has been implicated in the regulation of IRS-1, but the molecular basis of this dephosphorylation is not fully understood. Here, we demonstrate that the cellular phosphatase activity of C1-Ten/Tensin2 on IRS-1 is mediated by the binding of the C1-Ten/Tensin2 Src-homology 2 (SH2) domain to phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ). We show that the role of C1-Ten/Tensin2 is dependent on insulin-induced phosphoinositide 3-kinase activity. The C1-Ten/Tensin2 SH2 domain showed strong preference and high affinity for PtdIns(3,4,5)P 3 . Using site-directed mutagenesis, we identified three basic residues in the C1-Ten/Tensin2 SH2 domain that were critical for PtdIns(3,4,5)P 3 binding but were not involved in phosphotyrosine binding and PTP activity. Using a PtdIns(3,4,5)P 3 binding-deficient mutant, we showed that the specific binding of the C1-Ten/Tensin2 SH2 domain to PtdIns(3,4,5)P 3 allowed C1-Ten/Tensin2 to function as a PTP in cells. Collectively, our findings suggest that the interaction between the C1-Ten/Tensin2 SH2 domain and PtdIns(3,4,5)P 3 produces a negative feedback loop of insulin signaling through IRS-1., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: There are limitations to current colorectal cancer (CRC)-specific diagnostic methods and therapies. Tumorigenesis proceeds because of interaction between cancer cells and various surrounding cells; discovering new molecular mediators through studies of the CRC secretome is a promising approach for the development of CRC diagnostics and therapies., Materials and Methods: A comparative secretomic analysis was performed using primary and metastatic human isogenic CRC cells. Proliferation was determined by MTT and thymidine incorporation assay, migration was determined by wound-healing assay (ELISA). The level of palmitoleoyl-protein carboxylesterase (NOTUM) in plasma from patients with CRC was determined by enzyme-linked immunosorbent assay., Results: NOTUM expression was increased in metastatic cells. Proliferation was suppressed by inhibiting expression of NOTUM. Knockdown of NOTUM genes inhibited proliferation as well as migration, with possible involvement of p38 and c-JUN N-terminal kinase in this process. The result was verified in patients with CRC., Conclusion: NOTUM may be a new candidate for diagnostics and therapy of CRC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: Previous findings suggest that hand movement laterality is reversed during sleep. The present study aimed to verify this phenomenon and evaluate whether the extent of reversal is correlated with the severity of sleep apnea., Methods: A total of 184 participants (mean age: 44.5±13.0 years; 81.5% males) wore actigraphs on both hands during sleep, and nocturnal polysomnography was simultaneously performed., Results: Actigraphic indices of hand movement were significantly higher for the left hand than those for the right hand (p<0.001), including total activity score, mean activity score, mean score in active periods and fragmentation index. Additionally, calculated differences between the fragmentation index for the left versus right hands were significantly correlated with the apnea-hypopnea index (AHI, r=0.149, p=0.032). The AHI was not significantly correlated with differences in hand movement between both hands movement assessed by total activity score (r=0.004, p=0.957), mean activity score (r=0.011, p=0.876), mean score in active periods (r=-0.080, p=0.255)., Conclusion: More severe symptoms of obstructive sleep apnea was associated with larger degree of hand movement reversal at night. This result support the theory that homeostatic deactivation occurs in the dominant hemisphere during sleep.

The circular F-type mitochondrial genome (15,761 bp) was completely sequenced for a Korean freshwater mussel Nodularia douglasiae (synonym Unio douglasiae ; Unionidae, Unionida, Bivalvia). It contains 13 PCGs, two rRNA genes, and 22 tRNA genes, as generally shown in metazoan mitochondrial genomes. Its gene order is identical to that of F-type mitochondrial genomes observed in other freshwater mussels. With nucleotide and amino acid sequences of the complete F-type mitochondrial genomes obtained from 38 unionid species reported so far, phylogenetic analyses were done and discussed. The present study may give valuable helps to explore genetic diversity and population structures of other freshwater mussels as well as N. douglasiae ., Competing Interests: The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper., (© 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

The gastrointestinal tract is a specialized organ in which dynamic interactions between host cells and the complex environment occur in addition to food digestion. Together with the chemical barrier of the mucosal layer and the cellular immune system, the epithelial cell layer performs a pivotal role as the first physical barrier against external factors and maintains a symbiotic relationship with commensal bacteria. The tight junction proteins, including occludin, claudins, and zonula occludens, are crucial for the maintenance of epithelial barrier integrity. To allow the transport of essential molecules and restrict harmful substances, the intracellular signaling transduction system and a number of extracellular stimuli such as cytokines, small GTPases, and post-translational modifications dynamically modulate the tight junction protein complexes. An imbalance in these regulations leads to compromised barrier integrity and is linked with pathological conditions. Despite the obscurity of the causal relationship, the loss of barrier integrity is considered to contribute to inflammatory bowel disease, obesity, and metabolic disorders. The elucidation of the role of diseases in barrier integrity and the underlying regulatory mechanisms have improved our understanding of the intestinal barrier to allow the development of novel and potent therapeutic approaches.

Objective: To investigate the effects of completed pregnancy with childbirth and incomplete pregnancy without childbirth on the late-life cognition and the risk of Alzheimer disease (AD) in women., Methods: Using the pooled data of 3,549 women provided by 2 population-based cohort studies, we conducted logistic regression analyses to examine retrospectively the associations of completed and incomplete pregnancy with the risks of mild cognitive impairment and AD. For women without dementia, we also conducted analyses of covariance to examine the associations of completed and incomplete pregnancy with Mini-Mental State Examination (MMSE) score., Results: Grand multiparous women who experienced ≥5 completed pregnancies showed an ≈1.7-fold higher risk of AD than those who experienced 1 to 4 completed pregnancies (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.04-2.72), while those who had incomplete pregnancies showed half the level of AD risk compared with those who never experienced an incomplete pregnancy (OR 0.43, 95% CI 0.24-0.76 for 1 incomplete pregnancy; OR 0.56, 95% CI 0.34-0.92 for ≥2 incomplete pregnancies). In women without dementia, the grand multiparous had worse MMSE scores than those with 1 to 4 completed pregnancies ( p < 0.001), while those who experienced ≥1 incomplete pregnancies had better MMSE scores than those who never experienced an incomplete pregnancy ( p = 0.008)., Conclusions: Grand multiparity was associated with high risk of AD, while incomplete pregnancy was associated with low risk of AD in late life., (© 2018 American Academy of Neurology.)

Increased fatty acid (FA) is often observed in highly proliferative tumors. FAs have been shown to modulate the secretion of proteins from tumor cells, contributing to tumor survival. However, the secreted factors affected by FA have not been systematically explored. Here, we found that treatment of oleate, a monounsaturated omega-9 FA, promoted the proliferation of HepG2 cells. To examine the secreted factors associated with oleate-induced cell proliferation, we performed a comprehensive secretome profiling of oleate-treated and untreated HepG2 cells. A comparison of the secretomes identified 349 differentially secreted proteins (DSPs; 145 upregulated and 192 downregulated) in oleate-treated samples, compared to untreated samples. The functional enrichment and network analyses of the DSPs revealed that the 145 upregulated secreted proteins by oleate treatment were mainly associated with cell proliferation-related processes, such as lipid metabolism, inflammatory response, and ER stress. Based on the network models of the DSPs, we selected six DSPs (MIF, THBS1, PDIA3, APOA1, FASN, and EEF2) that can represent such processes related to cell proliferation. Thus, our results provided a secretome profile indicative of an oleate-induced proliferation of HepG2 cells.

Objective: Due to an unprecedented rate of population aging, South Korea is facing a dementia epidemic. For this reason, the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD) was launched in 2009 with support from the Korean Health Industry Development Institute to investigate the epidemiology, biopsychosocial risk factors, and outcomes of dementia and dementia-related conditions., Methods: The KLOSCAD is the first nationwide multi-center population-based prospective cohort study. In October 2010, 12,694 individuals were randomly sampled from residents aged 60 years or older who lived in 13 districts across South Korea. In the baseline assessment, which was conducted from November 2010 through October 2012, 6,818 (53.7%) individuals participated. Follow-up assessments have been conducted every two years, with the first follow-up assessment conducted between November 2012 and October 2014, and the second between November 2014 and October 2016. The third is now in progress, and will span from November 2016 to October 2018. Diagnosis of cognitive disorders, neuropsychological battery, behavioral and psychological symptoms of dementia, activities of daily living, physical and neurologic examination and laboratory tests, life styles, quality of life, and identification of death were evaluated in each assessment., Results: The cumulative drop-out rate at the second follow-up assessment was 38.7%. Dementia and mild cognitive impairment were 5.0% and 27.0%, respectively., Conclusion: The KLOSCAD may provide strong scientific evidence for advancing the fight against dementia both in Korea and globally.

Two-dimensional (2D) crystals have emerged as a class of materials with tunable carrier density 1 . Carrier doping to 2D semiconductors can be used to modulate many-body interactions 2 and to explore novel composite particles. The Holstein polaron is a small composite particle of an electron that carries a cloud of self-induced lattice deformation (or phonons) 3-5 , which has been proposed to play a key role in high-temperature superconductivity 6 and carrier mobility in devices 7 . Here we report the discovery of Holstein polarons in a surface-doped layered semiconductor, MoS 2 , in which a puzzling 2D superconducting dome with the critical temperature of 12 K was found recently 8-11 . Using a high-resolution band mapping of charge carriers, we found strong band renormalizations collectively identified as a hitherto unobserved spectral function of Holstein polarons 12-18 . The short-range nature of electron-phonon (e-ph) coupling in MoS 2 can be explained by its valley degeneracy, which enables strong intervalley coupling mediated by acoustic phonons. The coupling strength is found to increase gradually along the superconducting dome up to the intermediate regime, which suggests a bipolaronic pairing in the 2D superconductivity.

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.

Voltage-gated Ca 2+ channels (Ca v ) are essential for pancreatic beta cell function as they mediate Ca 2+ influx, which leads to insulin exocytosis. The β3 subunit of Ca v (Ca v β 3 ) has been suggested to regulate cytosolic Ca 2+ ([Ca 2+ ] i ) oscillation frequency and insulin secretion under physiological conditions, but its role in diabetes is unclear. Here, we report that islets from diabetic mice show Ca v β 3 overexpression, altered [Ca 2+ ] i dynamics, and impaired insulin secretion upon glucose stimulation. Consequently, in high-fat diet (HFD)-induced diabetes, Ca v β 3 -deficient (Ca v β 3 -/- ) mice showed improved islet function and enhanced glucose tolerance. Normalization of Ca v β 3 expression in ob/ob islets by an antisense oligonucleotide rescued the altered [Ca 2+ ] i dynamics and impaired insulin secretion. Importantly, transplantation of Ca v β 3 -/- islets into the anterior chamber of the eye improved glucose tolerance in HFD-fed mice. Ca v β 3 overexpression in human islets also impaired insulin secretion. We thus suggest that Ca v β 3 may serve as a druggable target for diabetes treatment., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Molybdenum cofactor (Moco), molybdopterin (MPT) complexed with molybdenum, is an essential cofactor required for the catalytic center of diverse enzymes in all domains of life. Since Moco cannot be taken up as a nutrient unlike many other cofactors, Moco requires de novo biosynthesis. During the synthesis of MPT, the sulfur atom on the C-terminus of MoaD is transferred to cyclic pyranopterin monophosphate (cPMP) which is bound in the substrate pocket of MoaE. MoaD is a ubiquitin-like (Ubl) protein and has a C-terminal di-Gly motif which is a common feature of Ubl proteins. Despite the importance of free C terminal di-Gly motif of MoaD as a sulfur carrier, some bacteria encode a fused MPT synthase in which MoaD- and MoaE-like domains are located on a single peptide. Although it has recently been reported that the fused MPT synthase MoaX from Mycobacterium tuberculosis is posttranslationally cleaved into functional MoaD and MoaE in M. smegmatis, the protease responsible for the cleavage of MoaD-MoaE fusion protein has remained unknown to date. Here we report that the JAMM/MPN + domain containing metalloprotease DR0402 (JAMM DR ) from Deinococcus radiodurans can cleave the MoaD-MoaE fusion protein DR2607, the sole MPT synthase in D. radiodurans, generating the MoaD having a C-terminal di-Gly motif. Furthermore, JAMM DR can also cleave off the MoaD from MoaD-eGFP fusion protein suggesting that JAMM DR recognizes the MoaD region rather than MoaE region in the cleaving process of MoaD-MoaE fusion protein., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: We investigated the prevalence and risk factors of physically abusive behaviors (PhAB) and psychologically abusive behaviors (PsAB) towards people with dementia (PWD) in family caregivers, and compared their prevalences between East Asian and Western countries., Methods: We estimated the prevalence and risk factors of PhAB and PsAB in 467 Korean pairs of community-dwelling PWD and their primary family caregivers. We evaluated abusive behaviors using the Modified Conflict Tactics Scale. In addition, we compared the prevalence of abusive behaviors between Asian and Western countries through a meta-analysis on 12 studies including the current one., Results: More than a half of the caregivers reported PsAB and about one out of seven caregivers admitted PhAB within past three months. PsAB and PhAB were slightly more prevalent in East Asian countries than in Western countries. Non-Alzheimer type and moderate to severe behavioral and psychological symptoms of dementia were associated with the risk of PhAB but not with the risk of PsAB. Severe care burden and low income were associated with the risk of PhAB and PsAB., Conclusion: PhAB and PsAB were as prevalent in the family caregivers of PWD in Asian countries including Korea as in Western countries. Prevention strategies should be implemented according to the type of abusive behaviors.

PerR is a metal-dependent peroxide sensing transcription factor which controls the expression of genes involved in peroxide resistance. The function of Bacillus subtilis PerR is mainly dictated by the regulatory metal ion (Fe 2+ or Mn 2+ ) coordinated by three N-donor ligands (His37, His91, and His93) and two O-donor ligands (Asp85 and Asp104). While H 2 O 2 sensing by PerR is mediated by Fe 2+ -dependent oxidation of N-donor ligand (either His37 or His91), one of the O-donor ligands (Asp104), but not Asp85, has been proposed as the key residue that regulates the sensitivity of PerR to H 2 O 2 . Here we systematically investigated the relative roles of two O-donor ligands of PerR in metal-binding affinity and H 2 O 2 sensitivity in vivo and in vitro. Consistent with the previous report, in vitro the D104E-PerR could not sense low levels of H 2 O 2 in the presence of excess Fe 2+ sufficient for the formation of the Fe 2+ -bound D104E-PerR. However, the expression of PerR-regulated reporter fusion was not repressed by D104E-PerR in the presence of Fe 2+ , suggesting that Fe 2+ is not an effective corepressor for this mutant protein in vivo. Furthermore, in vitro metal titration assays indicate that D104E-PerR has a significantly reduced affinity for Fe 2+ , but not for Mn 2+ , when compared to wild type PerR. These data indicate that the type of O-donor ligand (Asp vs. Glu) at position 104 is an important determinant in providing high Fe 2+ -binding affinity required for the sensing of the physiologically relevant Fe 2+ -levels, in addition to its role in rendering PerR highly sensitive to physiological levels of H 2 O 2 . In comparison, the D85E-PerR did not show a perturbed change in Fe 2+ -binding affinity, however, it displayed a slightly decreased sensitivity to H 2 O 2 both in vivo and in vitro, suggesting that the type of O-donor ligand (Asp vs. Glu) at position 85 may be important for the fine-tuning of H 2 O 2 sensitivity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Diphosphoinositol pentakisphosphate (IP 7 ) is critical for the exocytotic capacity of the pancreatic β-cell, but its regulation by the primary instigator of β-cell exocytosis, glucose, is unknown. The high K m for ATP of the IP 7 -generating enzymes, the inositol hexakisphosphate kinases (IP6K1 and 2) suggests that these enzymes might serve as metabolic sensors in insulin secreting β-cells and act as translators of disrupted metabolism in diabetes. We investigated this hypothesis and now show that glucose stimulation, which increases the ATP/ADP ratio, leads to an early rise in IP 7 concentration in β-cells. RNAi mediated knock down of the IP6K1 isoform inhibits both glucose-mediated increase in IP 7 and first phase insulin secretion, demonstrating that IP6K1 integrates glucose metabolism and insulin exocytosis. In diabetic mouse islets the deranged ATP/ADP levels under both basal and glucose-stimulated conditions are mirrored in both disrupted IP 7 generation and insulin release. Thus the unique metabolic sensing properties of IP6K1 guarantees appropriate concentrations of IP 7 and thereby both correct basal insulin secretion and intact first phase insulin release. In addition, our data suggest that a specific cell signaling defect, namely, inappropriate IP 7 generation may be an essential convergence point integrating multiple metabolic defects into the commonly observed phenotype in diabetes., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate appropriate treatment time and useful bone turnover markers (BTMs) for monitoring bone turnover during the postmenopausal period, we analyzed changes of two bone resorption markers; serum carboxyterminal telopeptide of collagen I (s-CTX), urine deoxypyridinoline (u-DPD), one bone formation marker; serum osteocalcin (s-OC), and bone mineral density (BMD) in Korean postmenopausal women., Methods: Seventy-eight menopausal women were divided into three groups according to postmenopausal period: group I (0-5 years), group II (6-10 years), group III (≥10 years). All groups were subdivided into an osteoporosis group (T-score≤-2.5) and a non-osteoporosis group (T-score>-2.5). BTMs such as s-CTX, u-DPD, s-OC, and BMD (g/cm 2 ) were measured by dual-energy X-ray absorptiometry (DXA) in all patients. Analysis of variables among groups based on the postmenopausal period was performed using ANOVA., Results: There was significant negative correlation between BMD and postmenopausal period. The levels of all BTMs including s-CTX, u-DPD, and s-OC were highest in group II and the increased levels of all BTMs subsequently declined in group III. The levels of BTMs were higher in the osteoporosis groups than in the non-osteoporosis groups in all subjects. It was statistically significant that the level of s-CTX in group I was higher in the osteoporosis group than in the non-osteoporosis group., Conclusion: This study showed that bone resorption and bone formation were the highest 5-10 years after menopause, and s-CTX is more useful than u-DPD among the bone resorption markers. It's important to measure serially both BMD and BTM within 10 years after menopause for accurate diagnosis and management for postmenopausal osteoporosis.

Background: We investigated the effects of lifetime cumulative ginseng intake on cognitive function in a community-dwelling population-based prospective cohort of Korean elders., Methods: Community-dwelling elders (N = 6422; mean age = 70.2 ± 6.9 years, education = 8.0 ± 5.3 years, female = 56.8%) from the Korean Longitudinal Study on Cognitive Aging and Dementia were included. Among them, 3918 participants (61.0%) completed the 2-year and 4-year follow-up evaluations. Subjects were categorized according to cumulative ginseng intake at baseline evaluation; no use group, low use (< 5 years) group, and high use (≥ 5 years) group. One-way analysis of covariance (ANCOVA) was conducted to compare the impact of cumulative ginseng intake on baseline Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet neuropsychological battery total score (CERAD total score) and Mini-Mental State Examination (MMSE) score among the three groups while adjusting for potential covariates. A repeated-measures ANCOVA was performed to investigate the impacts on the changes in CERAD total scores and MMSE scores during the 4 years of follow-up., Results: The high use group showed higher CERAD total scores compared to the no use group after controlling for age, sex, education years, socioeconomic status, smoking, alcohol intake, presence of hypertension, stroke history, Geriatric Depression Scale, Cumulative Illness Rating Scale, and presence of the APOE e4 allele (F(2, 4762) = 3.978, p = 0.019). The changes of CERAD total score for 2 or 4 years of follow-up did not differ according to the use of ginseng., Conclusions: Cumulative ginseng use for longer than 5 years may be beneficial to cognitive function in late life.

Combinatorial post-translational modifications (PTMs), which can serve as dynamic "molecular barcodes", have been proposed to regulate distinct protein functions. However, studies of combinatorial PTMs on single protein molecules have been hindered by a lack of suitable analytical methods. Here, we describe erasable single-molecule blotting (eSiMBlot) for combinatorial PTM profiling. This assay is performed in a highly multiplexed manner and leverages the benefits of covalent protein immobilization, cyclic probing with different antibodies, and single molecule fluorescence imaging. Especially, facile and efficient covalent immobilization on a surface using Cu-free click chemistry permits multiple rounds (>10) of antibody erasing/reprobing without loss of antigenicity. Moreover, cumulative detection of coregistered multiple data sets for immobilized single-epitope molecules, such as HA peptide, can be used to increase the antibody detection rate. Finally, eSiMBlot enables direct visualization and quantitative profiling of combinatorial PTM codes at the single-molecule level, as we demonstrate by revealing the novel phospho-codes of ligand-induced epidermal growth factor receptor. Thus, eSiMBlot provides an unprecedentedly simple, rapid, and versatile platform for analyzing the vast number of combinatorial PTMs in biological pathways., Competing Interests: The authors declare no competing financial interest.

Two biological activities of butyrate in the colon (suppression of proliferation of colonic epithelial stem cells and inflammation) correlate with inhibition of the activity of histone deacetylases. Cellular and biochemical studies of molecules similar in structure to butyrate, but different in molecular details (functional groups, chain-length, deuteration, oxidation level, fluorination, or degree of unsaturation), demonstrated that these activities were sensitive to molecular structure, and were compatible with the hypothesis that butyrate acts by binding to the Zn 2+ in the catalytic site of histone deacetylases. Structure-activity relationships drawn from a set of 36 compounds offer a starting point for the design of new compounds targeting the inhibition of histone deacetylases. The observation that butyrate was more potent than other short-chain fatty acids is compatible with the hypothesis that crypts evolved (at least in part), to separate stem cells at the base of crypts from butyrate produced by commensal bacteria.

The insulin receptor is an important regulator of metabolic processes in the body, and in particular of glucose homeostasis, including glucose uptake into peripheral tissues. Thus, insulin administration is an effective treatment for diabetes, which is characterized by chronic elevation of blood glucose. However, insulin is not only a metabolic regulator, but also functions as a growth hormone. Accordingly, studies of long-term insulin administration and of the hyperinsulinemia associated with type 2 diabetes have raised concerns about possible increases in the risks of cancer and atherosclerosis, due to excessive stimulation of cell proliferation. Interestingly, some insulin receptor ligands that have been developed based on a peptide, an antibody, and an aptamer selectively have metabolic effects exerted through the insulin receptor but do not cause significant cellular proliferation. Although these ligands therefore have potential as anti-diabetic drugs for advanced diabetes care, the mechanism whereby they specifically activate the insulin receptor is still unclear. Recently, studies of the structure of the insulin receptor have progressed considerably, and have provided further mechanistic understanding of insulin receptor activation. Based on this progress, we propose a mechanistic model of this specificity and discuss the potential for the development of novel anti-diabetic drugs that would not have the adverse effects caused by excessive mitogenic action., (Copyright © 2017 Elsevier Inc. All rights reserved.)