Search

Female pattern hair loss (FPHL), the most common cause of alopecia in adult women, is classified into two subtypes: early onset and late onset (or postmenopausal). Little is known about the clinical features and genetic characteristics of early onset female pattern hair loss (eFPHL).To investigate the clinical features and genetic characteristics of eFPHL.Patients with eFPHL and controls without eFPHL were prospectively recruited. The demographic and clinical features were collected. Single nucleotide polymorphisms (SNPs) located around the selected 30 candidate genes potentially associated with eFPHL were evaluated.eFPHL patients (n = 63) manifested a decreased hair shaft density and cross-sectional area of the hair shaft compared to the control group (n = 341). eFPHL is associated with androgen-related features, including scalp greasiness, folliculitis, hirsutism, and polycystic ovary syndrome. Scalp pain and itching have been reported more frequently in patients with eFPHL. Forty-nine SNPs located around PPARGC1A, ABCC4, CYP11B2, FSHB, and CYP19A1 were found to be significant for eFPHL, including two PPARGC1A-associated SNPs: rs186530605 and rs192713767 (p = 3.94 × 10This study provided clinical features and genetic variants for eFPHL, which could provide insight into the underlying pathologic etiology. Considering the limited number of patients, a large-scale study is required in the future.

Although prime editors are a powerful tool for genome editing, which can generate various types of mutations such as nucleotide substitutions, insertions, and deletions in the genome without double-strand breaks or donor DNA, the conventional prime editors are still limited to their target scopes because of the PAM preference of the Streptococcus pyogenes Cas9 (spCas9) protein. Here, we describe the engineered prime editors to expand the range of their target sites using various PAM-flexible Cas9 variants. Using the engineered prime editors, we could successfully generate more than 50 types of mutations with up to 51.7% prime-editing activity in HEK293T cells. In addition, we successfully introduced the BRAF V600E mutation, which could not be induced by conventional prime editors. These variants of prime editors will broaden the applicability of CRISPR-based prime editing technologies in biological research.

Credit card fraud detection is an essential part of screening fraudulent transactions in advance of their authorization by card issuers. Although credit card frauds occur extremely infrequently, they result in huge losses as most fraudulent transactions have large values. An adequate detection of fraud allows investigators to take timely actions that can potentially prevent additional fraud or financial losses. In practice, however, investigators can only check a few alerts per day since the investigation process can be long and tedious. Thus, the primary goal of the fraud detection model is to return accurate alerts with fewer false alarms and missed frauds. Conventional fraud detection is mainly based on the hybrid ensemble of diverse machine learning models. Recently, several studies have compared deep learning and traditional machine learning models including ensemble. However, these studies used evaluation methods without considering that the real-world fraud detection system operated with the constraints: (i) the number of investigators who check the high-risk transactions from the data-driven scoring models are limited and (ii) the two types of misclassification, false alarms and missed frauds, have different costs. In this study, we conducted an in-depth comparison between the hybrid ensemble and deep learning method to determine whether or not to adopt the latter in our partner’s system that currently operates with the hybrid ensemble model. To compare the two, we introduced the champion-challenger framework and the development process of the two models. After developing the two models, we evaluated them on large transaction data sets taken from our partner, a major card issuing company in South Korea. We used various practical evaluation metrics appropriate for this domain that has severe class and cost imbalances. Moreover, we deployed these models in a real-world fraud detection system to check the post-launch performance for one month. The challenger outperformed the champion on both in off-line and post-launch tests.

The effect of Y addition on Fe-removal effect in magnesium melt was investigated using pure magnesium with a high level of Fe impurity. It was confirmed that Fe concentration was significantly reduced even at relatively high melting and holding temperatures and even with very small amounts of Y. It was also found that Fe contents of magnesium alloys are proportional to the corrosion rates. Hence, magnesium alloys containing Y, which has the strongest Fe-removal ability, have the lowest corrosion rates. The corrosion rate of Mg-3Al-0.2Y is only 1.4 mm/y, corresponding to 0.6% of that of the Mg-3Al alloy (214.9 mm/y).

Associations between air pollution and blood pressure (BP) traits can be modified by several candidate genes, which might explain differences in individual genetic susceptibility. Based on recent evidence hypothesized to link air pollution and BP traits, we examined whether the polymorphisms of CDH13—a candidate gene—would modify the relationship between them in adult Korean men. A total of 1816 subjects were included. We divided them into two groups of high or low to moderate exposure using the annual average concentration of particulate matter with an aerodynamic diameter ≤10 μm (PM10). We conducted an interaction analysis of PM10 exposure using 200 single-nucleotide polymorphisms (SNPs), located within CDH13, in subjects with regard to BP traits and hypertension. The rs7500599 intronic SNP of CDH13 had the strongest signals for all BP traits including systolic blood pressure (SBP), diastolic blood pressure, and hypertension, by interacting with PM10 exposure. An additional stratified analysis showed that the effects of PM10 exposure on elevated BP and hypertension increased gradually in proportion to the number of minor alleles in this SNP. In addition, PM10 exposure in the TT or GT genotype groups did not show significant associations with BP traits, whereas in a homozygous risk allele (GG) group, PM10 exposure was significantly associated with BP traits and hypertension. For SBP, these patterns were reproducible at two independent sampling sites. This CDH13 polymorphism amplifies the negative associations of PM10 exposure and elevated BP or hypertension in Korean men.

In this study, the oxidation resistance of nuclear grade graphite (IG-430U) and NITE-SiC/SiC composites with/without CVD-SiC outer coating were evaluated at various temperatures (400–1000 °C) under high oxygen contents (O2 1% and O2 21%). The effect of CVD-SiC outer coating on the oxidation of NITE-SiC/SiC composite was also investigated in the atmosphere of partial oxygen. The weight change of NITE-SiC/SiC composites was mainly dominated by the active oxidation at the interphase of PyC. The weight change speed of these materials significantly decreased with increasing the oxidation time. The oxygen concentration was not sensitive for the oxidation behavior of NITE-SiC/SiC composites, because these materials were affected by oxygen supply rate and CO2 gas evaporation rate through fine channels between fiber and matrix. The PyC interphase of NITE-SiC/SiC composites with a CVD-SiC outer coating remained after the oxidation test. It could be confirmed that the CVD-SiC environmental coating on the surface of NITE-SiC/SiC was very effective for the suppression of oxidation weight loss.

Tungsten carbide-Cobalt (WC-Co), also known as cemented carbide, is a widely used alloy to manufacture high-performance tools for mining, drilling, cutting, and machining applications. Due to the high melting point of WC, it is challenging to cast it to manufacture products. Therefore, in this study, we investigated a method for manufacturing cutting tools from WC-Co alloy using high-precision digital light processing-based three-dimensional (3D) printing technology. The high refractive index of WC renders it difficult to directly apply it to photocurable 3D printing. Therefore, a polymer mold was fabricated via 3D printing to obtain a WC-Co slurry cast. Rheological studies were performed to optimize the slurry composition. After slurry casting and drying, a green body was formed, which was sintered at 1400 °C to obtain a defect-free sample with a shape identical to that of the 3D model. The cast sample exhibited identical characteristics (microstructure, hardness, and fracture toughness) to those of conventional press-molded sample. The results of this study confirm that complex cutting tool manufacturing is possible without using expensive metal molds. The presented approach is expected to significantly reduce the cost and time incurred during the product development stage involving multiple designs.

Genetic epidemiological studies have provided evidence that several genes modify the link between air pollution and lung function. We assessed whether the adverse impacts of particulate matter with an aerodynamic diameter ≤10 μm (PM10) on lung function are modified by CYP1A1 gene polymorphisms in Korean adults. We used health check-up data from 1817 men, and the annual mean concentrations of ambient PM10 estimated from the ambient data. Three single nucleotide polymorphisms (SNPs) of CYP1A1 were selected for our study. We identified significant CYP1A1 SNPs-by-PM10 interactions for forced expiratory volume 1 s (FEV1) and forced vital capacity (FVC) (all pint 0.05), whereas in heterozygous or homozygous alternate genotype groups, PM10 was significantly associated with decreased FEV1 (all passoc for FEV1

Background: This research investigates the degrees of slipperiness felt by the participants who walk on contaminants applied to a floor surface to decide degrees of slipperiness for various contaminants. Methods: For the experiment, 30 participants walked on a floor to which six contaminants were applied. All participants took the analytic hierarchy process (AHP)–based slipperiness questionnaire survey for the six kinds of contaminants, and the results were compared with the coefficient of friction. Results: The results of slip risk from the AHP indicate that grease is the most slippery of the six contaminants, followed by diesel engine oil, hydraulic oil, cooking oil, water-soluble cutting oil, and water in a decreasing order of slipperiness. When the results of slip risk from the AHP are compared with the static coefficient of friction for each contaminant, the order of slip risk follows the same trend. Although the results of slip risk from the AHP coincide with the static coefficient of friction, further study would be needed to investigate this relationship. Conclusion: This study will contribute as reference material for future research on preventing industrial accidents that result in falls from high places due to slipping. Keywords: AHP, Coefficient of friction, Contaminants, Slip accidents, Slipperiness

Objectives To assess Asian data from Global Prevalence Study on Infections in Urology (GPIU study) which has been performed more than 10 years. Methods Seventeen Asian countries participated in the GPIU study between 2004 and 2013. Data for these countries were collected from the web-based GPIU database. The point prevalence of urinary tract infections (UTI) and antimicrobial susceptibility of representative pathogens were analysed for Asian geographic regions. Results A total of 6706 patients (5271 male, 1435 female) were assessed during the study period, and 659 patients were diagnosed with a UTI (9.8%). Of these UTI patients, 436 were male and 223 were female. Mean patient age was 54.9 ± 19.3 years. Pyelonephritis and cystitis were the most common clinical diagnoses, representing 30.7% and 29.9% of patients, respectively. Escherichia coli was the most frequently identified uropathogen (38.7%). For the patients with urinary tract infection, cephalosporins were the most frequently used antibiotics (34.4%), followed by fluoroquinolones (24.1%), aminoglycosides (16.8%). Fluoroquinolone resistance was relatively high (ciprofloxacin 54.9%, levofloxacin 39.0%), and cephalosporin resistance 42% (42.5–49.4%). Of the antibiotics evaluated, uropathogens had maintained the highest level of susceptibility to amikacin and imipenem (24.9% and 11.3% resistance rates, respectively). Conclusion Uropathogens in many Asian countries had high resistance to broad-spectrum antibiotics. Knowledge of regional and local resistance data and prudent use of antibiotics are important for proper management of UTI in Asian countries.

Development of the Helium Cooled Ceramic Reflector (HCCR) breeding blanket is underway according to the development strategy of core technology for K-DEMO under the fusion energy development roadmap in Korea. The main goals are to validate integrated design tools and to develop core technologies in the field of materials, manufacturing and joining technologies, helium cooling and tritium technologies, system integration, and safety technologies. A unique graphite reflector concept was adopted to save cost by reducing the amount of beryllium neutron multiplier. The main functions and design concepts of the HCCR breeding blanket are to be verified in ITER through the HCCR Test Blanket Module (TBM) program. Not only breeder modules are to be tested in ITER but also the technologies of cooling, coolant purification, tritium extraction, etc. are to be tested or proved in ITER before employed in DEMO. This paper introduces the current updates of the design and R&D activities of the HCCR TBM systems in the preliminary design stage.

Lung function can be influenced by genetic factors, which may explain individual differences in susceptibility to the effects of air pollution. This study investigated whether the effect of particulate matter with an aerodynamic diameter ≤10 μm (PM10) on lung function is modified by Cadherin 13 (CDH13) genetic variants in Korean men. This study included a total of 1827 men who were recruited from two health check-up centers, and the annual average PM10 concentrations were used. A total of 200 single-nucleotide polymorphisms (SNPs) of the CDH13 gene were selected for this study. We found that a SNP in CHD13 intron, rs1862830, had the strongest associations with both forced expiratory volume in 1 s (FEV1) (pint = 1.90 × 10−4) and forced vital capacity (FVC) (pint = 1.88 × 10−3) by interacting with PM10 in a recessive model. A stratified association analysis according to this SNP showed that PM10 in the AG or GG genotype group was not significantly associated with either FEV1 or FVC, whereas in homozygous risk-allele carriers (AA), FEV1 and FVC decreased significantly (by 3.8% and 3.1%, respectively) per 10 μg/m3 of increase in PM10 concentration. This pattern was also reproducible in the independent subgroups that were classified according to recruitment site. The present study replicated the CDH13 gene-by-PM10 interaction effect on lung function at the gene level, revealing that a genetic variant of CDH13 modified the relationship between PM10 and lung function decline in Korean men.

Aims There could be an overlap of monogenic diabetes and early onset type 2 diabetes in those who are diagnosed before age of 30years. Genetic diagnosis in these patients might improve the quality of care. A limited number of studies have used whole exome sequencing (WES) in Asian patients with early onset diabetes, and the clinical utility of WES is largely unknown. Methods We performed whole exome capture and massive parallel sequencing in 28 patients with early onset diabetes. Those who had a strong family history of diabetes were preferentially enrolled. Rare and non-silent variants in 29 genes known to cause monogenic diabetes, including 12 maturity-onset diabetes of the young (MODY) genes, were investigated for pathogenicity. Results The average depth of on-target WES reads was 97 X. A total of four pathogenic or likely pathogenic rare missense variants (p.Leu319Pro in HNF4A , p.His103Tyr and p.Arg74Gln in ABCC8 , and p.Leu139Val in HNF1A ) in MODY genes were identified in three patients. Although four rare non-silent variants in MODY genes (p.Arg183Cys in PAX4 , p.Val139Ile and p.Pro740fs in CEL , and p.Val147Ile in HNF4A ) and two rare non-silent variants in monogenic diabetes genes (p.Glu169Lys in WFS1 , and p.Pro407Gln in GATA4 ) were identified, their pathogenicity was uncertain or likely benign. Conclusions WES could be an initial option for genetic testing in patients with early onset diabetes. However, sufficient and universal coverage of genes of interest is required. In addition, it could be difficult to interpret variant pathogenicity, and these cases might require further validation.

To improve the hemostatic function of chitosan nanofiber mats, we studied the synergetic effects of gelatin blending and porosity control. Gelatin-blended-chitosan (Chi-Gel) nanofiber mats were evaluated with respect to surface morphology, mechanical properties and wettability, and functionally tested in a blood clotting study. The blood clotting efficiency of Chi-Gel nanofiber mats using rabbit whole blood in vitro was superior to that of chitosan nanofibers. Moreover, Chi-Gel nanofiber mats with enlarged porosity, produced by ultra-sonication, showed improved blood clotting efficiency, cell viability and cell infiltration compared with non-sonicated Chi-Gel nanofiber mats. Field-emission scanning electron microscopy revealed a richer density of platelets on sonicated nanofiber mats than on non-sonicated nanofiber mats after 3 min of blood clotting. The proliferation of human dermal fibroblast cells on sonicated Chi-Gel nanofiber mats using the DNA assay was higher than that on non-sonicated chitosan nanofiber mats after 7 days of culture. Confocal z-stack images showed that sonicated Chi-Gel nanofiber mats with high porosity supported active cell migration and infiltration into the 3-dimensional nanofiber mats. These results suggest that hydrophilic gelatin blending and sonication of chitosan nanofiber mats yields synergistic effects that not only improve hemostatic function but also promote wound repair.

Recently, targeting deregulated energy metabolism is an emerging strategy for cancer therapy. In the present study, combination of DCA and metformin markedly induced cell death, compared with each drug alone. Furthermore, the expression levels of glycolytic enzymes including HK2, LDHA and ENO1 were downregulated by two drugs. Interestingly, HIF-1α activation markedly suppressed DCA/metformin-induced cell death and recovered the expressions of glycolytic enzymes that were decreased by two drugs. Based on these findings, we propose that targeting HIF-1α is necessary for cancer metabolism targeted therapy.

Lithium meta-titanate (Li2TiO3) have been proposed as candidate breeder materials for fusion breeding blankets. For the efficient tritium release, the breeder materials are recommended to have homogeneous microstructure with small grain sizes which can be strongly affected by the sintering conditions such as temperature, heating rate, atmosphere and so on. The Li2TiO3 pebbles were fabricated by the slurry droplet wetting method with nano-powder. In this study, the effects of sintering conditions on the microstructure of sintered pebbles were investigated. Phase analysis and morphological observation were carried out by X-ray diffraction and electron microscopy, respectively. The grain growth is strongly affected by the increasing temperature and heating rate. The sintering temperature of 900 °C and 10 °C/min were optimal condition for small grain size.

Although several genome-wide interaction studies (GWIS) have been performed in specific European populations to understand the missing link between genetic and environmental factors for lung function, GWIS of Asian samples remain rare. Therefore, we performed a GWIS of exposure to air pollution to identify loci for lung function in Korean adult men. A total of 1826 adult men recruited from two health check-up centers were included in the analysis and the annual mean concentrations of ambient particulate matter with an aerodynamic diameter ≤10 μm (PM10) were used. In case of forced vital capacity (FVC), one SNP (rs12312730) that passed our genome-wide threshold of pint

Diols with short aliphatic chains were known to exhibit antimicrobial activities, which were found to depend on the chain length and the position of the hydroxyl groups. We carried out the conformational preferences of 1,n-hexanediols (n = 2–6) and (S)-3-alkoxypropane-1,2-diols in the gas phase and in water using density functional methods and explored the factors important to exhibit antimicrobial activities. In the case of 1,2-, 1,3-, and 1,4-hexanediols, intramolecular H-bonds played a role in stabilizing their preferred conformers in the gas phase, whereas they were remarkably depopulated in water. For 1,5-, and 1,6-hexanediols, no H-bonded conformers were favored both in the gas phase and in water. The C–H⋯O interactions appeared to be of consequence in determining the preferred structures of 1,n-hexanediols (n = 3–6) in water. The stabilization of the preferred conformers of (S)-3-alkoxypropane-1,2-diols could be ascribed to the bifurcated H-bonds both in the gas phase and in water. However, their populations were decreased and the –CH2–O–(CH2)m–CH3 chain became more extended in water. In the optimized structures of dimers and trimers of 1,2-hexanediol and (S)-3-(hexyloxy)propane-1,2-diol in water, the head OH groups are oriented to each other to form intermolecular H-bonds and the aliphatic tails are stretched out away from the head groups, which are likely to form micelle-like structures in water. When two hydroxyl groups become closer and the aliphatic chain becomes longer, the amphipathicity of alkanediol is increased and thus, it is likely to penetrate more easily into membrane bilayers of the microbial cell and may disrupt the membrane structure.

Anaplastic lymphoma receptor tyrosine kinase ( ALK ) is located on chromosome 2p23; the chromosomal rearrangements of this gene are common genetic alterations, resulting in the creation of multiple fusion genes involved in tumorigenesis. However, the presence of an ALK fusion in myeloid malignancies is extremely rare. We report a case of acute myelomonocytic leukemia in a 31-year-old woman with an unusual rearrangement between RAN-binding protein 2 ( RANBP2 ) and ALK and a karyotype of 45,XX,inv(2)(p23q21),–7[20]. We detected an ALK rearrangement using fluorescence in situ hybridization, identified the ALK fusion partner by using RNA transcriptome sequencing, and demonstrated the RANBP2 – ALK fusion transcript by reverse transcriptase–PCR and Sanger sequencing. Immunohistochemistry for ALK showed strong staining of the nuclear membrane in leukemic cells. The patient had an unfavorable clinical course. Our results, together with a literature review, suggest the RANBP2 - ALK fusion combined with monosomy 7 may be related to a unique clonal hematologic disorder of childhood and adolescence, characterized by myelomonocytic leukemia and a poor prognosis.

Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using metabolic profiling, we found that exposure to amyloid-β triggers acute microglial inflammation accompanied by metabolic reprogramming from oxidative phosphorylation to glycolysis. It was dependent on the mTOR-HIF-1α pathway. However, once activated, microglia reached a chronic tolerant phase as a result of broad defects in energy metabolisms and subsequently diminished immune responses, including cytokine secretion and phagocytosis. Using genome-wide RNA sequencing and multiphoton microscopy techniques, we further identified metabolically defective microglia in 5XFAD mice, an AD mouse model. Finally, we showed that metabolic boosting with recombinant interferon-γ treatment reversed the defective glycolytic metabolism and inflammatory functions of microglia, thereby mitigating the AD pathology of 5XFAD mice. Collectively, metabolic reprogramming is crucial for microglial functions in AD, and modulating metabolism might be a new therapeutic strategy for AD.

Herein, we show that the constitutive overexpression of Redd1, a negative regulator of mTORC1, induces Akt activation in lung cancer cells. Akt phosphorylation was reduced to basal levels by Rictor siRNA, suggesting the involvement of mTORC2 in this process. Perifosine and PP242, selective inhibitors of Akt and mTORC1/2, respectively, efficiently suppressed the Akt phosphorylation that was induced by the sustained overexpression of Redd1 and increased the sensitivity of the cells to cisplatin. Therefore, the sustained overexpression of Redd1 leads to mTORC1 inhibition and to consequent Akt activation that is involved in cell survival. This finding highlights the importance of Akt activation as a therapeutic target to overcome resistance to chemotherapy.

Resistance of estrogen receptor-positive breast cancer cells to tamoxifen represents a major barrier to the successful treatment of breast cancer. In the present study, we found that vacuolar H+ ATPase (vATPase) inhibitors, bafilomycin A1 and concanamycin A, sensitize tamoxifen-induced cell death. siRNA targeting ATP6V0C, a 16-kDa hydrophobic proteolipid subunit of vATPase that plays a central role in H+ transport, markedly increased cell death induced by tamoxifen. Interestingly, bafilomycin A1 induced up-regulation of DR4/DR5 and CHOP. Knock-down of CHOP by siRNA suppressed the cell death induced by bafilomycin A1 and tamoxifen, suggesting that bafilomycin A1-mediated CHOP activation sensitizes to tamoxifen. In addition, we found that bafilomycin A1 enhances TRAIL-induced cell death in breast cancer cells. Furthermore, we showed that combination of vATPase inhibitors with tamoxifen also effectively induced cell death in HER2- and ERα-overexpressing breast cancer cells. Overall, our results demonstrate that inhibition of vATPase can potentiate the apoptotic effects of tamoxifen through up-regulation of CHOP.

Targeted resequencing using next-generation sequencing technology is being rapidly applied to the molecular diagnosis of human genetic diseases. The group of muscular dystrophies may be an appropriate candidate for this approach because these diseases exhibit genotype–phenotype heterogeneity. To perform a proof-of-concept study, we selected four patients with congenital muscular dystrophies with defective glycosylation of alpha-dystroglycan. A custom-solution-based target enrichment kit was designed to capture whole-genic regions of the 26 muscular-dystrophy-related genes, including six genes implicated in alpha-dystroglycanopathies. Although approximately 95% of both coding and noncoding regions were covered with at least 15-read depth, parts of the coding exons of FKRP and POMT2 were insufficiently covered. Homozygous and compound heterozygous POMGnT1 mutations were found in two patients. Two novel noncoding variants of FKTN were identified in one patient who had a retrotransposon insertion mutation of FKTN in only one allele. The current targeted resequencing strategy yielded promising results for the extension of this method to other muscular dystrophies. As suboptimal coverage in a small subset of coding regions may affect the sensitivity of the method, complementary Sanger sequencing may be required.

The estimated glomerular filtration rate is a well-known measure of renal function and is widely used to follow the course of disease. Although there have been several investigations establishing the genetic background contributing to renal function, Asian populations have rarely been used in these genome-wide studies. Here, we aimed to find candidate genetic determinants of renal function in 1007 individuals from 73 extended families of Mongolian origin. Linkage analysis found two suggestive regions near 9q21 (logarithm of odds (LOD) 2.82) and 15q15 (LOD 2.70). The subsequent family-based association study found 2 and 10 significant single-nucleotide polymorphisms (SNPs) in each region, respectively. The strongest SNPs on chromosome 9 and 15 were rs17400257 and rs1153831 with P -values of 7.21 × 10 -9 and 2.47 × 10 -11 , respectively. Genes located near these SNPs are considered candidates for determining renal function and include FRMD3 , GATM , and SPATA5L1 . Thus, we identified possible loci that determine renal function in an isolated Asian population. Consistent with previous reports, our study found genes linked and associated with renal function in other populations.

Purpose The purpose of this study was to demonstrate a negative association between intraocular pressure (IOP) and age in 2 Asian populations. In addition, we evaluated genetic and nongenetic factors associated with IOP. Design Family-based cohort study. Participants Study subjects >10 years of age from one Korean ( The Healthy Twin ; n=1431) and 2 Mongolian populations ( The GENDISCAN ; n=859 and 806) with IOP values. Methods The IOP values were measured with a noncontact tonometer. Each participant received a standard health examination and received questionnaires, which include candidate risk factors on IOP. Mixed models were used to identify risk factors for IOP. Variance-component methods were applied to estimate the heritability of IOP. Main Outcome Measures The negative trend of IOP with aging and evaluation of impact of genetic and nongenetic components on IOP. Results The mean ages were 43.6, 34.1, and 36.3 years for the Korean, Orhontuul, and Dashbalbar populations, respectively. The mean IOPs were 14.4 mmHg (95% confidence interval [CI], 14.3–14.6) in the Koreans and 14.1 mmHg (95% CI, 13.9–14.3) and 12.6 mmHg (95% CI, 12.4–12.9) in the Orhontuul and Dashbalbar populations, respectively. In the 3 populations, the IOP decreased as age increased. We replicated an association of systolic blood pressure (SBP) with IOP. In addition, components of the metabolic syndrome (MS), such as plasma glucose, lipid level, and body mass index, showed positive associations with IOP, after adjusting for age and SBP. The IOP also had strong genetic contributions in all populations (heritability, 0.47–0.51). Conclusions Negative associations between age and IOP were observed in all 3 populations, which cannot be explained by the increasing prevalence of myopia in the younger generation. The different age trend in IOP may in part be responsible for differences in the prevalence of glaucoma subtypes. Our findings suggest that associations between IOP and MS components were independent of established risk factors such as SBP or age. In addition, the importance of inherited risks requires further genetic dissection of IOP determinants for biological understandings of underlying pathophysiology. Financial Disclosure(s) The authors have no proprietary or commercial interest in any materials discussed in this article.

Peripheral nerve injury often results in neuropathic pain that is manifested as hyperalgesia, and allodynia. Several studies suggest a functional role for neuronal nitric oxide synthase (nNOS) in the development or maintenance of neuropathic pain, but such a contribution remains unclear. In our current study, we found that intraplantar injection of the NOS substrate L-arginine or NO donor 3-morpholino-synonimine (SIN-1) produced mechanical hypersensitivity that lasted more than 24 h. Following L5 spinal nerve ligation (L5 SNL), immunoreactivity for nNOS in the ipsilateral L5 but not L4 dorsal root ganglion (DRG) was dramatically increased in mainly small- and medium-sized neurons and non-neuronal cells. L5 SNL caused increased nNOS immunoreactivity in the ipsilateral sciatic nerve, mainly in Schwann cells and the ipsilateral glabrous hind paw skin, mainly on the basement membrane. Furthermore, total nNOS protein and mRNA in the ipsilateral sciatic nerve and hind paw skin were markedly upregulated following nerve injury. Intraplantar injection of the NOS inhibitor 7-nitroindazole (7-NI) or the non-specific NOS inhibitor L-N(G)-nitro-arginine methyl ester (L-NAME) effectively suppressed SNL-induced mechanical allodynia. Collectively, these data suggest that in the periphery nNOS upregulation induced by peripheral nerve injury contributes to mechanical hypersensitivity during the maintenance phase of neuropathic pain. Blocking nNOS signaling in the periphery may thus be a novel therapeutic strategy for the treatment of neuropathic pain.

Carbon dioxide is one of the global warming gases. Utilization of a sustainable energy is one of the effective technologies for the mitigation of CO 2 accumulation in the atmosphere. If renewable energy can be used for methane synthesis, H 2 is converted to methane by reducing CO 2 . We investigated the conversion of CO 2 to CH 4 using a novel hollow-fiber membrane biofilm reactor. We have converted CO 2 to CH 4 with autotrophic methanogens using CO 2 and H 2 . All the gases were diffused into water through the membrane without bubbles. We have successfully operated the Hf-MBfR for stable methane production from CO 2 and H 2 under continuous operations for 60-70 days at acidic and neutral pH. The methane ratio of the gas produced depended on the pH condition and reached about 60% at neutral pH and 80-90% at acidic pH. The produced methane contents were 751 mL day -1 on average from 20 to 58 days at neutral pH and 135 mL day -1 on average from 36 to 43 days, 247 mL day -1 on average from 44 to 70 days at acidic pH. At neutral pH, during the operating periods, acetic acid was continuously produced to 4000-7000 mg/L so that produced methane was considered to have been produced by hydrogenotrophic methanogens and acetoclastic methanogens. At acidic pH, during the initial operating periods, pH was maintained to 5.9-6.6 so that acetic acid was produced by acetogens. After adjusting to less than pH 5.5, however, it was decreased. At the same time, the methane contents produced were considered to have increased by acetoclastic methanogens.

Despite considerable excitement over the potential functional significance of copy-number variants (CNVs), we still lack knowledge of the fine-scale architecture of the large majority of CNV regions in the human genome. In this study, we used a high-resolution array-based comparative genomic hybridization (aCGH) platform that targeted known CNV regions of the human genome at approximately 1 kb resolution to interrogate the genomic DNAs of 30 individuals from four HapMap populations. Our results revealed that 1020 of 1153 CNV loci (88%) were actually smaller in size than what is recorded in the Database of Genomic Variants based on previously published studies. A reduction in size of more than 50% was observed for 876 CNV regions (76%). We conclude that the total genomic content of currently known common human CNVs is likely smaller than previously thought. In addition, approximately 8% of the CNV regions observed in multiple individuals exhibited genomic architectural complexity in the form of smaller CNVs within larger ones and CNVs with interindividual variation in breakpoints. Future association studies that aim to capture the potential influences of CNVs on disease phenotypes will need to consider how to best ascertain this previously uncharacterized complexity.

In the heteroepitaxy deposited adatoms in the first layer migrate on a substrate with a heterodiffusion coefficient, while those in all the next layers – with a self-diffusion coefficient. In this paper the effect of two different adatom surface mobilities on the layer heteroepitaxial growth in the presence of an Ehrlich–Schwoebel barrier is studied quantitatively using kinetic model based on rate equations for adatom and 2D island density and coverage in successive layers combined with a feeding zone taking into account interlayer mass transport. It is shown that this effect is essential in the first few monolayers and strongly depends on a ratio hetero-to-self-diffusion coefficient and Ehrlich–Schwoebel barrier. A faster heterodiffusion leads to a more rough initial growth whereas a slower heterodiffusion – to a smoother initial growth. In a transient (homoepitaxial) growth regime from smooth layer-by-layer – to rough growth a slower heterodiffusion retards this transition, while a faster heterodiffusion promotes it, especially at higher Ehrlich–Schwoebel barrier. It is shown that a critical coverage for the next layer nucleation is more appropriate parameter for characterization growth mode transition than a widely used critical island radius because it does not depend on island density and uniquely determines growth mode transition and its dependence on hetero- and self-diffusion coefficients and a critical nucleus size is obtained. The results suggest an opportunity for improving ultrathin (a few monolayers) film surface morphology by manipulating growth mode during deposition by initial (first layer) deposition either at low substrate temperature (low diffusivity) or with high deposition rate and consecutive one either at higher temperature (high diffusivity) or with a lower deposition rate.

The surface spectroscopic methods, e.g. AES and XPS, are widely used in studies of thin film growth. In experiments spectroscopic data are recorded as intensity–film thickness curves. Much theoretical effort had been devoted to calculation AES intensity–thickness functions for different growth modes. A key element of such calculations is finding coverage in each layer. Recently, we developed two models of thin film growth that allow exact determining of coverage in all layers of a growing film. In island growth model the lateral islands growth occurs via capture of migrating adatoms whereas their vertical growth-owing to direct impingement of deposited atoms. Analysis of arising film morphology yields coverage in each layer in analytic form. In layer growth model based on rate equation approach combined with a feeding zone accounting for interlayer mass transport coverage in successive layers are calculated in a straightforward manner. Thus the AES intensity–film thickness functions were derived analytically for island growth and computed numerically for layer growth in various growth regimes (complete/incomplete condensation) and modes (smooth/rough), enabling experimental data to be examined quantitatively and in greater detail than has previously been reported.

Recently, promising results for epitaxial cobalt and nickel silicide formation have been obtained using a thin titanium interlayer and as a mechanism for such an interlayer promoting effect the removal of a native oxide from a silicon substrate due to the gettering effect of titanium was suggested. However, detailed information about transformations in the Ti layer during its growth and annealing process still lacks. In this paper, phase and structure transformations in the Ti interlayer during growth and consequent silicidation annealing are studied on the system Ni/Ti/Si(1 0 0). The Ni (4 nm)/Ti (1.4 nm) bilayers were deposited onto unheated (1 0 0) Si substrate with a native oxide layer by rf sputtering inside the AES – microscope and analyzed by in situ Auger electron spectroscopy, X-ray photoelectron spectroscopy and ex situ transmission electron microscopy. During the Ti interlayer deposition process a following sequence of the growth mechanism and phases were revealed. Initially, small 3D TiO 2 islands are formed due to reduction of a native silicon oxide followed by the formation of the TiO and TiO x phase between TiO 2 islands as well as on their top. During the silicidation annealing at 300 °C the continuous Ti-related interlayer, composed mainly (∼85%) of Ti oxides (TiO and TiO 2 ) transforms into less compact island-like TiO 2 layer what promotes Ni diffusion into silicon resulting in the nickel silicide, NiSi 2 formation.

The initial growth stages of materials non-active to a substrate has been extensively studied for decades, whereas there had been fewer studies on the initial growth of active metals on silicon substrate, despite its technological importance. In this paper the very early growth stages of transition metal (Ti, V and Nb) films deposited by rf sputtering on unheated (100) Si substrate were studied by in situ X-ray photoelectron spectroscopy. The following sequence of the phase composition and the growth mechanism changes during deposition process was revealed. Initially in a submonolayer regime, small 3D TiO2 islands are formed via reduction of a native silicon oxide layer on a substrate followed by formation of a TiO phase between TiO2 islands and on their top. After deposition of ca. 2 monolayers a metallic Ti phase appears and later only the metal Ti film grows. The same growth behavior takes place at Nb and V deposition with a difference that in the case of Nb the above changes occur at earlier stages what can be explained by the highest niobium activity to the reduction of silicon oxide in the row V, Nb, Ti.

The objective of this study is to examine the effects of regulation policy on online gambling, an increasingly popular type of entertainment in the online game industry. Prior information systems (IS) studies on online game focus primarily on user behavior. However, there is a growing need to investigate the effects of regulation policy on dynamic changes of games or service providers instead of ad hoc heuristic approaches on individual behavior. Going beyond the approaches of previous studies, this study empirically test the regulation policy effect with three theoretical perspectives: social influence, prior experience and perceived switching cost. A vector autoregression (VAR) methodology is used to forecast game usage and to model several patterns of the co-movement of online games. Evidence is also provided of strong Granger-causal interdependencies within games and service providers. This study provides one of the first empirical evidences that examine the effects of regulation policies on online game. In research methodology aspect, this study also introduce an exposition of VAR methodology in IS research. Therefore, it provides advanced knowledge on gambling behavior and helps develop suitable regulation policy to protect users of online gambling as well as to satisfy policy makers.

Survivin, a member of the inhibitor of apoptosis protein (IAP) family, may be a good target for cancer therapy because it is expressed in a variety of human tumors but not in differentiated adult tissues. In the present study, we show that a combination of sulindac and arsenic trioxide (ATO) induces more extensive apoptosis than either drug alone in A549 human non-small cell lung carcinoma (NSCLC) cells. Treatment with sulindac/ATO reduced the expression of survivin and promoted major apoptotic signaling events, namely, collapse of the mitochondrial membrane potential, release of cytochrome c, and activation of caspases. Combined sulindac/ATO treatment did not significantly affect the levels of other members of the IAP family (XIAP, cIAP1 and cIAP2), indicating that the effects were specific to survivin. In addition, sulindac/ATO treatment induced the production of reactive oxygen species and the antioxidant N-acetyl-l-cysteine blocked the down-regulation of survivin and induction of apoptotic signaling by the combination of sulindac and ATO. Combined sulindac/ATO treatment also activated p53 expression, and inhibition of p53 expression by small interfering RNA (siRNA) prevented sulindac/ATO-induced down-regulation of survivin, suggesting that survivin expression is negatively regulated by p53. Overexpression of survivin reduced sulindac/ATO-induced apoptosis in A549 cells and reduction of survivin levels by siRNA sensitized the cells to sulindac/ATO-induced cell death. These results demonstrate that, in A549 human NSCLC cells, sulindac/ATO-induced apoptosis is mediated by the reactive oxygen species-dependent down-regulation of survivin.

The expression of heat shock proteins (HSPs) is known to be increased via activation of heat shock factor 1 (HSF1), and excess expression of HSPs exerts feedback inhibition of HSF1. However, the molecular mechanism to modulate such relationships between HSPs and HSF1 is not clear. In the present study, we show that stable transfection of either Hsp25 or inducible Hsp70 (Hsp70i) increased expression of endogenous HSPs such as HSP25 and HSP70i through HSF1 activation. However, these phenomena were abolished when the dominant negative Hsf1 mutant was transfected to HSP25 or HSP70i overexpressed cells. Moreover, the increased HSF1 activity by either HSP25 or HSP70i was found to result from dephosphorylation of HSF1 on serine 307 that increased the stability of HSF1. Either HSP25 or HSP70i inhibited ERK1/2 phosphorylation because of increased MKP1 phosphorylation by direct interaction of these HSPs with MKP1. Treatment of HOS and NCI-H358 cells, which showed high expressions of endogenous HSF1, with small interfering RNA (siRNA) of either HSP27 (siHSP27)or HSP70i (siHSP70i) inhibited both HSP27 and HSP70i proteins; this was because of increased ERK1/2 phosphorylation and serine phosphorylation of HSF1. The results, therefore, suggested that when the HSF1 protein level was high in cancer cells, excess expression of HSP27 or HSP70i strongly facilitates the expression of HSP proteins through HSF1 activation, resulting in severe radio- or chemoresistance.

A model for crystallization kinetics of thin amorphous film is developed by extension the Kolmogorov–Johnson–Mehl–Avrami (KJMA) model to take into account a finite film thickness. Two model versions, volume induced crystallization (VIC) and surface induced one (SIC), are explored. Finite film thickness effects lead to important consequences in the VIC: the crystallization profile reaches maximum in film middle, the crystallites population in a film is always higher than in a bulk material, the thinner film the slower it crystallizes and a spatially inhomogeneous structure with a fine-grained subsurface layer is formed. A VIC-kinetics follows a generalized KJMA equation with parameters depending on a film thickness and a range of the KJMA model validity is found. A SIC-kinetics obeys 2D KJMA equation in sufficiently thin film and is almost linear in a thick film. The model is extended to the case of non-constant growth rate and crystallization of subsurface film layer, and is shown to be consistent with experimental data.

A quantitative description of mesoscopic surface roughness generated in thin film growing via 3D island mechanism is presented. Analysis is based on the statistical model of a random nucleation and growth of hemispherical islands accounting for their collisions at late stages. Analytical expressions for a number of surface relief parameters: the rms roughness, the roughness coefficient, the surface height (depth) distribution and the package density factor providing a rather complete quantitative description of the evolving surface morphology during growth process in different condensation regimes are derived. It is shown that the surface height distribution is a non-Gaussian with a negative skewness and that the rms roughness and the roughness coefficient kinetics can be represented as a universal (independent of a condensation regime) unimodal function of either coverage or film thickness with a maximum just prior the completed film formation. The non-monotonic surface roughness dynamics in a growth process predicted by the model is consistent with experimental data.

Recently we have proposed a simple kinetic model for layer epitaxial growth, which combines a rate equation approach and a concept of a feeding zone. With this model it has distinctively been shown on how with decreasing adatom surface diffusivity and/or increasing the Ehrlich–Schwoebel (ES) barrier height the growth mode crosses over from a smooth layer-by-layer (LL) growth to a rough 3D growth, and a “phase diagram” of the growth mode in the parameter space has been constructed. This paper reports on a systematic study the effect of a critical nucleus size, the growing island collision behaviour (impingement/coalescence) and the existence (in the case of heteroepitaxy) of two different adatom surface mobilities (heterodiffusion in the first layer and self-diffusion in all the next ones) on the epitaxial growth. It is shown that the increase of a critical nucleus size expands a rough growth region, whereas the island collision behaviour weakly affects on the growth mode transition but significantly influences on the nucleation kinetics. The effect of two adatom mobilities is essential at initial stages and dramatically depends on the relation between them: a slower heterodiffusion results in a smoother initial growth and thus retards the transition to a rough growth, whereas a faster heterodiffusion promotes it especially at a higher ES barrier.

Phagocytosis is accompanied by the production of superoxide by the NADPH oxidase complex, for which GTP-bound Rac is essential. We wanted to determine whether Rho is also involved in the production of superoxide during phagocytosis. Inhibition of Rho by Tat-C3 exoenzyme (Tat-C3) blocked superoxide formation and curtailed the phagocytosis of serum- (SOZ), C3bi- (COZ), and IgG-opsonized zymosan (IOZ) particles. Tat-C3 did not affect superoxide formation in response to phorbol myristate acetate (PMA), formyl Met-Leu-Phe (fMLP), or macrophage colony-stimulating factor (M-CSF). Superoxide formation was also reduced in J774 cells transfected with a cDNA expressing dominant-negative form of RhoA (N19RhoA). However, purified prenylated recombinant RhoA did not activate NADPH oxidase in vitro, suggesting that Rho does not interact directly with NADPH oxidase. Tat-C3 inhibited the activity of RhoA, but did not affect that of Rac in vitro or in vivo. It also inhibited the phosphorylation of p47(PHOX), one of the cytosolic components of NADPH oxidase. Taken together, these results suggest that Rho plays an important role in superoxide formation during phagocytosis of SOZ, COZ, and IOZ via phosphorylation of p47(PHOX).

The growth and optical properties of InAs/GaAs(0 0 1) quantum dot (QD) structures depending on the deposition parameters are investigated. The epitaxial layers were grown in a Riber 32P MBE system and studied by atomic force microscopy and photoluminescence (PL). For a single QD with 2.7 monolayers (ML) of InAs deposited at a rate of 0.25 ML/s the dots have a dome shape and with increasing substrate temperature T s from 460 to 520 °C their surface density decreases from 2×10 10 to 1.2×10 10 cm −2 and the mean lateral size increases from 40 to 70 nm, the dots height does not exceed 8 nm. At low beam equivalent pressure of As (below 3×10 −6 Torr) and higher T s the segregation of In occurs. The multiple stacked QD structures (2.7 or 4 ML of InAs with 4 ML GaAs spacer) with the more uniform morphology in the upper layers providing the intense and narrow PL spectrum are formed at T s =490 °C and the flux ratio As 4 /In=25. The high-quality modulated Si-doped InAs/GaAs QDs-based multilayer heterostructures N -AlGaAs/GaAs/InAs/GaAs/InAs/GaAs/ … /GaAs with the two-dimensional (2D) electron gas of high-density were grown and studied for the first time and in their low-temperature PL spectra the features associated with quantum confinement effects were observed.

In studies of phase transformation kinetics in thin films, e.g. crystallization of amorphous films, until recent time is widely used familiar Kolmogorov–Johnson–Mehl–Avrami (KJMA) statistical model of crystallization despite it is applicable only to an infinite medium. In this paper a model of transformation kinetics in thin films based on a concept of the survival probability for randomly chosen point during transformation process is presented. Two model versions: volume induced transformation (VIT) when the second-phase grains nucleate over a whole film volume and surface induced transformation (SIT) when they form on an interface with two nucleation mode: instantaneous nucleation at transformation onset and continuous one during all the process are studied. At VIT-process due to the finite film thickness effects the transformation profile has a maximum in a film middle, whereas that of the grains population reaches a minimum inhere, the grains density is always higher than in a volume material, and the thinner film the slower it transforms. The transformation kinetics in a thin film obeys a generalized KJMA equation with parameters depending on a film thickness and in limiting cases of extremely thin and thick film it reduces to classical KJMA equation for 2D- and 3D-system, respectively.

Xvent homeobox proteins are induced by BMP-4 signaling and have been known to mediate many BMP-4 activities as key downstream transcriptional factors. In order to investigate the regulatory mode of Xvent transcription, we isolated genomic DNA of the Xbr-1a/Xvent-2 containing the promoter region responsive to BMP-4 signaling. The cis-acting elements located within the Xbr-1a/Xvent-2 promoter and the regulation modes by BMP-4 signaling were analyzed by serial deletion and site-directed mutagenesis experiments. The upstream )235 bp of the promoter retained the full transcriptional activity and BMP-4-response when compared with the longest promoter construct. Further analysis indicated that two separated 15 bp regions contained a strong positive element and BMP-4-response element. Site-directed mutagenesis of those regions suggests that those two regions cooperate for the promoter activity and BMP-4-response. Moreover, we found that the transcription factors, Oaz and PEBP2aA, were able to elicit additive effects with BMP-4 signaling on Xbr-1a/Xvent-2 reporter activities. These results indicate that transcriptional regulation of the Xbr-1a/Xvent-2 gene occurs in a complex mode through the cooperation of various transcription factors. 2002 Elsevier Science (USA). All rights reserved.

Objectives. The cadherin/catenin adhesion complex is fundamentally involved in epithelial cancer invasion and metastasis. Much evidence suggesting that epidermal growth factor (EGF) induced the scattering and invasion of cancer cells, probably by affecting E-cadherin function, has been reported. The present study aimed to confirm the hypothesis that EGF/epidermal growth factor receptor (EGFR) was related with the E-cadherin adhesion system in cervical cancer cells and that EGF might induce tyrosine phosphorylation of β- and γ-catenin. Methods. Cervical cancer cells were treated for different time durations with 30 ng/ml of EGF. Alteration of the cell morphology was examined by light microscopy and the expression of E-cadherin, β-catenin, γ-catenin, EGFR, and activated EGFR was assayed using Western blotting. Tyrosine phosphorylation of β- and γ-catenin was also examined using immunoprecipitation. Results. E-cadherin and EGFR were expressed in CaSki, HT-3, and ME-180 cell lines, which showed epithelial contact growth. The expression of E-cadherin and β- and γ-catenin did not change after treatment with EGF. The expression of EGFR decreased and activated EGFR expression increased in 30 min and then decreased subsequently. The simultaneous expression of activated EGFR and tyrosine phosphorylation of β- and γ-catenin was found. Conclusions. EGF-induced scattering of the E-cadherin-positive cervical cancer cells might be the result of tyrosine phosphorylation of the β- and γ-catenin. Phosphorylation of the β- and γ-catenin may hamper the adhesive function of the E-cadherin–catenin complex.

Heat shock protein 70 (HSP70) has been shown to act as an inhibitor of apoptosis. We have also observed an inhibitory effect of HSP70 on apoptotic cell death both in preheated U937 and stably transfected HSP70-overexpressing U937 (U937/HSP70) cells. However, the molecular mechanism whereby HSP70 prevents apoptosis still remains to be solved. To address this issue, we investigated the effect of HSP70 on apoptotic processes in an in vitro system. Caspase-3 cleavage and DNA fragmentation were detected in cytosolic fractions from normal cells upon addition of dATP, but not from preheated U937 or U937/hsp70 cells. Moreover, the addition of purified recombinant HSP70 to normal cytosolic fractions prevented caspase-3 cleavage and DNA fragmentation, suggesting that HSP70 prevents apoptosis upstream of caspase-3 processing. Because cytochrome c was still released from mitochondria into the cytosol by lethal heat shock despite prevention of caspase-3 activation and cell death in both preheated U937 and U937/hsp70 cells, it was evident that HSP70 acts downstream of cytochrome c release. Results obtained in vitro with purified deletion mutants of HSP70 showed that the carboxyl one-third region (from amino acids 438 to 641) including the peptide-binding domain and the carboxyl-terminal EEVD sequence was essential to prevent caspase-3 processing. From these results, we conclude that HSP70 acts as a strong suppressor of apoptosis acting downstream of cytochrome c release and upstream of caspase-3 activation.

Cultured human skin cells are a potentially useful model for skin irritancy testing. We have investigated the use of human skin fibroblasts for in vitro screening for skin toxicity. To assess the cytotoxic effects of surfactants, cell viability was measured by the NRU (neutral red uptake) assay and AB (Alamar blue) assay as in vitro methods. The skin irritation potential of surfactants by human skin patch test was assessed as in vivo methods. The close relationship was found between AB assay with human skin fibroblasts and human patch test (r=0.867). There was a relatively good agreement between the NRU and in vivo patch test (r=0.648). These results suggest that AB and NRU assay using cultured human fibroblast could be predictable methods for the irritancy of various surfactants in human.