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1. Cyclic Strain Mitigates Nanoparticle Internalization by Vascular Smooth Muscle Cells

Author

Tsai CL, Huang CY, Lu YC, Pai LM, Horák D, and Ma YH

Subjects
cyclic strain, magnetic nanoparticles, endocytosis, actin, Medicine (General), R5-920
Abstract

Chia-Liang Tsai,1 Ching-Yun Huang,2 Yi-Ching Lu,1 Li-Mei Pai,3,4 Daniel Horák,5 Yunn-Hwa Ma1,6 1Department of Physiology and Pharmacology, Chang Gung University, Taoyuan, 33302, Taiwan, Republic of China; 2Institute of Biomedical Sciences, Chang Gung University, Taoyuan, 33302, Taiwan, Republic of China; 3Department of Biochemistry & Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, 33302, Taiwan, Republic of China; 4Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan, Republic of China; 5Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague 6, 162 06, Czech Republic; 6Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan, Republic of ChinaCorrespondence: Yunn-Hwa Ma, Department of Physiology and Pharmacology, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan, Republic of China, Email yhma@mail.cgu.edu.twBackground: Intravascular delivery of nanoparticles for theranostic application permits direct interaction of nanoparticles and vascular cells. Since vascular smooth muscle cells (VSMCs), the major components of the vascular wall, are constantly subjected to mechanical stimulation from hemodynamic influence, we asked whether cyclic strain may modulate internalization of magnetic nanoparticles (MNPs) by cultured VSMCs.Methods: Cyclic strain (1 Hz and 10%) was applied with Flexcell system in cultured VSMCs from rats, with cell-associated MNPs (MNPcell) determined by a colorimetric iron assay. Transmission and scanning electron microscopy were used for morphology studies. Confocal microscopy was used to demonstrate distribution of actin assembly in VSMCs.Results: Incubation of poly(acrylic acid) (PAA)-coated MNPs with VSMCs for 4 h induced microvilli formation and MNP internalization. Application of cyclic strain for 4– 12 h significantly reduced MNPcell by up to 65% (p < 0.05), which was associated with blunted microvilli and reduced vesicle size/cell, but not vesicle numbers/cell. Confocal microscopy demonstrated that both cyclic strain and fibronectin coating of the culture plate reduced internalized MNPs, which were co-localized with vinculin. Furthermore, cytochalasin D reduced MNPcell, suggesting a role of actin polymerization in MNP uptake by VSMCs; however, a myosin II ATPase inhibitor, blebbistatin, exhibited no effect. Cyclic strain also attenuated uptake of PAA-MNPs by LN-229 cells and uptake of poly-L-lysine-coated MNPs by VSMCs.Conclusion: In such a dynamic milieu, cyclic strain may impede cellular internalization of nanocarriers, which spares the nanocarriers and augments their delivery to the target site in the lumen of vessels or outside of the circulatory system.Graphical Abstract: Keywords: cyclic strain, magnetic nanoparticles, endocytosis, actin

Published
2022

3. Common and Unique Factors and the Bidirectional Relationship Between Chronic Kidney Disease and Nonalcoholic Fatty Liver in Type 2 Diabetes Patients

Author

Lee YJ, Wang CP, Hung WC, Tang WH, Chang YH, Hu DW, Lu YC, Yu TH, Wu CC, Chung FM, and Hsu CC

Subjects
bidirectional relationship, chronic kidney disease, non-alcoholic fatty liver disease, risk factor, structural equation modeling, type 2 diabetes mellitus, Specialties of internal medicine, RC581-951
Abstract

Yau-Jiunn Lee,1 Chao-Ping Wang,2,3 Wei-Chin Hung,2,4 Wei-Hua Tang,1 Yu-Hung Chang,1 Der-Wei Hu,1 Yung-Chuan Lu,3,5 Teng-Hung Yu,2,4 Cheng-Ching Wu,2,4,6 Fu-Mei Chung,2 Chia-Chang Hsu4,7,8 1Lee’s Endocrinology Clinic, Pingtung 90000, Taiwan; 2Division of Cardiology, Department of Internal Medicine, E-Da Hospital, Kaohsiung 82445, Taiwan; 3School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan; 4The School of Chinese Medicine for Post Baccalaureate, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan; 5Division of Endocrinology and Metabolism, Department of Internal Medicine, E-Da Hospital, Kaohsiung 82445, Taiwan; 6Division of Cardiology, Department of Internal Medicine, E-Da Cancer Hospital, Kaohsiung 82445, Taiwan; 7Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital, Kaohsiung 82445, Taiwan; 8Health Examination Center, E-Da Dachang Hospital, Kaohsiung 80794, TaiwanCorrespondence: Chia-Chang HsuDivision of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital, Kaohsiung 82445, TaiwanTel +886-7-615-1100 ext. 5914 or 5018Email aladarhsu1107@gmail.comPurpose: This study aimed to investigate the common and unique risk factors and bidirectional relationship between chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM).Patients and Methods: This was a cross-sectional study of patients with T2DM enrolled in a disease management program at two specialized diabetes outpatient clinics. Common and unique risk factors for CKD and NAFLD were examined using structural equation models (SEMs). SEMs were also used to examine direct and indirect effects of NAFLD on CKD and those of CKD on NAFLD.Results: A total of 1992 subjects with T2DM were enrolled in this study. In multivariate analysis, NAFLD was independently associated with the odds of CKD (adjusted odds ratio=1.59, 95% confidence interval=1.12– 2.25, P=0.009). SEMs showed that age, triglyceride, uric acid (UA), albumin, and HbA1c levels had statistically significant direct effects on CKD, and the final model could explain 22% of the variability in CKD. Age, triglycerides, body mass index (BMI), UA, white blood cell (WBC) count, serum glutamic pyruvic transaminase (SGPT) level, and smoking status had statistically significant direct effects on NAFLD, and the final model could explain 43% of the variability in NAFLD. The common risk factors contributing to both CKD and NAFLD were age, triglycerides, and UA. The unique risk factors were albumin and HbA1c for CKD, and BMI, WBC, SGPT, and smoking for NAFLD. In addition, SEM analysis also confirmed the bidirectional causal relationship between NAFLD and CKD.Conclusion: Common and unique risk factors and a bidirectional relationship existed between CKD and NAFLD in our patients with T2DM.Keywords: bidirectional relationship, chronic kidney disease, nonalcoholic fatty liver disease, risk factor, structural equation modeling, type 2 diabetes mellitus

Published
2020

4. In vitro and in vivo Biological Responses to Graphene and Graphene Oxide: A Murine Calvarial Animal Study

Author

Chang TK, Lu YC, Yeh ST, Lin TC, and Huang CH

Subjects
biological response, graphene, graphene oxide, osteolysis, osteogenesis, Medicine (General), R5-920
Abstract

Ting-Kuo Chang,1–3,* Yung-Chang Lu,1–3,* Shu-Ting Yeh,2,3 Tzu-Chiao Lin,2,3 Chun-Hsiung Huang,2–4 Chang-Hung Huang1–3,5 1Department of Medicine, MacKay Medical College, New Taipei City, Taiwan; 2Department of Orthopaedic Surgery, MacKay Memorial Hospital, Taipei, Taiwan; 3Department of Medical Research, MacKay Memorial Hospital, Taipei County, Taiwan; 4Department of Orthopaedic Surgery, Changhua Christian Hospital, Changhua, Taiwan; 5Department of Dentistry, National Yang-Ming University, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Chang-Hung HuangDepartment of Medical Research, MacKay Memorial Hospital, No. 45, Minsheng Road, Tamshui District, New Taipei City, TaiwanEmail changhung0812@gmail.comBackground: Graphene and its derivatives have recently gained popularity in the biomedical field. Previous studies have confirmed that both the mechanical strength and wear resistance of graphene-containing polyethylene have been greatly improved. Therefore, it is being considered as an alternative for artificial joint replacement liners. Based on the literature, the wear debris generated from the traditional polymers used for orthopedic liners could lead to particle-induced osteolysis and, consequently, failure of joint replacement. However, the biological response of this novel graphene-based polymer is still unclear. Therefore, the current study aimed to investigate the in vitro and in vivo biological effects of graphene and graphene oxide (GO) particles on bone.Materials and Methods: The biological responses of graphene and GO particles were tested via in vitro and murine calvarial in vivo models. In the in vitro model, murine macrophage cells were mixed with particles and hydrogel and printed into two differently designed scaffolds; the induced proinflammatory cytokines were then tested. In the murine in vivo model, the particle size distribution was measured via SEM, and these particles were then administrated in the calvarial area, referring to our established model. A micro-CT and histological analysis were performed to examine the biological effects of the particles on bone health. The data were analyzed via the one-way analysis of variance to determine the differences between the groups.Results: Both graphene and GO induced significantly higher TNF-α and IL-6 secretion compared with the control in the three-dimensional in vitro model. In the murine calvarial in vivo test, the graphene and GO particles increased the bone mass compared with the sham groups in the micro-CT analysis. Bone formation was also observed in the histological analysis.Conclusion: In these in vivo and in vitro studies, the graphene and GO wear debris did not seem to induce harmful biological response effect to bone. Bone formation around the skull was observed in the calvarial model instead. Graphene-containing biomaterials could be a suitable new material for application in orthopedic prostheses due to their benefit of eliminating the risk of particle-induce osteolysis.Keywords: biological response, graphene, graphene oxide, osteolysis, osteogenesis

Published
2020

5. Simultaneous three Enterobacteriaceae with different bla NDM-1-encoding plasmids in a patient transferred from mainland China to Taiwan

Author

Lai CC, Chen CC, Lu YC, Chen HJ, Su BA, Weng TC, Chiu YH, Toh HS, Zhang CC, Chiang SR, Chuang YC, and Tang HJ

Subjects
NDM-1, plasmid, carbapenem-resistant Enterobacteriaceae, Infectious and parasitic diseases, RC109-216
Abstract

Chih-Cheng Lai,1 Chi-Chung Chen,2,3 Ying-Chen Lu,3 Hung-Jui Chen,4 Bo-An Su,4 Tzu-Chieh Weng,4 Yu-Hsin Chiu,5 Han-Siong Toh,4 Chun-Cheng Zhang,4 Shyh-Ren Chiang,4 Yin-Ching Chuang,2,5 Hung-Jen Tang2,4,6 1Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 2Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan; 3Department of Food Science, National Chiayi University, Chiayi, Taiwan; 4Department of Medicine, Chi Mei Medical Center, Tainan, Taiwan; 5Department of Internal Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 6Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan Abstract: New-Delhi metallo-β-lactamase1 (NDM-1) Enterobacteriaceae are increasing worldwide. Herein, we describe a single patient who carried three unusual NDM-1 carbapenem-resistant Enterobacteriaceae – Enterobacter cloacae (E. cloacae) yielded from a urine specimen and Klebsiella pneumoniae (K. pneumoniae) and Escherichia coli (E. coli) from stool specimens. For E. cloacae, its bla NDM-1-encoding plasmid was pKP04NDM with a size of ~54 kb replicons with an IncN backbone. For K. pneumoniae, its bla NDM-1-encoding plasmid was pNDM-BTR with a size of ~59.6 kb and belonged to IncN. For E. coli, its main bla NDM-1-encoding plasmid was pIMP-HK1500, and the NDM-1 gene was obtained from a part of pNDM-BTR (8439 bp). These three clinical strains are reported for the first time and are assumed to be imported from mainland China to Taiwan. The three different plasmids were never reported in K. pneumoniae, E. coli, and Citrobacter spp before. Owing to their associated multidrug resistance, appropriate measures of periodic, targeted surveillance, and development of new antimicrobial agents are urgently needed.Keywords: carbapenem-resistant Enterobacteriaceae, NDM-1, K. pneumoniae, E. coli, Citrobacter, plasmid

Published
2018

6. In vitro activity of cefoperazone and cefoperazone-sulbactam against carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa

Author

Lai CC, Chen CC, Lu YC, Chuang YC, and Tang HJ

Subjects
cefoperazone-sulbactam, Acinetobacter baumannii, Pseudomonas aeruginosa, Infectious and parasitic diseases, RC109-216
Abstract

Chih-Cheng Lai,1 Chi-Chung Chen,2,3 Ying-Chen Lu,3 Yin-Ching Chuang,2,4 Hung-Jen Tang5,6 1Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 2Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan; 3Department of Food Science, National Chiayi University, Chiayi, Taiwan; 4Department of Internal Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 5Department of Medicine, Chi Mei Medical Center, Tainan, Taiwan; 6Department of Health and Nutrition, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan Background: This study aimed to investigate the in vitro activity of cefoperazone–sulbactam against carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, and to evaluate the antibiotic resistance mechanisms of these bacteria. Materials and methods: In total, 21 isolates of carbapenem-resistant P. aeruginosa and 15 isolates of carbapenem-resistant A. baumannii with different pulsed-field gel electrophoresis types were collected for assessment of the in vitro antibacterial activities of cefoperazone and cefoperazone–sulbactam and the associated resistance mechanisms of the bacteria. Results: For carbapenem-resistant P. aeruginosa, the minimum inhibitory concentration (MIC) value and antibiotic susceptibility rate were similar for cefoperazone and cefoperazone–sulbactam (at 1:1 and 2:1 ratios). In contrast, for carbapenem-resistant A. baumannii, the MIC values, including the MIC range, MIC that inhibited 50% of isolates (MIC50) and MIC that inhibited 90% of isolates (MIC90), were reduced after treatment with sulbactam and cefoperazone. We screened resistance genes, including VIM-2, OXA-2 and OXA-10, in 21 carbapenem-resistant P. aeruginosa isolates. Only one (4.8%) of the isolates showed expression of VIM-2, and neither the OXA-2 nor the OXA-10 gene was detected. However, 20 (95.2%) isolates among the carbapenem-resistant P. aeruginosa isolates selected for oprD sequencing showed the phenomenon of nucleotide substitution or deletion. Among 15 carbapenem-resistant A. baumannii isolates, we found that ten (66.7%) isolates had concomitant expression of the OXA-23 and ISAba1-OXA-23 genes, and six (40.0%) isolates had expression of the OXA-24-like gene. All 15 isolates had OXA-51-like gene expression, and only 1 (6.7%) isolate had ISAba1-OXA-51-like gene expression. None of the isolates contained the IMP-1, IMP-8, KPC, NDM, VIM-1 or OXA-48 genes. Conclusion: The in vitro antibacterial activity of cefoperazone against carbapenem-resistant A. baumannii can be enhanced by adding sulbactam to cefoperazone, but the addition does not affect carbapenem-resistant P. aeruginosa. This significant difference can be explained by the different resistance mechanisms of carbapenem-resistant A. baumannii and P. aeruginosa. Keywords: cefoperazone–sulbactam, Acinetobacter baumannii, Pseudomonas aeruginosa

Published
2018

7. Appropriate composites of cefoperazone–sulbactam against multidrug-resistant organisms

Author

Lai CC, Chen CC, Lu YC, Lin TP, Chuang YC, and Tang HJ

Subjects
Cefoperazone-sulbactam, Extended-spectrum β-lactamases, Escherichia coli, Klebsiella pneumoniae, Infectious and parasitic diseases, RC109-216
Abstract

Chih-Cheng Lai,1 Chi-Chung Chen,2,3 Ying-Chen Lu,3 Tsuey-Pin Lin,4 Yin-Ching Chuang,2,5 Hung-Jen Tang4,6 1Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, 2Department of Medical Research, Chi Mei Medical Center, Tainan, 3Department of Food Science, National Chiayi University, Chiayi, 4Department of Health and Nutrition, Chia-Nan University of Pharmacy and Science, 5Department of Internal Medicine, Chi Mei Medical Center, Liouying, 6Department of Medicine, Chi Mei Medical Center, Tainan, Taiwan Objectives: This study aims to assess the in vitro activity of different cefoperazone–sulbactam ratios against different multidrug-resistant organisms (MDROs).Materials and methods: Minimum inhibitory concentrations (MICs) and susceptibility rates of cefoperazone, sulbactam and cefoperazone–sulbactam at fixed ratios of 2:1, 1:1 and 1:2 against 344 MDRO clinical isolates, including extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (n=58), ESBL-producing Klebsiella pneumoniae (n=58), carbapenem-resistant Enterobacteriaceae (n=57), carbapenem-resistant Pseudomonas aeruginosa (n=49) and carbapenem-resistant Acinetobacter baumannii (n=122), were measured.Results: Combined treatment with sulbactam and cefoperazone resulted in decreased MIC50 values across all MDROs, as well as decreases in most MIC90 values, except for carbapenem-resistant Enterobacteriaceae and carbapenem-resistant P. aeruginosa (MIC90 values remained >64 mg/L). Susceptibility rates of treatment with cefoperazone alone against all MDROs were much lower than that of cefoperazone–sulbactam combination (all P

Published
2018

8. SN38-loaded

Author

Fang YP, Chuang CH, Wu YJ, Lin HC, and Lu YC

Subjects
SN-38, targeted liposome, pharmacokinetics, human breast cancer, toxicity, Medicine (General), R5-920
Abstract

Yi-Ping Fang,1,2 Chih-Hung Chuang,3 Yi-Jhun Wu,1 Hsin-Che Lin,1 Yun-Chi Lu4 1School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, 2Department of Medical Research, Kaohsiung Medical University Hospital, 3Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, 4Graduate Institute of Medicine, Collage of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Background: SN38 (7-ethyl-10-hydroxycamptothecin) is a camptothecin derivative acts against various tumors. However, SN38 is hydrolyzed in the physiological environment (pH 7.4), and this instability interferes with its potential therapeutic effect. Our objective was to investigate SN38-loaded liposomes to overcome the poor solubility of SN38 and its biodistribution, which further diminish its toxicity.Materials and methods: The sub-100 nm targeted liposomes was employed to deliver SN-38 and evaluate the characterization, release behaviors, cytotoxicity, in vivo pharmacokinetics and biochemical assay.Results: The SN38-loaded targeted liposomes consisted of small (100.49 nm) spherical nanoparticles with negative charge (-37.93 mV) and high entrapment efficiency (92.47%). The release behavior of the SN38-loaded targeted liposomes was fitted with Higuchi kinetics (R2=0.9860). Free SN38 presented initial burst release. The IC50 for the SN38-loaded targeted liposomes (0.11 µM) was significantly lower than for the SN38 solution (0.37 µM) in the MCF7 cell line (P

Published
2018

9. The clinical significance of silent mutations with respect to ciprofloxacin resistance in MRSA

Author

Lai CC, Chen CC, Lu YC, Chuang YC, and Tang HJ

Subjects
MRSA, silent mutation, rpoB474, ciprofloxacin, resistance, Infectious and parasitic diseases, RC109-216
Abstract

Chih-Cheng Lai,1 Chi-Chung Chen,2,3 Ying-Chen Lu,3 Yin-Ching Chuang,2,4 Hung-Jen Tang5,6 1Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 2Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan; 3Department of Food Science, National Chiayi University, Chiayi, Taiwan; 4Department of Internal Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 5Department of Health and Nutrition, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan; 6Department of Medicine, Chi Mei Medical Center, Tainan, Taiwan Background: The aim of this study was to investigate the genotypic differences between different sequence type MRSA isolates, especially focusing on silent rpoB474 mutations and the relationship between such mutations and ciprofloxacin resistance. Methods: Seventy-nine MRSA isolates were obtained for antibiotic susceptibility tests and molecular study. Results: Among these isolates, we found that the MIC50, MIC90, and minimum inhibitory concentration (MIC) range of ciprofloxacin were much higher for the isolates without the rpoB474 mutation than for isolates with the rpoB474 mutation. A total of 87.5% of the isolates with the rpoB474 mutation were susceptible to ciprofloxacin, but none of the isolates without the rpoB474 mutation were susceptible to ciprofloxacin. For 27 MRSA isolates without rpo474 silent mutation but with gyrA86/126 silent mutation, all of them belonged to SCCmec III, and had high ciprofloxacin MIC levels. For another 44 MRSA isolates with rpo474 silent mutation but without gyrA86/126 silent mutation, all of them showed low ciprofloxacin MIC levels, all of them belonged to either SCCmec IV or V. Furthermore, MRSA ciprofloxacin resistance was found to be associated with the mutations gyrA S84L/parC S80F or gyrA S84L, and S85P/parC S80Y. Conclusion: Most occurrences of this rpoB474 silent mutation were found in community acquired-MRSA (CA-MRSA) isolates with susceptibility to most antibiotics, especially for ciprofloxacin and vice versa. Thus, this mutation may help to differentiate the different microbiologic characteristics of MRSA clinical isolates. Keywords: MRSA, silent mutation, rpoB474, ciprofloxacin, resistance

Published
2018

10. Interaction of poly-L-lysine coating and heparan sulfate proteoglycan on magnetic nanoparticle uptake by tumor cells

Author

Siow WX, Chang YT, Babič M, Lu YC, Horák D, and Ma YH

Subjects
magnetic nanoparticles, poly-L-lysine, tea catechin, glycoconjugate, heparan sulfate proteoglycan, Medicine (General), R5-920
Abstract

Wei Xiong Siow,1,2 Yi-Ting Chang,1,2 Michal Babič,3 Yi-Ching Lu,2 Daniel Horák,3 Yunn-Hwa Ma1,2,4 1Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Guishan, Taoyuan, Taiwan, Republic of China; 2Department of Physiology and Pharmacology and Healthy Aging Research Center, College of Medicine, Chang Gung University, Guishan, Taoyuan, Taiwan, Republic of China; 3Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic; 4Department of Neurology, Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwan, Republic of China Background: Poly-L-lysine (PLL) enhances nanoparticle (NP) uptake, but the molecular mechanism remains unresolved. We asked whether PLL may interact with negatively charged glycoconjugates on the cell surface and facilitate uptake of magnetic NPs (MNPs) by tumor cells.Methods: PLL-coated MNPs (PLL-MNPs) with positive and negative ζ-potential were prepared and characterized. Confocal and transmission electron microscopy was used to analyze cellular internalization of MNPs. A colorimetric iron assay was used to quantitate cell-associated MNPs (MNPcell).Results: Coadministration of PLL and dextran-coated MNPs in culture enhanced cellular internalization of MNPs, with increased vesicle size and numbers/cell. MNPcell was increased by eight- to 12-fold in response to PLL in a concentration-dependent manner in human glioma and HeLa cells. However, the application of a magnetic field attenuated PLL-induced increase in MNPcell. PLL-coating increased MNPcell regardless of ζ-potential of PLL-MNPs, whereas magnetic force did not enhance MNPcell. In contrast, epigallocatechin gallate and magnetic force synergistically enhanced PLL-MNP uptake. In addition, heparin, but not sialic acid, greatly reduced the enhancement effects of PLL; however, removal of heparan sulfate from heparan sulfate proteoglycans of the cell surface by heparinase III significantly reduced MNPcell.Conclusion: Our results suggest that PLL-heparan sulfate proteoglycan interaction may be the first step mediating PLL-MNP internalization by tumor cells. Given these results, PLL may facilitate NP interaction with tumor cells via a molecular mechanism shared by infection machinery of certain viruses. Keywords: magnetic nanoparticles, poly-L-lysine, tea catechin, glycoconjugate, heparan sulfate proteoglycan

Published
2018

11. Extending the Heat Index

Author

Lu, YC, Lu, YC, Romps, DM, Lu, YC, Lu, YC, and Romps, DM

Abstract

The heat index is a widely used measure of apparent temperature that accounts for the effects of humidity using Steadman’s model of human thermoregulation. Steadman’s model, however, gives unphysical results when the air is too hot and humid or too cold and dry, leading to an undefined heat index. For example, at a relative humidity of 80%, the heat index is only defined for temperatures in the range of 288–304 K (598–888F). Here, Steadman’s thermoregulation model is extended to define the heat index for all combinations of temperature and humidity, allowing for an assessment of Earth’s future habitability. The extended heat index can be mapped onto physiological responses of an idealized human, such as heat exhaustion, heat stroke, and even heat death, providing an indication of regional health outcomes for different degrees of global warming. SIGNIFICANCE STATEMENT: The existing heat index is well-defined for most combinations of high temperature and humidity experienced on Earth in the preindustrial climate, but global warming is increasingly generating conditions for which the heat index is undefined. Therefore, an extension of the original heat index is needed. When extending the heat index, we use the same physiological model as in the original work of Steadman to ensure backward compatibility. Following Steadman, each value of the heat index is mapped onto a measurable physiological variable, which can be useful for assessing the health impacts of various combinations of temperature and humidity, especially for outdoor workers.

Published
2022

12. Chronically underestimated: A reassessment of US heat waves using the extended heat index

Author

Romps, DM, Romps, DM, Lu, YC, Romps, DM, Romps, DM, and Lu, YC

Abstract

The heat index, or apparent temperature, was never defined for extreme heat and humidity, leading to the widespread adoption of a polynomial extrapolation designed by the United States National Weather Service. Recently, however, the heat index has been extended to all combinations of temperature and humidity, presenting an opportunity to reassess past heat waves. Here, three-hourly temperature and humidity are used to evaluate the extended heat index over the contiguous United States during the years 1984-2020. It is found that the 99.9th percentile of the daily maximum heat index is highest over the Midwest. Identifying and ranking heat waves by the spatially integrated exceedance of that percentile, the Midwest once again stands out as home to the most extreme heat waves, including the top-ranked July 2011 and July 1995 heat waves. The extended heat index can also be used to evaluate the physiological stress induced by heat and humidity. It is found that the most extreme Midwest heat waves tax the cardiovascular system with a skin blood flow that is elevated severalfold, approaching the physiological limit. These effects are not captured by the National Weather Service's polynomial extrapolation, which also underestimates the heat index by as much as 10 °C (20 °F) during severe heat waves.

Published
2022

13. Action of the insecticide cyfluthrin on Ca2+signal transduction and cytotoxicity in human osteosarcoma cells

Author

Kuo Cc, Chung-Ren Jan, Wei-Zhe Liang, Lu Yc, Hao Lj, and Chou Ct

Subjects
0301 basic medicine, Thapsigargin, Phospholipase C, Activator (genetics), Health, Toxicology and Mutagenesis, Endoplasmic reticulum, General Medicine, Cyfluthrin, Toxicology, Molecular biology, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, chemistry, Phorbol, Viability assay, 030217 neurology & neurosurgery, Protein kinase C
Abstract

Cyfluthrin is a pyrethroid insecticide and common household pesticide. The effect of cyfluthrin on Ca2+-related physiology in human osteosarcoma is unclear. This study investigated the effect of cyfluthrin on cytosolic-free Ca2+concentrations ([Ca2+]i) and viability in MG63 human osteosarcoma cells. Cyfluthrin concentration-dependently induced [Ca2+]irises. Cyfluthrin-induced Ca2+entry was confirmed by the Mn2+-induced quench of fura-2 fluorescence. Cyfluthrin at concentrations of 10–100 μM induced [Ca2+]irises. Ca2+removal reduced the signal by approximately 50%. Cyfluthrin (100 μM) induced Mn2+influx suggesting Ca2+entry. Cyfluthrin-induced Ca2+entry was inhibited 50% by protein kinase C (PKC) activator (phorbol 12-myristate 13-acetate) and inhibitor (GF109203X) and also by three inhibitors of store-operated Ca2+channels: nifedipine, econazole, and SKF96365. In Ca2+-free medium, treatment with the endoplasmic reticulum Ca2+pump inhibitor thapsigargin (TG) completely inhibited cyfluthrin-evoked [Ca2+]irises. Conversely, treatment with cyfluthrin abolished TG-evoked [Ca2+]irises. Inhibition of phospholipase C (PLC) with 1-[6-[((17β)-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl]-1H-pyrrole-2,5-dion abolished cyfluthrin-induced [Ca2+]irises. Cyfluthrin at 25–65 μM decreased cell viability, which was not reversed by pretreatment with the Ca2+chelator 1,2-bis(2-aminophenoxy)ethane- N, N, N′, N′-tetraacetic acid–acetoxymethyl ester. Together, in MG63 cells, cyfluthrin induced [Ca2+]irises by evoking PLC-dependent Ca2+release from the endoplasmic reticulum and Ca2+entry via PKC-sensitive store-operated Ca2+entry. Cyfluthrin also caused Ca2+-independent cell death.

Published
2020

14. Bioconjugation of recombinant tissue plasminogen activator to magnetic nanocarriers for targeted thrombolysis

Author

Yang HW, Hua MY, Lin KJ, Wey SP, Tsai RY, Wu SY, Lu YC, Liu HL, Wu T, and Ma YH

Subjects
Medicine (General), R5-920
Abstract

Hung-Wei Yang,1,* Mu-Yi Hua,1,* Kun-Ju Lin,2,* Shiaw-Pyng Wey,3 Rung-Ywan Tsai,4 Siao-Yun Wu,5 Yi-Ching Lu,5 Hao-Li Liu,6 Tony Wu,7 Yunn-Hwa Ma5 1Chang Gung Molecular Medicine Research Center, Department of Chemical and Materials Engineering, 2Molecular Imaging Center, Department of Nuclear Medicine, Chang Gung Memorial Hospital, Kuei-Shan, Tao-Yuan, Taiwan, Republic of China; 3Department of Medical Imaging and Radiological Sciences, 4Electronics and Optoelectronics Research Laboratories, Industrial Technology Research Institute, Hsin-chu, Taiwan, Republic of China; 5Department of Physiology and Pharmacology and Healthy Aging Research Center, 6Department of Electrical Engineering, Chang Gung University, Kuei-Shan, Tao-Yuan, Taiwan, Republic of China; 7Department of Neurology, Chang Gung University College of Medicine and Memorial Hospital, Tao-Yuan, Taiwan, Republic of China*These authors contributed equally to this workAbstract: Low-toxicity magnetic nanocarriers (MNCs) composed of a shell of poly [aniline-co-N-(1-one-butyric acid) aniline] over a Fe3O4 magnetic nanoparticle core were developed to carry recombinant tissue plasminogen activator (rtPA) in MNC-rtPA for targeted thrombolysis. With an average diameter of 14.8 nm, the MNCs exerted superparamagnetic properties. Up to 276 µg of active rtPA was immobilized per mg of MNCs, and the stability of the immobilized rtPA was greatly improved during storage at 4°C and 25°C. In vitro thrombolysis testing with a tubing system demonstrated that magnet-guided MNC-rtPA showed significantly improved thrombolysis compared with free rtPA and reduced the clot lysis time from 39.2 ± 3.2 minutes to 10.8 ± 4.2 minutes. In addition, magnet-guided MNC-rtPA at 20% of the regular rtPA dose restored blood flow within 15–25 minutes of treatment in a rat embolism model without triggering hematological toxicity. In conclusion, this improved system is based on magnetic targeting accelerated thrombolysis and is potentially amenable to therapeutic applications in thromboembolic diseases.Keywords: thrombolysis, recombinant tissue plasminogen activator, magnetic nanocarriers, magnetic targeting, targeting therapy

Published
2012

15. Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose

Author

Wu, PT, Rybin, D, Bielak, LF, Feitosa, MF, Franceschini, N, Li, YZ, Lu, YC, Marten, J, Musani, S, Noordam, R, Raghavan, S, Rose, L, Schwander, K, Smith, AV, Tajuddin, S M, Vojinovic, Dina, Amin, Najaf, Arnett, D, Bottinger, EP, Demirkan, Ayse, Florez, J, Ghanbari, Mohsen, Harris, TB, Launer, LJ, Liu, JM, Liu, Jun, Mook-Kanamori, DO, Murray, AD, Nalls, M, Peyser, PA, Uitterlinden, André, Voortman, Trudy, Bouchard, C, Chasman, D, Correa, A, de Mutsert, R, Evans, MK, Gudnason, V, Hayward, C, Kao, L, Kardia, SLR, Kooperberg, C, Loos, RJ, Province, M, Rankinen, T, Redline, S, Ridker, P, Rotter, J, Siscovick, D, Smith, BH, Duijn, Cornelia, Zonderman, AB, Rao, DC, Wilson, J, Dupuis, J, Meigs, JB, Liu, CT, Vassy, JL, Wu, PT, Rybin, D, Bielak, LF, Feitosa, MF, Franceschini, N, Li, YZ, Lu, YC, Marten, J, Musani, S, Noordam, R, Raghavan, S, Rose, L, Schwander, K, Smith, AV, Tajuddin, S M, Vojinovic, Dina, Amin, Najaf, Arnett, D, Bottinger, EP, Demirkan, Ayse, Florez, J, Ghanbari, Mohsen, Harris, TB, Launer, LJ, Liu, JM, Liu, Jun, Mook-Kanamori, DO, Murray, AD, Nalls, M, Peyser, PA, Uitterlinden, André, Voortman, Trudy, Bouchard, C, Chasman, D, Correa, A, de Mutsert, R, Evans, MK, Gudnason, V, Hayward, C, Kao, L, Kardia, SLR, Kooperberg, C, Loos, RJ, Province, M, Rankinen, T, Redline, S, Ridker, P, Rotter, J, Siscovick, D, Smith, BH, Duijn, Cornelia, Zonderman, AB, Rao, DC, Wilson, J, Dupuis, J, Meigs, JB, Liu, CT, and Vassy, JL

Published
2020

16. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

Author

Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. J. L., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., Cannon, C. P., Capuano, G., Chu, P. -L., De Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Meininger, G., Brenner, B. M., Mahaffey, K. W., Perkovic, V, Mahaffey, Kw, Agarwal, R, Bakris, G, Brenner, Bm, Cannon, Cp, Charytan, Dm, de Zeeuw, D, Greene, T, Jardine, Mj, Heerspink, Hjl, Levin, A, Meininger, G, Neal, B, Pollock, C, Wheeler, Dc, Zhang, H, Zinman, B, Mcguire, Dk, Holman, R, Home, P, Scharfstein, D, Parfrey, P, Shahinfar, S, August, P, Chang, T, Sinha, Ad, Januzzi, J, Kolansky, D, Amerena, J, Hillis, G, Gorelick, P, Kissela, B, Kasner, S, Lindley, R, Fulcher, G, Ounadjela, S, Hufert, K, von Ingersleben, G, Gaglia, J, Harris, R, Hudson, M, Turchin, A, Cheifetz, A, Sheth, S, Feuerstein, J, Cohen, S, Jardine, M, Li, N, Kolesnyk, I, Aizenberg, D, Pecoits-Filho, R, Cherney, D 3rd, Obrador, G, Chertow, G, Hawley, C, Ji, L, Wada, T, Jha, V, Lim, Sk, Lim-Abrahan, Ma, Santos, F, Chae, Dw, Hwang, Sj, Vazelov, E, Rychlík, I, Hadjadj, S, Krane, V, Rosivall, L, De Nicola, L, Dreval, A, Nowicki, M, Schiller, A, Distiller, L, Górriz, Jl, Kolesnyk, M, Morren, F, Goykhman, S, David, C, Yost, L, Wang, H, Hettiarachchi, M, Thimmaiah, R, Koppolu, D, George, S, Schmidt, M, Ignjatovic, J, Chapin, L, Travis, K, Destree, M, Sood, V, Coffee, L, De Brouwer, K, Zaviriukha, V, Starzec, A, Koizumi, M, Lin, G, Chen, E, Lin, P, Leia, C, Mascaro, D, Amigo, A, Limos, A, Abrahamsen, I, Jaffer, S, Ahuad Guerrero RA, Albisu, Jp, Alvarisqueta, A, Bartolacci, I, Berli, Ma, Bordonava, A, Calella, P, Cantero, Mc, Cartasegna, Lr, Cercos, E, Coloma, Gc, Colombo, H, Commendatore, V, Cuadrado, J, Cuneo, Ca, Cusumano, Am, Douthat, Wg, Dran, Rd, Farias, E, Fernandez, Mf, Finkelstein, H, Fragale, G, Fretes, Jo, Garcia, Nh, Gastaldi, A, Gelersztein, E, Glenny, Ja, Gonzalez, Jp, Gonzalez Colaso PDC, Goycoa, C, Greloni, Gc, Guinsburg, A, Hermida, S, Juncos, Li, Klyver, Mi, Kraft, F, Krynski, F, Lanchiotti, Pv, Leon de la Fuente RA, Marchetta, N, Mele, P, Nicolai, S, Novoa, Pa, Orio, Si, Otreras, F, Oviedo, A, Raffaele, P, Resk, Jh, Rista, L, Rodriguez Papini, N, Sala, J, Santos, Jc, Schiavi, Lb, Sessa, H, Smith Casabella, T, Ulla, Mr, Valdez, M, Vallejos, A, Villarino, A, Visco, Ve, Wassermann, A, Zaidman, Cj, Cheung, Nw, Droste, C, Fraser, I, Johnson, D, Mah, Pm, Nicholls, K, Packham, D, Proietto, J, Roberts, A, Roger, S, Tsang, V, Raduan, Ra, Alves da Costa FA, Amodeo, C, Andreotti Turatti LA, Bregman, R, Camelo Sanches FC, Canani, Lh, Chacra, Ar, Cunha Borges JL, Cunha Vêncio SA, da Silva Franco RJ, D'Avila, D, de Souza Portes, E, de Souza, P, Deboni, Lm, Filho, Ff, Geloneze Neto, B, Gomes, M, Kohara, Sk, Keitel, E, Kerr Saraiva JF, Kurtz Lisboa HR, de Carvalho Contieri FL, Milagres, R, Montenegro Junior, R, Moreira de Brito, C, Nazzer Hissa, M, Nazario Sabbag ÂR, Noronha, I, Panarotto, D, Pecoits Filho, R, Pereira, Ma, Saporito, W, Scotton, As, Schuch, T, Simões de Almeida, R, Slompo Ramos, C, Soares Felício, J, Thomé, F, Tibes Hachmann JC, Yamada, S, Yoiti Hayashida, C, Zanata Petry TB, Zanella, Mt, Andreeva, V, Angelova, A, Dimitrov, S, Genadieva, V, Genova-Hristova, G, Hristozov, K, Kamenov, Z, Koundurdjiev, A, Lozanov, L, Margaritov, V, Nonchev, B, Rangelov, R, Shinkov, A, Temelkova, M, Velichkova, E, Yakov, A, Aggarwal, N, Aronson, R, Bajaj, H, Chouinard, G, Conway, J, Cournoyer, S, Daroza, G, De Serres, S, Dubé, F, Goldenberg, R, Gupta, A, Gupta, M, Henein, S, Khandwala, H, Leiter, L, Madore, F, Mcmahon, A, Muirhead, N, Pichette, V, Rabasa-Lhoret, R, Steele, A, Tangri, N, Torshizi, A, Woo, V, Zalunardo, N, Fernández Montenegro MA, Godoy Jorquera JG, Medina Fariña, M, Saavedra Gajardo, V, Vejar, M, Chen, N, Chen, Q, Gan, S, Kong, Y, Li, D, Li, W, Li, X, Lin, H, Liu, J, Lu, W, Mao, H, Ren, Y, Song, W, Sun, J, Sun, L, Tu, P, Wang, G, Yang, J, Yin, A, Yu, X, Zhao, M, Zheng, H, Accini Mendoza JL, Arcos, E, Avendano, J, Diaz Ruiz JEA, Garcia Ortiz LH, Gonzalez, A, Hernandez Triana, E, Higuera, Jd, Malaver, N, Molina de Salazar DI, Rosero, R, Terront Lozano MA, Valderrama Cometa, L, Valenzuela, A, Vargas Alonso RD, Villegas, I, Yupanqui, H, Bartaskova, D, Barton, P, Belobradkova, J, Dohnalova, L, Drasnar, T, Ferkl, R, Halciakova, K, Klokocnikova, V, Kovar, R, Lastuvka, J, Lukac, M, Pesickova, S, Peterka, K, Pumprla, J, Rychlik, I, Saudek, F, Tesar, V, Valis, M, Weiner, P, Zemek, S, Alamartine, E, Borot, S, Cariou, B, Dussol, B, Fauvel, Jp, Gourdy, P, Klein, A, Le Meur, Y, Penfornis, A, Roussel, R, Saulnier, Pj, Thervet, E, Zaoui, P, Burst, V, Faghih, M, Faulmann, G, Haller, H, Jerwan-Keim, R, Maxeiner, S, Paschen, B, Plassmann, G, Rose, L, Gonzalez Orellana RA, Haase, Fp, Moreira Diaz JP, Ramirez Roca LA, Sánchez Arenales JA, Sanchez Polo JV, Turcios Juarez, E, Csecsei, G, Csiky, B, Danos, P, Deak, L, Dudas, M, Harcsa, E, Keltai, K, Keresztesi, S, Kiss, K, Konyves, L, Major, L, Mileder, M, Molnar, M, Mucsi, J, Oroszlan, T, Ory, I, Paragh, G, Peterfai, E, Petro, G, Revesz, K, Takacs, R, Vangel, S, Vasas, S, Zsom, M, Abraham, O, Bhushan, Rs, Deepak, D, Edwin, Fm, Gopalakrishnan, N, Gracious, N, Hansraj, A, Jain, D, Keshavamurthy, Cb, Khullar, D, Manisha, S, Peringat, J, Prasad, N, Satyanarayana, Rk, Sreedhar, R, Sreelatha, M, Sudhakar, B, Vyasam, Rc, Bonadonna, R, Castellino, P, Ceriello, A, Chiovato, L, De Cosmo, S, Derosa, G, Di Carlo, A, Di Cianni, G, Frascà, G, Fuiano, G, Gambaro, G, Garibotto, G, Giorda, C, Malberti, F, Mandreoli, M, Mannucci, E, Orsi, E, Piatti, P, Santoro, D, Sasso, Fc, Serviddio, G, Stella, A, Trevisan, R, Veronelli, Am, Zanoli, L, Akiyama, H, Aoki, H, Asano, A, Iitsuka, T, Kajiyama, S, Kashine, S, Kawada, T, Kodera, T, Kono, H, Koyama, K, Kumeda, Y, Miyauchi, S, Mizuyama, K, Niiya, T, Oishi, H, Ota, S, Sakakibara, T, Takai, M, Tomonaga, O, Tsujimoto, M, Wakasugi, M, Wakida, Y, Watanabe, T, Yamada, M, Yanagida, K, Yanase, T, Yumita, W, Gaupsiene, E, Kozloviene, D, Navickas, A, Urbanaviciene, E, Abdul Ghani, R, Abdul Kadir, K, Ali, N, Che Yusof MD, Gan, Cl, Ismail, M, Kong, Wy, Lam, Sw, Lee, Ly, Loh, Cl, Manocha, Ab, Ng, Ks, Nik Ahmad NNF, Ratnasingam, V, Bin Shudim SS, Vengadasalam, P, Abraira Munoz LD, Salazar, Ma, Cruz, Jb, Soto, Mb, Ramos, Jc, Wong, Ac, Correa Rotter JR, Diaz Escalante, T, Enriquez Sosa FE, Flores Lozano, F, Flota Cervera LF, Frenk Baron, P, Garcia Ballesteros, C, Gomez Rangel JD, Herrera Jimenez LE, Irizar Santana SS, Jimenez Florez, F, Laviada Molina, H, Luna Ceballos RI, Martin Del Camp Blanco, B, Morales Franco, G, Moreno Loza OT, Mustieles Rocha, C, Obrador Vera, G, Orozco Castellanos, R, Peralta Calcaneo, J, Reyes Rosano MA, Rodriguez Pattzi, H, Rosas Guzman, J, Rucker Joerg IE, Saaveddra Sanchez SB, Sanchez Mijangos JH, Serrano Sanson, P, Tamayo, Y Orozco JA, Tellez Chavez, E, Valdes Depeda, A, Venegas Carrillo, L, Villagordoa Mesa, J, Zamarripa Escobedo, R, Baker, J, Noonan, P, Scott, R, Walker, R, Watson, E, Williams, M, Young, S, Abejuela, Z, Agra, J, Aquitania, G, Caringal, C, Comia, Rs, Delos Santos, L, Gomez, O, Jimeno, C, Tan, G, Tolentino, M, Yao, C, Yap, Ye, Ygpuara, Mdl, Bijata-Bronisz, R, Hotlos, L, Januszewicz, A, Kaczmarek, B, Kaminska, A, Lazuka, L, Madej, A, Mazur, S, Mlodawska-Choluj, D, Orlowska-Kowalik, G, Popenda, G, Rewerska, B, Sowinski, D, Angelescu, Lm, Anghel, V, Avram, Ri, Busegeanu, Mm, Cif, A, Cosma, D, Crisan, C, Demian, Ld, Ferariu, Ie, Halmagyi, I, Hancu, N, Munteanu, M, Negru, D, Onaca, Ag, Petrica, L, Popa, Ar, Ranetti, Ae, Serafinceanu, C, Toarba, C, Agafyina, A, Barbarash, O, Barysheva, O, Chizhov, D, Dobronravov, V, Glinkina, I, Grineva, E, Khirmanov, V, Kolmakova, E, Koroleva, T, Kvitkova, L, Marasaev, V, Mkrtumyan, A, Morugova, T, Nagibovich, G, Nagibovich, O, Nedogoda, S, Osipova, I, Raskina, T, Samoylova, Y, Sazonova, O, Shamkhalova, M, Shutemova, E, Shwartz, Y, Uriasyev, O, Vorobyev, S, Zateyshchikova, A, Zateyshshikov, D, Zykova, T, Antic, S, Djordjevic, M, Kendereski, A, Lalic, K, Lalic, N, Popovic-Radinovic, V, Babikova, J, Benusova, O, Buganova, I, Culak, J, Dzupina, A, Dzuponova, J, Fulop, P, Ilavska, A, Martinka, E, Ochodnicka, Z, Pella, D, Smatanova, I, Ahmed, F, Badat, A, Breedt, J, Govender, V, Govender, R, Joshi, M, Jurgens, J, Latiff, G, Lombard, L, Mookadam, M, Ngcakani, N, Nortje, H, Oosthuizen, H, Pillay-Ramaya, L, Prozesky, H, Reddy, J, Rheeder, P, Seeber, M, Cho, Ym, Jeong, Ik, Kim, Sg, Kim, Yh, Kwon, Hs, Kwon, Mj, Lee, Bw, Lee, J, Lee, Mk, Nam, Ms, Oh, Kh, Park, Cy, Park, Sh, Yoon, Kh, Alvarez Garcia, P, Asmarats Mercadal, L, Barrios, C, Cereto Castro, F, Cigarran Guldris, S, Dominquez Lopez, M, Egido de Los Rios, J, Fernandez Fresnedo, G, Galan Serrano, A, Garcia, I, Gonzalez Martinez FJ, Jodar Gimeno JE, Muñoz Lopez Mendoza, M, Malek Marin, T, Morales Portillo, C, Munar Vila MA, Muñoz Torres, M, Nieto Iglesias, J, Pantoja Perez, J, Perez Vera, M, Portoles Perez JM, Quesada Simón MA, Simo Canonge, R, Soto Gonzalez, A, Terns Riera, M, Tinahones Madueno FJ, Plaza, Mv, Chang, Ct, Chuang, Lm, Hsia, Tl, Hsieh, Ch, Lin, Cc, Lu, Yc, Sheu, Wh, Barna, O, Bilyk, Sd, Botsyurko, V, Dudar, I, Fushtey, I, Godlevska, O, Golovchenko, O, Gyrina, O, Kazmirchuk, A, Komisarenko, I, Korzh, O, Kravchun, N, Legun, O, Mankovskyy, B, Martynyuk, L, Mostovoy, Y, Pashkovska, N, Pererva, L, Pertseva, T, Samoylov, O, Smirnov, I, Svyshchenko, Y, Tomashkevych, H, Topchii, I, Tryshchuk, N, Tseluyko, V, Vizir, V, Vlasenko, M, Zlova, T, Zub, L, Abusnana, S, Railey, M, Abouglila, K, Ainsworth, P, Ali, Z, Arutchelvam, V, Barnard, M, Bellary, S, Davies, E, Davies, M, Davies, S, Dawson, A, El Kossi, M, English, P, Fraser, D, Gnudi, L, Gunstone, A, Hall, T, Hanif, W, Jackson, A, Johnson, A, Joseph, F, Krishnan, S, Kumwenda, M, Macdougall, I, Nixon, P, O'Hare, J, Philip, S, Ramtoola, S, Saxena, M, Sennik, D, Simon, G, Singh, B, Stephens, J, Strzelecka, A, Symonds, R, Turner, W, Wahba, M, Wakeling, J, Wheeler, D, Winocour, P, Abdallah, J, Abdullah, R, Abramowitz, M, Acosta, I, Aiello, J, Akright, L, Akyea-Djamson, A, Alappan, R, Alicic, R, Al-Karadsheh, A, Allison, Dc, Arauz-Pacheco, C, Arfeen, S, Arif, A, Arvind, M, Atray, N, Awad, A, Barnhill, P, Barranco, E, Barrera, C, Beacom, M, Behara, V, Belo, D, Bentley-Lewis, R, Berenguer, R, Bermudez, L, Bernardo, M, Biscoveanu, M, Bowman-Stroud, C, Brandon, D, Brusco, O, Busch, R, Canaan, Y, Chilito, A, Christensen, T, Christiano, C, Christofides, E, Chuateco, C, Cohen, K, Cohen, R, Cohen-Stein, D, Cook, C, Coyne, D, Daboul, N, Darwish, R, Daswani, A, Deck, K, Desouza, C, Dev, D, Dhillon, M, Dua, S, Eder, F, Elosegui, Am, El-Shahawy, M, Ervin, J, Esquenazi, A, Evans, J, Fishbane, S, Frias, J, Galindo-Ramos, E, Galphin, C, Ghazi, A, Gonzalez, E, Gorson, D, Gowda, A, Greco, B, Grubb, S, Gulati, R, Hammoud, J, Handelsman, S, Hartman, I, Hershon, K, Hiser, D, Hon, G, Jacob, R, Jaime, M, Jamal, A, Kaupke, C, Keightley, G, Kern, E, Khanna, R, Khitan, Z, Kim, S, Kopyt, N, Kovesdy, C, Krishna, G, Kropp, J, Kumar, A, Kumar, J, Kumar, N, Kusnir, J, Lane, W, Lawrence, M, Lehrner, L, Lentz, J, Levinson, D, Lewis, D, Liss, K, Maddux, A, Maheshwari, H, Mandayam, S, Marar, I, Mehta, B, Middleton, J, Mordujovich, J, Moreda, R, Moustafa, M, Mujica Trenche, S, Narayanan, M, Narvarte, J, Nassar, T, Newman, G, Nichol, B, Nicol, P, Nisnisan, J, Nossuli, Ak, Obialo, C, Olelewe, S, Oliver, M, O'Shaughnessy, A, Padron, J, Pankhaniya, R, Parker, R, Patel, D, Patel, G, Patel, N, Pavon, H, Perez, A, Perez, C, Perlman, A, Pettis, K, Pharr, W, Phillips, A, Purighalla, R, Quesada-Suarez, L, Ranjan, R, Rastogi, S, Rendell, M, Rich, L, Robinson, M, Rodriguez, H, Rosas, S, Saba, F, Sankaram, R, Sarin, R, Schreiman, R, Scott, D, Sekkarie, M, Sensenbrenner, J, Shakeel, M, Shanik, M, Shaw, S, Smith, S, Solomon, R, Sprague, A, Spry, L, Suchinda, P, Sultan, S, Surampudi, P, Sussman, S, Tan, A, Terrelonge, A, Thompson, M, Trespalacios, F, Trippe, B, Trueba, P, Twahirwa, M, Updegrove, J, Van Buren, P, Vannorsdall, M, Varghese, F, Velasquez-Mieyer, P, Ventrapragada, S, Vukotic, G, Wadud, K, Warren, M, Watson, H, Watts, R, Weiner, D, Welker, J, Welsh, J, Williams, S, Zaniewski-Singh, M., Perkovic, Vlado, Jardine, Meg J, Neal, Bruce, Bompoint, Severine, Heerspink, Hiddo J L, Charytan, David M, Edwards, Robert, Agarwal, Rajiv, Bakris, George, Bull, Scott, Cannon, Christopher P, Capuano, George, Chu, Pei-Ling, de Zeeuw, Dick, Greene, Tom, Levin, Adeera, Pollock, Carol, Wheeler, David C, Yavin, Yshai, Zhang, Hong, Zinman, Bernard, Meininger, Gary, Brenner, Barry M, Mahaffey, Kenneth W, collaborator: Perkovic, V, Mahaffey, Kw, Agarwal, R, Bakris, G, Brenner, Bm, Cannon, Cp, Charytan, Dm, de Zeeuw, D, Greene, T, Jardine, Mj, Heerspink, Hjl, Levin, A, Meininger, G, Neal, B, Pollock, C, Wheeler, Dc, Zhang, H, Zinman, B, Mcguire, Dk, Holman, R, Home, P, Scharfstein, D, Parfrey, P, Shahinfar, S, August, P, Chang, T, Sinha, Ad, Januzzi, J, Kolansky, D, Amerena, J, Hillis, G, Gorelick, P, Kissela, B, Kasner, S, Lindley, R, Fulcher, G, Ounadjela, S, Hufert, K, von Ingersleben, G, Gaglia, J, Harris, R, Hudson, M, Turchin, A, Cheifetz, A, Sheth, S, Feuerstein, J, Cohen, S, Jardine, M, Li, N, Kolesnyk, I, Aizenberg, D, Pecoits-Filho, R, Cherney, D 3rd, Obrador, G, Chertow, G, Hawley, C, Ji, L, Wada, T, Jha, V, Lim, Sk, Lim-Abrahan, Ma, Santos, F, Chae, Dw, Hwang, Sj, Vazelov, E, Rychlík, I, Hadjadj, S, Krane, V, Rosivall, L, De Nicola, L, Dreval, A, Nowicki, M, Schiller, A, Distiller, L, Górriz, Jl, Kolesnyk, M, Morren, F, Goykhman, S, David, C, Yost, L, Wang, H, Hettiarachchi, M, Thimmaiah, R, Koppolu, D, George, S, Schmidt, M, Ignjatovic, J, Chapin, L, Travis, K, Destree, M, Sood, V, Coffee, L, De Brouwer, K, Zaviriukha, V, Starzec, A, Koizumi, M, Lin, G, Chen, E, Lin, P, Leia, C, Mascaro, D, Amigo, A, Limos, A, Abrahamsen, I, Jaffer, S, Ahuad Guerrero, Ra, Albisu, Jp, Alvarisqueta, A, Bartolacci, I, Berli, Ma, Bordonava, A, Calella, P, Cantero, Mc, Cartasegna, Lr, Cercos, E, Coloma, Gc, Colombo, H, Commendatore, V, Cuadrado, J, Cuneo, Ca, Cusumano, Am, Douthat, Wg, Dran, Rd, Farias, E, Fernandez, Mf, Finkelstein, H, Fragale, G, Fretes, Jo, Garcia, Nh, Gastaldi, A, Gelersztein, E, Glenny, Ja, Gonzalez, Jp, Gonzalez Colaso, 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Subjects
Aged, Canagliflozin, Cardiovascular Diseases, Creatinine, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Double-Blind Method, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Sodium-Glucose Transporter 2 Inhibitors, Type 2 diabetes, 030204 cardiovascular system & hematology, Diabetic nephropathy, Kidney Failure, chemistry.chemical_compound, 0302 clinical medicine, 030212 general & internal medicine, 03.02. Klinikai orvostan, Dapagliflozin, Chronic, 11 Medical and Health Sciences, EMPAGLIFLOZIN, General Medicine, Life Sciences & Biomedicine, Type 2, medicine.drug, medicine.medical_specialty, Nephropathy, 03 medical and health sciences, Medicine, General & Internal, Internal medicine, Diabetes mellitus, General & Internal Medicine, CREDENCE Trial Investigators, medicine, Diabetes Mellitus, Science & Technology, business.industry, urogenital system, diabetic nephropathy, Type 2 Diabetes Mellitus, KIDNEY-DISEASE, medicine.disease, chemistry, business, Kidney disease
Abstract

BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS: In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of

Published
2019

17. Multimodal fuzzy fusion for enhancing the motor-imagery-based brain computer interface

Author

Ko, LW, Lu, YC, Bustince, H, Chang, YC, Chang, Y, Ferandez, J, Wang, YK, Sanz, JA, Pereira Dimuro, G, Lin, CT, Ko, LW, Lu, YC, Bustince, H, Chang, YC, Chang, Y, Ferandez, J, Wang, YK, Sanz, JA, Pereira Dimuro, G, and Lin, CT

Abstract

© 2005-2012 IEEE. Brain-computer interface technologies, such as steady-state visually evoked potential, P300, and motor imagery are methods of communication between the human brain and the external devices. Motor imagery-based brain-computer interfaces are popular because they avoid unnecessary external stimuli. Although feature extraction methods have been illustrated in several machine intelligent systems in motor imagery-based brain-computer interface studies, the performance remains unsatisfactory. There is increasing interest in the use of the fuzzy integrals, the Choquet and Sugeno integrals, that are appropriate for use in applications in which fusion of data must consider possible data interactions. To enhance the classification accuracy of brain-computer interfaces, we adopted fuzzy integrals, after employing the classification method of traditional brain-computer interfaces, to consider possible links between the data. Subsequently, we proposed a novel classification framework called the multimodal fuzzy fusion-based brain-computer interface system. Ten volunteers performed a motor imagery-based brain-computer interface experiment, and we acquired electroencephalography signals simultaneously. The multimodal fuzzy fusion-based brain-computer interface system enhanced performance compared with traditional brain-computer interface systems. Furthermore, when using the motor imagery-relevant electroencephalography frequency alpha and beta bands for the input features, the system achieved the highest accuracy, up to 78.81% and 78.45% with the Choquet and Sugeno integrals, respectively. Herein, we present a novel concept for enhancing brain-computer interface systems that adopts fuzzy integrals, especially in the fusion for classifying brain-computer interface commands.

Published
2019

18. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics

Author

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Borges, Jl, Cunha Vêncio, Sa, Cusumano, Am, da Silva Franco, Rj, Daboul, N, Danos, P, Daroza, G, Davies, E, Davies, M, Davies, S, Dawson, A, De Cosmo, S, De Nicola, L, De Serres, S, de Souza Portes, E, Deak, L, Deck, K, Deepak, D, Derosa, G, Desouza, C, Dev, D, Dhillon, M, DI CARLO, Alfonso, Di Cianni, G, Diaz Escalante, T, Dimitrov, S, Distiller, L, Djordjevic, M, Dobronravov, V, Dohnalova, L, Dominguez Lopez, M, Douthat, Wg, Dran, Rd, Drasnar, T, Dreval, A, Droste, C, Dua, S, Dube, F, Dudar, I, Dudas, M, Dussol, B, Dzupina, A, Eder, F, Egido de Los Rios, J, El Kossi, M, El-Shahawy, M, English, P, Enriquez Sosa, Fe, Ervin, J, Esquenazi, A, Evans, J, Faghih, M, Farias, E, Faulmann, G, Fauvel, Jp, Ferariu, Ie, Fernandez, Mf, Fernandez Fresnedo, G, Fernandez Montenegro, Ma, Finkelstein, H, Flores Lozano, F, Flota Cervera, L, Fraige Filho, F, Fraser, D, Frenk Baron, P, Fretes, Jo, Frias, J, Fuiano, G, Fulop, P, Fushtey, I, Galan Serrano, A, Galphin, C, Gan, S, Gan, Cl, Garcia, Nh, Garcia, I, Garcia Ballesteros, C, Garcia Ortiz, Lh, Garrido, N, Gastaldi, A, Gelersztein, E, Geloneze Neto, B, Genadieva, V, Genova-Hristova, G, Genovese, S, Ghazi, A, Giorda, C, Glenny, Ja, Glinkina, I, Godlevska, O, Godoy Jorquera, Jg, Goldenberg, R, Golovchenko, O, Gomes Bastos, M, Gomez, O, Gomez Rangel, Jd, Gonzalez, E, Gonzalez Dorado, A, Gonzalez Martinez, Fj, Gonzalez Orellana, Ra, Gopalakrishnan, N, Gorriz, Jl, Gorson, D, Govender, V, Gracious, N, Greco, B, Gregar, R, Greloni, Gc, Grineva, E, Guinsburg, A, Gulati, R, Gunstone, A, Gupta, A, Gupta, M, Gyrina, O, Hadjadj, S, Halciakova, K, Hall, T, Haller, H, Halmagyi, I, Hammoud, J, Hancu, N, Hanif, W, Hansraj, A, Hawley, C, Henein, S, Hermida, S, Hernandez Triana, E, Herrera Jimenez, Le, Hershon, K, Higuera Cobos, Jd, Hiser, D, Hocking, S, Hon, G, Hristozov, K, Hsieh, Ch, Hura, C, Hwang, Sj, Ilavska, A, Irizar Santana, S, Ismail, M, Jackson, A, Jain, D, Jamal, A, Januszewicz, A, Jeong, Ik, Jha, V, Jimenez Flores, F, Jodar Gimeno, Je, Johnson, A, Joseph, F, Joshi, M, Juncos, Li, Jurgens, J, Kajiyama, S, Kaminska, A, Kashine, S, Kaupke, C, Kawada, T, Keiko Kohara, S, Keitel, E, Keltai, K, Kendereski, A, Keresztesi, S, Kern, E, Kerr Saraiva, Jf, Keshavamurthy, Cb, Khandwala, H, Khanna, R, Khitan, Z, Khullar, D, Kim, Sg, Kim, Yh, Kim, S, Kiss, K, Klein, A, Klyver, Mi, Kodera, T, Kolesnyk, M, Kolmakova, E, Komisarenko, I, Kong, Y, Kong, Wy, Kono, H, Konyves, L, Kopyt, N, Korzh, O, Kovar, R, Kovesdy, C, Koyama, K, Kozloviene, D, Kraft, F, Krane, V, Kravchun, N, Krishna, G, Krishnan, S, Kropp, Jj, Kumar, A, Kumar, J, Kumeda, Y, Kumwenda, M, Kurtz Lisboa, Hr, Kvitkova, L, Kwon, H, Kwon, Mj, Lalic, K, Lalic, N, Lanchiotti, Pv, Lastuvka, J, Laviada Molina, H, Lawrence, M, Le Meur, Y, Lee, Ly, Lee, Bw, Lee, J, Lee, Mk, Legun, O, Leiter, L, Lentz, J, Leon de la Fuente, Ra, Levin, A, Lewis, D, Li, D, Li, W, Li, X, Lim, Sk, Lin, H, Lin, Cc, Liss, K, Liu, J, Loh, Cl, Lombard, L, Lopez Mendoza, M, Lopez Tarabay, C, Lorenzoni d'avila, Do, Loss de Carvalho Contieri, F, Lu, W, Lu, Yc, Luna Ceballos, R, M., Edwin F, Macdougall, I, Macedo de Souza, Pa, Madej, A, Madore, F, Magalhaes Montenegro Junior, R, Mah, Pm, Maheshwari, H, Major, L, Malberti, F, Malek Marin, T, Mandayam, S, Mandreoli, M, Manisha, S, Mankovskyy, B, Mannucci, E, Manocha, Ab, Mao, H, Marar, I, Marasaev, V, Marchetta, N, Martin Del Campo Blanco, B, Martinka, E, Martynyuk, L, Maxeiner, S, Mazur, S, Mcmahon, A, Medina Farina, M, Mehta, B, Middleton, J, Mileder, M, Miyauchi, S, Mizuyama, K, Mkrtumyan, A, Mlodawska-Choluj, D, Molina de Salazar, Di, Molnar, M, Mookadam, M, Morales Franco, G, Morales Portillo, C, Mordujovich, J, Moreira de Brito, C, Moreira Diaz, Jp, Moreno Loza, Ot, Mostovoy, Y, Moustafa, M, Muirhead, N, Mujica Trenche, S, Munar Vila, Ma, Munoz Torres, M, Munteanu, M, Mustieles Rocha, C, Nagibovich, G, Nam, M, Narvarte, J, Nasser Hissa, M, Navickas, A, Nazario Sabbag, Âr, Nedogoda, S, Negru, D, Newman, G, Ng, K, Ngcakani, N, Nicholls, K, Nicol, P, Nieto Iglesias, J, Niiya, T, Nik Ahmad, Nnf, Nisnisan, J, Nonchev, B, Noronha, Il, Nortje, H, Nossuli, Ak, Nowicki, M, Obialo, C, Obrador Vera, G, Ochodnicka, Z, Oh, Kh, Oishi, H, Olelewe, S, Oliver, M, Oosthuizen, H, Orio, Si, Orlowska-Kowalik, G, Oroszlan, T, Orozco Castellanos, R, Orsi, E, Ory, I, O'Shaughnessy, A, Ota, S, Otreras, F, Oviedo, A, Packham, D, Padron, J, Panarotto, D, Pankhaniya, R, Pantoja Perez, J, Paragh, G, Park, Cy, Park, Sh, Pashkovska, N, Patel, D, Patel, G, Pavon, H, Pei, D, Pella, D, Penfornis, A, Peralta Calcaneo, J, Pereira, Ma, Pererva, L, Perez Vera, M, Peringat, J, Pertseva, T, Pesickova, S, Peterfai, E, Peterka, K, Petrica, L, Petro, G, Pettis, K, Pharr, W, Philip, S, Phillips, A, Piatti, P, Pichette, V, Pontiroli, A, Popa, Ar, Popenda, G, Popovic-Radinovic, V, Portoles Perez, Jm, Prasad, N, Proietto, J, Prozesky, H, Pumprla, J, Purighalla, R, Quesada Simon, Ma, Quesada-Suarez, L, Rabasa-Lhoret, R, Ramirez Roca, La, Ramtoola, S, Ranetti, Ae, Rangelov, R, Ranjan, R, Raskina, T, Rastogi, S, Ratnasingam, V, Reddy, J, Ren, Y, Resk, Jh, Rewerska, B, Reyes Rosano, Ma, Rich, L, Rista, L, Roberts, A, Robinson, M, Rodelo, J, Rodriguez, H, Rodriguez Papini, N, Roger, S, Rosas, S, Rosas Guzman, J, Rosivall, L, Roussel, R, Rucker Joerg, Ie, Rychlik, I, Saavedra Gajardo, V, Saavedra Sanchez, Sb, Sala, J, Samoylov, O, Samoylova, Y, Sanchez Arenales, Ja, Sanchez Mijangos, Jh, Sanchez Polo, Jv, Sankaram, R, Santoro, D, Santos, Jc, Santos, F, Sarin, R, Saudek, F, Saumell, F, Saxena, M, Sazonova, O, Schiavi, Lb, Schiller, A, Schuch, T, Scott, R, Scott, D, Seeber, M, Seiji Yamada, S, Sekkarie, M, Sensenbrenner, J, Serafinceanu, C, Serrano Sanson, P, Sessa, H, Shakeel, M, Shamkhalova, M, Shanik, M, Shaw, S, Sheu, Wh, Shinkov, A, Shutemova, E, Silva Pecoits Filho, Rf, Simo Canonge, R, Simoes de Almeida, R, Simon, G, Singh, B, Slompo Ramos, C, Smatanova, I, Smirnov, I, Smith, S, Smith Casabella, T, Soares Felicio, J, Soler Romeo, Mj, Solomon, R, Song, W, Soto Gonzalez, A, Sowinski, D, Sprague, A, Sree Bhushan, R, Sreedhar, R, Sreelatha, M, Steele, A, Spedding, Stephen John, Strzelecka, A, Suchinda, P, Sudhakar, B, Sun, J, Sun, L, Surampudi, P, Sussman, S, Svyshchenko, Y, Symonds, R, Szlachcic, Y, Takacs, R, Takai, M, Tamayo Y., Orozco J, Tan, G, Tellez Chavez, E, Temelkova, M, Terns Riera, M, Terront Lozano, Ma, Tesar, V, Thompson, M, Tibes Hachmann, Jc, Tinahones Madueno, Fj, Tolentino, M, Tomashkevych, H, Tomonaga, O, Topchii, I, Torshizi, A, Trespalacios, F, Trevisan, R, Trueba, P, Tryshchuk, N, Tseluyko, V, Tsujimoto, M, Tu, P, Turcios Juarez, E, Turner, W, Twahirwa, M, Ulla, Mr, Updegrove, J, Urbanaviciene, E, Valderrama Cometa, L, Valdes Cepeda, A, Valenzuela, A, Valis, M, Vallejos, A, Vangel, S, Vannorsdall, M, Vargas Alonso, Rd, Varghese, F, Vasas, S, Vazelov, E, Vejar, M, Velasquez-Mieyer, P, Velichkova, E, Velo, M, Venegas Carrillo, L, Vengadasalam, P, Ventrapragada, S, Villagordoa Mesa, J, Villarino, Aa, Villegas, I, Visco, Ve, Vizir, V, Vlasenko, M, Vyasam, Rc, Wada, T, Wadud, K, Wahba, M, Wakasugi, M, Wakeling, J, Wakida, Y, Walker, JOHN RICHARD, Wang, G, Warren, M, Wassermann, A, Watanabe, T, Watson, E, Watts, R, Weiner, P, Weiner, D, Welsh, J, Wheeler, D, Williams, M, Winocour, P, Woo, V, Yamada, M, Yanagida, K, Yanase, T, Yang, J, Yao, C, Yap, Ye, Ygpuara, Mdl, Yin, A, Yoiti Hayashida, C, Yoon, Kh, Young, S, Yu, X, Yumita, W, Yupanqui, H, Zaidman, Cj, Zamarripa Escobedo, R, Zanata Petry, Tb, Zanella, Mt, Zaoui, P, Zavaroni, I, Zemek, S, Zhang, H, Zhao, M, Zheng, H, Zlova, T, Zsom, M, and Zykova, T.

Subjects
medicine.medical_specialty, ALBUMINURIA, Urology, Renal function, 030209 endocrinology & metabolism, PROGRESSION, Type 2 diabetes, Diabetic nephropathy, 030204 cardiovascular system & hematology, GLOMERULAR-FILTRATION-RATE, CARDIOVASCULAR OUTCOMES, Nephropathy, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Chronic kidney disease, medicine, 03.02. Klinikai orvostan, Renal outcome, Canagliflozin, Science & Technology, ATRIAL-NATRIURETIC-PEPTIDE, IRBESARTAN, GFR DECLINE, business.industry, 1103 Clinical Sciences, KIDNEY-DISEASE, Urology & Nephrology, medicine.disease, Renal outcomes, Nephrology, COLLABORATIVE METAANALYSIS, Albuminuria, Original Report: Patient-Oriented, Translational Research, LOSARTAN, medicine.symptom, business, Life Sciences & Biomedicine, CREDENCE study investigators, medicine.drug, Kidney disease
Abstract

Background: People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. Methods: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin ­versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of ∼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate ≥30 to 2, and albuminuria (urinary albumin:creatinine ratio >300 to ≤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. Conclusion: CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease. Trial Registration: EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791.

Published
2017

19. AKT2-knockdown suppressed viability with enhanced apoptosis, and attenuated chemoresistance to temozolomide of human glioblastoma cells in vitro and in vivo

Author

Cui Y, Lin J, Zuo JL, Zhang L, Dong Y, Hu GH, Luo C, Chen JX, and Lu YC

Subjects
embryonic structures, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, hormones, hormone substitutes, and hormone antagonists
Abstract

Yong Cui,1,* Jing Lin,1,* Jianling Zuo,2 Lei Zhang,1 Yan Dong,1 Guohan Hu,1 Chun Luo,1 Juxiang Chen,1 Yicheng Lu1 1Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, People’s Republic of China; 2Department of Neurosurgery, First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China *These authors contributed equally tothis work Abstract: The AKT2 kinase (protein kinase Bβ) is overexpressed in high-grade gliomas. Upregulation of the AKT2 gene has been previously observed in glioblastoma patients suffering from chemotherapy failure and tumor progress. In this study, we aimed to evaluate the effect of AKT2 on viability and chemoresistance in the human glioblastoma cell line U251. The U251 cell line was stably transfected with short hairpin RNA (shRNA) targeting AKT2. U251 cells underexpressing AKT2 were then examined for viability with temozolomide (TMZ) treatment, and tested for cell apoptosis both in vitro and in tumor-implanted mice. Next, expressions of several chemoresistance-related molecules were measured by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blot analysis. The results showed that the 50% inhibitory concentration (IC50) of AKT2 shRNA-transfected cells was significantly lower compared with Lenti-GFP-transfected and nontransfected controls and that the tumor growth of the AKT2-shRNA and TMZ combined-treated mice was obviously suppressed in either mass or volume. Concomitantly, the apoptosis of TMZ-treated tumor cells was significantly enhanced after knockdown of AKT2, as measured by flow cytometry and in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. Furthermore, AKT2-inhibition in TMZ-treated glioblastoma U251 cells upregulated apoptotic effector caspase-3, whereas it downregulated antiapoptotic protein Bcl-2, DNA repairing protein MGMT, and drug efflux pump protein MRP1. Our study identified AKT2 as an important gene in presenting chemoresistance in glioblastoma, and a potential target to potentiate the clinical effect of chemotherapy in glioma treatment. Keywords: AKT2, glioma, chemoresistance, TMZ, mice&nbsp

Published
2015

20. Monetary reward and punishment to response inhibition modulate activation and synchronization within the inhibitory brain network

Author

Chikara, RK, Chang, EC, Lu, YC, Lin, DS, Lin, CT, Ko, LW, Chikara, RK, Chang, EC, Lu, YC, Lin, DS, Lin, CT, and Ko, LW

Abstract

© 2018 Chikara, Chang, Lu, Lin, Lin and Ko. A reward or punishment can modulate motivation and emotions, which in turn affect cognitive processing. The present simultaneous functional magnetic resonance imaging-electroencephalography study examines neural mechanisms of response inhibition under the influence of a monetary reward or punishment by implementing a modified stop-signal task in a virtual battlefield scenario. The participants were instructed to play as snipers who open fire at a terrorist target but withhold shooting in the presence of a hostage. The participants performed the task under three different feedback conditions in counterbalanced order: a reward condition where each successfully withheld response added a bonus (i.e., positive feedback) to the startup credit, a punishment condition where each failure in stopping deduced a penalty (i.e., negative feedback), and a no-feedback condition where response outcome had no consequences and served as a control setting. Behaviorally both reward and punishment conditions led to significantly down-regulated inhibitory function in terms of the critical stop-signal delay. As for the neuroimaging results, increased activities were found for the no-feedback condition in regions previously reported to be associated with response inhibition, including the right inferior frontal gyrus and the pre-supplementary motor area. Moreover, higher activation of the lingual gyrus, posterior cingulate gyrus (PCG) and inferior parietal lobule were found in the reward condition, while stronger activation of the precuneus gyrus was found in the punishment condition. The positive feedback was also associated with stronger changes of delta, theta, and alpha synchronization in the PCG than were the negative or no-feedback conditions. These findings depicted the intertwining relationship between response inhibition and motivation networks.

Published
2018

21. Prognostic significance of p62/SQSTM1 subcellular localization and LC3B in oral squamous cell carcinoma

Author

Lu Yc, Chao-Hung Hung, Chen Ff, Lo Ch, Lee Fh, Liu Jl, and Jrhau Lung

Subjects
squamous cell carcinoma, Adult, Male, Cancer Research, autophagy, Cytoplasm, Cell Survival, p62/SQSTM1, Biology, oral, Sequestosome-1 Protein, medicine, Carcinoma, LC3, Biomarkers, Tumor, Humans, Basal cell, Molecular Diagnostics, Cell survival, Adaptor Proteins, Signal Transducing, Retrospective Studies, Mouth neoplasm, Cell Nucleus, Hyperplasia, Mouth Mucosa, Middle Aged, Subcellular localization, medicine.disease, Prognosis, Survival Rate, Cell nucleus, stomatognathic diseases, medicine.anatomical_structure, Oncology, Immunology, immunohistochemistry, Cancer research, Carcinoma, Squamous Cell, Female, Mouth Neoplasms, in situ hybridization, Microtubule-Associated Proteins
Abstract

Background: Autophagy is a programmed cell survival mechanism that has a key role in both physiologic and pathologic conditions. The relationship between autophagy and cancer is complex because autophagy can act as either a tumour suppressor or as a tumour promoter. The role of autophagy in oral squamous cell carcinoma (OSCC) is controversial. Several studies have claimed that either a high or low expression of autophagy-related proteins was associated with poor prognosis of OSCCs. The aims of the study were to compare autophagy in OSCCs, verrucous hyperplasias, and normal oral mucosas, and to inspect the prognostic role of autophagy in OSCCs. Methods: We used the autophagosome marker, LC3B, and autophagy flux marker, p62/SQSTM1 (p62), by using immunohistochemistry, and examined p62 mRNA by RNA in situ hybridization, to evaluate autophagy in 195 OSCCs, 47 verrucous hyperplasias, and 37 normal oral mucosas. The prognostic roles of LC3B and p62 protein expressions in OSCCs were investigated. Results: We discovered that the normal oral mucosa exhibited limited LC3B punctae and weak cytoplasmic p62 staining, whereas the OSCCs exhibited a marked increase in LC3B punctae and cytoplasmic p62 expression. The expression pattern of LC3B and cytoplasmic p62 of the verrucous hyperplasias were between normal oral mucosas and OSCCs. The normal oral mucosas, verrucous hyperplasias, and OSCCs presented no differences in nuclear p62 expression and the p62 mRNA level. p62 mRNA expression was elevated in a minority of cases. High p62 mRNA expression was associated with high p62 protein expression in the cytoplasm. Increased LC3B punctae, high cytoplasmic p62, and low nuclear p62 expressions in OSCCs were associated with aggressive clinicopathologic features and unfavourable prognosis. In addition, low nuclear p62 expression was an independent prognostic factor for overall and disease-specific survival rates. Furthermore, we disclosed that high cytoplasmic p62 expression accompanied with either a low or high LC3B expression, which indicated autophagy impairment under basal or activated autophagic activity, was associated with aggressive behaviour in advanced OSCCs. Conclusions: We suggested that autophagy was altered during cancer initiation and progression. Autophagy impairment contributed to cancer progression in advanced OSCCs.

Published
2014

22. Celecoxib-induced increase in cytosolic Ca2+ levels and apoptosis in HA59T human hepatoma cells

Author

Cheng Js, Kuo Cc, Wei-Zhe Liang, Liu Si, He-Hsiung Cheng, Tseng Ll, Chi Cc, Lu Yc, Chung-Ren Jan, Chiang-Ting Chou, and Lu T

Subjects
Carcinoma, Hepatocellular, Thapsigargin, Cell Survival, Health, Toxicology and Mutagenesis, Antineoplastic Agents, Apoptosis, Phospholipase, Biology, Pharmacology, Endoplasmic Reticulum, Toxicology, chemistry.chemical_compound, BAPTA, Cell Line, Tumor, Humans, Protein kinase A, Protein Kinase C, Protein kinase C, Sulfonamides, Cyclooxygenase 2 Inhibitors, Phospholipase C, Endoplasmic reticulum, Liver Neoplasms, General Medicine, chemistry, Celecoxib, Type C Phospholipases, Pyrazoles, Calcium
Abstract

Celecoxib has been shown to have antitumor effect in previous studies but the mechanisms are unclear. The effect of celecoxib on cytosolic Ca2+ concentrations ([Ca2+]i) and viability in HA59T human hepatoma cells was explored. The Ca2+-sensitive fluorescent dye fura-2 was applied to measure [Ca2+]i. Celecoxib at concentrations of 10–50 μM induced a [Ca2+]i rise in a concentration-dependent manner. The response was reduced by 80% by removing Ca2+. Celecoxib induced Mn2+ influx, leading to quenching of fura-2 fluorescence. Celecoxib-evoked Ca2+ entry was suppressed by nifedipine, econazole, SK&F96365, and protein kinase C modulators. In the absence of extracellular Ca2+, incubation with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin nearly abolished celecoxib-induced [Ca2+]i rise. Incubation with celecoxib abolished thapsigargin-induced [Ca2+]i rise. Inhibition of phospholipase C with U73122 abolished celecoxib-induced [Ca2+]i rise. At 1–50 μM, celecoxib inhibited cell viability by less than 20%, which was not reversed by chelating cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N, N, N′, N′-tetraacetic acid/acetoxy methyl (BAPTA/AM). Celecoxib (10–50 μM) also induced apoptosis. In sum, in HA59T hepatoma cells, celecoxib induced a [Ca2+]i rise by evoking phospholipase C-dependent Ca2+ release from the endoplasmic reticulum and Ca2+ entry via protein kinase C-sensitive store-operated Ca2+ channels. Celecoxib also caused cell death via apoptosis.

Published
2014

23. 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

Author

Gorski, M, van der Most, PJ, Teumer, A, Chu, AY, Li, M, Mijatovic, V, Nolte, IM, Cocca, M, Taliun, D, Gomez, F, Li, Y, Tayo, B, Tin, A, Feitosa, MF, Aspelund, T, Attia, J, Biffar, R, Bochud, M, Boerwinkle, E, Borecki, I, Bottinger, EP, Chen, MH, Chouraki, V, Ciullo, M, Coresh, J, Cornelis, MC, Curhan, GC, d'Adamo, AP, Dehghan, A, Dengler, L, Ding, JZ (Jing Zhong), Eiriksdottir, G, Endlich, K, Enroth, S, Esko, T, Franco Duran, OH, Gasparini, P, Gieger, C, Girotto, G, Gottesman, O, Gudnason, V, Gyllensten, U, Hancock, S J, Harris, TB, Helmer, C, Hollerer, S, Hofer, E, Hofman, Bert, Holliday, EG, Homuth, G, Hu, FB, Huth, C, Hutri-Kahonen, N, Hwang, SJ, Imboden, M, Johansson, A, Kahonen, M, Konig, W, Kramer, H, Kramer, BK, Kumar, A, Kutalik, Z, Lambert, JC, Launer, LJ, Lehtimaki, T, Borst, Marja, Navis, G, Swertz, M, Liu, YM, Lohman, K, Loos, RJF, Lu, YC, Lyytikainen, LP, McEvoy, M A, Meisinger, C, Meitinger, T, Metspalu, A, Metzger, M, Mihailov, E, Mitchell, P, Nauck, M, Oldehinkel, AJ, Olden, M, Penninx, B, Pistis, G, Pramstaller, PP, Probst-Hensch, N, Raitakari, OT, Rettig, R, Ridker, PM, Rivadeneira, Fernando, Robino, A, Rosas, SE, Ruderfer, D, Ruggiero, D, Saba, Y, Sala, C, Schmidt, H, Schmidt, R, Scott, RJ, Sedaghat, Sanaz, Smith, AV, Sorice, R, Stengel, B, Stracke, S, Strauch, K, Toniolo, D, Uitterlinden, André, Ulivi, S, Viikari, JS, Volker, U, Vollenweider, P, Volzke, H, Vuckovic, D, Waldenberger, M, Wang, JJ, Yang, QO, Chasman, DI, Tromp, G, Snieder, H, Heid, IM, Fox, CS, Kottgen, A, Pattaro, C, Boger, CA, Fuchsberger, C, Gorski, M, van der Most, PJ, Teumer, A, Chu, AY, Li, M, Mijatovic, V, Nolte, IM, Cocca, M, Taliun, D, Gomez, F, Li, Y, Tayo, B, Tin, A, Feitosa, MF, Aspelund, T, Attia, J, Biffar, R, Bochud, M, Boerwinkle, E, Borecki, I, Bottinger, EP, Chen, MH, Chouraki, V, Ciullo, M, Coresh, J, Cornelis, MC, Curhan, GC, d'Adamo, AP, Dehghan, A, Dengler, L, Ding, JZ (Jing Zhong), Eiriksdottir, G, Endlich, K, Enroth, S, Esko, T, Franco Duran, OH, Gasparini, P, Gieger, C, Girotto, G, Gottesman, O, Gudnason, V, Gyllensten, U, Hancock, S J, Harris, TB, Helmer, C, Hollerer, S, Hofer, E, Hofman, Bert, Holliday, EG, Homuth, G, Hu, FB, Huth, C, Hutri-Kahonen, N, Hwang, SJ, Imboden, M, Johansson, A, Kahonen, M, Konig, W, Kramer, H, Kramer, BK, Kumar, A, Kutalik, Z, Lambert, JC, Launer, LJ, Lehtimaki, T, Borst, Marja, Navis, G, Swertz, M, Liu, YM, Lohman, K, Loos, RJF, Lu, YC, Lyytikainen, LP, McEvoy, M A, Meisinger, C, Meitinger, T, Metspalu, A, Metzger, M, Mihailov, E, Mitchell, P, Nauck, M, Oldehinkel, AJ, Olden, M, Penninx, B, Pistis, G, Pramstaller, PP, Probst-Hensch, N, Raitakari, OT, Rettig, R, Ridker, PM, Rivadeneira, Fernando, Robino, A, Rosas, SE, Ruderfer, D, Ruggiero, D, Saba, Y, Sala, C, Schmidt, H, Schmidt, R, Scott, RJ, Sedaghat, Sanaz, Smith, AV, Sorice, R, Stengel, B, Stracke, S, Strauch, K, Toniolo, D, Uitterlinden, André, Ulivi, S, Viikari, JS, Volker, U, Vollenweider, P, Volzke, H, Vuckovic, D, Waldenberger, M, Wang, JJ, Yang, QO, Chasman, DI, Tromp, G, Snieder, H, Heid, IM, Fox, CS, Kottgen, A, Pattaro, C, Boger, CA, and Fuchsberger, C

Published
2017

24. Single channel wireless EEG device for real-time fatigue level detection

Author

Ko, LW, Lai, WK, Liang, WG, Chuang, CH, Lu, SW, Lu, YC, Hsiung, TY, Wu, HH, and Lin, CT

Abstract

© 2015 IEEE. Driver fatigue problem is one of the important factors of traffic accidents. Recent years, many research had investigated that using EEG signals can effectively detect driver's drowsiness level. However, real-time monitoring system is required to apply these fatigue level detection techniques in the practical application, especially in the real-road driving. Therefore, it required less channels, portable and wireless, real-time monitoring and processing techniques for developing the real-time monitoring system. In this study, we develop a single channel wireless EEG device which can real-time detect driver's fatigue level on the mobile device such as smart phone or tablet. The developed device is investigated to obtain a better and precise understanding of brain activities of mental fatigue under driving, which is of great benefit for devolvement of detection of driving fatigue system. This system consists of a Bluetooth-enabled one channel EEG, a regression model, and smartphone, which was a platform recording and transforming the raw EEG data to useful driving status. In the experiment, this was a sustained-attention driving task to implement in a virtual-reality (VR) driving simulator. To training model and develop the system, we were performed for 15 subjects to study Electroencephalography (EEG) brain dynamics by using a mobile and wireless EEG device. Based on the outstanding training results, the leave-one-subject-out cross validation test obtained 90% fatigue detection accuracy. These results indicate that the combination of a smartphone and wireless EEG device constitutes an effective and easy wearable solution for detecting and preventing driver fatigue in real driving environments.

Published
2015

25. Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

Author

Teumer, A, Qi, QB, Nethander, M, Aschard, H, Bandinelli, S, Beekman, M, Berndt, SI, Bidlingmaier, M, Broer, Linda, Cappola, A, Ceda, G P, Chanock, S, Chen, MH, Chen, T C, Chen, YDI, Chung, JW, Miglianico, F D, Eriksson, J, Ferrucci, L, Friedrich, N, Gnewuch, C, Goodarzi, MO, Grarup, N, Guo, T W, Hammer, E, Hayes, RB, Hicks, AA, Hofman, Bert, Houwing-Duistermaat, JJ, Hu, F, Hunter, DJ, Husemoen, LL, Isaacs, Aaron, Jacobs, KB, Janssen, J.A.M.J.L., Jansson, JO, Jehmlich, N, Johnson, S, Juul, A, Karlsson, M, Kilpelainen, TO, Kovacs, P, Kraft, P, Li, C, Linneberg, A, Liu, YM, Loos, RJF, Lorentzon, M, Lu, YC, Maggio, M, Magi, R, Meigs, J, Mellstrom, D, Nauck, M, Newman, AB, Pollak, MN, Pramstaller, PP, Prokopenko, I, Psaty, BM, Reincke, M, Rimm, EB, Rotter, JI, Saint Pierre, A, Schurmann, C, Seshadri, S, Sjogren, K, Slagboom, PE (Eline), Strickler, H D, Stumvoll, M, Suh, Y S, Sun, Q, Zhang, CL, Svensson, J, Tanaka, T, Tare, A, Tonjes, A, Uh, HW, Duijn, Cornelia, van Heemst, D, Vandenput, L, Vasan, RS, Volker, U, Willems, SM, Ohlsson, C, Wallaschofski, H, Kaplan, RC, Teumer, A, Qi, QB, Nethander, M, Aschard, H, Bandinelli, S, Beekman, M, Berndt, SI, Bidlingmaier, M, Broer, Linda, Cappola, A, Ceda, G P, Chanock, S, Chen, MH, Chen, T C, Chen, YDI, Chung, JW, Miglianico, F D, Eriksson, J, Ferrucci, L, Friedrich, N, Gnewuch, C, Goodarzi, MO, Grarup, N, Guo, T W, Hammer, E, Hayes, RB, Hicks, AA, Hofman, Bert, Houwing-Duistermaat, JJ, Hu, F, Hunter, DJ, Husemoen, LL, Isaacs, Aaron, Jacobs, KB, Janssen, J.A.M.J.L., Jansson, JO, Jehmlich, N, Johnson, S, Juul, A, Karlsson, M, Kilpelainen, TO, Kovacs, P, Kraft, P, Li, C, Linneberg, A, Liu, YM, Loos, RJF, Lorentzon, M, Lu, YC, Maggio, M, Magi, R, Meigs, J, Mellstrom, D, Nauck, M, Newman, AB, Pollak, MN, Pramstaller, PP, Prokopenko, I, Psaty, BM, Reincke, M, Rimm, EB, Rotter, JI, Saint Pierre, A, Schurmann, C, Seshadri, S, Sjogren, K, Slagboom, PE (Eline), Strickler, H D, Stumvoll, M, Suh, Y S, Sun, Q, Zhang, CL, Svensson, J, Tanaka, T, Tare, A, Tonjes, A, Uh, HW, Duijn, Cornelia, van Heemst, D, Vandenput, L, Vasan, RS, Volker, U, Willems, SM, Ohlsson, C, Wallaschofski, H, and Kaplan, RC

Published
2016

26. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Author

Kilpelainen, TO, Carli, J F M, Skowronski, A A, Sun, Q, Kriebel, J, Feitosa, MF, Hedman, AK, Drong, AW, Hayes, J E, Zhao, JH, Pers, TH, Schick, U, Grarup, N, Kutalik, Z, Trompet, S, Mangino, M, Kristiansson, K, Beekman, M, Lyytikainen, LP, Eriksson, J, Henneman, Peter, Lahti, J, Tanaka, T, Luan, JA, Del Greco, F, Pasko, D, Renstrom, F, Willems, SM, Mahajan, A, Rose, LM, Guo, XQ, Liu, YM, Kleber, ME, Perusse, L, Gaunt, T, Ahluwalia, TS, Sung, YJ, Ramos, YF, Amin, Najaf, Amuzu, A, Barroso, I, Bellis, C, Blangero, J, Buckley, BM, Bohringer, S, Chen, YDI, de Craen, A J N, Crosslin, DR, Dale, CE, Dastani, Z, Day, FR, Deelen, J, Delgado, GE, Demirkan, Ayse, Finucane, FM, Ford, I, Garcia, ME, Gieger, C, Gustafsson, S, Hallmans, G, Hankinson, SE, Havulinna, AS, Herder, Cindy, Hernandez, D, Hicks, AA, Hunter, DJ, Illig, T, Ingelsson, E, Ioan-Facsinay, A, Jansson, JO, Jenny, NS, Jorgensen, ME, Jorgensen, T, Karlsson, M, Koenig, W, Kraft, P, Kwekkeboom, J, Laatikainen, T, Ladwig, KH, LeDuc, C A, Lowe, G, Lu, YC, Marques-Vidal, P, Meisinger, C, Menni, C, Morris, AP, Myers, RH, Mannisto, S, Nalls, MA, Paternoster, L, Peters, A, Pradhan, A D, Rankinen, T, Rasmussen-Torvik, LJ, Rathmann, W, Rice, TK, Richards, JB, Ridker, PM, Sattar, N, Savage, DB, Soderberg, S, Timpson, NJ, Vandenput, L, van Heemst, D, Uh, HW, Vohl, MC, Walker, M, Wichmann, HE, Widen, E, Wood, AR, Yao, J, Zeller, T, Zhang, YY, Meulenbelt, I, Kloppenburg, M, Astrup, A, Sorensen, TIA, Sarzynski, MA, Rao, DC, Jousilahti, P, Vartiainen, E, Hofman, Bert, Rivadeneira, Fernando, Uitterlinden, André, Kajantie, E, Osmond, C, Palotie, A, Eriksson, JG, Heliovaara, M, Knekt, PB, Koskinen, S, Jula, A, Perola, M, Huupponen, R K, Viikari, JS, Kahonen, M, Lehtimaki, T, Raitakari, OT, Mellstrom, D, Lorentzon, M, Casas, JP, Bandinelli, S, Marz, W, Isaacs, Aaron, van Dijk, KW, Duijn, Cornelia, Harris, TB, Bouchard, C, Allison, MA, Chasman, DI, Ohlsson, C, Lind, L, Scott, RA, Langenberg, C, Wareham, NJ, Ferrucci, L, Frayling, TM, Pramstaller, PP, Borecki, IB, Waterworth, DM, Bergmann, S, Waeber, G, Vollenweider, P, Vestergaard, H, Hansen, T, Pedersen, O, Hu, FB, Slagboom, PE (Eline), Grallert, H, Spector, TD, Jukema, JW, Klein, RJ, Schadt, EE, Franks, PW, Lindgren, CM, Leibel, R L, Loos, RJF, Kilpelainen, TO, Carli, J F M, Skowronski, A A, Sun, Q, Kriebel, J, Feitosa, MF, Hedman, AK, Drong, AW, Hayes, J E, Zhao, JH, Pers, TH, Schick, U, Grarup, N, Kutalik, Z, Trompet, S, Mangino, M, Kristiansson, K, Beekman, M, Lyytikainen, LP, Eriksson, J, Henneman, Peter, Lahti, J, Tanaka, T, Luan, JA, Del Greco, F, Pasko, D, Renstrom, F, Willems, SM, Mahajan, A, Rose, LM, Guo, XQ, Liu, YM, Kleber, ME, Perusse, L, Gaunt, T, Ahluwalia, TS, Sung, YJ, Ramos, YF, Amin, Najaf, Amuzu, A, Barroso, I, Bellis, C, Blangero, J, Buckley, BM, Bohringer, S, Chen, YDI, de Craen, A J N, Crosslin, DR, Dale, CE, Dastani, Z, Day, FR, Deelen, J, Delgado, GE, Demirkan, Ayse, Finucane, FM, Ford, I, Garcia, ME, Gieger, C, Gustafsson, S, Hallmans, G, Hankinson, SE, Havulinna, AS, Herder, Cindy, Hernandez, D, Hicks, AA, Hunter, DJ, Illig, T, Ingelsson, E, Ioan-Facsinay, A, Jansson, JO, Jenny, NS, Jorgensen, ME, Jorgensen, T, Karlsson, M, Koenig, W, Kraft, P, Kwekkeboom, J, Laatikainen, T, Ladwig, KH, LeDuc, C A, Lowe, G, Lu, YC, Marques-Vidal, P, Meisinger, C, Menni, C, Morris, AP, Myers, RH, Mannisto, S, Nalls, MA, Paternoster, L, Peters, A, Pradhan, A D, Rankinen, T, Rasmussen-Torvik, LJ, Rathmann, W, Rice, TK, Richards, JB, Ridker, PM, Sattar, N, Savage, DB, Soderberg, S, Timpson, NJ, Vandenput, L, van Heemst, D, Uh, HW, Vohl, MC, Walker, M, Wichmann, HE, Widen, E, Wood, AR, Yao, J, Zeller, T, Zhang, YY, Meulenbelt, I, Kloppenburg, M, Astrup, A, Sorensen, TIA, Sarzynski, MA, Rao, DC, Jousilahti, P, Vartiainen, E, Hofman, Bert, Rivadeneira, Fernando, Uitterlinden, André, Kajantie, E, Osmond, C, Palotie, A, Eriksson, JG, Heliovaara, M, Knekt, PB, Koskinen, S, Jula, A, Perola, M, Huupponen, R K, Viikari, JS, Kahonen, M, Lehtimaki, T, Raitakari, OT, Mellstrom, D, Lorentzon, M, Casas, JP, Bandinelli, S, Marz, W, Isaacs, Aaron, van Dijk, KW, Duijn, Cornelia, Harris, TB, Bouchard, C, Allison, MA, Chasman, DI, Ohlsson, C, Lind, L, Scott, RA, Langenberg, C, Wareham, NJ, Ferrucci, L, Frayling, TM, Pramstaller, PP, Borecki, IB, Waterworth, DM, Bergmann, S, Waeber, G, Vollenweider, P, Vestergaard, H, Hansen, T, Pedersen, O, Hu, FB, Slagboom, PE (Eline), Grallert, H, Spector, TD, Jukema, JW, Klein, RJ, Schadt, EE, Franks, PW, Lindgren, CM, Leibel, R L, and Loos, RJF

Published
2016

27. y New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author

Lu, YC, Day, FR, Gustafsson, S, Buchkovich, ML, Na, JB, Bataille, V, Cousminer, DL, Dastani, Z, Drong, AW, Esko, T, Evans, DM, Falchi, M, Feitosa, MF, Ferreira, T, Hedman, AK, Haring, R, Hysi, PG, Iles, MM, Justice, AE, Kanoni, S, Lagou, V, Li, R, Li, X, Locke, A, Lu, C, Magi, R, Perry, JRB, Pers, TH, Qi, QB, Sanna, M, Schmidt, EM, Scott, WR, Shungin, D, Teumer, A, Vinkhuyzen, AAE, Walker, RW, Westra, HJ, Zhang, MF, Zhang, WH, Zhao, JH, Zhu, ZH, Afzal, U, Ahluwalia, TS, Bakker, SJL, Bellis, C, Bonnefond, A, Borodulin, K, Buchman, AS, Cederholm, T, Choh, AC, Choi, HJ, Curran, JE, de Groot, LCPGM (Lisette), De Jager, PL, Dhonukshe-Rutten, RAM, Enneman, Anke, Eury, E, Evans, DS, Forsen, T, Friedrich, N, Fumeron, F, Garcia, ME, Gartner, S, Han, BG, Havulinna, AS, Hayward, C, Hernandez, D, Hillege, H, Ittermann, T, Kent, JW, Kolcic, I, Laatikainen, T, Lahti, J, Leach, IM, Lee, CG, Lee, JY, Liu, T, Liu, YF, Lobbens, S, Loh, M, Lyytikainen, LP, Medina-Gomez, C, Michaelsson, K, Nalls, MA, Nielson, CM, Oozageer, L, Pascoe, L, Paternoster, L, Polasek, O, Ripatti, S, Sarzynski, MA, Shin, CS, Narancic, NS, Spira, D, Srikanth, P, Steinhagen-Thiessen, E, Sung, YJ, Swart, KMA, Taittonen, L, Tanaka, T, Tikkanen, E, van der Velde, Nathalie, Schoor, NM, Verweij, N (Niek), Wright, AF, Yu, L, Zmuda, JM, Eklund, N, Forrester, T, Grarup, N, Jackson, AU, Kristiansson, K, Kuulasmaa, T, Kuusisto, J, Lichtner, P, Luan, JA, Mahajan, A, Mannisto, S, Palmer, CD, Ried, JS, Scott, RA, Stancakova, A, Wagner, PJ, Demirkan, Ayse, Doring, A, Gudnason, V, Kiel, DP, Kuhnel, B, Mangino, M, McKnight, B, Menni, C, O'Connell, JR, Oostra, Ben, Shuldiner, AR, Song, KJ, Vandenput, L, Duijn, Cornelia, Vollenweider, P, White, CC, Boehnke, M, Boettcher, Y, Cooper, RS, Forouhi, NG, Gieger, C, Grallert, H, Hingorani, A, Jorgensen, T, Jousilahti, P, Kivimaki, M, Kumari, M, Laakso, M, Langenberg, C, Linneberg, A, Luke, A, McKenzie, CA, Palotie, A, Pedersen, O, Peters, A, Strauch, K, Tayo, BO, Wareham, NJ, Bennett, DA, Bertram, L, Blangero, J, Bluher, M, Bouchard, C, Campbell, H, Cho, NH, Cummings, SR, Czerwinski, SA, Demuth, I, Eckardt, R, Eriksson, JG, Ferrucci, L, Franco Duran, OH, Froguel, P, Gansevoort, RT, Hansen, T, Harris, TB, Hastie, N, Heliovaara, M, Hofman, Bert, Jordan, JM, Jula, A, Kahonen, M, Kajantie, E, Knekt, PB, Koskinen, S, Kovacs, P, Lehtimaki, T, Lind, L, Liu, YM, Orwoll, ES, Osmond, C, Perola, M, Perusse, L, Raitakari, OT, Rankinen, T, Rao, DC, Rice, TK, Rivadeneira, Fernando, Rudan, I, Salomaa, V, Sorensen, TIA, Stumvoll, M, Tonjes, A, Towne, B, Tranah, GJ, Tremblay, A, Uitterlinden, André, van der Harst, P, Vartiainen, E, Viikari, JS, Vitart, V, Vohl, MC, Volzke, H, Walker, M, Wallaschofski, H, Wild, S, Wilson, JF, Yengo, L, Bishop, DT, Borecki, IB, Chambers, JC, Cupples, LA, Dehghan, Abbas, Deloukas, P, Fatemifar, G, Fox, C, Furey, TS, Franke, L, Han, JL, Hunter, DJ, Karjalainen, J, Karpe, F, Kaplan, RC, Kooner, JS, McCarthy, MI, Murabito, JM, Morris, AP, Bishop, JAN, North, KE, Ohlsson, C, Ong, KK, Prokopenko, I, Richards, JB, Schadt, EE, Spector, TD, Widen, E, Willer, CJ, Yang, Jiaqi, Ingelsson, E, Mohlke, KL, Hirschhorn, JN, Pospisilik, JA, Zillikens, M.C., Lindgren, C, Kilpelainen, TO, Loos, RJF, Lu, YC, Day, FR, Gustafsson, S, Buchkovich, ML, Na, JB, Bataille, V, Cousminer, DL, Dastani, Z, Drong, AW, Esko, T, Evans, DM, Falchi, M, Feitosa, MF, Ferreira, T, Hedman, AK, Haring, R, Hysi, PG, Iles, MM, Justice, AE, Kanoni, S, Lagou, V, Li, R, Li, X, Locke, A, Lu, C, Magi, R, Perry, JRB, Pers, TH, Qi, QB, Sanna, M, Schmidt, EM, Scott, WR, Shungin, D, Teumer, A, Vinkhuyzen, AAE, Walker, RW, Westra, HJ, Zhang, MF, Zhang, WH, Zhao, JH, Zhu, ZH, Afzal, U, Ahluwalia, TS, Bakker, SJL, Bellis, C, Bonnefond, A, Borodulin, K, Buchman, AS, Cederholm, T, Choh, AC, Choi, HJ, Curran, JE, de Groot, LCPGM (Lisette), De Jager, PL, Dhonukshe-Rutten, RAM, Enneman, Anke, Eury, E, Evans, DS, Forsen, T, Friedrich, N, Fumeron, F, Garcia, ME, Gartner, S, Han, BG, Havulinna, AS, Hayward, C, Hernandez, D, Hillege, H, Ittermann, T, Kent, JW, Kolcic, I, Laatikainen, T, Lahti, J, Leach, IM, Lee, CG, Lee, JY, Liu, T, Liu, YF, Lobbens, S, Loh, M, Lyytikainen, LP, Medina-Gomez, C, Michaelsson, K, Nalls, MA, Nielson, CM, Oozageer, L, Pascoe, L, Paternoster, L, Polasek, O, Ripatti, S, Sarzynski, MA, Shin, CS, Narancic, NS, Spira, D, Srikanth, P, Steinhagen-Thiessen, E, Sung, YJ, Swart, KMA, Taittonen, L, Tanaka, T, Tikkanen, E, van der Velde, Nathalie, Schoor, NM, Verweij, N (Niek), Wright, AF, Yu, L, Zmuda, JM, Eklund, N, Forrester, T, Grarup, N, Jackson, AU, Kristiansson, K, Kuulasmaa, T, Kuusisto, J, Lichtner, P, Luan, JA, Mahajan, A, Mannisto, S, Palmer, CD, Ried, JS, Scott, RA, Stancakova, A, Wagner, PJ, Demirkan, Ayse, Doring, A, Gudnason, V, Kiel, DP, Kuhnel, B, Mangino, M, McKnight, B, Menni, C, O'Connell, JR, Oostra, Ben, Shuldiner, AR, Song, KJ, Vandenput, L, Duijn, Cornelia, Vollenweider, P, White, CC, Boehnke, M, Boettcher, Y, Cooper, RS, Forouhi, NG, Gieger, C, Grallert, H, Hingorani, A, Jorgensen, T, Jousilahti, P, Kivimaki, M, Kumari, M, Laakso, M, Langenberg, C, Linneberg, A, Luke, A, McKenzie, CA, Palotie, A, Pedersen, O, Peters, A, Strauch, K, Tayo, BO, Wareham, NJ, Bennett, DA, Bertram, L, Blangero, J, Bluher, M, Bouchard, C, Campbell, H, Cho, NH, Cummings, SR, Czerwinski, SA, Demuth, I, Eckardt, R, Eriksson, JG, Ferrucci, L, Franco Duran, OH, Froguel, P, Gansevoort, RT, Hansen, T, Harris, TB, Hastie, N, Heliovaara, M, Hofman, Bert, Jordan, JM, Jula, A, Kahonen, M, Kajantie, E, Knekt, PB, Koskinen, S, Kovacs, P, Lehtimaki, T, Lind, L, Liu, YM, Orwoll, ES, Osmond, C, Perola, M, Perusse, L, Raitakari, OT, Rankinen, T, Rao, DC, Rice, TK, Rivadeneira, Fernando, Rudan, I, Salomaa, V, Sorensen, TIA, Stumvoll, M, Tonjes, A, Towne, B, Tranah, GJ, Tremblay, A, Uitterlinden, André, van der Harst, P, Vartiainen, E, Viikari, JS, Vitart, V, Vohl, MC, Volzke, H, Walker, M, Wallaschofski, H, Wild, S, Wilson, JF, Yengo, L, Bishop, DT, Borecki, IB, Chambers, JC, Cupples, LA, Dehghan, Abbas, Deloukas, P, Fatemifar, G, Fox, C, Furey, TS, Franke, L, Han, JL, Hunter, DJ, Karjalainen, J, Karpe, F, Kaplan, RC, Kooner, JS, McCarthy, MI, Murabito, JM, Morris, AP, Bishop, JAN, North, KE, Ohlsson, C, Ong, KK, Prokopenko, I, Richards, JB, Schadt, EE, Spector, TD, Widen, E, Willer, CJ, Yang, Jiaqi, Ingelsson, E, Mohlke, KL, Hirschhorn, JN, Pospisilik, JA, Zillikens, M.C., Lindgren, C, Kilpelainen, TO, and Loos, RJF

Abstract

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P < 5 x 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

Published
2016

28. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, TW, Justice, AE, Graff, M, Barata, L, Feitosa, MF, Chu, S, Czajkowski, J, Esko, T, Fall, T, Kilpelainen, TO, Lu, YC, Magi, R, Mihailov, E, Pers, TH, Rueger, S, Teumer, A, Ehret, GB, Ferreira, T, Heard-Costa, NL, Karjalainen, J, Lagou, V, Mahajan, A, Neinast, MD, Prokopenko, I, Simino, J, Teslovich, TM, Jansen, R, Westra, HJ, White, CC, Absher, D, Ahluwalia, TS, Ahmad, Shahzad, Albrecht, E, Alves, AC, Bragg-Gresham, JL, de Craen, AJM, Bis, JC, Bonnefond, A, Boucher, G, Cadby, G, Cheng, YC, Chiang, CWK, Delgado, G, Demirkan, Ayse, Dueker, N, Eklund, N, Eiriksdottir, G, Eriksson, J, Feenstra, B, Fischer, K (Kirsten), Frau, F, Galesloot, TE, Geller, F, Goel, A, Gorski, M, Grammer, TB, Gustafsson, S, Haitjema, S, Hottenga, JJ (Jouke Jan), Huffman, JE, Jackson, AU, Jacobs, KB, Johansson, A, Kaakinen, M, Kleber, ME, Lahti, J, Leach, IM, Lehne, B, Liu, YF, Lo, KS, Lorentzon, M, Luan, J, Madden, PAF, Mangino, M, McKnight, B, Medina Gomez, Maria, Monda, KL, Montasser, ME, Muller, G, Muller-Nurasyid, M, Nolte, IM (Ilja), Panoutsopoulou, K, Pascoe, L, Paternoster, L, Rayner, NW, Renstrom, F, Rizzi, F, Rose, LM, Ryan, KA, Salo, P, Sanna, S, Scharnagl, H, Shi, JX, Smith, AV, Southam, L, Stancakova, A, Steinthorsdottir, V, Strawbridge, RJ, Sung, YJ, Tachmazidou, I, Tanaka, T, Thorleifsson, G, Trompet, S, Pervjakova, N, Tyrer, JP, Vandenput, L, Laan, Sander, van der Velde, Nathalie, van Setten, J, van Vliet-Ostaptchouk, JV, Verweij, N (Niek), Vlachopoulou, E, Waite, LL, Wang, SR, Wang, ZM, Wild, SH, Willenborg, C, Wilson, JF, Wong, A, Yang, Jiaqi, Yengo, L, Yerges-Armstrong, LM, Yu, L, Zhang, WH, Zhao, JH, Andersson, EA, Bakker, SJL, Baldassarre, D, Banasik, K, Barcella, M, Barlassina, C, Bellis, C, Benaglio, P, Blangero, J, Bluher, M, Bonnet, F, Bonnycastle, LL, Boyd, HA, Bruinenberg, M, Buchman, AS, Campbell, H, Chen, YDI, Chines, PS, Claudi-Boehm, S, Cole, J, Collins, FS, de Geus, EJC, de Groot, LCPGM (Lisette), Dimitriou, M, Duan, J, Enroth, S, Eury, E, Farmaki, AE, Forouhi, NG, Friedrich, N, Gejman, PV, Gigante, B, Glorioso, N, Go, AS, Gottesman, O, Grassler, J, Grallert, H, Grarup, N, Gu, YM, Broer, Linda, Ham, Annelies, Hansen, T, Harris, TB, Hartman, CA, Hassinen, M, Hastie, N, Hattersley, AT, Heath, AC, Henders, AK, Hernandez, D, Hillege, H, Holmen, O, Hovingh, KG, Hui, J, Husemoen, LL, Hutri-Kahonen, N, Hysi, PG, Illig, T, De Jager, PL, Jalilzadeh, S, Jorgensen, T, Jukema, JW, Juonala, M, Kanoni, S, Karaleftheri, M, Khaw, KT, Kinnunen, L, Kittner, SJ, Koenig, W, Kolcic, I, Kovacs, P, Krarup, NT, Kratzer, W, Kruger, J, Kuh, D, Kumari, M, Kyriakou, T, Langenberg, C, Lannfelt, L, Lanzani, C, Lotay, V, Launer, LJ (Lenore), Leander, K, Lindstrom, J, Linneberg, A, Liu, YP, Lobbens, S, Luben, R, Lyssenko, V, Mannisto, S, Magnusson, PK, McArdle, WL, Menni, C, Merger, S, Milani, L, Montgomery, GW, Morris, AP, Narisu, N, Nelis, M, Ong, KK, Palotie, A, Perusse, L, Pichler, I, Pilia, MG, Pouta, A, Rheinberger, M, Ribel-Madsen, R, Richards, M, Rice, KM, Rice, TK, Rivolta, C, Salomaa, V, Sanders, AR, Sarzynski, MA, Scholtens, s, Scott, RA, Scott, WR, Sebert, S, Sengupta, S, Sennblad, B, Seufferlein, T, Silveira, A, Slagboom, PE (Eline), Smit, JH, Sparso, TH, Stirrups, K, Stolk, RP (Ronald), Stringham, HM, Swertz, MA, Swift, AJ, Syvanen, AC, Tan, ST, Thorand, B, Tonjes, A, Tremblay, A, Tsafantakis, E, van der Most, PJ, Volker, U, Vohl, MC, Vonk, JM, Waldenberger, M, Walker, RW, Wennauer, R, Widen, E, Willemsen, G, Wilsgaard, T, Wright, AF, Zillikens, M.C., Boon - van Dijk, Suzanne, Schoor, NM, Asselbergs, FW, de Bakker, PIW, Beckmann, JS, Beilby, J, Bennett, DA, Bergman, RN, Bergmann, S, Boger, CA, Boehm, BO, Boerwinkle, E, Boomsma, DI, Bornstein, SR, Bottinger, EP, Bouchard, C, Chambers, JC, Chanock, SJ, Chasman, DI, Cucca, F, Cusi, D, Dedoussis, G, Erdmann, J, Eriksson, JG, Evans, DA, de Faire, U, Farrall, M, Ferrucci, L, Ford, I, Franke, L, Franks, PW, Froguel, P, Gansevoort, RT, Gieger, C, Gronberg, H, Gudnason, V, Gyllensten, U, Hall, P, Hamsten, A, van der Harst, P, Hayward, C, Heliovaara, M, Hengstenberg, C, Hicks, AA, Hingorani, A, Hofman, Bert, Hu, F, Huikuri, HV, Hveem, K, James, AL, Jordan, JM, Jula, A, Kahonen, M, Kajantie, E, Kathiresan, S, Kiemeney, LALM, Kivimaki, M, Knekt, PB, Koistinen, HA, Kooner, JS, Koskinen, S, Kuusisto, J, Maerz, W, Martin, NG, Laakso, M, Lakka, TA, Lehtimaki, T, Lettre, G, Levinson, DF, Lind, L, Lokki, ML, Mantyselka, P, Melbye, M, Metspalu, A, Mitchell, BD, Moll, FL, Murray, JC, Musk, AW, Nieminen, MS, Njolstad, I, Ohlsson, C, Oldehinkel, AJ (A.), Oostra, Ben, Palmer, LJ, Pankow, JS, Pasterkamp, G, Pedersen, NL, Pedersen, O, Penninx, BW, Perola, M, Peters, A, Polasek, O, Pramstaller, PP, Psaty, BM, Qi, L, Quertermous, T, Raitakari, OT, Rankinen, T, Rauramaa, R, Ridker, PM, Rioux, JD, Rivadeneira, Fernando, Rotter, JI, Rudan, I, den Ruijter, HM, Saltevo, J, Sattar, N, Schunkert, H, Schwarz, PEH, Shuldiner, AR, Sinisalo, J, Snieder, H, Sorensen, TIA, Spector, TD, Staessen, JA, Stefania, B, Thorsteinsdottir, U, Stumvoll, M, Tardif, JC, Tremoli, E, Tuomilehto, J, Uitterlinden, André, Uusitupa, M, Verbeek, ALM, Vermeulen, SH, Viikari, JS, Vitart, V, Volzke, H, Vollenweider, P, Waeber, G, Walker, M, Wallaschofski, H, Wareham, NJ, Watkins, H, Zeggini, E, Chakravarti, A, Clegg, DJ, Cupples, LA, Gordon-Larsen, P, Jaquish, CE, Rao, DC, Abecasis, GR, Assimes, TL, Barroso, I, Berndt, SI, Boehnke, M, Deloukas, P, Fox, CS, Groop, LC, Hunter, DJ, Ingelsson, E, Kaplan, RC, McCarthy, MI, Mohlke, KL, O'Connell, JR, Schlessinger, D, Strachan, DP, Stefansson, K, Duijn, Cornelia, Hirschhorn, JN, Lindgren, CM, Heid, IM, North, KE, Borecki, IB, Kutalik, Z, Loos, RJF, Winkler, TW, Justice, AE, Graff, M, Barata, L, Feitosa, MF, Chu, S, Czajkowski, J, Esko, T, Fall, T, Kilpelainen, TO, Lu, YC, Magi, R, Mihailov, E, Pers, TH, Rueger, S, Teumer, A, Ehret, GB, Ferreira, T, Heard-Costa, NL, Karjalainen, J, Lagou, V, Mahajan, A, Neinast, MD, Prokopenko, I, Simino, J, Teslovich, TM, Jansen, R, Westra, HJ, White, CC, Absher, D, Ahluwalia, TS, Ahmad, Shahzad, Albrecht, E, Alves, AC, Bragg-Gresham, JL, de Craen, AJM, Bis, JC, Bonnefond, A, Boucher, G, Cadby, G, Cheng, YC, Chiang, CWK, Delgado, G, Demirkan, Ayse, Dueker, N, Eklund, N, Eiriksdottir, G, Eriksson, J, Feenstra, B, Fischer, K (Kirsten), Frau, F, Galesloot, TE, Geller, F, Goel, A, Gorski, M, Grammer, TB, Gustafsson, S, Haitjema, S, Hottenga, JJ (Jouke Jan), Huffman, JE, Jackson, AU, Jacobs, KB, Johansson, A, Kaakinen, M, Kleber, ME, Lahti, J, Leach, IM, Lehne, B, Liu, YF, Lo, KS, Lorentzon, M, Luan, J, Madden, PAF, Mangino, M, McKnight, B, Medina Gomez, Maria, Monda, KL, Montasser, ME, Muller, G, Muller-Nurasyid, M, Nolte, IM (Ilja), Panoutsopoulou, K, Pascoe, L, Paternoster, L, Rayner, NW, Renstrom, F, Rizzi, F, Rose, LM, Ryan, KA, Salo, P, Sanna, S, Scharnagl, H, Shi, JX, Smith, AV, Southam, L, Stancakova, A, Steinthorsdottir, V, Strawbridge, RJ, Sung, YJ, Tachmazidou, I, Tanaka, T, Thorleifsson, G, Trompet, S, Pervjakova, N, Tyrer, JP, Vandenput, L, Laan, Sander, van der Velde, Nathalie, van Setten, J, van Vliet-Ostaptchouk, JV, Verweij, N (Niek), Vlachopoulou, E, Waite, LL, Wang, SR, Wang, ZM, Wild, SH, Willenborg, C, Wilson, JF, Wong, A, Yang, Jiaqi, Yengo, L, Yerges-Armstrong, LM, Yu, L, Zhang, WH, Zhao, JH, Andersson, EA, Bakker, SJL, Baldassarre, D, Banasik, K, Barcella, M, Barlassina, C, Bellis, C, Benaglio, P, Blangero, J, Bluher, M, Bonnet, F, Bonnycastle, LL, Boyd, HA, Bruinenberg, M, Buchman, AS, Campbell, H, Chen, YDI, Chines, PS, Claudi-Boehm, S, Cole, J, Collins, FS, de Geus, EJC, de Groot, LCPGM (Lisette), Dimitriou, M, Duan, J, Enroth, S, Eury, E, Farmaki, AE, Forouhi, NG, Friedrich, N, Gejman, PV, Gigante, B, Glorioso, N, Go, AS, Gottesman, O, Grassler, J, Grallert, H, Grarup, N, Gu, YM, Broer, Linda, Ham, Annelies, Hansen, T, Harris, TB, Hartman, CA, Hassinen, M, Hastie, N, Hattersley, AT, Heath, AC, Henders, AK, Hernandez, D, Hillege, H, Holmen, O, Hovingh, KG, Hui, J, Husemoen, LL, Hutri-Kahonen, N, Hysi, PG, Illig, T, De Jager, PL, Jalilzadeh, S, Jorgensen, T, Jukema, JW, Juonala, M, Kanoni, S, Karaleftheri, M, Khaw, KT, Kinnunen, L, Kittner, SJ, Koenig, W, Kolcic, I, Kovacs, P, Krarup, NT, Kratzer, W, Kruger, J, Kuh, D, Kumari, M, Kyriakou, T, Langenberg, C, Lannfelt, L, Lanzani, C, Lotay, V, Launer, LJ (Lenore), Leander, K, Lindstrom, J, Linneberg, A, Liu, YP, Lobbens, S, Luben, R, Lyssenko, V, Mannisto, S, Magnusson, PK, McArdle, WL, Menni, C, Merger, S, Milani, L, Montgomery, GW, Morris, AP, Narisu, N, Nelis, M, Ong, KK, Palotie, A, Perusse, L, Pichler, I, Pilia, MG, Pouta, A, Rheinberger, M, Ribel-Madsen, R, Richards, M, Rice, KM, Rice, TK, Rivolta, C, Salomaa, V, Sanders, AR, Sarzynski, MA, Scholtens, s, Scott, RA, Scott, WR, Sebert, S, Sengupta, S, Sennblad, B, Seufferlein, T, Silveira, A, Slagboom, PE (Eline), Smit, JH, Sparso, TH, Stirrups, K, Stolk, RP (Ronald), Stringham, HM, Swertz, MA, Swift, AJ, Syvanen, AC, Tan, ST, Thorand, B, Tonjes, A, Tremblay, A, Tsafantakis, E, van der Most, PJ, Volker, U, Vohl, MC, Vonk, JM, Waldenberger, M, Walker, RW, Wennauer, R, Widen, E, Willemsen, G, Wilsgaard, T, Wright, AF, Zillikens, M.C., Boon - van Dijk, Suzanne, Schoor, NM, Asselbergs, FW, de Bakker, PIW, Beckmann, JS, Beilby, J, Bennett, DA, Bergman, RN, Bergmann, S, Boger, CA, Boehm, BO, Boerwinkle, E, Boomsma, DI, Bornstein, SR, Bottinger, EP, Bouchard, C, Chambers, JC, Chanock, SJ, Chasman, DI, Cucca, F, Cusi, D, Dedoussis, G, Erdmann, J, Eriksson, JG, Evans, DA, de Faire, U, Farrall, M, Ferrucci, L, Ford, I, Franke, L, Franks, PW, Froguel, P, Gansevoort, RT, Gieger, C, Gronberg, H, Gudnason, V, Gyllensten, U, Hall, P, Hamsten, A, van der Harst, P, Hayward, C, Heliovaara, M, Hengstenberg, C, Hicks, AA, Hingorani, A, Hofman, Bert, Hu, F, Huikuri, HV, Hveem, K, James, AL, Jordan, JM, Jula, A, Kahonen, M, Kajantie, E, Kathiresan, S, Kiemeney, LALM, Kivimaki, M, Knekt, PB, Koistinen, HA, Kooner, JS, Koskinen, S, Kuusisto, J, Maerz, W, Martin, NG, Laakso, M, Lakka, TA, Lehtimaki, T, Lettre, G, Levinson, DF, Lind, L, Lokki, ML, Mantyselka, P, Melbye, M, Metspalu, A, Mitchell, BD, Moll, FL, Murray, JC, Musk, AW, Nieminen, MS, Njolstad, I, Ohlsson, C, Oldehinkel, AJ (A.), Oostra, Ben, Palmer, LJ, Pankow, JS, Pasterkamp, G, Pedersen, NL, Pedersen, O, Penninx, BW, Perola, M, Peters, A, Polasek, O, Pramstaller, PP, Psaty, BM, Qi, L, Quertermous, T, Raitakari, OT, Rankinen, T, Rauramaa, R, Ridker, PM, Rioux, JD, Rivadeneira, Fernando, Rotter, JI, Rudan, I, den Ruijter, HM, Saltevo, J, Sattar, N, Schunkert, H, Schwarz, PEH, Shuldiner, AR, Sinisalo, J, Snieder, H, Sorensen, TIA, Spector, TD, Staessen, JA, Stefania, B, Thorsteinsdottir, U, Stumvoll, M, Tardif, JC, Tremoli, E, Tuomilehto, J, Uitterlinden, André, Uusitupa, M, Verbeek, ALM, Vermeulen, SH, Viikari, JS, Vitart, V, Volzke, H, Vollenweider, P, Waeber, G, Walker, M, Wallaschofski, H, Wareham, NJ, Watkins, H, Zeggini, E, Chakravarti, A, Clegg, DJ, Cupples, LA, Gordon-Larsen, P, Jaquish, CE, Rao, DC, Abecasis, GR, Assimes, TL, Barroso, I, Berndt, SI, Boehnke, M, Deloukas, P, Fox, CS, Groop, LC, Hunter, DJ, Ingelsson, E, Kaplan, RC, McCarthy, MI, Mohlke, KL, O'Connell, JR, Schlessinger, D, Strachan, DP, Stefansson, K, Duijn, Cornelia, Hirschhorn, JN, Lindgren, CM, Heid, IM, North, KE, Borecki, IB, Kutalik, Z, and Loos, RJF

Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men <= 50y, men > 50y, women <= 50y, women > 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR< 5%) age-specific effects, of which 11 had larger effects in younger (< 50y) than in older adults (>= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shap

Published
2015

29. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Author

Wessel, J, Chu, AY, Willems, SM, Wang, S, Yaghootkar, H, Brody, JA, Dauriz, M, Hivert, MF, Raghavan, S, Lipovich, L, Hidalgo, B, Fox, K, Huffman, JE, An, P, Lu, YC, Rasmussen-Torvik, LJ, Grarup, N, Ehm, MG, Li, Li, Baldridge, AS, Stancakova, A, Abrol, R, Besse, CL, Boland, A, Bork-Jensen, J, Fornage, M, Freitag, DF, Garcia, ME, Guo, XQ, Hara, K, Isaacs, Aaron, Jakobsdottir, J, Lange, LA, Layton, JC, Li, M, Zhao, JH, Meidtner, K, Morrison, AC, Nalls, MA, Peters, Marjolein, Sabater-Lleal, M, Schurmann, C, Silveira, A, Smith, AV, Southam, L, Stoiber, MH, Strawbridge, RJ, Taylor, KD, Varga, TV, Allin, KH, Amin, Najaf, Aponte, JL, Aung, T, Barbieri, C, Bihlmeyer, NA, Boehnke, M, Bombieri, C, Bowden, DW, Burns, SM, Chen, YN, Chen, YD, Cheng, CY (Ching-Yu), Correa, A, Czajkowski, J, Dehghan, Abbas, Ehret, GB, Eiriksdottir, G, Escher, SA, Farmaki, AE, Franberg, M, Gambaro, G, Giulianini, F, Goddard, WA, Goel, A, Gottesman, O, Grove, ML, Gustafsson, S, Hai, Y, Hallmans, G, Heo, J, Hoffmann, P, Ikram, MK, Jensen, RA, Jorgensen, ME, Jorgensen, T, Karaleftheri, M, Khor, CC, Kirkpatrick, A, Kraja, AT, Kuusisto, J, Lange, Edmee, Lee, IT, Lee, WJ, Leong, A, Liao, JM, Liu, CY, Liu, YM, Lindgren, CM, Linneberg, A, Malerba, G, Mamakou, V, Marouli, E, Maruthur, NM, Matchan, A, McKean-Cowdin, R, McLeod, O, Metcalf, GA, Mohlke, KL, Muzny, DM, Ntalla, I, Palmer, ND, Pasko, D, Peter, A, Rayner, NW, Renstrom, F, Rice, K, Sala, CF, Sennblad, B, Serafetinidis, I, Smith, JA, Soranzo, N, Speliotes, EK, Stahl, EA, Stirrups, K, Tentolouris, N, Thanopoulou, A, Torres, M, Traglia, M, Tsafantakis, E, Javad, S, Yanek, LR, Zengini, E, Becker, DM, Bis, JC, Brown, JB, Cupples, LA, Hansen, T, Ingelsson, E, Karter, AJ, Lorenzo, C, Mathias, RA, Norris, JM, Peloso, GM, Sheu, WHH, Toniolo, D, Vaidya, D, Varma, R, Wagenknecht, LE, Boeing, H, Bottinger, EP, Dedoussis, G, Deloukas, P, Ferrannini, E, Franco Duran, OH, Franks, PW, Gibbs, RA, Gudnason, V, Hamsten, A, Harris, TB, Hattersley, AT, Hayward, C, Hofman, Bert, Jansson, JH, Langenberg, C, Launer, LJ (Lenore), Levy, D, Oostra, Ben, O'Donnell, CJ, O'Rahilly, S, Padmanabhan, S, Pankow, JS, Polasek, O, Province, MA, Rich, SS, Ridker, PM, Rudan, I, Schulze, MB, Smith, BH, Uitterlinden, André, Walker, M, Watkins, H, Wong, TY (Tien Yin), Zeggini, E, Laakso, M, Borecki, IB, Chasman, DI, Pedersen, O, Psaty, BM, Tai, ES, Duijn, Cornelia, Wareham, NJ, Waterworth, DM, Boerwinkle, E, Kao, WHL, Florez, JC, Loos, RJF, Wilson, JG, Frayling, TM, Siscovick, DS, Dupuis, J, Rotter, JI, Meigs, JB, Scott, RA, Goodarzi, MO, Sharp, SJ, Forouhi, NG, Kerrison, ND, Lucarelli, DM, Sims, M, Barroso, I, McCarthy, MI, Arriola, L, Balkau, B, Barricarte, A, Gonzalez, C, Grioni, S, Kaaks, R, Key, TJ, Navarro, C, Nilsson, PM, Overvad, K, Palli, D, Panico, S, Quiros, JR, Rolandsson, O, Sacerdote, C, Sanchez, MJ (Maria-Jose), Slimani, N, Tjonneland, A, Tumino, R, van der A, DL, van der Schouw, YT, Riboli, E, Wessel, J, Chu, AY, Willems, SM, Wang, S, Yaghootkar, H, Brody, JA, Dauriz, M, Hivert, MF, Raghavan, S, Lipovich, L, Hidalgo, B, Fox, K, Huffman, JE, An, P, Lu, YC, Rasmussen-Torvik, LJ, Grarup, N, Ehm, MG, Li, Li, Baldridge, AS, Stancakova, A, Abrol, R, Besse, CL, Boland, A, Bork-Jensen, J, Fornage, M, Freitag, DF, Garcia, ME, Guo, XQ, Hara, K, Isaacs, Aaron, Jakobsdottir, J, Lange, LA, Layton, JC, Li, M, Zhao, JH, Meidtner, K, Morrison, AC, Nalls, MA, Peters, Marjolein, Sabater-Lleal, M, Schurmann, C, Silveira, A, Smith, AV, Southam, L, Stoiber, MH, Strawbridge, RJ, Taylor, KD, Varga, TV, Allin, KH, Amin, Najaf, Aponte, JL, Aung, T, Barbieri, C, Bihlmeyer, NA, Boehnke, M, Bombieri, C, Bowden, DW, Burns, SM, Chen, YN, Chen, YD, Cheng, CY (Ching-Yu), Correa, A, Czajkowski, J, Dehghan, Abbas, Ehret, GB, Eiriksdottir, G, Escher, SA, Farmaki, AE, Franberg, M, Gambaro, G, Giulianini, F, Goddard, WA, Goel, A, Gottesman, O, Grove, ML, Gustafsson, S, Hai, Y, Hallmans, G, Heo, J, Hoffmann, P, Ikram, MK, Jensen, RA, Jorgensen, ME, Jorgensen, T, Karaleftheri, M, Khor, CC, Kirkpatrick, A, Kraja, AT, Kuusisto, J, Lange, Edmee, Lee, IT, Lee, WJ, Leong, A, Liao, JM, Liu, CY, Liu, YM, Lindgren, CM, Linneberg, A, Malerba, G, Mamakou, V, Marouli, E, Maruthur, NM, Matchan, A, McKean-Cowdin, R, McLeod, O, Metcalf, GA, Mohlke, KL, Muzny, DM, Ntalla, I, Palmer, ND, Pasko, D, Peter, A, Rayner, NW, Renstrom, F, Rice, K, Sala, CF, Sennblad, B, Serafetinidis, I, Smith, JA, Soranzo, N, Speliotes, EK, Stahl, EA, Stirrups, K, Tentolouris, N, Thanopoulou, A, Torres, M, Traglia, M, Tsafantakis, E, Javad, S, Yanek, LR, Zengini, E, Becker, DM, Bis, JC, Brown, JB, Cupples, LA, Hansen, T, Ingelsson, E, Karter, AJ, Lorenzo, C, Mathias, RA, Norris, JM, Peloso, GM, Sheu, WHH, Toniolo, D, Vaidya, D, Varma, R, Wagenknecht, LE, Boeing, H, Bottinger, EP, Dedoussis, G, Deloukas, P, Ferrannini, E, Franco Duran, OH, Franks, PW, Gibbs, RA, Gudnason, V, Hamsten, A, Harris, TB, Hattersley, AT, Hayward, C, Hofman, Bert, Jansson, JH, Langenberg, C, Launer, LJ (Lenore), Levy, D, Oostra, Ben, O'Donnell, CJ, O'Rahilly, S, Padmanabhan, S, Pankow, JS, Polasek, O, Province, MA, Rich, SS, Ridker, PM, Rudan, I, Schulze, MB, Smith, BH, Uitterlinden, André, Walker, M, Watkins, H, Wong, TY (Tien Yin), Zeggini, E, Laakso, M, Borecki, IB, Chasman, DI, Pedersen, O, Psaty, BM, Tai, ES, Duijn, Cornelia, Wareham, NJ, Waterworth, DM, Boerwinkle, E, Kao, WHL, Florez, JC, Loos, RJF, Wilson, JG, Frayling, TM, Siscovick, DS, Dupuis, J, Rotter, JI, Meigs, JB, Scott, RA, Goodarzi, MO, Sharp, SJ, Forouhi, NG, Kerrison, ND, Lucarelli, DM, Sims, M, Barroso, I, McCarthy, MI, Arriola, L, Balkau, B, Barricarte, A, Gonzalez, C, Grioni, S, Kaaks, R, Key, TJ, Navarro, C, Nilsson, PM, Overvad, K, Palli, D, Panico, S, Quiros, JR, Rolandsson, O, Sacerdote, C, Sanchez, MJ (Maria-Jose), Slimani, N, Tjonneland, A, Tumino, R, van der A, DL, van der Schouw, YT, and Riboli, E

Abstract

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

Published
2015

30. Directional dominance on stature and cognition in diverse human populations

Author

Joshi, PK, Esko, T, Mattsson, H, Eklund, N, Gandin, I, Nutile, T, Jackson, AU, Schurmann, C, Smith, AV, Zhang, WH, Okada, Y, Stancakova, A, Faul, JD, Zhao, W, Bartz, TM, Concas, MP, Franceschini, N, Enroth, S, Vitart, V, Trompet, S, Guo, XQ, Chasman, DI, O'Connel, JR, Corre, T, Nongmaithem, SS, Chen, Y, Mangino, M, Ruggiero, D, Michela, T, Farmaki, AE, Kacprowski, T, Bjonnes, A, van der Spek, Ashley, Wu, Y, Giri, AK, Yanek, LR, Wang, LH, Hofer, E, Rietveld, CA, McLeod, O, Cornelis, MC, Pattaro, C, Verweij, N, Baumbach, C, Abdellaoui, A, Warren, HR, Vuckovic, D, Mei, H, Bouchard, C, Perry, JRB, Cappellani, S, Mirza, Saira, Benton, MC, Broeckel, U, Medland, SE, Lind, P, Malerba, G, Drong, A, Yengo, L, Bielak, LF, Zhi, DG, van der Most, PJ, Shriner, D, Magi, R, Hemani, G, Karaderi, T, Wang, ZM, Liu, T, Demuth, I, Zhao, JH, Meng, WH, Lataniotis, L, Laan, Sander, Bradfield, JP, Wood, AR, Bonnefond, A, Ahluwalia, TS, Hall, L, Salvi, E, Yazar, S, Carstensen, L, de Haan, HG, Abney, M, Afzal, U, Allison, MA, Amin, Najaf, Asselbergs, FW, Bakker, SJL, Barr, RG, Baumeister, SE, Benjamin, DJ, Bergmann, S, Boerwinkle, E, Bottinger, EP, Campbell, A (Archie), Chakravarti, A, Chan, YL, Chanock, SJ, Chen, C (Christopher Li Hsian), Chen, YDI, Collins, FS, Connell, J, Correa, A, Cupples, LA, Smith, GD, Davies, G, Dorr, M, Ehret, G, Ellis, SB, Feenstra, B, Feitosa, MF, Ford, I, Fox, CS, Frayling, TM, Friedrich, N, Geller, F, Scotland, G, Gillham-Nasenya, I, Gottesman, O, Graff, M, Grodstein, F, Gu, C, Haley, C, Hammond, CJ, Harris, SE, Harris, TB, Hastie, ND, Heard-Costa, NL, Heikkila, K, Hocking, LJ, Homuth, G, Hottenga, Jouke-Jan, Huang, JY, Huffman, JE, Hysi, Pirro G., Arfan Ikram, M., Ingelsson, E, Joensuu, A, Johansson, A, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kanoni, S, Kerr, SM, Khan, NM, Koellinger, P, Koistinen, HA, Kooner, MK, Kubo, M, Kuusisto, J, Lahti, J, Launer, Lenore J., Lea, RA, Lehne, B, Lehtimaki, T, Liewald, DCM, Lind, L, Loh, M, Lokki, ML, London, SJ, Loomis, SJ, Loukola, A, Lu, YC, Lumley, T, Lundqvist, A, Mannisto, S, Marques-Vidal, P, Masciullo, C, Matchan, A, Mathias, RA, Matsuda, K, Meigs, JB, Meisinger, C, Meitinger, T, Menni, C, Mentch, FD, Mihailov, E, Milani, L, Montasser, ME, Montgomery, G, Morrison, A, Myers, RH, Nadukuru, R, Navarro, P, Nelis, M, Nieminen, MS, Nolte, Ilja M., O'Connor, GT, Ogunniyi, A, Padmanabhan, S, Palmas, WR, Pankow, JS, Patarcic, I, Pavani, F, Peyser, PA, Pietilainen, K, Poulter, N, Prokopenko, I, Ralhan, S, Redmond, P, Rich, SS, Rissanen, H, Robino, A, Rose, LM, Rose, R, Sala, C, Salako, B, Salomaa, V, Sarin, AP, Saxena, R, Schmidt, Heléna, Scott, LJ, Scott, WR, Sennblad, B, Seshadri, S, Sever, P, Shrestha, S, Smith, BH, Smith, JA, Soranzo, N, Sotoodehnia, N, Southam, L, Stanton, AV, Stathopoulou, MG, Strauch, K, Strawbridge, RJ, Suderman, MJ, Tandon, N, Tang, ST, Taylor, KD, Tayo, BO, Toglhofer, AM, Tomaszewski, M, Tsernikova, N, Tuomilehto, J, Uitterlinden, André, Vaidya, D, Vlieg, AV, van Setten, J, Vasankari, T, Vedantam, S, Vlachopoulou, E, Vozzi, D, Vuoksimaa, E, Waldenberger, M, Ware, EB, Wentworth-Shields, W, Whitfield, JB, Wild, S, Willemsen, G, Yajnik, CS, Yao, J, Zaza, G, Zhu, XF, Salem, RM, Melbye, M, Bisgaard, H, Samani, NJ, Cusi, D, Mackey, DA, Cooper, RS, Froguel, P, Pasterkamp, G, Grant, SFA, Hakonarson, H, Ferrucci, L, Scott, RA, Morris, AD, Palmer, CNA, Dedoussis, G, Deloukas, P, Bertram, L, Lindenberger, U, Berndt, SI, Lindgren, CM, Timpson, NJ, Tonjes, A, Munroe, PB, Sorensen, TIA, Rotimi, CN, Arnett, DK, Oldehinkel, Albertine J., Kardia, SLR, Balkau, B, Gambaro, G, Morris, AP, Eriksson, JG, Wright, MJ, Martin, NG, Hunt, SC, Starr, JM, Deary, IJ, Griffiths, LR, Tiemeier, Henning, Pirastu, N, Kaprio, J, Wareham, NJ, Peerusse, L, Wilson, JG, Girotto, G, Caulfield, MJ, Raitakari, O, Boomsma, DI, Gieger, C, van der Harst, P, Hicks, AA, Kraft, P, Sinisalo, J, Knekt, P, Johannesson, M, Magnusson, PKE, Hamsten, A, Schmidt, R, Borecki, IB, Vartiainen, E, Becker, DM, Bharadwaj, D, Mohlke, KL, Boehnke, M, van Duijn, Cornelia M., Sanghera, DK, Teumer, A, Zeggini, E, Metspalu, A, Gasparini, P, Ulivi, S, Ober, C, Toniolo, D, Rudan, I, Porteous, DJ, Ciullo, M, Spector, Tim D., Hayward, C, Dupuis, J, Loos, RJF, Wright, AF, Chandak, GR, Vollenweider, P, Shuldiner, AR, Ridker, PM, Rotter, JI, Sattar, N, Gyllensten, U, North, KE, Pirastu, M, Psaty, Bruce M., Weir, DR, Laakso, M, Gudnason, V, Takahashi, A, Chambers, JC, Kooner, JS, Strachan, DP, Campbell, H, Hirschhorn, JN, Perola, M, Polasek, O, Wilson, JF, Joshi, PK, Esko, T, Mattsson, H, Eklund, N, Gandin, I, Nutile, T, Jackson, AU, Schurmann, C, Smith, AV, Zhang, WH, Okada, Y, Stancakova, A, Faul, JD, Zhao, W, Bartz, TM, Concas, MP, Franceschini, N, Enroth, S, Vitart, V, Trompet, S, Guo, XQ, Chasman, DI, O'Connel, JR, Corre, T, Nongmaithem, SS, Chen, Y, Mangino, M, Ruggiero, D, Michela, T, Farmaki, AE, Kacprowski, T, Bjonnes, A, van der Spek, Ashley, Wu, Y, Giri, AK, Yanek, LR, Wang, LH, Hofer, E, Rietveld, CA, McLeod, O, Cornelis, MC, Pattaro, C, Verweij, N, Baumbach, C, Abdellaoui, A, Warren, HR, Vuckovic, D, Mei, H, Bouchard, C, Perry, JRB, Cappellani, S, Mirza, Saira, Benton, MC, Broeckel, U, Medland, SE, Lind, P, Malerba, G, Drong, A, Yengo, L, Bielak, LF, Zhi, DG, van der Most, PJ, Shriner, D, Magi, R, Hemani, G, Karaderi, T, Wang, ZM, Liu, T, Demuth, I, Zhao, JH, Meng, WH, Lataniotis, L, Laan, Sander, Bradfield, JP, Wood, AR, Bonnefond, A, Ahluwalia, TS, Hall, L, Salvi, E, Yazar, S, Carstensen, L, de Haan, HG, Abney, M, Afzal, U, Allison, MA, Amin, Najaf, Asselbergs, FW, Bakker, SJL, Barr, RG, Baumeister, SE, Benjamin, DJ, Bergmann, S, Boerwinkle, E, Bottinger, EP, Campbell, A (Archie), Chakravarti, A, Chan, YL, Chanock, SJ, Chen, C (Christopher Li Hsian), Chen, YDI, Collins, FS, Connell, J, Correa, A, Cupples, LA, Smith, GD, Davies, G, Dorr, M, Ehret, G, Ellis, SB, Feenstra, B, Feitosa, MF, Ford, I, Fox, CS, Frayling, TM, Friedrich, N, Geller, F, Scotland, G, Gillham-Nasenya, I, Gottesman, O, Graff, M, Grodstein, F, Gu, C, Haley, C, Hammond, CJ, Harris, SE, Harris, TB, Hastie, ND, Heard-Costa, NL, Heikkila, K, Hocking, LJ, Homuth, G, Hottenga, Jouke-Jan, Huang, JY, Huffman, JE, Hysi, Pirro G., Arfan Ikram, M., Ingelsson, E, Joensuu, A, Johansson, A, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kanoni, S, Kerr, SM, Khan, NM, Koellinger, P, Koistinen, HA, Kooner, MK, Kubo, M, Kuusisto, J, Lahti, J, Launer, Lenore J., Lea, RA, Lehne, B, Lehtimaki, T, Liewald, DCM, Lind, L, Loh, M, Lokki, ML, London, SJ, Loomis, SJ, Loukola, A, Lu, YC, Lumley, T, Lundqvist, A, Mannisto, S, Marques-Vidal, P, Masciullo, C, Matchan, A, Mathias, RA, Matsuda, K, Meigs, JB, Meisinger, C, Meitinger, T, Menni, C, Mentch, FD, Mihailov, E, Milani, L, Montasser, ME, Montgomery, G, Morrison, A, Myers, RH, Nadukuru, R, Navarro, P, Nelis, M, Nieminen, MS, Nolte, Ilja M., O'Connor, GT, Ogunniyi, A, Padmanabhan, S, Palmas, WR, Pankow, JS, Patarcic, I, Pavani, F, Peyser, PA, Pietilainen, K, Poulter, N, Prokopenko, I, Ralhan, S, Redmond, P, Rich, SS, Rissanen, H, Robino, A, Rose, LM, Rose, R, Sala, C, Salako, B, Salomaa, V, Sarin, AP, Saxena, R, Schmidt, Heléna, Scott, LJ, Scott, WR, Sennblad, B, Seshadri, S, Sever, P, Shrestha, S, Smith, BH, Smith, JA, Soranzo, N, Sotoodehnia, N, Southam, L, Stanton, AV, Stathopoulou, MG, Strauch, K, Strawbridge, RJ, Suderman, MJ, Tandon, N, Tang, ST, Taylor, KD, Tayo, BO, Toglhofer, AM, Tomaszewski, M, Tsernikova, N, Tuomilehto, J, Uitterlinden, André, Vaidya, D, Vlieg, AV, van Setten, J, Vasankari, T, Vedantam, S, Vlachopoulou, E, Vozzi, D, Vuoksimaa, E, Waldenberger, M, Ware, EB, Wentworth-Shields, W, Whitfield, JB, Wild, S, Willemsen, G, Yajnik, CS, Yao, J, Zaza, G, Zhu, XF, Salem, RM, Melbye, M, Bisgaard, H, Samani, NJ, Cusi, D, Mackey, DA, Cooper, RS, Froguel, P, Pasterkamp, G, Grant, SFA, Hakonarson, H, Ferrucci, L, Scott, RA, Morris, AD, Palmer, CNA, Dedoussis, G, Deloukas, P, Bertram, L, Lindenberger, U, Berndt, SI, Lindgren, CM, Timpson, NJ, Tonjes, A, Munroe, PB, Sorensen, TIA, Rotimi, CN, Arnett, DK, Oldehinkel, Albertine J., Kardia, SLR, Balkau, B, Gambaro, G, Morris, AP, Eriksson, JG, Wright, MJ, Martin, NG, Hunt, SC, Starr, JM, Deary, IJ, Griffiths, LR, Tiemeier, Henning, Pirastu, N, Kaprio, J, Wareham, NJ, Peerusse, L, Wilson, JG, Girotto, G, Caulfield, MJ, Raitakari, O, Boomsma, DI, Gieger, C, van der Harst, P, Hicks, AA, Kraft, P, Sinisalo, J, Knekt, P, Johannesson, M, Magnusson, PKE, Hamsten, A, Schmidt, R, Borecki, IB, Vartiainen, E, Becker, DM, Bharadwaj, D, Mohlke, KL, Boehnke, M, van Duijn, Cornelia M., Sanghera, DK, Teumer, A, Zeggini, E, Metspalu, A, Gasparini, P, Ulivi, S, Ober, C, Toniolo, D, Rudan, I, Porteous, DJ, Ciullo, M, Spector, Tim D., Hayward, C, Dupuis, J, Loos, RJF, Wright, AF, Chandak, GR, Vollenweider, P, Shuldiner, AR, Ridker, PM, Rotter, JI, Sattar, N, Gyllensten, U, North, KE, Pirastu, M, Psaty, Bruce M., Weir, DR, Laakso, M, Gudnason, V, Takahashi, A, Chambers, JC, Kooner, JS, Strachan, DP, Campbell, H, Hirschhorn, JN, Perola, M, Polasek, O, and Wilson, JF

Abstract

Homozygosity has long been associated with rare, often devastating, Mendelian disorders(1), and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness(2). However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power(3,4). Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 x 10(-300), 2.1 x 10(-6), 2.5 x 10(-10) and 1.8 x 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples(5,6), no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection(7), this study provides evidence that increased stature and cognitive function have been positively sele

Published
2015

31. Effect of diindolylmethane on Ca(2+) homeostasis and viability in MDCK renal tubular cells

Author

Chung-Ren Jan, Lu Yc, Yi-Chien Fang, Chiang-Ting Chou, Kuo Cc, Li Yd, Cheng Js, Chi Cc, Lin Kl, and He-Hsiung Cheng

Subjects
Thapsigargin, Indoles, Cell Survival, Health, Toxicology and Mutagenesis, Diindolylmethane, Biology, Toxicology, Endoplasmic Reticulum, Madin Darby Canine Kidney Cells, chemistry.chemical_compound, Dogs, Extracellular, Animals, Homeostasis, Protein kinase C, Biological Products, Phospholipase C, Cell growth, Endoplasmic reticulum, General Medicine, Cell biology, Cytosol, Kidney Tubules, chemistry, Type C Phospholipases, Biophysics, Calcium
Abstract

The effect of the natural product diindolylmethane (DIM) on cytosolic Ca2+ concentrations ([Ca2+]i) and viability in MDCK renal tubular cells was explored. The Ca2+-sensitive fluorescent dye fura-2 was applied to measure [Ca2+]i. DIM at concentrations 1–50 μM induced a [Ca2+]i rise in a concentration-dependent manner. The response was reduced partly by removing Ca2+. DIM induced Mn2+ influx leading to quenching of fura-2 fluorescence. DIM-evoked Ca2+ entry was suppressed by nifedipine, econazole, SK&F96365 and protein kinase C modulators. In the absence of extracellular Ca2+, incubation with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin (TG) or 2,5-di-tert-butylhydroquinone (BHQ) greatly inhibited DIM-induced [Ca2+]i rise. Incubation with DIM abolished TG or BHQ-induced [Ca2+]i rise. Inhibition of phospholipase C with U73122 reduced DIM-induced [Ca2+]i rise by 50%. At 1, 10, 40 and 50 μM, DIM slightly enhanced cell proliferation. The effect of 50 μM DIM was reversed by chelating cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane- N, N, N', N'-tetraacetic acid. In sum, in MDCK cells, DIM induced a [Ca2+]i rise by evoking phospholipase C-dependent Ca2+ release from the endoplasmic reticulum and Ca2+ entry via protein kinase C-sensitive store-operated Ca2+ channels. DIM did not induce cell death.

Published
2013

39. Structures and connections of enkephalin- and γ-aminobutyric acid-immunoreactive profiles in the gustatory region of the nucleus tractus solitarius: a light and electron microscopic study.

Author

Huang W, Chen JX, Li YM, Lu YC, Wu XJ, Huang, Wei, Chen, Ju-Xiang, Li, Yi-Ming, Lu, Yi-Cheng, and Wu, Xiao-Jun

Abstract

GABA and enkephalin (ENK) are principle inhibitory transmitters in the rostral portion of the nucleus tractus solitarius (rNTS) for regulating the gustatory information. Although the existence of GABA- and ENK-immunoreactive (ir) profiles in the rNTS has been demonstrated, there are no morphological data revealing the connections between them. In the present study, using immunofluorescent and electron microscopic methods, we examined their relationship in the rNTS of rat. Results showed the following: (1) dense ENK-ir fibers and terminals and GABA-ir cell bodies, fibers, and terminals were observed in the rNTS; (2) ENK-ir terminals mainly make symmetric synapses with GABA-ir and immunonegative somas and dendrites; (3) co-existence of ENK/GABA-ir axon terminals and convergence of ENK- and GABA-ir terminals on one immunonegative soma or dendrite can also be observed. These results suggest that ENK should inhibit directly or excite indirectly (by blocking the inhibition of the GABAergic neurons) the gustatory neurons in the rNTS. [ABSTRACT FROM AUTHOR]

Published
2011
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41. Application of SNaPshot multiplex assays for simultaneous multigene mutation screening in patients with idiopathic sensorineural hearing impairment.

Author

Wu CC, Lu YC, Chen PJ, Liu AY, Hwu WL, Hsu CJ, Wu, Chen-Chi, Lu, Ying-Chang, Chen, Pei-Jer, Liu, Alyssa Yan-Zhen, Hwu, Wuh-Liang, and Hsu, Chuan-Jen

Abstract

Objectives/hypothesis: To develop a cost-effective and robust genetic diagnostic tool for patients with idiopathic nonsyndromic sensorineural hearing impairment.Study Design: Development of a diagnostic tool and validation in a prospective cohort.Methods: Twenty common sequence variants in GJB2, SLC26A4, and the mitochondrial 12S rRNA gene were selected based on our previous epidemiological study. These variants were analyzed using the SNaPshot technique. The efficacies of the SNaPshot multiplex assays were determined by using a prospective cohort composed of 214 unrelated Taiwanese patients with idiopathic sensorineural hearing impairment. The results of the assays were compared to the results obtained by direct sequencing.Results: We developed a diagnostic technique consisting of two consecutive panels of SNaPshot multiplex assays, with each panel screening 10 common sequence variants. Theoretically, this design can detect more than 98% of the known deafness-associated sequence variants in Taiwanese individuals. A total of 126 (58.9%) patients were diagnosed as having at least one sequence variant using the SNaPshot multiplex assays. In total, the SNaPshot assays yielded an accuracy of more than 99%.Conclusions: The strengths of SNaPshot multiplex assays include high accuracy, high sensitivity, high flexibility (the examination panel can be easily expanded for additional mutations), low cost (less than US $10 per patient), and easy implementation for any institute with a DNA sequencer. Although only 20 to 30 mutations can be examined in two to three runs of the SNaPshot assay, this technology may be suitable for first-pass screening of deafness-associated mutations in populations with a relatively homogeneous ethnic background. [ABSTRACT FROM AUTHOR]

Published
2009
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42. Prospective mutation screening of three common deafness genes in a large Taiwanese Cohort with idiopathic bilateral sensorineural hearing impairment reveals a difference in the results between families from hospitals and those from rehabilitation facilities.

Author

Wu CC, Chen PJ, Chiu YH, Lu YC, Wu MC, Hsu CJ, Wu, Chen-Chi, Chen, Pei-Jer, Chiu, Yu-Hsun, Lu, Ying-Chang, Wu, Ming-Chueh, and Hsu, Chuan-Jen

Abstract

Accurate epidemiological data on common deafness genes are essential to improve the efficiency and to reduce the cost of molecular diagnosis. They may depend on several factors, including a clear delineation of the source of patients being studied. In the present study, we hypothesize that patients with idiopathic sensorineural hearing loss recruited from different sources might reveal discrepancies in the epidemiological results of genetic screening, because patients from different sources might demonstrate distinct clinical or audiologic features and thus result in biased selection of subjects. To elucidate the relative importance of common deafness genes in Taiwanese and to verify our hypothesis, we conducted a prospective project screening mutations in GJB2, SLC26A4 and mitochondrial 12S rRNA gene in a total of 420 Taiwanese families with idiopathic bilateral sensorineural hearing loss, of which 325 families were recruited from hospitals and 95 from hearing rehabilitation facilities. Allele frequencies of common mutations in these three genes and distributions of the corresponding genotypes were then compared between the two groups. The allele frequencies of mutations in SLC26A4, GJB2 and mitochondrial 12S rRNA in the probands of the 420 families were 14.4, 21.7 and 3.8%, respectively. The allele frequency of SLC26A4 mutations in the hospital group was significantly higher than that in the rehabilitation facility group (16.2 vs. 8.4%, chi(2)-test, p < 0.05), whereas no difference in the frequencies of GJB2 mutations and mitochondrial 12S rRNA mutations was found between the two groups. Distributions of probands classified by SLC26A4 genotypes were also different between the two groups (chi(2)-test, p < 0.05). Accordingly, a discrepancy in the genetic screening results might exist between different sources of idiopathic hearing-impaired patients. Further analysis of audiological results and construction of a logistic regression model showed that different audiological features, namely hearing levels and hearing loss patterns, might be responsible for the unequal distributions of mutations and probands between the hospital and rehabilitation facility groups. [ABSTRACT FROM AUTHOR]

Published
2008

43. Microstructural Instability in Mosi2/Sic Nanolayers

Author

Lu, YC, Kung, H, Hirvonen, J-P, Jervis, TR, Nastasi, M, Ruck, D, and Mitchell, T E

Abstract

Thin film multilayers have been the focus of extensive studies recently due to the interesting properties they exhibit. Since the improvement in properties can be attributed directly to the unique nanoscale microstructures, it is essential to understand the factors affecting the microstructural stability in these nanolayer structures. The intermetallic compound, MoSi2, despite its superior oxidation resistance and high melting point, suffers from inadequate high temperature strength and low temperature ductility, properties which hinder its high temperature structural applications [1]. SiC is a potential second phase reinforcement due to its high temperature strength and thermal compatibility with MoSi2. The addition of SiC in a nanolayered configuration has been shown to exhibit significant increase in hardness after annealing [2]. It has also been shown that when annealed above 900°C, the layers break down and grain growth sets in, with a significant decrease in hardness and. Due to the lack of a thermochemical driving force, the two phases remain separate at all temperatures investigated. In this study, the stability of the MoSi2/SiC nanolayers structure under ion irradiation has been investigated.

Published
1997
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44. Genome-wide identification of a MADS-box transcription factor family and their expression during floral development in Coptis teeta wall.

Author

Duan SF, Yu JC, Baldwin TC, Yuan Y, Xiang GS, Cui R, Zhao Y, Mo XC, Lu YC, and Liang YL

Subjects
Phylogeny, Multigene Family, Genome, Plant, Gene Expression Profiling, Transcription Factors genetics, Transcription Factors metabolism, MADS Domain Proteins genetics, MADS Domain Proteins metabolism, Flowers genetics, Flowers growth & development, Gene Expression Regulation, Plant, Plant Proteins genetics, Plant Proteins metabolism, Coptis genetics, Coptis growth & development, Coptis metabolism
Abstract

Background: MADS-box transcription factors have been shown to be involved in multiple developmental processes, including the regulation of floral organ formation and pollen maturation. However, the role of the MADS-box gene family in floral development of the alpine plant species Coptis teeta Wall, which is widely used in Traditional Chinese Medicine (TCM), is unknown., Results: Sixty-six MADS-box genes were identified in the C. teeta genome. These genes were shown to be unevenly distributed throughout the genome of C. teeta. The majority of which (49) were classified as type I MADS-box genes and were further subdivided into four groups (Mα, Mβ, Mγ and Mδ). The remainder were identified as belonging to the type II MADS-box gene category. It was observed that four pairs of segmental and tandem duplication had occurred in the C. teeta MADS-box gene family, and that the ratios of Ka/Ks were less than 1, suggesting that these genes may have experienced purifying selection during evolution. Gene expression profiling analysis revealed that 38 MADS-box genes displayed differential expression patterns between the M and F floral phenotypes. Sixteen of these MADS-box genes were further verified by RT-qPCR. The 3D structure of each subfamily gene was predicted, further indicating that MADS-box genes of the same type possess structural similarities to the known template., Conclusions: These data provide new insights into the molecular mechanism of dichogamy and herkogamy formation in C. teeta and establish a solid foundation for future studies of the MADS-box genes family in this medicinal plant species., (© 2024. The Author(s).)

Published
2024
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45. CDK9 phosphorylates RUNX1 to promote megakaryocytic fate in megakaryocytic-erythroid progenitors.

Author

Kwon N, Lu YC, Thompson EN, Mancuso RI, Wang L, Zhang PX, and Krause DS

Subjects
Humans, Phosphorylation, Megakaryocyte-Erythroid Progenitor Cells metabolism, Megakaryocyte-Erythroid Progenitor Cells cytology, Cell Differentiation, Core Binding Factor Alpha 2 Subunit metabolism, Core Binding Factor Alpha 2 Subunit genetics, Megakaryocytes metabolism, Megakaryocytes cytology, Cyclin-Dependent Kinase 9 metabolism, Cyclin-Dependent Kinase 9 genetics
Abstract

Abstract: The specification of megakaryocytic (Mk) or erythroid (E) lineages from primary human megakaryocytic-erythroid progenitors (MEPs) is crucial for hematopoietic homeostasis, yet the underlying mechanisms regulating fate specification remain elusive. In this study, we identify RUNX1 as a key modulator of gene expression during MEP fate specification. Overexpression of RUNX1 in primary human MEPs promotes Mk specification, whereas pan-RUNX inhibition favors E specification. Although total RUNX1 levels do not differ between Mk progenitors (MkPs) and E progenitors (ErPs), there are higher levels of serine-phosphorylated RUNX1 in MkPs than ErPs, and mutant RUNX1 with phosphorylated-serine/threonine mimetic mutations (RUNX1-4D) significantly enhances the functional efficacy of RUNX1. To model the effects of RUNX1 variants, we use human erythroleukemia (HEL) cell lines expressing wild-type (WT), phosphomimetic (RUNX1-4D), and nonphosphorylatable (RUNX1-4A) mutants showing that the 3 forms of RUNX1 differentially regulate expression of 2625 genes. Both WT and RUNX1-4D variants increase expression in 40%, and decrease expression in another 40%, with lesser effects of RUNX1-4A. We find a significant overlap between the upregulated genes in WT and RUNX1-4D-expressing HEL cells and those upregulated in primary human MkPs vs MEPs. Although inhibition of known RUNX1 serine/threonine kinases does not affect phosphoserine RUNX1 levels in primary MEPs, specific inhibition of cyclin dependent kinase 9 (CDK9) in MEPs leads to both decreased RUNX1 phosphorylation and increased E commitment. Collectively, our findings show that serine/threonine phosphorylation of RUNX1 promotes Mk fate specification and introduce a novel kinase for RUNX1 linking the fundamental transcriptional machinery with activation of a cell type-specific transcription factor., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Published
2024
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46. Fixel-Based Analysis of White Matter Alterations in Facial Palsy.

Author

Wang YF, Wang W, Ma H, Zhang CH, and Lu YC

Abstract

Predicting individual prognosis is difficult despite various risk factor studies, due to the complex recovery involving peripheral nerve restoration and cerebral plasticity. This study uses fixel-based analysis (FBA) to better understand neural pathway alterations, hypothesizing that FBA can effectively link functional outcomes with diffusion metrics in the process of rehabilitation. The authors recruited 50 participants including 30 patients and 20 healthy controls into the study. All of them underwent assessment 3 months and 6 months after injury. Both whole-brain fixel-based analysis and tract of interest analysis were performed. The authors observed multiple regions including the superior corona radiata, posterior limb of the internal capsule, and cerebral peduncle displaying significant changes of FD (fiber density), FC (fiber-bundle cross-section), and FDC (fiber density and cross-section). Patients with unfavorable outcomes showed increased FD in the ipsilesional side and decreased FD in the contralesional side compared with patients with favorable outcomes. In addition, FD values of the contralesional side exhibited positive correlations with differences in FGS at 3 months and 6 months. Conversely, FD values in the ipsilesional side showed a negative correlation. Our findings suggest that FD metrics within the corticobulbar tract could serve as predictive biomarkers for symmetry outcomes. Thus, FBA holds promise for early estimation of behavioral outcomes in facial palsy, guiding more targeted interventions., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Published
2024
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47. Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes.

Author

Yang CY, Tseng YC, Tu YF, Kuo BJ, Hsu LC, Lien CI, Lin YS, Wang YT, Lu YC, Su TW, Lo YC, and Lin SC

Subjects
Humans, Apoptosis, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Signal Transduction, HEK293 Cells, Crystallography, X-Ray, Models, Molecular, Necroptosis, CASP8 and FADD-Like Apoptosis Regulating Protein metabolism, CASP8 and FADD-Like Apoptosis Regulating Protein genetics, Caspase 8 metabolism, Caspase 8 genetics, Fas-Associated Death Domain Protein metabolism, Fas-Associated Death Domain Protein genetics, Cryoelectron Microscopy
Abstract

cFLIP, a master anti-apoptotic regulator, targets the FADD-induced DED complexes of procaspase-8 in death receptor and ripoptosome signaling pathways. Several tumor cells maintain relatively high levels of cFLIP in achieving their immortality. However, understanding the three-dimensional regulatory mechanism initiated or mediated by elevated levels of cFLIP has been limited by the absence of the atomic coordinates for cFLIP-induced DED complexes. Here we report the crystal plus cryo-EM structures to uncover an unconventional mechanism where cFLIP and procaspase-8 autonomously form a binary tandem DED complex, independent of FADD. This complex gains the ability to recruit FADD, thereby allosterically modulating cFLIP assembly and partially activating caspase-8 for RIPK1 cleavage. Our structure-guided mutagenesis experiments provide critical insights into these regulatory mechanisms, elucidating the resistance to apoptosis and necroptosis in achieving immortality. Finally, this research offers a unified model for the intricate bidirectional hierarchy-based processes using multiprotein helical assembly to govern cell fate decisions., (© 2024. The Author(s).)

Published
2024
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48. Facile synthesis of tantalum decorated on iron selenide with nitrogen-doped graphene hybrid for the sensitive detection of trolox in berries: Density functional theory interpretation.

Author

Sakthivel R, Chou CC, Prasanna SB, Krishnegowda HM, Ramaraj SK, Lin LY, Liu X, Lu YC, Wen HW, Liu TY, and Chung RJ

Subjects
Density Functional Theory, Electrochemical Techniques, Limit of Detection, Electrodes, Iron chemistry, Iron analysis, Graphite chemistry, Fruit chemistry, Nitrogen chemistry, Tantalum chemistry, Chromans chemistry, Chromans analysis
Abstract

This work presents a hydrothermal method followed by a sonochemical treatment for synthesizing tantalum decorated on iron selenide (Ta/FeSe 2 ) integrated with nitrogen-doped graphene (NGR) as a susceptible electrode material for detecting trolox (TRX) in berries samples. The surface morphology, structural characterizations, and electrochemical performances of the synthesized Ta/FeSe 2 /NGR composite were analyzed via spectrophotometric and voltammetry techniques. The GCE modified with Ta/FeSe 2 /NGR demonstrated an impressive linear range of 0.1 to 580.3 μM for TRX detection. Additionally, it achieved a remarkable limit of detection (LOD) of 0.059 μM, and it shows a high sensitivity of 2.266 μA μМ -1  cm -2 . Here, we used density functional theory (DFT) to investigate the structures of TRX and TRX quinone and the locations of energy levels and electron transfer sites. The developed sensor exhibits significant selectivity, satisfactory cyclic and storage stability, and notable reproducibility. Moreover, the practicality of TRX was assessed in different types of berries, yielding satisfactory recoveries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Published
2024
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49. Potential role of calcium sulfate/β-tricalcium phosphate/graphene oxide nanocomposite for bone graft application&#95;mechanical and biological analyses.

Author

Lu YC, Chang TK, Lin TC, Yeh ST, Lin HS, Cheng QP, Huang CH, Fang HW, and Huang CH

Subjects
Animals, Bone Transplantation methods, Osteogenesis drug effects, Osteogenesis physiology, Bone Substitutes, Skull surgery, Materials Testing, Male, Compressive Strength, Calcium Phosphates, Calcium Sulfate, Graphite, Nanocomposites
Abstract

Background: Bone grafts are extensively used for repairing bone defects and voids in orthopedics and dentistry. Moldable bone grafts offer a promising solution for treating irregular bone defects, which are often difficult to fill with traditional rigid grafts. However, practical applications have been limited by insufficient mechanical strength and rapid degradation., Methods: This study developed a ceramic composite bone graft composed of calcium sulfate (CS), β-tricalcium phosphate (β-TCP) with/without graphene oxide (GO) nano-particles. The biomechanical properties, degradation rate, and in-vitro cellular responses were investigated. In addition, the graft was implanted in-vivo in a critical-sized calvarial defect model., Results: The results showed that the compressive strength significantly improved by 135% and the degradation rate slowed by 25.5% in comparison to the control model. The addition of GO nanoparticles also improved cell compatibility and promoted osteogenic differentiation in the in-vitro cell culture study and was found to be effective at promoting bone repair in the in-vivo animal model., Conclusions: The mixed ceramic composites presented in this study can be considered as a promising alternative for bone graft applications., (© 2024. The Author(s).)

Published
2024
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50. Chitosan-glucose derivative membrane obtained by Maillard reaction improves cartilage repair in a rabbit model.

Author

Chuang PY, Chang SF, Lu YC, and Huang KC

Subjects
Animals, Rabbits, Disease Models, Animal, Regeneration drug effects, Membranes, Artificial, Biocompatible Materials therapeutic use, Male, Chitosan pharmacology, Cartilage, Articular injuries, Cartilage, Articular drug effects, Cartilage, Articular surgery, Maillard Reaction, Glucose
Abstract

Background: Treatment of articular cartilage injury remains a challenging clinical problem in orthopedics. Chitosan-derived biomaterial could be a potential adjuvant treatment to improve cartilage repair. In the current study, we examined the effects of two potential chitosan-derived materials on cartilage regeneration of osteochondral defects in rabbits., Methods: An osteochondral defect was created over the rabbit knee and treated using three approaches: group A received no material (n = 24), group B received chitosan membranes with glucose absorption (CGA; n = 25), and group C received chitosan-glucose derivative membranes obtained via the Maillard reaction (CGMR; n = 25). Cartilage repair over the osteochondral defect was analyzed 12 weeks post-surgery via histological analysis, immunostaining, and reverse transcription-qualitative polymerase chain reaction (RT-qPCR) for type-I and type-II collagen mRNA., Results: According to histological analysis, CGMR-treated defects showed significantly improved modified O'Driscoll scoring when compared with no material- and CGA-treated defects (20.9 ± 4.3 vs. 13.00 ± 2.5 and 17.7 ± 4.6, p < 0.001). Moreover, group C exhibited higher intensity of type-II collagen immunohistochemical staining over the regenerated cartilage than groups A and B, along with increased expression of type-II collagen mRNA by RT-qPCR., Conclusions: CGMR might improve cartilage regeneration in osteochondral defects., (© 2024. The Author(s).)

Published
2024
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