Search

Your search keyword '"C.Y. Lee"' showing total 331 results
Start Over Author "C.Y. Lee"
Sorry, I don't understand your search. ×
331 results on '"C.Y. Lee"'

1. Overview of the KSTAR experiments toward fusion reactor

Author

Won-Ha Ko, S.W. Yoon, W.C. Kim, J.G. Kwak, K.L. Park, Y.U. Nam, S.J. Wang, J. Chung, B.H. Park, G.Y. Park, H.H. Lee, H.S. Han, M.J. Choi, Y.S. Na, Y. In, C.Y. Lee, M. Kim, G.S. Yun, Y.-C. Ghim, W.H. Choe, J.M. Kwon, J.P. Lee, W.C. Lee, Y.M. Jeon, K. Kim, J.H. Lee, G.W. Shin, J. Kim, J. Lee, S.H. Hahn, J.W. Lee, H.S. Kim, J.G. Bak, S.G. Lee, Y.H. Lee, J.H. Jeong, M.H. Woo, J.H. Kim, J.W. Juhn, J.S. Ko, C. Sung, H.W. Shin, J.M. Park, S.K. Kim, J.K. Park, N.C. Logan, S.M. Yang, E. Kolemen, Q.M. Hu, R. Shousha, J. Barr, C. Paz-Soldan, Y.S. Park, S.A. Sabbagh, K. Ida, S. Kim, A. Loarte, E. Gilson, D. Eldon, T. Nakano, T. Tala, and KSTAR Team

Subjects
FIRE-mode, machine learning (ML) control algorithm, long ELM-suppression, tungsten divertor, virtual KSTAR, high beta long pulse, Nuclear and particle physics. Atomic energy. Radioactivity, QC770-798
Abstract

The Korean Superconducting Tokamak Advanced Research has been focused on exploring the key physics and engineering issues for future fusion reactors by demonstrating the long pulse operation of high beta steady-state discharge. Advanced scenarios are being developed with the goal for steady-state operation, and significant progress has been made in high ℓ _i , hybrid and high beta scenarios with β _N of 3. In the new operation scenario called fast ion regulated enhanced (FIRE), fast ions play an essential role in confinement enhancement. GK simulations show a significant reduction of the thermal energy flux when the thermal ion fraction decreases and the main ion density gradient is reversed by the fast ions in FIRE mode. Optimization of 3D magnetic field techniques, including adaptive control and real-time machine learning control algorithm, enabled long-pulse operation and high-performance ELM-suppressed discharge. Symmetric multiple shattered pellet injections (SPIs) and real-time disruption event characterization and forecasting are being performed to mitigate and avoid the disruptions associated with high-performance, long-pulse ITER-like scenarios. Finally, the near-term research plan will be addressed with the actively cooled tungsten divertor, a major upgrade of the NBI and helicon current drive heating, and transition to a full metallic wall.

Published
2024
Full Text
View/download PDF

2. IMC microstructure modification and mechanical reinforcement of Sn–Ag–Cu/Cu microelectronic joints through an advanced surface finish technique

Author

C.E. Ho, S.P. Yang, P.T. Lee, C.Y. Lee, C.C. Chen, and T.T. Kuo

Subjects
Cu, Surface finish, IGEPIG, IMC, Molten solder channel, HSBS, Mining engineering. Metallurgy, TN1-997
Abstract

Intermetallic compound(s) (IMC) that nucleates at the interface between solder and Cu trace during a soldering reaction, is one of the most crucial factors for microelectronic packaging reliability. This study was conducted to modify the IMC microstructure and to reinforce the mechanical strength of Sn–Ag–Cu/Cu microelectronic joints through various surface finish coatings, including organic solderability preservative (OSP), immersion Ag (ImAg), immersion Sn (ImSn), Au/Pd (electroless palladium/immersion gold, EPIG), and Au/Pd/Au (IGEPIG) layer(s). We confirmed that the type of surface finish dominated the IMC growth morphology and mechanical characteristics of the Sn–Ag–Cu/Cu solder joints, even though these surface finishes were eliminated in a few seconds of the soldering process. A dense Cu6Sn5 layer with a scallop-like appearance was obtained for the traditional OSP case, while a prismatic, loose Cu6Sn5 microstructure was produced for the alternative cases (metal films). This loose Cu6Sn5 microstructure offered numerous molten solder channels for the in-diffusion of Sn to Cu, retarding undesired Cu3Sn growth at the Cu6Sn5/Cu interface; consequently, a brittle-to-ductile transition in the joint fracture mode with a high shear strength and fracture energy was obtained in the high-speed ball shear (HSBS) test. A significant mechanical reinforcement of the Sn–Ag–Cu/Cu microelectronic joints can be achieved with the replacement of the traditional OSP coating by the newly developed IGEPIG trilayer surface finish.

Published
2021
Full Text
View/download PDF

3. Investigation of performance enhancement by balanced double-null shaping in KSTAR

Author

Boseong Kim, M.S. Park, Y.H. Lee, S.K. Kim, C.Y. Lee, S.C. Hong, J. Seo, J.G. Lee, S.J. Park, H.-S. Kim, and Yong-Su Na

Subjects
KSTAR, plasma shaping, double-null, performance enhancement, pedestal, ELM characteristic, Nuclear and particle physics. Atomic energy. Radioactivity, QC770-798
Abstract

We report experimental observations on the effect of plasma boundary shaping towards balanced double-null (DN) configuration on the plasma performance in KSTAR. The transition from a single-null to a DN configuration resulted in improved plasma performance, manifested through changes in the pedestal region, decreased density, and core MHD activity variation. Specifically, the DN transition led to a wider and higher pedestal structure, accompanied by grassy edge-localized modes (ELMs) characteristics. The density decrease was a prerequisite for performance enhancement during DN shaping, increasing fast ion confinement. Optimizing the plasma near the core region was associated with the suppression of sawtooth instabilities and the occurrence of fishbone modes during the DN transition. Integrated modeling demonstrated that secondary effects of the DN shaping could increase core thermal energy confinement.

Published
2023
Full Text
View/download PDF

4. Effect of coherent edge-localized mode on transition to high-performance hybrid scenarios in KSTAR

Author

Youngho Lee, S.K. Kim, J.W. Kim, B. Kim, M.S. Park, J.M. Kwon, M.J. Choi, S.H. Hahn, M.W. Lee, S.M. Yang, S.C. Hong, C.Y. Lee, S.J. Park, C.S. Byun, H.-S. Kim, J. Chung, and Yong-Su Na

Subjects
KSTAR, advanced scenarios, hybrid scenarios, performance improvement, coherent edge-localized mode, confinement, Nuclear and particle physics. Atomic energy. Radioactivity, QC770-798
Abstract

This paper deals with one of the origins and trigger mechanisms responsible for the observed performance enhancements in the hybrid scenario experiments conducted in Korea Superconducting Tokamak Advanced Research (KSTAR). The major contribution to the performance improvement comes from a broader and higher pedestal formation. The increase of fast ion pressure due to a plasma density decrease also contributes substantially to the global beta. Although the reduced core plasma volume resulting from the pedestal expansion has a negative effect on the core thermal energy, a considerable confinement improvement observed in the inner core region limits the degradation. The one significant characteristic of high-performance discharges is the presence of Coherent Edge-localized Mode (CEM) activity. CEM is triggered during the pedestal recovery phase between typical ELM crashes and has been found to be related to the increase of particle and heat transport. It appears to underlie two commonly observed phenomena in high-performance hybrid scenario discharges in KSTAR; pedestal broadening and continuous density decrease. Despite the associated transport increase, CEM activities can induce performance enhancement. With the pedestal broadening, ELM crashes become delayed and weakened, which, in turn, allows for a higher pedestal. Moreover, the density decrease directly increases fast ion pressure by extending the beam-slowing-down time. The linear gyrokinetic analysis reveals that the increase of fast ions could initiate positive feedback loops, leading to the stabilization of Ion Temperature Gradient mode in the inner core region.

Published
2023
Full Text
View/download PDF

5. Cyclic stress-controlled tests on offshore clay

Author

S.Y. Thian and C.Y. Lee

Subjects
Offshore clay, Cyclic degradation, Undrained cyclic loading, Shear strength, Pore pressure, Overconsolidation ratio (OCR), Engineering geology. Rock mechanics. Soil mechanics. Underground construction, TA703-712
Abstract

One of the main concerns in cyclic behavior of soft clay is gradual degradation with the progression of loading cycle. A series of cyclic constant-volume direct simple shear (CDSS) loading tests was performed on Malaysia offshore clay to study its undrained degradation. The testing program consists of stress-controlled tests with cyclic shear ratio ranging from 0.34 to 0.83 at different overconsolidation ratios (OCRs). For a given cyclic stress ratio in stress-controlled tests, the accumulated cyclic strain and pore water pressure increase with elevated number of cycles. In heavily overconsolidated clay specimens, the negative cyclic pore water pressure is generated followed by positive cyclic pore water pressure as cyclic tests progress. The post-cyclic strength of offshore clay specimens is reduced by undrained cyclic stress-controlled loading.

Published
2017
Full Text
View/download PDF

6. Modelling and Measuring Dielectric Constants for Very Thin Materials Using a Coaxial Probe

Author

K. Y. You, Z. Abbas, C.Y. Lee, M. F. A. Malek, K. Y. Lee, and E. M. Cheng

Subjects
Relative effective permittivity, one-port calibration, measured reflection coefficient, open-ended coaxial probe, thin dielectric substrate, Electrical engineering. Electronics. Nuclear engineering, TK1-9971
Abstract

This paper is focused on the non-destructive measurement of the dielectric constants (relative permittivities) of thin dielectric material (0.1 mm – 0.5 mm) using an open-ended coaxial probe with an outer diameter of 4.1 mm. Normalized de-embedding and network error calibration procedures were applied to the coaxial probe. The measured reflection coefficients for the thin samples were taken with a vector network analyzer up to 7 GHz, and the calibrated reflection coefficients were converted to relative dielectric constant using an empirical reflection-coefficient model. The empirical model was created using the regression method and expressed as a polynomial model, and the coefficients of model were obtained by fitting with the data using the Finite Element Method (FEM).

Published
2014

7. Fasting and sampling time affect liver gene expression of high-fat diet-fed mice

Author

C.Y. Lee

Subjects
fasting, gene expression, high-fat diet, mice, sampling time, Animal culture, SF1-1100
Abstract

Several physiological and biological variables are known to affect peroxisome proliferator-activated receptor (PPAR)-α-dependent signaling pathway and plasma biochemical profiles. However, less is known about the effect of these variables on high-fat diet-fed mice. In a 5-week study, C57BL/6 mice were divided into control (C) and high-fat diet-fed (H) groups, whereby before dissection, each group was subdivided into non-fasted (nC and nH) and a 15-h fasted mice (fC and fH) killed in the early light cycle, and a 15-h fasted mice (eC and eH) killed in the late phase of the light cycle. Liver and blood from the vena cava were collected. Non-fasted nC and nH mice have a marginal difference in their body weight gain, whereas significant differences were found for fasted mice. In nH mice, PPAR-α, acyl-CoA oxidase and insulin-like growth factor-binding protein expressions were significantly elevated, in contrast to fatty acid synthase (Fasn), stearoyl CoA-desaturase (SCD)-1, and elongase (ELOVL)-6 expressions. Fasn was profoundly induced in fH mice, while decreased sterol regulatory-binding protein-1 and SCD-1 were found only in eH mice. Different from the gene expression profiles, plasma total cholesterol level of the eH mice was higher than controls, whereas nH mice have increased plasma non-esterified fatty acids. Only glucose level of the fH mice was higher than that observed for controls. Results showed that fasting and sampling time have significantly affected liver gene expression and plasma biochemical indices of the high-fat diet-treated mice. An overlook in these aspects can cause serious discrepancies in the experimental data and their interpretations.

Published
2010
Full Text
View/download PDF

8. The C-Terminal Domain of Thrombomodulin Regulates Monocyte Migration with Interleukin-6 Stimulation

Author

Y.W. Lin, C.Y. Huang, C.M. Shih, W.L. Chang, S.K. Shyue, Y.T. Tsai, C.Y. Lin, C.Y. Lee, Y.J. Chang, N.C. Chang, F.Y. Lin, and C.S. Tsai

Subjects
Medicine
Abstract

Thrombomodulin (TM) is expressed on the surface of monocyte, which is important in the regulation of cell migration, proliferation, and inflammatory responses. In a previous study, we demonstrated that TM on monocyte is negatively associated with cell migration. However, the mechanisms involved in this process are unclear, therefore, we explored the mechanisms in this study. Chemotactic assays and immunofluorescence showed that TM siRNA increased the Chemotaxis of the IL-6-activated THP-1, and aggravated actin assembly relative to the IL-6-treated control. In contrast, cells overexpressing plasmids containing full-length or domain 5 of TM followed by IL-6 treatment displayed lower Chemotaxis and less actin assembly. Western blot analysis showed that TM knockdown markedly increased cytoskeleton components cofilin and LIMK1 phosphorylation in IL-6-treated THP-1, whereas, transfected cells with HA-TM FL or HA-TM D5, but not HA-TM Dl-3 plasmids, reversed the effects. Activation of ERK1/2 and JNK/SAPK, upstream regulators of cytoskeleton components, were also inhibited in overexpressed group. Immunoprecipitation assay demonstrated that actin interacts with TM and intersectin1 in THP-1. Decreased interaction between intersectin1 and actin in TM knockdowns suggested that the interaction is mediated by TM. Our findings indicate that TM domain 5 is a negative regulator and seems to have the ability to inhibit paxillin, cofilin, LIMK1, and actin activation. The mechanisms for the repression effect of domain 5 may be mediated by inhibition of the ERK1/2 and JNK/SAPK activation. Expression of domain 5 of TM may represent a promising approach for controlling monocyte migration, and TM may have potential applications in treatment of inflammatory diseases.

Published
2014
Full Text
View/download PDF

9. Thrombomodulin Gene Polymorphism (C1418T) is Associated with the Development of Coronary Allograft Vasculopathy

Author

C.S. Tsai, Y.W. Lin, C.C. Shih, Y.H. Chen, C.Y. Lin, Y.T. Tsai, C.Y. Lee, C.M. Shih, C.Y. Huang, H.H. Chung, and F.Y. Lin

Subjects
Medicine
Abstract

Thrombomodulin (TM) is the endothelial cell membrane-bound anticoagulant protein cofactor in the thrombin-mediated activation of protein C. Previous evidence has been reported regarding the association between TM polymorphisms and coronary artery disease. Allograft rejection-mediated vasculopathy is the main cause of death at more than one year after heart transplantation. However, whether TM polymorphism is associated with allograft rejection is still unclear. We analyzed the TM gene polymorphism C1418T using allele-specific primers in a PCR assay in 60 patients who underwent heart transplantation. The retrospective clinical data were collected and tested for any correlations with the TM gene polymorphism. We separated the patients into 2 groups according to their TM genotype (group 1: CC genotype; group 2: CT or TT genotype). Additionally, we generated expression constructs (TM full length-C1418 and TM full length-T1418) and performed in vitro studies to explore the correlation between the TM C1418T polymorphism and the migration of smooth muscle progenitor cells and monocytes, which may be involved in the development of vasculopathy. The results showed that the levels of CD68, C4d, PAS, and Masson staining in the CT/TT genotype group increased at year 1 and continued to increase throughout the 3 years. These levels were higher than those observed in the CC genotype group. The ISHLT-WF2004 grade of the CT/TT genotype group was significantly different from that of the CC genotype group at the same time point post-transplantation. The coronary allograft vasculopathy (CAV) score was significantly different between the CC and CT/TT genotype groups at 1 and 3 years post-transplantation. Our in vitro studies demonstrate that both smooth muscle progenitor cells and monocytic THP-1 cells with either the CT-1418 or the TT-1418 TM genotype have higher migratory abilities than cells with the CC-1418 genotype. Our results support a significant association between the TM C1418T polymorphism and the development of CAV after heart transplantation in the short- to medium-term.

Published
2013
Full Text
View/download PDF

11. Supplementary Figure 3 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Author

Calvin D. Roskelley, Michael R. Gold, Donna-Marie McCafferty, Paul Kubes, Brandie Millen-Martin, Crystal C.Y. Lee, Pamela Austin, Janet Dukowski, Sarah J. McLeod, and Spencer A. Freeman

Abstract

Supplementary Figure 3 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Published
2023

12. Supplementary Figure Legends 1-6 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Author

Calvin D. Roskelley, Michael R. Gold, Donna-Marie McCafferty, Paul Kubes, Brandie Millen-Martin, Crystal C.Y. Lee, Pamela Austin, Janet Dukowski, Sarah J. McLeod, and Spencer A. Freeman

Abstract

Supplementary Figure Legends 1-6 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Published
2023

13. Supplementary Figure 1 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Author

Calvin D. Roskelley, Michael R. Gold, Donna-Marie McCafferty, Paul Kubes, Brandie Millen-Martin, Crystal C.Y. Lee, Pamela Austin, Janet Dukowski, Sarah J. McLeod, and Spencer A. Freeman

Abstract

Supplementary Figure 1 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Published
2023

14. Supplementary Figure 5 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Author

Calvin D. Roskelley, Michael R. Gold, Donna-Marie McCafferty, Paul Kubes, Brandie Millen-Martin, Crystal C.Y. Lee, Pamela Austin, Janet Dukowski, Sarah J. McLeod, and Spencer A. Freeman

Abstract

Supplementary Figure 5 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Published
2023

15. Supplementary Figure 4 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Author

Calvin D. Roskelley, Michael R. Gold, Donna-Marie McCafferty, Paul Kubes, Brandie Millen-Martin, Crystal C.Y. Lee, Pamela Austin, Janet Dukowski, Sarah J. McLeod, and Spencer A. Freeman

Abstract

Supplementary Figure 4 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Published
2023

16. Supplementary Figure 2 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Author

Calvin D. Roskelley, Michael R. Gold, Donna-Marie McCafferty, Paul Kubes, Brandie Millen-Martin, Crystal C.Y. Lee, Pamela Austin, Janet Dukowski, Sarah J. McLeod, and Spencer A. Freeman

Abstract

Supplementary Figure 2 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Published
2023

17. Supplementary Figure 6 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Author

Calvin D. Roskelley, Michael R. Gold, Donna-Marie McCafferty, Paul Kubes, Brandie Millen-Martin, Crystal C.Y. Lee, Pamela Austin, Janet Dukowski, Sarah J. McLeod, and Spencer A. Freeman

Abstract

Supplementary Figure 6 from Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs

Published
2023

18. List of Contributors

Author

Els Acke, Christopher B. Adolph, Maria Afonso, Kelly E. Allen, Boaz Arzi, Ingrid Balsa, Gad Baneth, Renee Barber, Emi N. Barker, Vanessa R. Barrs, Julia A. Beatty, Mikael Berg, Adam J. Birkenheuer, Byron L. Blagburn, Ross Bond, Dwight D. Bowman, Edward B. Breitschwerdt, Canio Buonavoglia, Brandy A. Burgess, Jamie M. Burkitt Creedon, Barbara A. Byrne, Margret L. Casal, Victoria J. Chalker, Bruno B. Chomel, Leah A. Cohn, Lynette K. Cole, Stephen D. Cole, Gary A. Conboy, Roberto Cortinas, Kimberly Coyner, William T.N. Culp, Joshua B. Daniels, Autumn P. Davidson, Jonathan D. Dear, Nicola Decaro, Amy E. DeClue, Dubraska Diaz-Campos, Pedro Paulo V.P. Diniz, Jitender P. Dubey, Edward J. Dubovi, Chrissy Eckstrand, John A. Ellis, David A. Elsemore, Steven E. Epstein, James F. Evermann, Janet E. Foley, Urs Giger, Ellie J.C. Goldstein, Jennifer Granick, Isabella D.F. Gremião, Amy M. Grooters, Danièlle A. Gunn-Moore, Lynn Guptill, Sarah A. Hamer, Shimon Harrus, Katrin Hartmann, Diana Henke, Emir Hodzic, Regina Hofmann-Lehmann, Elizabeth W. Howerth, Karin Hultin Jäderlund, Kate F. Hurley, Linda S. Jacobson, Jonas Johansson Wensman, Amy S. Kapatkin, Marc Kent, Jennifer K. Ketzis, Linda Kidd, Stacy Kraus, Mark Krockenberger, Michael R. Lappin, Alice C.Y. Lee, Tekla Lee-Fowler, Susan E. Little, Meryl P. Littman, Remo Lobetti, Araceli Lucio-Forster, Jennifer A. Luff, Hans Lutz, Mary Marcondes, Stanley L. Marks, Sina Marsilio, Patrick L. McDonough, Rodrigo C. Menezes, Lindsay Merkel, W. Zach Mills, Luisa H.M. Miranda, George E. Moore, Karen A. Moriello, Alyssa C. Mourning, John S. Munday, Mathios E. Mylonakis, Yoko Nagamori, C. Thomas Nelson, Anne B. Nordstoga, Jacqueline M. Norris, Carolyn R. O’Brien, Conor O’Halloran, Cynthia M. Otto, Mark G. Papich, Colin R. Parrish, Niels C. Pedersen, Andrew S. Peregrine, Sandro A. Pereira, Christine Petersen, John F. Prescott, Simon L. Priestnall, Barbara Qurollo, Alan Radford, Shelley C. Rankin, Krystle L. Reagan, Mason V. Reichard, Carol Reinero, Meriam N. Saleh, Sarah G.H. Sapp, Ashley B. Saunders, Tânia M.P. Schubach, Simone Schuller, Valeria Scorza, Rance K. Sellon, Claire R. Sharp, Deborah Silverstein, Ameet Singh, Virginia Sinnott-Stutzman, Karen F. Snowden, Laia Solano-Gallego, Miranda Spindel, Lindsay A. Starkey, Joshua A. Stern, Jean Stiles, Reinhard K. Straubinger, Jason W. Stull, Jane E. Sykes, Séverine Tasker, Jennifer E. Thomas, Sara M. Thomasy, Andrea Tipold, M. Katherine Tolbert, Thomas W. Vahlenkamp, Marc Vandevelde, Nancy Vincent-Johnson, Polina Vishkautsan, Trevor Waner, J. Scott Weese, Jodi L. Westropp, Stephen D. White, Jenessa A. Winston, Judit M. Wulcan, and Michael J. Yabsley

Published
2023

19. Nonlinear MHD modeling of n = 1 RMP-induced pedestal transport and mode coupling effects on ELM suppression in KSTAR

Author

S.K. Kim, S. Pamela, N.C. Logan, Y.-S. Na, C.Y. Lee, J.-K. Park, S.M. Yang, Q. Hu, M. Becoulet, G. Huijsmans, M. Hoelzl, Y. In, M.W. Kim, H.H. Lee, J. Lee, J.H. Lee, O. Kwon, E. Kolemen, null the JOREK Team, Science and Technology of Nuclear Fusion, EIRES Eng. for Sustainable Energy Systems, Magneto-Hydro-Dynamic Stability of Fusion Plasmas, and JOREK Team

Subjects
neoclassical toroidal viscosity, Nuclear and High Energy Physics, KSTAR, nonlinear MHD, peeling ballooning mode, RMP, mode coupling, Condensed Matter Physics, edge localized mode
Abstract

Fully suppressing edge-localized modes (ELMs), e.g., with resonant magnetic perturbations (RMPs), is essential to reach and sustain high-performance steady-state H-mode plasmas because large ELMs can significantly reduce the lifetime of divertor components in future tokamak reactors. RMP-driven ELM suppression in KSTAR has been modeled by coupling the neoclassical transport code PENTRC to the nonlinear 3D MHD code JOREK. We have found that the radial transport from the combined effects of the kink-peeling, tearing response, and neoclassical toroidal viscosity can explain the pedestal degradation observed in experiments. In addition, it has been found that the RMP response can increase the inter-ELM heat flux on the lower outer divertor by redistributing the heat transport between the divertor plates. In addition to the degraded pedestal, ELM suppression is also attributable to the RMP-induced mode interactions. While the linear stability of peeling-ballooning mode (PBMs) improves owing to the degraded pedestal, the PBM and RMP interaction increases the spectral transfer between edge harmonics, preventing catastrophic growth and the crash of unstable modes. Here, it turns out that the magnetic islands near the pedestal top can play a vital role in mediating the mode interactions.

Published
2022

20. A practical methodology to improve the dosimetric accuracy of MR-based radiotherapy simulation for brain tumors

Author

Annie M. Tang, Jeffrey C.F. Lui, Kam-Hung Wong, Francis Kar-ho Lee, Jeffrey Chiu, Chi Ching Law, and Jonan C.Y. Lee

Subjects
medicine.medical_treatment, Biophysics, General Physics and Astronomy, Computed tomography, Dose distribution, computer.software_genre, Voxel, Planning study, medicine, Humans, Radiology, Nuclear Medicine and imaging, Radiation treatment planning, medicine.diagnostic_test, Brain Neoplasms, business.industry, Radiotherapy Planning, Computer-Assisted, Significant difference, Radiotherapy Dosage, General Medicine, Magnetic Resonance Imaging, Volumetric modulated arc therapy, Radiation therapy, Radiotherapy, Intensity-Modulated, business, Nuclear medicine, therapeutics, computer
Abstract

Purpose To investigate the dosimetric accuracy of synthetic computed tomography (sCT) images generated by a clinically-ready voxel-based MRI simulation package, and to develop a simple and feasible method to improve the accuracy. Methods 20 patients with brain tumor were selected to undergo CT and MRI simulation. sCT images were generated by a clinical MRI simulation package. The discrepancy between planning CT and sCT in CT number and body contour were evaluated. To resolve the discrepancies, an sCT specific CT-relative electron density (RED) calibration curve was used, and a layer of pseudo-skin was created on the sCT. The dosimetric impact of these discrepancies, and the improvement brought about by the modifications, were evaluated by a planning study. Volumetric modulated arc therapy (VMAT) treatment plans for each patient were created and optimized on the planning CT, which were then transferred to the original sCT and the modified-sCT for dose re-calculation. Dosimetric comparisons and gamma analysis between the calculated doses in different images were performed. Results The average gamma passing rate with 1%/1 mm criteria was only 70.8% for the comparison of dose distribution between planning CT and original sCT. The mean dose difference between the planning CT and the original sCT were −1.2% for PTV D95 and −1.7% for PTV Dmax, while the mean dose difference was within 0.7 Gy for all relevant OARs. After applying the modifications on the sCT, the average gamma passing rate was increased to 92.2%. Mean dose difference in PTV D95 and Dmax were reduced to −0.1% and −0.3% respectively. The mean dose difference was within 0.2 Gy for all OAR structures and no statistically significant difference were found. Conclusions The modified-sCT demonstrated improved dosimetric agreement with the planning CT. These results indicated the overall dosimetric accuracy and practicality of this improved MR-based treatment planning method.

Published
2021

21. HNRNPH1 regulates the neuroprotective cold-shock protein RBM3 expression through poison exon exclusion

Author

Julie Qiaojin Lin, Deepak Khuperkar, Sofia Pavlou, Stanislaw Makarchuk, Nikolaos Patikas, Flora C.Y. Lee, Jianning Kang, Sarah F. Field, Julia M. Zbiegly, Joshua L. Freeman, Jernej Ule, Emmanouil Metzakopian, Marc-David Ruepp, and Giovanna R. Mallucci

Abstract

SummaryEnhanced expression of the cold-shock protein RNA binding motif 3 (RBM3) is highly neuroprotective bothin vitroandin vivo. Whilst upstream signalling pathways leading to RBM3 expression have been described, the precise molecular mechanism of RBM3 induction during cooling remains elusive. To identify temperature-dependent modulators of RBM3, we performed a genome-wide CRISPR-Cas9 knockout screen using RBM3-reporter human iPSC-derived neurons. We found that RBM3 mRNA and protein levels are robustly regulated by several splicing factors, with heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) being the strongest positive regulator. Splicing analysis revealed that moderate hypothermia significantly represses the inclusion of a poison exon, which, when retained, targets the mRNA for nonsense-mediated decay. Importantly, we show that HNRNPH1 mediates this cold-dependent exon skipping via its interaction with a G-rich motif within the poison exon. Our study provides novel mechanistic insights into the regulation of RBM3 and provides further targets for neuroprotective therapeutic strategies.Graphical Abstract

Published
2022

23. Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening

Author

Shilpi Arora, Anna Kohlmann, Christopher D. Hupp, Julie Liu, Christelle Huguet, Allison Olszewski, Moritz von Rechenberg, John W. Cuozzo, Ying Zhang, Katy E Georgiadis, Matthew A. Clark, Esther C.Y. Lee, Charles J. Eyermann, Andrew J. McRiner, Paolo A. Centrella, Michael I Monteiro, Anthony D. Keefe, Benjamin Levin, Andrew D. Ferguson, Zooey Wang, and Yanbin Liu

Subjects
Male, Indoles, Crystallography, X-Ray, 01 natural sciences, Chemical library, Small Molecule Libraries, Mice, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Pharmacokinetics, Drug Discovery, Animals, Humans, Structure–activity relationship, Potency, Transaminases, 030304 developmental biology, ADME, 0303 health sciences, Oxidase test, Binding Sites, Chemistry, DNA, Metabolism, 0104 chemical sciences, Molecular Docking Simulation, Alcohol Oxidoreductases, Thiazoles, 010404 medicinal & biomolecular chemistry, Biochemistry, Drug Design, Hyperoxaluria, Primary, Molecular Medicine, Glucuronide, Half-Life
Abstract

Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds 3-6. Compound 5 was further optimized via various structure-activity relationship (SAR) exploration methods to 29, a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound 5 led to the identification of a nonacid inhibitor of HAO1, 31, which has weaker potency and increased permeability.

Published
2021

24. Bispecific Estrogen Receptor α Degraders Incorporating Novel Binders Identified Using DNA-Encoded Chemical Library Screening

Author

Diana Gikunju, John W. Cuozzo, Yelena A Arnautova, Sarah A Talcott, Neil Westlund, Andrew J. McRiner, Anthony D. Keefe, Yan Yu, Christelle Huguet, Moritz von Rechenberg, Fei Zhou, Jennifer M Duffy, Shilpi Arora, Esther C.Y. Lee, Ying Zhang, Benjamin Levin, Matthew A. Clark, Jeremy S. Disch, Junyi Zhang, Yanbin Liu, Anton Kozhushnyan, Betty Chan, Anthony C Lau, Michael I Monteiro, Patrick B. Mullins, and Anna Kohlmann

Subjects
Indoles, Cell Survival, Estrogen receptor, Breast Neoplasms, Chemical library, Small Molecule Libraries, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Cell Line, Tumor, Drug Discovery, Animals, Humans, Structure–activity relationship, Aromatase, biology, Chemistry, DNA-encoded chemical library, Estrogen Antagonists, Estrogen Receptor alpha, DNA, Xenograft Model Antitumor Assays, Small molecule, Kinetics, Biochemistry, Click chemistry, biology.protein, Molecular Medicine, Click Chemistry, Female, Linker, Half-Life
Abstract

Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening ∼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ERα, with PROTACs 18 and 21 inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.

Published
2021

25. Consumer brand engagement in the US–China trade war

Author

Ya-Yun Cheng, Bruce C.Y. Lee, Chiou-Fong Wei, Yi Hsuan Lee, and Yao Chen

Subjects
Trade war, business.industry, Political science, 0502 economics and business, 05 social sciences, 050211 marketing, General Medicine, International trade, business, China, 050203 business & management, Country of origin, Brand engagement
Abstract

PurposeThis study examines whether consumer brand engagement (CBE) can mitigate the negative effects of economic animosity (EA) on purchase intention (PI) and strengthen the positive effect of country-of-origin (COO) on PI.Design/methodology/approachUsing questionnaires distributed to 372 young Chinese adults, the study collected PI data for US products in the Chinese market. Partial least square structural equation modeling was adopted.FindingsThis study found a positive relationship between COO and CBE and a negative relationship between EA and CBE. CBE exhibits a partial mediating effect in the relationship between COO and PI and a full suppression effect on EA toward PI.Research limitations/implicationsThis research is limited to China; future research could extend this framework to the United States.Practical implicationsThis study contributes to relationship marketing knowledge. Furthermore, it provides new tools for multinational corporations to deploy their marketing strategies and avoid negative consequences stemming from the EA effect in the Chinese market following the US–China trade war.Originality/valueThis study is the first to extend COO and EA research to CBE discipline.

Published
2021

26. High frequency of anti-DSG 2 antibodies in post COVID-19 serum samples

Author

Edward C.Y. Lee, Ryan E. Tyler, Derrick Johnson, Natalie Koh, Biauw Chi Ong, Shi Yin Foo, and Jack W.C. Tan

Subjects
Desmoglein 2, Post-Acute COVID-19 Syndrome, COVID-19, Humans, Cardiology and Cardiovascular Medicine, Molecular Biology, Autoantibodies
Abstract

There is growing recognition that COVID-19 does cause cardiac sequelae. The underlying mechanisms involved are still poorly understood to date. Viral infections, including COVID-19, have been hypothesized to contribute to autoimmunity, by exposing previously hidden cryptic epitopes on damaged cells to an activated immune system. Given the high incidence of cardiac involvement seen in COVID-19, our aim was to determine the frequency of anti-DSG2 antibodies in a population of post COVID-19 patients.300 convalescent serum samples were obtained from a group of post COVID-19 infected patients from October 2020 to February 2021. 154 samples were drawn 6 months post-COVID-19 infection and 146 samples were drawn 9 months post COVID infection. 17 samples were obtained from the same patient at the 6- and 9- month mark. An electrochemiluminescent-based immunoassay utilizing the extracellular domain of DSG2 for antibody capture was used. The mean signal intensity of anti-DSG2 antibodies in the post COVID-19 samples was significantly higher than that of a healthy control population (19 ± 83.2 in the post-COVID-19 sample vs. 2.1 ± 7.2 (p 0. 0001) in the negative control healthy population). Of note, 29.3% of the post COVID-19 infection samples demonstrated a signal higher than the 90th percentile of the control population and 8.7% were higher than the median found in ARVC patients. The signal intensity between the 6-month and 9-month samples did not differ significantly.We report for the first time that recovered COVID-19 patients demonstrate significantly higher and sustained levels of anti-DSG2 autoantibodies as compared to a healthy control population, comparable to that of a diagnosed ARVC group.

Published
2022

27. A Liquid Chromatography-Tandem Mass Spectrometry Method for the Analysis of Dehydroepiandrosterone Sulphate (Dheas) in Serum and Plasma with Comparison to an Immunoassay Method in a Neonatal Population

Author

Craig Livie, Louisa C.Y. Lee, Malika Alimussina, Carina Conceicao, Chui Ha Leung, Jane McNeilly, Syed Faisal Ahmed, Charlotte Syme, Karen Smith, and Susan Johnston

Subjects
History, Polymers and Plastics, Clinical Biochemistry, Cell Biology, General Medicine, Business and International Management, Biochemistry, Industrial and Manufacturing Engineering, Analytical Chemistry
Published
2022

29. TDP-43 condensation properties specify its RNA-binding and regulatory repertoire

Author

Hana M. Odeh, Martina Hallegger, Aram G. Amalietti, Bo Lim Lee, Bede Portz, Nicholas M. Luscombe, Klara Kuret, Jack D. Rubien, James Shorter, Frédérique Rau, Nicolas L. Fawzi, Rickie Patani, Ina Huppertz, Jernej Ule, Katie E. Copley, Anob M. Chakrabarti, and Flora C.Y. Lee

Subjects
amyotrophic lateral sclerosis, TDP-43, RNA-binding protein, kemija, Gene Expression, 0302 clinical medicine, Ecology,Evolution & Ethology, Homeostasis, 3' Untranslated Regions, Sequence Deletion, 0303 health sciences, Stem Cells, alternative polyadenylation, RNA granules, RNA-Binding Proteins, multivalency, intrinsically disordered region, Cell biology, DNA-Binding Proteins, ICLIP, Genetics & Genomics, Protein Binding, iCLIP, Context (language use), Biology, Biochemistry & Proteomics, General Biochemistry, Genetics and Molecular Biology, Phase Transition, Article, 03 medical and health sciences, udc:5, Homomeric, Humans, Point Mutation, RNA, Messenger, Nucleotide Motifs, 030304 developmental biology, Computational & Systems Biology, Cell Nucleus, Messenger RNA, Base Sequence, FOS: Clinical medicine, Condensation, Neurosciences, RNA, Cell Biology, Tumour Biology, condensation, HEK293 Cells, RNA-binding protei, Mutation, Protein Multimerization, phase separation, Poly A, 030217 neurology & neurosurgery, Function (biology), HeLa Cells
Abstract

Summary Mutations causing amyotrophic lateral sclerosis (ALS) often affect the condensation properties of RNA-binding proteins (RBPs). However, the role of RBP condensation in the specificity and function of protein-RNA complexes remains unclear. We created a series of TDP-43 C-terminal domain (CTD) variants that exhibited a gradient of low to high condensation propensity, as observed in vitro and by nuclear mobility and foci formation. Notably, a capacity for condensation was required for efficient TDP-43 assembly on subsets of RNA-binding regions, which contain unusually long clusters of motifs of characteristic types and density. These “binding-region condensates” are promoted by homomeric CTD-driven interactions and required for efficient regulation of a subset of bound transcripts, including autoregulation of TDP-43 mRNA. We establish that RBP condensation can occur in a binding-region-specific manner to selectively modulate transcriptome-wide RNA regulation, which has implications for remodeling RNA networks in the context of signaling, disease, and evolution., Graphical abstract, Highlights • TDP-43 mutants affect condensation properties to a similar extent at multiple scales • Binding-region condensates form on long RNA regions with dispersed UG-rich motifs • RBPchimera-CLIP indicates homomeric interactions promote molecular-scale condensates • Condensation selectively tunes the regulatory capacity of TDP-43; e.g., autoregulation, The condensation propensity of an RNA-binding protein tunes its binding to specific RNA regions across the transcriptome and affects its RNA processing functions. Formation of these “binding-region condensates,” promoted by specific motif types that are dispersed across long RNA regions, expands the ways in which RNA binding can be selectively controlled beyond canonical RNA-binding domains.

Published
2021

30. An improved iCLIP protocol

Author

Heike Hänel, Christopher R. Sibley, Martina Hallegger, Martin R Turner, Patrick Toolan-Kerr, Christoph Sadee, Federica Capraro, Julian König, Cristina Militti, Flora C.Y. Lee, Elisa Monzón-Casanova, Anob M. Chakrabarti, Oscar G. Wilkins, and Jernej Ule

Subjects
Exon, Immunoprecipitation, Computer science, cDNA library, RNA, RNA-binding protein, Computational biology, PTBP1, Binding site, ICLIP
Abstract

Crosslinking and Immunoprecipitation (CLIP) is a powerful technique to obtain transcriptome-wide maps of in vivo protein-RNA interactions, which are important to understand the post-transcriptional mechanisms mediated by RNA binding proteins (RBPs). Many variant CLIP protocols have been developed to improve the efficiency and convenience of cDNA library preparation. Here we describe an improved individual nucleotide resolution CLIP protocol (iiCLIP), which can be completed within 4 days from UV crosslinking to libraries for sequencing. For benchmarking, we directly compared PTBP1 iiCLIP libraries with the iCLIP2 protocol produced under standardised conditions, and with public eCLIP and iCLIP PTBP1 data. We visualised enriched motifs surrounding the identified crosslink positions and RNA maps of these crosslinks around the alternative exons regulated by PTBP1. Notably, motif enrichment was higher in iiCLIP and iCLIP2 in comparison to public eCLIP and iCLIP, and we show how this impacts the specificity of RNA maps. In conclusion, iiCLIP is technically convenient and efficient, and enables production of highly specific datasets for identifying RBP binding sites.

Published
2021

31. Discovery and evaluation of non-basic small molecule modulators of the atypical chemokine receptor CXCR7

Author

Chris Limberakis, Allyn T. Londregan, Steven B. Coffey, Gary Erik Aspnes, Janice A. Brown, Kevin D. Hesp, Rhys M. Jones, Elnaz Menhaji-Klotz, Esther C.Y. Lee, and Markus Boehm

Subjects
Male, Models, Molecular, Clinical Biochemistry, Pharmaceutical Science, Computational biology, Biochemistry, Chemokine receptor, Mice, Structure-Activity Relationship, Drug Delivery Systems, In vivo, Drug Discovery, Animals, Immunologic Factors, Molecular Biology, Receptors, CXCR, Molecular Structure, Chemistry, Organic Chemistry, Small molecule, Mice, Inbred C57BL, Drug Design, Lipophilicity, Molecular Medicine, Immunological diseases, Signal Transduction
Abstract

The atypical chemokine receptor C-X-C chemokine receptor type 7 (CXCR7) is an attractive therapeutic target for a variety of cardiac and immunological diseases. As a strategy to mitigate known risks associated with the development of higher molecular weight, basic compounds, a series of pyrrolidinyl-azolopyrazines were identified as promising small-molecule CXCR7 modulators. Using a highly enabled parallel medicinal chemistry strategy, structure-activity relationship studies geared towards a reduction in lipophilicity and incorporation of saturated heterocycles led to the identification of representative tool compound 20. Notably, compound 20 maintained good potency against CXCR7 with a suitable balance of physicochemical properties to support in vivo pharmacokinetic studies.

Published
2021

34. Development of an operation trajectory design algorithm for control of multiple 0D parameters using deep reinforcement learning in KSTAR

Author

J. Seo, Y.-S. Na, B. Kim, C.Y. Lee, M.S. Park, S.J. Park, and Y.H. Lee

Subjects
Nuclear and High Energy Physics, Condensed Matter Physics
Abstract

This work develops an artificially intelligent (AI) tokamak operation design algorithm that provides an adequate operation trajectory to control multiple plasma parameters simultaneously into different targets. An AI is trained with the reinforcement learning technique in the data-driven tokamak simulator, searching for the best action policy to get a higher reward. By setting the reward function to increase as the achieved β p, q 95, and l i are close to the given target values, the AI tries to properly determine the plasma current and boundary shape to reach the given targets. After training the AI with various targets and conditions in the simulation environment, we demonstrated that we could successfully achieve the target plasma states with the AI-designed operation trajectory in a real KSTAR experiment. The developed algorithm would replace the human task of searching for an operation setting for given objectives, provide clues for developing advanced operation scenarios, and serve as a basis for the autonomous operation of a fusion reactor.

Published
2022

35. Sonoporation of Immune Cells: Heterogeneous Impact on Lymphocytes, Monocytes and Granulocytes

Author

Xinxing Duan, Shun Yu Lo, Jetty C.Y. Lee, Jennifer M.F. Wan, and Alfred C.H. Yu

Subjects
Sonication, Microbubbles, Acoustics and Ultrasonics, Radiological and Ultrasound Technology, Biophysics, Radiology, Nuclear Medicine and imaging, Lymphocytes, Monocytes, Granulocytes
Abstract

Microbubble-mediated ultrasound (MB-US) can be used to realize sonoporation and, in turn, facilitate the transfection of leukocytes in the immune system. Nevertheless, the bio-effects that can be induced by MB-US exposure on leukocytes have not been adequately studied, particularly for different leukocyte lineage subsets with distinct cytological characteristics. Here, we describe how that same set of MB-US exposure conditions would induce heterogeneous bio-effects on the three main leukocyte subsets: lymphocytes, monocytes and granulocytes. MB-US exposure was delivered by applying 1-MHz pulsed ultrasound (0.50-MPa peak negative pressure, 10% duty cycle, 30-s exposure period) in the presence of microbubbles (1:1 cell-to-bubble ratio); sonoporated and non-viable leukocytes were respectively labeled using calcein and propidium iodide. Flow cytometry was then performed to classify leukocytes into their corresponding subsets and to analyze each subset's post-exposure viability, sonoporation rate, uptake characteristics and morphology. Results revealed that, when subjected to MB-US exposure, granulocytes experienced the highest loss of viability (64.0 ± 11.0%) and the lowest sonoporation rate (6.3 ± 2.5%), despite maintaining their size and granularity. In contrast, lymphocytes exhibited the lowest loss of viability (20.9 ± 7.0%), while monocytes had the highest sonoporation rate (24.1 ± 13.6%). For these two sonoporated leukocyte subsets, their cell size and granularity were found to be reduced. Also, they exhibited graded levels of calcein uptake, whereas sonoporated granulocytes achieved only mild calcein uptake. These heterogeneous bio-effects should be accounted for when using MB-US and sonoporation in immunomodulation applications.

Published
2021

36. Common ALS/FTD risk variants in UNC13A exacerbate its cryptic splicing and loss upon TDP-43 mislocalization

Author

Tammaryn Lashley, Maria Secrier, Giampietro Schiavo, Pietro Fratta, Hemali Phatnani, Flora C.Y. Lee, Sam Byrce-Smith, Anna-Leigh Brown, Matthew Keuss, Yue Qi, Laura Masino, Sarah C. Hill, Ariana Gatt, Alexander Bampton, Towfique Raj, Michael E. Ward, Elizabeth M. C. Fisher, Jernej Ule, Emanuele Buratti, Jack Humphrey, Oscar G. Wilkins, Weaverly Colleen Lee, and Matteo Zanovello

Subjects
Genetics, Mechanism (biology), Intron, nutritional and metabolic diseases, Disease, Biology, medicine.disease, nervous system diseases, mental disorders, medicine, Cryptic splicing, Amyotrophic lateral sclerosis, Gene, Function (biology), Frontotemporal dementia
Abstract

Variants within the UNC13A gene have long been known to increase risk of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43. Here, we show that TDP-43 depletion induces robust inclusion of a cryptic exon (CE) within UNC13A, a critical synaptic gene, resulting in nonsense-mediated decay and protein loss. Strikingly, two common polymorphisms strongly associated with ALS/FTD risk directly alter TDP-43 binding within the CE or downstream intron, increasing CE inclusion in cultured cells and in patient brains. Our findings, which are the first to demonstrate a genetic link specifically between loss of TDP-43 nuclear function and disease, reveal both the mechanism by which UNC13A variants exacerbate the effects of decreased nuclear TDP-43 function, and provide a promising therapeutic target for TDP-43 proteinopathies. One-Sentence Summary Shared ALS/FTD risk variants increase the sensitivity of a cryptic exon in the synaptic gene UNC13A to TDP-43 depletion.

Published
2021

37. The analysis of Taiwan emergency physician’s core competencies base on the ACGME idea

Author

Kuo-Fang Hsu, Ping-Lung Huang, Tian-Shyug Lee, and Bruce C.Y. Lee

Abstract

The development of the core competence of physicians is related to the practice of medical quality. As the most important field for cultivating the core competence of physicians, how to achieve the construction and evaluation of core competence is an important issue for medical education and management. This study uses the large core competence framework proposed by the ACGME (Accreditation Council for Graduate Medical Education), and use Fuzzy AHP (FAHP) and DEMANTEL method to analyze the weight and priority, and the cause and effect cluster. Study result shows that the FAHP’s importance factor ranking is (1).patient care (C1) (27.83%), (2).medical knowledge (C2) (20.77%), (3).professionalism (C5) (17.93%), (4). Interpersonal and communication skills (C4) (17.41%), (5). practice-based learning and improvement (C3) (15.52%), and (6). systems-based practice (C6) (8.233%). In terms of DEMANTEL, the effect cluster include Patient Care (C1), Professionalism (C5) and Systems-based practice (C6), and the cause cluster includes Medical Knowledge (C2), Practice-based learning and improvement (C3) and Interpersonal and Communication skills (C4). According to finding, the patient care (C1) is the result of attitude, patience, and other five ACGME Core Competence Items. Therefore, the development of emergency physicians’ also needs humanities and ethics training and practice to follows the practice-based learning (C3). This study demonstrates to show on importance factor in emergency physician’s core competencies cultivate. Furthermore, the current findings can serve as a reference for future research in the other specialists physicians cultivate.

Published
2021

38. RGS4 RNA secondary structure mediates staufen2 RNP assembly in neurons

Author

Rico Schieweck, Sandra M. Fernández-Moya, Flora C.Y. Lee, Janina Ehses, Max Harner, Karl E. Bauer, Nicholas M. Luscombe, Michael A. Kiebler, Christin Illig, Jernej Ule, and Anob M. Chakrabarti

Subjects
Untranslated region, RNA localization, QH301-705.5, RNA-binding protein, Gene Expression, Biochemistry & Proteomics, Staufen2, neuronal RNA granule, RNP assembly, in vivo RNA binding, Catalysis, Article, Nucleic acid secondary structure, Inorganic Chemistry, Turn (biochemistry), RGS4, 03 medical and health sciences, 0302 clinical medicine, Ecology,Evolution & Ethology, Physical and Theoretical Chemistry, Biology (General), Molecular Biology, QD1-999, Spectroscopy, 030304 developmental biology, Computational & Systems Biology, 0303 health sciences, biology, Chemistry, FOS: Clinical medicine, Stem Cells, Organic Chemistry, Neurosciences, RNA, Translation (biology), General Medicine, Tumour Biology, Computer Science Applications, Cell biology, biology.protein, Genetics & Genomics, 030217 neurology & neurosurgery
Abstract

RNA-binding proteins (RBPs) act as posttranscriptional regulators controlling the fate of target mRNAs. Unraveling how RNAs are recognized by RBPs and in turn are assembled into neuronal RNA granules is therefore key to understanding the underlying mechanism. While RNA sequence elements have been extensively characterized, the functional impact of RNA secondary structures is only recently being explored. Here, we show that Staufen2 binds complex, long-ranged RNA hairpins in the 3′-untranslated region (UTR) of its targets. These structures are involved in the assembly of Staufen2 into RNA granules. Furthermore, we provide direct evidence that a defined Rgs4 RNA duplex regulates Staufen2-dependent RNA localization to distal dendrites. Importantly, disrupting the RNA hairpin impairs the observed effects. Finally, we show that these secondary structures differently affect protein expression in neurons. In conclusion, our data reveal the importance of RNA secondary structure in regulating RNA granule assembly, localization and eventually translation. It is therefore tempting to speculate that secondary structures represent an important code for cells to control the intracellular fate of their mRNAs.

Published
2021
Full Text
View/download PDF

39. Hookworms

Author

Dwight D. Bowman, Araceli Lucio-Forster, and Alice C.Y. Lee

Published
2021

40. TDP-43 condensation properties specify its RNA-binding and regulatory repertoire

Author

Martina, Hallegger, Anob M., Chakrabarti, Flora C.Y., Lee, Bo Lim, Lee, Aram G., Amalietti, Hana M., Odeh, Katie E., Copley, Jack D., Rubien, Bede, Portz, Klara, Kuret, Ina, Huppertz, Frédérique, Rau, Rickie, Patani, Nicolas L., Fawzi, James, Shorter, Nicholas M., Luscombe, Jernej, Ule, Martina, Hallegger, Anob M., Chakrabarti, Flora C.Y., Lee, Bo Lim, Lee, Aram G., Amalietti, Hana M., Odeh, Katie E., Copley, Jack D., Rubien, Bede, Portz, Klara, Kuret, Ina, Huppertz, Frédérique, Rau, Rickie, Patani, Nicolas L., Fawzi, James, Shorter, Nicholas M., Luscombe, and Jernej, Ule

Abstract

Mutations causing amyotrophic lateral sclerosis (ALS) often affect the condensation properties of RNA-binding proteins (RBPs). However, the role of RBP condensation in the specificity and function of protein-RNA complexes remains unclear. We created a series of TDP-43 C-terminal domain (CTD) variants that exhibited a gradient of low to high condensation propensity, as observed in vitro and by nuclear mobility and foci formation. Notably, a capacity for condensation was required for efficient TDP-43 assembly on subsets of RNA-binding regions, which contain unusually long clusters of motifs of characteristic types and density. These “binding-region condensates” are promoted by homomeric CTD-driven interactions and required for efficient regulation of a subset of bound transcripts, including autoregulation of TDP-43 mRNA. We establish that RBP condensation can occur in a binding-region-specific manner to selectively modulate transcriptome-wide RNA regulation, which has implications for remodeling RNA networks in the context of signaling, disease, and evolution., source:https://www.sciencedirect.com/science/article/pii/S0092867421008771

Published
2021

41. Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Author

Götz Thomalla, Florent Boutitie, Henry Ma, Masatoshi Koga, Peter Ringleb, Lee H Schwamm, Ona Wu, Martin Bendszus, Christopher F Bladin, Bruce C V Campbell, Bastian Cheng, Leonid Churilov, Martin Ebinger, Matthias Endres, Jochen B Fiebach, Mayumi Fukuda-Doi, Manabu Inoue, Timothy J Kleinig, Lawrence L Latour, Robin Lemmens, Christopher R Levi, Didier Leys, Kaori Miwa, Carlos A Molina, Keith W Muir, Norbert Nighoghossian, Mark W Parsons, Salvador Pedraza, Peter D Schellinger, Stefan Schwab, Claus Z Simonsen, Shlee S Song, Vincent Thijs, Danilo Toni, Chung Y Hsu, Nils Wahlgren, Haruko Yamamoto, Nawaf Yassi, Sohei Yoshimura, Steven Warach, Werner Hacke, Kazunori Toyoda, Geoffrey A Donnan, Stephen M Davis, Christian Gerloff, Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L. Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bharath Cheripelli, Tae-Hee Cho, Chi-un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B. Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M. Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K. Mueller, Keith W. Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H. Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H. Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z. Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Keizo Yasui, Toshiro Yonehara, Shinichi Yoshimura, K. Aarnio, F. Alemseged, C. Anderson, T. Ang, M.L. Archer, J. Attia, P. Bailey, A. Balabanski, A. Barber, P.A. Barber, J. Bernhardt, A. Bivard, D. Blacker, C.F. Bladin, A. Brodtmann, D. Cadilhac, B.C.V. Campbell, L. Carey, S. Celestino, L. Chan, W.H. Chang, A. ChangI, C.H. Chen, C.-I. Chen, H.F. Chen, T.C. Chen, W.H. Chen, Y.Y. Chen, C.A. Cheng, E. Cheong, Y.W. Chiou, P.M. Choi, H.J. Chu, C.S. Chuang, T.C. Chung, L. Churilov, B. Clissold, A. Connelly, S. Coote, B. Coulton, E. Cowley, J. Cranefield, S. Curtze, C. D'Este, S.M. Davis, S. Day, P.M. Desmond, H.M. Dewey, C. Ding, G.A. Donnan, R. Drew, S. Eirola, D. Field, T. Frost, C. Garcia-Esperon, K. George, R. Gerraty, R. Grimley, Y.C. Guo, G. Hankey, J. Harvey, S.C. Ho, K. Hogan, D. Howells, P.M. Hsiao, C.H. Hsu, C.T. Hsu, C.-S. Hsu, J.P. Hsu, Y.D. Hsu, Y.T. Hsu, C.J. Hu, C.C. Huang, H.Y. Huang, M.Y. Huang, S.C. Huang, W.S. Huang, D. Jackson, J.S. Jeng, S.K. Jiang, L. Kaauwai, O. Kasari, J. King, T.J. Kleinig, M. Koivu, J. Kolbe, M. Krause, C.W. Kuan, W.L. Kung, C. Kyndt, C.L. Lau, A. Lee, C.Y. Lee, J.T. Lee, Y. Lee, Y.C. Lee, C. Levi, C.R. Levi, L.M. Lien, J.C. Lim, C.C. Lin, C.H. Lin, C.M. Lin, D. Lin, C.H. Liu, J. Liu, Y.C. Lo, P.S. Loh, E. Low, C.H. Lu, C.J. Lu, M.K. Lu, J. Ly, H. Ma, L. Macaulay, R. Macdonnell, E. Mackey, M. Macleod, J. Mahadevan, V. Maxwell, R. McCoy, A. McDonald, S. McModie, A. Meretoja, S. Mishra, P.J. Mitchell, F. Miteff, A. Moore, C. Muller, F. Ng, F.C. Ng, J-L. Ng, W. O'Brian, V. O'Collins, T.J. Oxley, M.W. Parsons, S. Patel, G.S. Peng, L. Pesavento, T. Phan, E. Rodrigues, Z. Ross, A. Sabet, M. Sallaberger, P. Salvaris, D. Shah, G. Sharma, G. Sibolt, M. Simpson, S. Singhal, B. Snow, N. Spratt, R. Stark, J. Sturm, M.C. Sun, Y. Sun, P.S. Sung, Y.F. Sung, M. Suzuki, M. Tan, S.C. Tang, T. Tatlisumak, V. Thijs, M. Tiainen, C.H. Tsai, C.K. Tsai, C.L. Tsai, H.T. Tsai, L.K. Tsai, C.H. Tseng, L.T. Tseng, J. Tsoleridis, H. Tu, H.T-H. Tu, W. Vallat, J. Virta, W.C. Wang, Y.T. Wang, M. Waters, L. Weir, T. Wijeratne, C. Williams, W. Wilson, A.A. Wong, K. Wong, T.Y. Wu, Y.H. Wu, B. Yan, F.C. Yang, Y.W. Yang, N. Yassi, H.L. Yeh, J.H. Yeh, S.J. Yeh, C.H. Yen, D. Young, C.L. Ysai, W.W. Zhang, H. Zhao, L. Zhao, Katharina Althaus-Knaurer, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A. Dixit, Geoffrey Donnan, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R. Lees, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Peter Schellinger, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Rüdiger von Kummer, Joanna Wardlaw, Rebecca A. Betensky, Gregoire Boulouis, Raphael A. Carandang, William A. Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L. Ford, John Hallenbeck, Gordon J. Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Michael H. Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H. Schwamm, Eric Searls, Shlee S. Song, Sidney Starkman, Albert J. Yoo, Ramin Zand, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Monash University [Melbourne], National Cerebral and Cardiovascular Center (NCCC - OSAKA), Osaka University [Osaka], University of Heidelberg, Medical Faculty, Massachusetts General Hospital [Boston], University of Melbourne, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Royal Adelaide Hospital [Adelaide Australia], National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Flanders Make [Leuven], Flanders Make, University of Newcastle [Australia] (UoN), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Vall d'Hebron University Hospital [Barcelona], University of Glasgow, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Girona Biomedical Research Institute [Girona, Spain] (IDIBGI), Ruhr-Universität Bochum [Bochum], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Aarhus University Hospital, Cedars-Sinai Medical Center, Florey Institute of Neuroscience and Mental Health [Melbourne, Victoria, Australia], Austin Health, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], China Medical University Hospital [Taichung], Karolinska Institutet [Stockholm], The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Texas at Austin [Austin], Collaborators Evaluation of unknown Onset Stroke thrombolysis trials (EOS) investigators: Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Florent Boutitie, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bastian Cheng, Bharath Cheripelli, Tae-Hee Cho, Chi-Un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria Del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Martin Ebinger, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Matthias Endres, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Christian Gerloff, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Robin Lemmens, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-Cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K Mueller, Keith W Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Norbert Nighoghossian, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Peter Ringleb, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Vincent Thijs, Götz Thomalla, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Mayumi Fukuda-Doi, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Manabu Inoue, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Masatoshi Koga, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Kaori Miwa, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Kazunori Toyoda, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Haruko Yamamoto, Keizo Yasui, Toshiro Yonehara, Sohei Yoshimura, Shinichi Yoshimura, K Aarnio, F Alemseged, C Anderson, T Ang, M L Archer, J Attia, P Bailey, A Balabanski, A Barber, P A Barber, J Bernhardt, A Bivard, D Blacker, C F Bladin, A Brodtmann, D Cadilhac, B C V Campbell, L Carey, S Celestino, L Chan, W H Chang, A ChangI, C H Chen, C-I Chen, H F Chen, T C Chen, W H Chen, Y Y Chen, C A Cheng, E Cheong, Y W Chiou, P M Choi, H J Chu, C S Chuang, T C Chung, L Churilov, B Clissold, A Connelly, S Coote, B Coulton, E Cowley, J Cranefield, S Curtze, C D'Este, S M Davis, S Day, P M Desmond, H M Dewey, C Ding, G A Donnan, R Drew, S Eirola, D Field, T Frost, C Garcia-Esperon, K George, R Gerraty, R Grimley, Y C Guo, G Hankey, J Harvey, S C Ho, K Hogan, D Howells, P M Hsiao, C H Hsu, C T Hsu, C-S Hsu, J P Hsu, Y D Hsu, Y T Hsu, C J Hu, C C Huang, H Y Huang, M Y Huang, S C Huang, W S Huang, D Jackson, J S Jeng, S K Jiang, L Kaauwai, O Kasari, J King, T J Kleinig, M Koivu, J Kolbe, M Krause, C W Kuan, W L Kung, C Kyndt, C L Lau, A Lee, C Y Lee, J T Lee, Y Lee, Y C Lee, C Levi, C R Levi, L M Lien, J C Lim, C C Lin, C H Lin, C M Lin, D Lin, C H Liu, J Liu, Y C Lo, P S Loh, E Low, C H Lu, C J Lu, M K Lu, J Ly, H Ma, L Macaulay, R Macdonnell, E Mackey, M Macleod, J Mahadevan, V Maxwell, R McCoy, A McDonald, S McModie, A Meretoja, S Mishra, P J Mitchell, F Miteff, A Moore, C Muller, F Ng, F C Ng, J-L Ng, W O'Brian, V O'Collins, T J Oxley, M W Parsons, S Patel, G S Peng, L Pesavento, T Phan, E Rodrigues, Z Ross, A Sabet, M Sallaberger, P Salvaris, D Shah, G Sharma, G Sibolt, M Simpson, S Singhal, B Snow, N Spratt, R Stark, J Sturm, M C Sun, Y Sun, P S Sung, Y F Sung, M Suzuki, M Tan, S C Tang, T Tatlisumak, V Thijs, M Tiainen, C H Tsai, C K Tsai, C L Tsai, H T Tsai, L K Tsai, C H Tseng, L T Tseng, J Tsoleridis, H Tu, H T-H Tu, W Vallat, J Virta, W C Wang, Y T Wang, M Waters, L Weir, T Wijeratne, C Williams, W Wilson, A A Wong, K Wong, T Y Wu, Y H Wu, B Yan, F C Yang, Y W Yang, N Yassi, H L Yeh, J H Yeh, S J Yeh, C H Yen, D Young, C L Ysai, W W Zhang, H Zhao, L Zhao, Katharina Althaus-Knaurer, Martin Bendszus, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A Dixit, Geoffrey Donnan, Rainer Dziewas, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Werner Hacke, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R Lees, Didier Leys, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Catherine Oppenheim, Sven Poli, Peter Ringleb, Peter Schellinger, Stefan Schwab, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Danilo Toni, Roland Veltkamp, Rüdiger von Kummer, Nils Wahlgren, Joanna Wardlaw, Rebecca A Betensky, Gregoire Boulouis, Raphael A Carandang, William A Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L Ford, John Hallenbeck, Gordon J Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Arne Lauer, Michael H Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H Schwamm, Eric Searls, Shlee S Song, Sidney Starkman, Steven Warach, Ona Wu, Albert J Yoo, Ramin Zand, University of Newcastle [Callaghan, Australia] (UoN), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CarMeN, laboratoire, Yperzeele, Laetitia, Evaluation of Unknown Onset Stroke Thrombolysis trials (EOS) investigators, UCL - SSS/IONS - Institute of NeuroScience, UCL - (MGD) Service de neurologie, Supporting clinical sciences, UZB Other, Physical Medicine and Rehabilitation, Clinical sciences, Neuroprotection & Neuromodulation, Radiology and Nuclear Medicine, ANS - Neurovascular Disorders, Neurology, ACS - Atherosclerosis & ischemic syndromes, Graduate School, Center of Experimental and Molecular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Microcirculation

Subjects
medicine.medical_treatment, [SDV]Life Sciences [q-bio], Ischemic Stroke/*diagnostic imaging/*drug therapy, Tomography, X-Ray Computed/methods, Fibrinolytic Agents/adverse effects/*therapeutic use, 030204 cardiovascular system & hematology, Ischemic Stroke/diagnostic imaging, surgery, 0302 clinical medicine, Modified Rankin Scale, 030212 general & internal medicine, 10. No inequality, Infusions, Intravenous, Stroke, Tomography, Time-to-Treatment, General Medicine, Thrombolysis, X-Ray Computed/methods, Tissue Plasminogen Activator/adverse effects, 3. Good health, [SDV] Life Sciences [q-bio], Diffusion Magnetic Resonance Imaging/methods, Treatment Outcome, Meta-analysis, Tissue Plasminogen Activator, Intravenous, medicine.medical_specialty, Infusions, Intravenous thrombolysis, Neuroimaging, Neuroscience(all), Placebo, Tissue Plasminogen Activator/adverse effects/*therapeutic use, 03 medical and health sciences, Fibrinolytic Agents, Internal medicine, medicine, Humans, ddc:610, Ischemic Stroke, business.industry, neurology, Fibrinolytic Agents/adverse effects, Odds ratio, Recovery of Function, medicine.disease, Clinical research, Diffusion Magnetic Resonance Imaging, Human medicine, business, Tomography, X-Ray Computed, Fibrinolytic agent
Abstract

International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Published
2020

42. Subcellular mRNA Localization Regulates Ribosome Biogenesis In Migrating Cells

Author

J. Louise Jones, Maria Dermit, Martin Dodel, Muhammad S. Azman, Jernej Ule, Flora C.Y. Lee, Faraz K. Mardakheh, Hagen Schwenzer, and Sarah P. Blagden

Subjects
Messenger RNA, RNA localization, Chemistry, Protein biosynthesis, Ribosome biogenesis, RNA-binding protein, Cell migration, Translation (biology), LARP1, Cell biology
Abstract

Translation of Ribosomal Protein-coding mRNAs (RP-mRNAs) constitutes a key step in ribosome biogenesis, but the mechanisms which modulate RP-mRNA translation in coordination with other cellular processes are poorly defined. Here we show that the subcellular localization of RP-mRNAs acts as a key regulator of their translation during cell migration. As cells migrate into their surroundings, RP-mRNAs localize to the actin-rich protrusive fronts of the cells. This localization is mediated by La-related protein 6 (LARP6), an RNA binding protein that is enriched in protrusions. Protrusions act as hotspots of translation for RP-mRNAs, resulting in enhancement of RP synthesis, ribosome biogenesis, and overall protein synthetic capacity of migratory cells, required for supporting efficient migration and proliferation. In human breast carcinomas, Epithelial to Mesenchymal Transition (EMT) upregulates LARP6 expression to enhance protein synthesis and support invasive growth. Our findings reveal LARP6 mediated mRNA localization as a key regulator of ribosome biogenesis during cell migration, and demonstrate a role for this process in cancer progression downstream of EMT.

Published
2020

43. Optimization of 3D controlled ELM-free state with recovered global confinement for KSTAR with n = 1 resonant magnetic field perturbation

Author

S.K. Kim, R. Shousha, S.H. Hahn, A.O. Nelson, J. Wai, S.M. Yang, J.-K. Park, R. Nazikian, N.C. Logan, Y.M. Jeon, Y. In, J.H. Lee, J. Kim, C.Y. Lee, Y.-S. Na, and E. Kolemen

Subjects
Nuclear and High Energy Physics, Condensed Matter Physics
Abstract

Mitigation of deleterious heat flux from edge-localized modes (ELMs) on fusion reactors is often attempted with 3D perturbations of the confining magnetic fields. However, the established technique of resonant magnetic perturbations (RMPs) also degrades plasma performance, complicating implementation on future fusion reactors. In this paper, we introduce an adaptive real-time control scheme on the KSTAR tokamak as a viable approach to achieve an ELM-free state and simultaneously recover high-confinement (β N ∼ 1.91, β p ∼ 1.53, and H 98 ∼ 0.9), demonstrating successful handling of a volatile complex system through adaptive measures. We show that, by exploiting a salient hysteresis process to adaptively minimize the RMP strength, stable ELM suppression can be achieved while actively encouraging confinement recovery. This is made possible by a self-organized transport response in the plasma edge which reinforces the confinement improvement through a widening of the ion temperature pedestal and promotes control stability, in contrast to the deteriorating effect on performance observed in standard RMP experiments. These results establish the real-time approach as an up-and-coming solution toward an optimized ELM-free state, which is an important step for the operation of ITER and reactor-grade tokamak plasmas.

Published
2022

44. Study of the emission of visible light from perovskite zirconate nanocrystals with Cu-ion implantation

Author

C.Y. Lee, Young-Kuk Lee, Junhwi Lim, Sangwon Wi, and J.-S. Chung

Subjects
010302 applied physics, Photoluminescence, Materials science, Absorption spectroscopy, Band gap, Annealing (metallurgy), Biophysics, Analytical chemistry, 02 engineering and technology, General Chemistry, 021001 nanoscience & nanotechnology, Condensed Matter Physics, 01 natural sciences, Biochemistry, Atomic and Molecular Physics, and Optics, Zirconate, Ion, 0103 physical sciences, 0210 nano-technology, Visible spectrum, Perovskite (structure)
Abstract

We investigated the emission of visible light from perovskite zirconate CaZrO3 and BaZrO3 nanocrystals (NCs) implanted with Cu ions. The CaZrO3 and BaZrO3 NCs were synthesized by using the combustion method, and were post-annealed at various temperatures for the purpose of changing their structural properties. The annealed NCs were subjected to Cu-ion implantation with ion doses from 0 up to 1 × 1016 particles/cm2. The XRD patterns of the NCs indicated that the Cu-ion implantation did not affect the structural properties of the NCs. In their photoluminescence spectra, we identified sizable yellow and green/blue emissions, which were caused by the Cu-ion implantation, in addition to a violet emission which was due to structural defects of the host compound. As the Cu-ion dose and annealing temperature were increased, the implantation-induced emission became stronger from both the CaZrO3 and BaZrO3 NCs. In comparison with the case of the previously studied implanted SrZrO3 NCs, the intensity and the spectral shape of the Cu-ion emission were found to depend strongly on the identity of the divalent cation (A in AZrO3) in close relation to the structural properties of the host zirconate. Analysis of absorption coefficient spectra of the NC samples showed that their band gaps were not affected by Cu-ion implantation. From the measured PL spectra, we calculated the CIE color coordinates, and found that colors of the light emitted from the NCs changed from violet-blue to white (close to yellow).

Published
2018

45. Bacillus thuringiensis Cry5B protein as a new pan-hookworm cure

Author

Jason B. Noon, Joseph F. Urban, Dwight D. Bowman, Raffi V. Aroian, Bin Zhan, Gary R. Ostroff, Alice C.Y. Lee, Melanie M. Miller, Thanh-Thanh Nguyen, David Koch, Ambily Abraham, Yan Hu, and Ricardo Toshio Fujiwara

Subjects
Ancylostomatoidea, 0301 basic medicine, Hookworm, Veterinary medicine, Ancylostoma, Necator americanus, 030231 tropical medicine, Bacillus thuringiensis, Article, Ancylostomiasis, lcsh:Infectious and parasitic diseases, Necatoriasis, Hemolysin Proteins, Hookworm Infections, 03 medical and health sciences, Dogs, 0302 clinical medicine, Bacterial Proteins, Cricetinae, parasitic diseases, Anthelmintic, medicine, Animals, Pharmacology (medical), lcsh:RC109-216, Intestinal Diseases, Parasitic, Cry5B, Ancylostoma ceylanicum, Anthelmintics, Pharmacology, Bacillus thuringiensis Toxins, biology, Necator, medicine.disease, biology.organism_classification, 3. Good health, Endotoxins, 030104 developmental biology, Infectious Diseases, Parasitology, Ancylostoma caninum, medicine.drug
Abstract

Hookworms are intestinal nematode parasites that infect nearly half a billion people and are globally one of the most important contributors to iron-deficiency anemia. These parasites have significant impacts in developing children, pregnant women and working adults. Of all the soil-transmitted helminths or nematodes (STNs), hookworms are by far the most important, with disease burdens conservatively estimated at four million DALYs (Disability-Adjusted Life Years) and with productivity losses of up to US$139 billion annually. To date, mainly one drug, albendazole is used for hookworm therapy in mass drug administration, which has on average ∼80% cure rate that is lower (, Graphical abstract Image 1, Highlights • Bacillus thuringiensis (Bt) Cry5B is a new pan-hookworm cure. • Bt Cry5B is highly active against Ancylostoma caninum hookworm infections in dogs. • Bt Cry5B is highly active against Necator americanus. • Cry5B acts independent of the host immune system and directly on hookworms. • Cry5B retains full bioactivity after repeated dosing.

Published
2018

46. Patterns and coherence resonance in the stochastic Swift–Hohenberg equation with Pyragas control: The Turing bifurcation case

Author

C.Y. Lee, Rachel Kuske, and Vivi Rottschäfer

Subjects
Scale (ratio), Pattern formation, Statistical and Nonlinear Physics, Context (language use), Condensed Matter Physics, 01 natural sciences, Stability (probability), Noise (electronics), 010305 fluids & plasmas, Swift–Hohenberg equation, Control theory, 0103 physical sciences, Modulation (music), Statistical physics, 010306 general physics, Bifurcation, Mathematics
Abstract

We provide a multiple time scales analysis for the Swift–Hohenberg equation with delayed feedback via Pyragas control, with and without additive noise. An analysis of the pattern formation near onset indicates both the possibility of either standing waves (rolls) or traveling waves via Turing or Turing–Hopf bifurcations, respectively, depending on the product of the strength of the feedback and the length of the delay. The remainder of the paper is focused on Turing bifurcations, where the delay can drive the appearance of an additional time scale, intermediate to the usual slow and fast time scales observed in the modulation of rolls without delay. In the deterministic case, a Ginzburg–Landau-type modulation equation is derived that inherits Pyragas control terms from the original equation. The Eckhaus stability criteria is obtained for the rolls, with the intermediate time scale observed in the transients. In the stochastic context, slow modulation equations are derived for the amplitudes of the primary modes that are coupled to a fast Ornstein–Uhlenbeck-type equation with delay for the zero mode driven by the additive noise. By deriving an averaging approximation for the amplitude of the primary mode, we show how the interaction of noise and delay influences the existence and stability range for the noisy roll-type patterns. Furthermore, approximations for the spectral densities of the primary and zero modes show that oscillations on the intermediate times scale are sustained through the phenomenon of coherence resonance. These dynamics on the intermediate time scale are sustained through the interaction of noise and delay, in contrast to the deterministic context where dynamics on the intermediate times scale are transient.

Published
2018

Catalog

Books, media, physical & digital resources
See catalog results