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The High Luminosity phase of the Large Hadron Collider will deliver 10 times more integrated luminosity than the existing collider, posing significant challenges for radiation tolerance and event pileup on detectors, especially for forward calorimetry. As part of its upgrade program, the Compact Muon Solenoid collaboration is designing a high-granularity calorimeter (HGCAL) to replace the existing endcap calorimeters. It will feature unprecedented transverse and longitudinal readout and triggering segmentation for both electromagnetic and hadronic sections. The electromagnetic section and a large fraction of the hadronic section will be based on hexagonal silicon sensors of 0.5-1 cm2 cell size, with the remainder of the hadronic section being based on highly-segmented scintillators with silicon photomultiplier readout. The intrinsic high-precision timing capabilities of the silicon sensors will add an extra dimension to event reconstruction, especially in terms of pileup rejection. First hexagonal silicon modules, using the existing Skiroc2 front-end ASIC developed for CALICE, have been tested in beams at Fermilab and CERN in 2016. We present results from these tests, in terms of system stability, calibration with minimum-ionizing particles and resolution (energy, position and timing) for electrons, and the comparisons of these quantities with GEANT4-based simulation. © 2018 CERN for the benefit of the CMS collaboration.. Nuclear Physics Collegio Ghislieri di Pavia China Medical University, Taiwan Institute for Research in Fundamental Sciences aInsitute for High Energy Physics, Beijing, China bLaboratoire Leprince-Ringuet, Palaiseau, France cOrganization for Microelectronics design and Applications (OMEGA), Palaiseau, France dSaha Institute of Nuclear Physics, Kolkata, India eTata Institute for Fundamental Research, Bombay, India fUniversity of Pavia, Pavia, Italy gCERN, Geneva, Switzerland hNational Central University, Chung-Li, Taiwan iNational Taiwan University, Taipei, Taiwan jCukurova University, Adana, Turkey kImperial College of Science, Technology and Medicine, London, U.K. lBoston University, Boston, U.S.A. mCalifornia Insitute of Technology, Pasadena, U.S.A. nCarnegie Mellon University, Pittsburg, U.S.A. oFermi National Accelerator Laboratory, Batavia, U.S.A. pFlorida State University, Tallahassee, U.S.A. qNorthwestern University, Evanston, U.S.A.

The main aim of this study is to simulate the response of a micro-PEMFC numerically by utilizing a 3-D FEM model while the micro-PEMFC was assembled by three pairs of bolt along the upper and lower portions, respectively, of the end plates. The effects of different bolts locking sequences on the deformation and pressure distributions at flow-channel plates in a micro-PEMFC were investigated. The simulated results showed that if one locked the middle bolt either on the upper or lower portion first, then the obtained warpage, uniformities of deformation and von Mises equivalent stress were superior than those results if one locked either one of the four corner bolts first. Also, among the three pairs of bolts used for assembling the cell, the first locking bolt of the first pair of locking bolt and the first locking bolt of the rest of two pairs of locking bolt were to minimize the warpage and stress should locate on the different portions of the end plates.

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP. Acknowledgements Marie Loh71,72 (Institute of Health Sciences, University of Oulu, P.O.Box 5000FI-90014 Oulu, Finland and Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK), Niek Verweij73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Weihua Zhang72,74 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK), Benjamin Lehne72 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK), Irene Mateo Leach73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Alexander Drong75 (Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK), James Abbott76 (Bioinformatics Support Service, Imperial College London, South Kensington, London SW7 2AZ, UK), Sian-Tsung Tan74,77 (Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK and National Heart and Lung Institute, Imperial College London, London W12 0NN, UK), William R. Scott72,77 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Lung Institute, Imperial College London, London W12 0NN, UK), Gianluca Campanella72 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK), Marc Chadeau-Hyam72 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK), Uzma Afzal72,74 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK), Tõnu Esko78,79,80,81 (Estonian Genome Center, University of Tartu, Riia 23c, 51010 Tartu, Estonia and Division of Endocrinology, Children’s Hospital Boston, Longwood 300, Boston, MA 02115, USA and Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA), Sarah E. Harris82,83 (Medical Genetics Section, University of Edinburgh Molecular Medicine Centre and MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK and Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK), Jaana Hartiala84,85 (Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA and Institute for Genetic Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA), Marcus E. Kleber86 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany), Richa Saxena87 (Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA), Alexandre F.R. Stewart88,89 (University of Ottawa Heart Institute, Cardiovascular Research Methods Centre, Ontario K1Y 4W7, Canada and Ruddy Canadian Cardiovascular Genetics Centre, Ontario K1Y 4W7, Canada), Tarunveer S. Ahluwalia90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark), Imke Aits91 (Institute of Epidemiology and Biobank Popgen, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany), Alexessander Da Silva Couto Alves92 (Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London SW7 2AZ, UK), Shikta Das92 (Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London SW7 2AZ, UK), Jemma C. Hopewell93 (Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK), Robert W. Koivula94 (Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, SE-205 02 Malmö, Sweden), Leo-Pekka Lyytikäinen95,96 (Department of Clinical Chemistry, Fimlab Laboratories, FI-33520 Tampere, Finland and Department of Clinical Chemistry, University of Tampere School of Medicine, FI-33014 Tampere, Finland), Iris Postmus97,98 (Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC Leiden, Netherlands and Netherlands Consortium for Healthy Ageing, Leiden 2333 ZC, Netherlands), Olli T. Raitakari99,100 (Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, FI-20521 Turku, Finland and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, FI-20520 Turku, Finland), Robert A. Scott101 (MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK), Rossella Sorice102 (Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, 80131 Naples, Italy), Vinicius Tragante103 (Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands), Michela Traglia104,105 (Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy and Institute for Maternal and Child Health—IRCCS ‘‘Burlo Garofolo’’—Trieste, 34137 Trieste, Italy), Jon White106 (UCL Genetics Institute, Department of Genetics, Environment and Evolution, UCL, London WC1E 6BT, UK), Inês Barroso107,108,109 (Metabolic Disease Group, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK), Andrew Bjonnes87 (Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA), Rory Collins103 (Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands), Gail Davies110 (Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK), Graciela Delgado86 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany), Pieter A. Doevendans103 (Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands), Lude Franke111 (Department of Genetics, University Medical Center, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Ron T. Gansevoort112 (Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Tanja B. Grammer86 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany), Niels Grarup86 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany), Jagvir Grewal72,74 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK), Anna-Liisa Hartikainen113,114 (Department of Obstetrics and Gynecology, University Hospital of Oulu, University of Oulu, Oulu FI-90014, Finland and Department of Clinical Sciences/Obsterics and Gynecology, University of Oulu, Oulu FI-90014, Finland), Stanley L. Hazen115,116 (Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA and Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA), Chris Hsu117 (Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA), Lise L.N. Husemoen118 (Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark), Johanne M. Justesen90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark), Meena Kumari119 (Department of Epidemiology and Public Health, UCL, London WC1E 6BT, UK), Wolfgang Lieb91 (Institute of Epidemiology and Biobank Popgen, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany), David C.M. Liewald110 (Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK), Evelin Mihailov78 (Estonian Genome Center, University of Tartu, Riia 23c, 51010 Tartu, Estonia), Lili Milani78 (Estonian Genome Center, University of Tartu, Riia 23c, 51010 Tartu, Estonia), Rebecca Mills74 (Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK), Nina Mononen95,96 (Department of Clinical Chemistry, Fimlab Laboratories, FI-33520 Tampere, Finland and Department of Clinical Chemistry, University of Tampere School of Medicine, FI-33014 Tampere, Finland), Kjell Nikus120 (Heart Centre, Department of Cardiology, Tampere University Hospital, and University of Tampere School of Medicine, FI-33521 Tampere, Finland), Teresa Nutile102 (Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, 80131 Naples, Italy), Sarah Parish93 (Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK), Olov Rolandsson121 (Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå universitet, SE-901 85 Umeå, Sweden), Daniela Ruggiero102 (Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, 80131 Naples, Italy), Cinzia F. Sala104 (Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy), Harold Snieder122 (Department of Epidemiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Thomas H.W. Spasø90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark), Wilko Spiering123 (Department of Vascular Medicine, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands), John M. Starr83,124 (Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK and Alzheimer Scotland Dementia Research Centre, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK), David J. Stott125 (Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow G4 0SF, UK), Daniel O. Stram117 (Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA), Silke Szymczak126 (Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany), W.H.Wilson Tang115,116 (Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA and Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA), Stella Trompet127 (Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands), Väinö Turjanmaa128,129 (Department of Clinical Physiology, Tampere University Hospital, FI-33521 Tampere, Finland and Department of Clinical Physiology, University of Tampere School of Medicine, FI-33014 Tampere, Finland), Marja Vaarasmaki130 (Department of Obstetrics and Gynecology, Oulu University Hospital, PO Box 23FI-90029 Oulu, Finland), Wiek H. van Gilst73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Dirk J. van Veldhuisen73 (Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Jorma S. Viikari131,132 (Department of Medicine, Turku University Hospital, FI-20521 Turku, Finland and Department of Medicine, University of Turku, FI-20014 Turku, Finland), Folkert W. Asselbergs103,133,134 (Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, Netherlands and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London WC1E 6BT, UK), Marina Ciullo102 (Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, 80131 Naples, Italy), Andre Franke126 (Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany), Paul W. Franks94,121,135 (Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, SE-205 02 Malmö, Sweden and Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå universitet, SE-901 85 Umeå, Sweden and Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA), Steve Franks136 (Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London W120HS, UK), Myron D. Gross137 (School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA), Torben Hansen90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark), Marjo-Riitta Jarvelin72,92,138,139,140 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK and Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London SW7 2AZ, UK and Biocenter Oulu, University of Oulu, P.O. Box 5000 Aapistie 5A, FI-90014 Oulu, Finland and Unit of Primary Care, Oulu University Hospital, Kajaanintie 50 P.O.Box 20FI-90220 Oulu, Finland and Department of Children and Young People and Families, National Institute for Health and Welfare, Aapistie 1, Box 310, FI-90101 Oulu, Finland), Torben Jørgensen118 (Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark), Wouter J. Jukema127,133,141 (Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht 3511 EP, Netherlands), Mika Kähönen128,129 (Department of Clinical Physiology, Tampere University Hospital, FI-33521 Tampere, Finland and Department of Clinical Physiology, University of Tampere School of Medicine, FI-33014 Tampere, Finland), Mika Kivimaki119 (Department of Epidemiology and Public Health, UCL, London WC1E 6BT, UK), Terho Lehtimäki95,96 (Department of Clinical Chemistry, Fimlab Laboratories, FI-33520 Tampere, Finland and Department of Clinical Chemistry, University of Tampere School of Medicine, FI-33014 Tampere, Finland), Allan Linneberg118 (Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark), Oluf Pedersen90 (Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark), Nilesh J. Samani142,143 (Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK), Daniela Toniolo104,144 (Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy and Institute of Molecular GeneticsCNR, 27100 Pavia, Italy), Hooman Allayee84,85 (Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA and Institute for Genetic Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA), Ian J. Deary83,110 (Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK and Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK), Winfried März86,145,146 (Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria and Synlab Academy, Synlab Services GmbH, Gottlieb-Daimler-Straße 25, 68165 Mannheim, Germany), Andres Metspalu78 (Estonian Genome Center, University of Tartu, Riia 23c, 51010 Tartu, Estonia), Cisca Wijmenga111 (Department of Genetics, University Medical Center, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Bruce H.W. Wolffenbuttel147 (Department of Endocrinology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands), Paolo Vineis72 (Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK), Soterios A. KyrtopoulosNational Hellenic Research Foundation, Institute of Biological Research and Biotechnology, Athens 116 35, Greece), Jos C.S. Kleinjans149 (Department of Toxicogenomics, Maastricht University, Universiteitssingel 50, 6229ER Maastricht, Netherlands), Mark I. McCarthy75,150 (Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK and Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK), James Scott77 (National Heart and Lung Institute, Imperial College London, London W12 0NN, UK)

A novel backside-illuminated CMOS image sensor (BSI-CIS) scheme and process are developed and demonstrated. This innovative scheme can be realized without fusion oxide bonding and through-silicon via (TSV) fabrication. This wafer-level TSV-less BSI-CIS scheme includes transparent ultrathin silicon $(\sim\hbox{3.6} \ \mu\hbox{m})$ and uses several bonding technologies. The characterization and assessment results indicate that the integration scheme possesses excellent electrical integrity and reliability. In addition, good quality results of the image functional test demonstrate the excellent performance of this scheme. This novel scheme also provides a realizable low-cost solution for the next-generation CIS and further 3-D novel BSI-CIS scheme.

Calorimetry in high-energy physics is rapidly evolving, with new challenges and a wide variety of technologies being employed, both for signal creation and detection. Advances in large-area highly-segmented detectors are providing possibilities for high-granularity calorimetry. The CMS HGCAL, being designed to replace the existing CMS endcap calorimeters for the HL-LHC era, is one example. It is a sampling calorimeter, featuring unprecedented transverse and longitudinal readout segmentation for both electromagnetic (CE-E) and hadronic (CE-H) compartments. This will facilitate particle-flow calorimetry, where the fine structure of showers can be measured and used to enhance pileup rejection and particle identification, whilst still achieving good energy resolution. The CE-E and a large fraction of CE-H will use hexagonal silicon sensors as active detector material. The lower-radiation environment will be instrumented with scintillator tiles with on-tile SiPM readout. An overview of the HGCAL project will be presented, covering motivation, engineering design, readout and trigger concepts, and performance in simulation.

The feasibility of a 3D IC integration SiP has been demonstrated in this investigation. The heart of this SiP is a TSV (through-silicon via) interposer with an RDL (redistribution layer) on both sides, IPD (integrated passive devices), and SS (stress sensors). This interposer is used to support (with microbumps) a stack of four memory chips with TSVs, one thermal chip with heater and one mechanical chip with SS, and is then overmolded on its top side for pick and place purposes. The interposer's bottom side is attached to an organic substrate (with ordinary lead-free solder bumps), which is lead-free solder-balled on a PCB (printed circuit board). Key enabling technologies such as TSV etching, chemical mechanical polishing (CMP), thin-wafer handling, thermal management, and microbumping, assembly, and reliability are highlighted.

In this study, thin wafer handling of 300mm wafer for 3D IC Integration is investigated. Emphasis is placed on the determination of the effect of a dicing tape on thin-wafer handling of wafers with Cu-Au pads, Cu-Ni-Au UBM, and TSV interposer with RDL. Also, thin-wafer handling critical issues such as the chip/interposer wafer, carrier wafer, temporary bonding, thinning, backside process, de-bonding, and assembly are presented and their potential solutions are discussed. Finally, state-of-the-art of materials and equipments for thin-wafer handling are examined.

The feasibility of a 3D IC integration SiP has been demonstrated in this investigation. The heart of this SiP is a TSV (through-silicon via) interposer with RDL (redistribution layer) on both sides, IPD (integrated passive devices) and SS (stress sensors). This interposer is used to support (with microbumps) a stack of four memory chips with TSVs, one thermal chip with heater and one mechanical chip with SS, and then overmolded on its top side for pick and place purposes. The interposer’s bottom-side is attached to an organic substrate (with ordinary lead-free solder bumps), which is lead-free solder-balled on a PCB (printed circuit board). Key enabling technologies such as TSV etching, chemical mechanical polishing (CMP), thin-wafer handling, thermal management, and microbumping, assembly and reliability are highlighted.

The purpose of this paper is to numerically and experimentally analyze the three-dimensional fluid motion and temperature distributions in a built-in motorized high-speed spindle with a helical water cooling channel. The effects of different heat sources ( q = 60 W, 120 W and 240 W, which correspond to heat flux q ″ of 1.43 W/cm 2 , 2.8652 W/cm 2 and 5.7304 W/cm 2 , respectively), cooling water flow rate (0.4 L/min, 0.8 L/min and 1.2 L/min, which correspond to cooling water velocity 0.24 m/s, 0.48 m/s and 0.72 m/s, respectively) are examined in detail. The model is based upon a custom-built high performance spindle, which is used in the printed-circuit board (PCB) industry, of 1.5 kW and a maximum speed of 160,000 rpm. The results indicated that almost all the hot spots are concentrated near the center of the spindle axis, and temperature increase can be significantly reduced with helical water-cooling. The predicted temperature distribution of the spindle housing is in good agreement with the result obtained from experiments. It is also shown that the heat transfer coefficient h varies with V 0.184 . Regression analysis was conducted to obtain Nu = 4.63 Re 0.184 , which can be applied for 5 × 10 4 Re 5 .

People use cars so frequently that they always consider the air-conditioning, and thermal comfort of the driver and passenger when buying a new car. Therefore accurate simulation of the thermal performance of automobile air conditioners to improve human comfort has become increasingly important. In order to improve the thermal comfort of passengers, 3-D flow motion and thermal behavior within vehicles must be analyzed. In this paper, a numerical simulation was used to investigate thermal behavior in a vehicle. Because air temperature at an air vent is related to the cooling capacity of the air conditioner, the cooling capacity was calculated using ɛ-NTU (effective number of transfer unit) theoretical equations. Using the air temperature relationship between inlet and outlet vents as boundary conditions, a 3-D unsteady κ-ɛ turbulent model was used to give a transient analysis simulation of the temperature field and flow conditions in a vehicle’s passenger cabin. Cooling cycle analysis and conjugate heat transfer analysis at the inside surface of the cabin’s ceiling, floor and sides were also considered. The predicted temperature distributions in the vehicles passenger cabin were in good agreement with those obtained experimentally.

Molecular dynamics (MD) simulations are applied to elucidate the anisotropic characteristics in the material responses for crystallographic nickel substrates with (100), (110) and (111) surface orientations during nanoindentation, compensating for the experimental limitation of nanoindentation—particularly for pure nickel substrates of three crystallographic orientations. This study examines several factors under indentation: three-dimensional phases of plastic deformation which correspond to atomic stress distributions, pile-up patterns at maximum indentation depth, and extracted material properties at different crystallographic orientations. The present results reveal that the strain energy of the substrate exerted by the tip is stored by the formation of the homogeneous nucleation, and is dissipated by the dislocation sliding of the {111} plane. The steep variations of the indentation curve from the local peak to the local minimums are affected by the numbers of slip angle of {111} sliding plane. The pile-up patterns of the three nickel substrates prove that the crystalline nickel materials demonstrate the pile-up phenomenon from nanoindentation on the nano-scale. The three crystallographic nickel substrates exhibit differing amounts of pile-up dislocation spreading at different crystallographic orientations. Finally, the effects of surface orientation in material properties of FCC nickel material on the nano-scale are observable through the slip angle numbers of {111} sliding planes which influence hardness values, as well as the cohesive energy of different crystallographic surfaces that indicate Young’s modulus.

Tremella mesenterica (TM), a yellow jelly mushroom, has been traditionally used as food and crude medicine to improve several kinds of symptoms in Chinese society for a long time. Recent studies have illustrated that the fractions of fruiting bodies of TM exhibit a significant hypoglycemic activity in diabetic mouse models, which usually suffer from sexual dysfunction. In a previous study, we showed that TM reduced plasma testosterone production in normal rats without any positive effect in diabetic rats. It evolved a question of TM directly regulating Leydig cell steroidogenesis. In this study, MA-10 mouse Leydig tumor cells were treated with vehicle, different dosages of TM with or without human chorionic gonadotropin (hCG 50 ng/ml) to clarify the effects. Results showed that TM at different dosages (0.01-10 mg/ml) did not have any effect on MA-10 cell steroidogenesis (p0.05). In the presence of hCG, there was an inhibitory trend that TA suppressed MA-10 cell progesterone production at 3 hr treatment with a statistically significant difference by the 10 mg/ml TM (p0.05). In time course effect, TM alone did not have any effect on MA-10 cell steroidogenesis from at 1, 2, 3, 6 and 12 hr (p0.05). However, TM did reduce hCG-treated MA-10 cell progesterone production at 1, 2 and 3 hr (p0.05), respectively. To determine whether TM would have adverse effects on MA-10 cell steroidogenesis in the presence of hCG, MTT assay and recovery studies were conducted. MTT assay indicated that TM had no effect on surviving cells. In addition, with the removal of TM, and then the addition of hCG (2 and 4 hr), progesterone levels were restored within 4 hr. Taken together, present studies suggested that TM suppressed hCG-treated steroidogenesis in MA-10 cells without any toxicity effect.

In this research, a new structure and process integration for backside illuminated CMOS image sensor by using thin wafer handling technology is proposed. First of all, the wafer of a 3 Mega pixel CMOS image sensor is temporary bonded to a silicon carrier wafer with thermal plastic material and ZoneBond technology. Then the CMOS wafer is thinned down to less than 5 µm for light detection from the backside. After thinning process, the backside is permanently bonded to a 500μm-thick glass carrier substrate with a transparent thermal set bonding material. After thinning, the total thickness variation of 1μm is obtained because the thermal plastic material flow during bonding process resulted in excellent thickness uniformity. The proposed backside illuminated CMOS image sensor structure and process integration are processed in wafer level, therefore enabling a low cost technology which can be manufactured using existing infrastructure. In the assembly process of CMOS image sensor stack, firstly the analog-to-digital conversion chip was stacked onto the image signal processor chip by thermal compression bonding. Optimized bonding conditions of 250 ℃/5 sec under the bonding force of 13N were chosen and determined. Subsequently, after the stack of analogto-digital conversion chip onto the image signal processor chip, the CMOS image sensor chip was bonded onto the image signal processor/analog-to-digital conversion stack. To connect all the solder bumps between CMOS image sensor and analog-to-digital conversion chip, the higher bonding force of 18N was selected. Joined-well solder joints between these two chips could be achieved. Finally, the stacked CMOS image sensor module was attached to a print circuit board by adhesive material and wire bonding was conducted to finish the electrical connectivity between CMOS image sensor stack and print circuit board.

In this research, a new structure and process integration for backside illuminated CMOS image sensor by using thin wafer handling technology is proposed. First of all, the wafer of a 3 Mega pixel CMOS image sensor is temporary bonded to a silicon carrier wafer with thermal plastic material and ZoneBond technology. Then the CMOS wafer is thinned down to few microns to detect the light from the backside. The backside is then permanently bonded to a glass carrier substrate with a transparent thermal set bonding material. After the glass permanent bonding process, the temporary bonded silicon carrier could be removed. Cu/Sn micro-bump is fabricated at the front-side of the CMOS image sensor, thus no TSVs are needed in the proposed structure. A 3 Mega pixel CMOS wafer with micro-bumps bonded on 500µm-thick glass wafer is demonstrated. Void-free bonding is obtained both in temporary bonding and permanent bonding processes. The thickness of the CMOS image sensor wafer is less than 10 µm after thinning and the total thickness variation is around 1 µm. Thermal plastic material is used for temporary bonding because it flows during bonding process and resulted in excellent planarization. From the cross-section SEM image, Cu/Sn micro-bump is formed at the front-side of the CMOS image sensor and the ENIG UBM is formed on the front side of the Analog-to-Digital Conversion wafer. A 3 Mega pixel image is captured and demonstrated in this research. The proposed backside illuminated CMOS image sensor structure and process integration are processed in wafer level, therefore enabling a low cost technology which can be manufactured using existing infrastructure. By using thin wafer handling technology, direct fusion bond and TSV processes are not needed which provides a low cost wafer level solution.

In this letter, a new transport layer mechanism is proposed to improve the performance of transport control protocol (TCP) in mobile networks. The proposed mechanism is comprised of two parts: a loss classifier (LC) and a congestion window extrapolator (CWE). Based on LC, the cause of packet loss during roaming is determined. If the loss is considered to be caused by congestion in the wireline, the congestion window is halved; otherwise, the packet is considered to be lost in the last hop, the wireless portion, and the sender adjusts the size of the congestion window based on CWE. We conduct simulations to evaluate the performance of the proposed mechanism. The results show that our mechanism significantly improves TCP performance as compared with existing solutions for mobile networks.

One of the key processes of 3-D IC technology is the implementation of a temporary bonding solution that gives the ability to handle and process thinned Si wafers. Figure 1 depicts thin composite wafers going through a typical process from bare wafer through micro-bumping. The thin composite wafers are processed (Figure 1, steps 7 to 11) sequentially including PECVD, sputtering, patterning, electro-plating, photoresist (PR) stripping, and reflow. In general, the dielectric quality and surface conformity of most plasma-deposited insulators increases significantly as the temperature increases from 200°C to 300°C [1]. Hence, the process of PECVD includes higher temperatures (>200°C) and longer times (~10 minutes) compared with other processes. Chipping or cracking may occur at the wafer edge after the PECVD process [2]. Some dishing as large as a chip size (5 mm × 5 mm) can also randomly occur at the wafer surface, as shown in Figure 2 [3], presumably caused by outgassing from the adhesive layer [2]. Therefore, it is critical to account for PECVD when designing the temporary bonding process. Due to the long high-temperature thermal treatment in the PECVD process, bonding materials play a critical role. The work described here utilized WaferBOND® advanced bonding material and ZoneBOND® technology from Brewer Science, Inc. The impact of the bonding materials with different thermal stability, provided by Brewer Science, are studied in this paper. Glass total thickness variation (TTV) and flatness impacts the overall performance of temporary bonding technology [4]. Also, deposition of certain coatings can impact the flatness (warp/bow) of high-aspect-ratio wafers. Finally, mismatch of the coefficient of thermal expansion (CTE) of the various components of a bonded stack will also affect the overall flatness as a function of process temperature. For these reasons, a study was conducted to better understand the impact of warpage and CTE of the glass carrier wafer, as well as the impact of coating-induced warpage on the performance of a temporary bonding/debonding process. An L9 Taguchi experiment method was used with split condition design to understand the parameters of this study. A PECVD process at 250°C with different thickness was performed in the Electronics and Optoelectronics Lab (EOL) within the Industrial Technology Research Institute (ITRI) to coat the Si wafers. Corning® Semiconductor Glass Wafers and simulated silicon (Si) wafers were carefully treated and coated with ZoneBOND® advanced materials and WaferBOND® bonding material. After bonding, simulated processes (e.g., silicon nitride coating) were performed. At each step, Corning's FlatMaster® MSP 300 tool was used to collect thickness variation and warpage data to evaluate the performance of the temporary bonding process.

Through glass via (TGV) interposer fabrication processes are critical techniques in 3D-IC integration, providing the short interconnection among different stacked chips and substrate. Nowadays, silicon is a mature material in semiconductor technology, but glass, a dielectric material, provides an attractive option due to its intrinsic characteristics for the advantages of electrical isolation, better RF performance, flexibility with CTE and most importantly low cost solution. In this investigation, the glass interposer by using TSV industry equipment and tooling was evaluated and developed and there are many challenges for processing. For process, the major differences between Glass and Si interposer are method for via formation and isolation. The test vehicle for Glass interposer is successfully processed. Glass material is composed with SiOx, it is good isolation for electrical current. The polymer-based PBO is used for passivation. For structure of glass interposer, there is one RDL on the front-side and backside, respectively. The other structure is 2 RDL on the front-side and one RDL one the backside. The CD of through glass via is 30 μm, it is formed by Corning Co. Cu overburden and Ti barrier are removed by wet etching process. For top RDL (line-width = 20μm), Cu plating process with seed layer (Ti/Cu) wet-etching process is applied. The PBO material is used for passivation, the process temperature is blow 200°C. Top UBM (15μm in diameter; 4μm/5μm-thick Cu/Sn) is formed with a top passivation opening (15μm). The structure is analyzed and demonstrated by SEM analysis. All the results indicate that the glass interposer with polymer passivation can be preceded and the cost for process is cheaper than Si interposer.

Primary approach of 3DIC packaging usually adopts organic substrates or silicon interposer as the intermedium between multi-integrated circuits (ICs) and printed circuit board. Current organic substrates face the limitations in poor dimensional stability, trace density and CTE mismatch to silicon. Silicon interposer is a good solution for high-pin-count ICs and high performance applications based on the mature Si technology of advance via formation and fine line Cu damascene multilevel interconnection process, but silicon interposer is limited by high cost. Glass is proposed as ideal interposer material due to high resistivity, low dielectric constant, low insertion loss and adjustable coefficient of thermal expansion (CTE) for the 3DIC assembly integration and most importantly low cost solution, [1-4]. The main focus of this paper is on (a) TGV electrical design, simulation and characterization, (b) wafer level integration in TGV formation, two RDL on the front-side, one RDL on the backside and polymer-based PBO for the passivation, (c) assembly process of silicon chip stack on the glass interposer with Kelvin resistance measurement. The glass interposer was assessed to have excellent electrical characteristics and is potentially to be applied for 3D product applications.

This paper presents a new zero-voltage switching (ZVS) DC/DC converter with three resonant tanks for high input voltage and high load current applications. Two series half-bridge legs and two split capacitors in order to limit the voltage stress of active switches at a half of input voltage. These resonant circuits are operated by an interleaved PWM scheme. The output sides of these resonant circuits are connected in parallel to evenly distribute the input power, lessen current stresses on rectifier diodes and reduce copper losses of transformers. The ZVS turn-on through power switches and zero-current switching (ZCS) turn-off for rectifier diodes are accomplished through three series resonant tanks. Therefore, switching losses of MOSFETs and reverse recovery problem of rectifier diodes are reduced. The primary windings of two transformers are series-connected to balance the secondary winding currents. Finally, experiments based on a scale-down prototype are provided to verify the performance of the proposed converter.

This paper describes the development status of a prototype supervised intelligent robot for space application for purposes of (1) helping the crew of a spacecraft such as the Space Station with various tasks such as holding objects and retrieving/replacing tools and other objects from/into storage, and for purposes of (2) retrieving detached objects, such as equipment or crew, that have become separated from their spacecraft. In addition to this set of tasks in this low Earth orbiting spacecraft environment, it is argued that certain aspects of the technology can be viewed as generic in approach, thereby offering insight into intelligent robots for other tasks and environments. Some candidate requirements for the space applications are presented which will be refined by the results of the prototype development and evaluation testing. Our development approach is described, including space simulation environments used in developmental testing. Candidate software architectures and their key technical issues which enable real work in real environments to be accomplished safely and robustly are addressed. Results of computer simulations of retrieving detached objects, including the situated reasoning/reaction plan approach used, are presented, as well as the results of an air bearing floor simulation of retrieving detached objects. Also described are characterization results on the usable reduced gravity environment in an aircraft flying parabolas (to simulate weightlessness) and results on hardware performance there. These results show it is feasible to use that environment for evaluative testing of dexterous grasping based on real-time vision of freely rotating and translating objects.

After temporary bonding and thinning process, many backside processes will be conducted on the thinned wafer. The critical processes for thin wafer handling material are high temperature and high vacuum processes. In this article, a quick adhesive selecting method is proposed. Backside process of PECVD SiO 2 is identified as the most critical process for thin wafer handling material selection. Two thermal plastic thin wafer handling materials are used in this study for 300 mm wafers and thermal compress bonding in a vacuum chamber is used for bonding process. After bonding, the wafer is thinned down to 50 µm by a commercialized grinder and the PECVD SiO 2 process is conducted on the thinned wafer. Many dishes were found after PECVD SiO 2 process because there is outgassing from the thin wafer handling material or from the device/carrier wafer surface. In this research, an additional hold time is proposed to reduce the dishing after PECVD SiO 2 process. Different hold time at 210 °C and different bonding time are evaluated. For the bonding process without hold time, large voids are observed. There are also 29 dishes on the surface of the wafer. By adding additional 5 minutes hold time before bonding, the number of the dishing on the wafer surface reduced from 29 to 6. If the hold time is set to 10 minutes, only 4 dishes were found on the wafer surface. From the evaluation result of these two thermal plastic thin wafer handling materials, B-glue seems much better than A-glue. The hold time seems very critical on void reduction during bonding process. From B-glue on PECVD SiO 2 experiment, 10 minutes hold time has the better performance for void reduction. The bonding process with zero hold time has the worst performance which has many voids after PECVD SiO 2 process. An ultra-thin 300 mm wafer with a thickness less than 7 µm is also demonstrated in this research by using B-glue and 10 minutes hold time.

The goal of temporary wafer bonding for 3DIC thin wafer handling is less topographic issues and high temperature resistance. The wafer thinning and process in vacuum chamber with high temperature are the key for the 3DIC thin wafer handling. In this article a quick adhesive selecting methods, and process improvement results are evaluated and discussed.

Cerebral endothelial cells are quiescent under normal conditions; they are stimulated to proliferate around an infarct, although the mechanism is unclear. In the present study we explored the relation between angiogenesis and the expression of basic fibroblast growth factor (bFGF) by participating cells in brain infarct. Brain infarct was created in rats by ligation of a branch of the left middle cerebral artery followed by permanent occlusion of the left common carotid artery and temporary occlusion of the right common carotid artery. The brains were removed after 1 to 14 days and studied with histological and immunohistochemical methods. Bromodeoxyuridine (BRdU) was used as an S-phase marker for the proliferative cells. Enhanced bFGF immunoreactivity was observed in neurons adjacent to the infarct after 1 day, and the change subsequently spread to distant neurons in the ipsilateral hemisphere. After 2 days blood vessels and glial cells around the infarct began to incorporate BRdU. During the first week new capillaries accompanied by macrophages extended into the infarct. The macrophages, endothelial cells, and reactive astrocytes expressed mild to moderate bFGF immunoreactivity. The spatial and temporal correlation between bFGF expression and angiogenesis in conjunction with the well-known biological properties of bFGF suggest that bFGF produced by neurons, macrophages, and glial cells may participate in angiogenesis in brain infarct.

Churg-Strauss syndrome (CSS), or allergic granulomatous angiitis, is an uncommon vasculitic syndrome that is found mainly in middle-aged adults. We describe a 15-year-old girl with CSS, diagnosed by histological findings and characteristic clinical features. The patient experienced two episodes of catastrophic gastrointestinal vasculitis, resulting in resection of 150 cm of small intestine and right hemicolectomy. Colonoscopic examination showed multiple colonic ulcers with active bleeding. The clinical course of the patient was grave and refractory to the therapy of steroid and cytotoxic drugs. In the world literature only two patients with multiple colonic ulcers caused by CSS have been reported, and very rare cases of childhood-onset CSS have been published. We reviewed CSS in children and found that the prognosis was poorer than that in adults.

2-methoxyestradiol (2-ME), an endogenous estradiol metabolite, has potent antiproliferative effects on cancer cells. However, its usefulness for treating endometrial cancer has not yet been fully explored. We investigated for the first time whether in vitro combinations of 2-ME with various chemotherapeutic agents might result in a synergistic inhibitory effect on the proliferation of human endometrial cancer cells.As a model, two different human endometrial cancer cell lines, HEC-1-A and RL95-2, were used. These cells were treated with 2-ME alone or in combination with paclitaxel, cisplatin, or doxorubicin. Measurements to detect an antiproliferative effect were performed after 24, 48, and 72 hours using the MTT assays.In both endometrial cancer cell lines a significant synergistic effect of 2-ME with paclitaxel was observed. The combination of 2-ME and cisplatin was not synergistic and provided only additive effects. The antiproliferative effect of 2-ME was somewhat antagonized by doxorubicin.Our study shows that 2-ME has a direct antiproliferative effect on endometrial cancer cells. Our results also show a potential anticancer synergy between 2-ME and paclitaxel in vitro. On the other hand, no remarkable synergistic actions were observed between 2-ME and doxorubicin, suggesting that 2-ME may selectively enhance the anticancer actions of certain chemotherapeutic agents in human endometrial cancer. Therefore, combination therapy should be investigated further as an additional therapeutic option for advanced or recurrent endometrial cancer.

A methodology has been developed for the analysis of operational flexibility of a continuous processing plant. An application has been demonstrated for a multipurpose plant with uncertain operating conditions. A practical flexibility analysis procedure using a direct search optimization algorithm is proposed to solve the problem. The method provides a heuristic screening technique that makes it possible to avoid the exhaustive enumeration of every constraint vertex, while the direct search optimization offers a simple and effective means to identify bottlenecks. A refinery multiperiod plant problem has been investigated in order to highlight the procedures which lead to the construction of flexibility indices for each operating mode. On a mis au point une methodologie pour l'analyse de la flexibilite operationnelle d'une unite de traitement continue. Une application est demontree pour une unite a usages multiples dans des conditions operatoires incertaines. Une procedure pratique d'analyse de la flexibilite utilisant un algorithme de recherche direct est proposee pour resoudre le probleme. La methode fournit une technique de selection heuristique qui permet d'eiter l'enumeration exhaustive de chaque sommet de contraintes, tandis que l'optimisation par recherche directe offre un moyen simple et efficace d'identifier les goulots d'etranglement. On a etudie une probleme pour une unite de raffinage a periodes multiples dans le but de mettre en evidence les procedures qui menent a l'etablissement des indices de flexibilite pour chaque mode operatoire.

A dynamic simulation model for the bioleaching of uranium ore in a stope leaching process has been developed. The model incorporates design and operating conditions, reaction kinetics enhanced by Thiobacillus ferrooxidans present in the leaching solution and transport properties. Model predictions agree well with experimental data with an average deviation of about ± 3%. The model is sensitive to small errors in the estimates of fragment size and ore grade. Because accurate estimates are difficult to obtain a parameter estimation approach was developed to update the value of fragment size and ore grade using on-line plant information.

The relationship(s) between nodavirus infection and myostatin expression in the skeletal muscle tissue of grouper is unclear. To investigate, the grouper (Epinephelus coioides) myostatin gene was cloned and cDNA was utilized to examine the expression of the gene in skeletal muscle and serum of healthy (uninfected) grouper and fish naturally infected with nodavirus. The myostatin gene comprises three exons and two introns and is transcribed as a 2778-bp mRNA length that encodes a 376-aa precursor protein. All exon–intron boundaries conformed to the consensus sequences. Alignment of the upstream sequences indicated that the grouper myostatin promoter has been highly conserved during evolution. Sequence analyses of 1936 bp of the upstream region revealed ten E-box motifs. The protein was consistent with the predicted molecular weight (approximately 42 kDa) of the unprocessed monomeric precursor protein and the processed myostatin form of the protein secreted into the plasma. Transient transfection studies revealed that the activity of the myostatin promoter decreased in a subset of viral titers. Grouper naturally infected with nodavirus displayed downregulation of the myostatin protein.

The hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH) serves a key role in regulating mammalian reproductive function. An extrapituitary role for GnRH in the normal and malignant reproductive tissues has been postulated. The purpose of our study is to demonstrate the presence and levels of GnRH receptor (RGnRH) protein and its mRNA in normal and malignant tissues of ovary. Normal human ovarian tissues (n = 13), as well as epithelial ovarian cancer specimens from stages I–IV (n = 39), were obtained from appropriate patients at operation room. Monoclonal antibodies against RGnRH were used for immunohistochemical evaluation of paraffin-embedded ovarian tissue sections by methods of streptavidin–biotin immunostaining. The molecular size and levels of RGnRH were determined by enhanced chemiluminescence-Western blot assay. The amount of RGnRH mRNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The rate of positive immunostaining in ovarian cancers was 53.8% (21/39). The rate of positive staining in the late stage (stages III and IV) was significantly higher than that in the early stage (stages I and II). A single band of molecular weight of about 60 kDa was detected from protein extracts of ovarian cancer as well as from normal ovary. The mean values of fold increase of signal intensities of 60 kDa detected by Western blots in stages I–IV ovarian cancers were 2.39, 2.42, 2.78, and 3.62, respectively, as compared with normal ovarian tissues. The overall positive rate of Western blot analysis for ovarian cancers was 59% (23/39). The mean values of signal intensity of RT-PCR products of RGnRH mRNA in stages I–IV were 2.24, 2.58, 3.10, and 3.20, respectively. The positive rate of overexpression of RGnRH mRNA in ovarian cancer was 70% (21/30). The differences of mean values of signal intensities of Western blot staining (2.41 versus 2.85) as well as RT-PCR products (2.40 versus 3.11) between the early stage and the late stage of ovarian cancers were statistically nonsignificant. Mechanism of autocrine regulation of tumor growth in human epithelial ovarian cancer can be explained by the coexistence of GnRH, RGnRH, and its mRNA, according to our own and other studies. The level of RGnRH expressed by ovarian cancer might be used for targeting chemotherapeutic agents to those patients who harbor RGnRH-positive tumors.

A compact dual-wideband bandpass filter using an asymmetrical resonator is presented. The proposed resonator consists of three uniform microstrip lines of different lengths, and provides not only three transmission poles but also two transmission zeros for each passband. Thus, the bandpass filter has wide bandwidths and sharp cutoff responses. Theory as well as experimential results are given to validate this design concept.

S-petasin, a kind of sesquiterpene ester, is the anti-inflammatory ann analgesic component of the butterbur (Petasites hybridus). The clinical benefit of S-petasin is the spasmolytic activity, but its side effects on the reproductive endocrinology are not clear yet. The present study was to explore the effects of S-petasin on the secretion of testosterone in vivo and in vitro. We found that single intravenous injection of S-petasin (1 microg/kg) decreased basal plasma testosterone concentration in adult male rats. The enzymatically dispersed rat testicular interstitial cells were incubated with S-petasin (0-4.3 x 10(-5)M) in the presence or absence of human chorionic gonadotropin (hCG, 0.05 IU/ml), forskolin (adenylyl cyclase activator, 10(-5) M), and androstenedione (testosterone biosynthesis precursor, 10(-9) M) at 34 degrees C for 1 h. The concentrations of testosterone in the incubation medium were measured by radioimmunoassay. S-petasin at 4.3 x 10(-7) M was effective to reduce the basal and hCG-stimulated release of testosterone in rat testicular interstitial cells. The stimulatory effects of testosterone secretion induced by forskolin and androstenedione were significantly reduced by S-petasin at 4.3 x 10(-5) M and 4.3 x 10(-6) M, respectively. These results suggest that S-petasin inhibits the production of testosterone in rat testicular interstitial cells in part through diminishing the activities of adenylyl cyclase and 17-ketosteroid reductase.

The effects of a thyroidectomy and thyroxine (T4) replacement on the spontaneous and human chorionic gonadotropin (hCG)-stimulated secretion of testosterone and the production of adenosine 3',5'-cyclic monophosphate (cAMP) in rat testes were studied. Thyroidectomy decreased the basal levels of plasma luteinizing hormone (LH) and testosterone, which delayed the maximal response of testosterone to gonadotropin-releasing hormone (GnRH) and hCG in male rats. T4 replacement in thyroparathyroidectomized (Tx) rats restored the concentrations of plasma LH and testosterone to euthyroid levels. Thyroidectomy decreased the basal release of hypothalamic GnRH, pituitary LH, and testicular testosterone as well as the LH response to GnRH and testosterone response to hCG in vitro. T4 replacement in Tx rats restored the in vitro release of GnRH, GnRH-stimulated LH release as well as hCG-stimulated testosterone release. Administration of T4 in vitro restored the release of testosterone by rat testicular interstitial cells (TICs). The increase of testosterone release in response to forskolin and androstenedione was less in TICs from Tx rats than in that from sham Tx rats. Administration of nifedipine in vitro resulted in a decrease of testosterone release by TICs from sham Tx but not from Tx rats. The basal level of cAMP in TICs was decreased by thyroidectomy. The increased accumulation of cAMP in TICs following administration of forskolin was eliminated in Tx rats. T4 replacement in Tx restored the testosterone response to forskolin. But the testosterone response to androstenedione and the cAMP response to forskolin in TICs was not restored by T4 in Tx rats. These results suggest that the inhibitory effect of a thyroidectomy on the production of testosterone in rat TICs is in part due to: 1) the decreased basal secretion of pituitary LH and its response to GnRH; 2) the decreased response of TICs to gonadotropin; and 3) the diminished production of cAMP, influx of calcium, and activity of 17beta-HSD. T4 may enhance testosterone production by acting directly at the testicular interstitial cells of Tx rats.

The increase of intracellular free calcium concentration ([Ca(2+)](i)) and protein kinase C (PKC) activity are two major early mitogenic signals to initiate proliferation of human peripheral T cells. Bacterial lipopolysaccharide (LPS) is nonmitogenic in human T cells. However, in the presence of monocytes, LPS becomes mitogenic to proliferate T cells. The aim of this study was to define the incompetency of LPS on two mitogenic signals in human peripheral T cells. T cells were isolated from human peripheral blood. [Ca(2+)](i) and pH(i) were determined by loading the cells with the fluorescent dyes, Fura-2 acetoxymethyl ester (Fura-2/AM) and 2',7'-bis(2-carboxyethyl)-5-(and 6)carboxyfluorescein acetoxymethyl ester (BCECF/AM). PKC activity was determined by protein kinase assay and cell proliferation was estimated from the incorporation of [(3)H]-thymidine. The results indicated that (1) LPS (10 microg/ml) stimulated PKC activity significantly within 5 min, reached a plateau at 30 min, and maintained that level for at least 2 h; and (2) LPS stimulated cytoplasmic alkalinization but did not affect the levels of [Ca(2+)](i) and [(3)H]-thymidine incorporation into T cells. Moreover, the combination of calcium ionophore A23187 with LPS significantly stimulated [(3)H]-thymidine incorporation into T cells. Thus, the results demonstrate that LPS failed to proliferate T cells, probably because of a lack of the machinery necessary to stimulate the mitogenic signal on [Ca(2+)](i) elevation.

We investigated the effects of two prokinetic agents, metoclopramide and cisapride, on the contractile response of isolated guinea pig tracheal segments exposed to electrical field stimulation (EFS). Tracheal segments were suspended between two platinum electrodes in organ baths. Frequency-response curves were obtained by increasing the frequency of the stimuli on equilibrated tracheal segments, in a stepwise manner. Metoclopramide potentialed the EFS-induced contraction of the tracheal; the potentiation was more prominent at lower stimulation frequencies (or = 10 Hz). Cisapride significantly inhibited the electrically stimulated contraction in trachea strips when the frequency of the stimulus was higher than 10 Hz. In the presence of both metoclopramide and cisapride, there was a potentiation of the contractile response at lower frequencies, and this potentiation was reduced when the frequency was higher than 10 Hz. These results demonstrate that metoclopramide enhances and cisapride reduces the airway tonicity elicited by EFS in isolated guinea pig trachea segments. Further studies are needed to verify the effects of these prokinetic agents on EFS-induced contraction of isolated guinea pig trachea and to determine the mechanisms involved.

This study demonstrates immunocytochemically that protein gene product 9.5 (PGP 9.5), a neuronal marker, is expressed by various populations of retinal cells in Stenella coeruleoalba (striped dolphin) and Lagenodelphis hosei (Fraser dolphin): one in the retinal ganglion cells and the other in the inner nuclear layer, resembling horizontal and amacrine cells. The specific distribution of PGP 9.5 in a dolphin closely resembles that in rodents and carnivores; however, some differences arise among these animals. In a dolphin's retina, for example, only a few of giant ganglion cells are immunoreacted while almost all the small ganglion cells are stained strongly. The processes of horizontal cells, identified according to their localization, appear not to connect entirely in a dolphin. Instead, PGP 9.5 positive cells are widely distributed in the small to moderate ganglion cells and have distinct processes which are ramified extensively in the outer plexiform layer in rodents and carnivores. The high levels of PGP 9.5 expressing in the inner part of dolphin retina, including ganglion cells and their axons as well as distinct sublamination in the inner plexiform layer, indicate that this molecule markedly influences the retinal system, possibly in visual connection. Although mammals have various visual behavior, i.e., living marine vs. terrestrial environment, and active during daytime vs. in the night, the retina is a common model to characterize the neurochemical properties.

To determine whether gastric cardia biopsy may improve the detection of Helicobacter pylori (H. pylori) before and after eradication therapy.A total of 150 dyspeptic patients with H. pylori infection completing a 2-week course of dual therapy (amoxicillin plus omeprazole) were studied. Endoscopy was carried out at the initial stage and 4 weeks after the completion of dual therapy. During each endoscopy, gastric biopsies were sampled in order from cardia, lower body, and antrum and stored separately to survey the distribution of H. pylori by histology.Before treatment, 88% (132/150) of the study cases had H. pylori found in antrum and 3.3% (5/150) of cases presented with bacteria only in cardia. After treatment, 38 cases had failure of dual therapy. The detection rates of H. pylori by biopsies without cardia decreased after the dual therapy (by antrum only: 88% to 60.5%, p0.05; antrum and body: 96.7% to 81.6%, p0.05). In contrast, the incidence of patients with only cardia involvement by H. pylori significantly increased from 3.3% (5/150) before to 18.4% (7/38) after treatment (p0.01). Among the 7 patients with H. pylori only in cardia after dual therapy, 3 cases had recurrent dyspepsia during follow-up because of no further anti-H. pylori therapy. Two of these 3 cases disclosed diffuse bacterial involvement in antrum and body besides cardia; the last case later had a positive result of urea breath test.Biopsy obtained from gastric cardia can improve the detection rate of H. pylori especially after dual therapy, which encounters antibiotics with possible sanctuary sites here. Thus, it will be useful to prevent over diagnosis of H. pylori eradication.

The bcl-2 proto-oncogene is a known inhibitor of apoptosis that may allow the accumulation and propagation of cells containing genetic alterations.An immunohistochemical study was performed to examine the role of BCL-2 protein expression in normal colonic mucosa, adenoma, and adenocarcinoma.BCL-2 was present in the crypt base of normal mucosal glands, while diffuse expression of protein product was observed in 69 cases (65.1%) of adenoma and 29 cases (60%) of adenocarcinoma (p0.5). A diffuse expression pattern was often noted in adenomas of the tubular type, solitary lesions, small lesions (1 cm), and those with mild glandular dysplasia (p0.05, respectively). There was, however, no apparent difference as to location, Yamada type of gross appearance, and gender of patients (p0.05, respectively). Patterns of BCL-2 expression did not correlate with the biologic indicators of adenocarcinoma (p0.1, respectively).Our results support that bcl-2 may play an important role in the early stage of the adenoma-carcinoma sequence. Down-regulation of bcl-2 is associated with the risk of malignant transformation for colorectal adenoma.

Regulation of thyrotropin (TSH) release by thyrotropin releasing hormone (TRH) in the anterior pituitary gland (AP) of pregnant rats was studied. The pregnant (day 7, 14, and 21) and diestrous rats were decapitated. AP was divided into 2 halves, and then incubated with Locke's solution at 37 degrees C for 30 min following a preincubation. After replacing with media, APs were incubated with Locke's solution containing 0, or 10 nM TRH for 30 min. Both basal and TRH-stimulated media were collected at the end of incubation. Medial basal hypothalamus (MBH) was incubated with Locke's medium at 37 degrees C for 30 min. Concentrations of TSH in medium and plasma samples as well as the cyclic 3':5' adenosine monophosphate (cAMP) content in APs and the levels of TRH in MBH medium were measured by radioimmunoassay. The levels of plasma TSH were higher in pregnant rats of day 21 than in diestrous rats. The spontaneous release of TSH in vitro was unaltered by pregnancy. TRH increased the release of TSH by AP, which was higher in pregnant than in diestrous rats. Maternal serum concentration of total T3 was decreased during the pregnancy. The basal release of hypothalamic TRH in vitro was greater in late pregnant rats than in diestrous rats. After TRH stimulation, the increase of the content of pituitary cAMP was greater in late pregnant rats than in diestrus animals. These results suggest that the greater secretion of TSH in pregnant rats is in part due to an increase of spontaneous release of TRH by MBH and a decrease of plasma thyroid hormones. Moreover, the higher level of plasma TSH in rats during late pregnancy is associated with the greater response of pituitary cAMP and TSH to TRH.

To investigate the effectiveness of an educational videotape on preterm mothers' knowledge, confidence, perceived stress, and social support, mothers who had given birth prematurely were recruited to participate in this study. Sixty-two mothers were randomly assigned to a control or experimental group. During hospitalization, mothers assigned to the experimental group received additional educational videotape which was designed by researchers for this particular study, regarding the knowledge and skills of caring for premature infants. While mothers in the control group received routine educational care. Both groups of mothers filled out the questionnaire including knowledge of prematurity, maternal confidence, perceived stress and perceived social support at three time periods (before discharge, one week after discharge, and one month after discharge). The findings indicated that mothers who received a videotape education reported having higher knowledge and confidence of caring for their preterm babies than mothers who were in the control group. Moreover, mothers in the experimental group perceived lower stress than the control group mothers when their babies were one month old. The scores of perception of stress, parity, and receiving a videotape education are the best predictors to maternal confidence a week after discharge. Further, the mothers' perception of stress, parity, and the perception of social support can predict and explain 47.1% of the variance of the maternal confidence. These results can apply to clinical practice for nursing mothers who have given preterm births. A convenient videotape education can improve mothers' knowledge and confidence of caring for their premature babies at home.