Development of monolithic pixel detector with SOI technology for the ILC vertex detector

NASA Astrophysics Data System (ADS)

Yamada, M.; Ono, S.; Tsuboyama, T.; Arai, Y.; Haba, J.; Ikegami, Y.; Kurachi, I.; Togawa, M.; Mori, T.; Aoyagi, W.; Endo, S.; Hara, K.; Honda, S.; Sekigawa, D.

2018-01-01

We have been developing a monolithic pixel sensor for the International Linear Collider (ILC) vertex detector with the 0.2 μm FD-SOI CMOS process by LAPIS Semiconductor Co., Ltd. We aim to achieve a 3 μm single-point resolution required for the ILC with a 20×20 μm2 pixel. Beam bunch crossing at the ILC occurs every 554 ns in 1-msec-long bunch trains with an interval of 200 ms. Each pixel must record the charge and time stamp of a hit to identify a collision bunch for event reconstruction. Necessary functions include the amplifier, comparator, shift register, analog memory and time stamp implementation in each pixel, and column ADC and Zero-suppression logic on the chip. We tested the first prototype sensor, SOFIST ver.1, with a 120 GeV proton beam at the Fermilab Test Beam Facility in January 2017. SOFIST ver.1 has a charge sensitive amplifier and two analog memories in each pixel, and an 8-bit Wilkinson-type ADC is implemented for each column on the chip. We measured the residual of the hit position to the reconstructed track. The standard deviation of the residual distribution fitted by a Gaussian is better than 3 μm.

ADC interface for data server with data preselection for luminosity detector in AIDA-2020 project

NASA Astrophysics Data System (ADS)

Daniluk, W.; Dziedzic, B.; Korcyl, G.; Wojtoń, T.; Zawiejski, L.

2017-08-01

Main aim of the AIDA-2020 project is development of detectors for future accelerators. In FCAL Colaboration we are working on forward subdetectors for ILC and CLIC accelerators. My team is developing prototype module which receives data from ADC, provides the data preselection, and transmits them as packages to the data server for further their analysis. Common prototype is based on AC701 evaluation board which contains Artix-7 FPGA and is equipped with SMA connectors for gigabit transceivers and ethernet connector. In my talk I will describe architecture of the device and current state of module development.

Particle Flow Calorimetry for the ILC

NASA Astrophysics Data System (ADS)

Magill, Stephen

2006-04-01

The Particle Flow approach to detector design is seen as the best way to achieve dijet mass resolutions suitable for the precision measurements anticipated at a future e^+e^- Linear Collider (LC). Particle Flow Algorithms (PFAs) affect not only the way data is analyzed, but are necessary and crucial elements used even in initial stages of detector design. In particular, the Calorimeter design parameters are almost entirely dependent on the optimized performance of the PFA. Use of PFAs imposes constraints on the granularity and segmentation of the readout cells, the choices of absorber and active media, and overall detector parameters such as the strength of the B-field, magnet bore, hermeticity, etc. PFAs must be flexible and modular in order to evaluate many detector models in simulation. The influence of PFA development on calorimetry is presented here with particular emphasis on results from the use of PFAs on several LC detector models.

3D simulation of electron and ion transmission of GEM-based detectors

NASA Astrophysics Data System (ADS)

Bhattacharya, Purba; Mohanty, Bedangadas; Mukhopadhyay, Supratik; Majumdar, Nayana; da Luz, Hugo Natal

2017-10-01

Time Projection Chamber (TPC) has been chosen as the main tracking system in several high-flux and high repetition rate experiments. These include on-going experiments such as ALICE and future experiments such as PANDA at FAIR and ILC. Different R&D activities were carried out on the adoption of Gas Electron Multiplier (GEM) as the gas amplification stage of the ALICE-TPC upgrade version. The requirement of low ion feedback has been established through these activities. Low ion feedback minimizes distortions due to space charge and maintains the necessary values of detector gain and energy resolution. In the present work, Garfield simulation framework has been used to study the related physical processes occurring within single, triple and quadruple GEM detectors. Ion backflow and electron transmission of quadruple GEMs, made up of foils with different hole pitch under different electromagnetic field configurations (the projected solutions for the ALICE TPC) have been studied. Finally a new triple GEM detector configuration with low ion backflow fraction and good electron transmission properties has been proposed as a simpler GEM-based alternative suitable for TPCs for future collider experiments.

Optimization of the beam crossing angle at the ILC for e+e‑ and γ γ collisions

NASA Astrophysics Data System (ADS)

Telnov, V. I.

2018-03-01

At this time, the design of the International Linear Collider (ILC) is optimized for e+e‑ collisions; the photon collider (γ γ and >=) is considered as an option. Unexpected discoveries, such as the diphoton excess digamma(750) seen at the LHC, could strongly motivate the construction of a photon collider. In order to enable the γ γ collision option, the ILC design should be compatible with it from the very beginning. In this paper, we discuss the problem of the beam crossing angle. In the ILC technical design [1], this angle is 14 mrad, which is just enough to provide enough space for the final quadrupoles and outgoing beams. For γ γ collisions, the crossing angle must be larger because the low-energy electrons that result from multiple Compton scattering get large disruption angles in collisions with the opposing electron beam and some deflection in the solenoidal detector field. For a 2E0=500 GeV collider, the required crossing angle is about 25 mrad. In this paper, we consider the factors that determine the crossing angle as well as its minimum permissible value that does not yet cause a considerable reduction of the γ γ luminosity. It is shown that the best solution is to increase the laser wavelength from the current 1 μm (which is optimal for 2E0=500 GeV) to 2 μm as this makes possible achieving high γ γ luminosities at a crossing angle of 20 mrad, which is also quite comfortable for e+e‑ collisions, does not cause any degradation of the e+e‑ luminosity and opens the possibility for a more energetic future collider in the same tunnel (e.g., CLIC). Moreover, the 2 μm wavelength is optimal for a 2E0 = 1 TeV collider, e.g., a possible ILC energy upgrade. Please consider this paper an appeal to increase the ILC crossing angle from 14 to 20 mrad.

Innate lymphoid cells in atherosclerosis.

PubMed

Engelbertsen, Daniel; Lichtman, Andrew H

2017-12-05

The family of innate lymphoid cells (ILCs) consisting of NK cells, lymphoid tissue inducer cells and the 'helper'-like ILC subsets ILC1, ILC2 and ILC3 have been shown to have important roles in protection against microbes, regulation of inflammatory diseases and involved in allergic reactions. ILC1s produce IFN-γ upon stimulation with IL-12 and IL-18, ILC2s produce IL-5 and IL-13 responding to IL-33 and IL-25 while ILC3s produce IL-17 and IL-22 after stimulation with IL-23 or IL-1. Although few studies have directly investigated the role for ILCs in atherosclerosis, several studies have investigated transcription factors and cytokines shared by ILCs and T helper cells. In this review we summarize our current understanding of the role of ILC in atherosclerosis and discuss future directions. Copyright © 2017. Published by Elsevier B.V.

Construction and performance of a silicon photomultiplier/extruded scintillator tail-catcher and muon-tracker

NASA Astrophysics Data System (ADS)

Adloff, C.; Blaha, J.; Blaising, J.-J.; Drancourt, C.; Espargilière, A.; Gaglione, R.; Geffroy, N.; Karyotakis, Y.; Prast, J.; Vouters, G.; Bilki, B.; Francis, K.; Repond, J.; Smith, J.; Xia, L.; Baldolemar, E.; Li, J.; Park, S. T.; Sosebee, M.; White, A. P.; Yu, J.; Buanes, T.; Eigen, G.; Mikami, Y.; Watson, N. K.; Mavromanolakis, G.; Thomson, M. A.; Ward, D. R.; Yan, W.; Benchekroun, D.; Hoummada, A.; Khoulaki, Y.; Benyamna, M.; Cârloganu, C.; Fehr, F.; Gay, P.; Manen, S.; Royer, L.; Blazey, G. C.; Boona, S.; Chakraborty, D.; Dyshkant, A.; Hedin, D.; Lima, J. G. R.; Powell, J.; Rykalin, V.; Scurti, N.; Smith, M.; Tran, N.; Zutshi, V.; Hostachy, J.-Y.; Morin, L.; Cornett, U.; David, D.; Dietrich, J.; Falley, G.; Gadow, K.; Göttlicher, P.; Günter, C.; Hermberg, B.; Karstensen, S.; Krivan, F.; Lucaci-Timoce, A.-I.; Lu, S.; Lutz, B.; Marchesini, I.; Morozov, S.; Morgunov, V.; Reinecke, M.; Sefkow, F.; Smirnov, P.; Terwort, M.; Vargas-Trevino, A.; Feege, N.; Garutti, E.; Eckert, P.; Kaplan, A.; Schultz-Coulon, H.-Ch; Shen, W.; Stamen, R.; Tadday, A.; Norbeck, E.; Onel, Y.; Wilson, G. W.; Kawagoe, K.; Uozumi, S.; Dauncey, P. D.; Magnan, A.-M.; Bartsch, V.; Wing, M.; Salvatore, F.; Calvo Alamillo, E.; Fouz, M.-C.; Puerta-Pelayo, J.; Bobchenko, B.; Chadeeva, M.; Danilov, M.; Epifantsev, A.; Markin, O.; Mizuk, R.; Novikov, E.; Rusinov, V.; Tarkovsky, E.; Kirikova, N.; Kozlov, V.; Soloviev, Y.; Buzhan, P.; Dolgoshein, B.; Ilyin, A.; Kantserov, V.; Kaplin, V.; Karakash, A.; Popova, E.; Smirnov, S.; Frey, A.; Kiesling, C.; Seidel, K.; Simon, F.; Soldner, C.; Weuste, L.; Bonis, J.; Bouquet, B.; Callier, S.; Cornebise, P.; Doublet, Ph; Dulucq, F.; Faucci Giannelli, M.; Fleury, J.; Li, H.; Martin-Chassard, G.; Richard, F.; de la Taille, Ch; Pöschl, R.; Raux, L.; Seguin-Moreau, N.; Wicek, F.; Anduze, M.; Boudry, V.; Brient, J.-C.; Jeans, D.; Mora de Freitas, P.; Musat, G.; Reinhard, M.; Ruan, M.; Videau, H.; Bulanek, B.; Zacek, J.; Cvach, J.; Gallus, P.; Havranek, M.; Janata, M.; Kvasnicka, J.; Lednicky, D.; Marcisovsky, M.; Polak, I.; Popule, J.; Tomasek, L.; Tomasek, M.; Ruzicka, P.; Sicho, P.; Smolik, J.; Vrba, V.; Zalesak, J.; Belhorma, B.; Ghazlane, H.; Takeshita, T.

2012-04-01

A prototype module for an International Linear Collider (ILC) detector was built, installed, and tested between 2006 and 2009 at CERN and Fermilab as part of the CALICE test beam program, in order to study the possibilities of extending energy sampling behind a hadronic calorimeter and to study the possibilities of providing muon tracking. The ``tail catcher/muon tracker'' (TCMT) is composed of 320 extruded scintillator strips (dimensions 1000 × 50 × 5 mm3) packaged in 16 one-meter square planes interleaved between steel plates. The scintillator strips were read out with wavelength shifting fibers and silicon photomultipliers. The planes were arranged with alternating horizontal and vertical strip orientations. Data were collected for muons and pions in the energy range 6 GeV to 80 GeV. Utilizing data taken in 2006, this paper describes the design and construction of the TCMT, performance characteristics, and a beam-based evaluation of the ability of the TCMT to improve hadronic energy resolution in a prototype ILC detector. For a typical configuration of an ILC detector with a coil situated outside a calorimeter system with a thickness of 5.5 nuclear interaction lengths, a TCMT would improve relative energy resolution by 6-16% for pions between 20 and 80 GeV.

ATCA for Machines-- Advanced Telecommunications Computing Architecture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Larsen, R.S.; /SLAC

2008-04-22

The Advanced Telecommunications Computing Architecture is a new industry open standard for electronics instrument modules and shelves being evaluated for the International Linear Collider (ILC). It is the first industrial standard designed for High Availability (HA). ILC availability simulations have shown clearly that the capabilities of ATCA are needed in order to achieve acceptable integrated luminosity. The ATCA architecture looks attractive for beam instruments and detector applications as well. This paper provides an overview of ongoing R&D including application of HA principles to power electronics systems.

A CMOS pixel sensor prototype for the outer layers of linear collider vertex detector

NASA Astrophysics Data System (ADS)

Zhang, L.; Morel, F.; Hu-Guo, C.; Himmi, A.; Dorokhov, A.; Hu, Y.

2015-01-01

The International Linear Collider (ILC) expresses a stringent requirement for high precision vertex detectors (VXD). CMOS pixel sensors (CPS) have been considered as an option for the VXD of the International Large Detector (ILD), one of the detector concepts proposed for the ILC. MIMOSA-31 developed at IPHC-Strasbourg is the first CPS integrated with 4-bit column-level ADC for the outer layers of the VXD, adapted to an original concept minimizing the power consumption. It is composed of a matrix of 64 rows and 48 columns. The pixel concept combines in-pixel amplification with a correlated double sampling (CDS) operation in order to reduce the temporal noise and fixed pattern noise (FPN). At the bottom of the pixel array, each column is terminated with a self-triggered analog-to-digital converter (ADC). The ADC design was optimized for power saving at a sampling frequency of 6.25 MS/s. The prototype chip is fabricated in a 0.35 μm CMOS technology. This paper presents the details of the prototype chip and its test results.

Migration and Tissue Tropism of Innate Lymphoid Cells

PubMed Central

Kim, Chang H.; Hashimoto-Hill, Seika; Kim, Myunghoo

2016-01-01

Innate lymphoid cell (ILCs) subsets differentially populate various barrier and non-barrier tissues, where they play important roles in tissue homeostasis and tissue-specific responses to pathogen attack. Recent findings have provided insight into the molecular mechanisms that guide ILC migration into peripheral tissues, revealing common features among different ILC subsets as well as important distinctions. Recent studies have also highlighted the impact of tissue-specific cues on ILC migration, and the importance of the local immunological milieu. We review these findings here and discuss how the migratory patterns and tissue tropism of different ILC subsets relate to the development and differentiation of these cells, and to ILC-mediated tissue-specific regulation of innate and adaptive immune responses. In this context we outline open questions and important areas of future research. PMID:26708278

CCD-based vertex detector for ILC

NASA Astrophysics Data System (ADS)

Stefanov, Konstantin D.

2006-12-01

Charge Coupled Devices (CCDs) have been successfully used in several high-energy physics experiments over the last 20 years. Their small pixel size and excellent precision provide a superb tool for studying of short-lived particles and understanding the nature at fundamental level. Over the last few years the Linear Collider Flavour Identification (LCFI) collaboration has developed Column-Parallel CCDs (CPCCD) and CMOS readout chips, to be used for the vertex detector at the International Linear Collider (ILC). The CPCCDs are very fast devices capable of satisfying the challenging requirements imposed by the beam structure of the superconducting accelerator. The first set of prototype devices have been successfully designed, manufactured and tested, with second generation chips on the way. Another idea for CCD-based device, the In-situ Storage Image Sensor (ISIS) is also under development and the first prototype has been manufactured.

SiD Linear Collider Detector R&D, DOE Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brau, James E.; Demarteau, Marcel

2015-05-15

The Department of Energy’s Office of High Energy Physics supported the SiD university detector R&D projects in FY10, FY11, and FY12 with no-cost extensions through February, 2015. The R&D projects were designed to advance the SiD capabilities to address the fundamental questions of particle physics at the International Linear Collider (ILC): • What is the mechanism responsible for electroweak symmetry breaking and the generation of mass? • How do the forces unify? • Does the structure of space-time at small distances show evidence for extra dimensions? • What are the connections between the fundamental particles and forces and cosmology? Siliconmore » detectors are used extensively in SiD and are well-matched to the challenges presented by ILC physics and the ILC machine environment. They are fast, robust against machine-induced background, and capable of very fine segmentation. SiD is based on silicon tracking and silicon-tungsten sampling calorimetry, complemented by powerful pixel vertex detection, and outer hadronic calorimetry and muon detection. Radiation hard forward detectors which can be read out pulse by pulse are required. Advanced calorimetry based on a particle flow algorithm (PFA) provides excellent jet energy resolution. The 5 Tesla solenoid is outside the calorimeter to improve energy resolution. PFA calorimetry requires fine granularity for both electromagnetic and hadronic calorimeters, leading naturally to finely segmented silicon-tungsten electromagnetic calorimetry. Since silicon-tungsten calorimetry is expensive, the detector architecture is compact. Precise tracking is achieved with the large magnetic field and high precision silicon microstrips. An ancillary benefit of the large magnetic field is better control of the e⁺e⁻ pair backgrounds, permitting a smaller radius beampipe and improved impact parameter resolution. Finally, SiD is designed with a cost constraint in mind. Significant advances and new capabilities have been made and are described in this report.« less

Detector Outline Document for the Fourth Concept Detector ("4th") at the International Linear Collider

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barbareschi, Daniele; et al.

We describe a general purpose detector ( "Fourth Concept") at the International Linear Collider (ILC) that can measure with high precision all the fundamental fermions and bosons of the standard model, and thereby access all known physics processes. The 4th concept consists of four basic subsystems: a pixel vertex detector for high precision vertex definitions, impact parameter tagging and near-beam occupancy reduction; a Time Projection Chamber for robust pattern recognition augmented with three high-precision pad rows for precision momentum measurement; a high precision multiple-readout fiber calorimeter, complemented with an EM dual-readout crystal calorimeter, for the energy measurement of hadrons, jets,more » electrons, photons, missing momentum, and the tagging of muons; and, an iron-free dual-solenoid muon system for the inverse direction bending of muons in a gas volume to achieve high acceptance and good muon momentum resolution. The pixel vertex chamber, TPC and calorimeter are inside the solenoidal magnetic field. All four subsytems separately achieve the important scientific goal to be 2-to-10 times better than the already excellent LEP detectors, ALEPH, DELPHI, L3 and OPAL. All four basic subsystems contribute to the identification of standard model partons, some in unique ways, such that consequent physics studies are cogent. As an integrated detector concept, we achieve comprehensive physics capabilities that puts all conceivable physics at the ILC within reach.« less

Emerging concepts and future challenges in innate lymphoid cell biology

PubMed Central

Artis, David

2016-01-01

Innate lymphoid cells (ILCs) are innate immune cells that are ubiquitously distributed in lymphoid and nonlymphoid tissues and enriched at mucosal and barrier surfaces. Three major ILC subsets are recognized in mice and humans. Each of these subsets interacts with innate and adaptive immune cells and integrates cues from the epithelium, the microbiota, and pathogens to regulate inflammation, immunity, tissue repair, and metabolic homeostasis. Although intense study has elucidated many aspects of ILC development, phenotype, and function, numerous challenges remain in the field of ILC biology. In particular, recent work has highlighted key new questions regarding how these cells communicate with their environment and other cell types during health and disease. This review summarizes new findings in this rapidly developing field that showcase the critical role ILCs play in directing immune responses through their ability to interact with a variety of hematopoietic and nonhematopoietic cells. In addition, we define remaining challenges and emerging questions facing the field. Finally, this review discusses the potential application of basic studies of ILC biology to the development of new treatments for human patients with inflammatory and infectious diseases in which ILCs play a role. PMID:27811053

Emerging roles of innate lymphoid cells in inflammatory diseases: Clinical implications.

PubMed

Kortekaas Krohn, I; Shikhagaie, M M; Golebski, K; Bernink, J H; Breynaert, C; Creyns, B; Diamant, Z; Fokkens, W J; Gevaert, P; Hellings, P; Hendriks, R W; Klimek, L; Mjösberg, J; Morita, H; Ogg, G S; O'Mahony, L; Schwarze, J; Seys, S F; Shamji, M H; Bal, S M

2018-04-01

Innate lymphoid cells (ILC) represent a group of lymphocytes that lack specific antigen receptors and are relatively rare as compared to adaptive lymphocytes. ILCs play important roles in allergic and nonallergic inflammatory diseases due to their location at barrier surfaces within the airways, gut, and skin, and they respond to cytokines produced by activated cells in their local environment. Innate lymphoid cells contribute to the immune response by the release of cytokines and other mediators, forming a link between innate and adaptive immunity. In recent years, these cells have been extensively characterized and their role in animal models of disease has been investigated. Data to translate the relevance of ILCs in human pathology, and the potential role of ILCs in diagnosis, as biomarkers and/or as future treatment targets are also emerging. This review, produced by a task force of the Immunology Section of the European Academy of Allergy and Clinical Immunology (EAACI), encompassing clinicians and researchers, highlights the role of ILCs in human allergic and nonallergic diseases in the airways, gastrointestinal tract, and skin, with a focus on new insights into clinical implications, therapeutic options, and future research opportunities. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Design study of an optical cavity for a future photon collider at ILC

NASA Astrophysics Data System (ADS)

Klemz, G.; Mönig, K.; Will, I.

2006-08-01

Hard photons well above 100 GeV have to be generated in a future photon collider which essentially will be based on the infrastructure of the planned International Linear Collider (ILC). The energy of near-infrared laser photons will be boosted by Compton backscattering against a high-energy relativistic electron beam. For high effectiveness, a very powerful laser system is required that exceeds today's state-of-the-art capabilities. In this paper a design of an auxiliary passive cavity is discussed that resonantly enhances the peak-power of the laser. The properties and prospects of such a cavity are addressed on the basis of the specifications for the European TeV Energy Superconducting Linear Accelerator (TESLA) proposal. Those of the ILC are expected to be similar.

Proceedings of the 2005 International Linear Collider Workshop (LCWS05)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hewett, JoAnne,; /SLAC

2006-12-18

Exploration of physics at the TeV scale holds the promise of addressing some of our most basic questions about the nature of matter, space, time, and energy. Discoveries of the Electroweak Symmetry Breaking mechanism, Supersymmetry, Extra Dimensions of space, Dark Matter particles, and new forces of nature are all possible. We have been waiting and planning for this exploration for over 20 years. In 2007 the Large Hadron Collider at CERN will begin its operation and will break into this new energy frontier. A new era of understanding will emerge as the LHC data maps out the Terascale. With themore » LHC discoveries, new compelling questions will arise. Responding to these questions will call for a new tool with greater sensitivity--the International Linear Collider. Historically, the most striking progress in the exploration of new energy frontiers has been made from combining results from hadron and electron-positron colliders. The precision measurements possible at the ILC will reveal the underlying theory which gave rise to the particles discovered at the LHC and will open the window to even higher energies. The world High Energy Physics community has reached an accord that an e+e- linear collider operating at 0.5-1.0 TeV would provide both unique and essential scientific opportunities; the community has endorsed with highest priority the construction of such a machine. A major milestone toward this goal was reached in August 2004 when the International Committee on Future Accelerators approved a recommendation for the technology of the future International Linear Collider. A global research and design effort is now underway to construct a global design report for the ILC. This endeavor is directed by Barry Barrish of the California Institute of Technology. The offer, made by Jonathan Dorfan on the behalf of ICFA, and acceptance of this directorship took place during the opening plenary session of this workshop. The 2005 International Linear Collider Workshop was held at Stanford University from 18 March through 22 March, 2005. This workshop was hosted by the Stanford Linear Accelerator Center and sponsored by the World Wide Study for future e+e- linear colliders. It was the eighth in a series of International Workshops (the first was held in Saariselka, Finland in 1991) devoted to the physics and detectors associated with high energy e+e- linear colliders. 397 physicists from 24 countries participated in the workshop. These proceedings represent the presentations and discussions which took place during the workshop. The contributions are comprised of physics studies, detector specifications, and accelerator design for the ILC. These proceedings are organized in two Volumes and include contributions from both the plenary and parallel sessions.« less

BCG vaccination drives accumulation and effector function of innate lymphoid cells in murine lungs.

PubMed

Steigler, Pia; Daniels, Naomi J; McCulloch, Tim R; Ryder, Brin M; Sandford, Sarah K; Kirman, Joanna R

2018-04-01

The tuberculosis (TB) vaccine bacille Calmette-Guérin (BCG) prevents disseminated childhood TB; however, it fails to protect against the more prevalent pulmonary TB. Limited understanding of the immune response to Mycobacterium tuberculosis, the causative agent of TB, has hindered development of improved vaccines. Although memory CD4 T cells are considered the main mediators of protection against TB, recent studies suggest there are other key subsets that contribute to antimycobacterial immunity. To that end, innate cells may be involved in the protective response. In this study, we investigated the primary response of innate lymphoid cells (ILCs) to BCG exposure. Using a murine model, we showed that ILCs increased in number in the lungs and lymph nodes in response to BCG vaccination. Additionally, there was significant production of the antimycobacterial cytokine IFN-γ by ILCs. As ILCs are located at mucosal sites, it was investigated whether mucosal vaccination (intranasal) stimulated an enhanced response compared to the traditional vaccination approach (intradermal or subcutaneous). Indeed, in response to intranasal vaccination, the number of ILCs, and IFN-γ production in NK cells and ILC1s in the lungs and lymph nodes, were higher than that provoked through intradermal or subcutaneous vaccination. This work provides the first evidence that BCG vaccination activates ILCs, paving the way for future research to elucidate the protective potential of ILCs against mycobacterial infection. Additionally, the finding that lung ILCs respond rigorously to mucosal vaccination may have implications for the delivery of novel TB vaccines. © 2018 Australasian Society for Immunology Inc.

MICROROC: MICRO-mesh gaseous structure Read-Out Chip

NASA Astrophysics Data System (ADS)

Adloff, C.; Blaha, J.; Chefdeville, M.; Dalmaz, A.; Drancourt, C.; Dulucq, F.; Espargilière, A.; Gaglione, R.; Geffroy, N.; Jacquemier, J.; Karyotakis, Y.; Martin-Chassard, G.; Prast, J.; Seguin-Moreau, N.; de La Taille, Ch; Vouters, G.

2012-01-01

MICRO MEsh GAseous Structure (MICROMEGAS) and Gas Electron Multipliers (GEM) detectors are two candidates for the active medium of a Digital Hadronic CALorimeter (DHCAL) as part of a high energy physics experiment at a future linear collider (ILC/CLIC). Physics requirements lead to a highly granular hadronic calorimeter with up to thirty million channels with probably only hit information (digital readout calorimeter). To validate the concept of digital hadronic calorimetry with such small cell size, the construction and test of a cubic meter technological prototype, made of 40 planes of one square meter each, is necessary. This technological prototype would contain about 400 000 electronic channels, thus requiring the development of front-end ASIC. Based on the experience gained with previous ASIC that were mounted on detectors and tested in particle beams, a new ASIC called MICROROC has been developped. This paper summarizes the caracterisation campaign that was conducted on this new chip as well as its integration into a large area Micromegas chamber of one square meter.

Aryl Hydrocarbon Receptor Promotes RORγt+ ILCs and Controls Intestinal Immunity and Inflammation

PubMed Central

Qiu, Ju; Zhou, Liang

2013-01-01

Unlike adaptive immune cells that require antigen recognition and functional maturation during infection, innate lymphoid cells (ILCs) usually respond to pathogens promptly and serve as the first line of defense in infectious diseases. RAR-related orphan receptors (RORγt)+ ILCs are one of the innate cell populations that have recently been intensively studied. During the fetal stage of development, RORγt+ ILCs (e.g., lymphoid tissue inducer-LTi cells) are required for lymphoid organogenesis. In adult mice, RORγt+ ILCs are abundantly present in the gut to exert immune defensive functions. Under certain circumstances, however, RORγt+ ILCs can be pathogenic and contribute to intestinal inflammation. Aryl hydrocarbon receptor (Ahr), a ligand-dependent transcriptional factor, is widely expressed by various immune and non-immune cells. In the gut, the ligand for Ahr can be derived/generated from diet, microflora, and/or host cells. Ahr has been shown to regulate different cell populations in the immune system including RORγt+ ILCs, T helper (Th)17/22 cells, γδT cells, regulatory T cells (Tregs), Tr1 cells, and antigen presenting cells (APCs). In this review, we will focus on the development and function of RORγt+ ILCs, and discuss the role of Ahr in intestinal immunity and inflammation in mice and in humans. Better understanding the function of Ahr in the gut is important for developing new therapeutic means to target Ahr in future treatment of infectious and autoimmune diseases. PMID:23975386

Interstitial laser coagulation of benign prostatic hyperplasia: a minimally invasive treatment alternative

NASA Astrophysics Data System (ADS)

Ordonez, Robert F.; Mittemeyer, Bernhard T.; Aronoff, David R.; de Riese, Werner T. W.

2003-06-01

The use of minimally invasive treatments for benign prostatic hyperplasia (BPH) have been introduced into the medical community. Over the last decade several minimally invasive treatment techniques have been approved for use. In particular, interstitial laser coagulation (ILC) has shown pomise as an alternative to the current gold standard, transurethral resection of prostate (TURP). Studies show ILC to have equal efficacy as TURP while causing less side effects. Future technical advances as well as increased physician experience with ILC could lead to the replacement of TURP as the gold standard in trestment of BPH.

A Laser Cavity for a Future Photon Collider at ILC

NASA Astrophysics Data System (ADS)

Klemz, G.; Moenig, K.

2006-04-01

Within a future photon-collider based on the infrastructure of ILC the energy of near-infrared laser photons will be boosted by Compton backscattering on a high energy electron beam to well above 100 GeV. By reason of luminosity, an extremely powerful lasersystem is required that will exceed today's state-of-the-art capabilities. An auxiliary cavity for resonantly enhancing the optical peak-power can relax demands on the power output of the laser. In this paper a possible design and the static aspects of a passive cavity are discussed.

Searching for the doubly charged scalars in the Georgi-Machacek model via γγ collisions at the ILC

NASA Astrophysics Data System (ADS)

Cao, Jun; Li, Yu-Qi; Liu, Yao-Bei

2018-04-01

The Georgi-Machacek (GM) model predicts the existence of the doubly-charged scalars H5±±, which can be seen the typical particles in this model and their diboson decay channels are one of the most promising ways to discover such new doubly-charged scalars. Based on the constraints of the latest combined ATLAS and CMS Higgs boson diphoton signal strength data at 2σ confidence level, we focus on the study of the triple scalar production in γγ collisions at the future International Linear collider (ILC): γγ → hH5++H 5‑‑, where the production cross-sections are very sensitive to the triple scalar coupling parameter ghHH. Considering the typical same-sign diboson decay modes for the doubly-charged scalars, the possible final signals might be detected via this process at the future ILC experiments.

Model identification of new heavy Z‧ bosons at ILC with polarized beams

NASA Astrophysics Data System (ADS)

Pankov, A. A.; Tsytrinov, A. V.

2017-12-01

Extra neutral gauge bosons, Z‧s, are predicted by many theoretical scenarios of physics beyond the Standard Model, and intensive searches for their signatures will be performed at present and future high energy colliders. It is quite possible that Z‧s are heavy enough to lie beyond the discovery reach expected at the CERN Large Hadron Collider LHC, in which case only indirect signatures of Z‧ exchanges may occur at future colliders, through deviations of the measured cross sections from the Standard Model predictions. We here discuss in this context the expected sensitivity to Z‧ parameters of fermion-pair production cross sections at the planned International Linear Collider (ILC), especially as regards the potential of distinguishing different Z‧ models once such deviations are observed. Specifically, we evaluate the discovery and identification reaches on Z‧ gauge bosons pertinent to the E 6, LR, ALR, and SSM classes of models at the ILC.

Aryl hydrocarbon receptor promotes RORγt⁺ group 3 ILCs and controls intestinal immunity and inflammation.

PubMed

Qiu, Ju; Zhou, Liang

2013-11-01

Unlike adaptive immune cells that require antigen recognition and functional maturation during infection, innate lymphoid cells (ILCs) usually respond to pathogens promptly and serve as the first line of defense in infectious diseases. RAR-related orphan receptor (RORγt)⁺ group 3 ILCs are one of the innate cell populations that have recently been intensively studied. During the fetal stage of development, RORγt⁺ group 3 ILCs (e.g., lymphoid tissue inducer cells) are required for lymphoid organogenesis. In adult mice, RORγt⁺ group 3 ILCs are abundantly present in the gut to exert immune defensive functions. Under certain circumstances, however, RORγt⁺ group 3 ILCs can be pathogenic and contribute to intestinal inflammation. Aryl hydrocarbon receptor (Ahr), a ligand-dependent transcriptional factor, is widely expressed by various immune and non-immune cells. In the gut, the ligand for Ahr can be derived/generated from diet, microflora, and/or host cells. Ahr has been shown to regulate different cell populations in the immune system including RORγt⁺ group 3 ILCs, T helper (Th)17/22 cells, γδT cells, regulatory T cells (Tregs), Tr1 cells, and antigen presenting cells. In this review, we will focus on the development and function of RORγt⁺ group 3 ILCs, and discuss the role of Ahr in intestinal immunity and inflammation in mice and in humans. A better understanding of the function of Ahr in the gut is important for developing new therapeutic means to target Ahr in future treatment of infectious and autoimmune diseases.

The GeantV project: Preparing the future of simulation

DOE PAGES

Amadio, G.; J. Apostolakis; Bandieramonte, M.; ...

2015-12-23

Detector simulation is consuming at least half of the HEP computing cycles, and even so, experiments have to take hard decisions on what to simulate, as their needs greatly surpass the availability of computing resources. New experiments still in the design phase such as FCC, CLIC and ILC as well as upgraded versions of the existing LHC detectors will push further the simulation requirements. Since the increase in computing resources is not likely to keep pace with our needs, it is therefore necessary to explore innovative ways of speeding up simulation in order to sustain the progress of High Energymore » Physics. The GeantV project aims at developing a high performance detector simulation system integrating fast and full simulation that can be ported on different computing architectures, including CPU accelerators. After more than two years of R&D the project has produced a prototype capable of transporting particles in complex geometries exploiting micro-parallelism, SIMD and multithreading. Portability is obtained via C++ template techniques that allow the development of machine- independent computational kernels. Furthermore, a set of tables derived from Geant4 for cross sections and final states provides a realistic shower development and, having been ported into a Geant4 physics list, can be used as a basis for a direct performance comparison.« less

Majorana neutrino signals at Belle-II and ILC

NASA Astrophysics Data System (ADS)

Yue, Chong-Xing; Guo, Yu-Chen; Zhao, Zhen-Hua

2017-12-01

For some theoretical and experimental considerations, the relatively light Majorana neutrinos at the GeV scale have been attracting some interest. In this article we consider a scenario with only one Majorana neutrino N, negligible mixing with the active neutrinos νL, where the Majorana neutrino interactions could be described in a model independent approach based on an effective theory. Under such a framework, we particularly study the feasibility of observing the N with mass in the range 0-30 GeV via the process e+e- → νN → γ + E̸ in the future Belle-II and ILC experiments. The results show that it is unpromising for Belle-II to observe the signal, while ILC may easily make a discovery for the Majorana neutrino.

Report of the Fermilab ILC Citizens' Task Force

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

Fermi National Accelerator Laboratory convened the ILC Citizens' Task Force to provide guidance and advice to the laboratory to ensure that community concerns and ideas are included in all public aspects of planning and design for a proposed future accelerator, the International Linear Collider. In this report, the members of the Task Force describe the process they used to gather and analyze information on all aspects of the proposed accelerator and its potential location at Fermilab in northern Illinois. They present the conclusions and recommendations they reached as a result of the learning process and their subsequent discussions and deliberations.more » While the Task Force was charged to provide guidance on the ILC, it became clear during the process that the high cost of the proposed accelerator made a near-term start for the project at Fermilab unlikely. Nevertheless, based on a year of extensive learning and dialogue, the Task Force developed a series of recommendations for Fermilab to consider as the laboratory develops all successor projects to the Tevatron. The Task Force recognizes that bringing a next-generation particle physics project to Fermilab will require both a large international effort and the support of the local community. While the Task Force developed its recommendations in response to the parameters of a future ILC, the principles they set forth apply directly to any large project that may be conceived at Fermilab, or at other laboratories, in the future. With this report, the Task Force fulfills its task of guiding Fermilab from the perspective of the local community on how to move forward with a large-scale project while building positive relationships with surrounding communities. The report summarizes the benefits, concerns and potential impacts of bringing a large-scale scientific project to northern Illinois.« less

Development of micromegas muon chambers for the ATLAS upgrade

NASA Astrophysics Data System (ADS)

Wotschack, J.

2012-02-01

Large-area particle detectors based on the bulk-micromegas technology are an attractive choice for the upgrade of LHC detectors and/or detectors for the ILC or other experiments. In the context of the R&D for the ATLAS Muon System upgrade, we have built detectors of order 1 m2. In order to overcome the spark problem in micromegas a novel protection scheme using resistive strips above the readout electrode has been developed. This technology has undergone extensive tests with hadron beams at the CERN-SPS, X-rays in the lab, as well as in a neutron beam. In addition, four 10 × 10 cm2 micromegas chambers have been installed in the ATLAS cavern and are taking data under LHC conditions. We will discuss the underlying design of the chambers and present results on the performance of these chambers.

Cutting Edge: Notch Signaling Promotes the Plasticity of Group-2 Innate Lymphoid Cells.

PubMed

Zhang, Kangning; Xu, Xingyuan; Pasha, Muhammad Asghar; Siebel, Christian W; Costello, Angelica; Haczku, Angela; MacNamara, Katherine; Liang, Tingbo; Zhu, Jinfang; Bhandoola, Avinash; Maillard, Ivan; Yang, Qi

2017-03-01

The mechanisms underlying lymphocyte lineage stability and plasticity remain elusive. Recent work indicates that innate lymphoid cells (ILC) possess substantial plasticity. Whereas natural ILC2 (nILC2) produce type-2 cytokines, plastic inflammatory ILC2 (iILC2) can coproduce both type-2 cytokines and the ILC3-characteristic cytokine, IL-17. Mechanisms that elicit this lineage plasticity, and the importance in health and disease, remain unclear. In this study we show that iILC2 are potent inducers of airway inflammation in response to acute house dust mite challenge. We find that Notch signaling induces lineage plasticity of mature ILC2 and drives the conversion of nILC2 into iILC2. Acute blockade of Notch signaling abolished functional iILC2, but not nILC2, in vivo. Exposure of isolated nILC2 to Notch ligands induced Rorc expression and elicited dual IL-13/IL-17 production, converting nILC2 into iILC2. Together these results reveal a novel role for Notch signaling in eliciting ILC2 plasticity and driving the emergence of highly proinflammatory innate lymphocytes. Copyright © 2017 by The American Association of Immunologists, Inc.

Group 3 innate lymphoid cells (ILC3s): Origin, differentiation, and plasticity in humans and mice.

PubMed

Montaldo, Elisa; Juelke, Kerstin; Romagnani, Chiara

2015-08-01

Since their discovery, innate lymphoid cells (ILCs) have been the subject of intense research. As their name implies, ILCs are innate cells of lymphoid origin, and can be grouped into subsets based on their cytotoxic activity, cytokine profile, and the transcriptional requirements during ILC differentiation. The main ILC groups are "killer" ILCs, comprising NK cells, and "helper-like" ILCs (including ILC1s, ILC2s, and ILC3s). This review examines the origin, differentiation stages, and plasticity of murine and human ILC3s. ILC3s express the retinoic acid receptor (RAR) related orphan receptor RORγt and the signature cytokines IL-22 and IL-17. Fetal ILC3s or lymphoid tissue inducer cells are required for lymphoid organogenesis, while postnatally developing ILC3s are important for the generation of intestinal cryptopatches and isolated lymphoid follicles as well as for the defence against pathogens and epithelial homeostasis. Here, we discuss the transcription factors and exogenous signals (including cytokines, nutrients and cell-to-cell interaction) that drive ILC3 lineage commitment and acquisition of their distinctive effector program. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Reliability of Upright and Supine Power Measurements Using an Inertial Load Cycle Ergometer

NASA Technical Reports Server (NTRS)

Wickwire, P. J.; Leach, M.; Ryder, J.; Ploutz-Snyder, R.; Ploutz-Snyder, L.

2011-01-01

Practical, reliable, and time efficient methods of measuring muscular power are desirable for both research and applied testing situations. The inertial-load cycling method (ILC; Power/Cycle, Austin, TX) requires subjects to pedal as fast as possible against the inertial load of a flywheel for only 3-5 seconds, which could help reduce the time and effort required for maximal power testing. PURPOSE: 1) To test the intramachine reliability of ILC over 3 separate sessions, 2) to compare postural stance (upright vs. supine) during testing, and 3) to compare the maximal power (Pmax) output measured using ILC to that obtained from traditional isokinetic and leg press testing. METHODS: Subjects (n = 12) were tested on 4 non-consecutive days. The following tests were done on the first day of testing: isometric knee extension, isokinetic knee extension at several speeds, isokinetic power/endurance at 180/sec (Biodex System 4), leg press maximal isometric force, and leg press power/endurance. The other 3 days consisted exclusively of ILC testing. Subjects performed 6 ILC tests in an upright position and 6 ILC tests in a supine position on each day. The starting position was counterbalanced. Mixed-effects linear modeling was used to determine if any differences existed between testing days and between upright and supine for Pmax and revolutions per minute at Pmax (RPMpk). Mixed-modeling was also used to calculate intraclass correlation coefficients (ICC) to determine the reliability of the ILC on each testing day for Pmax and RPMpk (ICCs were calculated separately for upright and supine). gKendall fs Tau a h was used to determine the association between ILC Pmax and isokinetic and leg press data. RESULTS: For Pmax, significant differences were found between days 1 and 2 (upright: p = 0.018; supine: p = 0.014) and between days 1 and 3 (upright: p = 0.001; supine: p = 0.002), but not between days 2 and 3 (upright: p = 0.422; supine: p = 0.501). Pmax ICC values were greater than or equal to 0.97 for all days in both positions. Also, no significant differences between upright and supine postures were found for Pmax. No significant differences between days were found for RPMpk; however, there was a significant posture effect (upright greater than supine). Moderate correlations were observed between ILC Pmax and isokinetic and leg press tests (upright: 0.64-0.79, supine: 0.52-0.82). CONCLUSIONS: Overall, ILC is a very reliable test. Since a significant difference was found between day 1 and the other ILC testing days, it is suggested that day 1 of ILC testing should be used as a familiarization session to allow for subject learning. No significant difference in Pmax was seen from test 3 to test 6. However, an increase of 1.3% was observed from test 4 to test 6. Therefore, although 4 tests may be sufficient for most subjects to produce Pmax, in some cases 6 tests may be required. PRACTICAL APPLICATIONS: No differences were seen in Pmax between upright and supine positions despite differing RPMpk. This suggests that ILC testing can be used to provide reliable testing both in an upright position (appropriate for athletes) and in research (e.g., bed rest) or rehabilitation settings where supine testing is necessary. Future research should evaluate whether peak power measurements obtained with the ILC are sensitive to changes such as that observed with training and de-training.

2009 Linear Collider Workshop of the Americas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seidel, Sally

The 2009 Linear Collider Workshop of the Americas was held on the campus of the University of New Mexico from 29 September to 3 October, 2009. This was a joint meeting of the American Linear Collider Physics Group and the ILC Global Design Effort. Two hundred fifty people attended. The number of scientific contributions was 333. The complete agenda, with links to all of the presentations, is available at physics.unm.edu/LCWA09/. The meeting brought together international experts as well as junior scientists, to discuss the physics potential of the linear collider and advances in detector technology. The validation of detector designsmore » was announced, and the detector design groups planned the next phase of the effort. Detector R&D teams reported on progress on many topics including calorimetry and tracking. Recent accelerator design considerations were discussed in a special session for experimentalists and theorists.« less

Development, differentiation and diversity of innate lymphoid cells

PubMed Central

Diefenbach, Andreas; Colonna, Marco; Koyasu, Shigeo

2014-01-01

Recent years have witnessed the discovery of an unprecedented complexity in innate lymphocyte lineages, now collectively referred to as innate lymphoid cells (ILC). ILC are preferentially located at barrier surfaces and are important for protection against pathogens and for the maintenance of organ homeostasis. Inappropriate activation of ILC has been linked to the pathogenesis of inflammatory and autoimmune disorders. Recent evidence suggests that ILC can be grouped into two separate lineages, cytotoxic ILC represented by conventional natural killer (cNK) cells and cytokine-producing helper-like ILC (i.e., ILC1, ILC2, ILC3). We will focus here on current work in humans and mice that has identified core transcriptional circuitry required for the commitment of lymphoid progenitors to the ILC lineage. The striking similarities in transcriptional control of ILC and T cell lineages reveal important insights into the evolution of transcriptional programs required to protect multicellular organisms against infections and to fortify barrier surfaces. PMID:25238093

Alleviation of streptozotocin-induced diabetes in nude mice by stem cells derived from human first trimester umbilical cord.

PubMed

Cao, M; Zhang, J B; Dong, D D; Mou, Y; Li, K; Fang, J; Wang, Z Y; Chen, C; Zhao, J; Yie, S M

2015-10-16

Cells isolated from human first trimester umbilical cord perivascular layer (hFTM-PV) tissues display the pluripotent characteristics of stem cells. In this study, we examined whether hFTM-PV cells can differentiate into islet-like clusters (ILCs) in vitro, and whether transplantation of the hFTM-PV cells with and without differentiation in vitro can alleviate diabetes in nude mice. The hFTM-PV cells were differentiated into ILCs in vitro through a simple stepwise culture protocol. To examine the in vivo effects of the cells, the hFTM-PV cells with and without differentiation in vitro were transplanted into the abdominal cavity of nude mice with streptozotocin (STZ)-induced diabetes. Blood glucose levels, body weight, and the survival probability of the diabetic nude mice were then statistically analyzed. The hFTM-PV cells were successfully induced into ILCs that could release insulin in response to elevated concentrations of glucose in vitro. In transplantation experiments, we observed that mice transplanted with the undifferentiated hFTM-PV cells, embryonic body-like cell aggregations, or ILCs all demonstrated normalized hyperglycemia and showed improved survival rate compared with those without cell transplantation. The hFTM-PV cells have the ability to differentiate into ILCs in vitro and transplantations of undifferentiated and differentiated cells can alleviate STZ-induced diabetes in nude mice. This may offer a potential cell source for stem cell-based therapy for treating diabetes in the future.

The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing.

PubMed

Björklund, Åsa K; Forkel, Marianne; Picelli, Simone; Konya, Viktoria; Theorell, Jakob; Friberg, Danielle; Sandberg, Rickard; Mjösberg, Jenny

2016-04-01

Innate lymphoid cells (ILCs) are increasingly appreciated as important participants in homeostasis and inflammation. Substantial plasticity and heterogeneity among ILC populations have been reported. Here we have delineated the heterogeneity of human ILCs through single-cell RNA sequencing of several hundreds of individual tonsil CD127(+) ILCs and natural killer (NK) cells. Unbiased transcriptional clustering revealed four distinct populations, corresponding to ILC1 cells, ILC2 cells, ILC3 cells and NK cells, with their respective transcriptomes recapitulating known as well as unknown transcriptional profiles. The single-cell resolution additionally divulged three transcriptionally and functionally diverse subpopulations of ILC3 cells. Our systematic comparison of single-cell transcriptional variation within and between ILC populations provides new insight into ILC biology during homeostasis, with additional implications for dysregulation of the immune system.

Innate Lymphoid Cells (ILCs) as Mediators of Inflammation, Release of Cytokines and Lytic Molecules

PubMed Central

Elemam, Noha Mousaad

2017-01-01

Innate lymphoid cells (ILCs) are an emerging group of immune cells that provide the first line of defense against various pathogens as well as contributing to tissue repair and inflammation. ILCs have been classically divided into three subgroups based on their cytokine secretion and transcription factor profiles. ILC nomenclature is analogous to that of T helper cells. Group 1 ILCs composed of natural killer (NK) cells as well as IFN-γ secreting ILC1s. ILC2s have the capability to produce TH2 cytokines while ILC3s and lymphoid tissue inducer (LTis) are subsets of cells that are able to secrete IL-17 and/or IL-22. A recent subset of ILC known as ILC4 was discovered, and the cells of this subset were designated as NK17/NK1 due to their release of IL-17 and IFN-γ. In this review, we sought to explain the subclasses of ILCs and their roles as mediators of lytic enzymes and inflammation. PMID:29232860

Innate Lymphoid Cells (ILCs) as Mediators of Inflammation, Release of Cytokines and Lytic Molecules.

PubMed

Elemam, Noha Mousaad; Hannawi, Suad; Maghazachi, Azzam A

2017-12-10

Innate lymphoid cells (ILCs) are an emerging group of immune cells that provide the first line of defense against various pathogens as well as contributing to tissue repair and inflammation. ILCs have been classically divided into three subgroups based on their cytokine secretion and transcription factor profiles. ILC nomenclature is analogous to that of T helper cells. Group 1 ILCs composed of natural killer (NK) cells as well as IFN-γ secreting ILC1s. ILC2s have the capability to produce T H 2 cytokines while ILC3s and lymphoid tissue inducer (LTis) are subsets of cells that are able to secrete IL-17 and/or IL-22. A recent subset of ILC known as ILC4 was discovered, and the cells of this subset were designated as NK17/NK1 due to their release of IL-17 and IFN-γ. In this review, we sought to explain the subclasses of ILCs and their roles as mediators of lytic enzymes and inflammation.

Reduced numbers of circulating group 2 innate lymphoid cells in patients with common variable immunodeficiency.

PubMed

Geier, Christoph B; Kraupp, Sophie; Bra, David; Eibl, Martha M; Farmer, Jocelyn R; Csomos, Krisztian; Walter, Jolan E; Wolf, Hermann M

2017-11-01

Recent studies identified an emerging role of group 2 and 3 innate lymphoid cells (ILCs) as key players in the generation of T-dependent and T-independent antibody production. In this retrospective case-control study, CD117 + ILCs (including the majority of ILC2 and ILC3) were reduced in patients with common variable immunodeficiency (CVID). The reduction in CD117 + ILCs was distinctive to CVID and could not be observed in patients with X-linked agammaglobulinemia. Patients with a more pronounced reduction in CD117 + ILC numbers showed significantly lower numbers of peripheral MZ-like B cells and an increased prevalence of chronic, non-infectious enteropathy. Subsequent phenotyping of ILC subsets in CVID revealed that the reduction in CD117 + ILC numbers is due to a reduction in ILC2 numbers. In vitro expansion of CVID ILC2 in response to IL-2, IL-7, IL-25 and IL-33 was impaired. Furthermore, upregulation of MHCII and IL-2RA in response to IL-2, IL-7, IL-25 and IL-33 was impaired in CVID ILC2. Thus, our results indicate a dysregulation of ILC subsets with a reduction in ILC2 numbers in CVID, however, further studies are needed to explore whether ILC abnormalities are a primary finding or secondary to disease complications encountered in CVID. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

IL-33, IL-25, and TSLP induce a distinct phenotypic and activation profile in human type 2 innate lymphoid cells.

PubMed

Camelo, Ana; Rosignoli, Guglielmo; Ohne, Yoichiro; Stewart, Ross A; Overed-Sayer, Catherine; Sleeman, Matthew A; May, Richard D

2017-04-11

Innate lymphoid cells (ILCs) represent a distinct branch of the lymphoid lineage composed of 3 major subpopulations: ILC1, ILC2, and ILC3. ILCs are mainly described as tissue-resident cells but can be detected at low levels in human blood. However, unlike mouse ILCs, there is still no consistent methodology to purify and culture these cells that enables in-depth analysis of their intrinsic biology. Here, we describe defined culture conditions for ILC2s, which allowed us to dissect the roles of interleukin 2 (IL-2), IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) individually, or in combination, in modulating ILC2 phenotype and function. We show that TSLP is important for ILC2 survival, while ILC2 activation is more dependent on IL-33, especially when in combination with IL-2 or TSLP. We found that activation of ILC2s by IL-33 and TSLP dramatically upregulated their surface expression of c-Kit and downregulated expression of the canonical markers IL-7Rα and CRTH2. IL-2 further amplified ILC2 production of IL-5, IL-13, and granulocyte-macrophage colony-stimulating factor but also induced a more natural killer (NK)-like phenotype in ILC2, with upregulation of granzyme B production by these cells. Furthermore, ILC2 plasticity was observed in serum-free SFEM II media in response to IL-33, IL-25, and TSLP stimulation and independently of IL-12 and IL-1β. This is the first comprehensive report of an in vitro culture system for human ILC2s, without the use of feeder layers, which additionally evaluates the impact of IL-25, IL-33, and TSLP alone or in combination on ILC2 surface phenotype and activation status.

CXCR6 Expression Is Important for Retention and Circulation of ILC Precursors.

PubMed

Chea, Sylvestre; Possot, Cécilie; Perchet, Thibaut; Petit, Maxime; Cumano, Ana; Golub, Rachel

2015-01-01

Innate lymphoid cells are present at mucosal sites and represent the first immune barrier against infections, but what contributes to their circulation and homing is still unclear. Using Rag2(-/-) Cxcr6(Gfp/+) reporter mice, we assessed the expression and role of CXCR6 in the circulation of ILC precursors and their progeny. We identify CXCR6 expressing ILC precursors in the bone marrow and characterize their significant increase in CXCR6-deficient mice at steady state, indicating their partial retention in the bone marrow after CXCR6 ablation. Circulation was also impaired during embryonic life as fetal liver from CXCR6-deficient embryos displayed decreased numbers of ILC3 precursors. When injected, fetal CXCR6-deficient ILC3 precursors also fail to home and reconstitute ILC compartments in vivo. We show that adult intestinal ILC subsets have heterogeneous expression pattern of CXCR6, integrin α 4 β 7, CD62L, CD69, and CD44, with ILC1 and ILC3 being more likely tissue resident lymphocytes. Intestinal ILC subsets were unchanged in percentages and numbers in both mice. We demonstrate that the ILC frequency is maintained due to a significant increase of ILC peripheral proliferation, as well as an increased proliferation of the in situ ILC precursors to compensate their retention in the bone marrow.

Isolation of Human Innate Lymphoid Cells.

PubMed

Krabbendam, Lisette; Nagasawa, Maho; Spits, Hergen; Bal, Suzanne M

2018-06-29

Innate lymphoid cells (ILCs) are innate immune cells of lymphoid origin that have important effector and regulatory functions in the first line of defense against pathogens, but also regulate tissue homeostasis, remodeling, and repair. Their function mirrors T helper cells and cytotoxic CD8 + T lymphocytes, but they lack expression of rearranged antigen-specific receptors. Distinct ILC subsets are classified in group 1 ILCs (ILC1s), group 2 ILCs (ILC2s), and group 3 ILCs (ILC3s and lymphoid tissue-inducer cells), based on the expression of transcription factors and the cytokines they produce. As the frequency of ILCs is low, their isolation requires extensive depletion of other cell types. The lack of unique cell surface antigens further complicates the identification of these cells. Here, methods for ILC isolation and characterization from human peripheral blood and different tissues are described. © 2018 by John Wiley & Sons, Inc. © 2018 John Wiley & Sons, Inc.

The Role of Innate Lymphoid Cells in Immune-Mediated Liver Diseases

PubMed Central

Liu, Meifang; Zhang, Cai

2017-01-01

Innate lymphoid cells (ILCs) are a recently identified group of innate immune cells lacking antigen-specific receptors that can mediate immune responses and regulate tissue homeostasis and inflammation. ILCs comprise group 1 ILCs, group 2 ILCs, and group 3 ILCs. These ILCs usually localize at mucosal surfaces and combat pathogens by the rapid release of certain cytokines. However, the uncontrolled activation of ILCs can also lead to damaging inflammation, especially in the gut, lung, and skin. Although the physiological and pathogenic roles of ILCs in liver diseases have been attracting increasing attention recently, there has been no systematic review regarding the roles of ILCs in immune-mediated liver diseases. Here, we review the relationships between the ILC subsets and their functions in immune-mediated liver diseases, and discuss their therapeutic potential based on current knowledge about the functional roles of these cells in liver diseases. PMID:28659927

Testosterone Attenuates Group 2 Innate Lymphoid Cell-Mediated Airway Inflammation.

PubMed

Cephus, Jacqueline-Yvonne; Stier, Matthew T; Fuseini, Hubaida; Yung, Jeffrey A; Toki, Shinji; Bloodworth, Melissa H; Zhou, Weisong; Goleniewska, Kasia; Zhang, Jian; Garon, Sarah L; Hamilton, Robert G; Poloshukin, Vasiliy V; Boyd, Kelli L; Peebles, R Stokes; Newcomb, Dawn C

2017-11-28

Sex hormones regulate many autoimmune and inflammatory diseases, including asthma. As adults, asthma prevalence is 2-fold greater in women compared to men. The number of group 2 innate lymphoid cells (ILC2) is increased in patients with asthma, and we investigate how testosterone attenuates ILC2 function. In patients with moderate to severe asthma, we determine that women have an increased number of circulating ILC2 compared to men. ILC2 from adult female mice have increased IL-2-mediated ILC2 proliferation versus ILC2 from adult male mice, as well as pre-pubescent females and males. Further, 5α-dihydrotestosterone, a hormone downstream of testosterone, decreases lung ILC2 numbers and IL-5 and IL-13 expression from ILC2. In vivo, testosterone attenuated Alternaria-extract-induced IL-5+ and IL-13+ ILC2 numbers and lung eosinophils by intrinsically decreasing lung ILC2 numbers, as well as by decreasing expression of IL-33 and thymic stromal lymphopoietin (TSLP), ILC2-stimulating cytokines. Collectively, these findings provide a foundational understanding of sexual dimorphism in ILC2 function. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Interactive laboratory classes enhance neurophysiological knowledge in Thai medical students.

PubMed

Wongjarupong, Nicha; Niyomnaitham, Danai; Vilaisaktipakorn, Pitchamol; Suksiriworaboot, Tanawin; Qureshi, Shaun Peter; Bongsebandhu-Phubhakdi, Saknan

2018-03-01

Interactive laboratory class (ILC) is a two-way communication teaching method that encourages students to correlate laboratory findings with materials from lectures. In Thai medical education, active learning methods are uncommon. This paper aims to establish 1) if ILCs would effectively promote physiology learning; 2) if effectiveness would be found in both previously academically high-performing and low-performing students; and 3) the acceptability of ILCs to Thai medical students as a novel learning method. Two hundred seventy-eight second-year medical students were recruited to this study. We conducted three ILC sessions, which followed corresponding lectures. We carried out multiple-choice pre- and post-ILC assessments of knowledge and compared by repeated-measures ANOVA and unpaired t-test. Subgroup analysis was performed to compare high-performance (HighP) and low-performance (LowP) students. After the ILCs, participants self-rated their knowledge and satisfaction. Post-ILC test scores increased significantly compared with pre-ILC test scores in all three sessions. Mean scores of each post-ILC test increased significantly from pre-ILC test in both LowP and HighP groups. More students self-reported a "very high" and "high" level of knowledge after ILCs. Most students agreed that ILCs provided more discussion opportunity, motivated their learning, and made lessons more enjoyable. As an adjunct to lectures, ILCs can enhance knowledge in medical students, regardless of previous academic performance. Students perceived ILC as useful and acceptable. This study supports the active learning methods in physiology education, regardless of cultural context.

CXCR6 Expression Is Important for Retention and Circulation of ILC Precursors

PubMed Central

Chea, Sylvestre; Possot, Cécilie; Perchet, Thibaut; Petit, Maxime; Cumano, Ana; Golub, Rachel

2015-01-01

Innate lymphoid cells are present at mucosal sites and represent the first immune barrier against infections, but what contributes to their circulation and homing is still unclear. Using Rag2 −/− Cxcr6 Gfp/+ reporter mice, we assessed the expression and role of CXCR6 in the circulation of ILC precursors and their progeny. We identify CXCR6 expressing ILC precursors in the bone marrow and characterize their significant increase in CXCR6-deficient mice at steady state, indicating their partial retention in the bone marrow after CXCR6 ablation. Circulation was also impaired during embryonic life as fetal liver from CXCR6-deficient embryos displayed decreased numbers of ILC3 precursors. When injected, fetal CXCR6-deficient ILC3 precursors also fail to home and reconstitute ILC compartments in vivo. We show that adult intestinal ILC subsets have heterogeneous expression pattern of CXCR6, integrin α 4 β 7, CD62L, CD69, and CD44, with ILC1 and ILC3 being more likely tissue resident lymphocytes. Intestinal ILC subsets were unchanged in percentages and numbers in both mice. We demonstrate that the ILC frequency is maintained due to a significant increase of ILC peripheral proliferation, as well as an increased proliferation of the in situ ILC precursors to compensate their retention in the bone marrow. PMID:26494947

A Major Population of Functional KLRG1- ILC2s in Female Lungs Contributes to a Sex Bias in ILC2 Numbers.

PubMed

Kadel, Sapana; Ainsua-Enrich, Erola; Hatipoglu, Ibrahim; Turner, Sean; Singh, Simar; Khan, Sohaib; Kovats, Susan

2018-02-01

Humans show significant sex differences in the incidence and severity of respiratory diseases, including asthma and virus infection. Sex hormones contribute to the female sex bias in type 2 inflammation associated with respiratory diseases, consistent with recent reports that female lungs harbor greater numbers of GATA-3-dependent group 2 innate lymphoid cells (ILC2s). In this study, we determined whether sex hormone levels govern sex differences in the numbers, phenotype, and function of ILC2s in the murine lung and bone marrow (BM). Our data show that lungs of female mice harbor significantly greater ILC2 numbers in homeostasis, in part due to a major subset of ILC2s lacking killer-cell lectin like receptor G1 (KLRG1), a population largely absent in male lungs. The KLRG1 - ILC2s were capable of type 2 cytokine production and increased with age after sexual maturity, suggesting that a unique functional subset exists in females. Experiments with gonadectomized mice or mice bearing either global or lymphocyte restricted estrogen receptor α ( Esr1 ) deficiency showed that androgens rather than estrogens regulated numbers of the KLRG1 - ILC2 subset and ILC2 functional capacity in the lung and BM, as well as levels of GATA-3 expression in BM ILC2s. Furthermore, the frequency of BM PLZF + ILC precursors was higher in males and increased by excess androgens, suggesting that androgens act to inhibit the transition of ILC precursors to ILC2s. Taken together, these data show that a functional subset of KLRG1 - ILC2s in females contributes to the sex bias in lung ILC2s that is observed after reproductive age.

Incoherent pair generation in a beam-beam interaction simulation

NASA Astrophysics Data System (ADS)

Rimbault, C.; Bambade, P.; Mönig, K.; Schulte, D.

2006-03-01

This paper deals with two topics: the generation of incoherent pairs in two beam-beam simulation programs, GUINEA-PIG and CAIN, and the influence of the International Linear Collider (ILC) beam parameter choices on the background in the micro vertex detector (VD) induced by direct hits. One of the processes involved in incoherent pair creation (IPC) is equivalent to a four fermions interaction and its cross section can be calculated exactly with a dedicated generator, BDK. A comparison of GUINEA-PIG and CAIN results with BDK allows to identify and quantify the uncertainties on IPC background predictions and to benchmark the GUINEA-PIG calculation. Based on this simulation and different VD designs, the five currently suggested ILC beam parameter sets have been compared regarding IPC background induced in the VD by direct IPC hits. We emphasize that the high luminosity set, as it is currently defined, would constrain both the choices of magnetic field and VD inner layer radius.

Cytokine and Lipid Mediator Regulation of Group 2 Innate Lymphoid Cells (ILC2s) in Human Allergic Airway Disease.

PubMed

Cavagnero, Kellen; Doherty, Taylor A

2017-08-01

The recent discovery of group 2 innate lymphoid cells (ILC2s) has caused a paradigm shift in the understanding of allergic airway disease pathogenesis. Prior to the discovery of ILC2s, Th2 cells were largely thought to be the primary source of type 2 cytokines; however, activated ILC2s have since been shown to contribute significantly, and in some cases, dominantly to type 2 cytokine production. Since the discovery of ILC2s in 2010, many mediators have been shown to regulate their effector functions. Initial studies identified the epithelial derived cytokines IL-25, IL-33, and TSLP as activators of ILC2s, and recent studies have identified many additional cytokine and lipid mediators that are involved in ILC2 regulation. ILC2s and their mediators represent novel therapeutic targets for allergic airway diseases and intensive investigation is underway to better understand ILC2 biology and upstream and downstream pathways that lead to ILC2-driven airway pathology. In this review, we will focus on the cytokine and lipid mediators that regulate ILC2s in human allergic airway disease, as well as highlight newly discovered mediators of mouse ILC2s that may eventually translate to humans.

Identification of innate lymphoid cells in single-cell RNA-Seq data.

PubMed

Suffiotti, Madeleine; Carmona, Santiago J; Jandus, Camilla; Gfeller, David

2017-07-01

Innate lymphoid cells (ILCs) consist of natural killer (NK) cells and non-cytotoxic ILCs that are broadly classified into ILC1, ILC2, and ILC3 subtypes. These cells recently emerged as important early effectors of innate immunity for their roles in tissue homeostasis and inflammation. Over the last few years, ILCs have been extensively studied in mouse and human at the functional and molecular level, including gene expression profiling. However, sorting ILCs with flow cytometry for gene expression analysis is a delicate and time-consuming process. Here we propose and validate a novel framework for studying ILCs at the transcriptomic level using single-cell RNA-Seq data. Our approach combines unsupervised clustering and a new cell type classifier trained on mouse ILC gene expression data. We show that this approach can accurately identify different ILCs, especially ILC2 cells, in human lymphocyte single-cell RNA-Seq data. Our new model relies only on genes conserved across vertebrates, thereby making it in principle applicable in any vertebrate species. Considering the rapid increase in throughput of single-cell RNA-Seq technology, our work provides a computational framework for studying ILC2 cells in single-cell transcriptomic data and may help exploring their conservation in distant vertebrate species.

Ambiguous roles of innate lymphoid cells in chronic development of liver diseases.

PubMed

Shen, Yue; Li, Jing; Wang, Si-Qi; Jiang, Wei

2018-05-14

Innate lymphoid cells (ILCs) are defined as a distinct arm of innate immunity. According to their profile of secreted cytokines and lineage-specific transcriptional factors, ILCs can be categorized into the following three groups: group 1 ILCs (including natural killer (NK) cells and ILC1s) are dependent on T-bet and can produce interferon-γ; group 2 ILCs (ILC2s) are dependent on GATA3 and can produce type 2 cytokines, including interleukin (IL)-5 and IL-13; and, group 3 ILCs (including lymphoid tissue-like cells and ILC3s) are dependent on RORγt and can produce IL-22 and IL-17. Collaborative with adaptive immunity, ILCs are highly reactive innate effectors that promptly orchestrate immunity, inflammation and tissue repair. Dysregulation of ILCs might result in inflammatory disorders. Evidence regarding the function of intrahepatic ILCs is emerging from longitudinal studies of inflammatory liver diseases wherein they exert both physiological and pathological functions, including immune homeostasis, defenses and surveillance. Their overall effect on the liver depends on the balance of their proinflammatory and antiinflammatory populations, specific microenvironment and stages of immune responses. Here, we review the current data about ILCs in chronic liver disease progression, to reveal their roles in different stages as well as to discuss their therapeutic potency as intervention targets.

Ambiguous roles of innate lymphoid cells in chronic development of liver diseases

PubMed Central

Shen, Yue; Li, Jing; Wang, Si-Qi; Jiang, Wei

2018-01-01

Innate lymphoid cells (ILCs) are defined as a distinct arm of innate immunity. According to their profile of secreted cytokines and lineage-specific transcriptional factors, ILCs can be categorized into the following three groups: group 1 ILCs (including natural killer (NK) cells and ILC1s) are dependent on T-bet and can produce interferon-γ; group 2 ILCs (ILC2s) are dependent on GATA3 and can produce type 2 cytokines, including interleukin (IL)-5 and IL-13; and, group 3 ILCs (including lymphoid tissue-like cells and ILC3s) are dependent on RORγt and can produce IL-22 and IL-17. Collaborative with adaptive immunity, ILCs are highly reactive innate effectors that promptly orchestrate immunity, inflammation and tissue repair. Dysregulation of ILCs might result in inflammatory disorders. Evidence regarding the function of intrahepatic ILCs is emerging from longitudinal studies of inflammatory liver diseases wherein they exert both physiological and pathological functions, including immune homeostasis, defenses and surveillance. Their overall effect on the liver depends on the balance of their proinflammatory and antiinflammatory populations, specific microenvironment and stages of immune responses. Here, we review the current data about ILCs in chronic liver disease progression, to reveal their roles in different stages as well as to discuss their therapeutic potency as intervention targets. PMID:29760540

Characteristics of innate lymphoid cells (ILCs) and their role in immunological disorders (an update).

PubMed

Yazdani, Reza; Sharifi, Mehri; Shirvan, Aylar Saba; Azizi, Gholamreza; Ganjalikhani-Hakemi, Mazdak

2015-01-01

Innate lymphoid cells (ILCs) are a novel family of hematopoietic effectors and regulators of innate immunity. Although these cells are morphologically similar to B cells and T cells, however they do not express antigen receptors. ILCs seems to have emerging roles in innate immune responses against infectious or non-infectious microorganisms, protection of the epithelial barrier, lymphoid organogenesis and inflammation, tissue remodeling and regulating homeostasis of tissue stromal cells. In addition, it has recently been reported that ILCs have a crucial role in several disorders such as allergy and autoimmunity. Based on their phenotype and functions, ILCs are classified into three major groups called ILCs1, ILCs2, and ILCs3. Here we reviewed the most recent data concerning diverse ILC phenotypes, subclasses, functions in immune responses as well as in immune mediated disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

Regulation of Innate Lymphoid Cells by Aryl Hydrocarbon Receptor

PubMed Central

Li, Shiyang; Bostick, John W.; Zhou, Liang

2018-01-01

With striking similarity to their adaptive T helper cell counterparts, innate lymphoid cells (ILCs) represent an emerging family of cell types that express signature transcription factors, including T-bet+ Eomes+ natural killer cells, T-bet+ Eomes− group 1 ILCs, GATA3+ group 2 ILCs, RORγt+ group 3 ILCs, and newly identified Id3+ regulatory ILC. ILCs are abundantly present in barrier tissues of the host (e.g., the lung, gut, and skin) at the interface of host–environment interactions. Active research has been conducted to elucidate molecular mechanisms underlying the development and function of ILCs. The aryl hydrocarbon receptor (Ahr) is a ligand-dependent transcription factor, best known to mediate the effects of xenobiotic environmental toxins and endogenous microbial and dietary metabolites. Here, we review recent progresses regarding Ahr function in ILCs. We focus on the Ahr-mediated cross talk between ILCs and other immune/non-immune cells in host tissues especially in the gut. We discuss the molecular mechanisms of the action of Ahr expression and activity in regulation of ILCs in immunity and inflammation, and the interaction between Ahr and other pathways/transcription factors in ILC development and function with their implication in disease. PMID:29354125

Isolation and characterization of mouse innate lymphoid cells.

PubMed

Halim, Timotheus Y F; Takei, Fumio

2014-08-01

Innate lymphoid cells (ILCs) are rare populations of cytokine-producing lymphocytes and are divided into three groups, namely ILC1, ILC2, and ILC3, based on the cytokines that they produce. They comprise less than 1% of lymphocytes in mucosal tissues and express no unique cell surface markers. Therefore, they can only be identified by combinations of multiple cell surface markers and further characterized by cytokine production in vitro. Thus, multicolor flow cytometry is the only reliable method to purify and characterize ILCs. Here we describe the methods for cell preparation, flow cytometric analysis, and purification of murine ILC2 and ILC3. Copyright © 2014 John Wiley & Sons, Inc.

Governance of the International Linear Collider Project

DOE Office of Scientific and Technical Information (OSTI.GOV)

Foster, B.; /Oxford U.; Barish, B.

Governance models for the International Linear Collider Project are examined in the light of experience from similar international projects around the world. Recommendations for one path which could be followed to realize the ILC successfully are outlined. The International Linear Collider (ILC) is a unique endeavour in particle physics; fully international from the outset, it has no 'host laboratory' to provide infrastructure and support. The realization of this project therefore presents unique challenges, in scientific, technical and political arenas. This document outlines the main questions that need to be answered if the ILC is to become a reality. It describesmore » the methodology used to harness the wisdom displayed and lessons learned from current and previous large international projects. From this basis, it suggests both general principles and outlines a specific model to realize the ILC. It recognizes that there is no unique model for such a laboratory and that there are often several solutions to a particular problem. Nevertheless it proposes concrete solutions that the authors believe are currently the best choices in order to stimulate discussion and catalyze proposals as to how to bring the ILC project to fruition. The ILC Laboratory would be set up by international treaty and be governed by a strong Council to whom a Director General and an associated Directorate would report. Council would empower the Director General to give strong management to the project. It would take its decisions in a timely manner, giving appropriate weight to the financial contributions of the member states. The ILC Laboratory would be set up for a fixed term, capable of extension by agreement of all the partners. The construction of the machine would be based on a Work Breakdown Structure and value engineering and would have a common cash fund sufficiently large to allow the management flexibility to optimize the project's construction. Appropriate contingency, clearly apportioned at both a national and global level, is essential if the project is to be realised. Finally, models for running costs and decommissioning at the conclusion of the ILC project are proposed. This document represents an interim report of the bodies and individuals studying these questions inside the structure set up and supervised by the International Committee for Future Accelerators (ICFA). It represents a request for comment to the international community in all relevant disciplines, scientific, technical and most importantly, political. Many areas require further study and some, in particular the site selection process, have not yet progressed sufficiently to be addressed in detail in this document. Discussion raised by this document will be vital in framing the final proposals due to be published in 2012 in the Technical Design Report being prepared by the Global Design Effort of the ILC.« less

Comparison of sentinel lymph node biopsy between invasive lobular carcinoma and invasive ductal carcinoma.

PubMed

Adachi, Yayoi; Sawaki, Masataka; Hattori, Masaya; Yoshimura, Akiyo; Gondo, Noami; Kotani, Haruru; Iwase, Madoka; Kataoka, Ayumi; Onishi, Sakura; Sugino, Kayoko; Terada, Mitsuo; Horisawa, Nanae; Mori, Makiko; Oze, Isao; Iwata, Hiroji

2018-03-13

Recent studies suggested that ALND (axillary lymph node dissection) can be avoided in breast cancer patients with limited SLN (sentinel lymph node) metastasis. However, these trials included only several invasive lobular carcinoma (ILC) cases, and the validity of omitting ALND for ILC remains controversial. Here, we examined whether omitting ALND is feasible in ILC treatment. A total of 3771 breast cancer patients underwent surgery for breast cancer at the Aichi Cancer Center Hospital between January 2006 and December 2015. We excluded patients with neoadjuvant therapy or without axillary management, and identified 184 ILC patients and 2402 invasive ductal carcinoma (IDC) patients. We compared SLN and non-SLN metastasis rates and the number of total ALN metastases between the ILC and IDC cohorts, and we examined the factors that influenced non-SLN metastasis in the SLN micrometastasis group. SLN biopsies were performed in 171 (93%) ILC and 2168 (90%) IDC cases, and 31 (18%) ILC and 457 (21%) IDC cases were SLN micrometastasis and macrometastasis (p = 0.36). Among SLN macrometastasis patients, 17 (68%) ILC cases and 163 (46%) IDC cases showed non-SLN metastasis (p = 0.03). The number of non-SLN metastases was greater in ILC cases compared with IDC cases. Multivariate analysis showed that ILC was the influential factor predicting non-SLN metastasis in patients with SLN macrometastasis. ILC cases had more non-SLN metastasis than IDC cases among SLN-positive cases, and ILC was an important factor for the prediction of non-SLN positivity in SLN macrometastasis cases. Omitting ALND for ILC with positive SLNs requires more consideration.

Innate Lymphoid Cells in Intestinal Inflammation

PubMed Central

Geremia, Alessandra; Arancibia-Cárcamo, Carolina V.

2017-01-01

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestine that encompasses Crohn’s disease (CD) and ulcerative colitis. The cause of IBD is unknown, but the evidence suggests that an aberrant immune response toward the commensal bacterial flora is responsible for disease in genetically susceptible individuals. Results from animal models of colitis and human studies indicate a role for innate lymphoid cells (ILC) in the pathogenesis of chronic intestinal inflammation in IBD. ILC are a population of lymphocytes that are enriched at mucosal sites, where they play a protective role against pathogens including extracellular bacteria, helminthes, and viruses. ILC lack an antigen-specific receptor, but can respond to environmental stress signals contributing to the rapid orchestration of an early immune response. Several subsets of ILC reflecting functional characteristics of T helper subsets have been described. ILC1 express the transcription factor T-bet and are characterized by secretion of IFNγ, ILC2 are GATA3+ and secrete IL5 and IL13 and ILC3 depend on expression of RORγt and secrete IL17 and IL22. However, ILC retain a degree of plasticity depending on exposure to cytokines and environmental factors. IL23 responsive ILC have been implicated in the pathogenesis of colitis in several innate murine models through the production of IL17, IFNγ, and GM-CSF. We have previously identified IL23 responsive ILC in the human intestine and found that they accumulate in the inflamed colon and small bowel of patients with CD. Other studies have confirmed accumulation of ILC in CD with increased frequencies of IFNγ-secreting ILC1 in both the intestinal lamina propria and the epithelium. Moreover, IL23 driven IL22 producing ILC have been shown to drive bacteria-induced colitis-associated cancer in mice. Interestingly, our data show increased ILC accumulation in patients with IBD and primary sclerosing cholangitis, who carry an increased risk of developing colorectal cancer. ILC may play an important amplifying role in IBD and IBD-associated cancer, through secretion of inflammatory cytokines and interaction with other immune and non-immune cells. Here, we will review the evidence indicating a role for ILC in the pathogenesis of chronic intestinal inflammation. PMID:29081776

The Yin and Yang of Innate Lymphoid Cells in Cancer.

PubMed

Carrega, Paolo; Campana, Stefania; Bonaccorsi, Irene; Ferlazzo, Guido

2016-11-01

The recent appreciation of novel subsets of innate lymphoid cells (ILCs) as important regulators of tissue homeostasis, inflammation and repair, raise questions regarding the presence and role of these cells in cancer tissues. In addition to natural killer and fetal lymphoid tissue inducer (LTi) cells, the ILC family comprises non-cytolytic, cytokine-producing cells that are classified into ILC1, ILC2 and ILC3 based on phenotypic and functional characteristics. Differently from natural killer cells, which are the prototypical members of ILC1 and whose role in tumors is better established, the involvement of other ILC subsets in cancer progression or resistance is still fuzzy and in several instances controversial, since current studies indicate both context-dependent beneficial or pathogenic effects. Here, we review the current knowledge regarding the involvement of these novel ILC subsets in the context of tumor immunology, highlighting how ILC subsets might behave either as friends or foes. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Human innate lymphoid cells.

PubMed

Montaldo, Elisa; Vacca, Paola; Vitale, Chiara; Moretta, Francesca; Locatelli, Franco; Mingari, Maria Cristina; Moretta, Lorenzo

2016-11-01

The interest in innate lymphoid cells (ILC) has rapidly grown during the last decade. ILC include distinct cell types that are collectively involved in host protection against pathogens and tumor cells and in the regulation of tissue homeostasis. Studies in mice enabled a broad characterization of ILC function and of their developmental requirements. In humans all mature ILC subsets have been characterized and their role in the pathogenesis of certain disease is emerging. Nonetheless, still limited information is available on human ILC development. Indeed, only the cell precursors committed toward NK cells or ILC3 have been described. Here, we review the most recent finding on human mature ILC, discussing their tissue localization and function. Moreover, we summarize the available data regarding human ILC development. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Group 2 innate lymphoid cells in disease

PubMed Central

2016-01-01

Abstract Group 2 innate lymphoid cells (ILC2) are now recognized as an important innate source of type-2 effector cytokines. Although initially associated with mucosal tissues, it is clear that ILC2 are present in diverse anatomical locations. The function of ILC2 at these sites is equally varied, and although ILC2 represent a relatively minor population, they are fundamentally important regulators of innate and adaptive immune processes. As such, there is much interest to understand the role of ILC2 in diseases with a type-2 inflammatory component. This review explores the known roles of ILC2 in disease, and the diseases that show associations or other strong evidence for the involvement of ILC2. PMID:26306498

Human intrahepatic ILC2 are IL-13positive amphiregulinpositive and their frequency correlates with model of end stage liver disease score.

PubMed

Jeffery, Hannah C; McDowell, Patrick; Lutz, Philipp; Wawman, Rebecca E; Roberts, Sheree; Bagnall, Chris; Birtwistle, Jane; Adams, David H; Oo, Ye Htun

2017-01-01

Innate lymphoid cells (ILC) have been implicated in the initiation of inflammation and fibrosis in mice. However, ILC have not been characterized in inflamed human liver tissue. Human intrahepatic lymphocytes were isolated by mechanical digestion and phenotyped by flow cytometry. Conditioned medium from cultures of primary human biliary epithelial cells, stellate cells, fibroblasts and inflamed human liver tissue was used to model the effects of the inflammatory liver environment of ILC phenotype and function. All three ILC subsets were present in the human liver, with the ILC1 (CRTH2negCD117neg) subset constituting around 70% of intrahepatic ILCs. Both NCRpos (NKp44+) and NCRneg ILC3 (CRTH2negCD117pos) subsets were also detected. ILC2 (CRTH2pos) frequency correlated with disease severity measured by model of end stage liver disease (MELD) scoring leading us to study this subset in more detail. ILC2 displayed a tissue resident CD69+ CD161++ phenotype and expressed chemokine receptor CCR6 allowing them to respond to CCL20 secreted by cholangiocytes and stellate cells. ILC2 expressed integrins VLA-5 and VLA-6 and the IL-2 and IL-7 cytokine receptors CD25 and CD127 although IL-2 and IL-7 were barely detectable in inflamed liver tissue. Although biliary epithelial cells secrete IL-33, intrahepatic ILC2 had low expression of the ST2 receptor. Intrahepatic ILC2 secreted the immunoregulatory and repair cytokines IL-13 and amphiregulin. Intrahepatic ILC2 express receptors allowing them to be recruited to bile ducts in inflamed portal tracts. Their frequencies increased with worsening liver function. Their secretion of IL-13 and amphiregulin suggests they may be recruited to promote resolution and repair and thereby they may contribute to ongoing fibrogenesis in liver disease.

Characterization of innate lymphoid cells (ILC) in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis

PubMed Central

Tosi, Isabella; Grys, Katarzyna; Sreeneebus, Hemawtee; Perera, Gayathri K; Chapman, Anna; Smith, Catherine H; Di Meglio, Paola; Nestle, Frank O

2013-01-01

Innate lymphoid cells (ILC) are increasingly appreciated as key regulators of tissue immunity. However, their role in human tissue homeostasis and disease remains to be fully elucidated. Here we characterise the ILC in human skin from healthy individuals and from the inflammatory skin disease psoriasis. We show that a substantial proportion of IL-17A and IL-22 producing cells in skin and blood of normal individuals and psoriasis patients are CD3 negative innate lymphocytes. Deep immunophenotyping of human ILC subsets showed a statistically significant increase in the frequency of circulating NKp44+ ILC3 in blood of psoriasis patients compared to healthy individuals or atopic dermatitis patients. More than 50% of circulating NKp44+ ILC3 expressed cutaneous lymphocyte-associated antigen indicating their potential for skin homing. Analysis of skin tissue revealed a significantly increased frequency of total ILC in skin compared to blood. Moreover the frequency of NKp44+ ILC3 was significantly increased in non-lesional psoriatic skin compared to normal skin. A detailed time course of a psoriasis patient treated with anti-TNF showed a close association between therapeutic response, decrease in inflammatory skin lesions, and decrease of circulating NKp44+ ILC3. Overall, data from this initial observational study suggest a potential role for NKp44+ ILC3 in psoriasis pathogenesis. PMID:24352038

Innate lymphoid cells in normal and disease: An introductory overview.

PubMed

Moretta, Lorenzo; Locatelli, Franco

2016-11-01

Innate lymphoid cells (ILC) represent a novel group of lymphocytes that, different from T and B-lymphocytes lack recombinant activating genes (RAG-1 or RAG-2) and thus do not express rearranged antigen-specific receptors. Members of this family, i.e. NK cells, have been known since long time, while the other ILCs have been discovered only in recent years, possibly because of their predominant localization in tissues, primarily in mucosal tissues, skin and mucosa-associated lymphoid organs. ILC have been grouped in three major subsets on the basis of their phenotypic and functional features as well as of their dependency on given transcription factors (TF). Briefly, ILC-1 are dependent on T-bet TF and produce interferon (IFN)-γ. Group 2 ILC (ILC2) express GATA-3 TF and produce IL-5, IL-4 and IL-13 (Type 2) cytokines while group 3 ILC (ILC3) express RORγt TF and produce IL-17 and IL-22. ILC provide early defenses against pathogens and intervene in the repair of damaged tissues. ILC activation is mediated by cytokines (specifically acting on different ILC groups) and/or by activating receptors that are, at least in part, the same that had been previously identified in NK cells [1]. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Matter, Energy, Space and Time: The International Linear Collider Physics Prospects and International Aspects

NASA Astrophysics Data System (ADS)

Wagner, Albrecht

2006-04-01

Over the past century, physicists have sought to explain the character of the matter and energy in our universe, to show how the basic forces of nature and the building blocks of matter come about, and to explore the fabric of space and time. In the past three decades, experiments at laboratories around the world have given us a precise confirmation of the underlying theory called the standard model. These particle physics advances have a direct impact for our understanding of the structure of the universe, both at its inception in the Big Bang, and in its evolution to the present and future. The final synthesis is not yet fully clear, but we know with confidence that major discoveries expanding the standard model framework will occur at the next generation of accelerators. The Large Hadron Collider (LHC) being built at CERN will take us into the discovery realm. The proposed International Linear Collider (ILC) will extend the discoveries and provide a wealth of precision measurements that are essential for giving deeper understanding of their meaning, and pointing the way to further evolution of particle physics in the future. A world-wide consensus has formed for a baseline ILC project at energies of 500 GeV and beyond. The choice of the superconducting technology as basis for the ILC has paved the way for a global design effort which has now taken full speed.

Innate Lymphoid Cells in Tumor Immunity.

PubMed

van Beek, Jasper J P; Martens, Anne W J; Bakdash, Ghaith; de Vries, I Jolanda M

2016-02-25

Innate lymphoid cells (ILCs) are a group of immune cells of the lymphoid lineage that do not possess antigen specificity. The group includes natural killer (NK) cells, lymphoid tissue inducer (LTi) cells and the recently identified ILC1s, ILC2s and ILC3s. Although the role of NK cells in the context of cancer has been well established, the involvement of other ILC subsets in cancer progression and resistance is just emerging. Here, we review the literature on the role of the different ILC subsets in tumor immunity and discuss its implications for cancer treatment and monitoring.

Innate Lymphoid Cells in Tumor Immunity

PubMed Central

van Beek, Jasper J. P.; Martens, Anne W. J.; Bakdash, Ghaith; de Vries, I. Jolanda M.

2016-01-01

Innate lymphoid cells (ILCs) are a group of immune cells of the lymphoid lineage that do not possess antigen specificity. The group includes natural killer (NK) cells, lymphoid tissue inducer (LTi) cells and the recently identified ILC1s, ILC2s and ILC3s. Although the role of NK cells in the context of cancer has been well established, the involvement of other ILC subsets in cancer progression and resistance is just emerging. Here, we review the literature on the role of the different ILC subsets in tumor immunity and discuss its implications for cancer treatment and monitoring. PMID:28536374

Innate Lymphoid Cells in HIV/SIV Infections.

PubMed

Shah, Spandan V; Manickam, Cordelia; Ram, Daniel R; Reeves, R Keith

2017-01-01

Over the past several years, new populations of innate lymphocytes have been described in mice and primates that are critical for mucosal homeostasis, microbial regulation, and immune defense. Generally conserved from mice to humans, innate lymphoid cells (ILC) have been divided primarily into three subpopulations based on phenotypic and functional repertoires: ILC1 bear similarities to natural killer cells; ILC2 have overlapping functions with TH2 cells; and ILC3 that share many functions with TH17/TH22 cells. ILC are specifically enriched at mucosal surfaces and are possibly one of the earliest responders during viral infections besides being involved in the homeostasis of gut-associated lymphoid tissue and maintenance of gut epithelial barrier integrity. Burgeoning evidence also suggests that there is an early and sustained abrogation of ILC function and numbers during HIV and pathogenic SIV infections, most notably ILC3 in the gastrointestinal tract, which leads to disruption of the mucosal barrier and dysregulation of the local immune system. A better understanding of the direct or indirect mechanisms of loss and dysfunction will be critical to immunotherapeutics aimed at restoring these cells. Herein, we review the current literature on ILC with a particular emphasis on ILC3 and their role(s) in mucosal immunology and the significance of disrupting the ILC niche during HIV and SIV infections.

Innate lymphoid cells in tissue homeostasis and diseases.

PubMed

Ignacio, Aline; Breda, Cristiane Naffah Souza; Camara, Niels Olsen Saraiva

2017-08-18

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells. They are a part of the innate immune system, but develop from the lymphoid lineage. They lack pattern-recognition receptors and rearranged receptors, and therefore cannot directly mediate antigen specific responses. The progenitors specifically associated with the ILCs lineage have been uncovered, enabling the distinction between ILCs and natural killer cells. Based on the requirement of specific transcription factors and their patterns of cytokine production, ILCs are categorized into three subsets (ILC1, ILC2 and ILC3). First observed in mucosal surfaces, these cell populations interact with hematopoietic and non-hematopoietic cells throughout the body during homeostasis and diseases, promoting immunity, commensal microbiota tolerance, tissue repair and inflammation. Over the last 8 years, ILCs came into the spotlight as an essential cell type able to integrate diverse host immune responses. Recently, it became known that ILC subsets play a key role in immune responses at barrier surfaces, interacting with the microbiota, nutrients and metabolites. Since the liver receives the venous blood directly from the intestinal vein, the intestine and liver are essential to maintain tolerance and can rapidly respond to infections or tissue damage. Therefore, in this review, we discuss recent findings regarding ILC functions in homeostasis and disease, with a focus on the intestine and liver.

Innate Lymphoid Cells in HIV/SIV Infections

PubMed Central

Shah, Spandan V.; Manickam, Cordelia; Ram, Daniel R.; Reeves, R. Keith

2017-01-01

Over the past several years, new populations of innate lymphocytes have been described in mice and primates that are critical for mucosal homeostasis, microbial regulation, and immune defense. Generally conserved from mice to humans, innate lymphoid cells (ILC) have been divided primarily into three subpopulations based on phenotypic and functional repertoires: ILC1 bear similarities to natural killer cells; ILC2 have overlapping functions with TH2 cells; and ILC3 that share many functions with TH17/TH22 cells. ILC are specifically enriched at mucosal surfaces and are possibly one of the earliest responders during viral infections besides being involved in the homeostasis of gut-associated lymphoid tissue and maintenance of gut epithelial barrier integrity. Burgeoning evidence also suggests that there is an early and sustained abrogation of ILC function and numbers during HIV and pathogenic SIV infections, most notably ILC3 in the gastrointestinal tract, which leads to disruption of the mucosal barrier and dysregulation of the local immune system. A better understanding of the direct or indirect mechanisms of loss and dysfunction will be critical to immunotherapeutics aimed at restoring these cells. Herein, we review the current literature on ILC with a particular emphasis on ILC3 and their role(s) in mucosal immunology and the significance of disrupting the ILC niche during HIV and SIV infections. PMID:29326704

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells.

PubMed

Melo-Gonzalez, Felipe; Hepworth, Matthew R

2017-03-01

Group 3 innate lymphoid cells (ILC3), defined by expression of the transcription factor retinoid-related orphan receptor γt, play key roles in the regulation of inflammation and immunity in the gastrointestinal tract and associated lymphoid tissues. ILC3 consist largely of two major subsets, NCR + ILC3 and LTi-like ILC3, but also demonstrate significant plasticity and heterogeneity. Recent advances have begun to dissect the relationship between ILC3 subsets and to define distinct functional states within the intestinal tissue microenvironment. In this review we discuss the ever-expanding roles of ILC3 in the context of intestinal homeostasis, infection and inflammation - with a focus on comparing and contrasting the relative contributions of ILC3 subsets. © 2016 The Authors. Immunology published by John Wiley & Sons Ltd.

Seven-year survey of classical and pleomorphic invasive lobular breast carcinomas in women from southeastern Serbia: Differences in clinicopathological and immunohistochemical features.

PubMed

Ilic, Ivan R; Djordjevic, Nebojsa P; Randjelovic, Pavle J; Stojanovic, Nikola M; Radulovic, Niko S; Ilic, Ratko S

2016-01-01

The occurrence of different variants of invasive lobular carcinoma (ILC) of the breast is variable. For example, the pleomorphic variant of ILC has an incidence of around 5%; however, the number of analyzed cases of ILC is shadowed by the number of ductal type carcinoma (IDC). Thus, we aimed to analyze the classical and pleomorphic ILCs in women from southeastern Serbia. Analyzed were 296 cases (11.91%) diagnosed with ILC, out of 2486 cases of all breast cancers (BCs), during a 7-year period (2005-2011) from southeastern Serbia. The differences in clinicopathological and immunohistochemical features (estrogen receptor/ER, progesterone receptor/ PR, HER-2, Ki-67, BRCA-1, p53 and E-cadherin) of these cases of ILCs were assessed and compared. Pleomorphic ILC occurred relatively rarely compared to other variants, however almost one fifth of the ILC cases were pleomorphic. No statistically significant correlation was found between patient age, tumor stage and the presence/absence of multifocality (MFC), multicentricity (MCC) and bilaterality (BL) on one side, and ILC variant on the other. Only the expression of two prognostic and predictive immunohistochemical markers, important for endocrine therapy, ER and PR, showed significant correlation with the ILC variant. Although higher tumor stage, incidence of multicentricity, overexpression of HER2 and higher p53 positivity were deemed to be characteristic of pleomorphic ILC, in our study that included a much larger number of cases than previous studies did, such correlations were not observed. Thus, it appears that the only two features of pleomorphic ILCs is absence of ER and PR positivity.

Expansion of CD25+ Innate Lymphoid Cells Reduces Atherosclerosis

PubMed Central

Engelbertsen, Daniel; Foks, Amanda C.; Alberts-Grill, Noah; Kuperwaser, Felicia; Chen, Tao; Lederer, James A.; Jarolim, Petr; Grabie, Nir; Lichtman, Andrew H.

2015-01-01

Objective Innate lymphoid cells (ILCs) are a newly discovered subset of immune cells that promote tissue homeostasis and protect against pathogens. ILCs produce cytokines also produced by T lymphocytes that have been shown to affect atherosclerosis, but the influence of ILCs on atherosclerosis has not been explored. Approach and Results We demonstrate that CD25+ ILCs that produce type 2 cytokines (ILC2s) are present in the aorta of atherosclerotic immunodeficient ldlr−/−rag1−/− mice. To investigate the role of ILCs in atherosclerosis, ldlr−/−rag1−/− mice were concurrently fed an atherogenic diet and treated with either ILC-depleting anti-CD90.2 antibodies or with IL-2/anti-IL-2 complexes that expand CD25+ ILCs. Lesion development was not affected by anti-CD90.2 treatment, but was reduced in IL-2/anti-IL-2 -treated mice. These IL-2 treated mice had reduced VLDL cholesterol and increased triglycerides compared to controls and reduced apolipoprotein B100 gene expression in the liver. IL-2/anti-IL-2 treatment caused expansion of ILC2s in aorta and other tissues, elevated levels of IL-5, systemic eosinophila and hepatic eosinophilic inflammation. Blockade of IL-5 reversed the IL-2-complex-induced eosinophilia but did not change lesion size. Conclusions This study demonstrates that expansion of CD25-expressing ILCs by IL-2/anti-IL-2 complexes leads to a reduction in VLDL cholesterol and atherosclerosis. Global depletion of ILCs by anti-CD90.2 did not significantly affect lesion size indicating that different ILC subsets may have divergent effects on atherosclerosis. PMID:26494229

IL-4 production by group 2 innate lymphoid cells promotes food allergy by blocking regulatory T-cell function.

PubMed

Noval Rivas, Magali; Burton, Oliver T; Oettgen, Hans C; Chatila, Talal

2016-09-01

Food allergy is a major health issue, but its pathogenesis remains obscure. Group 2 innate lymphoid cells (ILC2s) promote allergic inflammation. However their role in food allergy is largely unknown. We sought to investigate the role of ILC2s in food allergy. Food allergy-prone mice with a gain-of-function mutation in the IL-4 receptor α chain (Il4raF709) were orally sensitized with food allergens, and the ILC2 compartment was analyzed. The requirement for ILC2s in food allergy was investigated by using Il4raF709, IL-33 receptor-deficient (Il1rl1(-/-)), IL-13-deficient (Il13(-/-)), and IL-4-deficient (Il4(-/-)) mice and by adoptive transfer of in vitro-expanded ILC2s. Direct effects of ILC2s on regulatory T (Treg) cells and mast cells were analyzed in coculture experiments. Treg cell control of ILC2s was assessed in vitro and in vivo. Il4raF709 mice with food allergy exhibit increased numbers of ILC2s. IL-4 secretion by ILC2s contributes to the allergic response by reducing allergen-specific Treg cell and activating mast cell counts. IL-33 receptor deficiency in Il4raF709 Il1rl1(-/-) mice protects against allergen sensitization and anaphylaxis while reducing ILC2 induction. Adoptive transfer of wild-type and Il13(-/-) but not Il4(-/-) ILC2s restored sensitization in Il4raF709 Il1rl1(-/-) mice. Treg cells suppress ILC2s in vitro and in vivo. IL-4 production by IL-33-stimulated ILC2s blocks the generation of allergen-specific Treg cells and favors food allergy. Strategies to block ILC2 activation or the IL-33/IL-33 receptor pathway can lead to innovative therapies in the treatment of food allergy. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Innate lymphoid cells at the interface between obesity and asthma.

PubMed

Everaere, Laetitia; Ait Yahia, Saliha; Bouté, Mélodie; Audousset, Camille; Chenivesse, Cécile; Tsicopoulos, Anne

2018-01-01

Obesity and asthma prevalence has dramatically and concomitantly increased over the last 25 years, and many epidemiological studies have highlighted obesity as an important risk factor for asthma. Although many studies have been performed, the underlying mechanisms remain poorly understood. Innate mechanisms have been involved in both diseases, in particular through the recently described innate lymphoid cells (ILCs). ILCs are subdivided into three groups that are defined by their cytokine production and by their master transcription factor expression, in sharp correlation with their T helper counterparts. However, unlike T helper cells, ILCs do not express antigen-specific receptors, but respond to damage-induced signals. ILCs have been found in target tissues of both diseases, and data have implicated these cells in the pathogenesis of both diseases. In particular group 2 ILCs (ILC2) are activated in both the adipose and lung tissues under the effect of interleukin-33 and interleukin-25 expression. However, counter-intuitively to the well-known association between obesity and asthma, ILC2 are beneficial for obesity but deleterious for asthma. This review will examine the roles of ILCs in each disease and recent data highlighting ILCs as a putative link between obesity and asthma. © 2017 John Wiley & Sons Ltd.

Type 2 innate lymphoid cells-new members of the "type 2 franchise" that mediate allergic airway inflammation.

PubMed

Mjösberg, Jenny; Spits, Hergen

2012-05-01

Type 2 innate lymphoid cells (ILC2s) are members of an ILC family, which contains NK cells and Rorγt(+) ILCs, the latter including lymphoid tissue inducer (LTi) cells and ILCs producing IL-17 and IL-22. ILC2s are dedicated to the production of IL-5 and IL-13 and, as such, ILC2s provide an early and important source of type 2 cytokines critical for helminth expulsion in the gut. Several studies have also demonstrated a role for ILC2s in airway inflammation. In this issue of the European Journal of Immunology, Klein Wolterink et al. [Eur. J. Immunol. 2012. 42: 1106-1116] show that ILC2s are instrumental in several models of experimental asthma where they significantly contribute to production of IL-5 and IL-13, key cytokines in airway inflammation. This study sheds light over the relative contribution of ILC2s versus T helper type 2 cells (Th2) in type 2 mediated allergen-specific inflammation in the airways as discussed in this commentary. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Innate lymphoid cells in graft-versus-host disease.

PubMed

Konya, V; Mjösberg, J

2015-11-01

Innate lymphoid cells (ILC) are lymphocytes lacking rearranged antigen receptors such as those expressed by T and B cells. ILC are important effector and regulatory cells of the innate immune system, controlling lymphoid organogenesis, tissue inflammation, and homeostasis. The family of ILC consists of cytotoxic NK cells and the more recently described noncytotoxic group 1, 2, and 3 ILC. The classification of noncytotoxic ILC-in many aspects-mirrors that of T helper cells, which is based on the expression of master transcription factors and signature cytokines specific for each subset. The IL-22 producing RORγt(+) ILC3 subset was recently found to be critical in the prevention of intestinal graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT) via strengthening the intestinal mucosal barrier. In this review, we summarize the current view of the immunological functions of human noncytotoxic ILC subsets and discuss the potentially beneficial features of IL-22 producing ILC3 in improving allo-HCT efficacy by attenuating susceptibility to GVHD. In addition, we explore the possibility of other ILC subsets playing a role in GVHD. © 2015 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.

Group 2 Innate Lymphoid Cells Exhibit a Dynamic Phenotype in Allergic Airway Inflammation

PubMed Central

Li, Bobby W. S.; Stadhouders, Ralph; de Bruijn, Marjolein J. W.; Lukkes, Melanie; Beerens, Dior M. J. M.; Brem, Maarten D.; KleinJan, Alex; Bergen, Ingrid; Vroman, Heleen; Kool, Mirjam; van IJcken, Wilfred F. J.; Rao, Tata Nageswara; Fehling, Hans Jörg; Hendriks, Rudi W.

2017-01-01

Group 2 innate lymphoid cells (ILC2) are implicated in allergic asthma as an early innate source of the type 2 cytokines IL-5 and IL-13. However, their induction in house dust mite (HDM)-mediated airway inflammation additionally requires T cell activation. It is currently unknown whether phenotypic differences exist between ILC2s that are activated in a T cell-dependent or T cell-independent fashion. Here, we compared ILC2s in IL-33- and HDM-driven airway inflammation. Using flow cytometry, we found that surface expression levels of various markers frequently used to identify ILC2s were dependent on their mode of activation, highly variable over time, and differed between tissue compartments, including bronchoalveolar lavage (BAL) fluid, lung, draining lymph nodes, and spleen. Whereas in vivo IL-33-activated BAL fluid ILC2s exhibited an almost uniform CD25+CD127+T1/ST2+ICOS+KLRG1+ phenotype, at a comparable time point after HDM exposure BAL fluid ILC2s had a very heterogeneous surface marker phenotype. A major fraction of HDM-activated ILC2s were CD25lowCD127+T1/ST2low ICOSlowKLRG1low, but nevertheless had the capacity to produce large amounts of type 2 cytokines. HDM-activated CD25low ILC2s in BAL fluid and lung rapidly reverted to CD25high ILC2s upon in vivo stimulation with IL-33. Genome-wide transcriptional profiling of BAL ILC2s revealed ~1,600 differentially expressed genes: HDM-stimulated ILC2s specifically expressed genes involved in the regulation of adaptive immunity through B and T cell interactions, whereas IL-33-stimulated ILC2s expressed high levels of proliferation-related and cytokine genes. In both airway inflammation models ILC2s were present in the lung submucosa close to epithelial cells, as identified by confocal microscopy. In chronic HDM-driven airway inflammation ILC2s were also found inside organized cellular infiltrates near T cells. Collectively, our findings show that ILC2s are phenotypically more heterogeneous than previously thought, whereby their surface marker and gene expression profile are highly dynamic. PMID:29250067

Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis.

PubMed

Villanova, Federica; Flutter, Barry; Tosi, Isabella; Grys, Katarzyna; Sreeneebus, Hemawtee; Perera, Gayathri K; Chapman, Anna; Smith, Catherine H; Di Meglio, Paola; Nestle, Frank O

2014-04-01

Innate lymphoid cells (ILCs) are increasingly appreciated as key regulators of tissue immunity. However, their role in human tissue homeostasis and disease remains to be fully elucidated. Here we characterize the ILCs in human skin from healthy individuals and from the inflammatory skin disease psoriasis. We show that a substantial proportion of IL-17A and IL-22 producing cells in the skin and blood of normal individuals and psoriasis patients are CD3-negative innate lymphocytes. Deep immunophenotyping of human ILC subsets showed a statistically significant increase in the frequency of circulating NKp44+ ILC3 in the blood of psoriasis patients compared with healthy individuals or atopic dermatitis patients. More than 50% of circulating NKp44+ ILC3 expressed cutaneous lymphocyte-associated antigen, indicating their potential for skin homing. Analysis of skin tissue revealed a significantly increased frequency of total ILCs in the skin compared with blood. Moreover, the frequency of NKp44+ ILC3 was significantly increased in non-lesional psoriatic skin compared with normal skin. A detailed time course of a psoriasis patient treated with anti-tumor necrosis factor showed a close association between therapeutic response, decrease in inflammatory skin lesions, and decrease of circulating NKp44+ ILC3. Overall, data from this initial observational study suggest a potential role for NKp44+ ILC3 in psoriasis pathogenesis.

Innate lymphoid cells in tissue homeostasis and diseases

PubMed Central

Ignacio, Aline; Breda, Cristiane Naffah Souza; Camara, Niels Olsen Saraiva

2017-01-01

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells. They are a part of the innate immune system, but develop from the lymphoid lineage. They lack pattern-recognition receptors and rearranged receptors, and therefore cannot directly mediate antigen specific responses. The progenitors specifically associated with the ILCs lineage have been uncovered, enabling the distinction between ILCs and natural killer cells. Based on the requirement of specific transcription factors and their patterns of cytokine production, ILCs are categorized into three subsets (ILC1, ILC2 and ILC3). First observed in mucosal surfaces, these cell populations interact with hematopoietic and non-hematopoietic cells throughout the body during homeostasis and diseases, promoting immunity, commensal microbiota tolerance, tissue repair and inflammation. Over the last 8 years, ILCs came into the spotlight as an essential cell type able to integrate diverse host immune responses. Recently, it became known that ILC subsets play a key role in immune responses at barrier surfaces, interacting with the microbiota, nutrients and metabolites. Since the liver receives the venous blood directly from the intestinal vein, the intestine and liver are essential to maintain tolerance and can rapidly respond to infections or tissue damage. Therefore, in this review, we discuss recent findings regarding ILC functions in homeostasis and disease, with a focus on the intestine and liver. PMID:28878863

Down-regulation of E protein activity augments an ILC2 differentiation program in the thymus

USDA-ARS?s Scientific Manuscript database

Innate lymphoid cells (ILCs) are important regulators in various immune responses. Current paradigm states that all newly-made ILCs originate from common lymphoid progenitors (CLP) in the bone marrow. Id2, an inhibitor of E protein transcription factors, is indispensable for ILC differentiation. Une...

Exotic decays of the 125 GeV Higgs boson at future e +e – colliders

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Zhen; Wang, Lian -Tao; Zhang, Hao

Discovery of unexpected properties of the Higgs boson offers an intriguing opportunity of shedding light on some of the most profound puzzles in particle physics. The Beyond Standard Model (BSM) decays of the Higgs boson could reveal new physics in a direct manner. Future electron-positron lepton colliders operating as Higgs factories, including CEPC, FCC-ee and ILC, with the advantages of a clean collider environment and large statistics, could greatly enhance the sensitivity in searching for these BSM decays. In this work, we perform a general study of Higgs exotic decays at futuremore » $e^+e^-$ lepton colliders, focusing on the Higgs decays with hadronic final states and/or missing energy, which are very challenging for the High-Luminosity program of the Large Hadron Collider (HL-LHC). We show that with simple selection cuts, $$O(10^{-3}\\sim10^{-5})$$ limits on the Higgs exotic decay branching fractions can be achieved using the leptonic decaying spectator $Z$ boson in the associated production mode $$e^+e^-\\rightarrow Z H$$. We further discuss the interplay between the detector performance and Higgs exotic decay, and other possibilities of exotic decays. Finally, our work is a first step in a comprehensive study of Higgs exotic decays at future lepton colliders, which is a key ingredient of Higgs physics that deserves further investigation.« less

Exotic decays of the 125 GeV Higgs boson at future e +e – colliders

DOE PAGES

Liu, Zhen; Wang, Lian -Tao; Zhang, Hao

2017-06-01

Discovery of unexpected properties of the Higgs boson offers an intriguing opportunity of shedding light on some of the most profound puzzles in particle physics. The Beyond Standard Model (BSM) decays of the Higgs boson could reveal new physics in a direct manner. Future electron-positron lepton colliders operating as Higgs factories, including CEPC, FCC-ee and ILC, with the advantages of a clean collider environment and large statistics, could greatly enhance the sensitivity in searching for these BSM decays. In this work, we perform a general study of Higgs exotic decays at futuremore » $e^+e^-$ lepton colliders, focusing on the Higgs decays with hadronic final states and/or missing energy, which are very challenging for the High-Luminosity program of the Large Hadron Collider (HL-LHC). We show that with simple selection cuts, $$O(10^{-3}\\sim10^{-5})$$ limits on the Higgs exotic decay branching fractions can be achieved using the leptonic decaying spectator $Z$ boson in the associated production mode $$e^+e^-\\rightarrow Z H$$. We further discuss the interplay between the detector performance and Higgs exotic decay, and other possibilities of exotic decays. Finally, our work is a first step in a comprehensive study of Higgs exotic decays at future lepton colliders, which is a key ingredient of Higgs physics that deserves further investigation.« less

An open-closed-loop iterative learning control approach for nonlinear switched systems with application to freeway traffic control

NASA Astrophysics Data System (ADS)

Sun, Shu-Ting; Li, Xiao-Dong; Zhong, Ren-Xin

2017-10-01

For nonlinear switched discrete-time systems with input constraints, this paper presents an open-closed-loop iterative learning control (ILC) approach, which includes a feedforward ILC part and a feedback control part. Under a given switching rule, the mathematical induction is used to prove the convergence of ILC tracking error in each subsystem. It is demonstrated that the convergence of ILC tracking error is dependent on the feedforward control gain, but the feedback control can speed up the convergence process of ILC by a suitable selection of feedback control gain. A switched freeway traffic system is used to illustrate the effectiveness of the proposed ILC law.

Exotic decays of the 125 GeV Higgs boson at future e+e- colliders

NASA Astrophysics Data System (ADS)

Liu, Zhen; Wang, Lian-Tao; Zhang, Hao

2017-06-01

The discovery of unexpected properties of the Higgs boson would offer an intriguing opportunity to shed light on some of the most profound puzzles in particle physics. Beyond Standard Model (BSM) decays of the Higgs boson could reveal new physics in a direct manner. Future electron-positron lepton colliders operating as Higgs factories, including CEPC, FCC-ee and ILC, with the advantages of a clean collider environment and large statistics, could greatly enhance sensitivity in searching for these BSM decays. In this work, we perform a general study of Higgs exotic decays at future e+e- lepton colliders, focusing on the Higgs decays with hadronic final states and/or missing energy, which are very challenging for the High-Luminosity program of the Large Hadron Collider (HL-LHC). We show that with simple selection cuts, (10-3-10-5) limits on the Higgs exotic decay branching fractions can be achieved using the leptonic decaying spectator Z boson in the associated production mode e+e-→ ZH. We further discuss the interplay between detector performance and Higgs exotic decays, and other possibilities of exotic decays. Our work is a first step in a comprehensive study of Higgs exotic decays at future lepton colliders, which is a key area of Higgs physics that deserves further investigation. Supported by Fermi Research Alliance, LLC (DE-AC02-07CH11359) with the U.S. Department of Energy, DOE (DE-SC0013642), IHEP(Y6515580U1), and IHEP Innovation (Y4545171Y2)

Innate lymphoid cells in asthma: Will they take your breath away?

PubMed Central

Kim, Hye Young; Umetsu, Dale. T.; Dekruyff, Rosemarie H.

2016-01-01

Asthma is a complex and heterogeneous disease that is characterized by airway hyperreactivity (AHR) and airway inflammation. Although asthma was long thought to be driven by allergen-reactive Th2 cells, it has recently become clear that the pathogenesis of asthma is more complicated and associated with multiple pathways and cell types. A very exciting recent development was the discovery of innate lymphoid cells (ILCs) as key players in the pathogenesis of asthma. ILCs do not express antigen receptors but react promptly to “danger signals” from inflamed tissue and produce an array of cytokines that direct the ensuing immune response. The roles of ILCs may differ in distinct asthma phenotypes. ILC2s may be critical for initiation of adaptive immune responses in inhaled allergen-driven AHR, but may also function independently of adaptive immunity, mediating influenza-induced AHR. ILC2s also contribute to resolution of lung inflammation through their production of amphiregulin. Obesity-induced asthma, is associated with expansion of IL-17A-producing ILC3s in the lungs. Furthermore, ILCs may also contribute to steroid-resistant asthma. Although the precise roles of ILCs in different types of asthma are still under investigation, it is clear that inhibition of ILC function represents a potential target that could provide novel treatments for asthma. PMID:26891006

Essential, dose-dependent role for the transcription factor Gata3 in the development of IL-5+ and IL-13+ type 2 innate lymphoid cells

PubMed Central

Klein Wolterink, Roel G. J.; Serafini, Nicolas; van Nimwegen, Menno; Vosshenrich, Christian A. J.; de Bruijn, Marjolein J. W.; Fonseca Pereira, Diogo; Veiga Fernandes, Henrique; Hendriks, Rudi W.; Di Santo, James P.

2013-01-01

Group 2 innate lymphoid cells (ILC2s; also called nuocytes, innate helper cells, or natural helper cells) provide protective immunity during helminth infection and play an important role in influenza-induced and allergic airway hyperreactivity. Whereas the transcription factor GATA binding protein 3 (Gata3) is important for the production of IL-5 and -13 by ILC2s in response to IL-33 or -25 stimulation, it is not known whether Gata3 is required for ILC2 development from hematopoietic stem cells. Here, we show that chimeric mice generated with Gata3-deficient fetal liver hematopoietic stem cells fail to develop systemically dispersed ILC2s. In these chimeric mice, in vivo administration of IL-33 or -25 fails to expand ILC2 numbers or to induce characteristic ILC2-dependent IL-5 or -13 production. Moreover, cell-intrinsic Gata3 expression is required for ILC2 development in vitro and in vivo. Using mutant and transgenic mice in which Gata3 gene copy number is altered, we show that ILC2 generation from common lymphoid progenitors, as well as ILC2 homeostasis and cytokine production, is regulated by Gata3 expression levels in a dose-dependent fashion. Collectively, these results identify Gata3 as a critical early regulator of ILC2 development, thereby extending the paradigm of Gata3-dependent control of type 2 immunity to include both innate and adaptive lymphocytes. PMID:23733962

NK Cells and Other Innate Lymphoid Cells in Hematopoietic Stem Cell Transplantation.

PubMed

Vacca, Paola; Montaldo, Elisa; Croxatto, Daniele; Moretta, Francesca; Bertaina, Alice; Vitale, Chiara; Locatelli, Franco; Mingari, Maria Cristina; Moretta, Lorenzo

2016-01-01

Natural killer (NK) cells play a major role in the T-cell depleted haploidentical hematopoietic stem cell transplantation (haplo-HSCT) to cure high-risk leukemias. NK cells belong to the expanding family of innate lymphoid cells (ILCs). At variance with NK cells, the other ILC populations (ILC1/2/3) are non-cytolytic, while they secrete different patterns of cytokines. ILCs provide host defenses against viruses, bacteria, and parasites, drive lymphoid organogenesis, and contribute to tissue remodeling. In haplo-HSCT patients, the extensive T-cell depletion is required to prevent graft-versus-host disease (GvHD) but increases risks of developing a wide range of life-threatening infections. However, these patients may rely on innate defenses that are reconstituted more rapidly than the adaptive ones. In this context, ILCs may represent important players in the early phases following transplantation. They may contribute to tissue homeostasis/remodeling and lymphoid tissue reconstitution. While the reconstitution of NK cell repertoire and its role in haplo-HSCT have been largely investigated, little information is available on ILCs. Of note, CD34(+) cells isolated from different sources of HSC may differentiate in vitro toward various ILC subsets. Moreover, cytokines released from leukemia blasts (e.g., IL-1β) may alter the proportions of NK cells and ILC3, suggesting the possibility that leukemia may skew the ILC repertoire. Further studies are required to define the timing of ILC development and their potential protective role after HSCT.

Group 2 ILCs: A way of enhancing immune protection against human helminths?

PubMed

Nausch, N; Mutapi, F

2018-02-01

Group 2 innate lymphoid cells (ILC2s) play crucial roles in type 2 immune responses associated with allergic and autoimmune diseases, viral and helminth infections and tissue homoeostasis. Experimental models show that in helminth infections ILC2s provide an early source of type 2 cytokines and therefore are essential for the induction of potentially protective type 2 responses. Much of our knowledge of ILC2s in helminth infections has come from experimental mouse models with very few studies analysing ILC2s in natural human infections. In attempts to harness knowledge from paradigms of the development of protective immunity in human helminth infections for vaccine development, the role of ILC2 cells could be pivotal. So far, potential vaccines against human helminth infections have failed to provide effective protection when evaluated in human studies. In addition to appropriate antigen selection, it is apparent that more detailed knowledge on mechanisms of induction and maintenance of protective immune responses is required. Therefore, there is need to understand how ILC2 cells induce type 2 responses and subsequently support the development of a protective immune response in the context of immunizations. Within this review, we summarize the current knowledge of the biology of ILC2s, discuss the importance of ILC2s in human helminth infections and explore how ILC2 responses could be boosted to efficiently induce protective immunity. © 2017 The Authors. Parasite Immunology Published by John Wiley & Sons Ltd.

Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome.

PubMed

Arpino, Grazia; Bardou, Valerie J; Clark, Gary M; Elledge, Richard M

2004-01-01

Invasive lobular carcinoma (ILC) comprises approximately 10% of breast cancers and appears to have a distinct biology. Because it is less common than infiltrating ductal carcinoma (IDC), few data have been reported that address the biologic features of ILC in the context of their clinical outcome. In the present study we undertook an extensive comparison of ILC and IDC using a large database to provide a more complete and reliable assessment of their biologic phenotypes and clinical behaviors. The clinical and biological features of 4140 patients with ILC were compared with those of 45,169 patients with IDC (not otherwise specified). The median follow-up period was 87 months. In comparison with IDC, ILC was significantly more likely to occur in older patients, to be larger in size, to be estrogen and progesterone receptor positive, to have lower S-phase fraction, to be diploid, and to be HER-2, p53, and epidermal growth factor receptor negative. It was more common for ILC than for IDC to metastasize to the gastrointestinal tract and ovary. The incidence of contralateral breast cancer was higher for ILC patients than for IDC patients (20.9% versus 11.2%; P < 0.0001). Breast preservation was modestly less frequent in ILC patients than in IDC patients. The 5-year disease-free survival was 85.7% for ILC and 83.5% for IDC (P = 0.13). The 5-year overall survival was 85.6% for ILC and 84.1% for IDC (P = 0.64). Despite the fact that the biologic phenotype of ILC is quite favorable, these patients do not have better clinical outcomes than do patients with IDC. At present, management decisions should be based on individual patient and tumor biologic characteristics, and not on lobular histology.

Circulating activated innate lymphoid cells and mucosal-associated invariant T cells are associated with airflow limitation in patients with asthma.

PubMed

Ishimori, Ayako; Harada, Norihiro; Chiba, Asako; Harada, Sonoko; Matsuno, Kei; Makino, Fumihiko; Ito, Jun; Ohta, Shoichiro; Ono, Junya; Atsuta, Ryo; Izuhara, Kenji; Takahashi, Kazuhisa; Miyake, Sachiko

2017-04-01

A variety of innate subsets of lymphoid cells such as natural killer (NK) cells, several populations of innate lymphoid cells (ILCs), and mucosal-associated invariant T (MAIT) cells as innate-like T lymphocytes are involved in asthma and may have important effector functions in asthmatic immune responses. In the present study, we investigated whether NK cells, ILCs, and MAIT cells in the peripheral blood of patients with asthma would be associated with clinical asthma parameters. We recruited 75 adult patients with mild to severe asthma. The peripheral blood mononuclear cells in peripheral venous blood samples from the patients were purified and stained with different combinations of appropriate antibodies. The cells were analyzed by flow cytometry. The percentage of activated (i.e., CD69 + ) NK cells in the total NK cell population was negatively correlated with FEV 1 % which is calculated by the forced expiratory volume in 1 s (FEV 1 )/the forced vital capacity (FVC). The percentages of CD69 + ILC1s and ILC2s were negatively correlated with FEV 1 % and %FEV 1 . The percentage of CD69 + ILC3s was positively correlated with BMI, and the percentage of CD69 + MAIT cells was negatively correlated with FEV 1 %. Moreover, the percentage of CD69 + NK cells, ILC1s, ILC2s, ILC3s, and MAIT cells were positively correlated with each other. For the first time, our data showed that activated NK cells, ILC1s, ILC2s, ILC3s, and MAIT cells were positively correlated with each other and may be associated with airflow limitation in patients with asthma. Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

Preferential Reduction of Circulating Innate Lymphoid Cells Type 2 in Patients with Common Variable Immunodeficiency with Secondary Complications Is Part of a Broader Immune Dysregulation.

PubMed

Friedmann, David; Keller, Baerbel; Harder, Ina; Schupp, Jonas; Tanriver, Yakup; Unger, Susanne; Warnatz, Klaus

2017-11-01

Over a third of patients with common variable immunodeficiency (CVID) suffer from secondary complications like inflammatory organ disease, autoimmune manifestations, or lymphoproliferation contributing to increased morbidity and mortality in affected patients. Innate lymphoid cells (ILCs) have emerging roles in setting the milieu for physiological, but also pathological, immune responses and inflammation. We therefore sought to correlate the recently identified disturbed homeostasis of ILCs with alterations of the adaptive immune system in complex CVID patients (CVIDc). We quantified peripheral blood ILC and T helper cell subsets of 58 CVID patients by flow cytometry and compared the results to the clinical and immunological phenotype. Total ILCs were significantly reduced in peripheral blood of CVIDc patients compared to healthy individuals, but not to CVID patients who suffered only from infections (CVIDio). This reduction was mainly due to a decrease in ILC2s, while ILC3s were relatively increased in CVIDc compared to CVIDio patients. This alteration in ILC phenotype was more prominent in patients with an expansion of CD21 low B cells, but we could not detect an association of the altered ILC phenotype with a T H 1-shift among circulating CD4 T cells, which was also prominent in CVIDc patients. We confirm a relative shift in ILCs of CVIDc patients towards ILC3s which was associated with the expansion of CD21 low B cells, but not overtly with the relative expansion of T H 1-like T cells. Given the relative abundance of T H 1-like T cells compared to ILCs, these probably represent a more prominent source of the observed IFNγ-signature in CVIDc patients.

Type 2 innate lymphoid cell suppression by regulatory T cells attenuates airway hyperreactivity and requires inducible T-cell costimulator-inducible T-cell costimulator ligand interaction.

PubMed

Rigas, Diamanda; Lewis, Gavin; Aron, Jennifer L; Wang, Bowen; Banie, Homayon; Sankaranarayanan, Ishwarya; Galle-Treger, Lauriane; Maazi, Hadi; Lo, Richard; Freeman, Gordon J; Sharpe, Arlene H; Soroosh, Pejman; Akbari, Omid

2017-05-01

Atopic diseases, including asthma, exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T (Treg) cells and the emerging type 2 innate lymphoid cells (ILC2s). Although ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood. In the present study, for the first time, we evaluate how Treg cells interact with pulmonary ILC2s and control their function. ILC2s and Treg cells were evaluated by using in vitro suppression assays, cell-contact assays, and gene expression panels. Also, human ILC2s and Treg cells were adoptively transferred into NOD SCID γC-deficient mice, which were given isotype or anti-inducible T-cell costimulator ligand (ICOSL) antibodies and then challenged with IL-33 and assessed for airway hyperreactivity. We show that induced Treg cells, but not natural Treg cells, effectively suppress the production of the ILC2-driven proinflammatory cytokines IL-5 and IL-13 both in vitro and in vivo. Mechanistically, our data reveal the necessity of inducible T-cell costimulator (ICOS)-ICOS ligand cell contact for Treg cell-mediated ILC2 suppression alongside the suppressive cytokines TGF-β and IL-10. Using a translational approach, we then demonstrate that human induced Treg cells suppress syngeneic human ILC2s through ICOSL to control airway inflammation in a humanized ILC2 mouse model. These findings suggest that peripheral expansion of induced Treg cells can serve as a promising therapeutic target against ILC2-dependent asthma. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Human CD40 ligand-expressing type 3 innate lymphoid cells induce IL-10-producing immature transitional regulatory B cells.

PubMed

Komlósi, Zsolt I; Kovács, Nóra; van de Veen, Willem; Kirsch, Anna Isabella; Fahrner, Heinz Benedikt; Wawrzyniak, Marcin; Rebane, Ana; Stanic, Barbara; Palomares, Oscar; Rückert, Beate; Menz, Günter; Akdis, Mübeccel; Losonczy, György; Akdis, Cezmi A

2017-09-20

Type 3 innate lymphoid cells (ILC3s) are involved in maintenance of mucosal homeostasis; however, their role in immunoregulation has been unknown. Immature transitional regulatory B (itBreg) cells are innate-like B cells with immunosuppressive properties, and the in vivo mechanisms by which they are induced have not been fully clarified. We aimed to investigate the ILC3-B-cell interaction that probably takes place in human tonsils. ILC3s were isolated from peripheral blood and palatine tonsils, expanded, and cocultured with naive B cells. Tonsillar ILC3s and regulatory B cells were visualized with immunofluorescence histology. ILC3 frequencies were measured in tonsil tissue of allergic and nonallergic patients and in peripheral blood of allergic asthmatic patients and healthy control subjects. A mutually beneficial relationship was revealed between ILC3s and B cells: ILC3s induced IL-15 production in B cells through B cell-activating factor receptor, whereas IL-15, a potent growth factor for ILC3s, induced CD40 ligand (CD40L) expression on circulating and tonsillar ILC3s. IL-15-activated CD40L + ILC3s helped B-cell survival, proliferation, and differentiation of IL-10-secreting, PD-L1-expressing functional itBreg cells in a CD40L- and B cell-activating factor receptor-dependent manner. ILC3s and regulatory B cells were in close connection with each other in palatine tonsils. ILC3 frequency was reduced in tonsil tissue of allergic patients and in peripheral blood of allergic asthmatic patients. Human CD40L + ILC3s provide innate B-cell help and are involved in an innate immunoregulatory mechanism through induction of itBreg cell differentiation, which takes place in palatine tonsils in vivo. This mechanism, which can contribute to maintenance of immune tolerance, becomes insufficient in allergic diseases. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Innate lymphoid cells in the initiation, regulation and resolution of inflammation

PubMed Central

Sonnenberg, Gregory F.; Artis, David

2016-01-01

A previously unappreciated cell type of the innate immune system, termed innate lymphoid cells (ILCs), has been characterized in mice and humans, and found to profoundly influence the induction, regulation and resolution of inflammation. ILCs play an important role in these processes in murine models of infection, inflammatory disease and tissue repair. Further, disease association studies in defined patient populations have identified significant alterations in ILC responses, suggesting a potential role for these cell populations in human health and disease. In this review, we discuss the emerging family of ILCs, the role of ILCs in inflammation, and how current or novel therapeutic strategies could be employed to selectively modulate ILC responses and limit chronic inflammatory diseases in patients. PMID:26121198

Regulatory T cells and type 2 innate lymphoid cell-dependent asthma.

PubMed

Aron, J L; Akbari, O

2017-08-01

Group 2 innate lymphoid cells (ILC2s) are a recently identified group of cells with the potent capability to produce Th2-type cytokines such as interleukin (IL)-5 and IL-13. Several studies suggest that ILC2s play an important role in the development of allergic diseases and asthma. Activation of pulmonary ILC2s in murine models lacking T and B cells induces eosinophilia and airway hyper-reactivity (AHR), which are cardinal features of asthma. More importantly, numerous recent studies have highlighted the role of ILC2s in asthma persistence and exacerbation among human subjects, and thus, regulation of pulmonary ILC2s is a major area of investigation aimed at curbing allergic lung inflammation and exacerbation. Emerging evidence reveals that a group of regulatory T cells, induced Tregs (iTregs), effectively suppress the production of ILC2-driven, pro-inflammatory cytokines IL-5 and IL-13. The inhibitory effects of iTregs are blocked by preventing direct cellular contact or by inhibiting the ICOS-ICOS-ligand (ICOSL) pathway, suggesting that both direct contact and ICOS-ICOSL interaction are important in the regulation of ILC2 function. Also, cytokines such as IL-10 and TGF-β1 significantly reduce cytokine secretion by ILC2s. Altogether, these new findings uncover iTregs as potent regulators of ILC2 activation and implicate their utility as a therapeutic approach for the treatment of ILC2-mediated allergic asthma and respiratory disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Isolation and analysis of group 2 innate lymphoid cells in mice.

PubMed

Moro, Kazuyo; Ealey, Kafi N; Kabata, Hiroki; Koyasu, Shigeo

2015-05-01

Recent studies have identified distinct subsets of innate lymphocytes, collectively called innate lymphoid cells (ILCs), which lack antigen receptor expression but produce various effector cytokines. Group 2 ILCs (ILC2s) respond to epithelial cell-derived cytokines such as interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP), produce large amounts of type 2 cytokines, and have a key role in anti-helminth innate immunity and in the pathophysiology of allergic inflammation. The reported phenotypic characteristics of mouse ILC2s vary, depending on the tissue source and preparation method. This protocol describes improved methods for tissue-specific isolation and analysis of mouse ILC2s of high purity and yield from fat tissue, lung, bronchoalveolar lavage fluid (BALF) and small intestine. These improved methods are the result of our thorough investigation of enzymes used for tissue digestion, methods for the elimination of undesired cells, and a combination of antibodies for the detection and isolation of ILC2s. In addition, this new protocol now enables the isolation of ILC2s of high yield, even from inflamed tissues. Depending on the tissue being analyzed, it takes ∼2-4 h for isolation and flow cytometric analysis of ILC2s from the various tissues of a single mouse and ∼4-8 h to sort purified ILC2s from pooled tissues of multiple mice.

ICOS regulates the pool of group 2 innate lymphoid cells under homeostatic and inflammatory conditions in mice.

PubMed

Paclik, Daniela; Stehle, Christina; Lahmann, Annette; Hutloff, Andreas; Romagnani, Chiara

2015-10-01

Group 2 innate lymphoid cells (ILC2s) are innate effectors playing an important role in the defense against helminthic infections and in the pathogenesis of allergic inflammation. Cytokines have been identified as the major stimuli driving ILC2 activation and expansion. Conversely, it is unclear whether costimulatory molecules contribute to regulation of ILC2 functions. ILC2s display high expression of inducible T-cell costimulator (ICOS), which belongs to the CD28 superfamily, and which has been shown to control late effector T-cell functions, and is of utmost importance for the humoral immune response. However, the biological function of ICOS expression on ILC2s is unknown. Here, we show that ICOS signaling in mice regulates ILC2 homeostasis independently of T cells and B cells, by promoting proliferation and accumulation of mature ILC2s in lung and intestine. In a model of IL-33-induced airway inflammation, ICOS controls ILC2 activation and eosinophil infiltration in the lung. Our data identify a role of ICOS in innate immunity and indicate that not only cytokines, but also costimulatory pathways such as those involving ICOS, can contribute to regulate the ILC2 pool. Thus, ICOS costimulation blockade, which is currently under clinical evaluation for inhibiting the humoral immune response, could also target innate inflammatory circuits. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Innate lymphoid cells in secondary lymphoid organs.

PubMed

Bar-Ephraïm, Yotam E; Mebius, Reina E

2016-05-01

The family of innate lymphoid cells (ILCs) has attracted attention in recent years as its members are important regulators of immunity, while they can also cause pathology. In both mouse and man, ILCs were initially discovered in developing lymph nodes as lymphoid tissue inducer (LTi) cells. These cells form the prototypic members of the ILC family and play a central role in the formation of secondary lymphoid organs (SLOs). In the absence of LTi cells, lymph nodes (LN) and Peyer's Patches (PP) fail to form in mice, although the splenic white pulp can develop normally. Besides LTi cells, the ILC family encompasses helper-like ILCs with functional distinctions as seen by T-helper cells, as well as cytotoxic natural killer (NK) cells. ILCs are still present in adult SLOs where they have been shown to play a role in lymphoid tissue regeneration. Furthermore, ILCs were implicated to interact with adaptive lymphocytes and influence the adaptive immune response. Here, we review the recent literature on the role of ILCs in secondary lymphoid tissue from the formation of SLOs to mature SLOs in adults, during homeostasis and pathology. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

MHCII-Mediated Dialog between Group 2 Innate Lymphoid Cells and CD4+ T Cells Potentiates Type 2 Immunity and Promotes Parasitic Helminth Expulsion

PubMed Central

Oliphant, Christopher J.; Hwang, You Yi; Walker, Jennifer A.; Salimi, Maryam; Wong, See Heng; Brewer, James M.; Englezakis, Alexandros; Barlow, Jillian L.; Hams, Emily; Scanlon, Seth T.; Ogg, Graham S.; Fallon, Padraic G.; McKenzie, Andrew N.J.

2014-01-01

Summary Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity. PMID:25088770

Establishment and function of tissue-resident innate lymphoid cells in the skin.

PubMed

Yang, Jie; Zhao, Luming; Xu, Ming; Xiong, Na

2017-07-01

Innate lymphoid cells (ILCs) are a newly classified family of immune cells of the lymphoid lineage. While they could be found in both lymphoid organs and non-lymphoid tissues, ILCs are preferentially enriched in barrier tissues such as the skin, intestine, and lung where they could play important roles in maintenance of tissue integrity and function and protection against assaults of foreign agents. On the other hand, dysregulated activation of ILCs could contribute to tissue inflammatory diseases. In spite of recent progress towards understanding roles of ILCs in the health and disease, mechanisms regulating specific establishment, activation, and function of ILCs in barrier tissues are still poorly understood. We herein review the up-to-date understanding of tissue-specific relevance of ILCs. Particularly we will focus on resident ILCs of the skin, the outmost barrier tissue critical in protection against various foreign hazardous agents and maintenance of thermal and water balance. In addition, we will discuss remaining outstanding questions yet to be addressed.

Pathological and therapeutic roles of innate lymphoid cells in diverse diseases.

PubMed

Kim, Jisu; Kim, Geon; Min, Hyeyoung

2017-11-01

Innate lymphoid cells (ILCs) are a recently defined type of innate-immunity cells that belong to the lymphoid lineage and have lymphoid morphology but do not express an antigen-specific B cell or T-cell receptor. ILCs regulate immune functions prior to the formation of adaptive immunity and exert effector functions through a cytokine release. ILCs have been classified into three groups according to the transcription factors that regulate their development and function and the effector cytokines they produce. Of note, ILCs resemble T helper (Th) cells, such as Th1, Th2, and Th17 cells, and show a similar dependence on transcription factors and distinct cytokine production. Despite their short history in immunology, ILCs have received much attention, and numerous studies have revealed biological functions of ILCs including host defense against pathogens, inflammation, tissue repair, and metabolic homeostasis. Here, we describe recent findings about the roles of ILCs in the pathogenesis of various diseases and potential therapeutic targets.

ILC2 memory: Recollection of previous activation.

PubMed

Martinez-Gonzalez, Itziar; Ghaedi, Maryam; Steer, Catherine A; Mathä, Laura; Vivier, Eric; Takei, Fumio

2018-05-01

Immunological memory, traditionally thought to belong to T and B cells, has now been extended to innate lymphocytes, including NK cells and ILC2s, myeloid cells such as macrophages, also termed "trained immunity" and more recently to epithelial stem cells. In this review, we discuss the mechanisms underlying memory generation on ILC2s and speculate about their potential role in human allergic diseases, such as asthma. Moreover, we examine the relevance of the spontaneous ILC2 activation in the lung during the neonatal period in order to efficiently respond to stimuli later in life. These "training" of neonatal ILC2s may have an impact on the generation of memory ILC2s in the adulthood. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Determination of the Fate and Function of Innate Lymphoid Cells Following Adoptive Transfer of Innate Lymphoid Cell Precursors.

PubMed

O'Sullivan, Timothy E; Sun, Joseph C

2018-01-01

Innate lymphoid cells are a heterogeneous family of tissue-resident and circulating lymphocytes that play an important role in host immunity. Recent studies have profiled the developmental pathways of mature ILCs and have identified ILC progenitors in the bone marrow through the use of transcription factor reporter mice. Here we describe methodology to identify and isolate bone marrow CHILP and ILC2 progenitor (ILC2P) cells based on cell surface marker expression for adoptive transfer into lymphopenic mice to track the fate of developing ILCs.

Cysteinyl leukotriene E4 activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D2 and epithelial cytokines.

PubMed

Salimi, Maryam; Stöger, Linda; Liu, Wei; Go, Simei; Pavord, Ian; Klenerman, Paul; Ogg, Graham; Xue, Luzheng

2017-10-01

Group 2 innate lymphoid cells (ILC2s) are a potential innate source of type 2 cytokines in the pathogenesis of allergic conditions. Epithelial cytokines (IL-33, IL-25, and thymic stromal lymphopoietin [TSLP]) and mast cell mediators (prostaglandin D 2 [PGD 2 ]) are critical activators of ILC2s. Cysteinyl leukotrienes (cysLTs), including leukotriene (LT) C 4 , LTD 4 , and LTE 4 , are metabolites of arachidonic acid and mediate inflammatory responses. Their role in human ILC2s is still poorly understood. We sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s. For ex vivo studies, fresh blood from patients with atopic dermatitis and healthy control subjects was analyzed with flow cytometry. For in vitro studies, ILC2s were isolated and cultured. The effects of cysLTs, PGD 2 , IL-33, IL-25, TSLP, and IL-2 alone or in combination on ILC2s were defined by using chemotaxis, apoptosis, ELISA, Luminex, quantitative RT-PCR, and flow cytometric assays. The effect of endogenous cysLTs was assessed by using human mast cell supernatants. Human ILC2s expressed the LT receptor CysLT 1 , levels of which were increased in atopic subjects. CysLTs, particularly LTE 4 , induced migration, reduced apoptosis, and promoted cytokine production in human ILC2s in vitro. LTE 4 enhanced the effect of PGD 2 , IL-25, IL-33, and TSLP, resulting in increased production of type 2 and other proinflammatory cytokines. The effect of LTE 4 was inhibited by montelukast, a CysLT 1 antagonist. Interestingly, addition of IL-2 to LTE 4 and epithelial cytokines significantly amplified ILC2 activation and upregulated expression of the receptors for IL-33 and IL-25. CysLTs, particularly LTE 4 , are important contributors to the triggering of human ILC2s in inflammatory responses, particularly when combined with other ILC2 activators. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity.

PubMed

Everaere, Laetitia; Ait-Yahia, Saliha; Molendi-Coste, Olivier; Vorng, Han; Quemener, Sandrine; LeVu, Pauline; Fleury, Sebastien; Bouchaert, Emmanuel; Fan, Ying; Duez, Catherine; de Nadai, Patricia; Staels, Bart; Dombrowicz, David; Tsicopoulos, Anne

2016-11-01

Epidemiologic and clinical observations identify obesity as an important risk factor for asthma exacerbation, but the underlying mechanisms remain poorly understood. Type 2 innate lymphoid cells (ILC2s) and type 3 innate lymphoid cells (ILC3s) have been implicated, respectively, in asthma and adipose tissue homeostasis and in obesity-associated airway hyperresponsiveness (AHR). We sought to determine the potential involvement of innate lymphoid cells (ILCs) in allergic airway disease exacerbation caused by high-fat diet (HFD)-induced obesity. Obesity was induced by means of HFD feeding, and allergic airway inflammation was subsequently induced by means of intranasal administration of house dust mite (HDM) extract. AHR, lung and visceral adipose tissue inflammation, humoral response, cytokines, and innate and adaptive lymphoid populations were analyzed in the presence or absence of ILCs. HFD feeding exacerbated allergic airway disease features, including humoral response, airway and tissue eosinophilia, AHR, and T H 2 and T H 17 pulmonary profiles. Notably, nonsensitized obese mice already exhibited increased lung ILC counts and tissue eosinophil infiltration compared with values in lean mice in the absence of AHR. The numbers of total and cytokine-expressing lung ILC2s and ILC3s further increased in HDM-challenged obese mice compared with those in HDM-challenged lean mice, and this was accompanied by high IL-33 and IL-1β levels and decreased ILC markers in visceral adipose tissue. Furthermore, depletion of ILCs with an anti-CD90 antibody, followed by T-cell reconstitution, led to a profound decrease in allergic airway inflammatory features in obese mice, including T H 2 and T H 17 infiltration. These results indicate that HFD-induced obesity might exacerbate allergic airway inflammation through mechanisms involving ILC2s and ILC3s. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Latest R&D news and beam test performance of the highly granular SiW-ECAL technological prototype for the ILC

NASA Astrophysics Data System (ADS)

Irles, A.

2018-02-01

High precision physics at future colliders as the International Linear Collider (ILC) require unprecedented high precision in the determination of the energy of final state particles. The needed precision will be achieved thanks to the Particle Flow algorithms (PF) which require highly granular and hermetic calorimeters systems. The physical proof of concept of the PF was performed in the previous campaign of beam tests of physic prototypes within the CALICE collaboration. One of these prototypes was the physics prototype of the Silicon-Tungsten Electromagnetic Calorimeter (SiW-ECAL) for the ILC. In this document we present the latest news on R&D of the next generation prototype, the technological prototype with fully embedded very front-end (VFE) electronics, of the SiW-ECAL. Special emphasis is given to the presentation and discussion of the first results from the beam test done at DESY in June 2017. The physics program for such beam test consisted in the calibration and commissioning of the current set of available SiW ECAL modules; the test of performance of individual slabs under 1T magnetic fields; and the study of electromagnetic showers events.

Innate lymphoid cells: a paradigm for low SSI in cleft lip repair.

PubMed

Simmerman, Erika; Qin, Xu; Marshall, Brendan; Perry, Libby; Cai, Lei; Wang, Tailing; Yu, Jack; Akbari, Omid; Baban, Babak

2016-10-01

Cleft lip and palate reconstructions demonstrate significantly lower surgical site infection rates compared with clean-contaminated cases, prompting investigation into the pathophysiology causing this discrepancy. Recent studies have identified a new group of innate lymphocytes called innate lymphoid cells (ILCs), located in barrier surfaces of the skin, airways, and intestine. Our objectives were to explore for the first time the presence of ILCs in the vermillion of neonates and young children undergoing cleft lip reconstruction and characterize their composition by measuring the three classes of ILCs. Lip tissue samples were collected from 13 subjects undergoing vermillion resection during cleft lip reconstructive surgery. Preparative, transmission electron microscopy, and analytical flow cytometry were performed. The functionality of ILCs was tested in terms of their capacity to produce type 1 (IFN-γ/TNF-α), type 2 (IL-5/IL-13), and type 3 (IL-17/IL-22) cytokines. Data were analyzed using Student t test or the analysis of variance to establish significance (P < 0.05) among groups for all other data. All three classes of ILCs were detected and visualized in the tissue samples. In all samples, the level of ILC2 subset was significantly higher than the other two ILC subsets (P < 0.01), followed by the ILC1 subset, which was present in significantly higher levels than the ILC3 subset (P < 0.05). Our data place ILCs for the first time in the interface of oral mucosal immunity, tissue microenvironment, and homeostasis during and after tissue development, possibly explaining lower infection rates in cleft lip or palate reconstructions. Copyright © 2016 Elsevier Inc. All rights reserved.

Group 2 innate lymphoid cells promote beiging of adipose and limit obesity

PubMed Central

Brestoff, Jonathan R.; Kim, Brian S.; Saenz, Steven A.; Stine, Rachel R.; Monticelli, Laurel A.; Sonnenberg, Gregory F.; Thome, Joseph J.; Farber, Donna L.; Lutfy, Kabirullah; Seale, Patrick; Artis, David

2015-01-01

Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity1,2. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity3,4 and eosinophil and alternatively-activated macrophage responses5, and were recently identified in murine white adipose tissue (WAT)5 where they may act to limit the development of obesity6. However, ILC2s have not been identified in human adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here, we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1)+ beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure7–9. IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signaling. We found that ILC2s produce methionine-enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these studies indicate that in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging. PMID:25533952

Is there an association between invasive lobular carcinoma of the breast and a family history of gastric cancer?

PubMed

Chikman, Bar; Davidson, Tima; Kais, Hasan; Jeroukhimov, Igor; Leshno, Ari; Sandbank, Judith; Halevy, Ariel; Lavy, Ron

2016-01-01

CDH1 gene mutations have been found to be associated with diffuse type gastric cancer and invasive lobular carcinoma (ILC) of the breast. To the best of our knowledge, this is the only study relating a family history of gastric cancer to ILC of the breast. We conducted a retrospective study comparing the family history of malignancies in patients with invasive ductal carcinoma (IDC) of the breast and ILC treated in our Medical Center. The comparison was evaluated in both types of breast cancer groups, dividing the patients into two age groups, <50 and ≥50 years. One thousand one hundred and sixty-seven patients with IDC and ILC entered the study. A family history of malignancies was reported in 21.6 % of patients with IDC as opposed to 37.8 % of patients with ILC (P < 0.001). A history of gastric cancer was reported in 7.2 % in the ILC group as compared to 2.3 % in the IDC group, P < 0.008. A family history of breast cancer was more common in the ILC group as opposed to the IDC group, 18 versus 8.1 % respectively, P = 0.002 and persisted in both age groups. We conclude that a family history of malignancies in first degree relatives is more common in patients with ILC than IDC and that there is a significant association between a family history of gastric cancer and ILC.

T cell-derived IFN-γ downregulates protective group 2 innate lymphoid cells in murine lupus erythematosus.

PubMed

Düster, Mathis; Becker, Martina; Gnirck, Ann-Christin; Wunderlich, Malte; Panzer, Ulf; Turner, Jan-Eric

2018-04-19

Innate lymphoid cells (ILCs) are important regulators of the immune response and play a crucial role in the restoration of tissue homeostasis after injury. GATA-3 + IL-13- and IL-5-producing group 2 innate lymphoid cells (ILC2s) have been shown to promote tissue repair in barrier organs, but despite extensive research on ILCs in the recent years, their potential role in autoimmune diseases is still incompletely understood. In the present study, we investigate the role of ILC2s in the MRL/MpJ-Fas lpr (MRL-lpr) mouse model for severe organ manifestation of systemic lupus erythematosus (SLE). We show that in these MRL-lpr mice, progression of lupus nephritis is accompanied with a reduction of ILC2 abundance in the inflamed renal tissue. Proliferation/survival and cytokine production of kidney-residing ILC2s was suppressed by IFN-γ and, to a lesser extent, by IL-27 which were produced by activated T cells and myeloid cells in the nephritic kidney, respectively. Most importantly, restoration of ILC2 numbers by IL-33-mediated expansion ameliorated lupus nephritis and prevented mortality in MRL-lpr mice. In summary, we show here that development of SLE-like kidney inflammation leads to a downregulation of the renal ILC2 response and identify an ILC2-expanding therapy as a promising treatment approach for autoimmune diseases. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cytokine Networks between Innate Lymphoid Cells and Myeloid Cells

PubMed Central

Mortha, Arthur; Burrows, Kyle

2018-01-01

Innate lymphoid cells (ILCs) are an essential component of the innate immune system in vertebrates. They are developmentally rooted in the lymphoid lineage and can diverge into at least three transcriptionally distinct lineages. ILCs seed both lymphoid and non-lymphoid tissues and are locally self-maintained in tissue-resident pools. Tissue-resident ILCs execute important effector functions making them key regulator in tissue homeostasis, repair, remodeling, microbial defense, and anti-tumor immunity. Similar to T lymphocytes, ILCs possess only few sensory elements for the recognition of non-self and thus depend on extrinsic cellular sensory elements residing within the tissue. Myeloid cells, including mononuclear phagocytes (MNPs), are key sentinels of the tissue and are able to translate environmental cues into an effector profile that instructs lymphocyte responses. The adaptation of myeloid cells to the tissue state thus influences the effector program of ILCs and serves as an example of how environmental signals are integrated into the function of ILCs via a tissue-resident immune cell cross talks. This review summarizes our current knowledge on the role of myeloid cells in regulating ILC functions and discusses how feedback communication between ILCs and myeloid cells contribute to stabilize immune homeostasis in order to maintain the healthy state of an organ. PMID:29467768

Cytokine Networks between Innate Lymphoid Cells and Myeloid Cells.

PubMed

Mortha, Arthur; Burrows, Kyle

2018-01-01

Innate lymphoid cells (ILCs) are an essential component of the innate immune system in vertebrates. They are developmentally rooted in the lymphoid lineage and can diverge into at least three transcriptionally distinct lineages. ILCs seed both lymphoid and non-lymphoid tissues and are locally self-maintained in tissue-resident pools. Tissue-resident ILCs execute important effector functions making them key regulator in tissue homeostasis, repair, remodeling, microbial defense, and anti-tumor immunity. Similar to T lymphocytes, ILCs possess only few sensory elements for the recognition of non-self and thus depend on extrinsic cellular sensory elements residing within the tissue. Myeloid cells, including mononuclear phagocytes (MNPs), are key sentinels of the tissue and are able to translate environmental cues into an effector profile that instructs lymphocyte responses. The adaptation of myeloid cells to the tissue state thus influences the effector program of ILCs and serves as an example of how environmental signals are integrated into the function of ILCs via a tissue-resident immune cell cross talks. This review summarizes our current knowledge on the role of myeloid cells in regulating ILC functions and discusses how feedback communication between ILCs and myeloid cells contribute to stabilize immune homeostasis in order to maintain the healthy state of an organ.

Anti-microbial Functions of Group 3 Innate Lymphoid Cells in Gut-Associated Lymphoid Tissues Are Regulated by G-Protein-Coupled Receptor 183.

PubMed

Chu, Coco; Moriyama, Saya; Li, Zhi; Zhou, Lei; Flamar, Anne-Laure; Klose, Christoph S N; Moeller, Jesper B; Putzel, Gregory G; Withers, David R; Sonnenberg, Gregory F; Artis, David

2018-06-26

The intestinal tract is constantly exposed to various stimuli. Group 3 innate lymphoid cells (ILC3s) reside in lymphoid organs and in the intestinal tract and are required for immunity to enteric bacterial infection. However, the mechanisms that regulate the ILC3s in vivo remain incompletely defined. Here, we show that GPR183, a chemotactic receptor expressed on murine and human ILC3s, regulates ILC3 migration toward its ligand 7α,25-dihydroxycholesterol (7α,25-OHC) in vitro, and GPR183 deficiency in vivo leads to a disorganized distribution of ILC3s in mesenteric lymph nodes and decreased ILC3 accumulation in the intestine. GPR183 functions intrinsically in ILC3s, and GPR183-deficient mice are more susceptible to enteric bacterial infection. Together, these results reveal a role for the GPR183-7α,25-OHC pathway in regulating the accumulation, distribution, and anti-microbial and tissue-protective functions of ILC3s and define a critical role for this pathway in promoting innate immunity to enteric bacterial infection. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Role of innate lymphoid cells in obesity and metabolic disease

PubMed Central

Saetang, Jirakrit; Sangkhathat, Surasak

2018-01-01

The immune system has previously been demonstrated to be associated with the pathophysiological development of metabolic abnormalities. However, the mechanisms linking immunity to metabolic disease remain to be fully elucidated. It has previously been suggested that innate lymphoid cells (ILCs) may be involved in the progression of numerous types of metabolic diseases as these cells act as suppressors and promoters for obesity and associated conditions, and are particularly involved in adipose tissue inflammation, which is a major feature of metabolic imbalance. Group 2 ILCs (ILC2s) have been revealed as anti-obese immune regulators by secreting anti-inflammatory cytokines and promoting the polarization of M2 macrophages, whereas group 1 ILCs (ILC1s), including natural killer cells, may promote adipose tissue inflammation via production of interferon-γ, which in turn polarizes macrophages toward the M1 type. The majority of studies to date have demonstrated the pathological association between ILCs and obesity in the context of adipose tissue inflammation, whereas the roles of ILCs in other organs which participate in obesity development have not been fully characterized. Therefore, identifying the roles of all types of ILCs as central components mediating obesity-associated inflammation, is of primary concern, and may lead to the discovery of novel preventative and therapeutic interventions. PMID:29138853

TSLP elicits IL-33–independent innate lymphoid cell responses to promote skin inflammation

PubMed Central

Kim, Brian S.; Siracusa, Mark C.; Saenz, Steven A.; Noti, Mario; Monticelli, Laurel A.; Sonnenberg, Gregory F.; Hepworth, Matthew R.; Van Voorhees, Abby S.; Comeau, Michael R.

2013-01-01

Innate lymphoid cells (ILCs) are a recently identified family of heterogeneous immune cells that can be divided into three groups based on their differential developmental requirements and expression of effector cytokines. Among these, group 2 ILCs produce the type 2 cytokines IL-5 and IL-13 and promote type 2 inflammation in the lung and intestine. However, whether group 2 ILCs reside in the skin and contribute to skin inflammation has not been characterized. Here, we identify for the first time a population of skin-resident group 2 ILCs present in healthy human skin that are enriched in lesional human skin from atopic dermatitis (AD) patients. Group 2 ILCs were also found in normal murine skin and were critical for the development of inflammation in a murine model of AD-like disease. Remarkably, in contrast to group 2 ILC responses in the intestine and lung, which are critically regulated by IL-33 and IL-25, ILC responses in the skin and skin-draining lymph nodes were independent of these canonical cytokines but were critically dependent on thymic stromal lymphopoietin (TSLP). Collectively, these results demonstrate an essential role for IL-33– and IL-25–independent group 2 ILCs in promoting skin inflammation. PMID:23363980

MHCII-mediated dialog between group 2 innate lymphoid cells and CD4(+) T cells potentiates type 2 immunity and promotes parasitic helminth expulsion.

PubMed

Oliphant, Christopher J; Hwang, You Yi; Walker, Jennifer A; Salimi, Maryam; Wong, See Heng; Brewer, James M; Englezakis, Alexandros; Barlow, Jillian L; Hams, Emily; Scanlon, Seth T; Ogg, Graham S; Fallon, Padraic G; McKenzie, Andrew N J

2014-08-21

Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

β2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses.

PubMed

Moriyama, Saya; Brestoff, Jonathan R; Flamar, Anne-Laure; Moeller, Jesper B; Klose, Christoph S N; Rankin, Lucille C; Yudanin, Naomi A; Monticelli, Laurel A; Putzel, Gregory Garbès; Rodewald, Hans-Reimer; Artis, David

2018-03-02

The type 2 inflammatory response is induced by various environmental and infectious stimuli. Although recent studies identified group 2 innate lymphoid cells (ILC2s) as potent sources of type 2 cytokines, the molecular pathways controlling ILC2 responses are incompletely defined. Here we demonstrate that murine ILC2s express the β 2 -adrenergic receptor (β 2 AR) and colocalize with adrenergic neurons in the intestine. β 2 AR deficiency resulted in exaggerated ILC2 responses and type 2 inflammation in intestinal and lung tissues. Conversely, β 2 AR agonist treatment was associated with impaired ILC2 responses and reduced inflammation in vivo. Mechanistically, we demonstrate that the β 2 AR pathway is a cell-intrinsic negative regulator of ILC2 responses through inhibition of cell proliferation and effector function. Collectively, these data provide the first evidence of a neuronal-derived regulatory circuit that limits ILC2-dependent type 2 inflammation. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Long-term Persistence of Innate Lymphoid Cells in the Gut After Intestinal Transplantation.

PubMed

Weiner, Joshua; Zuber, Julien; Shonts, Brittany; Yang, Suxiao; Fu, Jianing; Martinez, Mercedes; Farber, Donna L; Kato, Tomoaki; Sykes, Megan

2017-10-01

Little is known about innate lymphoid cell (ILC) populations in the human gut, and the turnover of these cells and their subsets after transplantation has not been described. Intestinal samples were taken from 4 isolated intestine and 3 multivisceral transplant recipients at the time of any operative resection, such as stoma closure or revision. ILCs were isolated and analyzed by flow cytometry. The target population was defined as being negative for lineage markers and double-positive for CD45/CD127. Cells were further stained to define ILC subsets and a donor-specific or recipient-specific HLA marker to analyze chimerism. Donor-derived ILCs were found to persist greater than 8 years after transplantation. Additionally, the percentage of cells thought to be lymphoid tissue inducer cells among donor ILCs was far higher than that among recipient ILCs. Our findings demonstrate that donor-derived ILCs persist long-term after transplantation and support the notion that human lymphoid tissue inducer cells may form in the fetus and persist throughout life, as hypothesized in rodents. Correlation between chimerism and rejection, graft failure, and patient survival requires further study.

Transcription factors controlling innate lymphoid cell fate decisions.

PubMed

Klose, Christoph S N; Diefenbach, Andreas

2014-01-01

The mucosal epithelium is in direct contact with symbiotic and pathogenic microorganisms. Therefore, the mucosal surface is the principal portal of entry for invading pathogens and immune cells accumulated in the intestine to prevent infections. In addition to these conventional immune system functions, it has become clear that immune cells during steady-state continuously integrate microbial and nutrient-derived signals from the environment to support organ homeostasis. A major role in both processes is played by a recently discovered group of lymphocytes referred to as innate lymphoid cells (ILCs) Innate lymphoid cells (ILCs) that are specifically enriched at mucosal surfaces but are rather rare in secondary lymphoid organs. In analogy to the dichotomy between CD8 and CD4 T cells, we propose to classify ILCs into interleukin-7 receptor α-negative cytotoxic ILCs and IL-7Rα(+) helper-like ILCs. Dysregulated immune responses triggered by the various ILC subsets have been linked to inflammatory diseases such as inflammatory bowel disease, atopic dermatitis and airway hyperresponsiveness. Here, we will review recent progress in determining the transcriptional and developmental programs that control ILC fate decisions.

Selective programming of CCR10+ innate lymphoid cells in skin-draining lymph nodes for cutaneous homeostatic regulation

PubMed Central

Yang, Jie; Hu, Shaomin; Zhao, Luming; Kaplan, Daniel H.; Perdew, Gary H.; Xiong, Na

2016-01-01

Innate lymphoid cells (ILCs) are preferentially localized into barrier tissues where they function in tissue protection but can also contribute to inflammatory diseases. The mechanisms regulating the establishment of ILCs in barrier tissues are poorly understood. Here we show that under steady-state conditions ILCs in skin-draining lymph nodes (sLNs) were continuously activated to acquire regulatory properties and high expression of the chemokine receptor CCR10 for localization into the skin. CCR10+ ILCs promoted the homeostasis of skin-resident T cells and reciprocally, their establishment in the skin required T cell-regulated homeostatic environments. Foxn1-expressing CD207+ dendritic cells were required for the proper generation of CCR10+ ILCs. These observations reveal mechanisms underlying the specific programming and priming of skin-homing CCR10+ ILCs in the sLNs. PMID:26523865

Regulatory Innate Lymphoid Cells Control Innate Intestinal Inflammation.

PubMed

Wang, Shuo; Xia, Pengyan; Chen, Yi; Qu, Yuan; Xiong, Zhen; Ye, Buqing; Du, Ying; Tian, Yong; Yin, Zhinan; Xu, Zhiheng; Fan, Zusen

2017-09-21

An emerging family of innate lymphoid cells (termed ILCs) has an essential role in the initiation and regulation of inflammation. However, it is still unclear how ILCs are regulated in the duration of intestinal inflammation. Here, we identify a regulatory subpopulation of ILCs (called ILCregs) that exists in the gut and harbors a unique gene identity that is distinct from that of ILCs or regulatory T cells (Tregs). During inflammatory stimulation, ILCregs can be induced in the intestine and suppress the activation of ILC1s and ILC3s via secretion of IL-10, leading to protection against innate intestinal inflammation. Moreover, TGF-β1 is induced by ILCregs during the innate intestinal inflammation, and autocrine TGF-β1 sustains the maintenance and expansion of ILCregs. Therefore, ILCregs play an inhibitory role in the innate immune response, favoring the resolution of intestinal inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer

PubMed Central

Michaut, Magali; Chin, Suet-Feung; Majewski, Ian; Severson, Tesa M.; Bismeijer, Tycho; de Koning, Leanne; Peeters, Justine K.; Schouten, Philip C.; Rueda, Oscar M.; Bosma, Astrid J.; Tarrant, Finbarr; Fan, Yue; He, Beilei; Xue, Zheng; Mittempergher, Lorenza; Kluin, Roelof J.C.; Heijmans, Jeroen; Snel, Mireille; Pereira, Bernard; Schlicker, Andreas; Provenzano, Elena; Ali, Hamid Raza; Gaber, Alexander; O’Hurley, Gillian; Lehn, Sophie; Muris, Jettie J.F.; Wesseling, Jelle; Kay, Elaine; Sammut, Stephen John; Bardwell, Helen A.; Barbet, Aurélie S.; Bard, Floriane; Lecerf, Caroline; O’Connor, Darran P.; Vis, Daniël J.; Benes, Cyril H.; McDermott, Ultan; Garnett, Mathew J.; Simon, Iris M.; Jirström, Karin; Dubois, Thierry; Linn, Sabine C.; Gallagher, William M.; Wessels, Lodewyk F.A.; Caldas, Carlos; Bernards, Rene

2016-01-01

Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies. PMID:26729235

Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis.

PubMed

Trabanelli, Sara; Chevalier, Mathieu F; Martinez-Usatorre, Amaia; Gomez-Cadena, Alejandra; Salomé, Bérengère; Lecciso, Mariangela; Salvestrini, Valentina; Verdeil, Grégory; Racle, Julien; Papayannidis, Cristina; Morita, Hideaki; Pizzitola, Irene; Grandclément, Camille; Bohner, Perrine; Bruni, Elena; Girotra, Mukul; Pallavi, Rani; Falvo, Paolo; Leibundgut, Elisabeth Oppliger; Baerlocher, Gabriela M; Carlo-Stella, Carmelo; Taurino, Daniela; Santoro, Armando; Spinelli, Orietta; Rambaldi, Alessandro; Giarin, Emanuela; Basso, Giuseppe; Tresoldi, Cristina; Ciceri, Fabio; Gfeller, David; Akdis, Cezmi A; Mazzarella, Luca; Minucci, Saverio; Pelicci, Pier Giuseppe; Marcenaro, Emanuela; McKenzie, Andrew N J; Vanhecke, Dominique; Coukos, George; Mavilio, Domenico; Curti, Antonio; Derré, Laurent; Jandus, Camilla

2017-09-19

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer.Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth.

Innate Lymphoid Cells Mediate Pulmonary Eosinophilic Inflammation, Airway Mucous Cell Metaplasia, and Type 2 Immunity in Mice Exposed to Ozone.

PubMed

Kumagai, Kazuyoshi; Lewandowski, Ryan P; Jackson-Humbles, Daven N; Buglak, Nicholas; Li, Ning; White, Kaylin; Van Dyken, Steven J; Wagner, James G; Harkema, Jack R

2017-08-01

Exposure to elevated levels of ambient ozone in photochemical smog is associated with eosinophilic airway inflammation and nonatopic asthma in children. In the present study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced nonatopic asthma by using lymphoid cell-sufficient C57BL/6 mice, ILC-sufficient Rag2 -/- mice (devoid of T and B cells), and ILC-deficient Rag2 -/- Il2rg -/- mice (depleted of all lymphoid cells including ILCs). Mice were exposed to 0 or 0.8 parts per million ozone for 1 day or 9 consecutive weekdays (4 hr/day). A single exposure to ozone caused neutrophilic inflammation, airway epithelial injury, and reparative DNA synthesis in all strains of mice, irrespective of the presence or absence of ILCs. In contrast, 9-day exposures induced eosinophilic inflammation and mucous cell metaplasia only in the lungs of ILC-sufficient mice. Repeated ozone exposures also elicited increased messenger RNA expression of transcripts associated with type 2 immunity and airway mucus production in ILC-sufficient mice. ILC-deficient mice repeatedly exposed to ozone had no pulmonary pathology or increased gene expression related to type 2 immunity. These results suggest a new paradigm for the biologic mechanisms underlying the development of a phenotype of childhood nonatopic asthma that has been linked to ambient ozone exposures.

Microbiota-derived butyrate suppresses group 3 innate lymphoid cells in terminal ileal Peyer's patches.

PubMed

Kim, Sae-Hae; Cho, Byeol-Hee; Kiyono, Hiroshi; Jang, Yong-Suk

2017-06-21

The regional specialization of intestinal immune cells is affected by the longitudinal heterogeneity of environmental factors. Although the distribution of group 3 innate lymphoid cells (ILC3s) is well characterized in the lamina propria, it is poorly defined in Peyer's patches (PPs) along the intestine. Given that PP ILC3s are closely associated with mucosal immune regulation, it is important to characterize the regulatory mechanism of ILC3s. Here, we found that terminal ileal PPs of specific pathogen-free (SPF) mice have fewer NKp46 + ILC3s than jejunal PPs, while there was no difference in NKp46 + ILC3 numbers between terminal ileal and jejunal PPs in antibiotics (ABX)-treated mice. We also found that butyrate levels in the terminal ileal PPs of SPF mice were higher than those in the jejunal PPs of SPF mice and terminal ileal PPs of ABX-treated mice. The reduced number of NKp46 + ILC3s in terminal ileal PPs resulted in a decrease in Csf2 expression and, in turn, resulted in reduced regulatory T cells and enhanced antigen-specific T-cell proliferation. Thus, we suggest that NKp46 + ILC3s are negatively regulated by microbiota-derived butyrate in terminal ileal PPs and the reduced ILC3 frequency is closely associated with antigen-specific immune induction in terminal ileal PPs.

Effectiveness of Breast MRI and (18)F-FDG PET/CT for the Preoperative Staging of Invasive Lobular Carcinoma versus Ductal Carcinoma.

PubMed

Jung, Na Young; Kim, Sung Hoon; Kim, Sung Hun; Seo, Ye Young; Oh, Jin Kyoung; Choi, Hyun Su; You, Won Jong

2015-03-01

We evaluated the utility of magnetic resonance imaging (MRI) and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) for the preoperative staging of invasive lobular carcinoma (ILC) of the breast and compared the results with those of invasive ductal carcinoma (IDC). The study included pathologically proven 32 ILCs and 73 IDCs. We compared clinical and histopathological characteristics and the diagnostic performances of MRI and (18)F-FDG PET/CT for the primary mass, additional ipsilateral and/or contralateral lesion(s), and axillary lymph node metastasis between the ILC and IDC groups. Primary ILCs were greater in size, but demonstrated lower maximum standardized uptake values than IDCs. All primary masses were detected on MRI. The detection rate for ILCs (75.0%) was lower than that for IDCs (83.6%) on (18)F-FDG PET/CT, but the difference was not significant. For additional ipsilateral lesion(s), the sensitivities and specificities of MRI were 87.5% and 58.3% for ILC and 100.0% and 66.7% for IDC, respectively; whereas the sensitivities and specificities of (18)F-FDG PET/CT were 0% and 91.7% for ILC and 37.5% and 94.7% for IDC, respectively. The sensitivity of (18)F-FDG PET/CT for ipsilateral lesion(s) was significantly lower in the ILC group than the IDC group. The sensitivity for ipsilateral lesion(s) was significantly higher with MRI; however, specificity was higher with (18)F-FDG PET/CT in both tumor groups. There was no significant difference in the diagnostic performance for additional contralateral lesion(s) or axillary lymph node metastasis on MRI or (18)F-FDG PET/CT for ILC versus IDC. The MRI and (18)F-FDG PET/CT detection rates for the primary cancer do not differ between the ILC and IDC groups. Although (18)F-FDG PET/CT demonstrates lower sensitivity for primary and additional ipsilateral lesions, it shows higher specificity for additional ipsilateral lesions, and could play a complementary role in the staging of ILC as well as IDC.

A Fast Monte Carlo Simulation for the International Linear Collider Detector

DOE Office of Scientific and Technical Information (OSTI.GOV)

Furse, D.; /Georgia Tech

2005-12-15

The following paper contains details concerning the motivation for, implementation and performance of a Java-based fast Monte Carlo simulation for a detector designed to be used in the International Linear Collider. This simulation, presently included in the SLAC ILC group's org.lcsim package, reads in standard model or SUSY events in STDHEP file format, stochastically simulates the blurring in physics measurements caused by intrinsic detector error, and writes out an LCIO format file containing a set of final particles statistically similar to those that would have found by a full Monte Carlo simulation. In addition to the reconstructed particles themselves, descriptionsmore » of the calorimeter hit clusters and tracks that these particles would have produced are also included in the LCIO output. These output files can then be put through various analysis codes in order to characterize the effectiveness of a hypothetical detector at extracting relevant physical information about an event. Such a tool is extremely useful in preliminary detector research and development, as full simulations are extremely cumbersome and taxing on processor resources; a fast, efficient Monte Carlo can facilitate and even make possible detector physics studies that would be very impractical with the full simulation by sacrificing what is in many cases inappropriate attention to detail for valuable gains in time required for results.« less

Evidence of IL-17 producing innate lymphoid cells in peripheral blood from patients with enteropathic spondyloarthritis.

PubMed

Triggianese, Paola; Conigliaro, Paola; Chimenti, Maria Sole; Biancone, Livia; Monteleone, Giovanni; Perricone, Roberto; Monteleone, Ivan

2016-01-01

Both the innate and the adaptive immune responses contribute to the onset of chronic inflammation in spondyloarthritis (SpA). The association between SpA and inflammatory bowel disease (IBD, enteropathic SpA-ESpA) has been largely established and suggests a shared pathophysiology. There is evidence that innate lymphoid cells (ILC) are involved in the pathogenesis of both SpA and IBD while no evidence has been reported to date on ESpA. We aimed to analyse for the first time the frequency and cytokine expression of ILC in peripheral blood from ESpA patients compared with both IBD and healthy subjects. Correlations between immunophenotyping and disease activity were also explored. ESpA patients (n=20) were prospectively enrolled. Healthy controls (HC, n=10) and IBD patients (n=10) served as control groups. Peripheral blood Interferon (IFN)-γ and interleukin (IL)-17 expressing T and non-T cells as well as ILC subsets (ILC-1: IFN- γ +; ILC-3: IL-17+; natural killer-NK) were characterised by flowcytometry. Correlations between IL-17+ cells and SpA disease activity were analysed. ESpA patients showed higher levels of ROR-γ expressing non T-cells with the respect to the controls. IL-17 producing non-T cells were higher than the HC and positively correlated with IFN-γ expressing cells levels as well as with SpA disease activity. ESpA showed higher levels of ILC-1 and ILC-3 than both IBD and HC. IFN-γ expressing NK cells were higher in ESpA than HC. Our preliminary findings indicate that peripheral blood of ESpA patients is enriched for IL-17 expressing ILC which distinguishes the blood compartment from both IBD and HC. The increased IL-17 production by ILC indicates a novel role for ILC in ESpA.

Group-2 innate lymphoid cells mediate ozone induced airway inflammation and hyperresponsiveness in mice

PubMed Central

Yang, Qi; Ge, Moyar Q.; Kokalari, Blerina; Redai, Imre G.; Wang, Xinxin; Kemeny, David M.; Bhandoola, Avinash; Haczku, Angela

2015-01-01

Background Patients with asthma are highly susceptible to air pollution and in particular, to the effects of ozone (O3) inhalation, but the underlying mechanisms remain unclear. Objective Using mouse models of O3-induced airway inflammation and hyperresponsiveness (AHR), we sought to investigate the role of the recently discovered group 2 innate lymphoid cells (ILC2). Methods C57BL/6 and Balb/c mice were exposed to Aspergillus fumigatus and/or O3 (2ppm, 2h). ILC2 were isolated by FACS sorting and studied for IL-5 and IL-13 mRNA expression. ILC2 were depleted with anti-Thy1.2 mAb and replaced by intratracheal transfer of ex vivo expanded Thy1.1 ILC2. Cytokines (ELISA, qPCR), inflammatory cell profile and AHR (FlexiVent) were assessed in the mice. Results In addition to neutrophil influx, O3 inhalation elicited the appearance of eosinophils and IL-5 in the airways of Balb/c but not C57BL/6 mice. Although O3 induced expression of IL-33, a known activator of ILC2 in the lung was similar between these strains, isolated pulmonary ILC2 from O3 exposed Balb/c mice had significantly greater IL-5 and IL-13 mRNA expression than those of C57BL/6 mice. This suggested that an altered ILC2 function in Balb/c mice may mediate the increased O3 responsiveness. Indeed, anti-Thy1.2 treatment abolished, whereas ILC2 add-back dramatically enhanced O3-induced AHR. Conclusions O3-induced activation of pulmonary ILC2 was necessary and sufficient to mediate asthma-like changes in Balb/c mice. This previously unrecognized role of ILC2 may help explain the heightened susceptibility of human asthmatic airways to O3 exposure. PMID:26282284

A Proinflammatory Role of Type 2 Innate Lymphoid Cells in Murine Immune-Mediated Hepatitis.

PubMed

Neumann, Katrin; Karimi, Khalil; Meiners, Jana; Voetlause, Ruth; Steinmann, Silja; Dammermann, Werner; Lüth, Stefan; Asghari, Farahnaz; Wegscheid, Claudia; Horst, Andrea K; Tiegs, Gisa

2017-01-01

Type 2 innate lymphoid cells (ILC2) mediate inflammatory immune responses in the context of diseases triggered by the alarmin IL-33. In recent years, IL-33 has been implicated in the pathogenesis of immune-mediated liver diseases. However, the immunoregulatory function of ILC2s in the inflamed liver remains elusive. Using the murine model of Con A-induced immune-mediated hepatitis, we showed that selective expansion of ILC2s in the liver was associated with highly elevated hepatic IL-33 expression, severe liver inflammation, and infiltration of eosinophils. CD4 + T cell-mediated tissue damage and subsequent IL-33 release were responsible for the activation of hepatic ILC2s that produced the type 2 cytokines IL-5 and IL-13 during liver inflammation. Interestingly, ILC2 depletion correlated with less severe hepatitis and reduced accumulation of eosinophils in the liver, whereas adoptive transfer of hepatic ILC2s aggravated liver inflammation and tissue damage. We further showed that, despite expansion of hepatic ILC2s, 3-d IL-33 treatment before Con A challenge potently suppressed development of immune-mediated hepatitis. We found that IL-33 not only activated hepatic ILC2s but also expanded CD4 + Foxp3 + regulatory T cells (Treg) expressing the IL-33 receptor ST2 in the liver. This Treg subset also accumulated in the liver during resolution of immune-mediated hepatitis. In summary, hepatic ILC2s are poised to respond to the release of IL-33 upon liver tissue damage through expression of type 2 cytokines thereby participating in the pathogenesis of immune-mediated hepatitis. Inflammatory activity of ILC2s might be regulated by IL-33-elicited ST2 + Tregs that also arise in immune-mediated hepatitis. Copyright © 2016 by The American Association of Immunologists, Inc.

48 CFR 52.228-14 - Irrevocable Letter of Credit.

Code of Federal Regulations, 2014 CFR

2014-10-01

... past year, ILCs over $5 million must be confirmed by another acceptable financial institution that had letter of credit business of at least $25 million in the past year. (e) The following format shall be... extended without amendment for one year from the expiration date hereof, or any future expiration date...

Human innate lymphoid cells.

PubMed

Mjösberg, Jenny; Spits, Hergen

2016-11-01

Innate lymphoid cells (ILCs) are increasingly acknowledged as important mediators of immune homeostasis and pathology. ILCs act as early orchestrators of immunity, responding to epithelium-derived signals by expressing an array of cytokines and cell-surface receptors, which shape subsequent immune responses. As such, ILCs make up interesting therapeutic targets for several diseases. In patients with allergy and asthma, group 2 innate lymphoid cells produce high amounts of IL-5 and IL-13, thereby contributing to type 2-mediated inflammation. Group 3 innate lymphoid cells are implicated in intestinal homeostasis and psoriasis pathology through abundant IL-22 production, whereas group 1 innate lymphoid cells are accumulated in chronic inflammation of the gut (inflammatory bowel disease) and lung (chronic obstructive pulmonary disease), where they contribute to IFN-γ-mediated inflammation. Although the ontogeny of mouse ILCs is slowly unraveling, the development of human ILCs is far from understood. In addition, the growing complexity of the human ILC family in terms of previously unrecognized functional heterogeneity and plasticity has generated confusion within the field. Here we provide an updated view on the function and plasticity of human ILCs in tissue homeostasis and disease. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Group 2 Innate Lymphoid Cells in Pulmonary Immunity and Tissue Homeostasis.

PubMed

Mindt, Barbara C; Fritz, Jörg H; Duerr, Claudia U

2018-01-01

Group 2 innate lymphoid cells (ILC2) represent an evolutionary rather old but only recently identified member of the family of innate lymphoid cells and have received much attention since their detailed description in 2010. They can orchestrate innate as well as adaptive immune responses as they interact with and influence several immune and non-immune cell populations. Moreover, ILC2 are able to rapidly secrete large amounts of type 2 cytokines that can contribute to protective but also detrimental host immune responses depending on timing, location, and physiological context. Interestingly, ILC2, despite their scarcity, are the dominant innate lymphoid cell population in the lung, indicating a key role as first responders and amplifiers upon immune challenge at this site. In addition, the recently described tissue residency of ILC2 further underlines the importance of their respective microenvironment. In this review, we provide an overview of lung physiology including a description of the most prominent pulmonary resident cells together with a review of known and potential ILC2 interactions within this unique environment. We will further outline recent observations regarding pulmonary ILC2 during immune challenge including respiratory infections and discuss different models and approaches to study ILC2 biology in the lung.

Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation.

PubMed

Krishnamoorthy, Nandini; Burkett, Patrick R; Dalli, Jesmond; Abdulnour, Raja-Elie E; Colas, Romain; Ramon, Sesquile; Phipps, Richard P; Petasis, Nicos A; Kuchroo, Vijay K; Serhan, Charles N; Levy, Bruce D

2015-02-01

Asthma is a chronic inflammatory disease that fails to resolve. Recently, a key role for type 2 innate lymphoid cells (ILC2s) was linked to asthma pathogenesis; however, mechanisms for ILC2 regulation remain to be determined. In this study, metabololipidomics of murine lungs identified temporal changes in endogenous maresin 1 (MaR1) during self-limited allergic inflammation. Exogenous MaR1 reduced lung inflammation and ILC2 expression of IL-5 and IL-13 and increased amphiregulin. MaR1 augmented de novo generation of regulatory T cells (Tregs), which interacted with ILC2s to markedly suppress cytokine production in a TGF-β-dependent manner. Ab-mediated depletion of Tregs interrupted MaR1 control of ILC2 expression of IL-13 in vivo. Together, the findings uncover Tregs as potent regulators of ILC2 activation; MaR1 targets Tregs and ILC2s to restrain allergic lung inflammation, suggesting MaR1 as the basis for a new proresolving therapeutic approach to asthma and other chronic inflammatory diseases. Copyright © 2015 by The American Association of Immunologists, Inc.

Colonization and effector functions of innate lymphoid cells in mucosal tissues

PubMed Central

Kim, Myunghoo; Kim, Chang H.

2016-01-01

Innate lymphoid cells (ILCs) protect mucosal barrier tissues to fight infection and maintain tissue integrity. ILCs and their progenitors are developmentally programmed to migrate, differentiate and populate various mucosal tissues and associated lymphoid tissues. Functionally mature ILC subsets respond to diverse pathogens such as bacteria, viruses, fungi and parasites in subset-specific manners. In this review, we will discuss how ILCs populate mucosal tissues and regulate immune responses to distinct pathogens to protect the host and maintain tissue integrity. PMID:27365193

Lobular breast cancers lack the inverse relationship between ER/PR status and cell growth rate characteristic of ductal cancers in two independent patient cohorts: implications for tumor biology and adjuvant therapy.

PubMed

Wong, Hilda; Lau, Silvia; Cheung, Polly; Wong, Ting Ting; Parker, Andrew; Yau, Thomas; Epstein, Richard J

2014-11-10

Although invasive lobular carcinoma (ILC) of the breast differs from invasive ductal carcinoma (IDC) in numerous respects - including its genetics, clinical phenotype, metastatic pattern, and chemosensitivity - most experts continue to manage ILC and IDC identically in the adjuvant setting. Here we address this discrepancy by comparing early-stage ILC and IDC in two breast cancer patient cohorts of differing nationality and ethnicity. The clinicopathologic features of 2029 consecutive breast cancer patients diagnosed in Hong Kong (HK) and Australia (AUS) were compared. Interrelationships between tumor histology and other clinicopathologic variables, including ER/PR and Ki67, were analysed. Two hundred thirty-nine patients were identified with ILC (11.8%) and 1790 patients with IDC. AUS patients were older (p <0.001) and more often postmenopausal (p <0.03) than HK patients. As expected, ILC tumors were lower in grade and proliferative rate, and more often ER-positive and HER2-negative, than IDC (p <0.002); yet despite this, ILC tumors were as likely as IDC to present with nodal metastases (p >0.7). Moreover, whereas IDC tumors exhibited a strongly negative relationship between ER/PR and Ki67 status (p <0.0005), ILC tumors failed to demonstrate any such inverse relationship (p >0.6). These data imply that the primary adhesion defect in ILC underlies a secondary stromal-epithelial disconnect between hormonal signaling and tumor growth, suggesting in turn that this peritumoral feedback defect could reduce both the antimetastatic (adjuvant) and tumorilytic (palliative) efficacy of cytotoxic therapies for such tumors. Hence, we caution against assuming similar adjuvant chemotherapeutic survival benefits for ILC and IDC tumors with similar ER and Ki67, whether based on immunohistochemical or gene expression assays.

Group 3 Innate Lymphoid Cells: Communications Hubs of the Intestinal Immune System.

PubMed

Withers, David R; Hepworth, Matthew R

2017-01-01

The maintenance of mammalian health requires the generation of appropriate immune responses against a broad range of environmental and microbial challenges, which are continually encountered at barrier tissue sites including the skin, lung, and gastrointestinal tract. Dysregulated barrier immune responses result in inflammation, both locally and systemically in peripheral organs. Group 3 innate lymphoid cells (ILC3) are constitutively present at barrier sites and appear to be highly specialized in their ability to sense a range of environmental and host-derived signals. Under homeostatic conditions, ILC3 respond to local cues to maintain tissue homeostasis and restrict inflammatory responses. In contrast, perturbations in the tissue microenvironment resulting from disease, infection, or tissue damage can drive dysregulated pro-inflammatory ILC3 responses and contribute to immunopathology. The tone of the ILC3 response is dictated by a balance of "exogenous" signals, such as dietary metabolites and commensal microbes, and "endogenous" host-derived signals from stromal cells, immune cells, and the nervous system. ILC3 must therefore have the capacity to simultaneously integrate a wide array of complex and dynamic inputs in order to regulate barrier function and tissue health. In this review, we discuss the concept of ILC3 as a "communications hub" in the intestinal tract and associated lymphoid tissues and address the variety of signals, derived from multiple biological systems, which are interpreted by ILC3 to modulate the release of downstream effector molecules and regulate cell-cell crosstalk. Successful integration of environmental cues by ILC3 and downstream propagation to the broader immune system is required to maintain a tolerogenic and anti-inflammatory tone and reinforce barrier function, whereas dysregulation of ILC3 responses can contribute to the onset or progression of clinically relevant chronic inflammatory diseases.

Group 3 Innate Lymphoid Cells: Communications Hubs of the Intestinal Immune System

PubMed Central

Withers, David R.; Hepworth, Matthew R.

2017-01-01

The maintenance of mammalian health requires the generation of appropriate immune responses against a broad range of environmental and microbial challenges, which are continually encountered at barrier tissue sites including the skin, lung, and gastrointestinal tract. Dysregulated barrier immune responses result in inflammation, both locally and systemically in peripheral organs. Group 3 innate lymphoid cells (ILC3) are constitutively present at barrier sites and appear to be highly specialized in their ability to sense a range of environmental and host-derived signals. Under homeostatic conditions, ILC3 respond to local cues to maintain tissue homeostasis and restrict inflammatory responses. In contrast, perturbations in the tissue microenvironment resulting from disease, infection, or tissue damage can drive dysregulated pro-inflammatory ILC3 responses and contribute to immunopathology. The tone of the ILC3 response is dictated by a balance of “exogenous” signals, such as dietary metabolites and commensal microbes, and “endogenous” host-derived signals from stromal cells, immune cells, and the nervous system. ILC3 must therefore have the capacity to simultaneously integrate a wide array of complex and dynamic inputs in order to regulate barrier function and tissue health. In this review, we discuss the concept of ILC3 as a “communications hub” in the intestinal tract and associated lymphoid tissues and address the variety of signals, derived from multiple biological systems, which are interpreted by ILC3 to modulate the release of downstream effector molecules and regulate cell–cell crosstalk. Successful integration of environmental cues by ILC3 and downstream propagation to the broader immune system is required to maintain a tolerogenic and anti-inflammatory tone and reinforce barrier function, whereas dysregulation of ILC3 responses can contribute to the onset or progression of clinically relevant chronic inflammatory diseases. PMID:29085366

Innate Lymphoid Cells: a new paradigm in immunology

PubMed Central

Eberl, Gérard; Colonna, Marco; Di Santo, James P.; McKenzie, Andrew N.J.

2016-01-01

Summary Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. However, in contrast to T cells, ILCs do not express acquired antigen receptors or undergo clonal selection and expansion when stimulated. Instead, ILCs react promptly to signals from infected or injured tissues and produce an array of secreted proteins termed cytokines that direct the developing immune response into one that is adapted to the original insult. The complex crosstalk between microenvironment, ILCs and adaptive immunity remains to be fully deciphered. Only by understanding these complex regulatory networks can the power of ILCs be controlled or unleashed to regulate or enhance immune responses in disease prevention and therapy. PMID:25999512

[Function and modulation of type Ⅱ innate lymphoid cells and their role in chronic upper airway inflammatory diseases].

PubMed

Liu, Y; Liu, Z

2017-02-07

Type Ⅱ innate lymphoid cells (ILC2) is a family of innate immune lymphocytes, which provide effective immune responses to cytokines. ILC2 are regulated by the nuclear transcription factor ROR alpha and GATA3, secreting cytokines IL-5 and IL-13, etc. Animal models have shown that ILC2 are involved in allergic diseases, such as asthma and atopic dermatitis, and also play a very important role in the metabolic balance. In addition, recent reports suggest that ILC2 not only play a role in the initial stages of the disease, but also can lead to chronic pathological changes in the disease, such as fibrosis, and may have an effect on acquired immunity. This paper mainly focus in the role and regulation of ILC2 cells, and review the research status of ILC2 in the field of chronic upper airway inflammatory diseases including allergic rhinitis and chronic rhinosinusitis.

The International Linear Collider Technical Design Report - Volume 4: Detectors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Behnke, Ties

2013-06-26

The International Linear Collider Technical Design Report (TDR) describes in four volumes the physics case and the design of a 500 GeV centre-of-mass energy linear electron-positron collider based on superconducting radio-frequency technology using Niobium cavities as the accelerating structures. The accelerator can be extended to 1 TeV and also run as a Higgs factory at around 250 GeV and on the Z0 pole. A comprehensive value estimate of the accelerator is give, together with associated uncertainties. It is shown that no significant technical issues remain to be solved. Once a site is selected and the necessary site-dependent engineering is carriedmore » out, construction can begin immediately. The TDR also gives baseline documentation for two high-performance detectors that can share the ILC luminosity by being moved into and out of the beam line in a "push-pull" configuration. These detectors, ILD and SiD, are described in detail. They form the basis for a world-class experimental programme that promises to increase significantly our understanding of the fundamental processes that govern the evolution of the Universe.« less

Group 1 innate lymphoid cells in Toxoplasma gondii infection.

PubMed

Dunay, I R; Diefenbach, A

2018-02-01

Innate lymphoid cells (ILCs) are a group of lymphocytes that carry out important functions in immunity to infections and in organ homeostasis at epithelial barrier surfaces. ILCs are innate immune cells that provide an early source of cytokines to initiate immune responses against pathogens. Cytotoxic ILCs (i.e. conventional (c)NK cells) and several subsets of helper-like ILCs are the major branches of the ILC family. Conventional NK cells and group 1 ILCs share several characteristics such as surface receptors and the ability to produce IFN-γ upon activation, but they differ in their developmental paths and in their dependence on specific transcription factors. Infection of mice with the intracellular parasite Toxoplasma gondii is followed by a strong Th1-mediated immune response. Previous studies indicate that NK1.1 + cells contribute to the production of IFN-γ and TNF and cytotoxicity during acute T. gondii infection. Upon oral infection, the parasite infects intestinal enterocytes, and within the lamina propria, innate immune responses lead to initial parasite control although the infection disseminates widely and persists long-term in immune privileged sites despite adaptive immunity. Upon parasite entry into the small intestine, during the acute stage, ILC1 produce high levels of IFN-γ and TNF protecting barrier surfaces, thus essentially contributing to early parasite control. We will discuss here the role of innate lymphocytes during T. gondii infection in the context of the only recently appreciated diversity of ILC subsets. © 2018 John Wiley & Sons Ltd.

Potentiating Tissue-Resident Type 2 Innate Lymphoid Cells by IL-33 to Prevent Renal Ischemia-Reperfusion Injury.

PubMed

Cao, Qi; Wang, Yiping; Niu, Zhiguo; Wang, Chengshi; Wang, Ruifeng; Zhang, Zhiqiang; Chen, Titi; Wang, Xin Maggie; Li, Qing; Lee, Vincent W S; Huang, Qingsong; Tan, Jing; Guo, Minghao; Wang, Yuan Min; Zheng, Guoping; Yu, Di; Alexander, Stephen I; Wang, Hui; Harris, David C H

2018-03-01

The IL-33-type 2 innate lymphoid cell (ILC2) axis has an important role in tissue homeostasis, inflammation, and wound healing. However, the relative importance of this innate immune pathway for immunotherapy against inflammation and tissue damage remains unclear. Here, we show that treatment with recombinant mouse IL-33 prevented renal structural and functional injury and reduced mortality in mice subjected to ischemia-reperfusion injury (IRI). Compared with control-treated IRI mice, IL-33-treated IRI mice had increased levels of IL-4 and IL-13 in serum and kidney and more ILC2, regulatory T cells (Tregs), and anti-inflammatory (M2) macrophages. Depletion of ILC2, but not Tregs, substantially abolished the protective effect of IL-33 on renal IRI. Adoptive transfer of ex vivo -expanded ILC2 prevented renal injury in mice subjected to IRI. This protective effect associated with induction of M2 macrophages in kidney and required ILC2 production of amphiregulin. Treatment of mice with IL-33 or ILC2 after IRI was also renoprotective. Furthermore, in a humanized mouse model of renal IRI, treatment with human IL-33 or transfer of ex vivo -expanded human ILC2 ameliorated renal IRI. This study has uncovered a major protective role of the IL-33-ILC2 axis in renal IRI that could be potentiated as a therapeutic strategy. Copyright © 2018 by the American Society of Nephrology.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bane, K.L.F.; Adolphsen, C.; Li, Z.

In a future linear collider, such as the International Linear Collider (ILC), trains of high current, low emittance bunches will be accelerated in a linac before colliding at the interaction point. Asymmetries in the accelerating cavities of the linac will generate fields that will kick the beam transversely and degrade the beam emittance and thus the collider performance. In the main linac of the ILC, which is filled with TESLA-type superconducting cavities, it is the fundamental (FM) and higher mode (HM) couplers that are asymmetric and thus the source of such kicks. The kicks are of two types: one, duemore » to (the asymmetry in) the fundamental RF fields and the other, due to transverse wakefields that are generated by the beam even when it is on axis. In this report we calculate the strength of these kicks and estimate their effect on the ILC beam. The TESLA cavity comprises nine cells, one HM coupler in the upstream end, and one (identical, though rotated) HM coupler and one FM coupler in the downstream end (for their shapes and location see Figs. 1, 2) [1]. The cavity is 1.1 m long, the iris radius 35 mm, and the coupler beam pipe radius 39 mm. Note that the couplers reach closer to the axis than the irises, down to a distance of 30 mm.« less

Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

PubMed Central

Petridis, Christos; Brook, Mark N.; Nowinski, Salpie; Papouli, Efterpi; Fletcher, Olivia; Pinder, Sarah; Hanby, Andrew; Kohut, Kelly; Gorman, Patricia; Caneppele, Michele; Peto, Julian; dos Santos Silva, Isabel; Johnson, Nichola; Swann, Ruth; Dwek, Miriam; Perkins, Katherine-Anne; Gillett, Cheryl; Houlston, Richard; Ross, Gillian; De Ieso, Paolo; Southey, Melissa C.; Hopper, John L.; Provenzano, Elena; Apicella, Carmel; Wesseling, Jelle; Cornelissen, Sten; Keeman, Renske; Fasching, Peter A.; Jud, Sebastian M.; Ekici, Arif B.; Beckmann, Matthias W.; Kerin, Michael J.; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Guénel, Pascal; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Milne, Roger L.; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Benitez, Javier; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Lichtner, Peter; Schmutzler, Rita K.; Lochmann, Magdalena; Brauch, Hiltrud; Fischer, Hans-Peter; Ko, Yon-Dschun; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia V.; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Chenevix-Trench, Georgia; Investigators, kConFab; Lambrechts, Diether; Weltens, Caroline; Van Limbergen, Erik; Hatse, Sigrid; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Volorio, Sara; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; Mclean, Catriona A.; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Kristensen, Vessela; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Devillee, Peter; Tollenaar, Rob A. E. M.; Seynaeve, Caroline M.; Kriege, Mieke; Figueroa, Jonine; Chanock, Stephen J.; Sherman, Mark E.; Hooning, Maartje J.; Hollestelle, Antoinette; van den Ouweland, Ans M. W.; van Deurzen, Carolien H. M.; Li, Jingmei; Czene, Kamila; Humphreys, Keith; Cox, Angela; Cross, Simon S.; Reed, Malcolm W. R.; Shah, Mitul; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Swerdlow, Anthony; Ashworth, Alan; Orr, Nicholas; Schoemaker, Minouk; Couch, Fergus J.; Hallberg, Emily; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Michailidou, Kyriaki; Dunning, Alison M.; Hall, Per; Easton, Doug; Pharoah, Paul; Schmidt, Marjanka K.; Tomlinson, Ian; Garcia-Closas, Montserrat

2014-01-01

Invasive lobular breast cancer (ILC) accounts for 10–15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09–1.18), P = 6.0×10−10; P-het for ILC vs IDC ER+ tumors = 1.8×10−4). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes. PMID:24743323

Colonization and effector functions of innate lymphoid cells in mucosal tissues.

PubMed

Kim, Myunghoo; Kim, Chang H

2016-10-01

Innate lymphoid cells (ILCs) protect mucosal barrier tissues to fight infection and maintain tissue integrity. ILCs and their progenitors are developmentally programmed to migrate, differentiate and populate various mucosal tissues and associated lymphoid tissues. Functionally mature ILC subsets respond to diverse pathogens such as bacteria, viruses, fungi and parasites in subset-specific manners. In this review, we will discuss how ILCs populate mucosal tissues and regulate immune responses to distinct pathogens to protect the host and maintain tissue integrity. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Interactions between Innate Lymphoid Cells and Cells of the Innate and Adaptive Immune System

PubMed Central

Symowski, Cornelia; Voehringer, David

2017-01-01

Type 2 innate lymphoid cells (ILC2s) are a major source of cytokines, which are also produced by Th2 cells and several cell types of the innate immune system. Work over the past few years indicates that ILC2s play a central role in regulating type 2 immune responses against allergens and helminths. ILC2s can interact with a variety of cells types of the innate and adaptive immune system by cell–cell contacts or by communication via soluble factors. In this review, we provide an overview about recent advances in our understanding how ILC2s orchestrate type 2 immune responses with focus on direct interactions between ILC2s and other cells of the immune system. PMID:29163497

Interactions between Innate Lymphoid Cells and Cells of the Innate and Adaptive Immune System.

PubMed

Symowski, Cornelia; Voehringer, David

2017-01-01

Type 2 innate lymphoid cells (ILC2s) are a major source of cytokines, which are also produced by Th2 cells and several cell types of the innate immune system. Work over the past few years indicates that ILC2s play a central role in regulating type 2 immune responses against allergens and helminths. ILC2s can interact with a variety of cells types of the innate and adaptive immune system by cell-cell contacts or by communication via soluble factors. In this review, we provide an overview about recent advances in our understanding how ILC2s orchestrate type 2 immune responses with focus on direct interactions between ILC2s and other cells of the immune system.

Innate lymphoid cells in autoimmunity and chronic inflammatory diseases.

PubMed

Xiong, Tingting; Turner, Jan-Eric

2018-03-22

Abnormal activation of the innate immune system is a common feature of autoimmune and chronic inflammatory diseases. Since their identification as a separate family of leukocytes, innate lymphoid cells (ILCs) have emerged as important effector cells of the innate immune system. Alterations in ILC function and subtype distribution have been observed in a variety of immune-mediated diseases in humans and evidence from experimental models suggests a subtype specific role of ILCs in the pathophysiology of autoimmune inflammation. In this review, we discuss recent advances in the understanding of ILC biology in autoimmune and chronic inflammatory disorders, including multiple sclerosis, inflammatory bowel diseases, psoriasis, and rheumatic diseases, with a special focus on the potential of ILCs as therapeutic targets for the development of novel treatment strategies in humans.

Control of pathogens and microbiota by innate lymphoid cells.

PubMed

Cording, Sascha; Medvedovic, Jasna; Lecuyer, Emelyne; Aychek, Tegest; Eberl, Gérard

2018-05-28

Innate lymphoid cells (ILCs) are the innate counterpart of T cells. Upon infection or injury, ILCs react promptly to direct the developing immune response to the one most adapted to the threat facing the organism. Therefore, ILCs play an important role early in resistance to infection, but also to maintain homeostasis with the symbiotic microbiota following perturbations induced by diet and pathogens. Such roles of ILCs have been best characterized in the intestine and lung, mucosal sites that are exposed to the environment and are therefore colonized with diverse but specific types of microbes. Understanding the dialogue between pathogens, microbiota and ILCs may lead to new strategies to re-inforce immunity for prevention, vaccination and therapy. Copyright © 2018 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Group 2 Innate Lymphoid Cells in Pulmonary Immunity and Tissue Homeostasis

PubMed Central

Mindt, Barbara C.; Fritz, Jörg H.; Duerr, Claudia U.

2018-01-01

Group 2 innate lymphoid cells (ILC2) represent an evolutionary rather old but only recently identified member of the family of innate lymphoid cells and have received much attention since their detailed description in 2010. They can orchestrate innate as well as adaptive immune responses as they interact with and influence several immune and non-immune cell populations. Moreover, ILC2 are able to rapidly secrete large amounts of type 2 cytokines that can contribute to protective but also detrimental host immune responses depending on timing, location, and physiological context. Interestingly, ILC2, despite their scarcity, are the dominant innate lymphoid cell population in the lung, indicating a key role as first responders and amplifiers upon immune challenge at this site. In addition, the recently described tissue residency of ILC2 further underlines the importance of their respective microenvironment. In this review, we provide an overview of lung physiology including a description of the most prominent pulmonary resident cells together with a review of known and potential ILC2 interactions within this unique environment. We will further outline recent observations regarding pulmonary ILC2 during immune challenge including respiratory infections and discuss different models and approaches to study ILC2 biology in the lung. PMID:29760695

Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients.

PubMed

Sugita, Kazunari; Steer, Catherine A; Martinez-Gonzalez, Itziar; Altunbulakli, Can; Morita, Hideaki; Castro-Giner, Francesc; Kubo, Terufumi; Wawrzyniak, Paulina; Rückert, Beate; Sudo, Katsuko; Nakae, Susumu; Matsumoto, Kenji; O'Mahony, Liam; Akdis, Mübeccel; Takei, Fumio; Akdis, Cezmi A

2018-01-01

Bronchial epithelial barrier leakiness and type 2 innate lymphoid cells (ILC2s) have been separately linked to asthma pathogenesis; however, the influence of ILC2s on the bronchial epithelial barrier has not been investigated previously. We investigated the role of ILC2s in the regulation of bronchial epithelial tight junctions (TJs) and barrier function both in bronchial epithelial cells of asthmatic patients and healthy subjects and general innate lymphoid cell- and ILC2-deficient mice. Cocultures of human ILC2s and bronchial epithelial cells were used to determine transepithelial electrical resistance, paracellular flux, and TJ mRNA and protein expressions. The effect of ILC2s on TJs was examined by using a murine model of IL-33-induced airway inflammation in wild-type, recombination-activating gene 2 (Rag2) -/- , Rag2 -/- Il2rg -/- , and Rora sg/sg mice undergoing bone marrow transplantation to analyze the in vivo relevance of barrier disruption by ILC2s. ILC2s significantly impaired the epithelial barrier, as demonstrated by reduced transepithelial electrical resistance and increased fluorescein isothiocyanate-dextran permeability in air-liquid interface cultures of human bronchial epithelial cells. This was in parallel to decreased mRNAs and disrupted protein expression of TJ proteins and was restored by neutralization of IL-13. Intranasal administration of recombinant IL-33 to wild-type and Rag2 -/- mice lacking T and B cells triggered TJ disruption, whereas Rag2 -/- Il2rg -/- and Rora sg/sg mice undergoing bone marrow transplantation that lack ILC2s did not show any barrier leakiness. Direct nasal administration of IL-13 was sufficient to induce deficiency in the TJ barrier in the bronchial epithelium of mice in vivo. These data highlight an essential mechanism in asthma pathogenesis by demonstrating that ILC2s are responsible for bronchial epithelial TJ barrier leakiness through IL-13. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

The sensitivity of pre-operative axillary staging in breast cancer: comparison of invasive lobular and ductal carcinoma.

PubMed

Topps, A; Clay, V; Absar, M; Howe, M; Lim, Y; Johnson, R; Bundred, N

2014-07-01

Axillary ultrasound (AUS) with fine-needle aspiration (FNA) biopsy of abnormal lymph nodes is important for pre-operative staging and planning the surgical management of the axilla. Invasive lobular carcinoma (ILC) metastases are thought to be difficult to detect because the cells are small and on cytology resemble lymphocytes. To investigate this we directly compared the sensitivity of pre-operative axillary staging between ILC and invasive ductal carcinoma (IDC). Consecutive patients that presented in a single breast unit with pure IDC between April 2005 and December 2006 and pure ILC between January 2008 and December 2012 were retrospectively identified from pathology records. Pre-operative axillary ultrasound and FNA biopsy results were compared with post-operative histopathology from the sentinel node biopsy (SNB) or axillary lymph node dissection (ALND). A total of 275 and 142 axillae were identified in the IDC and ILC groups respectively. In the node positive patients there was no significant difference in the sensitivity of AUS (IDC vs. ILC; 58.7% vs. 52.8%). However, there was a significant difference in the sensitivity of ultrasound-guided FNA biopsy of abnormal nodes (IDC vs. ILC; 98.4% vs. 53.6%; p < 0.001). AUS has comparative sensitivities between IDC and ILC populations. In contrast, FNA biopsy of abnormal axillary nodes is clearly less sensitive in the ILC group. In these patients, who have abnormal AUS, we suggest that a core biopsy is required to improve the pre-operative staging and prevent unnecessary surgical procedures. Copyright © 2014 Elsevier Ltd. All rights reserved.

Type 2 innate lymphoid cells: at the cross-roads in allergic asthma.

PubMed

van Rijt, Leonie; von Richthofen, Helen; van Ree, Ronald

2016-07-01

Allergic asthma is a chronic inflammatory disease of the lower airways that affects millions of people worldwide. Allergic asthma is a T helper 2 cell (Th2)-mediated disease, in which Th2 cytokines interleukin (IL)-4, IL-5, and IL-13 are closely associated with the symptoms. IL-4 is needed by B cells to switch toward an IgE response, IL-5 recruits and activates eosinophils while IL-13 increases mucus production. The identification of type 2 innate lymphoid cells (ILC2), which are able to rapidly produce large amounts of IL-5 and IL-13 in response to epithelial derived cytokines, implicated a new key player besides Th2 cells. ILCs constitute a family of innate lymphocytes distinct from T and B cells. ILC2s are located in various epithelial compartments in mice and human, including the lung. The recent finding of increased numbers of ILC2s in the airways of severe asthma patients prompts further research to clarify their immunological function. Murine studies have shown that ILC2s are an early innate source of IL-5 and IL-13 after allergen exposure, which induce airway eosinophilic infiltration, mucus hyperproduction, and airway hyperresponsiveness but not allergen-specific IgE production. ILC2s contribute to the initiation as well as to the maintenance of the adaptive type 2 immune response. Here, we review the recent progress on our understanding of the role of ILC2s in the immunopathology of allergic asthma, in particular by studies using murine models which have elucidated fundamental mechanisms by which ILC2s act.

Type 3 innate lymphoid cell depletion is mediated by TLRs in lymphoid tissues of simian immunodeficiency virus-infected macaques.

PubMed

Xu, Huanbin; Wang, Xiaolei; Lackner, Andrew A; Veazey, Ronald S

2015-12-01

Innate lymphoid cells (ILCs) type 3, also known as lymphoid tissue inducer cells, plays a major role in both the development and remodeling of organized lymphoid tissues and the maintenance of adaptive immune responses. HIV/simian immunodeficiency virus (SIV) infection causes breakdown of intestinal barriers resulting in microbial translocation, leading to systemic immune activation and disease progression. However, the effects of HIV/SIV infection on ILC3 are unknown. Here, we analyzed ILC3 from mucosal and systemic lymphoid tissues in chronically SIV-infected macaques and uninfected controls. ILC3 cells were defined and identified in macaque lymphoid tissues as non-T, non-B (lineage-negative), c-Kit(+)IL-7Rα(+) (CD117(+)CD127(+)) cells. These ILC3 cells highly expressed CD90 (∼ 63%) and aryl hydrocarbon receptor and produced IL-17 (∼ 63%), IL-22 (∼ 36%), and TNF-α (∼ 72%) but did not coexpress CD4 or NK cell markers. The intestinal ILC3 cell loss correlated with the reduction of total CD4(+) T cells and T helper (Th)17 and Th22 cells in the gut during SIV infection (P < 0.001). Notably, ILC3 could be induced to undergo apoptosis by microbial products through the TLR2 (lipoteichoic acid) and/or TLR4 (LPS) pathway. These findings indicated that persistent microbial translocation may result in loss of ILC3 in lymphoid tissues in SIV-infected macaques, further contributing to the HIV-induced impairment of gut-associated lymphoid tissue structure and function, especially in mucosal tissues. © FASEB.

Critical role of fatty acid metabolism in ILC2 mediated barrier protection during malnutrition and helminth infection

USDA-ARS?s Scientific Manuscript database

Innate lymphoid cells (ILCs) play an important role in many immune processes, including control of infections, inflammation and tissue repair. To date little is known about the metabolism of ILCs under steady-state conditions and infection, and whether these cells can metabolically adapt in response...

S1P dependent inter organ trafficking of group 2 innate lymphoid cells suppots host defense

USDA-ARS?s Scientific Manuscript database

Innate lymphoid cells (ILCs) are considered to be the innate counterparts of adaptive T lymphocytes and play important roles in host defense, tissue repair, metabolic homeostasis, and inflammatory diseases. ILCs are generally thought of as tissue-resident cells, but whether ILCs strictly behave in a...

AHR prevents human IL-1R1hi ILC3 differentiation to natural killer cells

PubMed Central

Hughes, Tiffany; Briercheck, Edward L.; Freud, Aharon G.; Trotta, Rossana; McClory, Susan; Scoville, Steven D.; Keller, Karen; Deng, Youcai; Cole, Jordan; Harrison, Nicholas; Mao, Charlene; Zhang, Jianying; Benson, Don M.; Yu, Jianhua; Caligiuri, Michael A.

2014-01-01

SUMMARY Accumulating evidence indicates that human natural killer (NK) cells develop in secondary lymphoid tissue (SLT) through a so-called “stage 3” developmental intermediate minimally characterized by a CD34-CD117+CD94- immunophenotype that lacks mature NK cell function. This stage 3 population is heterogeneous, potentially composed of functionally distinct innate lymphoid cell (ILC) types that includes interleukin-1 receptor (IL-1R1) positive, IL-22-producing ILC3s. Whether human ILC3s are developmentally related to NK cells is a subject of ongoing investigation. Here we show that antagonism of the aryl hydrocarbon receptor (AHR) or silencing of AHR gene expression promotes differentiation of tonsillar IL-22-producing IL-1R1hi human ILC3s to CD56brightCD94+ IFN-gamma-producing cytolytic mature NK cells expressing eomesodermin (EOMES) and T-Box Protein 21 (TBX21 or TBET). Hence, AHR is a transcription factor that prevents human IL-1R1hi ILC3s from differentiating into NK cells. PMID:24953655

Nuclear p120-catenin regulates the anoikis resistance of mouse lobular breast cancer cells through Kaiso-dependent Wnt11 expression

PubMed Central

van de Ven, Robert A. H.; Tenhagen, Milou; Meuleman, Wouter; van Riel, Jeske J. G.; Schackmann, Ron C. J.; Derksen, Patrick W. B.

2015-01-01

E-cadherin inactivation underpins the progression of invasive lobular breast carcinoma (ILC). In ILC, p120-catenin (p120) translocates to the cytosol where it controls anchorage independence through the Rho-Rock signaling pathway, a key mechanism driving tumor growth and metastasis. We now demonstrate that anchorage-independent ILC cells show an increase in nuclear p120, which results in relief of transcriptional repression by Kaiso. To identify the Kaiso target genes that control anchorage independence we performed genome-wide mRNA profiling on anoikis-resistant mouse ILC cells, and identified 29 candidate target genes, including the established Kaiso target Wnt11. Our data indicate that anchorage-independent upregulation of Wnt11 in ILC cells is controlled by nuclear p120 through inhibition of Kaiso-mediated transcriptional repression. Finally, we show that Wnt11 promotes activation of RhoA, which causes ILC anoikis resistance. Our findings thereby establish a mechanistic link between E-cadherin loss and subsequent control of Rho-driven anoikis resistance through p120- and Kaiso-dependent expression of Wnt11. PMID:25713299

Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury

PubMed Central

Overall, Christopher C.

2017-01-01

The meningeal space is occupied by a diverse repertoire of immune cells. Central nervous system (CNS) injury elicits a rapid immune response that affects neuronal survival and recovery, but the role of meningeal inflammation remains poorly understood. Here, we describe type 2 innate lymphocytes (ILC2s) as a novel cell type resident in the healthy meninges that are activated after CNS injury. ILC2s are present throughout the naive mouse meninges, though are concentrated around the dural sinuses, and have a unique transcriptional profile. After spinal cord injury (SCI), meningeal ILC2s are activated in an IL-33–dependent manner, producing type 2 cytokines. Using RNAseq, we characterized the gene programs that underlie the ILC2 activation state. Finally, addition of wild-type lung-derived ILC2s into the meningeal space of IL-33R−/− animals partially improves recovery after SCI. These data characterize ILC2s as a novel meningeal cell type that responds to SCI and could lead to new therapeutic insights for neuroinflammatory conditions. PMID:27994070

Crosstalk between Innate Lymphoid Cells and Other Immune Cells in the Tumor Microenvironment

PubMed Central

Irshad, Sheeba; Gordon, Peter; Wong, Felix; Sheriff, Ibrahim; Tutt, Andrew; Ng, Tony

2016-01-01

Our knowledge and understanding of the tumor microenvironment (TME) have been recently expanded with the recognition of the important role of innate lymphoid cells (ILC). Three different groups of ILC have been described based on their ability to produce cytokines that mediate the interactions between innate and adaptive immune cells in a variety of immune responses in infection, allergy, and autoimmunity. However, recent evidence from experimental models and clinical studies has demonstrated that ILC contribute to the mechanisms that generate suppressive or tolerant environments that allow tumor regression or progression. Defining the complex network of interactions and crosstalk of ILC with other immune cells and understanding the specific contributions of each type of ILC leading to tumor development will allow the manipulation of their function and will be important to develop new interventions and therapeutic strategies. PMID:27882334

Flt3 Ligand Regulates the Development of Innate Lymphoid Cells in Fetal and Adult Mice.

PubMed

Baerenwaldt, Anne; von Burg, Nicole; Kreuzaler, Matthias; Sitte, Selina; Horvath, Edit; Peter, Annick; Voehringer, David; Rolink, Antonius G; Finke, Daniela

2016-03-15

Flt3 ligand (Flt3L) promotes survival of lymphoid progenitors in the bone marrow and differentiation of dendritic cells (DCs), but its role in regulating innate lymphoid cells (ILCs) during fetal and adult life is not understood. By using Flt3L knockout and transgenic mice, we demonstrate that Flt3L controls ILC numbers by regulating the pool of α4β7(-) and α4β7(+) lymphoid tissue inducer cell progenitors in the fetal liver and common lymphoid progenitors in the bone marrow. Deletion of flt3l severely reduced the number of fetal liver progenitors and lymphoid tissue inducer cells in the neonatal intestine, resulting in impaired development of Peyer's patches. In the adult intestine, NK cells and group 2 and 3 ILCs were severely reduced. This effect occurred independently of DCs as ILC numbers were normal in mice in which DCs were constitutively deleted. Finally, we could show that administration of Flt3L increased the number of NKp46(-) group 3 ILCs in wild-type and even in Il7(-/-) mice, which generally have reduced numbers of ILCs. Taken together, Flt3L significantly contributes to ILC and Peyer's patches development by targeting lymphoid progenitor cells during fetal and adult life. Copyright © 2016 by The American Association of Immunologists, Inc.

Characterizing Higgs portal dark matter models at the ILC

NASA Astrophysics Data System (ADS)

Kamon, Teruki; Ko, P.; Li, Jinmian

2017-09-01

We study the dark matter (DM) discovery prospect and its spin discrimination in the theoretical framework of gauge invariant and renormalizable Higgs portal DM models at the ILC with √{s} = 500 GeV. In such models, the DM pair is produced in association with a Z boson. In the case of the singlet scalar DM, the mediator is just the SM Higgs boson, whereas for the fermion or vector DM there is an additional singlet scalar mediator that mixes with the SM Higgs boson, which produces significant observable differences. After careful investigation of the signal and backgrounds both at parton level and at detector level, we find the signal with hadronically decaying Z boson provides a better search sensitivity than the signal with leptonically decaying Z boson. Taking the fermion DM model as a benchmark scenario, when the DM-mediator coupling g_χ is relatively small, the DM signals are discoverable only for benchmark points with relatively light scalar mediator H_2. The spin discriminating from scalar DM is always promising, while it is difficult to discriminate from vector DM. As for g_χ approaching the perturbative limit, benchmark points with the mediator H_2 in the full mass region of interest are discoverable. The spin discriminating aspects from both the scalar and the fermion DM are quite promising.

Type 3 innate lymphoid cell depletion is mediated by TLRs in lymphoid tissues of simian immunodeficiency virus–infected macaques

PubMed Central

Xu, Huanbin; Wang, Xiaolei; Lackner, Andrew A.; Veazey, Ronald S.

2015-01-01

Innate lymphoid cells (ILCs) type 3, also known as lymphoid tissue inducer cells, plays a major role in both the development and remodeling of organized lymphoid tissues and the maintenance of adaptive immune responses. HIV/simian immunodeficiency virus (SIV) infection causes breakdown of intestinal barriers resulting in microbial translocation, leading to systemic immune activation and disease progression. However, the effects of HIV/SIV infection on ILC3 are unknown. Here, we analyzed ILC3 from mucosal and systemic lymphoid tissues in chronically SIV-infected macaques and uninfected controls. ILC3 cells were defined and identified in macaque lymphoid tissues as non-T, non-B (lineage-negative), c-Kit+IL-7Rα+ (CD117+CD127+) cells. These ILC3 cells highly expressed CD90 (∼63%) and aryl hydrocarbon receptor and produced IL-17 (∼63%), IL-22 (∼36%), and TNF-α (∼72%) but did not coexpress CD4 or NK cell markers. The intestinal ILC3 cell loss correlated with the reduction of total CD4+ T cells and T helper (Th)17 and Th22 cells in the gut during SIV infection (P < 0.001). Notably, ILC3 could be induced to undergo apoptosis by microbial products through the TLR2 (lipoteichoic acid) and/or TLR4 (LPS) pathway. These findings indicated that persistent microbial translocation may result in loss of ILC3 in lymphoid tissues in SIV-infected macaques, further contributing to the HIV-induced impairment of gut-associated lymphoid tissue structure and function, especially in mucosal tissues.—Xu, H., Wang, X., Lackner, A. A., Veazey, R. S. Type 3 innate lymphoid cell depletion is mediated by TLRs in lymphoid tissues of simian immunodeficiency virus–infected macaques. PMID:26283536

Is There a Role for Oncotype Dx Testing in Invasive Lobular Carcinoma?

PubMed

Conlon, Niamh; Ross, Dara S; Howard, Jane; Catalano, Jeffrey P; Dickler, Maura N; Tan, Lee K

2015-01-01

Oncotype Dx Breast Cancer Assay is a 21-gene assay used in estrogen receptor (ER)-positive breast cancer to predict benefit from chemotherapy (CT). Tumors are placed into one of three risk categories based on their recurrence score (RS). This paper explores the impact of tumor histopathologic features and Oncotype Dx RS on the treatment plan for invasive lobular carcinoma (ILC). Invasive lobular carcinoma cases submitted for Oncotype Dx testing were identified from a clinical data base. The histopathologic and immunohistochemical features and RS subcategory of each tumor, and treatment regimen and medical oncologic assessments of each patient were reviewed. A total of 135 cases of ILC had RS testing, which represented 15% of all ILC diagnosed at the institution over the time period. 80% of ILC was of the classical subtype and all tumors were ER positive and human epidermal growth factor receptor 2 (HER-2) negative by immunohistochemistry. Sixty three percent of cases were low risk (LR), 35.5% were intermediate risk (IR) and 1.5% were high risk (HR). Both HR cases were pleomorphic ILC. Sixty eight percent of classical ILC had a LR score, while 70% of pleomorphic ILC had an IR score. Patients in the IR category were significantly more likely to undergo CT than patients in the LR category (54% versus 18%; p < 0.0001). In the LR category, those undergoing CT were significantly younger and more likely to have positive lymph nodes (p < 0.05). Qualitative analysis of medical oncologic assessments showed that RS played a role in decision-making on CT in 74% of cases overall. At our institution, Oncotype Dx RS currently plays a role in the management of a proportion of ILC and impacts on treatment decisions. © 2015 Wiley Periodicals, Inc.

Type 2 Innate Lymphoid Cells: Friends or Foes—Role in Airway Allergic Inflammation and Asthma

PubMed Central

Pishdadian, Abbas; Varasteh, Abdol-Reza; Sankian, Mojtaba

2012-01-01

Innate-like lymphocytes (ILLs) and innate lymphoid cells (ILCs) are two newly characterized families of lymphocytes with limited and no rearranged antigen receptors, respectively. These soldiers provide a first line of defense against foreign insults by triggering a prompt innate immune response and bridging the gap of innate and adaptive immunity. Type 2 innate lymphoid cells (ILCs2) are newly identified members of the ILC family that play a key role in type 2 immune responses by prompt production of type 2 cytokines (especially IL-5 and IL-13) in response to antigen-induced IL-25/33 and by recruiting type 2 “immune franchise.” Regarding the two different roles of type 2 cytokines, helminth expulsion and type 2-related diseases, here we review the latest advances in ILC2 biology and examine the pivotal role of resident ILCs2 in allergen-specific airway inflammation and asthma. PMID:23209480

Type 2 innate lymphoid cells: friends or foes-role in airway allergic inflammation and asthma.

PubMed

Pishdadian, Abbas; Varasteh, Abdol-Reza; Sankian, Mojtaba

2012-01-01

Innate-like lymphocytes (ILLs) and innate lymphoid cells (ILCs) are two newly characterized families of lymphocytes with limited and no rearranged antigen receptors, respectively. These soldiers provide a first line of defense against foreign insults by triggering a prompt innate immune response and bridging the gap of innate and adaptive immunity. Type 2 innate lymphoid cells (ILCs2) are newly identified members of the ILC family that play a key role in type 2 immune responses by prompt production of type 2 cytokines (especially IL-5 and IL-13) in response to antigen-induced IL-25/33 and by recruiting type 2 "immune franchise." Regarding the two different roles of type 2 cytokines, helminth expulsion and type 2-related diseases, here we review the latest advances in ILC2 biology and examine the pivotal role of resident ILCs2 in allergen-specific airway inflammation and asthma.

Role of Type 2 Innate Lymphoid Cells in Allergic Diseases.

PubMed

Cosmi, Lorenzo; Liotta, Francesco; Maggi, Laura; Annunziato, Francesco

2017-09-11

The adaptive immune response orchestrated by type 2 T helper (Th2) lymphocytes, strictly cooperates with the innate response of group 2 innate lymphoid cells (ILC2), in the protection from helminths infection, as well as in the pathogenesis of allergic disease. The aim of this review is to explore the pathogenic role of ILC2 in different type 2-mediated disorders. Recent studies have shown that epithelial cell-derived cytokines and their responding cells, ILC2, play a pathogenic role in bronchial asthma, chronic rhinosinusitis, and atopic dermatitis. The growing evidences of the contribution of ILC2 in the induction and maintenance of allergic inflammation in such disease suggest the possibility to target them in therapy. Biological therapies blocking ILC2 activation or neutralizing their effector cytokines are currently under evaluation to be used in patients with type 2-dominated diseases.

Beyond NK cells: the expanding universe of innate lymphoid cells.

PubMed

Cella, Marina; Miller, Hannah; Song, Christina

2014-01-01

For a long time, natural killer (NK) cells were thought to be the only innate immune lymphoid population capable of responding to invading pathogens under the influence of changing environmental cues. In the last few years, an increasing amount of evidence has shown that a number of different innate lymphoid cell (ILC) populations found at mucosal sites rapidly respond to locally produced cytokines in order to establish or maintain homeostasis. These ILC populations closely mirror the phenotype of adaptive T helper subsets in their repertoire of secreted soluble factors. Early in the immune response, ILCs are responsible for setting the stage to mount an adaptive T cell response that is appropriate for the incoming insult. Here, we review the diversity of ILC subsets and discuss similarities and differences between ILCs and NK cells in function and key transcriptional factors required for their development.

The chemokine receptor CXCR6 controls the functional topography of interleukin-22 producing intestinal innate lymphoid cells.

PubMed

Satoh-Takayama, Naoko; Serafini, Nicolas; Verrier, Thomas; Rekiki, Abdessalem; Renauld, Jean-Christophe; Frankel, Gad; Di Santo, James P

2014-11-20

Interleukin-22 (IL-22) plays a critical role in mucosal defense, although the molecular mechanisms that ensure IL-22 tissue distribution remain poorly understood. We show that the CXCL16-CXCR6 chemokine-chemokine receptor axis regulated group 3 innate lymphoid cell (ILC3) diversity and function. CXCL16 was constitutively expressed by CX3CR1(+) intestinal dendritic cells (DCs) and coexpressed with IL-23 after Citrobacter rodentium infection. Intestinal ILC3s expressed CXCR6 and its ablation generated a selective loss of the NKp46(+) ILC3 subset, a depletion of intestinal IL-22, and the inability to control C. rodentium infection. CD4(+) ILC3s were unaffected by CXCR6 deficiency and remained clustered within lymphoid follicles. In contrast, the lamina propria of Cxcr6(-/-) mice was devoid of ILC3s. The loss of ILC3-dependent IL-22 epithelial stimulation reduced antimicrobial peptide expression that explained the sensitivity of Cxcr6(-/-) mice to C. rodentium. Our results delineate a critical CXCL16-CXCR6 crosstalk that coordinates the intestinal topography of IL-22 secretion required for mucosal defense. Copyright © 2014 Elsevier Inc. All rights reserved.

Group 3 innate lymphoid cells accumulate and exhibit disease-induced activation in the meninges in EAE.

PubMed

Hatfield, Julianne K; Brown, Melissa A

2015-10-01

Innate lymphoid cells are immune cells that reside in tissues that interface with the external environment and contribute to the first line defense against pathogens. However, they also have roles in promoting chronic inflammation. Here we demonstrate that group 3 ILCs, (ILC3s - CD45+Lin-IL-7Rα+RORγt+), are normal residents of the meninges and exhibit disease-induced accumulation and activation in EAE. In addition to production of the pro-inflammatory cytokines IL-17 and GM-CSF, ILC3s constitutively express CD30L and OX40L, molecules required for memory T cell survival. We show that disease-induced trafficking of transferred wild type T cells to the meninges is impaired in ILC3-deficient Rorc-/- mice. Furthermore, lymphoid tissue inducer cells, a c-kit+ ILC3 subset that promotes ectopic lymphoid follicle development, a hallmark of many autoimmune diseases, are reduced in the meninges of EAE-resistant c-kit mutant Kit(W/Wv) mice. We propose that ILC3s sustain neuroinflammation by supporting T cell survival and reactivation in the meninges. Copyright © 2015 Elsevier Inc. All rights reserved.

Innate lymphoid cells: the role in respiratory infections and lung tissue damage.

PubMed

Głobińska, Anna; Kowalski, Marek L

2017-10-01

Innate lymphoid cells (ILCs) represent a diverse family of cells of the innate immune system, which play an important role in regulation of tissue homeostasis, immunity and inflammation. Emerging evidence has highlighted the importance of ILCs in both protective immunity to respiratory infections and their pathological roles in the lungs. Therefore, the aim of this review is to summarize the current knowledge, interpret and integrate it into broader perspective, enabling greater insight into the role of ILCs in respiratory diseases. Areas covered: In this review we highlighted the role of ILCs in the lungs, citing the most recent studies in this area. PubMed searches (2004- July 2017) were conducted using the term 'innate lymphoid cells respiratory viral infections' in combination with other relevant terms including various respiratory viruses. Expert commentary: Since studies of ILCs have opened new areas of investigation, understanding the role of ILCs in respiratory infections may help to clarify the mechanisms underlying viral-induced exacerbations of lung diseases, providing the basis for novel therapeutic strategies. Potential therapeutic targets have already been identified. So far, the most promising strategy is cytokine-targeting, although further clinical trials are needed to verify its effectiveness.

Oxysterol Sensing through the Receptor GPR183 Promotes the Lymphoid-Tissue-Inducing Function of Innate Lymphoid Cells and Colonic Inflammation.

PubMed

Emgård, Johanna; Kammoun, Hana; García-Cassani, Bethania; Chesné, Julie; Parigi, Sara M; Jacob, Jean-Marie; Cheng, Hung-Wei; Evren, Elza; Das, Srustidhar; Czarnewski, Paulo; Sleiers, Natalie; Melo-Gonzalez, Felipe; Kvedaraite, Egle; Svensson, Mattias; Scandella, Elke; Hepworth, Matthew R; Huber, Samuel; Ludewig, Burkhard; Peduto, Lucie; Villablanca, Eduardo J; Veiga-Fernandes, Henrique; Pereira, João P; Flavell, Richard A; Willinger, Tim

2018-01-16

Group 3 innate lymphoid cells (ILC3s) sense environmental signals and are critical for tissue integrity in the intestine. Yet, which signals are sensed and what receptors control ILC3 function remain poorly understood. Here, we show that ILC3s with a lymphoid-tissue-inducer (LTi) phenotype expressed G-protein-coupled receptor 183 (GPR183) and migrated to its oxysterol ligand 7α,25-hydroxycholesterol (7α,25-OHC). In mice lacking Gpr183 or 7α,25-OHC, ILC3s failed to localize to cryptopatches (CPs) and isolated lymphoid follicles (ILFs). Gpr183 deficiency in ILC3s caused a defect in CP and ILF formation in the colon, but not in the small intestine. Localized oxysterol production by fibroblastic stromal cells provided an essential signal for colonic lymphoid tissue development, and inflammation-induced increased oxysterol production caused colitis through GPR183-mediated cell recruitment. Our findings show that GPR183 promotes lymphoid organ development and indicate that oxysterol-GPR183-dependent positioning within tissues controls ILC3 activity and intestinal homeostasis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Analysis of actual healthcare costs of early versus interval cholecystectomy in acute cholecystitis.

PubMed

Tan, Cheryl H M; Pang, Tony C Y; Woon, Winston W L; Low, Jee Keem; Junnarkar, Sameer P

2015-03-01

Healthcare cost modeling have favored early (ELC) over interval laparoscopic cholecystectomy (ILC) for acute cholecystitis (AC). However, actual costs of treatment have never been studied. The aim of the present study was to compare actual hospital costs involved in ELC and ILC in patients with AC. Retrospective study of patients who underwent laparoscopic cholecystectomy for AC was conducted. Demographic, clinical, operative data and costs were extracted and analyzed. Between 2011 and 2013, 201 had laparoscopic surgery for AC at Tan Tock Seng Hospital, Singapore. One hundred and thirty-four (67%) patients underwent ELC (≤7 days of presentation, within index admission). Median total length of stay (LOS) was 4.6 and 6.8 days for ELC and ILC groups, respectively (P = 0.006). Patients who had ELC also had significantly lesser total number of admissions (P < 0.001). The median (IQR) total inpatient costs were €4.4 × 10(3) (3.6-5.6) and €5.5 × 10(3) (4.0-7.5) for ELC and ILC patients, respectively (P < 0.007). Costs associated with investigations were significantly higher in the ILC group (P = 0.039), of which serological costs made most difference (P < 0.005). The ward costs were also significantly higher in the ILC group. The cost differences reflect the significantly increased total LOS, and repeat presentations associated with ILC. Therefore, ELC should be the preferred management strategy for AC. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Prediction of final error level in learning and repetitive control

NASA Astrophysics Data System (ADS)

Levoci, Peter A.

Repetitive control (RC) is a field that creates controllers to eliminate the effects of periodic disturbances on a feedback control system. The methods have applications in spacecraft problems, to isolate fine pointing equipment from periodic vibration disturbances such as slight imbalances in momentum wheels or cryogenic pumps. A closely related field of control design is iterative learning control (ILC) which aims to eliminate tracking error in a task that repeats, each time starting from the same initial condition. Experiments done on a robot at NASA Langley Research Center showed that the final error levels produced by different candidate repetitive and learning controllers can be very different, even when each controller is analytically proven to converge to zero error in the deterministic case. Real world plant and measurement noise and quantization noise (from analog to digital and digital to analog converters) in these control methods are acted on as if they were error sources that will repeat and should be cancelled, which implies that the algorithms amplify such errors. Methods are developed that predict the final error levels of general first order ILC, of higher order ILC including current cycle learning, and of general RC, in the presence of noise, using frequency response methods. The method involves much less computation than the corresponding time domain approach that involves large matrices. The time domain approach was previously developed for ILC and handles a certain class of ILC methods. Here methods are created to include zero-phase filtering that is very important in creating practical designs. Also, time domain methods are developed for higher order ILC and for repetitive control. Since RC and ILC must be implemented digitally, all of these methods predict final error levels at the sample times. It is shown here that RC can easily converge to small error levels between sample times, but that ILC in most applications will have large and diverging intersample error if in fact zero error is reached at the sample times. This is independent of the ILC law used, and is purely a property of the physical system. Methods are developed to address this issue.

Circulating innate lymphoid cells are unchanged in response to DAC HYP therapy.

PubMed

Gillard, Geoffrey O; Saenz, Steven A; Huss, David J; Fontenot, Jason D

2016-05-15

Innate lymphoid cells (ILCs) play an important role in immunity, inflammation, and tissue remodeling and their dysregulation is implicated in autoimmune and inflammatory disorders. We analyzed the impact of daclizumab, a humanized monoclonal anti-CD25 antibody, on circulating natural killer (NK) cells and ILCs in a cohort of multiple sclerosis patients. An increase in CD56(bright) NK cells and CD56(hi)CD16(intermediate) transitional NK cells was observed. No significant change in total ILCs or major ILC subpopulations was observed. These results refine our understanding of the impact of daclizumab on innate lymphoid cell populations. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Radiation Requirements and Testing of Cryogenic Thermometers for the Ilc

NASA Astrophysics Data System (ADS)

Barnett, T.; Filippov, Yu. P.; Filippova, E. Yu.; Mokhov, N. V.; Nakao, N.; Klebaner, A. L.; Korenev, S. A.; Theilacker, J. C.; Trenikhina, J.; Vaziri, K.

2008-03-01

Large quantity of cryogenic temperature sensors will be used for operation of the International Linear Collider (ILC). Most of them will be subject to high radiation doses during the accelerator lifetime. Understanding of particle energy spectra, accumulated radiation dose in thermometers and its impact on performance are vital in establishing technical specification of cryogenic thermometry for the ILC. Realistic MARS15 computer simulations were performed to understand the ILC radiation environment. Simulation results were used to establish radiation dose requirements for commercially available cryogenic thermometers. Two types of thermometers, Cernox® and TVO, were calibrated prior to irradiation using different technique. The sensors were subjected then to up to 200 kGy electron beam irradiation with kinetic energy of 5 MeV, a representative of the situation at the ILC operation. A post-irradiation behavior of the sensors was studied. The paper describes the MARS15 model, simulation results, cryogenic test set-up, irradiation tests, and cryogenic test results.

Effects of iterative learning based signal control strategies on macroscopic fundamental diagrams of urban road networks

NASA Astrophysics Data System (ADS)

Yan, Fei; Tian, Fuli; Shi, Zhongke

2016-10-01

Urban traffic flows are inherently repeated on a daily or weekly basis. This repeatability can help improve the traffic conditions if it is used properly by the control system. In this paper, we propose a novel iterative learning control (ILC) strategy for traffic signals of urban road networks using the repeatability feature of traffic flow. To improve the control robustness, the ILC strategy is further integrated with an error feedback control law in a complementary manner. Theoretical analysis indicates that the ILC-based traffic signal control methods can guarantee the asymptotic learning convergence, despite the presence of modeling uncertainties and exogenous disturbances. Finally, the impacts of the ILC-based signal control strategies on the network macroscopic fundamental diagram (MFD) are examined. The results show that the proposed ILC-based control strategies can homogenously distribute the network accumulation by controlling the vehicle numbers in each link to the desired levels under different traffic demands, which can result in the network with high capacity and mobility.

Type two innate lymphoid cells; the Janus cells in health and disease

PubMed Central

Maazi, Hadi; Akbari, Omid

2017-01-01

Summary Innate lymphoid cells are functionally diverse subsets of immune cells including the conventional natural killer cells, lymphoid tissue inducers, type 1, 2 and 3 with significant roles in immunity and pathogenesis of inflammatory diseases. Type 2 innate lymphoid cells (ILC2s) resemble type 2 helper (Th2) cells in cytokine production and contribute to anti-helminth immunity, maintaining mucosal tissue integrity and adipose tissue browning. ILC2s play important roles in the pathogenesis of allergic diseases and asthma. Studying the pathways of activation and regulation of ILC2s are currently a priority for giving a better understanding of pathogenesis of diseases with immunological roots. Recently, our laboratory and others have shown several pathways of regulation of ILC2s by costimulatory molecules such as ICOS, regulatory T cells and by compounds such as nicotine. In this review, we summarize the current understanding of the mechanisms of activation and regulation of ILC2s and the role of these cells in health and disease. PMID:28658553

Epidermal Notch1 recruits RORγ(+) group 3 innate lymphoid cells to orchestrate normal skin repair.

PubMed

Li, Zhi; Hodgkinson, Tom; Gothard, Elizabeth J; Boroumand, Soulmaz; Lamb, Rebecca; Cummins, Ian; Narang, Priyanka; Sawtell, Amy; Coles, Jenny; Leonov, German; Reboldi, Andrea; Buckley, Christopher D; Cupedo, Tom; Siebel, Christian; Bayat, Ardeshir; Coles, Mark C; Ambler, Carrie A

2016-04-21

Notch has a well-defined role in controlling cell fate decisions in the embryo and the adult epidermis and immune systems, yet emerging evidence suggests Notch also directs non-cell-autonomous signalling in adult tissues. Here, we show that Notch1 works as a damage response signal. Epidermal Notch induces recruitment of immune cell subsets including RORγ(+) ILC3s into wounded dermis; RORγ(+) ILC3s are potent sources of IL17F in wounds and control immunological and epidermal cell responses. Mice deficient for RORγ(+) ILC3s heal wounds poorly resulting from delayed epidermal proliferation and macrophage recruitment in a CCL3-dependent process. Notch1 upregulates TNFα and the ILC3 recruitment chemokines CCL20 and CXCL13. TNFα, as a Notch1 effector, directs ILC3 localization and rates of wound healing. Altogether these findings suggest that Notch is a key stress/injury signal in skin epithelium driving innate immune cell recruitment and normal skin tissue repair.

SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling.

PubMed

Cortez, Victor S; Ulland, Tyler K; Cervantes-Barragan, Luisa; Bando, Jennifer K; Robinette, Michelle L; Wang, Qianli; White, Andrew J; Gilfillan, Susan; Cella, Marina; Colonna, Marco

2017-09-01

Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from natural killer (NK) cells is a gene signature indicative of 'imprinting' by cytokines of the TGF-β family. We studied mice in which ILC1s and NK cells lacked SMAD4, a signal transducer that facilitates the canonical signaling pathway common to all cytokines of the TGF-β family. While SMAD4 deficiency did not affect ILC1 differentiation, NK cells unexpectedly acquired an ILC1-like gene signature and were unable to control tumor metastasis or viral infection. Mechanistically, SMAD4 restrained non-canonical TGF-β signaling mediated by the cytokine receptor TGFβR1 in NK cells. NK cells from a SMAD4-deficient person affected by polyposis were also hyper-responsive to TGF-β. These results identify SMAD4 as a previously unknown regulator that restricts non-canonical TGF-β signaling in NK cells.

SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling

PubMed Central

Cortez, Victor S; Ulland, Tyler K; Cervantes-Barragan, Luisa; Bando, Jennifer K; Robinette, Michelle L; Wang, Qianli; White, Andrew J; Gilfillan, Susan; Cella, Marina; Colonna, Marco

2017-01-01

Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from natural killer (NK) cells is a gene signature indicative of ‘imprinting’ by cytokines of the TGF-β family. We examined mice in which ILC1s and NK cells lacked SMAD4, a signal transducer that facilitates the canonical signaling pathway common to all cytokines of the TGF-β family. While SMAD4 deficiency did not affect ILC1 differentiation, NK cells unexpectedly acquired an ILC1-like gene signature and were unable to control tumor metastasis or viral infection. Mechanistically, SMAD4 restrained non-canonical TGF-β signaling mediated by the cytokine receptor TGF-βR1 in NK cells. NK cells from a SMAD4-deficient person affected by polyposis were also hyper-responsive to TGF-β. These results identify SMAD4 as a previously unknown regulator that restricts non-canonical TGF-β signaling in NK cells. PMID:28759002

Evaluation of Calibration Laboratories Performance

NASA Astrophysics Data System (ADS)

Filipe, Eduarda

2011-12-01

One of the main goals of interlaboratory comparisons (ILCs) is the evaluation of the laboratories performance for the routine calibrations they perform for the clients. In the frame of Accreditation of Laboratories, the national accreditation boards (NABs) in collaboration with the national metrology institutes (NMIs) organize the ILCs needed to comply with the requirements of the international accreditation organizations. In order that an ILC is a reliable tool for a laboratory to validate its best measurement capability (BMC), it is needed that the NMI (reference laboratory) provides a better traveling standard—in terms of accuracy class or uncertainty—than the laboratories BMCs. Although this is the general situation, there are cases where the NABs ask the NMIs to evaluate the performance of the accredited laboratories when calibrating industrial measuring instruments. The aim of this article is to discuss the existing approaches for the evaluation of ILCs and propose a basis for the validation of the laboratories measurement capabilities. An example is drafted with the evaluation of the results of mercury-in-glass thermometers ILC with 12 participant laboratories.

Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells

PubMed Central

Rauber, Simon; Luber, Markus; Weber, Stefanie; Maul, Lisa; Soare, Alina; Wohlfahrt, Thomas; Lin, Neng-Yu; Dietel, Katharina; Bozec, Aline; Herrmann, Martin; Kaplan, Mark H.; Weigmann, Benno; Zaiss, Mario M.; Fearon, Ursula; Veale, Douglas J.; Canete, Juan D.; Distler, Oliver; Rivellese, Felice; Pitzalis, Costantino; Neurath, Markus F.; McKenzie, Andrew N.J.; Wirtz, Stefan; Schett, Georg; Distler, Jörg H.W.; Ramming, Andreas

2017-01-01

Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified IL-9-producing type 2 innate lymphoid cells (ILC2s) as a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation, activation of regulatory T cells (Treg) and resulted in chronic arthritis with excessive cartilage destruction and bone loss. In contrast, treatment with IL-9 promoted ILC2-dependent Treg activation and effectively induced resolution of inflammation and protection of bone. Rheumatoid arthritis patients in remission demonstrated high numbers of IL-9+ ILC2s in the joints and in the circulation. Hence, fostering IL-9-mediated ILC2 activation may offer a novel therapeutic approach inducing resolution of inflammation rather than suppression of inflammatory responses. PMID:28714991

Neuropilin-1 Is Expressed on Lymphoid Tissue Residing LTi-like Group 3 Innate Lymphoid Cells and Associated with Ectopic Lymphoid Aggregates.

PubMed

Shikhagaie, Medya Mara; Björklund, Åsa K; Mjösberg, Jenny; Erjefält, Jonas S; Cornelissen, Anne S; Ros, Xavier Romero; Bal, Suzanne M; Koning, Jasper J; Mebius, Reina E; Mori, Michiko; Bruchard, Melanie; Blom, Bianca; Spits, Hergen

2017-02-14

Here, we characterize a subset of ILC3s that express Neuropilin1 (NRP1) and are present in lymphoid tissues, but not in the peripheral blood or skin. NRP1 + group 3 innate lymphoid cells (ILC3s) display in vitro lymphoid tissue inducer (LTi) activity. In agreement with this, NRP1 + ILC3s are mainly located in proximity to high endothelial venules (HEVs) and express cell surface molecules involved in lymphocyte migration in secondary lymphoid tissues via HEVs. NRP1 was also expressed on mouse fetal LTi cells, indicating that NRP1 is a conserved marker for LTi cells. Human NRP1 + ILC3s are primed cells because they express CD45RO and produce higher amounts of cytokines than NRP1 - cells, which express CD45RA. The NRP1 ligand vascular endothelial growth factor A (VEGF-A) served as a chemotactic factor for NRP1 + ILC3s. NRP1 + ILC3s are present in lung tissues from smokers and patients with chronic obstructive pulmonary disease, suggesting a role in angiogenesis and/or the initiation of ectopic pulmonary lymphoid aggregates. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Cytotoxic Effects of PEGylated Anti-EGFR Immunoliposomes Combined with Doxorubicin and Rhenium-188 Against Cancer Cells.

PubMed

Hsu, Wei-Chuan; Cheng, Chu-Nian; Lee, Te-Wei; Hwang, Jeng-Jong

2015-09-01

We aimed to construct epidermal growth factor receptor (EGFR)-targeting cetuximab-immunoliposomes (IL-C225) for targeted delivery of doxorubicin and rhenium-188 (Re-188) to EGFR(+) cancer cells. Synthesized IL-C225 was analyzed by dynamic light scattering, transmission electron microscopy, and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy. Cell binding and internalization were examined using doxorubicin-loaded IL-C225 (DXR-IL-C225) with confocal microscopy. IL-C225 combined with doxorubicin and Re-188 ((188)Re-DXR-IL-C225) was synthesized, and the cytotoxic effects of (188)Re-DXR-IL-C225 were analyzed in EGFR(+) cancer cells using cell viability assays. IL-C225 bound to EGFR on A431 cancer cells and was rapidly internalized. Furthermore, IL-C225 localized within the tumor cells efficiently. (188)Re-DXR-IL-C225 exhibited outstanding cytotoxic effects against EGFR(+) cancer cells in vitro and showed superior cytotoxic effects compared to DXR-IL-C225 or (188)Re-IL-C225 alone. The new formulation of (188)Re-DXR-IL-C225 may be a potential theranostic vehicle for delivery of drugs in the treatment of EGFR-overexpressing human cancer. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

NKp46+ Innate Lymphoid Cells Dampen Vaginal CD8 T Cell Responses following Local Immunization with a Cholera Toxin-Based Vaccine

PubMed Central

Luci, Carmelo; Bekri, Selma; Bihl, Franck; Pini, Jonathan; Bourdely, Pierre; Nouhen, Kelly; Malgogne, Angélique; Walzer, Thierry; Braud, Véronique M.; Anjuère, Fabienne

2015-01-01

Innate and adaptive immune cells work in concert to generate efficient protection at mucosal surface. Vaginal mucosa is an epithelial tissue that contains innate and adaptive immune effector cells. Our previous studies demonstrated that vaginal administration of Cholera toxin -based vaccines generate antigen-specific CD8 T cells through the stimulation of local dendritic cells (DC). Innate lymphoid cells (ILC) are a group of lymphocytes localized in epithelial tissues that have important immune functions against pathogens and in tissue homeostasis. Their contribution to vaccine-induced mucosal T cell responses is an important issue for the design of protective vaccines. We report here that the vaginal mucosa contains a heterogeneous population of NKp46+ ILC that includes conventional NK cells and ILC1-like cells. We show that vaginal NKp46+ ILC dampen vaccine-induced CD8 T cell responses generated after local immunization. Indeed, in vivo depletion of NKp46+ ILC with anti-NK1.1 antibody or NKG2D blockade increases the magnitude of vaginal OVA-specific CD8 T cells. Furthermore, such treatments also increase the number of DC in the vagina. NKG2D ligands being expressed by vaginal DC but not by CD8 T cells, these results support that NKp46+ ILC limit mucosal CD8 T cell responses indirectly through the NKG2D-dependent elimination of vaginal DC. Our data reveal an unappreciated role of NKp46+ ILC in the regulation of mucosal CD8 T cell responses. PMID:26630176

Synergistically increased ILC2 and Th9 cells in lung tissue jointly promote the pathological process of asthma in mice.

PubMed

Ying, Xinyu; Su, Zhaoliang; Bie, Qingli; Zhang, Pan; Yang, Huijian; Wu, Yumin; Xu, Yunyun; Wu, Jing; Zhang, Mengying; Wang, Shengjun; Xu, Huaxi

2016-06-01

In recent years, T helper (Th) 9 cells have been demonstrated to be key mediators in immune responses in asthmatic lungs, and innate lymphoid cells 2 (ILC2s) have been described as a novel type of innate immunocyte with the ability to enhance immunoglobulin E (IgE) production. However, the interaction between ILC2s and Th9 cells in the pulmonary system of a mouse model of asthma remains to be elucidated. In the present study, the response state of lung tissue with regards to Th9 and ILC2s in a mouse model of asthma was investigated by detecting Th9‑ and ILC2‑associated cytokine receptors. The present study also investigated the association between the expression levels of the cytokine receptors in lung tissue samples and the IgE levels in sera samples from mouse models of asthma. Results from the present study demonstrated that the frequency of ILC2s and Th9 cells was significantly increased in the lung tissue samples, indicating that a Th2-type immune response had occurred. In addition, high mRNA expression levels of RAR‑related orphan receptor α, interleukin 1 receptor‑like 1, transcription factor PU.1 and interleukin (IL)‑9 were observed. Furthermore, IL‑5Rα, IL‑13Rα2 and high‑affinity IgE receptor were increased in mouse models of asthma, and a positive association was observed between the expression levels of ILC2‑ or Th9‑associated receptors in tissue samples and IgE levels in the sera. This indicated that ILC2s and Th9 were in a state of polarization and may promote each other in the lung tissue of mouse models of asthma, and that the lung tissue was responding to the two types of cells via increased expression of receptors.

Allergen-induced Increases in Sputum Levels of Group 2 Innate Lymphoid Cells in Subjects with Asthma.

PubMed

Chen, Ruchong; Smith, Steven G; Salter, Brittany; El-Gammal, Amani; Oliveria, John Paul; Obminski, Caitlin; Watson, Rick; O'Byrne, Paul M; Gauvreau, Gail M; Sehmi, Roma

2017-09-15

Group 2 innate lymphoid cells (ILC2), a major source of type 2 cytokines, initiate eosinophilic inflammatory responses in murine models of asthma. To investigate the role of ILC2 in allergen-induced airway eosinophilic responses in subjects with atopy and asthma. Using a diluent-controlled allergen challenge crossover study, where all subjects (n = 10) developed allergen-induced early and late responses, airway eosinophilia, and increased methacholine airway responsiveness, bone marrow, blood, and sputum samples were collected before and after inhalation challenge. ILC2 (lin - FcεRI - CD45 + CD127 + ST2 + ) and CD4 + T lymphocytes were enumerated by flow cytometry, as well as intracellular IL-5 and IL-13 expression. Steroid sensitivity of ILC2 and CD4 + T cells was investigated in vitro. A significant increase in total, IL-5 + , IL-13 + , and CRTH2 + ILC2 was found in sputum, 24 hours after allergen, coincident with a significant decrease in blood ILC2. Total, IL-5 + , and IL-13 + , but not CRTH2 + , CD4 + T cells significantly increased at 24 and 48 hours after allergen in sputum. In blood and bone marrow, only CD4 + cells demonstrated increased activation after allergen. Airway eosinophilia correlated with IL-5 + ILC2 at all time points and allergen-induced changes in IL-5 + CD4 + cells at 48 hours after allergen. Dexamethasone significantly attenuated IL-2- and IL-33-stimulated IL-5 and IL-13 production by both cell types. Innate and adaptive immune cells are increased in the airways associated with allergic asthmatic responses. Total and type 2 cytokine-positive ILC2 are increased only within the airways, whereas CD4 + T lymphocytes demonstrated local and systemic increases. Steroid sensitivity of both cells may explain effectiveness of this therapy in those with mild asthma.

Immune Modules Shared by Innate Lymphoid Cells and T Cells

PubMed Central

Robinette, Michelle L.; Colonna, Marco

2016-01-01

In recent years, innate lymphoid cells (ILCs) have emerged as innate correlates to T cells. The similarities between ILCs and T cells indicate that lymphocytes of fundamentally distinct lineages can share core “immune modules” that encompass transcriptional circuitry and effector functions, while utilizing non-redundant, complementary mechanisms of pattern recognition to enact these functions. We review modules currently recognized to be shared between ILCs and T cells. PMID:27817796

Higgs boson production in the littlest Higgs model with T-parity at the ILC

NASA Astrophysics Data System (ADS)

Han, Jinzhong; Yang, Guang; Meng, Ming; Wang, Weijian; Li, Jingyun

2018-04-01

We investigate the Higgs boson production processes e+e‑→ ZH, e+e‑→ νν¯H, e+e‑→ tt¯H, e+e‑→ ZHH and e+e‑→ νν¯HH in the littlest Higgs model with T-parity (LHT) at the International Linear Collider (ILC). We calculate the LHT model predictions on the production rate of these processes at the ILC in the case of (un)polarized beams and the signal strengths of the production processes ZH and νν¯H with Higgs decaying to bb¯(gg,γγ). In the allowed parameter space, we find that the signal strengths μgg is most likely approach to the expected precision of the ILC.

The pattern of invasive lobular carcinoma in the patients diagnosed with breast cancer from Balochistan.

PubMed

Baloch, A H; Khosa, A N; Bangulzai, N; Sadia, H; Ahmed, M; Khan, F; Jan, M; Tareen, M; Kakar, M H; Shuja, J; Naseeb, H K; Ahmad, J

2016-01-01

Invasive lobular carcinoma (ILC) is the second most common type of breast cancer accounting for 5%-15% of all the breast cancer cases. The present study was performed on 171 breast cancer patients from Balochistan registered in CENAR (Center for Nuclear Medicine and Radiotherapy), Quetta. Written consent was obtained from the patients. The history of the disease was taken from the patients, and the patients' enrollment files were retrieved. Of the 171 patients, 5 (2.96%) were diagnosed with ILC with tumor Grade II, and stage of the cancer reported was Grade III in all the 5 patients affected with ILC. ILC is the second most common type of breast cancer diagnosed with comparatively lower grade but almost reported infiltrating.

Characterizing Higgs portal dark matter models at the ILC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kamon, Teruki; Ko, P.; Li, Jinmian

For this article, we study the dark matter (DM) discovery prospect and its spin discrimination in the theoretical framework of gauge invariant and renormalizable Higgs portal DM models at the ILC withmore » $$\\sqrt{s}$$= 500 GeV. In such models, the DM pair is produced in association with a Z boson. In the case of the singlet scalar DM, the mediator is just the SM Higgs boson, whereas for the fermion or vector DM there is an additional singlet scalar mediator that mixes with the SM Higgs boson, which produces significant observable differences. After careful investigation of the signal and backgrounds both at parton level and at detector level, we find the signal with hadronically decaying Z boson provides a better search sensitivity than the signal with leptonically decaying Z boson. Taking the fermion DM model as a benchmark scenario, when the DM-mediator coupling g χ is relatively small, the DM signals are discoverable only for benchmark points with relatively light scalar mediator H 2. The spin discriminating from scalar DM is always promising, while it is difficult to discriminate from vector DM. As for g χ approaching the perturbative limit, benchmark points with the mediator H 2 in the full mass region of interest are discoverable. The spin discriminating aspects from both the scalar and the fermion DM are quite promising.« less

Characterizing Higgs portal dark matter models at the ILC

DOE PAGES

Kamon, Teruki; Ko, P.; Li, Jinmian

2017-09-27

For this article, we study the dark matter (DM) discovery prospect and its spin discrimination in the theoretical framework of gauge invariant and renormalizable Higgs portal DM models at the ILC withmore » $$\\sqrt{s}$$= 500 GeV. In such models, the DM pair is produced in association with a Z boson. In the case of the singlet scalar DM, the mediator is just the SM Higgs boson, whereas for the fermion or vector DM there is an additional singlet scalar mediator that mixes with the SM Higgs boson, which produces significant observable differences. After careful investigation of the signal and backgrounds both at parton level and at detector level, we find the signal with hadronically decaying Z boson provides a better search sensitivity than the signal with leptonically decaying Z boson. Taking the fermion DM model as a benchmark scenario, when the DM-mediator coupling g χ is relatively small, the DM signals are discoverable only for benchmark points with relatively light scalar mediator H 2. The spin discriminating from scalar DM is always promising, while it is difficult to discriminate from vector DM. As for g χ approaching the perturbative limit, benchmark points with the mediator H 2 in the full mass region of interest are discoverable. The spin discriminating aspects from both the scalar and the fermion DM are quite promising.« less

Intrinsic functional defects of type 2 innate lymphoid cells impair innate allergic inflammation in promyelocytic leukemia zinc finger (PLZF)-deficient mice.

PubMed

Verhoef, Philip A; Constantinides, Michael G; McDonald, Benjamin D; Urban, Joseph F; Sperling, Anne I; Bendelac, Albert

2016-02-01

The transcription factor promyelocytic leukemia zinc finger (PLZF) is transiently expressed during development of type 2 innate lymphoid cells (ILC2s) but is not present at the mature stage. We hypothesized that PLZF-deficient ILC2s have functional defects in the innate allergic response and represent a tool for studying innate immunity in a mouse with a functional adaptive immune response. We determined the consequences of PLZF deficiency on ILC2 function in response to innate and adaptive immune stimuli by using PLZF(-/-) mice and mixed wild-type:PLZF(-/-) bone marrow chimeras. PLZF(-/-) mice, wild-type littermates, or mixed bone marrow chimeras were treated with the protease allergen papain or the cytokines IL-25 and IL-33 or infected with the helminth Nippostrongylus brasiliensis to induce innate type 2 allergic responses. Mice were sensitized with intraperitoneal ovalbumin-alum, followed by intranasal challenge with ovalbumin alone, to induce adaptive TH2 responses. Lungs were analyzed for immune cell subsets, and alveolar lavage fluid was analyzed for ILC2-derived cytokines. In addition, ILC2s were stimulated ex vivo for their capacity to release type 2 cytokines. PLZF-deficient lung ILC2s exhibit a cell-intrinsic defect in the secretion of IL-5 and IL-13 in response to innate stimuli, resulting in defective recruitment of eosinophils and goblet cell hyperplasia. In contrast, the adaptive allergic inflammatory response to ovalbumin and alum was unimpaired. PLZF expression at the innate lymphoid cell precursor stage has a long-range effect on the functional properties of mature ILC2s and highlights the importance of these cells for innate allergic responses in otherwise immunocompetent mice. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. All rights reserved.

The Role of Magnetic Resonance Imaging in the Investigation and Management of Invasive Lobular Carcinoma-A 3-Year Retrospective Study in Two District General Hospitals.

PubMed

Derias, Mina; Subramanian, Ashok; Allan, Simon; Shah, Elizabeth; Teraifi, Hassan El; Howlett, David

2016-07-01

Invasive lobular carcinoma (ILC) accounts for 5-15% of breast cancers. In comparison to other types of breast cancer, ILC is more likely to be associated with multifocal and contralateral breast involvement as well as a tendency to a diffuse infiltrative growth pattern which can represent a diagnostic challenge. The National Institute of Clinical Excellence guidelines in 2009 recommended the use of magnetic resonance imaging (MRI) in the preoperative assessment of ILC. This study aims to assess compliance with the guidelines in two District General Hospitals and the utility of MRI in the investigation of ILC. All cases of ILC between 2011 and 2013 were retrospectively identified from the pathology database and their breast imaging findings, pathology report, and operative intervention were reviewed. A total of 126 patients were identified with ILC, of these 46 had MRI preoperatively (36.5%). MRI upgraded mammography/ultrasound diagnoses in 10 patients (21.7%). MRI showed multicentric unilateral disease in 17 patients (37.0%) occult on ultrasound/mammogram, with these patients undergoing mastectomy and 16/17 (94.1%) confirmed multifocality on pathology. MRI showed a contralateral lesion in 9 patients (19.6%), four (8.7%) of which were malignant and had bilateral surgery, and five (10.9%) were benign on further imaging/biopsy. MRI also downgraded three patients (6.5%) to unifocal disease with reported multifocal appearances on mammography/ultrasound, and these patients underwent breast-conserving surgery. MRI adds significant additional information to mammograms/ultrasound in ILC and should be undertaken in all such cases preoperatively assuming no contraindication. © 2016 Wiley Periodicals, Inc.

IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions.

PubMed

Monticelli, Laurel A; Osborne, Lisa C; Noti, Mario; Tran, Sara V; Zaiss, Dietmar M W; Artis, David

2015-08-25

The barrier surfaces of the skin, lung, and intestine are constantly exposed to environmental stimuli that can result in inflammation and tissue damage. Interleukin (IL)-33-dependent group 2 innate lymphoid cells (ILC2s) are enriched at barrier surfaces and have been implicated in promoting inflammation; however, the mechanisms underlying the tissue-protective roles of IL-33 or ILC2s at surfaces such as the intestine remain poorly defined. Here we demonstrate that, following activation with IL-33, expression of the growth factor amphiregulin (AREG) is a dominant functional signature of gut-associated ILC2s. In the context of a murine model of intestinal damage and inflammation, the frequency and number of AREG-expressing ILC2s increases following intestinal injury and genetic disruption of the endogenous AREG-epidermal growth factor receptor (EGFR) pathway exacerbated disease. Administration of exogenous AREG limited intestinal inflammation and decreased disease severity in both lymphocyte-sufficient and lymphocyte-deficient mice, revealing a previously unrecognized innate immune mechanism of intestinal tissue protection. Furthermore, treatment with IL-33 or transfer of ILC2s ameliorated intestinal disease severity in an AREG-dependent manner. Collectively, these data reveal a critical feedback loop in which cytokine cues from damaged epithelia activate innate immune cells to express growth factors essential for ILC-dependent restoration of epithelial barrier function and maintenance of tissue homeostasis.

Type two innate lymphoid cells: the Janus cells in health and disease.

PubMed

Maazi, Hadi; Akbari, Omid

2017-07-01

Innate lymphoid cells are functionally diverse subsets of immune cells including the conventional natural killer cells, lymphoid tissue inducers, type 1, 2, and 3 with significant roles in immunity and pathogenesis of inflammatory diseases. Type 2 innate lymphoid cells (ILC2s) resemble type 2 helper (Th2) cells in cytokine production and contribute to anti-helminth immunity, maintaining mucosal tissue integrity, and adipose tissue browning. ILC2s play important roles in the pathogenesis of allergic diseases and asthma. Studying the pathways of activation and regulation of ILC2s are currently a priority for giving a better understanding of pathogenesis of diseases with immunological roots. Recently, our laboratory and others have shown several pathways of regulation of ILC2s by co-stimulatory molecules such as ICOS, regulatory T cells and by compounds such as nicotine. In this review, we summarize the current understanding of the mechanisms of activation and regulation of ILC2s and the role of these cells in health and disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Guards at the gate: physiological and pathological roles of tissue-resident innate lymphoid cells in the lung.

PubMed

Cheng, Hang; Jin, Chengyan; Wu, Jing; Zhu, Shan; Liu, Yong-Jun; Chen, Jingtao

2017-12-01

The lung is an important open organ and the primary site of respiration. Many life-threatening diseases develop in the lung, e.g., pneumonia, asthma, chronic obstructive pulmonary diseases (COPDs), pulmonary fibrosis, and lung cancer. In the lung, innate immunity serves as the frontline in both anti-irritant response and anti-tumor defense and is also critical for mucosal homeostasis; thus, it plays an important role in containing these pulmonary diseases. Innate lymphoid cells (ILCs), characterized by their strict tissue residence and distinct function in the mucosa, are attracting increased attention in innate immunity. Upon sensing the danger signals from damaged epithelium, ILCs activate, proliferate, and release numerous cytokines with specific local functions; they also participate in mucosal immune-surveillance, immune-regulation, and homeostasis. However, when their functions become uncontrolled, ILCs can enhance pathological states and induce diseases. In this review, we discuss the physiological and pathological functions of ILC subsets 1 to 3 in the lung, and how the pathogenic environment affects the function and plasticity of ILCs.

Human innate lymphoid cells (ILCs) in filarial infections.

PubMed

Bonne-Année, S; Nutman, T B

2018-02-01

Filarial infections are characteristically chronic and can cause debilitating diseases governed by parasite-induced innate and adaptive immune responses. Filarial parasites traverse or establish niches in the skin (migrating infective larvae), in nonmucosal tissues (adult parasite niche) and in the blood or skin (circulating microfilariae) where they intersect with the host immune response. While several studies have demonstrated that filarial parasites and their antigens can modulate myeloid cells (monocyte, macrophage and dendritic cell subsets), T- and B-lymphocytes and skin resident cell populations, the role of innate lymphoid cells during filarial infections has only recently emerged. Despite the identification and characterization of innate lymphoid cells (ILCs) in murine helminth infections, little is actually known about the role of human ILCs during parasitic infections. The focus of this review will be to highlight the composition of ILCs in the skin, lymphatics and blood; where the host-parasite interaction is well-defined and to examine the role of ILCs during filarial infections. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Innate lymphoid cells and the MHC.

PubMed

Robinette, M L; Colonna, M

2016-01-01

Innate lymphoid cells (ILCs) are a new class of immune cells that include natural killer (NK) cells and appear to be the innate counterparts to CD4(+) helper T cells and CD8(+) cytotoxic T cells based on developmental and functional similarities. Like T cells, both NK cells and other ILCs also show connections to the major histocompatibility complex (MHC). In human and mouse, NK cells recognize and respond to classical and nonclassical MHC I molecules as well as structural homologues, whereas mouse ILCs have recently been shown to express MHC II. We describe the history of MHC I recognition by NK cells and discuss emerging roles for MHC II expression by ILC subsets, making comparisons between both mouse and human when possible. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Immune modules shared by innate lymphoid cells and T cells.

PubMed

Robinette, Michelle L; Colonna, Marco

2016-11-01

In recent years, innate lymphoid cells (ILCs) have emerged as innate correlates to T cells. The similarities between ILCs and T cells indicate that lymphocytes of fundamentally distinct lineages can share core "immune modules" that encompass transcriptional circuitry and effector functions while using nonredundant complementary mechanisms of pattern recognition to enact these functions. We review modules currently recognized to be shared between ILCs and T cells. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

A Descriptive Study of the DoD-Managed Freight Forwarder Concept.

DTIC Science & Technology

1986-09-01

AFLC/PMPO AMSAC-OL/ 7 AFLC ILC/ AWST MTMCEA/ ITEL AFLC ILC/EC MTMC-ITX AFLC ILC/GB USN/OP-632B AF IT! LSM USN/SUP-07C DISAM/DIC USASAC-NCAD (OL/T) SAAC...commercial insurance coverage for the protection of all purchaser-owned FMS materiel while in custody of the freight forwarder. r . Process FMS customer...export for each shipment. r . Provide export boxing and marking if required. s. Carry out freight rate negotiations as required. t. Retrieve freight from

Dysregulation of type 2 innate lymphoid cells and TH2 cells impairs pollutant-induced allergic airway responses.

PubMed

De Grove, Katrien C; Provoost, Sharen; Hendriks, Rudi W; McKenzie, Andrew N J; Seys, Leen J M; Kumar, Smitha; Maes, Tania; Brusselle, Guy G; Joos, Guy F

2017-01-01

Although the prominent role of T H 2 cells in type 2 immune responses is well established, the newly identified type 2 innate lymphoid cells (ILC2s) can also contribute to orchestration of allergic responses. Several experimental and epidemiologic studies have provided evidence that allergen-induced airway responses can be further enhanced on exposure to environmental pollutants, such as diesel exhaust particles (DEPs). However, the components and pathways responsible remain incompletely known. We sought to investigate the relative contribution of ILC2 and adaptive T H 2 cell responses in a murine model of DEP-enhanced allergic airway inflammation. Wild-type, Gata-3 +/nlslacZ (Gata-3-haploinsufficient), RAR-related orphan receptor α (RORα) fl/fl IL7R Cre (ILC2-deficient), and recombination-activating gene (Rag) 2 -/- mice were challenged with saline, DEPs, or house dust mite (HDM) or DEP+HDM. Airway hyperresponsiveness, as well as inflammation, and intracellular cytokine expression in ILC2s and T H 2 cells in the bronchoalveolar lavage fluid and lung tissue were assessed. Concomitant DEP+HDM exposure significantly enhanced allergic airway inflammation, as characterized by increased airway eosinophilia, goblet cell metaplasia, accumulation of ILC2s and T H 2 cells, type 2 cytokine production, and airway hyperresponsiveness compared with sole DEPs or HDM. Reduced Gata-3 expression decreased the number of functional ILC2s and T H 2 cells in DEP+HDM-exposed mice, resulting in an impaired DEP-enhanced allergic airway inflammation. Interestingly, although the DEP-enhanced allergic inflammation was marginally reduced in ILC2-deficient mice that received combined DEP+HDM, it was abolished in DEP+HDM-exposed Rag2 -/- mice. These data indicate that dysregulation of ILC2s and T H 2 cells attenuates DEP-enhanced allergic airway inflammation. In addition, a crucial role for the adaptive immune system was shown on concomitant DEP+HDM exposure. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Pair Production of the Doubly Charged Leptons Associated with a Gauge Boson γ or Z in e+e- and γγ Collisions at Future Linear Colliders

NASA Astrophysics Data System (ADS)

Zeng, Qing-Guo; Ji, Li; Yang, Shuo

2015-03-01

In this paper, we investigate the production of a pair of doubly charged leptons associated with a gauge boson V(γ or Z) at future linear colliders via e+e- and γγ collisions. The numerical results show that the possible signals of the doubly charged leptons may be detected via the processes e+e- → VX++X-- and γγ → VX++X-- at future ILC or CLIC experiments. Supported in part by the National Natural Science Foundation of China under Grants Nos. 11275088, 11205023, 11375248 and the Program for Liaoning Excellent Talents in University under Grant No. LJQ2014135

How to manage continuing education and retraining programs on optical physics and laser technology at a university: Moscow State experience

NASA Astrophysics Data System (ADS)

Zadkov, Victor N.; Koroteev, Nikolai I.

1995-10-01

An experience of managing the continuing education and retraining programs at the International Laser Center (ILC) of Moscow State University is discussed. The offered programs are in a wide range of areas, namely laser physics and technology, laser biophysics and biomedicine, laser chemistry, and computers in laser physics. The attendees who are presumably scientists, engineers, technical managers, and graduate students can join these programs through the annual ILC term (6 months), individual training and research programs (up to a year), annual ILC Laser Graduate School, graduate study, and post-docs program, which are reviewed in the paper. A curriculum that includes basic and specialized courses is described in detail. A brief description of the ILC Laser Teaching and Computer Labs that support all the educational courses is given as well.

Functional Differences between Human NKp44(-) and NKp44(+) RORC(+) Innate Lymphoid Cells.

PubMed

Hoorweg, Kerim; Peters, Charlotte P; Cornelissen, Ferry; Aparicio-Domingo, Patricia; Papazian, Natalie; Kazemier, Geert; Mjösberg, Jenny M; Spits, Hergen; Cupedo, Tom

2012-01-01

Human RORC(+) lymphoid tissue inducer cells are part of a rapidly expanding family of innate lymphoid cells (ILC) that participate in innate and adaptive immune responses as well as in lymphoid tissue (re) modeling. The assessment of a potential role for innate lymphocyte-derived cytokines in human homeostasis and disease is hampered by a poor characterization of RORC(+) innate cell subsets and a lack of knowledge on the distribution of these cells in adults. Here we show that functionally distinct subsets of human RORC(+) innate lymphoid cells are enriched for secretion of IL-17a or IL-22. Both subsets have an activated phenotype and can be distinguished based on the presence or absence of the natural cytotoxicity receptor NKp44. NKp44(+) IL-22 producing cells are present in tonsils while NKp44(-) IL-17a producing cells are present in fetal developing lymph nodes. Development of human intestinal NKp44(+) ILC is a programmed event that is independent of bacterial colonization and these cells colonize the fetal intestine during the first trimester. In the adult intestine, NKp44(+) ILC are the main ILC subset producing IL-22. NKp44(-) ILC remain present throughout adulthood in peripheral non-inflamed lymph nodes as resting, non-cytokine producing cells. However, upon stimulation lymph node ILC can swiftly initiate cytokine transcription suggesting that secondary human lymphoid organs may function as a reservoir for innate lymphoid cells capable of participating in inflammatory responses.

Prevention options for positives: the effects of a health communication intervention for men who have sex with men living with HIV/AIDS.

PubMed

Lapinski, Maria Knight; Randall, Liisa M; Peterson, Mark; Peterson, Amy; Klein, Katherine A

2009-09-01

This article reports the results of a small-scale quasi-experiment that tested the efficacy of the Prevention Options for Positives intervention. The experiment tested for the outcomes of group sessions combined with individual-level counseling (ILC) versus ILC-only for men who have sex with men who are HIV positive. Both arms of the intervention were based on behavior change theory and dealt specifically with communication outcomes. The results indicate that the group- and individual-level interventions combined have a greater impact on risk communication behaviors with main partners than did the ILC-only sessions. group-session/ILC participants were more likely to decide not to have sex if they were drunk or high, and more likely to tell their partner and ask their partner about HIV status than were participants in the ILC groups. Knowledge about HIV was relatively high, and there was little change across groups. The Prevention Options for Positives intervention influenced the relative importance of various referent groups, but normative beliefs were not affected. The implications of these findings for communication practice and research with HIV-positive men who have sex with men are addressed.

Autoimmune Th17 Cells Induced Synovial Stromal and Innate Lymphoid Cell Secretion of the Cytokine GM-CSF to Initiate and Augment Autoimmune Arthritis.

PubMed

Hirota, Keiji; Hashimoto, Motomu; Ito, Yoshinaga; Matsuura, Mayumi; Ito, Hiromu; Tanaka, Masao; Watanabe, Hitomi; Kondoh, Gen; Tanaka, Atsushi; Yasuda, Keiko; Kopf, Manfred; Potocnik, Alexandre J; Stockinger, Brigitta; Sakaguchi, Noriko; Sakaguchi, Shimon

2018-06-19

Despite the importance of Th17 cells in autoimmune diseases, it remains unclear how they control other inflammatory cells in autoimmune tissue damage. Using a model of spontaneous autoimmune arthritis, we showed that arthritogenic Th17 cells stimulated fibroblast-like synoviocytes via interleukin-17 (IL-17) to secrete the cytokine GM-CSF and also expanded synovial-resident innate lymphoid cells (ILCs) in inflamed joints. Activated synovial ILCs, which expressed CD25, IL-33Ra, and TLR9, produced abundant GM-CSF upon stimulation by IL-2, IL-33, or CpG DNA. Loss of GM-CSF production by either ILCs or radio-resistant stromal cells prevented Th17 cell-mediated arthritis. GM-CSF production by Th17 cells augmented chronic inflammation but was dispensable for the initiation of arthritis. We showed that GM-CSF-producing ILCs were present in inflamed joints of rheumatoid arthritis patients. Thus, a cellular cascade of autoimmune Th17 cells, ILCs, and stromal cells, via IL-17 and GM-CSF, mediates chronic joint inflammation and can be a target for therapeutic intervention. Copyright © 2018 Elsevier Inc. All rights reserved.

Epigenomic Views of Innate Lymphoid Cells.

PubMed

Sciumè, Giuseppe; Shih, Han-Yu; Mikami, Yohei; O'Shea, John J

2017-01-01

The discovery of innate lymphoid cells (ILCs) with selective production of cytokines typically attributed to subsets of T helper cells forces immunologists to reassess the mechanisms by which selective effector functions arise. The parallelism between ILCs and T cells extends beyond these two cell types and comprises other innate-like T lymphocytes. Beyond the recognition of specialized effector functionalities in diverse lymphocytes, features typical of T cells, such as plasticity and memory, are also relevant for innate lymphocytes. Herein, we review what we have learned in terms of the molecular mechanisms underlying these shared functions, focusing on insights provided by next generation sequencing technologies. We review data on the role of lineage-defining- and signal-dependent transcription factors (TFs). ILC regulomes emerge developmentally whereas the much of the open chromatin regions of T cells are generated acutely, in an activation-dependent manner. And yet, these regions of open chromatin in T cells and ILCs have remarkable overlaps, suggesting that though accessibility is acquired by distinct modes, the end result is that convergent signaling pathways may be involved. Although much is left to be learned, substantial progress has been made in understanding how TFs and epigenomic status contribute to ILC biology in terms of differentiation, specification, and plasticity.

Innate lymphoid cells, precursors and plasticity.

PubMed

Gronke, Konrad; Kofoed-Nielsen, Michael; Diefenbach, Andreas

2016-11-01

Innate lymphoid cells (ILC) have only recently been recognized as a separate entity of the lymphoid lineage. Their subpopulations share common characteristics in terms of early development and major transcriptional circuitry with their related cousins of the T cell world. It is currently hypothesized that ILCs constitute an evolutionary older version of the lymphoid immune system. They are found at all primary entry points for pathogens such as mucosal surfaces of the lung and gastrointestinal system, the skin and the liver, which is the central contact point for pathogens that breach the intestinal barrier and enter the circulation. There, ILC contribute to the first line defense as well as to organ homeostasis. However, ILC are not only involved in classical defense tasks, but also contribute to the organogenesis of lymphoid organs as well as tissue remodeling and even stem cell regeneration. ILC may, therefore, implement different functions according to their emergence in ontogeny, their development and their final tissue location. We will review here their early development from precursors of the fetal liver and the adult bone marrow as well as their late plasticity in adaptation to their environment. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Epigenomic Views of Innate Lymphoid Cells

PubMed Central

Sciumè, Giuseppe; Shih, Han-Yu; Mikami, Yohei; O’Shea, John J.

2017-01-01

The discovery of innate lymphoid cells (ILCs) with selective production of cytokines typically attributed to subsets of T helper cells forces immunologists to reassess the mechanisms by which selective effector functions arise. The parallelism between ILCs and T cells extends beyond these two cell types and comprises other innate-like T lymphocytes. Beyond the recognition of specialized effector functionalities in diverse lymphocytes, features typical of T cells, such as plasticity and memory, are also relevant for innate lymphocytes. Herein, we review what we have learned in terms of the molecular mechanisms underlying these shared functions, focusing on insights provided by next generation sequencing technologies. We review data on the role of lineage-defining- and signal-dependent transcription factors (TFs). ILC regulomes emerge developmentally whereas the much of the open chromatin regions of T cells are generated acutely, in an activation-dependent manner. And yet, these regions of open chromatin in T cells and ILCs have remarkable overlaps, suggesting that though accessibility is acquired by distinct modes, the end result is that convergent signaling pathways may be involved. Although much is left to be learned, substantial progress has been made in understanding how TFs and epigenomic status contribute to ILC biology in terms of differentiation, specification, and plasticity. PMID:29250060

Characterization and Comparison of Control Units for Piezo Actuators to be used for Lorentz Force Compensation inth ILC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhattacharyya, Sampriti; Pilipenko, Roman; /Fermilab

2010-01-01

Superconducting accelerators, such as the International Linear Collider (ILC), rely on very high Q accelerating cavities to achieve high electric fields at low RF power. Such cavities have very narrow resonances: a few kHz with a 1.3GHz resonance frequency for the ILC. Several mechanical factors cause tune shifts much larger than this: pressure variations in the liquid helium bath; microphonics from pumps and other mechanical devices; and for a pulsed machine such as the ILC, Lorentz force detuning (pressure from the contained RF field). Simple passive stiffening is limited by many manufacturing and material considerations. Therefore, active tuning using piezomore » actuators is needed. Here we study a supply for their operation. Since commercial power amplifiers are expensive, we analyzed the characteristics of four power amplifiers: (iPZD) built by Istituto Nazionale di Fisica Nucleare (Sezione di Pisa); and a DC-DC converter power supply built in Fermilab (Piezo Master); and two commercial amplifiers, Piezosystem jena and Piezomechanik. This paper presents an analysis and characterization of these amplifiers to understand the cost benefit and reliability when using in a large scale, pulsed beam accelerator like the ILC.« less

Relative effectiveness of adjuvant chemotherapy for invasive lobular compared with invasive ductal carcinoma of the breast.

PubMed

Marmor, Schelomo; Hui, Jane Yuet Ching; Huang, Jing Li; Kizy, Scott; Beckwith, Heather; Blaes, Anne H; Rueth, Natasha M; Tuttle, Todd M

2017-08-15

Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) have distinct clinical, pathologic, and genomic characteristics. The objective of the current study was to compare the relative impact of adjuvant chemotherapy on the survival of patients with ILC versus those with IDC. Women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 1 (HER2) -negative, stage I/II IDC and ILC who received endocrine therapy were identified from the 2000 to 2014 California Cancer Registry. Patient, tumor, and treatment characteristics were collected. Ten-year overall survival (OS) was estimated using the Kaplan-Meier method and Cox proportional-hazards modeling. In total, 32,997 women with IDC and 4638 with ILC were identified. The receipt of chemotherapy significantly decreased during the study for both subtypes. For patients with IDC, the 10-year OS rate was 95% among those who received endocrine therapy alone versus 93% (P < .01) among those who received endocrine therapy plus chemotherapy. For patients with ILC, the 10-year OS rate was 94% among those who received endocrine therapy alone versus 92% (P < .01) among those who received endocrine therapy plus chemotherapy. After adjusting for patient and treatment factors, adjuvant chemotherapy was significantly associated with a decreased 10-year hazard of death for patients with IDC (hazard ratio, 0.83; 95% confidence interval, 0.74-0.92). In contrast, adjuvant chemotherapy was not independently associated with the adjusted 10-year hazard of death for patients with ILC (hazard ratio, 1.14; 95% confidence interval, 0.90-1.46). Adjuvant chemotherapy was not associated with improved OS for patients with ER-positive, HER2-negative, stage I/II ILC. Avoidance of ineffective chemotherapy will markedly reduce the adverse effects and economic burden of breast cancer treatment for a large proportion of patients with breast cancer. Cancer 2017;123:3015-21. © 2017 American Cancer Society. © 2017 American Cancer Society.

Ozone-Induced Nasal Type 2 Immunity in Mice Is Dependent on Innate Lymphoid Cells.

PubMed

Kumagai, Kazuyoshi; Lewandowski, Ryan; Jackson-Humbles, Daven N; Li, Ning; Van Dyken, Steven J; Wagner, James G; Harkema, Jack R

2016-06-01

Epidemiological studies suggest that elevated ambient concentrations of ozone are associated with activation of eosinophils in the nasal airways of atopic and nonatopic children. Mice repeatedly exposed to ozone develop eosinophilic rhinitis and type 2 immune responses. In this study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced eosinophilic rhinitis by using lymphoid-sufficient C57BL/6 mice, Rag2(-/-) mice that are devoid of T cells and B cells, and Rag2(-/-)Il2rg(-/-) mice that are depleted of all lymphoid cells including ILCs. The animals were exposed to 0 or 0.8 ppm ozone for 9 consecutive weekdays (4 h/d). Mice were killed 24 hours after exposure, and nasal tissues were selected for histopathology and gene expression analysis. ILC-sufficient C57BL/6 and Rag2(-/-) mice exposed to ozone developed marked eosinophilic rhinitis and epithelial remodeling (e.g., epithelial hyperplasia and mucous cell metaplasia). Chitinase-like proteins and alarmins (IL-33, IL-25, and thymic stromal lymphopoietin) were also increased morphometrically in the nasal epithelium of ozone-exposed C57BL/6 and Rag2(-/-) mice. Ozone exposure elicited increased expression of Il4, Il5, Il13, St2, eotaxin, MCP-2, Gob5, Arg1, Fizz1, and Ym2 mRNA in C57BL/6 and Rag2(-/-) mice. In contrast, ozone-exposed ILC-deficient Rag2(-/-)Il2rg(-/-) mice had no nasal lesions or overexpression of Th2- or ILC2-related transcripts. These results indicate that ozone-induced eosinophilic rhinitis, nasal epithelial remodeling, and type 2 immune activation are dependent on ILCs. To the best of our knowledge, this is the first study to demonstrate that ILCs play an important role in the nasal pathology induced by repeated ozone exposure.

Comparison of Treatment Outcome Between Invasive Lobular and Ductal Carcinomas in Patients Receiving Partial Breast Irradiation With Intraoperative Electrons.

PubMed

Leonardi, Maria Cristina; Maisonneuve, Patrick; Mastropasqua, Mauro Giuseppe; Cattani, Federica; Fanetti, Giuseppe; Morra, Anna; Lazzari, Roberta; Bazzani, Federica; Caputo, Mariangela; Rotmensz, Nicole; Gerardi, Marianna Alessandra; Ricotti, Rosalinda; Enrica Galimberti, Viviana; Veronesi, Paolo; Dicuonzo, Samantha; Viale, Giuseppe; Jereczek-Fossa, Barbara Alicja; Orecchia, Roberto

2017-09-01

To investigate the local outcome of patients after accelerated partial breast irradiation with intraoperative electrons (IORT) for invasive lobular carcinoma (ILC) compared with invasive ductal carcinoma (IDC). From 1999 to 2007, 2173 patients were treated with breast-conserving surgery and IORT (21 Gy/1 fraction) as the sole local treatment: 252 patients with ILC (11.6%) were compared with 1921 patients with IDC in terms of local control. Compared with the IDC subgroup, patients with ILC had a low-risk profile and were more hormone responsive. The 5- and 10-year in-breast tumor reappearance (IBTR) rates were 5.5% and 14.4%, respectively, for the IDC group and 7.5% and 21.8%, respectively, for the ILC group (log-rank P=.03). The excess risk of IBTR associated with ILC was particularly high for small tumors (≤1 cm: hazard ratio [HR], 2.24; 95% confidence interval [CI], 1.03-4.85), elderly patients (60-69 years: HR, 2.27; 95% CI, 1.11-4.63; ≥70 years: HR, 3.28; 95% CI, 1.08-10.0), low-grade tumors (grade 1: HR, 3.50; 95% CI, 1.05-11.7), and luminal A molecular subtype (HR, 3.18; 95% CI, 1.49-6.77). Among the ILC histologic variants, no difference between classic and nonclassic subgroups was observed, although the signet ring cell and solid variants had the worst local control. Despite a favorable tumor profile, accelerated partial breast irradiation with IORT led to a higher incidence of IBTRs in patients with ILC compared with those with IDC. Our institutional experience emphasized the importance of the size of the irradiation field, pointing to the use of larger collimators, even when dealing with small tumors, to improve local control. Copyright © 2017 Elsevier Inc. All rights reserved.

The International Linear Collider Technical Design Report - Volume 2: Physics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baer, Howard; Barklow, Tim; Fujii, Keisuke

2013-06-26

The International Linear Collider Technical Design Report (TDR) describes in four volumes the physics case and the design of a 500 GeV centre-of-mass energy linear electron-positron collider based on superconducting radio-frequency technology using Niobium cavities as the accelerating structures. The accelerator can be extended to 1 TeV and also run as a Higgs factory at around 250 GeV and on the Z0 pole. A comprehensive value estimate of the accelerator is give, together with associated uncertainties. It is shown that no significant technical issues remain to be solved. Once a site is selected and the necessary site-dependent engineering is carriedmore » out, construction can begin immediately. The TDR also gives baseline documentation for two high-performance detectors that can share the ILC luminosity by being moved into and out of the beam line in a "push-pull" configuration. These detectors, ILD and SiD, are described in detail. They form the basis for a world-class experimental programme that promises to increase significantly our understanding of the fundamental processes that govern the evolution of the Universe.« less

Statistical tools and control of internal lubricant content of inhalation grade HPMC capsules during manufacture.

PubMed

Ayala, Guillermo; Díez, Fernando; Gassó, María T; Jones, Brian E; Martín-Portugués, Rafael; Ramiro-Aparicio, Juan

2016-04-30

The internal lubricant content (ILC) of inhalation grade HPMC capsules is a key factor to ensure good powder release when the patient inhales a medicine from a dry powder inhaler (DPI). Powder release from capsules has been shown to be influenced by the ILC. The characteristics used to measure this are the emitted dose, fine particle fraction and mass median aerodynamic diameter. In addition the ILC level is critical for capsule shell manufacture because it is an essential part of the process that cannot work without it. An experiment has been applied to the manufacture of inhalation capsules with the required ILC. A full factorial model was used to identify the controlling factors and from this a linear model has been proposed to improve control of the process. Copyright © 2016 Elsevier B.V. All rights reserved.

T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation.

PubMed

Kwong, Brandon; Rua, Rejane; Gao, Yuanyuan; Flickinger, John; Wang, Yan; Kruhlak, Michael J; Zhu, Jinfang; Vivier, Eric; McGavern, Dorian B; Lazarevic, Vanja

2017-10-01

The transcription factor T-bet has been associated with increased susceptibility to systemic and organ-specific autoimmunity, but the mechanism by which T-bet expression promotes neuroinflammation remains unknown. In this study, we demonstrate a cardinal role of T-bet-dependent NKp46 + innate lymphoid cells (ILCs) in the initiation of CD4 + T H 17-mediated neuroinflammation. Loss of T-bet specifically in NKp46 + ILCs profoundly impaired the ability of myelin-reactive T H 17 cells to invade central nervous system (CNS) tissue and protected the mice from autoimmunity. T-bet-dependent NKp46 + ILCs localized in the meninges and acted as chief coordinators of meningeal inflammation by inducing the expression of proinflammatory cytokines, chemokines and matrix metalloproteinases, which together facilitated T cell entry into CNS parenchyma. Our findings uncover a detrimental role of T-bet-dependent NKp46 + ILCs in the development of CNS autoimmune disease.

The Development of Adult Innate Lymphoid Cells

PubMed Central

Yang, Qi; Bhandoola, Avinash

2016-01-01

Innate lymphoid cells (ILC) are a specialized family of effector lymphocytes that transcriptionally and functionally mirror effector subsets of T cells, but differ from T cells in that they lack clonally-distributed adaptive antigen receptors. Our understanding of this family of lymphocytes is still in its infancy. In this review, we summarize current understanding and discuss recent insights into the cellular and molecular events that occur during early ILC development in adult mice. We discuss how these events overlap and diverge with the early development of adaptive T cells, and how they may influence the molecular and functional properties of mature ILC. PMID:26871595

Cryogenic system configuration for the International Linear Collider (ILC) at mountainous site

NASA Astrophysics Data System (ADS)

Nakai, H.; Okamura, T.; Delikaris, D.; Peterson, T.; Yamamoto, A.

2017-02-01

The International Linear Collider (ILC) plans to make use of ten cryoplants for its main linacs, each providing 19 kW at 4.5 K equivalent and among of it 3.6 kW at 2 K. Each cryoplant will consist of various cryogenic components such as a 4.5 K refrigerator cold box, a 2 K refrigerator cold box, and helium compressors and so on. In the technical design report (TDR) of the ILC, due to the mountainous topology, almost all cryogenic components would be installed in underground cryogenic caverns next to the main linac tunnels and only cooling towers on surface area. However, we would like to find a more effective and sophisticated configuration of the cryoplant components (cryogenic configuration). Under several constraints of technical, geographical, and environmental points of view, the cryogenic configuration should be considered carefully to satisfy such various conditions. After discussions on this topic conducted at various workshops and conferences, an updated cryogenic configuration is suggested. The proposed updated configuration may affect the total construction cost of the ILC and the entire structure of the ILC conventional facilities. The updated cryogenic configuration is presented and the on-going discussions with the conventional facilities and siting (CFS) colleagues for further improvement of the cryogenic configuration is introduced.

HMGB1 exacerbates experimental mouse colitis by enhancing innate lymphoid cells 3 inflammatory responses via promoted IL-23 production.

PubMed

Chen, Xiangyu; Li, Lingyun; Khan, Muhammad Noman; Shi, Lifeng; Wang, Zhongyan; Zheng, Fang; Gong, Feili; Fang, Min

2016-11-01

In inflammatory bowel diseases (IBD), high mobility group box 1 (HMGB1), as an endogenous inflammatory molecule, can promote inflammatory cytokines secretion by acting on TLR2/4 resulting in tissue damage. The underlying mechanisms remain unclear. Here we report a novel role of HMGB1 in controlling the maintenance and function of intestine-resident group-3 innate lymphoid cells (ILC3s) that are important innate effector cells implicated in mucosal homeostasis and IBD pathogenesis. We showed that mice treated with anti-HMGB1 Ab, or genetically deficient for TLR2 -/- or TLR4 -/- mice, displayed reduced intestinal inflammation. In these mice, the numbers of colonic ILC3s were significantly reduced, and the levels of IL-17 and IL-22 that can be secreted by ILC3s were also decreased in the colon tissues. Furthermore, HMGB1 promoted DCs via TLR2/4 signaling to produce IL-23, activating ILC3s to produce IL-17 and IL-22. Our data thus indicated that the HMGB1-TLR2/4-DCs-IL-23 cascade pathway enhances the functions of ILC3s to produce IL-17 and IL-22, and this signal way might play a vital role in the development of IBD.

High-bandwidth and flexible tracking control for precision motion with application to a piezo nanopositioner.

PubMed

Feng, Zhao; Ling, Jie; Ming, Min; Xiao, Xiao-Hui

2017-08-01

For precision motion, high-bandwidth and flexible tracking are the two important issues for significant performance improvement. Iterative learning control (ILC) is an effective feedforward control method only for systems that operate strictly repetitively. Although projection ILC can track varying references, the performance is still limited by the fixed-bandwidth Q-filter, especially for triangular waves tracking commonly used in a piezo nanopositioner. In this paper, a wavelet transform-based linear time-varying (LTV) Q-filter design for projection ILC is proposed to compensate high-frequency errors and improve the ability to tracking varying references simultaneously. The LVT Q-filter is designed based on the modulus maximum of wavelet detail coefficients calculated by wavelet transform to determine the high-frequency locations of each iteration with the advantages of avoiding cross-terms and segmenting manually. The proposed approach was verified on a piezo nanopositioner. Experimental results indicate that the proposed approach can locate the high-frequency regions accurately and achieve the best performance under varying references compared with traditional frequency-domain and projection ILC with a fixed-bandwidth Q-filter, which validates that through implementing the LTV filter on projection ILC, high-bandwidth and flexible tracking can be achieved simultaneously by the proposed approach.

The orphan nuclear receptor ROR alpha and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn's disease.

PubMed

Lo, Bernard C; Gold, Matthew J; Hughes, Michael R; Antignano, Frann; Valdez, Yanet; Zaph, Colby; Harder, Kenneth W; McNagny, Kelly M

2016-09-02

Fibrosis is the result of dysregulated tissue regeneration and is characterized by excessive accumulation of matrix proteins that become detrimental to tissue function. In Crohn's disease, this manifests itself as recurrent gastrointestinal strictures for which there is no effective therapy beyond surgical intervention. Using a model of infection-induced chronic gut inflammation, we show that Rora -deficient mice are protected from fibrosis; infected intestinal tissues display diminished pathology, attenuated collagen deposition and reduced fibroblast accumulation. Although Rora is best known for its role in ILC2 development, we find that Salmonella -induced fibrosis is independent of eosinophils, STAT6 signaling and Th2 cytokine production arguing that this process is largely ILC2-independent. Instead, we observe reduced levels of ILC3- and T cell-derived IL-17A and IL-22 in infected gut tissues. Furthermore, using Rora sg/sg / Rag1 -/- bone marrow chimeric mice, we show that restoring ILC function is sufficient to re-establish IL-17A and IL-22 production and a profibrotic phenotype. Our results show that RORα-dependent ILC3 functions are pivotal in mediating gut fibrosis and they offer an avenue for therapeutic intervention in Crohn's-like diseases.

Constraints from triple gauge couplings on vectorlike leptons

DOE PAGES

Bertuzzo, Enrico; Machado, Pedro A. N.; Perez-Gonzalez, Yuber F.; ...

2017-08-30

Here, we study the contributions of colorless vectorlike fermions to the triple gauge couplings W +W -γ and W +W -Z 0. We consider models in which their coupling to the Standard Model Higgs boson is allowed or forbidden by quantum numbers. We assess the sensitivity of the future accelerators FCC-ee, ILC, and CLIC to the parameters of these models, assuming they will be able to constrain the anomalous triple gauge couplings with precision δ κV~O(10 -4), V = γ,Z 0. We show that the combination of measurements at different center-of-mass energies helps to improve the sensitivity to the contributionmore » of vectorlike fermions, in particular when they couple to the Higgs. In fact, the measurements at the FCC-ee and, especially, the ILC and the CLIC, may turn the triple gauge couplings into a new set of precision parameters able to constrain the models better than the oblique parameters or the H → γγ decay, even assuming the considerable improvement of the latter measurements achievable at the new machines.« less

Constraints from triple gauge couplings on vectorlike leptons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bertuzzo, Enrico; Machado, Pedro A. N.; Perez-Gonzalez, Yuber F.

Here, we study the contributions of colorless vectorlike fermions to the triple gauge couplings W +W -γ and W +W -Z 0. We consider models in which their coupling to the Standard Model Higgs boson is allowed or forbidden by quantum numbers. We assess the sensitivity of the future accelerators FCC-ee, ILC, and CLIC to the parameters of these models, assuming they will be able to constrain the anomalous triple gauge couplings with precision δ κV~O(10 -4), V = γ,Z 0. We show that the combination of measurements at different center-of-mass energies helps to improve the sensitivity to the contributionmore » of vectorlike fermions, in particular when they couple to the Higgs. In fact, the measurements at the FCC-ee and, especially, the ILC and the CLIC, may turn the triple gauge couplings into a new set of precision parameters able to constrain the models better than the oblique parameters or the H → γγ decay, even assuming the considerable improvement of the latter measurements achievable at the new machines.« less

Impact of Strain Elastography on BI-RADS classification in small invasive lobular carcinoma.

PubMed

Chiorean, Angelica Rita; Szep, Mădălina Brîndușa; Feier, Diana Sorina; Duma, Magdalena; Chiorean, Marco Andrei; Strilciuc, Ștefan

2018-05-02

The purpose of this study was to determine the impact of strain elastography (SE) on the Breast Imaging Reporting Data System (BI-RADS) classification depending on invasive lobular carcinoma (ILC) lesion size. We performed a retrospective analysis on a sample of 152 female subjects examined between January 2010 - January 2017. SE was performed on all patients and ILC was subsequently diagnosed by surgical or ultrasound-guided biopsy. BI-RADS 1, 2, 6 and Tsukuba BGR cases were omitted. BI-RADS scores were recorded before and after the use of SE. The differences between scores were compared to the ILC tumor size using nonparametric tests and logistic binary regression. We controlled for age, focality, clinical assessment, heredo-collateral antecedents, B-mode and Doppler ultrasound examination. An ROC curve was used to identify the optimal cut-off point for size in relationship to BI-RADS classificationdifference using Youden's index. The histological subtypes of ILC lesions (n=180) included in the sample were luminal A (70%, n=126), luminal B (27.78%, n=50), triple negative (1.67%, n=3) and HER2+ (0.56%, n=1). The BI-RADS classification was higher when SE was performed (Z=- 6.629, p<0.000). The ROC curve identified a cut-off point of 13 mm for size in relationship to BI-RADS classification difference (J=0.670, p<0.000). Small ILC tumors were 17.92% more likely to influence BI-RADS classification (p<0.000). SE offers enhanced BI-RADS classification in small ILC tumors (<13 mm). Sonoelastography brings added value to B-mode breast ultrasound as an adjacent to mammography in breast cancer screening.

Vitamin A Controls the Presence of RORγ+ Innate Lymphoid Cells and Lymphoid Tissue in the Small Intestine.

PubMed

Goverse, Gera; Labao-Almeida, Carlos; Ferreira, Manuela; Molenaar, Rosalie; Wahlen, Sigrid; Konijn, Tanja; Koning, Jasper; Veiga-Fernandes, Henrique; Mebius, Reina E

2016-06-15

Changes in diet and microbiota have determining effects on the function of the mucosal immune system. For example, the active metabolite of vitamin A, retinoic acid (RA), has been described to maintain homeostasis in the intestine by its influence on both lymphocytes and myeloid cells. Additionally, innate lymphoid cells (ILCs), important producers of cytokines necessary for intestinal homeostasis, are also influenced by vitamin A in the small intestines. In this study, we show a reduction of both NCR(-) and NCR(+) ILC3 subsets in the small intestine of mice raised on a vitamin A-deficient diet. Additionally, the percentages of IL-22-producing ILCs were reduced in the absence of dietary vitamin A. Conversely, mice receiving additional RA had a specific increase in the NCR(-) ILC3 subset, which contains the lymphoid tissue inducer cells. The dependence of lymphoid tissue inducer cells on vitamin A was furthermore illustrated by impaired development of enteric lymphoid tissues in vitamin A-deficient mice. These effects were a direct consequence of ILC-intrinsic RA signaling, because retinoic acid-related orphan receptor γt-Cre × RARα-DN mice had reduced numbers of NCR(-) and NCR(+) ILC3 subsets within the small intestine. However, lymphoid tissue inducer cells were not affected in these mice nor was the formation of enteric lymphoid tissue, demonstrating that the onset of RA signaling might take place before retinoic acid-related orphan receptor γt is expressed on lymphoid tissue inducer cells. Taken together, our data show an important role for vitamin A in controlling innate lymphoid cells and, consequently, postnatal formed lymphoid tissues within the small intestines. Copyright © 2016 by The American Association of Immunologists, Inc.

Vancomycin pre-treatment impairs tissue healing in experimental colitis: Importance of innate lymphoid cells.

PubMed

Zhao, Di; Cai, Chenwen; Zheng, Qing; Jin, Shuang; Song, Dongjuan; Shen, Jun; Ran, Zhihua

2017-01-29

The interplay between luminal microbes and innate immunity during colonic epithelial repair has been well noted. At the same time, antibiotic has widely been used during flare-ups of ulcerative colitis. The possible effects of luminal microbiota disruption caused by antibiotics usage on epithelial repairing have been scarcely discussed. Innate lymphoid cells (ILCs) embedded in the lamina propria can be modulated by gut microbes, resulting in altered colonic IL-22/pSTAT3 levels, which is considered a prominent molecular axis in tissue repairing after epithelium damage. This study aimed to investigate whether antibiotics could interfere with ILCs-dependent tissue repair. Dextran sodium sulfate (DSS)-induced colitis was established in mice pre-treated with reagent of different antibiotic spectrum. Both morphological and molecular markers of tissue repair after DSS cessation were detected. ILCs population and function status were also recorded. Further attention was paid to the response of dendritic cells after antibiotics treatment, which were claimed to regulate colonic ILC3s in an IL-23 dependent way. Using of vancomycin resulted in delayed tissue repairing after experimental colitis. Both colonic IL-22/pSTAT3 axis and ILC3 population were found decreased in this situation. Vancomycin treatment diminished the upstream IL-23 and producer dendritic cell population. The reduced dendritic cell number may due to inadequate chemokines and colony-stimulating factors supply. Presence of vancomycin-sensitive microbiota is required for the maturation of ILC3-activating dendritic cells hence maintain the sufficient IL-22/pSTAT3 level in the colon during tissue healing. Manipulation of colonic microbiota may help achieve colonic mucosal healing post inflammation and injury. Copyright © 2016. Published by Elsevier Inc.

Gpr109a Limits Microbiota-Induced IL-23 Production To Constrain ILC3-Mediated Colonic Inflammation.

PubMed

Bhatt, Brinda; Zeng, Peng; Zhu, Huabin; Sivaprakasam, Sathish; Li, Siyi; Xiao, Haiyan; Dong, Lixin; Shiao, Pamela; Kolhe, Ravindra; Patel, Nikhil; Li, Honglin; Levy-Bercowski, Daniel; Ganapathy, Vadivel; Singh, Nagendra

2018-04-15

A set of coordinated interactions between gut microbiota and the immune cells surveilling the intestine play a key role in shaping local immune responses and intestinal health. Gpr109a is a G protein-coupled receptor expressed at a very high level on innate immune cells and previously shown to play a key role in the induction of colonic regulatory T cells. In this study, we show that Gpr109a -/- Rag1 -/- mice exhibit spontaneous rectal prolapse and colonic inflammation, characterized by the presence of an elevated number of IL-17-producing Rorγt + innate lymphoid cells (ILCs; ILC3). Genetic deletion of Rorγt alleviated the spontaneous colonic inflammation in Gpr109a -/- Rag1 -/- mice. Gpr109a-deficient colonic dendritic cells produce higher amounts of IL-23 and thereby promote ILC3. Moreover, the depletion of gut microbiota by antibiotics treatment decreased IL-23 production, ILC3, and colonic inflammation in Gpr109a -/- Rag1 -/- mice. The ceca of Gpr109a -/- Rag1 -/- mice showed significantly increased colonization by members of Bacteroidaceae , Porphyromonadaceae , Prevotellaceae, Streptococcaceae , Christensenellaceae , and Mogibacteriaceae , as well as IBD-associated microbiota such as Enterobacteriaceae and Mycoplasmataceae , compared with Rag1 -/- mice, housed in a facility positive for Helicobacter and murine norovirus. Niacin, a Gpr109a agonist, suppressed both IL-23 production by colonic DCs and ILC3 number in a Gpr109a-dependent manner. Collectively, our data present a model suggesting that targeting Gpr109a will be potentially beneficial in the suppression of IL-23-mediated immunopathologies. Copyright © 2018 by The American Association of Immunologists, Inc.

Dissociable contributions of the orbitofrontal and infralimbic cortex to pavlovian autoshaping and discrimination reversal learning: further evidence for the functional heterogeneity of the rodent frontal cortex.

PubMed

Chudasama, Y; Robbins, Trevor W

2003-09-24

To examine possible heterogeneity of function within the ventral regions of the rodent frontal cortex, the present study compared the effects of excitotoxic lesions of the orbitofrontal cortex (OFC) and the infralimbic cortex (ILC) on pavlovian autoshaping and discrimination reversal learning. During the pavlovian autoshaping task, in which rats learn to approach a stimulus predictive of reward [conditional stimulus (CS+)], only the OFC group failed to acquire discriminated approach but was unimpaired when preoperatively trained. In the visual discrimination learning and reversal task, rats were initially required to discriminate a stimulus positively associated with reward. There was no effect of either OFC or ILC lesions on discrimination learning. When the stimulus-reward contingencies were reversed, both groups of animals committed more errors, but only the OFC-lesioned animals were unable to suppress the previously rewarded stimulus-reward association, committing more "stimulus perseverative" errors. In contrast, the ILC group showed a pattern of errors that was more attributable to "learning" than perseveration. These findings suggest two types of dissociation between the effects of OFC and ILC lesions: (1) OFC lesions impaired the learning processes implicated in pavlovian autoshaping but not instrumental simultaneous discrimination learning, whereas ILC lesions were unimpaired at autoshaping and their reversal learning deficit did not reflect perseveration, and (2) OFC lesions induced perseverative responding in reversal learning but did not disinhibit responses to pavlovian CS-. In contrast, the ILC lesion had no effect on response inhibitory control in either of these settings. The findings are discussed in the context of dissociable executive functions in ventral sectors of the rat prefrontal cortex.

Interleukins 12 and 15 induce cytotoxicity and early NK-cell differentiation in type 3 innate lymphoid cells.

PubMed

Raykova, Ana; Carrega, Paolo; Lehmann, Frank M; Ivanek, Robert; Landtwing, Vanessa; Quast, Isaak; Lünemann, Jan D; Finke, Daniela; Ferlazzo, Guido; Chijioke, Obinna; Münz, Christian

2017-12-26

Type 3 innate lymphoid cells (ILC3s) fulfill protective functions at mucosal surfaces via cytokine production. Although their plasticity to become ILC1s, the innate counterparts of type 1 helper T cells, has been described previously, we report that they can differentiate into cytotoxic lymphocytes with many characteristics of early differentiated natural killer (NK) cells. This transition is promoted by the proinflammatory cytokines interleukin 12 (IL-12) and IL-15, and correlates with expression of the master transcription factor of cytotoxicity, eomesodermin (Eomes). As revealed by transcriptome analysis and flow cytometric profiling, differentiated ILC3s express CD94, NKG2A, NKG2C, CD56, and CD16 among other NK-cell receptors, and possess all components of the cytotoxic machinery. These characteristics allow them to recognize and kill leukemic cells with perforin and granzymes. Therefore, ILC3s can be harnessed for cytotoxic responses via differentiation under the influence of proinflammatory cytokines.

Active flow separation control by a position-based iterative learning control algorithm with experimental validation

NASA Astrophysics Data System (ADS)

Cai, Zhonglun; Chen, Peng; Angland, David; Zhang, Xin

2014-03-01

A novel iterative learning control (ILC) algorithm was developed and applied to an active flow control problem. The technique uses pulsed air jets to delay flow separation on a two-element high-lift wing. The ILC algorithm uses position-based pressure measurements to update the actuation. The method was experimentally tested on a wing model in a 0.9 m × 0.6 m low-speed wind tunnel at the University of Southampton. Compressed air and fast switching solenoid valves were used as actuators to excite the flow, and the pressure distribution around the chord of the wing was measured as a feedback control signal for the ILC controller. Experimental results showed that the actuation was able to delay the separation and increase the lift by approximately 10%-15%. By using the ILC algorithm, the controller was able to find the optimum control input and maintain the improvement despite sudden changes of the separation position.

T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation

PubMed Central

Kwong, Brandon; Rua, Rejane; Gao, Yuanyuan; Flickinger, John; Wang, Yan; Kruhlak, Michael J.; Zhu, Jinfang; Vivier, Eric; McGavern, Dorian B.; Lazarevic, Vanja

2017-01-01

The transcription factor T-bet has been linked to increased susceptibility to systemic and organ-specific autoimmunity, but the mechanism by which T-bet expression promotes neuroinflammation remains unknown. In this study, we demonstrate a cardinal role for T-bet-dependent NKp46+ innate lymphoid cells (ILCs) in the initiation of CD4+ TH17-mediated neuroinflammation. Loss of T-bet specifically in NKp46+ ILCs profoundly impaired the ability of myelin-reactive TH17 cells to invade the central nervous system (CNS) tissue and protected the mice from autoimmunity. T-bet-dependent NKp46+ ILCs were localized in the meninges and acted as chief coordinators of meningeal inflammation by inducing the expression of pro-inflammatory cytokines, chemokines and matrix metalloproteinases, which in a concerted fashion facilitated T cell entry into CNS parenchyma. Our findings uncover a detrimental role of T-bet-dependent NKp46+ ILCs in the development of CNS autoimmune disease. PMID:28805812

Why Innate Lymphoid Cells?

PubMed

Kotas, Maya E; Locksley, Richard M

2018-06-19

Innate lymphoid cells (ILCs) are positioned in tissues perinatally, constitutively express receptors responsive to their organ microenvironments, and perform an arsenal of effector functions that overlap those of adaptive CD4 + T cells. Based on knowledge regarding subsets of invariant-like lymphocytes (e.g., natural killer T [NKT] cells, γδ T cells, mucosal-associated invariant T [MAIT] cells, etc.) and fetally derived macrophages, we hypothesize that immune cells established during the perinatal period-including, but not limited to, ILCs-serve intimate roles in tissue that go beyond classical understanding of the immune system in microbial host defense. In this Perspective, we propose mechanisms by which the establishment of ILCs and the tissue lymphoid niche during early development may have consequences much later in life. Although definitive answers require better tools, efforts to achieve deeper understanding of ILC biology across the mammalian lifespan have the potential to lift the veil on the unknown breadth of immune cell functions. Copyright © 2018 Elsevier Inc. All rights reserved.

Back to the drawing board: Understanding the complexity of hepatic innate lymphoid cells.

PubMed

Marotel, Marie; Hasan, Uzma; Viel, Sébastien; Marçais, Antoine; Walzer, Thierry

2016-09-01

Recent studies of immune populations in nonlymphoid organs have highlighted the great diversity of the innate lymphoid system. It has also become apparent that mouse and human innate lymphoid cells (ILCs) have distinct phenotypes and properties. In this issue of the European Journal of Immunology, Harmon et al. [Eur. J. Immunol. 2016. 46: 2111-2120] characterized human hepatic NK-cell subsets. The authors report that hepatic CD56(bright) NK cells resemble mouse liver ILC1s in that they express CXCR6 and have an immature phenotype. However, unlike mouse ILC1s, they express high levels of Eomes and low levels of T-bet, and upon stimulation with tumor cells, secrete low amounts of cytokines. These unexpected findings further support the differences between human and mouse immune populations and prompt the study of the role of hepatic ILC subsets in immune responses. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Stromal Cell Niche for Human and Mouse Type 3 Innate Lymphoid Cells.

PubMed

Hoorweg, Kerim; Narang, Priyanka; Li, Zhi; Thuery, Anne; Papazian, Natalie; Withers, David R; Coles, Mark C; Cupedo, Tom

2015-11-01

Adaptive immunity critically depends on the functional compartmentalization of secondary lymphoid organs. Mesenchymal stromal cells create and maintain specialized niches that support survival, activation, and expansion of T and B cells, and integrated analysis of lymphocytes and their niche has been instrumental in understanding adaptive immunity. Lymphoid organs are also home to type 3 innate lymphoid cells (ILC3), innate effector cells essential for barrier immunity. However, a specialized stromal niche for ILC3 has not been identified. A novel lineage-tracing approach now identifies a subset of murine fetal lymphoid tissue organizer cells that gives rise exclusively to adult marginal reticular cells. Moreover, both cell types are conserved from mice to humans and colocalize with ILC3 in secondary lymphoid tissues throughout life. In sum, we provide evidence that fetal stromal organizers give rise to adult marginal reticular cells and form a dedicated stromal niche for innate ILC3 in adaptive lymphoid organs. Copyright © 2015 by The American Association of Immunologists, Inc.

Differentiation of Mesenchymal Stem Cells Derived from Pancreatic Islets and Bone Marrow into Islet-Like Cell Phenotype

PubMed Central

Zanini, Cristina; Bruno, Stefania; Mandili, Giorgia; Baci, Denisa; Cerutti, Francesco; Cenacchi, Giovanna; Izzi, Leo; Camussi, Giovanni; Forni, Marco

2011-01-01

Background Regarding regenerative medicine for diabetes, accessible sources of Mesenchymal Stem Cells (MSCs) for induction of insular beta cell differentiation may be as important as mastering the differentiation process itself. Methodology/Principal Findings In the present work, stem cells from pancreatic islets (human islet-mesenchymal stem cells, HI-MSCs) and from human bone marrow (bone marrow mesenchymal stem cells, BM-MSCs) were cultured in custom-made serum-free medium, using suitable conditions in order to induce differentiation into Islet-like Cells (ILCs). HI-MSCs and BM-MSCs were positive for the MSC markers CD105, CD73, CD90, CD29. Following this induction, HI-MSC and BM-MSC formed evident islet-like structures in the culture flasks. To investigate functional modifications after induction to ILCs, ultrastructural analysis and immunofluorescence were performed. PDX1 (pancreatic duodenal homeobox gene-1), insulin, C peptide and Glut-2 were detected in HI-ILCs whereas BM-ILCs only expressed Glut-2 and insulin. Insulin was also detected in the culture medium following glucose stimulation, confirming an initial differentiation that resulted in glucose-sensitive endocrine secretion. In order to identify proteins that were modified following differentiation from basal MSC (HI-MSCs and BM-MSCs) to their HI-ILCs and BM-ILCs counterparts, proteomic analysis was performed. Three new proteins (APOA1, ATL2 and SODM) were present in both ILC types, while other detected proteins were verified to be unique to the single individual differentiated cells lines. Hierarchical analysis underscored the limited similarities between HI-MSCs and BM-MSCs after induction of differentiation, and the persistence of relevant differences related to cells of different origin. Conclusions/Significance Proteomic analysis highlighted differences in the MSCs according to site of origin, reflecting spontaneous differentiation and commitment. A more detailed understanding of protein assets may provide insights required to master the differentiation process of HI-MSCs to functional beta cells based only upon culture conditioning. These findings may open new strategies for the clinical use of BM-MSCs in diabetes. PMID:22194812

Experimental asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin-driven IL-9+ and IL-13+ type 2 innate lymphoid cell subpopulations.

PubMed

Verma, Mukesh; Liu, Sucai; Michalec, Lidia; Sripada, Anand; Gorska, Magdalena M; Alam, Rafeul

2017-11-10

IL-33 plays an important role in the development of experimental asthma. We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of asthma in a mouse model. We studied allergen-induced experimental asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry. Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of experimental asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13 + CD4 T cells, forkhead box P3-positive regulatory T cells, and IL-5 + ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45 + lin - CD25 + cells) and IL-13 + ILC2s, emergence of a TSLP receptor-positive IL-9 + ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9 + and IL-13 + ILC2 numbers in the lung. Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9 + and IL-13 + ILC2s and mast cells and leads to development of chronic experimental asthma. An anti-TSLP antibody abrogates all pathologic features of asthma in this model. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Effects of HIV infection and ART on phenotype and function of circulating monocytes, natural killer, and innate lymphoid cells.

PubMed

Nabatanzi, Rose; Cose, Stephen; Joloba, Moses; Jones, Sarah Rowland; Nakanjako, Damalie

2018-03-15

HIV infection causes upregulation of markers of inflammation, immune activation and apoptosis of host adaptive, and innate immune cells particularly monocytes, natural killer (NK) and innate lymphoid cells (ILCs). Although antiretroviral therapy (ART) restores CD4 T-cell counts, the persistent aberrant activation of monocytes, NK and ILCs observed likely contributes to the incomplete recovery of T-cell effector functions. A better understanding of the effects of HIV infection and ART on the phenotype and function of circulating monocytes, NK, and ILCs is required to guide development of novel therapeutic interventions to optimize immune recovery.

CD1a presentation of endogenous antigens by group 2 innate lymphoid cells.

PubMed

Hardman, Clare S; Chen, Yi-Ling; Salimi, Maryam; Jarrett, Rachael; Johnson, David; Järvinen, Valtteri J; Owens, Raymond J; Repapi, Emmanouela; Cousins, David J; Barlow, Jillian L; McKenzie, Andrew N J; Ogg, Graham

2017-12-22

Group 2 innate lymphoid cells (ILC2) are effectors of barrier immunity, with roles in infection, wound healing, and allergy. A proportion of ILC2 express MHCII (major histocompatibility complex II) and are capable of presenting peptide antigens to T cells and amplifying the subsequent adaptive immune response. Recent studies have highlighted the importance of CD1a-reactive T cells in allergy and infection, activated by the presentation of endogenous neolipid antigens and bacterial components. Using a human skin challenge model, we unexpectedly show that human skin-derived ILC2 can express CD1a and are capable of presenting endogenous antigens to T cells. CD1a expression is up-regulated by TSLP (thymic stromal lymphopoietin) at levels observed in the skin of patients with atopic dermatitis, and the response is dependent on PLA2G4A. Furthermore, this pathway is used to sense Staphylococcus aureus by promoting Toll-like receptor-dependent CD1a-reactive T cell responses to endogenous ligands. These findings define a previously unrecognized role for ILC2 in lipid surveillance and identify shared pathways of CD1a- and PLA2G4A-dependent ILC2 inflammation amenable to therapeutic intervention. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

The orphan nuclear receptor RORα and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn's disease.

PubMed

Lo, Bernard C; Gold, Matthew J; Hughes, Michael R; Antignano, Frann; Valdez, Yanet; Zaph, Colby; Harder, Kenneth W; McNagny, Kelly M

2016-09-02

Fibrosis is the result of dysregulated tissue regeneration and is characterized by excessive accumulation of matrix proteins that become detrimental to tissue function. In Crohn's disease, this manifests itself as recurrent gastrointestinal strictures for which there is no effective therapy beyond surgical intervention. Using a model of infection-induced chronic gut inflammation, we show that Rora -deficient mice are protected from fibrosis; infected intestinal tissues display diminished pathology, attenuated collagen deposition, and reduced fibroblast accumulation. Although Rora is best known for its role in group 2 innate lymphoid cell (ILC2) development, we find that Salmonella -induced fibrosis is independent of eosinophils, signal transducer and activator of transcription 6 signaling, and T helper 2 cytokine production, arguing that this process is largely ILC2-independent. Instead, we observe reduced levels of ILC3- and T cell-derived interleukin-17A (IL-17A) and IL-22 in infected gut tissues. Furthermore, using Rora sg/sg / Rag1 -/- bone marrow chimeric mice, we show that restoring ILC function is sufficient to reestablish IL-17A and IL-22 production and a profibrotic phenotype. Our results show that RORα (retinoic acid receptor-related orphan receptor α)-dependent ILC3 functions are pivotal in mediating gut fibrosis, and they offer an avenue for therapeutic intervention in Crohn's-like diseases. Copyright © 2016, American Association for the Advancement of Science.

Measuring the Magnetic Center Behavior of an ILC Superconducting Quadrupole Prototype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spencer, Cherrill M.; Adolphsen, Chris; Berndt, Martin

2011-02-07

The main linacs of the proposed International Linear Collider (ILC) consist of superconducting cavities operated at 2K. The accelerating cavities are contained in a contiguous series of cryogenic modules that also house the main linac quadrupoles, thus the quadrupoles also need to be superconducting. In an early ILC design, these magnets are about 0.6 m long, have cos (2{theta}) coils, and operate at constant field gradients up to 60 T/m. In order to preserve the small beam emittances in the ILC linacs, the e+ and e- beams need to traverse the quadrupoles near their magnetic centers. A quadrupole shunting techniquemore » is used to measure the quadrupole alignment with the beams; this process requires the magnetic centers move by no more than about 5 micrometers when their strength is changed. To determine if such tight stability is achievable in a superconducting quadrupole, we at SLAC measured the magnetic center motions in a prototype ILC quadrupole built at CIEMAT in Spain. A rotating coil technique was used with a better than 0.1 micrometer precision in the relative field center position, and less than a 2 micrometer systematic error over 30 minutes. This paper describes the warm-bore cryomodule that houses the quadrupole in its Helium vessel, the magnetic center measurement system, the measured center data and strength and harmonics magnetic data.« less

Developmental acquisition of regulomes underlies innate lymphoid cell functionality

USDA-ARS?s Scientific Manuscript database

Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis, and they mirror adaptive CD4+ T helper (Th) cell subtypes in both usages of effector molecules and ·transcription factors. To better understand ILC subsets and their relationship with Th cells, we measur...

The Research Exchange, 2001.

ERIC Educational Resources Information Center

Research Exchange, 2001

2001-01-01

These three newsletters focus on advances and challenges in disability research. The first issue focuses on the results of a survey that investigated how many consumers with disabilities had a computer available in their home and their Internet use. The study involved administrators of Independent Living Centers (ILC) and ILC consumers. Findings…

Status Of the ILC Main Linac Design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saini, Arun; Kapin, Valery; Solyak, Nikolay

2017-05-01

International Linear collider (ILC) is a proposed accelerator facility which is primarily based on two 11-km long superconducting main linacs. In this paper we present recent updates on the main linac design and discuss changes made in order to meet specification outlined in the technical design report (TDR).

48 CFR 28.204-3 - Irrevocable letter of credit (ILC).

Code of Federal Regulations, 2010 CFR

2010-10-01

... no document other than a written demand and the ILC (and letter of confirmation, if any), expire only... by another acceptable financial institution that had letter of credit business of at least $25... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Irrevocable letter of...

Probing 6D operators at future e - e + colliders

NASA Astrophysics Data System (ADS)

Chiu, Wen Han; Leung, Sze Ching; Liu, Tao; Lyu, Kun-Feng; Wang, Lian-Tao

2018-05-01

We explore the sensitivities at future e - e + colliders to probe a set of six-dimensional operators which can modify the SM predictions on Higgs physics and electroweak precision measurements. We consider the case in which the operators are turned on simultaneously. Such an analysis yields a "conservative" interpretation on the collider sensitivities, complementary to the "optimistic" scenario where the operators are individually probed. After a detail analysis at CEPC in both "conservative" and "optimistic" scenarios, we also considered the sensitivities for FCC-ee and ILC. As an illustration of the potential of constraining new physics models, we applied sensitivity analysis to two benchmarks: holographic composite Higgs model and littlest Higgs model.

Discriminating leptonic Yukawa interactions with doubly charged scalar at the ILC

NASA Astrophysics Data System (ADS)

Nomura, Takaaki; Okada, Hiroshi; Yokoya, Hiroshi

2018-04-01

We explore discrimination of two types of leptonic Yukawa interactions associated with Higgs triplet, LbarLc ΔLL, and with SU (2) singlet doubly charged scalar, ebarRc k++eR. These interactions can be distinguished by measuring the effects of doubly charged scalar boson exchange in the e+e- →ℓ+ℓ- processes at polarized electron-positron colliders. We study a forward-backward asymmetry of scattering angular distribution to estimate the sensitivity for these effects at the ILC. In addition, we investigate prospects of upper bounds on the Yukawa couplings by combining the constraints of lepton flavor violation processes and the e+e- →ℓ+ℓ- processes at the LEP and the ILC.

Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? Vaccination Strategies Based on NK Cell and ILC Memory.

PubMed

Cooper, Megan A; Fehniger, Todd A; Colonna, Marco

2017-12-18

Studies over the last decade have decisively shown that innate immune natural killer (NK) cells exhibit enhanced long-lasting functional responses following a single activation event. With the increased recognition of memory and memory-like properties of NK cells, questions have arisen with regard to their ability to effectively mediate vaccination responses in humans. Moreover, recently discovered innate lymphoid cells (ILCs) could also potentially exhibit memory-like functions. Here, we review different forms of NK cell memory, and speculate about the ability of these cells and ILCs to meaningfully contribute to vaccination responses. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

CCD developments for particle colliders

NASA Astrophysics Data System (ADS)

Stefanov, Konstantin D.

2006-09-01

Charge Coupled Devices (CCDs) have been successfully used in several high-energy physics experiments over the last 20 years. Their small pixel size and excellent precision provide superb tool for studying of short-lived particles and understanding the nature at fundamental level. Over the last years the Linear Collider Flavour Identification (LCFI) collaboration has developed Column-Parallel CCDs (CPCCD) and CMOS readout chips to be used for the vertex detector at the International Linear Collider (ILC). The CPCCDs are very fast devices capable of satisfying the challenging requirements imposed by the beam structure of the superconducting accelerator. First set of prototype devices have been designed, manufactured and successfully tested, with second-generation chips on the way. Another idea for CCD-based device, the In-situ Storage Image Sensor (ISIS) is also under development and the first prototype is in production.

The International Linear Collider Technical Design Report - Volume 3.II: Accelerator Baseline Design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adolphsen, Chris

2013-06-26

The International Linear Collider Technical Design Report (TDR) describes in four volumes the physics case and the design of a 500 GeV centre-of-mass energy linear electron-positron collider based on superconducting radio-frequency technology using Niobium cavities as the accelerating structures. The accelerator can be extended to 1 TeV and also run as a Higgs factory at around 250 GeV and on the Z0 pole. A comprehensive value estimate of the accelerator is give, together with associated uncertainties. It is shown that no significant technical issues remain to be solved. Once a site is selected and the necessary site-dependent engineering is carriedmore » out, construction can begin immediately. The TDR also gives baseline documentation for two high-performance detectors that can share the ILC luminosity by being moved into and out of the beam line in a "push-pull" configuration. These detectors, ILD and SiD, are described in detail. They form the basis for a world-class experimental programme that promises to increase significantly our understanding of the fundamental processes that govern the evolution of the Universe.« less

The International Linear Collider Technical Design Report - Volume 1: Executive Summary

DOE Office of Scientific and Technical Information (OSTI.GOV)

Behnke, Ties; Brau, James E.; Foster, Brian

2013-06-26

The International Linear Collider Technical Design Report (TDR) describes in four volumes the physics case and the design of a 500 GeV centre-of-mass energy linear electron-positron collider based on superconducting radio-frequency technology using Niobium cavities as the accelerating structures. The accelerator can be extended to 1 TeV and also run as a Higgs factory at around 250 GeV and on the Z0 pole. A comprehensive value estimate of the accelerator is give, together with associated uncertainties. It is shown that no significant technical issues remain to be solved. Once a site is selected and the necessary site-dependent engineering is carriedmore » out, construction can begin immediately. The TDR also gives baseline documentation for two high-performance detectors that can share the ILC luminosity by being moved into and out of the beam line in a "push-pull" configuration. These detectors, ILD and SiD, are described in detail. They form the basis for a world-class experimental programme that promises to increase significantly our understanding of the fundamental processes that govern the evolution of the Universe.« less

The International Linear Collider Technical Design Report - Volume 3.I: Accelerator \\& in the Technical Design Phase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adolphsen, Chris

2013-06-26

The International Linear Collider Technical Design Report (TDR) describes in four volumes the physics case and the design of a 500 GeV centre-of-mass energy linear electron-positron collider based on superconducting radio-frequency technology using Niobium cavities as the accelerating structures. The accelerator can be extended to 1 TeV and also run as a Higgs factory at around 250 GeV and on the Z0 pole. A comprehensive value estimate of the accelerator is give, together with associated uncertainties. It is shown that no significant technical issues remain to be solved. Once a site is selected and the necessary site-dependent engineering is carriedmore » out, construction can begin immediately. The TDR also gives baseline documentation for two high-performance detectors that can share the ILC luminosity by being moved into and out of the beam line in a "push-pull" configuration. These detectors, ILD and SiD, are described in detail. They form the basis for a world-class experimental programme that promises to increase significantly our understanding of the fundamental processes that govern the evolution of the Universe.« less

Construction and beam-tests of silicon-tungsten prototype modules for the CMS High Granularity Calorimeter for HL-LHC

NASA Astrophysics Data System (ADS)

Quast, Thorben

2018-02-01

As part of its HL-LHC upgrade program, CMS is developing a High Granularity Calorimeter (HGCAL) to replace the existing endcap calorimeters. The HGCAL will be realised as a sampling calorimeter, including an electromagnetic compartment comprising 28 layers of silicon pad detectors with pad areas of 0.5-1.0 cm2 interspersed with absorbers. Prototype modules, based on 6-inch hexagonal silicon pad sensors with 128 channels, have been constructed and include many of the features required for this challenging detector. In 2016, beam tests of sampling configurations made from these modules have been conducted both at FNAL and at CERN using the Skiroc2 front-end ASIC (designed by the CALICE collaboration for ILC). In 2017, the setup has been extended with CALICE's AHCAL prototype, a scinitillator based sampling calorimeter, and it was further tested in dedicated beam tests at CERN. There, the new Skiroc2-CMS front-end ASIC was used for the first time. We highlight final results from our studies in 2016, including position resolution as well as precision timing-measurements. Furthermore, the extended setup in 2017 is discussed and first results from beam tests with electrons and pions are shown.

Construction and first beam-tests of silicon-tungsten prototype modules for the CMS High Granularity Calorimeter for HL-LHC

NASA Astrophysics Data System (ADS)

Jain, S.

2017-03-01

The High Granularity Calorimeter (HGCAL) is the technology choice of the CMS collaboration for the endcap calorimetry upgrade planned to cope with the harsh radiation and pileup environment at the High Luminosity-LHC . The HGCAL is realized as a sampling calorimeter, including an electromagnetic compartment comprising 28 layers of silicon pad detectors with pad areas of 0.5-01. cm2 interspersed with absorbers made from tungsten and copper to form a highly compact and granular device. Prototype modules, based on hexagonal silicon pad sensors, with 128 channels, have been constructed and tested in beams at FNAL and at CERN. The modules include many of the features required for this challenging detector, including a PCB glued directly to the sensor, using through-hole wire-bonding for signal readout and 5 mm spacing between layers—including the front-end electronics and all services. Tests in 2016 have used an existing front-end chip —Skiroc2 (designed for the CALICE experiment for ILC). We present results from first tests of these modules both in the laboratory and with beams of electrons, pions and protons, including noise performance, calibration with mips and electron signals.

The Next Linear Collider Program

Science.gov Websites

posted to the new SLAC ILC web site http://www-project.slac.stanford.edu/ilc/. Also, see the new site for . The NLC web site will remain accessible as an archive of important work done on the many systems | Navbar || || Documentation | NLC Playpen | Web Comments & Suggestions | Desktop Trouble Call | LC

The E-Id Protein Axis Specifies Adaptive Lymphoid Cell Identity and Suppresses Thymic Innate Lymphoid Cell Development.

PubMed

Miyazaki, Masaki; Miyazaki, Kazuko; Chen, Kenian; Jin, Yi; Turner, Jacob; Moore, Amanda J; Saito, Rintaro; Yoshida, Kenichi; Ogawa, Seishi; Rodewald, Hans-Reimer; Lin, Yin C; Kawamoto, Hiroshi; Murre, Cornelis

2017-05-16

Innate and adaptive lymphoid development is orchestrated by the activities of E proteins and their antagonist Id proteins, but how these factors regulate early T cell progenitor (ETP) and innate lymphoid cell (ILC) development remains unclear. Using multiple genetic strategies, we demonstrated that E proteins E2A and HEB acted in synergy in the thymus to establish T cell identity and to suppress the aberrant development of ILCs, including ILC2s and lymphoid-tissue-inducer-like cells. E2A and HEB orchestrated T cell fate and suppressed the ILC transcription signature by activating the expression of genes associated with Notch receptors, T cell receptor (TCR) assembly, and TCR-mediated signaling. E2A and HEB acted in ETPs to establish and maintain a T-cell-lineage-specific enhancer repertoire, including regulatory elements associated with the Notch1, Rag1, and Rag2 loci. On the basis of these and previous observations, we propose that the E-Id protein axis specifies innate and adaptive lymphoid cell fate. Copyright © 2017 Elsevier Inc. All rights reserved.

Integrated molecular analysis of Tamoxifen-resistant invasive lobular breast cancer cells identifies MAPK and GRM/mGluR signaling as therapeutic vulnerabilities.

PubMed

Stires, Hillary; Heckler, Mary M; Fu, Xiaoyong; Li, Zhao; Grasso, Catherine S; Quist, Michael J; Lewis, Joseph A; Klimach, Uwe; Zwart, Alan; Mahajan, Akanksha; Győrffy, Balázs; Cavalli, Luciane R; Riggins, Rebecca B

2018-08-15

Invasive lobular breast cancer (ILC) is an understudied malignancy with distinct clinical, pathological, and molecular features that distinguish it from the more common invasive ductal carcinoma (IDC). Mounting evidence suggests that estrogen receptor-alpha positive (ER+) ILC has a poor response to Tamoxifen (TAM), but the mechanistic drivers of this are undefined. In the current work, we comprehensively characterize the SUM44/LCCTam ILC cell model system through integrated analysis of gene expression, copy number, and mutation, with the goal of identifying actionable alterations relevant to clinical ILC that can be co-targeted along with ER to improve treatment outcomes. We show that TAM has several distinct effects on the transcriptome of LCCTam cells, that this resistant cell model has acquired copy number alterations and mutations that impinge on MAPK and metabotropic glutamate receptor (GRM/mGluR) signaling networks, and that pharmacological inhibition of either improves or restores the growth-inhibitory actions of endocrine therapy. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease.

PubMed

Dudakov, Jarrod A; Mertelsmann, Anna M; O'Connor, Margaret H; Jenq, Robert R; Velardi, Enrico; Young, Lauren F; Smith, Odette M; Boyd, Richard L; van den Brink, Marcel R M; Hanash, Alan M

2017-08-17

Graft-versus-host disease (GVHD) and posttransplant immunodeficiency are frequently related complications of allogeneic hematopoietic transplantation. Alloreactive donor T cells can damage thymic epithelium, thus limiting new T-cell development. Although the thymus has a remarkable capacity to regenerate after injury, endogenous thymic regeneration is impaired in GVHD. The mechanisms leading to this regenerative failure are largely unknown. Here we demonstrate in experimental mouse models that GVHD results in depletion of intrathymic group 3 innate lymphoid cells (ILC3s) necessary for thymic regeneration. Loss of thymic ILC3s resulted in deficiency of intrathymic interleukin-22 (IL-22) compared with transplant recipients without GVHD, thereby inhibiting IL-22-mediated protection of thymic epithelial cells (TECs) and impairing recovery of thymopoiesis. Conversely, abrogating IL-21 receptor signaling in donor T cells and inhibiting the elimination of thymic ILCs improved thymopoiesis in an IL-22-dependent fashion. We found that the thymopoietic impairment in GVHD associated with loss of ILCs could be improved by restoration of IL-22 signaling. Despite uninhibited alloreactivity, exogenous IL-22 administration posttransplant resulted in increased recovery of thymopoiesis and development of new thymus-derived peripheral T cells. Our study highlights the role of innate immune function in thymic regeneration and restoration of adaptive immunity posttransplant. Manipulation of the ILC-IL-22-TEC axis may be useful for augmenting immune reconstitution after clinical hematopoietic transplantation and other settings of T-cell deficiency. © 2017 by The American Society of Hematology.

Fast calculation of the `ILC norm' in iterative learning control

NASA Astrophysics Data System (ADS)

Rice, Justin K.; van Wingerden, Jan-Willem

2013-06-01

In this paper, we discuss and demonstrate a method for the exploitation of matrix structure in computations for iterative learning control (ILC). In Barton, Bristow, and Alleyne [International Journal of Control, 83(2), 1-8 (2010)], a special insight into the structure of the lifted convolution matrices involved in ILC is used along with a modified Lanczos method to achieve very fast computational bounds on the learning convergence, by calculating the 'ILC norm' in ? computational complexity. In this paper, we show how their method is equivalent to a special instance of the sequentially semi-separable (SSS) matrix arithmetic, and thus can be extended to many other computations in ILC, and specialised in some cases to even faster methods. Our SSS-based methodology will be demonstrated on two examples: a linear time-varying example resulting in the same ? complexity as in Barton et al., and a linear time-invariant example where our approach reduces the computational complexity to ?, thus decreasing the computation time, for an example, from the literature by a factor of almost 100. This improvement is achieved by transforming the norm computation via a linear matrix inequality into a check of positive definiteness - which allows us to further exploit the almost-Toeplitz properties of the matrix, and additionally provides explicit upper and lower bounds on the norm of the matrix, instead of the indirect Ritz estimate. These methods are now implemented in a MATLAB toolbox, freely available on the Internet.

IL-33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells.

PubMed

Hashiguchi, Masaaki; Kashiwakura, Yuji; Kojima, Hidefumi; Kobayashi, Ayano; Kanno, Yumiko; Kobata, Tetsuji

2015-03-01

Eosinophils are multifunctional leukocytes involved in allergic reactions as well as adipose tissue regulation. IL-5 is required for eosinophil survival; however, the in vivo mechanisms of eosinophil regulation are not fully understood. A tg mouse model with il5 promoter-driven EGFP expression was established for detecting the IL-5-producing cells in vivo. Il5-egfp tg mice expressed high levels of EGFP in gonadal adipose tissue (GAT) cells. EGFP(+) cells in GAT were mainly group 2 innate lymphoid cells (ILCs). IL-33 preferentially expanded EGFP(+) cells and eosinophils in GAT in vivo. EGFP(+) ILCs were found to upregulate prg2 mRNA expression in GAT eosinophils. These results demonstrate that ILCs activate eosinophils in GAT. The blockage of IL-33Rα, on the other hand, did not impair EGFP(+) ILC numbers but did impair eosinophil numbers in vivo. GAT eosinophils expressed IL-33Rα and IL-33 expanded eosinophil numbers in CD90(+) cell-depleted mice. IL-33 was further observed to induce the expression of retnla and epx mRNA in eosinophils. These findings demonstrate that IL-33 directly activates eosinophils in GAT, and together with our other findings described above, our findings show that IL-33 has dual pathways via which it activates eosinophils in vivo: a direct activation pathway and a group 2 ILC-mediated pathway. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Influence of semi-quantitative oestrogen receptor expression on adjuvant endocrine therapy efficacy in ductal and lobular breast cancer - a TEAM study analysis.

PubMed

van de Water, Willemien; Fontein, Duveken B Y; van Nes, Johanna G H; Bartlett, John M S; Hille, Elysée T M; Putter, Hein; Robson, Tammy; Liefers, Gerrit-Jan; Roumen, Rudi M H; Seynaeve, Caroline; Dirix, Luc Y; Paridaens, Robert; Kranenbarg, Elma Meershoek-Klein; Nortier, Johan W R; van de Velde, Cornelis J H

2013-01-01

Multiple studies suggest better efficacy of chemotherapy in invasive ductal breast carcinomas (IDC) than invasive lobular breast carcinomas (ILC). However, data on efficacy of adjuvant endocrine therapy regimens and histological subtypes are sparse. This study assessed endocrine therapy efficacy in IDC and ILC. The influence of semi-quantitative oestrogen receptor (ER) expression by Allred score was also investigated. Dutch and Belgian patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were randomized to exemestane (25mg daily) alone or following tamoxifen (20mg daily) for 5 years. Inclusion was restricted to IDC and ILC patients. Histological subtype was assessed locally; ER expression was centrally reviewed according to Allred score (ER-poor (<7; n=235); ER-rich (7; n=1789)). Primary end-point was relapse-free survival (RFS), which was the time from randomization to disease relapse. Overall, 2140 (82%) IDC and 463 (18%) ILC patients were included. RFS was similar for both endocrine treatment regimens in IDC (hazard ratio (HR) for exemestane was 0.83 (95%confidence interval (CI) 0.67-1.03)), and ILC (HR 0.69 (95%CI 0.45-1.06)). Irrespective of histological subtype, patients with ER-rich Allred scores allocated to exemestane alone had an improved RFS (multivariable HR 0.71 (95%CI 0.56-0.89)). In contrast, patients with ER-poor Allred scores allocated to exemestane had a worse RFS (multivariable HR 2.33 (95%CI 1.32-4.11)). Significant effect modification by ER-Allred score was confirmed (multivariable p=0.003). Efficacy of endocrine therapy regimens was similar for IDC and ILC. However, ER-rich patients showed superior efficacy to upfront exemestane, while ER-poor patients had better outcomes with sequential therapy, irrespective of histological subtype, emphasising the relevance of quantification of ER expression. Copyright © 2012 Elsevier Ltd. All rights reserved.

Distribution of Interleukin-22-secreting Immune Cells in Conjunctival Associated Lymphoid Tissue.

PubMed

Yoon, Chang Ho; Lee, Daeseung; Jeong, Hyun Jeong; Ryu, Jin Suk; Kim, Mee Kum

2018-04-01

Interleukin (IL)-22 is a cytokine involved in epithelial cell regeneration. Currently, no research studies have analyzed the distribution of the three distinct IL-22-secreting cell populations in human or mouse conjunctiva. This study investigated the distribution of the three main populations of IL-22-secreting immune cells, αβ Th cells, γδ T cells, or innate cells (innate lymphoid cells [ILCs] or natural killer cells), in conjunctival associated lymphoid tissues (CALTs) in human and mouse models. We collected discarded cadaveric bulbar conjunctival tissue specimens after preservation of the corneo-limbal tissue for keratoplasty from four enucleated eyes of the domestic donor. The bulbar conjunctiva tissue, including the cornea from normal (n = 27) or abraded (n = 4) B6 mice, were excised and pooled in RPMI 1640 media. After the lymphoid cells were gated in forward and side scattering, the αβ Th cells, γδ T cells, or innate lymphoid cells were positively or negatively gated using anti-CD3, anti-γδ TCR, and anti-IL-22 antibodies, with a FACSCanto flow cytometer. In normal human conjunctiva, the percentage and number of cells were highest in αβ Th cells, followed by γδ T cells and CD3- γδ TCR- IL-22+ innate cells (presumed ILCs, pILCs) (Kruskal-Wallis test, p = 0.012). In normal mice keratoconjunctiva, the percentage and total number were highest in γδ T cells, followed by αβ Th cells and pILCs (Kruskal-Wallis test, p = 0.0004); in corneal abraded mice, the population of αβ Th cells and pILCs tended to increase. This study suggests that three distinctive populations of IL-22-secreting immune cells are present in CALTs of both humans and mice, and the proportions of IL-22+αβ Th cells, γδ T cells, and pILCs in CALTs in humans might be differently distributed from those in normal mice. © 2018 The Korean Ophthalmological Society.

The Independent Living Movement in Asia: Solidarity from Japan

ERIC Educational Resources Information Center

Hayashi, Reiko; Okuhira, Masako

2008-01-01

Independent living movements of disabled people are emerging in Asian countries, supported by independent living centres (ILCs) in Japan. A study was conducted in Japan to explore the impact of the training program offered by Japanese ILCs to disabled people from other Asian countries. A sample of 35 people was selected by a snowballing method.…

Lymphoid microenvironments and innate lymphoid cells in the gut.

PubMed

Pearson, Claire; Uhlig, Holm H; Powrie, Fiona

2012-06-01

Gut-associated lymphoid tissue (GALT) is a sensor region for luminal content and plays an important role in lymphoid maturation, activation and differentiation. It comprises isolated and aggregated lymphoid follicles, cryptopatches (CPs) and tertiary lymphoid tissue. Innate lymphoid cells (ILCs) play a central role within GALT. Prenatal GALT development is dependent on ILC lymphoid-inducer function. Postnatally, these cells rapidly respond to commensal and pathogenic intestinal bacteria, parasites and food components by polarized cytokine production [such as interleukin (IL)-22, IL-17 or IL-13] and further contribute to GALT formation and function. Here, we discuss how ILCs shape lymphoid intestinal microenvironments and act as amplifier cells for innate and adaptive immune responses. Copyright © 2012. Published by Elsevier Ltd.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Woohyun; Katipamula, Srinivas; Lutes, Robert G.

This report describes how the intelligent load control (ILC) algorithm can be implemented to achieve peak demand reduction while minimizing impacts on occupant comfort. The algorithm was designed to minimize the additional sensors and minimum configuration requirements to enable a scalable and cost-effective implementation for both large and small-/medium-sized commercial buildings. The ILC algorithm uses an analytic hierarchy process (AHP) to dynamically prioritize the available curtailable loads based on both quantitative (deviation of zone conditions from set point) and qualitative rules (types of zone). Although the ILC algorithm described in this report was highly tailored to work with rooftop units,more » it can be generalized for application to other building loads such as variable-air-volume (VAV) boxes and lighting systems.« less

Higgs Particle: The Origin of Mass

NASA Astrophysics Data System (ADS)

Okada, Yasuhiro

2007-11-01

The Higgs particle is a new elementary particle predicted in the Standard Model of the elementary particle physics. It plays a special role in the theory of mass generation of quarks, leptons, and gauge bosons. In this article, theoretical issues on the Higgs mechanism are first discussed, and then experimental prospects on the Higgs particle study at the future collider experiments, LHC and ILC, are reviewed. The Higgs coupling determination is an essential step to establish the mass generation mechanism, which could lead to a deeper understanding of particle physics.

Contributions of Interleukin‐33 and TSLP in a papain‐soaked contact lens‐induced mouse conjunctival inflammation model

PubMed Central

Sugita, Jobu; Asada, Yosuke; Ishida, Waka; Iwamoto, Satoshi; Sudo, Katsuko; Suto, Hajime; Matsunaga, Toru; Fukuda, Ken; Fukushima, Atsuki; Yokoi, Norihiko; Ohno, Tatsukuni; Azuma, Miyuki; Ebihara, Nobuyuki; Saito, Hirohisa; Kubo, Masato; Nakae, Susumu

2017-01-01

Abstract Introduction Pathological changes of severe chronic allergic conjunctivitis are driven not only via acquired immunity but also via innate immunity. Type 2 immune response‐initiating cytokines may play some roles as innate immunity‐dependent components of the ocular surface inflammation. To investigate the involvement of type 2 immune response‐initiating cytokines in innate immunity‐dependent, papain‐induced conjunctival inflammation model using IL‐25‐, IL‐33‐, and TSLP receptor (TSLPR)‐knockout (KO) mice with reference to basophils and ILC2. Methods Papain‐soaked contact lenses (papain‐CLs) were installed in the conjunctival sacs of C57BL/6‐IL‐25 KO, IL‐33 KO, TSLPR KO, Rag2 KO, Bas‐TRECK, and wild‐type mice and their eyes were sampled at day 5. The eosinophil and basophil infiltration in papain‐CL model was evaluated histologically and cytokine expression was examined. To clarify the roles of basophils and ILC2, basophil/ILC2‐depletion experiments were carried out. Results Papain‐induced conjunctival inflammation exhibited eosinophil infiltration and upregulation of Th2 cytokine expression. Reduction of eosinophil and basophil infiltration and attenuated Th2 cytokine expression were observed in the papain‐CL model using IL‐33 KO and TSLPR KO mice. Depletion of basophils or ILC2s in the conjunctivae of the papain‐CL model reduced eosinophil infiltration. Conclusions Innate immunity‐driven type 2 immune responses of the ocular surface are dependent on IL‐33, TSLP, basophils, and ILC2. These components may be possible therapeutic targets for refractory allergic keratoconjunctivitis. PMID:28730605

The Next Linear Collider Program

Science.gov Websites

posted to the new SLAC ILC web site http://www-project.slac.stanford.edu/ilc/. Also, see the new site for . The NLC web site will remain accessible as an archive of important work done on the many systems to be complete by the end of the calendar year. NLC Website Search: Entire SLAC Web | Help Phonebook

Flavorful Z‧ signatures at LHC and ILC

NASA Astrophysics Data System (ADS)

Chen, Shao-Long; Okada, Nobuchika

2008-10-01

There are lots of new physics models which predict an extra neutral gauge boson, referred as Z‧-boson. In a certain class of these new physics models, the Z‧-boson has flavor-dependent couplings with the fermions in the Standard Model (SM). Based on a simple model in which couplings of the SM fermions in the third generation with the Z‧-boson are different from those of the corresponding fermions in the first two generations, we study the signatures of Z‧-boson at the Large Hadron Collider (LHC) and the International Linear Collider (ILC). We show that at the LHC, the Z‧-boson with mass around 1 TeV can be produced through the Drell-Yan processes and its dilepton decay modes provide us clean signatures not only for the resonant production of Z‧-boson but also for flavor-dependences of the production cross sections. We also study fermion pair productions at the ILC involving the virtual Z‧-boson exchange. Even though the center-of-energy of the ILC is much lower than a Z‧-boson mass, the angular distributions and the forward-backward asymmetries of fermion pair productions show not only sizable deviations from the SM predictions but also significant flavor-dependences.

Qualification of the Second Batch Production 9-Cell Cavities Manufactured by AES and Validation of the First US Industrial Cavity Vendor for ILC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geng, R. L.; Golden, B. A.; Kushnick, P.

2011-07-01

One of the major goals of ILC SRF cavity R&D is to develop industrial capabilities of cavity manufacture and processing in all three regions. In the past several years, Jefferson Lab, in collaboration with Fermi National Accelerator Laboratory, has processed and tested all the 9-cell cavities of the first batch (4 cavities) and second batch (6 cavities) production cavities manufactured by Advanced Energy Systems Inc. (AES). Over the course, close information feedback was maintained, resulting in changes in fabrication and processing procedures. A light buffered chemical polishing was introduced, removing the weld splatters that could not be effectively removed bymore » heavy EP alone. An 800 Celsius 2 hour vacuum furnace heat treatment procedure replaced the original 600 Celsius 10 hour procedure. Four out of the six 9-cell cavities of the second production bath achieved a gradient of 36-41 MV/m at a Q0 of more than 8E9 at 35 MV/m. This result validated AES as the first ''ILC certified'' industrial vendor in the US for ILC cavity manufacture.« less

Robust design of feedback feed-forward iterative learning control based on 2D system theory for linear uncertain systems

NASA Astrophysics Data System (ADS)

Li, Zhifu; Hu, Yueming; Li, Di

2016-08-01

For a class of linear discrete-time uncertain systems, a feedback feed-forward iterative learning control (ILC) scheme is proposed, which is comprised of an iterative learning controller and two current iteration feedback controllers. The iterative learning controller is used to improve the performance along the iteration direction and the feedback controllers are used to improve the performance along the time direction. First of all, the uncertain feedback feed-forward ILC system is presented by an uncertain two-dimensional Roesser model system. Then, two robust control schemes are proposed. One can ensure that the feedback feed-forward ILC system is bounded-input bounded-output stable along time direction, and the other can ensure that the feedback feed-forward ILC system is asymptotically stable along time direction. Both schemes can guarantee the system is robust monotonically convergent along the iteration direction. Third, the robust convergent sufficient conditions are given, which contains a linear matrix inequality (LMI). Moreover, the LMI can be used to determine the gain matrix of the feedback feed-forward iterative learning controller. Finally, the simulation results are presented to demonstrate the effectiveness of the proposed schemes.

2017 Topical Workshop on Electronics for Particle Physics

NASA Astrophysics Data System (ADS)

2017-09-01

The workshop will cover all aspects of electronics for particle physics experiments, and accelerator instrumentation of general interest to users. LHC experiments (and their operational experience) will remain a focus of the meeting but a strong emphasis on R&D for future experimentation will be maintained, such as SLHC, CLIC, ILC, neutrino facilities as well as other particle and astroparticle physics experiments. The purpose of the workshop is: To present results and original concepts for electronic research and development relevant to experiments as well as accelerator and beam instrumentation at future facilities; To review the status of electronics for the LHC experiments; To identify and encourage common efforts for the development of electronics; To promote information exchange and collaboration in the relevant engineering and physics communities.

Control of Innate and Adaptive Lymphocytes by the RAR-Retinoic Acid Axis.

PubMed

Kim, Chang H

2018-02-01

Lymphocytes, such as T cells, B cells, and innate lymphoid cells (ILCs), play central roles in regulating immune responses. Retinoic acids (RAs) are vitamin A metabolites, produced and metabolized by certain tissue cells and myeloid cells in a tissue-specific manner. It has been established that RAs induce gut-homing receptors on T cells, B cells, and ILCs. A mounting body of evidence indicates that RAs exert far-reaching effects on functional differentiation and fate of these lymphocytes. For example, RAs promote effector T cell maintenance, generation of induced gut-homing regulatory and effector T cell subsets, antibody production by B cells, and functional maturation of ILCs. Key functions of RAs in regulating major groups of innate and adaptive lymphocytes are highlighted in this article.

Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis.

PubMed

Mortha, Arthur; Chudnovskiy, Aleksey; Hashimoto, Daigo; Bogunovic, Milena; Spencer, Sean P; Belkaid, Yasmine; Merad, Miriam

2014-03-28

The intestinal microbiota and tissue-resident myeloid cells promote immune responses that maintain intestinal homeostasis in the host. However, the cellular cues that translate microbial signals into intestinal homeostasis remain unclear. Here, we show that deficient granulocyte-macrophage colony-stimulating factor (GM-CSF) production altered mononuclear phagocyte effector functions and led to reduced regulatory T cell (T(reg)) numbers and impaired oral tolerance. We observed that RORγt(+) innate lymphoid cells (ILCs) are the primary source of GM-CSF in the gut and that ILC-driven GM-CSF production was dependent on the ability of macrophages to sense microbial signals and produce interleukin-1β. Our findings reveal that commensal microbes promote a crosstalk between innate myeloid and lymphoid cells that leads to immune homeostasis in the intestine.

Innate Lymphoid Cells: A Promising New Regulator in Fibrotic Diseases.

PubMed

Zhang, Yi; Tang, Jun; Tian, Zhiqiang; van Velkinburgh, Jennifer C; Song, Jianxun; Wu, Yuzhang; Ni, Bing

2016-09-02

Fibrosis is a consequence of chronic inflammation and the persistent accumulation of extracellular matrix, for which the cycle of tissue injury and repair becomes a predominant feature. Both the innate and adaptive immune systems play key roles in the progress of fibrosis. The recently identified subsets of innate lymphoid cells (ILCs), which are mainly localize to epithelial surfaces, have been characterized as regulators of chronic inflammation and tissue remodeling, representing a functional bridge between the innate and adaptive immunity. Moreover, recent research has implicated ILCs as potential contributing factors to several kinds of fibrosis diseases, such as hepatic fibrosis and pulmonary fibrosis. Here, we will summarize and discuss the key roles of ILCs and their related factors in fibrotic diseases and their potential for translation to the clinic.

Exploration of very high gradient cavities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eremeev, Grigory

2011-07-01

Several of the 9-cell ILC cavities processed at Jlab within ongoing ILC R&D program have shown interesting behavior at high fields, such as mode mixing and sudden field emission turn-on during quench. Equipped with thermometry and oscillating superleak transducer (OST) system for quench detection, we couple our RF measurements with local dissipation measurements. In this contribution we report on our findings with high gradient SRF cavities.

Biometric analysis of pigment dispersion syndrome using anterior segment optical coherence tomography.

PubMed

Aptel, Florent; Beccat, Sylvain; Fortoul, Vincent; Denis, Philippe

2011-08-01

To compare anterior chamber volume (ACV), iris volume, and iridolenticular contact (ILC) area before and after laser peripheral iridotomy (LPI) in eyes with pigment dispersion syndrome (PDS) using anterior segment optical coherence tomography (AS OCT) and image processing software. Cross-sectional study. Eighteen eyes of 18 patients with PDS; 30 eyes of 30 controls matched for age, gender, and refraction. Anterior segment OCT imaging was performed in all eyes before LPI and 1, 4, and 12 weeks after LPI. At each visit, 12 cross-sectional images of the AS were taken: 4 in bright conditions with accommodation (accommodation), 4 in bright conditions without accommodation (physiological miosis), and 4 under dark conditions (physiologic mydriasis). Biometric parameters were estimated using AS OCT radial sections and customized image-processing software. Anterior chamber volume, iris volume-to-length ratio, ILC area, AS OCT anterior chamber depth, and A-scan ultrasonography axial length. Before LPI, PDS eyes had a significantly greater ACV and ILC area than control eyes (P<0.01) and a significantly smaller iris volume-to-length ratio than the controls (P<0.05). After LPI, ACV and ILC area decreased significantly in PDS eyes, but iris volume-to-length ratio increased significantly (P<0.02) and was not significantly different from that of controls. These biometric changes were stable over time. Iris volume-to-length ratio decreased significantly from accommodation to mydriasis and from miosis to mydriasis, both in PDS and control eyes (P<0.01). In PDS eyes, ILC area decreased significantly from accommodation to mydriasis, both before and after LPI (P<0.01). On multivariate analysis, greater anterior chamber (AC) volume (P<0.02) and larger AC depth (P<0.05) before LPI were significant predictors of a larger ILC area. Pigment dispersion syndrome eyes do not have an iris that is abnormally large, relative to the AS size, but have a weakly resistant iris that is stretched and pushed against the lens when there is a pressure difference across the iris. The author(s) have no proprietary or commercial interest in any materials discussed in this article. Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Expansion of inflammatory innate lymphoid cells in patients with common variable immune deficiency.

PubMed

Cols, Montserrat; Rahman, Adeeb; Maglione, Paul J; Garcia-Carmona, Yolanda; Simchoni, Noa; Ko, Huai-Bin M; Radigan, Lin; Cerutti, Andrea; Blankenship, Derek; Pascual, Virginia; Cunningham-Rundles, Charlotte

2016-04-01

Common variable immunodeficiency (CVID) is an antibody deficiency treated with immunoglobulin; however, patients can have noninfectious inflammatory conditions that lead to heightened morbidity and mortality. Modular analyses of RNA transcripts in whole blood previously identified an upregulation of many interferon-responsive genes. In this study we sought the cell populations leading to this signature. Lymphoid cells were measured in peripheral blood of 55 patients with CVID (31 with and 24 without inflammatory/autoimmune complications) by using mass cytometry and flow cytometry. Surface markers, cytokines, and transcriptional characteristics of sorted innate lymphoid cells (ILCs) were defined by using quantitative PCR. Gastrointestinal and lung biopsy specimens of subjects with inflammatory disease were stained to seek ILCs in tissues. The linage-negative, CD127(+), CD161(+) lymphoid population containing T-box transcription factor, retinoic acid-related orphan receptor (ROR) γt, IFN-γ, IL-17A, and IL-22, all hallmarks of type 3 innate lymphoid cells, were expanded in the blood of patients with CVID with inflammatory conditions (mean, 3.7% of PBMCs). ILCs contained detectable amounts of the transcription factors inhibitor of DNA binding 2, T-box transcription factor, and RORγt and increased mRNA transcripts for IL-23 receptor (IL-23R) and IL-26, demonstrating inflammatory potential. In gastrointestinal and lung biopsy tissues of patients with CVID, numerous IFN-γ(+)RORγt(+)CD3(-) cells were identified, suggesting a role in these mucosal inflammatory states. An expansion of this highly inflammatory ILC population is a characteristic of patients with CVID with inflammatory disease; ILCs and the interferon signature are markers for the uncontrolled inflammatory state in these patients. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Functional Defects in Type 3 Innate Lymphoid Cells and Classical Monocytes in a Patient with Hyper-IgE Syndrome.

PubMed

Chang, Yuna; Kang, Sung-Yoon; Kim, Jihyun; Kang, Hye-Ryun; Kim, Hye Young

2017-10-01

Hyper-IgE syndrome (HIES) is a very rare primary immune deficiency characterized by elevated serum IgE levels, recurrent bacterial infections, chronic dermatitis, and connective tissue abnormalities. Autosomal dominant (AD) HIES involves a mutation in signal transducer and activator of transcription 3 (STAT3) that leads to an impaired T H 17 response. STAT3 signaling is also involved in the function of RORγt + type 3 innate lymphoid cells (ILC3s) and RORγt + T H 17 cells. The aim of this study was to investigate the role of innate immune cells such as innate lymphoid cells (ILCs), granulocytes, and monocytes in a patient with HIES. Peripheral blood mononuclear cells (PBMCs) from a patient with HIES and three age-matched healthy controls were obtained for the analysis of the innate and adaptive immune cells. The frequencies of ILCs in PBMCs were lower in the patient with HIES than in the controls. Moreover, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-17A produced by ILC3s in PBMCs were lower in the patient with HIES than the controls. Compared with the controls, classical monocytes (CD14 + CD16 low ), which have a high antimicrobial capability, were also lower in the patient with HIES, while non-classical monocytes (CD14 low CD16 + ) as well as intermediate monocytes (CD14 + CD16 intermediate ) were higher. Taken together, these results indicate that the impaired immune defense against pathogenic microbes in the patient with HIES might be partially explained by functional defects in ILC3s and inflammatory monocytes.

Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of Ki67 assay according to histology: prognostic relevance for resected early stage 'pure' and 'mixed' lobular breast cancer.

PubMed

Carbognin, Luisa; Sperduti, Isabella; Brunelli, Matteo; Marcolini, Lisa; Nortilli, Rolando; Pilotto, Sara; Zampiva, Ilaria; Merler, Sara; Fiorio, Elena; Filippi, Elisa; Manfrin, Erminia; Pellini, Francesca; Bonetti, Franco; Pollini, Giovanni Paolo; Tortora, Giampaolo; Bria, Emilio

2016-03-22

The aim of this analysis was to investigate the potential impact of Ki67 assay in a series of patients affected by early stage invasive lobular carcinoma (ILC) undergone surgery. Clinical-pathological data were correlated with disease-free and overall survival (DFS/OS). The maximally selected Log-Rank statistics analysis was applied to the Ki67 continuous variable to estimate appropriate cut-offs. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed to assess the interaction between 'pure' or 'mixed' histology ILC and Ki67. At a median follow-up of 67 months, 10-years DFS and OS of 405 patients were 67.8 and 79.8%, respectively. Standardized Log-Rank statistics identified 2 optimal cut-offs (6 and 21%); 10-years DFS and OS were 75.1, 66.5, and 30.2% (p = 0.01) and 84.3, 76.4 and 59% (p = 0.003), for patients with a Ki67 < 6%, between 6 and 21%, and >21%, respectively. Ki67 and lymph-node status were independent predictor for longer DFS and OS at the multivariate analysis, with radiotherapy (for DFS) and age (for OS). Ki67 highly replicated at the internal cross-validation analysis (DFS 85%, OS 100%). The STEPP analysis showed that DFS rate decreases as Ki67 increases and those patients with 'pure' ILC performed worse than 'mixed' histology. Despite the retrospective and exploratory nature of the study, Ki67 was able to significantly discriminate the prognosis of patients with ILC, and the effect was more pronounced for patients with 'pure' ILC.

Probing Higgs-radion mixing in warped models through complementary searches at the LHC and the ILC

NASA Astrophysics Data System (ADS)

Frank, Mariana; Huitu, Katri; Maitra, Ushoshi; Patra, Monalisa

2016-09-01

We consider the Higgs-radion mixing in the context of warped space extradimensional models with custodial symmetry and investigate the prospects of detecting the mixed radion. Custodial symmetries allow the Kaluza-Klein excitations to be lighter and protect Z b b ¯ to be in agreement with experimental constraints. We perform a complementary study of discovery reaches of the Higgs-radion mixed state at the 13 and 14 TeV LHC and at the 500 and 1000 GeV International Linear Collider (ILC). We carry out a comprehensive analysis of the most significant production and decay modes of the mixed radion in the 80 GeV-1 TeV mass range and indicate the parameter space that can be probed at the LHC and the ILC. There exists a region of the parameter space which can be probed, at the LHC, through the diphoton channel even for a relatively low luminosity of 50 fb-1 . The reach of the four-lepton final state in probing the parameter space is also studied in the context of 14 TeV LHC, for a luminosity of 1000 fb-1 . At the ILC, with an integrated luminosity of 500 fb-1 , we analyze the Z -radion associated production and the W W fusion production, followed by the radion decay into b b ¯ and W+W-. The W W fusion production is favored over the Z -radion associated channel in probing regions of the parameter space beyond the LHC reach. The complementary study at the LHC and the ILC is useful both for the discovery of the radion and the understanding of its mixing sector.

Data-Driven Based Asynchronous Motor Control for Printing Servo Systems

NASA Astrophysics Data System (ADS)

Bian, Min; Guo, Qingyun

Modern digital printing equipment aims to the environmental-friendly industry with high dynamic performances and control precision and low vibration and abrasion. High performance motion control system of printing servo systems was required. Control system of asynchronous motor based on data acquisition was proposed. Iterative learning control (ILC) algorithm was studied. PID control was widely used in the motion control. However, it was sensitive to the disturbances and model parameters variation. The ILC applied the history error data and present control signals to approximate the control signal directly in order to fully track the expect trajectory without the system models and structures. The motor control algorithm based on the ILC and PID was constructed and simulation results were given. The results show that data-driven control method is effective dealing with bounded disturbances for the motion control of printing servo systems.

Crab cavities: Past, present, and future of a challenging device

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Q.

2015-05-03

In two-ring facilities operating with a crossing-angle collision scheme, luminosity can be limited due to an incomplete overlapping of the colliding bunches. Crab cavities then are introduced to restore head-on collisions by providing the destined opposite deflection to the head and tail of the bunch. An increase in luminosity was demonstrated at KEKB with global crab-crossing, while the Large Hardron Collider (LHC) at CERN currently is designing local crab crossing for the Hi-Lumi upgrade. Future colliders may investigate both approaches. In this paper, we review the challenges in the technology, and the implementation of crab cavities, while discussing experience inmore » earlier colliders, ongoing R&D, and proposed implementations for future facilities, such as HiLumi-LHC, CERN’s compact linear collider (CLIC), the international linear collider (ILC), and the electron-ion collider under design at BNL (eRHIC).« less

The Center for Informal Learning and Schools' Informal Learning Certificate (ILC) Program: Professional Development and Community for Informal Science Educators Working with Schools. An Evaluation Report

ERIC Educational Resources Information Center

Smith, Anita; Helms, Jenifer V.; St. John, Mark

2007-01-01

Inverness Research Associates served as external evaluators for the Center for Informal Learning and Schools (CILS) from its inception in 2002 as a National Science Foundation (NSF)-funded Center for Learning and Teaching. One of the programs that CILS developed was the Informal Learning Certificate (ILC) for informal science educators (mostly…

Implications of the 750 GeV γγ Resonance as a Case Study for the International Linear Collider

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fujii, Keisuke; Grojean, Christophe; Peskin, Michael E.

If the γγ resonance at 750 GeV suggested by 2015 LHC data turns out to be a real effect, what are the implications for the physics case and upgrade path of the International Linear Collider? Whether or not the resonance is confirmed, this question provides an interesting case study testing the robustness of the ILC physics case. In this note, we address this question with two points: (1) Almost all models proposed for the new 750 GeV particle require additional new particles with electroweak couplings. The key elements of the 500 GeV ILC physics program - precision measurements of themore » Higgs boson, the top quark, and 4-fermion interactions - will powerfully discriminate among these models. This information will be important in conjunction with new LHC data, or alone, if the new particles accompanying the 750 GeV resonance are beyond the mass reach of the LHC. (2) Over a longer term, the energy upgrade of the ILC to 1 TeV already discussed in the ILC TDR will enable experiments in γγ and e +e - collisions to directly produce and study the 750 GeV particle from these unique initial states.« less

IL-25 Elicits Innate Lymphoid Cells and Multipotent Progenitor Type 2 Cells That Reduce Renal Ischemic/Reperfusion Injury

PubMed Central

Huang, Qingsong; Niu, Zhiguo; Tan, Jing; Yang, Jun; Liu, Yun; Ma, Haijun; Lee, Vincent W.S.; Sun, Shuming; Song, Xiangfeng; Guo, Minghao; Wang, Yiping

2015-01-01

IL-25 is an important immune regulator that can promote Th2 immune response-dependent immunity, inflammation, and tissue repair in asthma, intestinal infection, and autoimmune diseases. In this study, we examined the effects of IL-25 in renal ischemic/reperfusion injury (IRI). Treating IRI mice with IL-25 significantly improved renal function and reduced renal injury. Furthermore, IL-25 treatment increased the levels of IL-4, IL-5, and IL-13 in serum and kidney and promoted induction of alternatively activated (M2) macrophages in kidney. Notably, IL-25 treatment also increased the frequency of type 2 innate lymphoid cells (ILC2s) and multipotent progenitor type 2 (MPPtype2) cells in kidney. IL-25–responsive ILC2 and MPPtype2 cells produced greater amounts of Th2 cytokines that associated with the induction of M2 macrophages and suppression of classically activated (M1) macrophages in vitro. Finally, adoptive transfer of ILC2s or MPPtype2 cells not only reduced renal functional and histologic injury in IRI mice but also induced M2 macrophages in kidney. In conclusion, our data identify a mechanism whereby IL-25-elicited ILC2 and MPPtype2 cells regulate macrophage phenotype in kidney and prevent renal IRI. PMID:25556172

Understanding Collagen Organization in Breast Tumors to Predict and Prevent Metastasis

DTIC Science & Technology

2012-09-01

metastasis. Specific Aim 2. Determine the role of Th1, Th2, and Tregs in governing collagen ordering in tumors, and their mechanism of action. (Months...surrounding tissue by penetrating through the basement membrane of the duct. Invasive Lobular Carcinoma ( ILC ) is the invasive growth of cancer...not as a predecessor to ILC , but rather a benign growth of abnormal cells that are commonly undetectable by mammograms but if detected (usually in

Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells

PubMed Central

Hepworth, Matthew R.; Fung, Thomas C.; Masur, Samuel H.; Kelsen, Judith R.; McConnell, Fiona M.; Dubrot, Juan; Withers, David R.; Hugues, Stephanie; Farrar, Michael A.; Reith, Walter; Eberl, Gerard; Baldassano, Robert N.; Laufer, Terri M.; Elson, Charles O.; Sonnenberg, Gregory F.

2015-01-01

Inflammatory CD4+ T cell responses to self or commensal bacteria underlie the pathogenesis of autoimmunity and inflammatory bowel disease (IBD), respectively. While selection of self-specific T cells in the thymus limits responses to tissue antigens, the mechanisms that control selection of commensal bacteria-specific T cells remain poorly understood. Here we demonstrate that group 3 innate lymphoid cell (ILC3)-intrinsic expression of major histocompatibility complex class II (MHCII) is regulated similarly to thymic epithelial cells, and that MHCII+ ILC3s directly induce cell death of activated commensal bacteria-specific T cells. Further, MHCII on human colonic ILC3s was reduced in pediatric IBD patients. Collectively, these results define a selection pathway for commensal bacteria-specific CD4+ T cells in the intestine, and suggest that this process is dysregulated in human IBD. PMID:25908663

Complement and Immunoregulation in Tissue Injury

DTIC Science & Technology

2014-10-01

and neutrophil infiltration represent the initiating events in this process (9). Recently, the role of different T cell subsets ( Tregs , Th17) and B...first tested the hypothesis that ILCs , which rapidly release IL-17A in response to epithelial injury, are the relevant source of IL- 17A in small...intestinal IRI. To address this question we took advantage of the Rag2-/-γc-/- mouse, which lacks ILCs because it is deficient in IL-7 signaling, which

Longitudinal Beam Diagnostics for the ILC Injectors and Bunch Compressors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Piot, Philippe; Bracke, Adam; Demir, Veysel

2010-12-01

We present a diagnostics suite and analyze techniques for setting up the longitudinal beam dynamics in ILC e⁻ injectors and e⁺ and e⁻ bunch compressors. Techniques to measure the first order moments and recover the first order longitudinal transfer map of the injector's intricate bunching scheme are presented. Coherent transition radiation diagnostics needed to measure and monitor the bunch length downstream of the ~5 GeV bunch compressor are investigated using a vector diffraction model.

DD-RT-PCR identifies 7-dehydrocholesterol reductase as a key marker of early Leydig cell steroidogenesis.

PubMed

Anbalagan, M; Yashwanth, R; Jagannadha Rao, A

2004-04-30

Postnatal Leydig cell development in rat involves an initial phase of proliferation of progenitor Leydig cells (PLCs) and subsequent differentiation of these cells into immature Leydig cells (ILCs) and adult Leydig cells (ALCs). With an objective to identify the molecular changes associated with Leydig cell differentiation, the mRNA population in PLCs and ILCs were analyzed by the technique of differential display reverse transcription polymerase chain reaction (DD-RT-PCR). Results revealed differential expression of several transcripts in PLCs and ILCs. Of the several differentially expressed transcripts, the expression of transcripts corresponding to collagen IV alpha6 (Col IV alpha6) and ribosomal protein L 41 (RpL41) decreased during the differentiation of PLC to ILC. Also there was an increase in the expression of transcripts encoding enzymes such as microsomal glutathione-S-transferase (mGST 1) and 7-dehydrocholesterol reductase (7-DHCR) during this process. While Col IV alpha6 and RpL41 are known to be involved in cellular proliferation, mGST 1 and 7-DHCR are essential for normal Leydig cell steroidogenesis. A detailed study on 7-DHCR expression in Leydig cells revealed that this enzyme plays a crucial role in steroidogenesis. Interestingly expression of this enzyme is not under acute regulation by Luteinizing hormone (LH). Copyright 2004 Elsevier Ireland Ltd.

Scalar production in association with a Z boson at the LHC and ILC: The mixed Higgs-radion case of warped models

NASA Astrophysics Data System (ADS)

Angelescu, Andrei; Moreau, Grégory; Richard, François

2017-07-01

The radion scalar field might be the lightest new particle predicted by extradimensional extensions of the standard model. It could thus lead to the first signatures of new physics at the LHC collider. We perform a complete study of the radion production in association with the Z gauge boson in the custodially protected warped model with a brane-localized Higgs boson addressing the gauge hierarchy problem. Radion-Higgs mixing effects are present. Such a radion production receives possibly resonant contributions from the Kaluza-Klein excitations of the Z boson as well as the extra neutral gauge boson (Z'). All the exchange and mixing effects induced by those heavy bosons are taken into account in the radion coupling and rate calculations. The investigation of the considered radion production at the LHC allows us to be sensitive to some parts of the parameter space but only the ILC program at high luminosity would cover most of the theoretically allowed parameter space via the studied reaction. Complementary tests of the same theoretical parameters can be realized through the high accuracy measurements of the Higgs couplings at the ILC. The generic sensitivity limits on the rates discussed for the LHC and ILC potential reach can be applied to the searches for other (light) exotic scalar bosons.

The Development and Psychometric Properties of the Immigration Law Concerns Scale (ILCS) for HIV Testing.

PubMed

Lechuga, Julia; Galletly, Carol L; Broaddus, Michelle R; Dickson-Gomez, Julia B; Glasman, Laura R; McAuliffe, Timothy L; Vega, Miriam Y; LeGrand, Sarah; Mena, Carla A; Barlow, Morgan L; Valera, Erik; Montenegro, Judith I

2017-11-08

To develop, pilot test, and conduct psychometric analyses of an innovative scale measuring the influence of perceived immigration laws on Latino migrants' HIV-testing behavior. The Immigration Law Concerns Scale (ILCS) was developed in three phases: Phase 1 involved a review of law and literature, generation of scale items, consultation with project advisors, and subsequent revision of the scale. Phase 2 involved systematic translation- back translation and consensus-based editorial processes conducted by members of a bilingual and multi-national study team. In Phase 3, 339 sexually active, HIV-negative Spanish-speaking, non-citizen Latino migrant adults (both documented and undocumented) completed the scale via audio computer-assisted self-interview. The psychometric properties of the scale were tested with exploratory factor analysis and estimates of reliability coefficients were generated. Bivariate correlations were conducted to test the discriminant and predictive validity of identified factors. Exploratory factor analysis revealed a three-factor, 17-item scale. subscale reliability ranged from 0.72 to 0.79. There were significant associations between the ILCS and the HIV-testing behaviors of participants. Results of the pilot test and psychometric analysis of the ILCS are promising. The scale is reliable and significantly associated with the HIV-testing behaviors of participants. Subscales related to unwanted government attention and concerns about meeting moral character requirements should be refined.

A Project to Design and Build the Magnets for a New Test Beamline, the ATF2, at KEK

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spencer, Cherrill M.; /slac; Sugahara, Ryuhei

2011-02-07

In order to achieve the high luminosity required at the proposed International Linear Collider (ILC), it is critical to focus the beams to nanometer size with the ILC Beam Delivery System, and to maintain the beams collisions with a nanometer-scale stability. To establish the technologies associated with this ultra-high precision beam handling, a special beamline has been designed and built as an extension of the existing extraction beamline of the Accelerator Test Facility at KEK, Japan. The ATF provides an adequate ultra-low emittance electron beam that is comparable to the ILC requirements; the ATF2 mimics the ILC final focus systemmore » to create a tightly focused, stable beam. There are 37 magnets in the ATF2, 29 quadrupoles, 5 sextupoles and 3 bends. These magnets had to be acquired in a short time and at minimum cost, which led to various acquisition strategies; but nevertheless they had to meet strict requirements on integrated strength, physical dimensions, compatibility with existing magnet movers and beam position monitors, mechanical stability and field stability and quality. This paper will describe how 2 styles of quadrupoles, 2 styles of sextupoles, one dipole style and their supports were designed, fabricated, refurbished or modified, measured and aligned by a small team of engineers from 3 continents.« less

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells

PubMed Central

Lefrançais, Emma; Duval, Anais; Mirey, Emilie; Roga, Stéphane; Espinosa, Eric; Cayrol, Corinne; Girard, Jean-Philippe

2014-01-01

Interleukin-33 (IL-33) is an alarmin cytokine from the IL-1 family. IL-33 activates many immune cell types expressing the interleukin 1 receptor-like 1 (IL1RL1) receptor ST2, including group-2 innate lymphoid cells (ILC2s, natural helper cells, nuocytes), the major producers of IL-5 and IL-13 during type-2 innate immune responses and allergic airway inflammation. IL-33 is likely to play a critical role in asthma because the IL33 and ST2/IL1RL1 genes have been reproducibly identified as major susceptibility loci in large-scale genome-wide association studies. A better understanding of the mechanisms regulating IL-33 activity is thus urgently needed. Here, we investigated the role of mast cells, critical effector cells in allergic disorders, known to interact with ILC2s in vivo. We found that serine proteases secreted by activated mast cells (chymase and tryptase) generate mature forms of IL-33 with potent activity on ILC2s. The major forms produced by mast cell proteases, IL-3395–270, IL-33107–270, and IL-33109–270, were 30-fold more potent than full-length human IL-331–270 for activation of ILC2s ex vivo. They induced a strong expansion of ILC2s and eosinophils in vivo, associated with elevated concentrations of IL-5 and IL-13. Murine IL-33 is also cleaved by mast cell tryptase, and a tryptase inhibitor reduced IL-33–dependent allergic airway inflammation in vivo. Our study identifies the central cleavage/activation domain of IL-33 (amino acids 66–111) as an important functional domain of the protein and suggests that interference with IL-33 cleavage and activation by mast cell and other inflammatory proteases could be useful to reduce IL-33–mediated responses in allergic asthma and other inflammatory diseases. PMID:25313073

The histone deacetylase inhibitor trichostatin A suppresses murine innate allergic inflammation by blocking group 2 innate lymphoid cell (ILC2) activation

PubMed Central

Toki, Shinji; Goleniewska, Kasia; Reiss, Sara; Zhou, Weisong; Newcomb, Dawn C; Bloodworth, Melissa H; Stier, Matthew T; Boyd, Kelli L; Polosukhin, Vasiliy V; Subramaniam, Sriram; Peebles, R Stokes

2016-01-01

Background Group 2 innate lymphoid cells (ILC2) are an important source of the type 2 cytokines interleukin (IL)-5 and IL-13 that are critical to the allergic airway phenotype. Previous studies reported that histone deacetylase (HDAC) inhibition by trichostatin A (TSA) downregulated adaptive allergic immune responses; however, the effect of HDAC inhibition on the early innate allergic immune response is unknown. Therefore, we investigated the effect of TSA on innate airway inflammation mediated by ILC2 activation. Methods BALB/c mice were challenged intranasally with Alternaria extract, exogenous recombinant mouse IL-33 (rmIL-33) or the respective vehicles for four consecutive days following TSA or vehicle treatment. Bronchoalveolar lavage (BAL) fluids and lungs were harvested 24 h after the last challenge. Results We found that TSA treatment significantly decreased the number of ILC2 expressing IL-5 and IL-13 in the lungs challenged with Alternaria extract or rmIL-33 compared with vehicle treatment (p<0.05). TSA treatment significantly decreased protein expression of IL-5, IL-13, CCL11 and CCL24 in the lung homogenates from Alternaria extract-challenged mice or rmIL-33-challenged mice compared with vehicle treatment (p<0.05). Further, TSA treatment significantly decreased the number of perivascular eosinophils and mucus production in the large airways that are critical components of the asthma phenotype (p<0.05). TSA did not change early IL-33 release in the BAL fluids; however, TSA decreased lung IL-33 expression from epithelial cells 24 h after last Alternaria extract challenge compared with vehicle treatment (p<0.05). Conclusions These results reveal that TSA reduces allergen-induced ILC2 activation and the early innate immune responses to an inhaled protease-containing aeroallergen. PMID:27071418

Direct-Conversion Molecular Breast Imaging of Invasive Breast Cancer: Imaging Features, Extent of Invasive Disease, and Comparison Between Invasive Ductal and Lobular Histology.

PubMed

Conners, Amy Lynn; Jones, Katie N; Hruska, Carrie B; Geske, Jennifer R; Boughey, Judy C; Rhodes, Deborah J

2015-09-01

The purposes of this study were to compare the tumor appearance of invasive breast cancer on direct-conversion molecular breast imaging using a standardized lexicon and to determine how often direct-conversion molecular breast imaging identifies all known invasive tumor foci in the breast, and whether this differs for invasive ductal versus lobular histologic profiles. Patients with prior invasive breast cancer and concurrent direct-conversion molecular breast imaging examinations were retrospectively reviewed. Blinded review of direct-conversion molecular breast imaging examinations was performed by one of two radiologists, according to a validated lexicon. Direct-conversion molecular breast imaging findings were matched with lesions described on the pathology report to exclude benign reasons for direct-conversion molecular breast imaging findings and to document direct-conversion molecular breast imaging-occult tumor foci. Associations between direct-conversion molecular breast imaging findings and tumor histologic profiles were examined using chi-square tests. In 286 patients, 390 invasive tumor foci were present in 294 breasts. A corresponding direct-conversion molecular breast imaging finding was present for 341 of 390 (87%) tumor foci described on the pathology report. Invasive ductal carcinoma (IDC) tumor foci were more likely to be a mass (40% IDC vs 15% invasive lobular carcinoma [ILC]; p < 0.001) and to have marked intensity than were ILC foci (63% IDC vs 32% ILC; p < 0.001). Direct-conversion molecular breast imaging correctly revealed all pathology-proven foci of invasive disease in 79.8% of cases and was more likely to do so for IDC than for ILC (86.1% vs 56.7%; p < 0.0001). Overall, direct-conversion molecular breast imaging showed all known invasive foci in 249 of 286 (87%) patients. Direct-conversion molecular breast imaging features of invasive cancer, including lesion type and intensity, differ by histologic subtype. Direct-conversion molecular breast imaging is less likely to show all foci of ILC compared with IDC.

IL-9-Producing Mast Cell Precursors and Food Allergy

DTIC Science & Technology

2016-10-01

that Stat6-/- BM progenitors in sensitized wild type recipients that were competent in GFP- CD4+ST2+TH2 and ILC2s ( innate lymphoid cells ) generation, and...report demonstrated that type 2 innate lymphoid cells (ILC2s) lack cell lineage markers and have the potential to pro- duce IL-9 (Wilhelm et al., 2011...Fujii, H., and Koyasu, S. (2010). Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells . Nature 463, 540–544

Role of Cathepsin C During Breast Cancer Metastasis

DTIC Science & Technology

2011-09-01

carcinomas ( ILC ) – mostly histological grade two or three – were obtained from patients with no prior exposure to CTX (CTX-naïve) at the time of primary...invasive lobular carcinomas ( ILC ) mostly histological grade two or three were obtained from patients with no prior exposure to CTX (CTX naïve) at the time...intratumoral Tregs for chemotherapy in patients with early breast cancer. Clin Cancer Res 16:1272–1280. 46. Macchetti AH, et al. (2006) Tumor

Probing top-Z dipole moments at the LHC and ILC

DOE PAGES

Röntsch, Raoul; Schulze, Markus

2015-08-11

We investigate the weak electric and magnetic dipole moments of top quark-Z boson interactions at the Large Hadron Collider (LHC) and the International Linear Collider (ILC). Their vanishingly small magnitude in the Standard Model makes these couplings ideal for probing New Physics interactions and for exploring the role of top quarks in electroweak symmetry breaking. In our analysis, we consider the production of two top quarks in association with a Z boson at the LHC, and top quark pairs mediated by neutral gauge bosons at the ILC. These processes yield direct sensitivity to top quark-Z boson interactions and complement indirectmore » constraints from electroweak precision data. Our computation is accurate to next-to-leading order in QCD, we include the full decay chain of top quarks and the Z boson, and account for theoretical uncertainties in our constraints. Furthermore, we find that LHC experiments will soon be able to probe weak dipole moments for the first time.« less

GATA-3 function in innate and adaptive immunity.

PubMed

Tindemans, Irma; Serafini, Nicolas; Di Santo, James P; Hendriks, Rudi W

2014-08-21

The zinc-finger transcription factor GATA-3 has received much attention as a master regulator of T helper 2 (Th2) cell differentiation, during which it controls interleukin-4 (IL-4), IL-5, and IL-13 expression. More recently, GATA-3 was shown to contribute to type 2 immunity through regulation of group 2 innate lymphoid cell (ILC2) development and function. Furthermore, during thymopoiesis, GATA-3 represses B cell potential in early T cell precursors, activates TCR signaling in pre-T cells, and promotes the CD4(+) T cell lineage after positive selection. GATA-3 also functions outside the thymus in hematopoietic stem cells, regulatory T cells, CD8(+) T cells, thymic natural killer cells, and ILC precursors. Here we discuss the varied functions of GATA-3 in innate and adaptive immune cells, with emphasis on its activity in T cells and ILCs, and examine the mechanistic basis for the dose-dependent, developmental-stage- and cell-lineage-specific activity of this transcription factor. Copyright © 2014 Elsevier Inc. All rights reserved.

Neutralino pair production at the photon-photon collider for the τ̃-coannihilation scenario

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sonmez, Nasuf, E-mail: nsonmez@cern.ch

Supersymmetry (SUSY) is a theory which gives an explanation for the strong and electroweak interactions from the grand unification scale down to the weak scale. The search for supersymmetric particles still continues at full speed at the LHC without success. The main task at the ILC is complementing the LHC result and also search for new physics. In this study, the neutralino pair production via photon-photon collision is studied for the t̃-coannihilation scenario in the context of MSSM at the ILC. In the calculation, all the possible one loop diagrams are taken into account for the photon-photon interaction. We presentmore » the production cross section and distribution of various observables for the lightest and next-to-lightest neutralino pairs for benchmark models which are specifically presented in the light of LHC8 data analysis, employing these benchmark models for neutralino pair production could show the potential of the ILC concerning the dark matter searches in supersymmetry.« less

The Impulsive Lifestyle Counseling Program for Antisocial Behavior in Outpatient Substance Abuse Treatment.

PubMed

Thylstrup, Birgitte; Hesse, Morten

2016-06-01

Antisocial behavior is associated with low quality of life for the patient and with adverse effects on society and those close to the antisocial patient. However, most patients with antisocial behavior are not seen in treatment settings that focus on their personality but rather in criminal justice settings, substance-abuse treatment, and social welfare settings. This article describes the adaptation and implementation of a highly structured manualized treatment, Impulsive Lifestyle Counseling (ILC), based on the Lifestyle Issues program, a 10-week psychoeducation program studied in prison settings. ILC consists of four sessions over 4 weeks and a booster session 8 weeks later. The goal of treatment is described to patients as "to help people identify their impulsive thoughts and lifestyle leading to problems with drug use, other people, and the police." Two clinical examples and reflections on our experiences with the training and implementation of the ILC program are presented. © The Author(s) 2011.

Mammary-specific inactivation of E-cadherin and p53 impairs functional gland development and leads to pleomorphic invasive lobular carcinoma in mice.

PubMed

Derksen, Patrick W B; Braumuller, Tanya M; van der Burg, Eline; Hornsveld, Marten; Mesman, Elly; Wesseling, Jelle; Krimpenfort, Paul; Jonkers, Jos

2011-05-01

Breast cancer is the most common malignancy in women of the Western world. Even though a large percentage of breast cancer patients show pathological complete remission after standard treatment regimes, approximately 30-40% are non-responsive and ultimately develop metastatic disease. To generate a good preclinical model of invasive breast cancer, we have taken a tissue-specific approach to somatically inactivate p53 and E-cadherin, the cardinal cell-cell adhesion receptor that is strongly associated with tumor invasiveness. In breast cancer, E-cadherin is found mutated or otherwise functionally silenced in invasive lobular carcinoma (ILC), which accounts for 10-15% of all breast cancers. We show that mammary-specific stochastic inactivation of conditional E-cadherin and p53 results in impaired mammary gland function during pregnancy through the induction of anoikis resistance of mammary epithelium, resulting in loss of epithelial organization and a dysfunctional mammary gland. Moreover, combined inactivation of E-cadherin and p53 induced lactation-independent development of invasive and metastatic mammary carcinomas, which showed strong resemblance to human pleomorphic ILC. Dissemination patterns of mouse ILC mimic the human malignancy, showing metastasis to the gastrointestinal tract, peritoneum, lung, lymph nodes and bone. Our results confirm that loss of E-cadherin contributes to both mammary tumor initiation and metastasis, and establish a preclinical mouse model of human ILC that can be used for the development of novel intervention strategies to treat invasive breast cancer.

Testing sterile neutrino extensions of the Standard Model at future lepton colliders

NASA Astrophysics Data System (ADS)

Antusch, Stefan; Fischer, Oliver

2015-05-01

Extending the Standard Model (SM) with sterile ("right-handed") neutrinos is one of the best motivated ways to account for the observed neutrino masses. We discuss the expected sensitivity of future lepton collider experiments for probing such extensions. An interesting testable scenario is given by "symmetry protected seesaw models", which theoretically allow for sterile neutrino masses around the electroweak scale with up to order one mixings with the light (SM) neutrinos. In addition to indirect tests, e.g. via electroweak precision observables, sterile neutrinos with masses around the electroweak scale can also be probed by direct searches, e.g. via sterile neutrino decays at the Z pole, deviations from the SM cross section for four lepton final states at and beyond the WW threshold and via Higgs boson decays. We study the present bounds on sterile neutrino properties from LEP and LHC as well as the expected sensitivities of possible future lepton colliders such as ILC, CEPC and FCC-ee (TLEP).

DOE Office of Scientific and Technical Information (OSTI.GOV)

Okihira, K.; Hara, H.; Ikeda, N.

MHI have supplied several 9-cell cavities for STF (R&D of ILC project at KEK) and have been considering production method for stable quality and cost reduction, seamless dumb-bell cavity was one of them. We had fabricated a 2 cell seamless dumb-bell cavity for cost reduction and measured RF performance in collaboration with JLab, KEK and MHI. Surface treatment recipe for ILC was applied for MHI 2-cell cavity and vertical test was performed at JLab. The cavity reached Eacc=32.4MV/m after BCP and EP. Details of the result are reported.

Complement and Immunoregulation in Tissue Injury

DTIC Science & Technology

2015-12-01

and IL-8. Cells that produce IL-17A include TCRα/β T cells , TCRγ/δ T cells and CD45+CD4+TCR-IL-7R+ innate lymphoid cells (ILCs), which reside at...cytokine IL-23. In contrast, IL-17A production by TCRγ/δ T cells ILCs and other innate cell is directly driven by IL-23 and is rapid. IL-23 is a...amplifies IL-17A production by T cells and drives its production by innate cells . We investigated the potential role of IL-23 in small intestinal IRI

Bibliography on Cold Regions Science and Technology. Volume 36, Part 1, 1982.

DTIC Science & Technology

1982-09-01

western MeNlurdo Sound. and the fact that thewe areas are truly rainless, many features Barrett, P I, ct al. .- lcr st fi p h ilc l I ,i,, . iss i and...beneath structures. Engi- 1981. Nir Mr. P 42 IlC Ressea equipment. ge rittund- leeriim utlmcog. Ertiten rick temperature. Snon Riesal’. A, \\. depth...i Jarri ii soc ctr im treg itjan ra irsd~rI-J River basins, Snot. cover distribution, Soon . water ik. \\iii s icrhr airIr i ii ’r~ ir~c rrrkrr .I

Magnet reliability in the Fermilab Main Injector and implications for the ILC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tartaglia, M.A.; Blowers, J.; Capista, D.

2007-08-01

The International Linear Collider reference design requires over 13000 magnets, of approximately 135 styles, which must operate with very high reliability. The Fermilab Main Injector represents a modern machine with many conventional magnet styles, each of significant quantity, that has now accumulated many hundreds of magnet-years of operation. We review here the performance of the magnets built for this machine, assess their reliability and categorize the failure modes, and discuss implications for reliability of similar magnet styles expected to be used at the ILC.

Probing the fermionic Higgs portal at lepton colliders

DOE PAGES

Fedderke, Michael A.; Lin, Tongyan; Wang, Lian -Tao

2016-04-26

Here, we study the sensitivity of future electron-positron colliders to UV completions of the fermionic Higgs portal operator H †Hχ¯χ. Measurements of precision electroweak S and T parameters and the e +e – → Zh cross-section at the CEPC, FCC-ee, and ILC are considered. The scalar completion of the fermionic Higgs portal is closely related to the scalar Higgs portal, and we summarize existing results. We devote the bulk of our analysis to a singlet-doublet fermion completion. Assuming the doublet is sufficiently heavy, we construct the effective field theory (EFT) at dimension-6 in order to compute contributions to the observables.more » We also provide full one-loop results for S and T in the general mass parameter space. In both completions, future precision measurements can probe the new states at the (multi-)TeV scale, beyond the direct reach of the LHC.« less

Probing the fermionic Higgs portal at lepton colliders

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fedderke, Michael A.; Lin, Tongyan; Wang, Lian -Tao

Here, we study the sensitivity of future electron-positron colliders to UV completions of the fermionic Higgs portal operator H †Hχ¯χ. Measurements of precision electroweak S and T parameters and the e +e – → Zh cross-section at the CEPC, FCC-ee, and ILC are considered. The scalar completion of the fermionic Higgs portal is closely related to the scalar Higgs portal, and we summarize existing results. We devote the bulk of our analysis to a singlet-doublet fermion completion. Assuming the doublet is sufficiently heavy, we construct the effective field theory (EFT) at dimension-6 in order to compute contributions to the observables.more » We also provide full one-loop results for S and T in the general mass parameter space. In both completions, future precision measurements can probe the new states at the (multi-)TeV scale, beyond the direct reach of the LHC.« less

Prospects of type-II seesaw models at future colliders in light of the DAMPE e+e- excess

NASA Astrophysics Data System (ADS)

Sui, Yicong; Zhang, Yongchao

2018-05-01

The DAMPE e+e- excess at around 1.4 TeV could be explained in the type-II seesaw model with a scalar dark mater D which is stabilized by a discrete Z2 symmetry. The simplest scenario is the annihilation D D →H++H- followed by the subsequent decay H±±→e±e±, with both the DM and triplet scalars roughly 3 TeV with a small mass splitting. In addition to the Drell-Yan process at future 100 TeV hadron colliders, the doubly charged components could also be produced at lepton colliders like ILC and CLIC in the off shell mode and mediate lepton flavor violating processes e+e-→ℓi±ℓj∓ (with i ≠j ). A wide range of parameter space of the type-II seesaw could be probed, which are well below the current stringent lepton flavor constraints.

Instruments, Detectors and the Future of Astronomy with Large Ground Based Telescopes

NASA Astrophysics Data System (ADS)

Simons, Douglas A.; Amico, Paola; Baade, Dietrich; Barden, Sam; Campbell, Randall; Finger, Gert; Gilmore, Kirk; Gredel, Roland; Hickson, Paul; Howell, Steve; Hubin, Norbert; Kaufer, Andreas; Kohley, Ralf; MacQueen, Philip; Markelov, Sergej; Merrill, Mike; Miyazaki, Satoshi; Nakaya, Hidehiko; O'Donoghue, Darragh; Oliva, Tino; Richichi, Andrea; Salmon, Derrick; Schmidt, Ricardo; Su, Hongjun; Tulloch, Simon; García Vargas, Maria Luisa; Wagner, R. Mark; Wiecha, Olivier; Ye, Binxun

2005-01-01

Results of a survey of instrumentation and detector systems, either currently deployed or planned for use at telescopes larger than 3.5 m, in ground based observatories world-wide, are presented. This survey revealed a number of instrumentation design trends at optical, near, and mid-infrared wavelengths. Some of the most prominent trends include the development of vastly larger optical detector systems (> 109 pixels) than anything built to date, and the frequent use of mosaics of near-infrared detectors - something that was quite rare only a decade ago in astronomy. Some future science applications for detectors are then explored, in an attempt to build a bridge between current detectors and what will be needed to support the research ambitions of astronomers in the future.

Impact of calibration errors on CMB component separation using FastICA and ILC

NASA Astrophysics Data System (ADS)

Dick, Jason; Remazeilles, Mathieu; Delabrouille, Jacques

2010-01-01

The separation of emissions from different astrophysical processes is an important step towards the understanding of observational data. This topic of component separation is of particular importance in the observation of the relic cosmic microwave background (CMB) radiation, as performed by the Wilkinson Microwave Anisotropy Probe satellite and the more recent Planck mission, launched on 2009 May 14 from Kourou and currently taking data. When performing any sort of component separation, some assumptions about the components must be used. One assumption that many techniques typically use is knowledge of the frequency scaling of one or more components. This assumption may be broken in the presence of calibration errors. Here we compare, in the context of imperfect calibration, the recovery of a clean map of emission of the CMB from observational data with two methods: FastICA (which makes no assumption of the frequency scaling of the components) and an `Internal Linear Combination' (ILC), which explicitly extracts a component with a given frequency scaling. We find that even in the presence of small calibration errors (less than 1 per cent) with a Planck-style mission, the ILC method can lead to inaccurate CMB reconstruction in the high signal-to-noise ratio regime, because of partial cancellation of the CMB emission in the recovered map. While there is no indication that the failure of the ILC will translate to other foreground cleaning or component separation techniques, we propose that all methods which assume knowledge of the frequency scaling of one or more components be careful to estimate the effects of calibration errors.

Modeling Human Natural Killer Cell Development in the Era of Innate Lymphoid Cells

PubMed Central

Scoville, Steven D.; Freud, Aharon G.; Caligiuri, Michael A.

2017-01-01

Decades after the discovery of natural killer (NK) cells, their developmental pathways in mice and humans have not yet been completely deciphered. Accumulating evidence indicates that NK cells can develop in multiple tissues throughout the body. Moreover, detailed and comprehensive models of NK cell development were proposed soon after the turn of the century. However, with the recent identification and characterization of other subtypes of innate lymphoid cells (ILCs), which show some overlapping functional and phenotypic features with NK cell developmental intermediates, the distinct stages through which human NK cells develop from early hematopoietic progenitor cells remain unclear. Thus, there is a need to reassess and refine older models of NK cell development in the context of new data and in the era of ILCs. Our group has focused on elucidating the developmental pathway of human NK cells in secondary lymphoid tissues (SLTs), including tonsils and lymph nodes. Here, we provide an update of recent progress that has been made with regard to human NK cell development in SLTs, and we discuss these new findings in the context of contemporary models of ILC development. PMID:28396671

Evaluation of three commercial microclimate cooling systems

NASA Astrophysics Data System (ADS)

Cadarette, Bruce S.; Decristofano, Barry S.; Speckman, Karen N.; Sawka, Michael N.

1988-11-01

Three commercially available microclimate cooling systems were evaluated for their ability to reduce heat stress in men exercising in a hot environment while wearing high insulative, low permeability clothing. The cooling systems were: (1) ILC Dover Model 19 Coolvest (ILC) (2) LSSI Coolhead(LSSI), and (3) Thermacor Cooling vest (THERM). Endurance Time (ET), Heart Rate (HR), rectal temperature (Tre), mean skin temperature (TSK), Sweating Rate (SR), Rated Perceived Exertion (RPE) and Thermal Sensation (TS) were measured. The subjects self-terminated on all LSSI tests because of headaches. Statistical analyses were performed on data collected at 60 minutes to have values on all subjects. There were no differences in HR, Tre, SR or TS values among the cooling vests. The subjects' TSK was lower (P less than 0.05) for the LSSI than THERM: and RPE values were higher (P less than 0.05) for LSSI than the other two vests. These data suggest an improved physiological response to exercise heat stress with all three commercial systems with the greatest benefit in performance time provided by the ILC cooling system.

Modeling Human Natural Killer Cell Development in the Era of Innate Lymphoid Cells.

PubMed

Scoville, Steven D; Freud, Aharon G; Caligiuri, Michael A

2017-01-01

Decades after the discovery of natural killer (NK) cells, their developmental pathways in mice and humans have not yet been completely deciphered. Accumulating evidence indicates that NK cells can develop in multiple tissues throughout the body. Moreover, detailed and comprehensive models of NK cell development were proposed soon after the turn of the century. However, with the recent identification and characterization of other subtypes of innate lymphoid cells (ILCs), which show some overlapping functional and phenotypic features with NK cell developmental intermediates, the distinct stages through which human NK cells develop from early hematopoietic progenitor cells remain unclear. Thus, there is a need to reassess and refine older models of NK cell development in the context of new data and in the era of ILCs. Our group has focused on elucidating the developmental pathway of human NK cells in secondary lymphoid tissues (SLTs), including tonsils and lymph nodes. Here, we provide an update of recent progress that has been made with regard to human NK cell development in SLTs, and we discuss these new findings in the context of contemporary models of ILC development.

Dynamic balance between master transcription factors determines the fates and functions of CD4 T cell and innate lymphoid cell subsets

PubMed Central

2017-01-01

CD4 T cells, including T regulatory cells (Treg cells) and effector T helper cells (Th cells), and recently identified innate lymphoid cells (ILCs) play important roles in host defense and inflammation. Both CD4 T cells and ILCs can be classified into distinct lineages based on their functions and the expression of lineage-specific genes, including those encoding effector cytokines, cell surface markers, and key transcription factors. It was first recognized that each lineage expresses a specific master transcription factor and the expression of these factors is mutually exclusive because of cross-regulation among these factors. However, recent studies indicate that the master regulators are often coexpressed. Furthermore, the expression of master regulators can be dynamic and quantitative. In this review, we will first discuss similarities and differences between the development and functions of CD4 T cell and ILC subsets and then summarize recent literature on quantitative, dynamic, and cell type–specific balance between the master transcription factors in determining heterogeneity and plasticity of these subsets. PMID:28630089

Interleukin-33-Activated Islet-Resident Innate Lymphoid Cells Promote Insulin Secretion through Myeloid Cell Retinoic Acid Production.

PubMed

Dalmas, Elise; Lehmann, Frank M; Dror, Erez; Wueest, Stephan; Thienel, Constanze; Borsigova, Marcela; Stawiski, Marc; Traunecker, Emmanuel; Lucchini, Fabrizio C; Dapito, Dianne H; Kallert, Sandra M; Guigas, Bruno; Pattou, Francois; Kerr-Conte, Julie; Maechler, Pierre; Girard, Jean-Philippe; Konrad, Daniel; Wolfrum, Christian; Böni-Schnetzler, Marianne; Finke, Daniela; Donath, Marc Y

2017-11-21

Pancreatic-islet inflammation contributes to the failure of β cell insulin secretion during obesity and type 2 diabetes. However, little is known about the nature and function of resident immune cells in this context or in homeostasis. Here we show that interleukin (IL)-33 was produced by islet mesenchymal cells and enhanced by a diabetes milieu (glucose, IL-1β, and palmitate). IL-33 promoted β cell function through islet-resident group 2 innate lymphoid cells (ILC2s) that elicited retinoic acid (RA)-producing capacities in macrophages and dendritic cells via the secretion of IL-13 and colony-stimulating factor 2. In turn, local RA signaled to the β cells to increase insulin secretion. This IL-33-ILC2 axis was activated after acute β cell stress but was defective during chronic obesity. Accordingly, IL-33 injections rescued islet function in obese mice. Our findings provide evidence that an immunometabolic crosstalk between islet-derived IL-33, ILC2s, and myeloid cells fosters insulin secretion. Copyright © 2017 Elsevier Inc. All rights reserved.

Status of the DIRAC Project

NASA Astrophysics Data System (ADS)

Casajus, A.; Ciba, K.; Fernandez, V.; Graciani, R.; Hamar, V.; Mendez, V.; Poss, S.; Sapunov, M.; Stagni, F.; Tsaregorodtsev, A.; Ubeda, M.

2012-12-01

The DIRAC Project was initiated to provide a data processing system for the LHCb Experiment at CERN. It provides all the necessary functionality and performance to satisfy the current and projected future requirements of the LHCb Computing Model. A considerable restructuring of the DIRAC software was undertaken in order to turn it into a general purpose framework for building distributed computing systems that can be used by various user communities in High Energy Physics and other scientific application domains. The CLIC and ILC-SID detector projects started to use DIRAC for their data production system. The Belle Collaboration at KEK, Japan, has adopted the Computing Model based on the DIRAC system for its second phase starting in 2015. The CTA Collaboration uses DIRAC for the data analysis tasks. A large number of other experiments are starting to use DIRAC or are evaluating this solution for their data processing tasks. DIRAC services are included as part of the production infrastructure of the GISELA Latin America grid. Similar services are provided for the users of the France-Grilles and IBERGrid National Grid Initiatives in France and Spain respectively. The new communities using DIRAC started to provide important contributions to its functionality. Among recent additions can be mentioned the support of the Amazon EC2 computing resources as well as other Cloud management systems; a versatile File Replica Catalog with File Metadata capabilities; support for running MPI jobs in the pilot based Workload Management System. Integration with existing application Web Portals, like WS-PGRADE, is demonstrated. In this paper we will describe the current status of the DIRAC Project, recent developments of its framework and functionality as well as the status of the rapidly evolving community of the DIRAC users.

The next detectors for gravitational wave astronomy

NASA Astrophysics Data System (ADS)

Blair, David; Ju, Li; Zhao, ChunNong; Wen, LinQing; Miao, HaiXing; Cai, RongGen; Gao, JiangRui; Lin, XueChun; Liu, Dong; Wu, Ling-An; Zhu, ZongHong; Hammond, Giles; Paik, Ho Jung; Fafone, Viviana; Rocchi, Alessio; Blair, Carl; Ma, YiQiu; Qin, JiaYi; Page, Michael

2015-12-01

This paper focuses on the next detectors for gravitational wave astronomy which will be required after the current ground based detectors have completed their initial observations, and probably achieved the first direct detection of gravitational waves. The next detectors will need to have greater sensitivity, while also enabling the world array of detectors to have improved angular resolution to allow localisation of signal sources. Sect. 1 of this paper begins by reviewing proposals for the next ground based detectors, and presents an analysis of the sensitivity of an 8 km armlength detector, which is proposed as a safe and cost-effective means to attain a 4-fold improvement in sensitivity. The scientific benefits of creating a pair of such detectors in China and Australia is emphasised. Sect. 2 of this paper discusses the high performance suspension systems for test masses that will be an essential component for future detectors, while sect. 3 discusses solutions to the problem of Newtonian noise which arise from fluctuations in gravity gradient forces acting on test masses. Such gravitational perturbations cannot be shielded, and set limits to low frequency sensitivity unless measured and suppressed. Sects. 4 and 5 address critical operational technologies that will be ongoing issues in future detectors. Sect. 4 addresses the design of thermal compensation systems needed in all high optical power interferometers operating at room temperature. Parametric instability control is addressed in sect. 5. Only recently proven to occur in Advanced LIGO, parametric instability phenomenon brings both risks and opportunities for future detectors. The path to future enhancements of detectors will come from quantum measurement technologies. Sect. 6 focuses on the use of optomechanical devices for obtaining enhanced sensitivity, while sect. 7 reviews a range of quantum measurement options.

Comparison of Detector Technologies for CAPS

NASA Technical Reports Server (NTRS)

Stockum, Jana L.

2005-01-01

In this paper, several different detectors are examined for use in a Comet/Asteroid Protection System (CAPS), a conceptual study for a possible future space-based system. Each detector will be examined for its future (25 years or more in the future) ability to find and track near-Earth Objects (NEOs) from a space-based detection platform. Within the CAPS study are several teams of people who each focus on different aspects of the system concept. This study s focus is on detection devices. In particular, evaluations on the following devices have been made: charge-coupled devices (CCDs), charge-injected devices (CIDs), superconducting tunneling junctions (STJs), and transition edge sensors (TESs). These devices can be separated into two main categories; the first category includes detectors that are currently being widely utilized, such as CCDs and CIDs. The second category includes experimental detectors, such as STJs and TESs. After the discussion of the detectors themselves, there will be a section devoted to the explicit use of these detectors with CAPS.

Relative Effectiveness of Letrozole Compared With Tamoxifen for Patients With Lobular Carcinoma in the BIG 1-98 Trial.

PubMed

Metzger Filho, Otto; Giobbie-Hurder, Anita; Mallon, Elizabeth; Gusterson, Barry; Viale, Giuseppe; Winer, Eric P; Thürlimann, Beat; Gelber, Richard D; Colleoni, Marco; Ejlertsen, Bent; Debled, Marc; Price, Karen N; Regan, Meredith M; Coates, Alan S; Goldhirsch, Aron

2015-09-01

To evaluate the relative effectiveness of letrozole compared with tamoxifen for patients with invasive ductal or lobular carcinoma. Patients diagnosed with early-stage invasive ductal carcinoma (IDC) or classic invasive lobular carcinoma (ILC) who were randomly assigned onto the Breast International Group (BIG) 1-98 trial and who had centrally reviewed pathology data were included (N = 2,923). HER2-negative IDC and ILC were additionally classified as hormone receptor-positive with high (luminal B [LB] -like) or low (luminal A [LA] -like) proliferative activity by Ki-67 labeling index. Survival analyses were performed with weighted Cox models that used inverse probability of censoring weighted modeling. The median follow-up time was 8.1 years. In multivariable models for disease-free survival (DFS), significant interactions between treatment and histology (ILC or IDC; P = .006) and treatment and subgroup (LB like or LA like; P = .01) were observed. In the ILC subset, there was a 66% reduction in the hazard of a DFS event with letrozole for LB (hazard ratio [HR], 0.34; 95% CI, 0.21 to 0.55) and a 50% reduction for LA subtypes (HR, 0.50; 95% CI, 0.32 to 0.78). In the IDC subset, there was a significant 35% reduction in the hazard of a DFS event with letrozole for the LB subtype (HR, 0.65; 95% CI, 0.53 to 0.79), but no difference between treatments was noted for IDC and the LA subtype (HR, 0.95; 95% CI, 0.76 to 1.20). The magnitude of benefit of adjuvant letrozole is greater for patients diagnosed with lobular carcinoma versus ductal carcinoma. © 2015 by American Society of Clinical Oncology.

Relative Effectiveness of Letrozole Compared With Tamoxifen for Patients With Lobular Carcinoma in the BIG 1-98 Trial

PubMed Central

Metzger Filho, Otto; Giobbie-Hurder, Anita; Mallon, Elizabeth; Gusterson, Barry; Viale, Giuseppe; Winer, Eric P.; Thürlimann, Beat; Gelber, Richard D.; Colleoni, Marco; Ejlertsen, Bent; Debled, Marc; Price, Karen N.; Regan, Meredith M.; Coates, Alan S.; Goldhirsch, Aron

2015-01-01

Purpose To evaluate the relative effectiveness of letrozole compared with tamoxifen for patients with invasive ductal or lobular carcinoma. Patients and Methods Patients diagnosed with early-stage invasive ductal carcinoma (IDC) or classic invasive lobular carcinoma (ILC) who were randomly assigned onto the Breast International Group (BIG) 1-98 trial and who had centrally reviewed pathology data were included (N = 2,923). HER2-negative IDC and ILC were additionally classified as hormone receptor–positive with high (luminal B [LB] –like) or low (luminal A [LA] –like) proliferative activity by Ki-67 labeling index. Survival analyses were performed with weighted Cox models that used inverse probability of censoring weighted modeling. Results The median follow-up time was 8.1 years. In multivariable models for disease-free survival (DFS), significant interactions between treatment and histology (ILC or IDC; P = .006) and treatment and subgroup (LB like or LA like; P = .01) were observed. In the ILC subset, there was a 66% reduction in the hazard of a DFS event with letrozole for LB (hazard ratio [HR], 0.34; 95% CI, 0.21 to 0.55) and a 50% reduction for LA subtypes (HR, 0.50; 95% CI, 0.32 to 0.78). In the IDC subset, there was a significant 35% reduction in the hazard of a DFS event with letrozole for the LB subtype (HR, 0.65; 95% CI, 0.53 to 0.79), but no difference between treatments was noted for IDC and the LA subtype (HR, 0.95; 95% CI, 0.76 to 1.20). Conclusion The magnitude of benefit of adjuvant letrozole is greater for patients diagnosed with lobular carcinoma versus ductal carcinoma. PMID:26215945

NGF induces adult stem Leydig cells to proliferate and differentiate during Leydig cell regeneration.

PubMed

Zhang, Lei; Wang, Huaxi; Yang, Yan; Liu, Hui; Zhang, Qihao; Xiang, Qi; Ge, Renshan; Su, Zhijian; Huang, Yadong

2013-06-28

Nerve growth factor (NGF) has been reported to be involved in male reproductive physiology. However, few reports have described the activity of NGF during Leydig cell development. The objective of the present study was to examine the role of NGF during stem-Leydig-cell (SLC) regeneration. We investigated the effects of NGF on Leydig-cell (LC) regeneration by measuring mRNA levels in the adult rat testis after ethane dimethanesulfonate (EDS) treatment. Furthermore, we used the established organ culture model of rat seminiferous tubules to examine the regulation of NGF during SLC proliferation and differentiation using EdU staining, real-time PCR and western blotting. Progenitor Leydig cells (PLCs) and immature Leydig cells (ILCs) were also used to investigate the effects of NGF on LCs at different developmental stages. NGF mRNA levels changed significantly during Leydig-cell regeneration in vivo. In vitro, NGF significantly promoted the proliferation of stem Leydig cells and also induced steroidogenic enzyme gene expression and 3β-HSD protein expression. The data from PLCs and ILCs showed that NGF could increase Cyclin D1 and Hsd 17b3 mRNA levels in PLCs and Cyclin D1 mRNA levels in ILCs. These results indicate that NGF may play an important role during LC regeneration by regulating the proliferation and differentiation of LCs at different developmental stages, from SLCs to PLCs and from PLCs to ILCs. The discovery of this effect of NGF on Leydig cells will provide useful information for developing new potential therapies for PADAM (Partial Androgen Deficiency in the Aging Male). Copyright © 2013 Elsevier Inc. All rights reserved.

Inverse relationship between body mass index and coronary artery calcification in patients with clinically significant coronary lesions.

PubMed

Kovacic, Jason C; Lee, Paul; Baber, Usman; Karajgikar, Rucha; Evrard, Solene M; Moreno, Pedro; Mehran, Roxana; Fuster, Valentin; Dangas, George; Sharma, Samin K; Kini, Annapoorna S

2012-03-01

Mounting data support a 'calcification paradox', whereby reduced bone mineral density is associated with increased vascular calcification. Furthermore, reduced bone mineral density is prevalent in older persons with lower body mass index (BMI). Therefore, although BMI and coronary artery calcification (CAC) exhibit a positive relationship in younger persons, it is predicted that in older persons and/or those at risk for osteoporosis, an inverse relationship between BMI and CAC may apply. We sought to explore this hypothesis in a large group of patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). We accessed our single-center registry for 07/01/1999 to 06/30/2009, extracting data on all patients that underwent PCI. To minimize bias we excluded those at the extremes of age or BMI and non-Black/Hispanic/Caucasians, leaving 9993 study subjects (age 66.6±9.9 years). Index lesion calcification (ILC) was analyzed with respect to BMI. Comparing index lesions with no angiographic calcification to those with the most severe, mean BMI decreased by 1.11 kgm(-2); a reduction of 3.9% (P<0.0001). By multivariable modeling, BMI was an independent inverse predictor of moderate-severe ILC (m-sILC; odds ratio [OR] 0.967, 95% CI 0.953-0.980, P<0.0001). Additional fully adjusted models identified that, compared to those with normal BMI, obese patients had an OR of 0.702 for m-sILC (95% CI 0.596-0.827, P<0.0001). In a large group of PCI patients, we identified an inverse correlation between BMI and index lesion calcification. These associations are consistent with established paradigms and suggest a complex interrelationship between BMI, body size and vascular calcification. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

High frequency of coexistence of columnar cell lesions, lobular neoplasia, and low grade ductal carcinoma in situ with invasive tubular carcinoma and invasive lobular carcinoma.

PubMed

Abdel-Fatah, Tarek M A; Powe, Desmond G; Hodi, Zsolt; Lee, Andrew H S; Reis-Filho, Jorge S; Ellis, Ian O

2007-03-01

This study was undertaken to determine the morphologic features and frequency of putative precursor lesions involved in the development of some pure forms of special types and low grade breast carcinoma. We reviewed 147 successive tumor cases, comprising tubular carcinoma (TC); pure type (n=56) and mixed type (n=20), invasive lobular carcinoma (ILC); classic type (n=57), and tubulolobular carcinoma (TLC; n=14). The presence of preinvasive lesions including columnar cell lesions (CCLs), usual epithelial hyperplasia, ductal carcinoma in situ (DCIS), and lobular neoplasia (LN) was determined. Estrogen receptor and E-cadherin immunohistochemistry was performed. Ninety-five percent (95%) of pure TCs had associated CCLs with the majority showing flat epithelial atypia. Atypical ductal hyperplasia (ADH)/DCIS was present in 89% patients. Colocalization of CCL, ADH/DCIS, and TC was seen in 85% patients, all displaying the same cytologic-nuclear morphology in most cases. LN was seen in 16%. In ILC, 91% cases showed LN. CCL and ADH/DCIS were seen in 60% and 42% cases, respectively. E-cadherin was positive in TLC but reduced in TC and completely absent in ILC. In conclusion, our findings support the hypothesis that CCLs are associated with pure and mixed forms of TC, and that LN is involved in ILC development. Our observations suggest that these lesions represent family members of low grade precursor, in situ and invasive neoplastic lesions of the breast. Molecular studies are being performed to substantiate the hypothesis that tubular and lobular carcinomas have direct evolutionary links to CCLs and flat epithelial atypia.

Left-handed and right-handed U(1) gauge symmetry

NASA Astrophysics Data System (ADS)

Nomura, Takaaki; Okada, Hiroshi

2018-01-01

We propose a model with the left-handed and right-handed continuous Abelian gauge symmetry; U(1) L × U(1) R . Then three right-handed neutrinos are naturally required to achieve U(1) R anomaly cancellations, while several mirror fermions are also needed to do U(1) L anomaly cancellations. Then we formulate the model, and discuss its testability of the new gauge interactions at collider physics such as the large hadron collider (LHC) and the international linear collider (ILC). In particular, we can investigate chiral structure of the interactions by the analysis of forward-backward asymmetry based on polarized beam at the ILC.

Flyback CCM inverter for AC module applications: iterative learning control and convergence analysis

NASA Astrophysics Data System (ADS)

Lee, Sung-Ho; Kim, Minsung

2017-12-01

This paper presents an iterative learning controller (ILC) for an interleaved flyback inverter operating in continuous conduction mode (CCM). The flyback CCM inverter features small output ripple current, high efficiency, and low cost, and hence it is well suited for photovoltaic power applications. However, it exhibits the non-minimum phase behaviour, because its transfer function from control duty to output current has the right-half-plane (RHP) zero. Moreover, the flyback CCM inverter suffers from the time-varying grid voltage disturbance. Thus, conventional control scheme results in inaccurate output tracking. To overcome these problems, the ILC is first developed and applied to the flyback inverter operating in CCM. The ILC makes use of both predictive and current learning terms which help the system output to converge to the reference trajectory. We take into account the nonlinear averaged model and use it to construct the proposed controller. It is proven that the system output globally converges to the reference trajectory in the absence of state disturbances, output noises, or initial state errors. Numerical simulations are performed to validate the proposed control scheme, and experiments using 400-W AC module prototype are carried out to demonstrate its practical feasibility.

ID’ing Innate and Innate-like Lymphoid Cells

PubMed Central

Verykokakis, Mihalis; Zook, Erin C.; Kee, Barbara L.

2014-01-01

Summary The immune system can be divided into innate and adaptive components that differ in their rate and mode of cellular activation, with innate immune cells being the first responders to invading pathogens. Recent advances in the identification and characterization of innate lymphoid cells have revealed reiterative developmental programs that result in cells with effector fates that parallel those of adaptive lymphoid cells and are tailored to effectively eliminate a broad spectrum of pathogenic challenges. However, activation of these cells can also be associated with pathologies such as autoimmune disease. One major distinction between innate and adaptive immune system cells is the constitutive expression of ID proteins in the former and inducible expression in the latter. ID proteins function as antagonists of the E protein transcription factors that play critical roles in lymphoid specification as well as B and T-lymphocyte development. In this review, we examine the transcriptional mechanisms controlling the development of innate lymphocytes, including natural killer cells and the recently identified innate lymphoid cells (ILC1, ILC2, and ILC3), and innate-like lymphocytes, including natural killer T cells, with an emphasis on the known requirements for the ID proteins. PMID:25123285

ID'ing innate and innate-like lymphoid cells.

PubMed

Verykokakis, Mihalis; Zook, Erin C; Kee, Barbara L

2014-09-01

The immune system can be divided into innate and adaptive components that differ in their rate and mode of cellular activation, with innate immune cells being the first responders to invading pathogens. Recent advances in the identification and characterization of innate lymphoid cells have revealed reiterative developmental programs that result in cells with effector fates that parallel those of adaptive lymphoid cells and are tailored to effectively eliminate a broad spectrum of pathogenic challenges. However, activation of these cells can also be associated with pathologies such as autoimmune disease. One major distinction between innate and adaptive immune system cells is the constitutive expression of ID proteins in the former and inducible expression in the latter. ID proteins function as antagonists of the E protein transcription factors that play critical roles in lymphoid specification as well as B- and T-lymphocyte development. In this review, we examine the transcriptional mechanisms controlling the development of innate lymphocytes, including natural killer cells and the recently identified innate lymphoid cells (ILC1, ILC2, and ILC3), and innate-like lymphocytes, including natural killer T cells, with an emphasis on the known requirements for the ID proteins. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

IL-33: biological properties, functions, and roles in airway disease.

PubMed

Drake, Li Yin; Kita, Hirohito

2017-07-01

Interleukin (IL)-33 is a key cytokine involved in type 2 immunity and allergic airway diseases. Abundantly expressed in lung epithelial cells, IL-33 plays critical roles in both innate and adaptive immune responses in mucosal organs. In innate immunity, IL-33 and group 2 innate lymphoid cells (ILC2s) provide an essential axis for rapid immune responses and tissue homeostasis. In adaptive immunity, IL-33 interacts with dendritic cells, Th2 cells, follicular T cells, and regulatory T cells, where IL-33 influences the development of chronic airway inflammation and tissue remodeling. The clinical findings that both the IL-33 and ILC2 levels are elevated in patients with allergic airway diseases suggest that IL-33 plays an important role in the pathogenesis of these diseases. IL-33 and ILC2 may also serve as biomarkers for disease classification and to monitor the progression of diseases. In this article, we reviewed the current knowledge of the biology of IL-33 and discussed the roles of the IL-33 in regulating airway immune responses and allergic airway diseases. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Quality of Life as reported by school children and their parents: a cross-sectional survey

PubMed Central

Jozefiak, Thomas; Larsson, Bo; Wichstrøm, Lars; Mattejat, Fritz; Ravens-Sieberer, Ulrike

2008-01-01

Background Comprehensive evidence exists regarding the discrepancy between children's reports and parents' by proxy reports on emotional and behavioural problems. However, little is yet known about factors influencing the extent to which child self- and parent by proxy reports differ in respect of child Quality of Life (QoL). The aim of the study was to investigate the degree of discrepancy between child and parent by proxy reports as measured by two different QoL instruments. Methods A representative Norwegian sample of 1997 school children aged 8–16 years, and their parents were studied using the Inventory of Life Quality (ILC) and the 'Kinder Lebensqualität Fragebogen' (KINDL). Child and parent reports were compared by t-test, and correlations were calculated by Pearson product moment coefficient. Psychometric aspects were examined in regard to both translated QoL instruments (internal consistency by Cronbach's alpha and test-retest reliability by intraclass correlation coefficients). Results Parents evaluated the QoL of their children significantly more positively than did the children. Correlations between mother-child and father-child reports were significant (p < 0.01) and similar but low to moderate (r = 0.32; and r = 0.30, respectively, for the KINDL, and r = 0.30 and r = 0.26, respectively, for the ILC). Mother and father reports correlated moderately highly (r = 0.54 and r = 0.61 for the KINDL and ILC, respectively). No significant differences between correlations of mother-daughter/son and father-daughter/son pairs in regard to reported child QoL were observed on either of the two instruments. Conclusion In the present general population sample, parents reported higher child QoL than did their children. Concordance between child and parent by proxy report was low to moderate. The level of agreement between mothers and fathers in regard to their child's QoL was moderate. No significant impact of parent and child gender in regard to agreement in ratings of child QoL was found. Both the child and parent versions of the Norwegian translations of the KINDL and ILC can be used in surveys of community populations, but in regard to the self-report of 9–10 years old children, only the KINDL total QoL scale or the ILC are recommended. PMID:18489777

Will there be energy frontier colliders after LHC?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shiltsev, Vladimir

2016-09-15

High energy particle colliders have been in the forefront of particle physics for more than three decades. At present the near term US, European and international strategies of the particle physics community are centered on full exploitation of the physics potential of the Large Hadron Collider (LHC) through its high-luminosity upgrade (HL-LHC). The future of the world-wide HEP community critically depends on the feasibility of possible post-LHC colliders. The concept of the feasibility is complex and includes at least three factors: feasibility of energy, feasibility of luminosity and feasibility of cost. Here we overview all current options for post-LHC collidersmore » from such perspective (ILC, CLIC, Muon Collider, plasma colliders, CEPC, FCC, HE-LHC) and discuss major challenges and accelerator R&D required to demonstrate feasibility of an energy frontier accelerator facility following the LHC. We conclude by taking a look into ultimate energy reach accelerators based on plasmas and crystals, and discussion on the perspectives for the far future of the accelerator-based particle physics.« less

CP-violating top quark couplings at future linear e^+e^- colliders

NASA Astrophysics Data System (ADS)

Bernreuther, W.; Chen, L.; García, I.; Perelló, M.; Poeschl, R.; Richard, F.; Ros, E.; Vos, M.

2018-02-01

We study the potential of future lepton colliders to probe violation of the CP symmetry in the top quark sector. In certain extensions of the Standard Model, such as the two-Higgs-doublet model (2HDM), sizeable anomalous top quark dipole moments can arise, which may be revealed by a precise measurement of top quark pair production. We present results from detailed Monte Carlo studies for the ILC at 500 GeV and CLIC at 380 GeV and use parton-level simulations to explore the potential of high-energy operation. We find that precise measurements in e^+e^- → t\\bar{t} production with subsequent decay to lepton plus jets final states can provide sufficient sensitivity to detect Higgs-boson-induced CP violation in a viable two-Higgs-doublet model. The potential of a linear e^+e^- collider to detect CP-violating electric and weak dipole form factors of the top quark exceeds the prospects of the HL-LHC by over an order of magnitude.

Extracting foreground-obscured μ-distortion anisotropies to constrain primordial non-Gaussianity

NASA Astrophysics Data System (ADS)

Remazeilles, M.; Chluba, J.

2018-07-01

Correlations between cosmic microwave background (CMB) temperature, polarization, and spectral distortion anisotropies can be used as a probe of primordial non-Gaussianity. Here, we perform a reconstruction of μ-distortion anisotropies in the presence of Galactic and extragalactic foregrounds, applying the so-called Constrained ILC component separation method to simulations of proposed CMB space missions (PIXIE, LiteBIRD, CORE, and PICO). Our sky simulations include Galactic dust, Galactic synchrotron, Galactic free-free, thermal Sunyaev-Zeldovich effect, as well as primary CMB temperature and μ-distortion anisotropies, the latter being added as correlated field. The Constrained ILC method allows us to null the CMB temperature anisotropies in the reconstructed μ-map (and vice versa), in addition to mitigating the contaminations from astrophysical foregrounds and instrumental noise. We compute the cross-power spectrum between the reconstructed (CMB-free) μ-distortion map and the (μ-free) CMB temperature map, after foreground removal and component separations. Since the cross-power spectrum is proportional to the primordial non-Gaussianity parameter, fNL, on scales k˜eq 740 Mpc^{-1}, this allows us to derive fNL-detection limits for the aforementioned future CMB experiments. Our analysis shows that foregrounds degrade the theoretical detection limits (based mostly on instrumental noise) by more than one order of magnitude, with PICO standing the best chance at placing upper limits on scale-dependent non-Gaussianity. We also discuss the dependence of the constraints on the channel sensitivities and chosen bands. Like for B-mode polarization measurements, extended coverage at frequencies ν ≲ 40 GHz and ν ≳ 400 GHz provides more leverage than increased channel sensitivity.

Extracting foreground-obscured μ-distortion anisotropies to constrain primordial non-Gaussianity

NASA Astrophysics Data System (ADS)

Remazeilles, M.; Chluba, J.

2018-04-01

Correlations between cosmic microwave background (CMB) temperature, polarization and spectral distortion anisotropies can be used as a probe of primordial non-Gaussianity. Here, we perform a reconstruction of μ-distortion anisotropies in the presence of Galactic and extragalactic foregrounds, applying the so-called Constrained ILC component separation method to simulations of proposed CMB space missions (PIXIE, LiteBIRD, CORE, PICO). Our sky simulations include Galactic dust, Galactic synchrotron, Galactic free-free, thermal Sunyaev-Zeldovich effect, as well as primary CMB temperature and μ-distortion anisotropies, the latter being added as correlated field. The Constrained ILC method allows us to null the CMB temperature anisotropies in the reconstructed μ-map (and vice versa), in addition to mitigating the contaminations from astrophysical foregrounds and instrumental noise. We compute the cross-power spectrum between the reconstructed (CMB-free) μ-distortion map and the (μ-free) CMB temperature map, after foreground removal and component separation. Since the cross-power spectrum is proportional to the primordial non-Gaussianity parameter, fNL, on scales k˜eq 740 Mpc^{-1}, this allows us to derive fNL-detection limits for the aforementioned future CMB experiments. Our analysis shows that foregrounds degrade the theoretical detection limits (based mostly on instrumental noise) by more than one order of magnitude, with PICO standing the best chance at placing upper limits on scale-dependent non-Gaussianity. We also discuss the dependence of the constraints on the channel sensitivities and chosen bands. Like for B-mode polarization measurements, extended coverage at frequencies ν ≲ 40 GHz and ν ≳ 400 GHz provides more leverage than increased channel sensitivity.

Trichoscopy of Steroid-Induced Atrophy.

PubMed

Pirmez, Rodrigo; Abraham, Leonardo S; Duque-Estrada, Bruna; Damasco, Patrícia; Farias, Débora Cadore; Kelly, Yanna; Doche, Isabella

2017-10-01

Intralesional corticosteroid (IL-CS) injections have been used to treat a variety of dermatological and nondermatological diseases. Although an important therapeutic tool in dermatology, a number of local side effects, including skin atrophy, have been reported following IL-CS injections. We recently noticed that a subset of patients with steroid-induced atrophy presented with ivory-colored areas under trichoscopy. We performed a retrospective analysis of trichoscopic images and medical records from patients presenting ivory-colored areas associated with atrophic scalp lesions. In this paper, we associate this feature with the presence of steroid deposits in the dermis and report additional trichoscopic features of steroid-induced atrophy on the scalp, such as prominent blood vessels and visualization of hair bulbs.

Corrosion on Fatigue and Fatigue Crack Growth in Aircraft Structural Materials

DTIC Science & Technology

1979-06-01

nmonth- of 1Q730 v,’ ilc th au!Ihor xas. a! !Lockhehed Rvye (anyon Adva.nce,1d tj;ion in(I Research Laboratory. Mr. Gary Gos’s andl Mr. WValter Fitze ti...frtaerltd o11 1~ a cuea o rnicr srruae. 150x.IILI’ r11da- o p sdo’ l-akddi pe.Fgrc ()id4()c hl’ micro,,ructura ’Setd ~ ila i l--n ig ilc to ~IiiCId...bart 16 iretorted increcascd fatigue 0 t C Id ’ L5 treg th fof t eiii I Ic iti:ci st to L)i poic ed lirfe r; irnod a Ipho -teta or f inef~t

Advanced technologies for future ground-based, laser-interferometric gravitational wave detectors

PubMed Central

Hammond, Giles; Hild, Stefan; Pitkin, Matthew

2014-01-01

We present a review of modern optical techniques being used and developed for the field of gravitational wave detection. We describe the current state-of-the-art of gravitational waves detector technologies with regard to optical layouts, suspensions and test masses. We discuss the dominant sources and noise in each of these subsystems and the developments that will help mitigate them for future generations of detectors. We very briefly summarise some of the novel astrophysics that will be possible with these upgraded detectors. PMID:25705087

HPV16-E7 Expression in skin induces TSLP secretion, type 2 ILC infiltration and atopic dermatitis-like lesions

PubMed Central

Bergot, Anne-Sophie; Monnet, Nastasia; Tran, Le Son; Mittal, Deepak; Al-Kouba, Jane; Steptoe, Raymond J.; Grimbaldeston, Michele A.; Frazer, Ian H.; Wells, James W.

2014-01-01

Atopic dermatitis is a common pruritic and inflammatory skin disorder with unknown etiology. Most commonly occurring during early childhood, atopic dermatitis is associated with eczematous lesions and lichenification, in which the epidermis becomes hypertrophied resulting in thickening of the skin. In this study, we report an atopic dermatitis-like pathophysiology results in a murine model following the expression of the high-risk Human Papillomavirus (HPV) 16 oncoprotein E7 in keratinocytes under the Keratin 14 promoter. We show that HPV 16 E7 expression in the skin is associated with skin thickening, acanthosis and light spongiosis. Locally, HPV 16 E7 expressing skin secreted high levels of TSLP and contained increased numbers of ILCs. High levels of circulating IgE were associated with increased susceptibility to skin allergy in a model of cutaneous challenge, and to airway bronchiolar inflammation, enhanced airway goblet cell metaplasia and mucus production in a model of atopic march. Surprisingly, skin pathology occurred independently of T-cells and mast cells. Thus, our findings suggest that the expression of a single HPV oncogene in the skin can drive the onset of atopic dermatitis-like pathology through the induction of TSLP and type 2 ILC infiltration. PMID:25601274

Cryogenic performance of a conduction-cooling splittable quadrupole magnet for ILC cryomodules

NASA Astrophysics Data System (ADS)

Kimura, N.; Andreev, N.; Kashikhin, V. S.; Kerby, J.; Takahashi, M.; Tartaglia, M. A.; Tosaka, T.; Yamamoto, A.

2014-01-01

A conduction-cooled splittable superconducting quadrupole magnet was designed and fabricated at Fermilab for use in cryomodules of the International Linear Collider (ILC) type, in which the magnet was to be assembled around the beam tube to avoid contaminating the ultraclean superconducting radio frequency cavity volume. This quadrupole was first tested in a liquid helium bath environment at Fermilab, where its quench and magnetic properties were characterized. Because the device is to be cooled by conduction when installed in cryomodules, a separate test with a conduction-cooled configuration was planned at KEK and Fermilab. The magnet was converted to a conduction-cooled configuration by adding conduction-cooling passages made of high-purity aluminum. Efforts to convert and refabricate the magnet into a cryostat equipped with a double-stage pulse-tube-type cryocooler began in 2011, and a thermal performance test, including a magnet excitation test of up to 30 A, was conducted at KEK. In this test, the magnet with the conduction-cooled configuration was successfully cooled to 4 K within 190 h, with an acceptable heat load of less than 1 W at 4 K. It was also confirmed that the conduction-cooled splittable superconducting quadrupole magnet was practical for use in ILC-type cryomodules.

Tissue-Restricted Adaptive Type 2 Immunity Is Orchestrated by Expression of the Costimulatory Molecule OX40L on Group 2 Innate Lymphoid Cells.

PubMed

Halim, Timotheus Y F; Rana, Batika M J; Walker, Jennifer A; Kerscher, Bernhard; Knolle, Martin D; Jolin, Helen E; Serrao, Eva M; Haim-Vilmovsky, Liora; Teichmann, Sarah A; Rodewald, Hans-Reimer; Botto, Marina; Vyse, Timothy J; Fallon, Padraic G; Li, Zhi; Withers, David R; McKenzie, Andrew N J

2018-06-19

The local regulation of type 2 immunity relies on dialog between the epithelium and the innate and adaptive immune cells. Here we found that alarmin-induced expression of the co-stimulatory molecule OX40L on group 2 innate lymphoid cells (ILC2s) provided tissue-restricted T cell co-stimulation that was indispensable for Th2 and regulatory T (Treg) cell responses in the lung and adipose tissue. Interleukin (IL)-33 administration resulted in organ-specific surface expression of OX40L on ILC2s and the concomitant expansion of Th2 and Treg cells, which was abolished upon deletion of OX40L on ILC2s (Il7ra Cre/+ Tnfsf4 fl/fl mice). Moreover, Il7ra Cre/+ Tnfsf4 fl/fl mice failed to mount effective Th2 and Treg cell responses and corresponding adaptive type 2 pulmonary inflammation arising from Nippostrongylus brasiliensis infection or allergen exposure. Thus, the increased expression of OX40L in response to IL-33 acts as a licensing signal in the orchestration of tissue-specific adaptive type 2 immunity, without which this response fails to establish. Copyright © 2018 MRC Laboratory of Molecular Biology. Published by Elsevier Inc. All rights reserved.

Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity

NASA Astrophysics Data System (ADS)

van de Pavert, Serge A.; Ferreira, Manuela; Domingues, Rita G.; Ribeiro, Hélder; Molenaar, Rosalie; Moreira-Santos, Lara; Almeida, Francisca F.; Ibiza, Sales; Barbosa, Inês; Goverse, Gera; Labão-Almeida, Carlos; Godinho-Silva, Cristina; Konijn, Tanja; Schooneman, Dennis; O'Toole, Tom; Mizee, Mark R.; Habani, Yasmin; Haak, Esther; Santori, Fabio R.; Littman, Dan R.; Schulte-Merker, Stefan; Dzierzak, Elaine; Simas, J. Pedro; Mebius, Reina E.; Veiga-Fernandes, Henrique

2014-04-01

The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.

Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity.

PubMed

van de Pavert, Serge A; Ferreira, Manuela; Domingues, Rita G; Ribeiro, Hélder; Molenaar, Rosalie; Moreira-Santos, Lara; Almeida, Francisca F; Ibiza, Sales; Barbosa, Inês; Goverse, Gera; Labão-Almeida, Carlos; Godinho-Silva, Cristina; Konijn, Tanja; Schooneman, Dennis; O'Toole, Tom; Mizee, Mark R; Habani, Yasmin; Haak, Esther; Santori, Fabio R; Littman, Dan R; Schulte-Merker, Stefan; Dzierzak, Elaine; Simas, J Pedro; Mebius, Reina E; Veiga-Fernandes, Henrique

2014-04-03

The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.

T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production

PubMed Central

Zhu, Jinfang

2015-01-01

Interleukin-4 (IL-4), IL-5 and IL-13, the signature cytokines that are produced during type 2 immune responses, are critical for protective immunity against infections of extracellular parasites and are responsible for asthma and many other allergic inflammatory diseases. Although many immune cell types within the myeloid lineage compartment including basophils, eosinophils and mast cells are capable of producing at least one of these cytokines, the production of these “type 2 immune response-related” cytokines by lymphoid lineages, CD4 T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) in particular, are the central events during type 2 immune responses. In this review, I will focus on the signaling pathways and key molecules that determine the differentiation of naïve CD4 T cells into Th2 cells, and how the expression of Th2 cytokines, especially IL-4 and IL-13, is regulated in Th2 cells. The similarities and differences in the differentiation of Th2 cells, IL-4-producing T follicular helper (Tfh) cells and ILC2s as well as their relationships will also be discussed. PMID:26044597

IL-33-mediated protection against experimental cerebral malaria is linked to induction of type 2 innate lymphoid cells, M2 macrophages and regulatory T cells.

PubMed

Besnard, Anne-Gaelle; Guabiraba, Rodrigo; Niedbala, Wanda; Palomo, Jennifer; Reverchon, Flora; Shaw, Tovah N; Couper, Kevin N; Ryffel, Bernhard; Liew, Foo Y

2015-02-01

Cerebral malaria (CM) is a complex parasitic disease caused by Plasmodium sp. Failure to establish an appropriate balance between pro- and anti-inflammatory immune responses is believed to contribute to the development of cerebral pathology. Using the blood-stage PbA (Plasmodium berghei ANKA) model of infection, we show here that administration of the pro-Th2 cytokine, IL-33, prevents the development of experimental cerebral malaria (ECM) in C57BL/6 mice and reduces the production of inflammatory mediators IFN-γ, IL-12 and TNF-α. IL-33 drives the expansion of type-2 innate lymphoid cells (ILC2) that produce Type-2 cytokines (IL-4, IL-5 and IL-13), leading to the polarization of the anti-inflammatory M2 macrophages, which in turn expand Foxp3 regulatory T cells (Tregs). PbA-infected mice adoptively transferred with ILC2 have elevated frequency of M2 and Tregs and are protected from ECM. Importantly, IL-33-treated mice deleted of Tregs (DEREG mice) are no longer able to resist ECM. Our data therefore provide evidence that IL-33 can prevent the development of ECM by orchestrating a protective immune response via ILC2, M2 macrophages and Tregs.

IL-33-Mediated Protection against Experimental Cerebral Malaria Is Linked to Induction of Type 2 Innate Lymphoid Cells, M2 Macrophages and Regulatory T Cells

PubMed Central

Besnard, Anne-Gaelle; Guabiraba, Rodrigo; Niedbala, Wanda; Palomo, Jennifer; Reverchon, Flora; Shaw, Tovah N.; Couper, Kevin N.; Ryffel, Bernhard; Liew, Foo Y.

2015-01-01

Cerebral malaria (CM) is a complex parasitic disease caused by Plasmodium sp. Failure to establish an appropriate balance between pro- and anti-inflammatory immune responses is believed to contribute to the development of cerebral pathology. Using the blood-stage PbA (Plasmodium berghei ANKA) model of infection, we show here that administration of the pro-Th2 cytokine, IL-33, prevents the development of experimental cerebral malaria (ECM) in C57BL/6 mice and reduces the production of inflammatory mediators IFN-γ, IL-12 and TNF-α. IL-33 drives the expansion of type-2 innate lymphoid cells (ILC2) that produce Type-2 cytokines (IL-4, IL-5 and IL-13), leading to the polarization of the anti-inflammatory M2 macrophages, which in turn expand Foxp3 regulatory T cells (Tregs). PbA-infected mice adoptively transferred with ILC2 have elevated frequency of M2 and Tregs and are protected from ECM. Importantly, IL-33-treated mice deleted of Tregs (DEREG mice) are no longer able to resist ECM. Our data therefore provide evidence that IL-33 can prevent the development of ECM by orchestrating a protective immune response via ILC2, M2 macrophages and Tregs. PMID:25659095

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Lei; Wang, Huaxi; Yang, Yan

Highlights: •Nerve growth factor has shown significant changes on mRNA levels during Adult Leydig cells regeneration. •We established the organ culture model of rat seminiferous tubules with ethane dimethyl sulphonate (EDS) treatment. •Nerve growth factor has shown proliferation and differentiation-promoting effects on Adult stem Leydig cells. •Nerve growth factor induces progenitor Leydig cells to proliferate and differentiate and immature Leydig cells to proliferate. -- Abstract: Nerve growth factor (NGF) has been reported to be involved in male reproductive physiology. However, few reports have described the activity of NGF during Leydig cell development. The objective of the present study was tomore » examine the role of NGF during stem-Leydig-cell (SLC) regeneration. We investigated the effects of NGF on Leydig-cell (LC) regeneration by measuring mRNA levels in the adult rat testis after ethane dimethanesulfonate (EDS) treatment. Furthermore, we used the established organ culture model of rat seminiferous tubules to examine the regulation of NGF during SLC proliferation and differentiation using EdU staining, real-time PCR and western blotting. Progenitor Leydig cells (PLCs) and immature Leydig cells (ILCs) were also used to investigate the effects of NGF on LCs at different developmental stages. NGF mRNA levels changed significantly during Leydig-cell regeneration in vivo. In vitro, NGF significantly promoted the proliferation of stem Leydig cells and also induced steroidogenic enzyme gene expression and 3β-HSD protein expression. The data from PLCs and ILCs showed that NGF could increase Cyclin D1 and Hsd 17b3 mRNA levels in PLCs and Cyclin D1 mRNA levels in ILCs. These results indicate that NGF may play an important role during LC regeneration by regulating the proliferation and differentiation of LCs at different developmental stages, from SLCs to PLCs and from PLCs to ILCs. The discovery of this effect of NGF on Leydig cells will provide useful information for developing new potential therapies for PADAM (Partial Androgen Deficiency in the Aging Male)« less

Interlaboratory comparison for the measurement of particle size and zeta potential of silica nanoparticles in an aqueous suspension

NASA Astrophysics Data System (ADS)

Lamberty, Andrée; Franks, Katrin; Braun, Adelina; Kestens, Vikram; Roebben, Gert; Linsinger, Thomas P. J.

2011-12-01

The Institute for Reference Materials and Measurements has organised an interlaboratory comparison (ILC) to allow the participating laboratories to demonstrate their proficiency in particle size and zeta potential measurements on monomodal aqueous suspensions of silica nanoparticles in the 10-100 nm size range. The main goal of this ILC was to identify competent collaborators for the production of certified nanoparticle reference materials. 38 laboratories from four different continents participated in the ILC with different methods for particle sizing and determination of zeta potential. Most of the laboratories submitted particle size results obtained with centrifugal liquid sedimentation (CLS), dynamic light scattering (DLS) or electron microscopy (EM), or zeta potential values obtained via electrophoretic light scattering (ELS). The results of the laboratories were evaluated using method-specific z scores, calculated on the basis of consensus values from the ILC. For CLS (13 results) and EM (13 results), all reported values were within the ±2 | z| interval. For DLS, 25 of the 27 results reported were within the ±2 | z| interval, the two other results were within the ±3 | z| interval. The standard deviations of the corresponding laboratory mean values varied between 3.7 and 6.5%, which demonstrates satisfactory interlaboratory comparability of CLS, DLS and EM particle size values. From the received test reports, a large discrepancy was observed in terms of the laboratory's quality assurance systems, which are equally important for the selection of collaborators in reference material certification projects. Only a minority of the participating laboratories is aware of all the items that are mandatory in test reports compliant to ISO/IEC 17025 (ISO General requirements for the competence of testing and calibration laboratories. International Organisation for Standardization, Geneva, 2005b). The absence of measurement uncertainty values in the reports, for example, hindered the calculation of zeta scores.

Selective magnetic resonance imaging (MRI) in invasive lobular breast cancer based on mammographic density: does it lead to an appropriate change in surgical treatment?

PubMed

Bansal, Gaurav J; Santosh, Divya; Davies, Eleri L

2016-01-01

The purpose of this study was to evaluate whether high mammographic density can be used as one of the selection criteria for MRI in invasive lobular breast cancer (ILC). In our institute, high breast density has been used as one of the indications for performing MRI scan in patients with ILC. We divided the patients in two groups, one with MRI performed pre-operatively and other without MRI. We compared their surgical procedures and analyzed whether surgical plan was altered after MRI. In case of alteration of plan, we analyzed whether the change was adequate by comparing post-operative histological findings. Between 2011 and 2015, there were a total of 1601 breast cancers with 97 lobular cancers, out of which 36 had pre-operative MRI and 61 had no MRI scan. 12 (33.3%) had mastectomy following MRI, out of which 9 (25%) had change in surgical plan from conservation to mastectomy following MRI. There were no unnecessary mastectomies in the MRI group. However, utilization of MRI in this cohort of patients did not reduce reoperation rate (19.3%). Lobular carcinoma in situ (LCIS) was identified in 60% of reoperations on post-surgical histology. Patients in the "No MRI" group had higher mastectomy rate 26 (42.6%), which was again appropriate. High mammographic density is a useful risk stratification criterion for selective MRI in ILC within a multidisciplinary team meeting setting. Provided additional lesions identified on MRI are confirmed with biopsy, pre-operative MRI does not cause unnecessary mastectomies. Used in this selective manner, reoperation rates were not eliminated, albeit reduced when compared to literature. High mammographic breast density can be used as one of the selection criteria for pre-operative MRI in ILC without an increase in inappropriate mastectomies with potential time and cost savings. In this cohort, re-excisions were not reduced markedly with pre-operative MRI.

Histologic heterogeneity of triple negative breast cancer: A National Cancer Centre Database analysis.

PubMed

Mills, Matthew N; Yang, George Q; Oliver, Daniel E; Liveringhouse, Casey L; Ahmed, Kamran A; Orman, Amber G; Laronga, Christine; Hoover, Susan J; Khakpour, Nazanin; Costa, Ricardo L B; Diaz, Roberto

2018-06-02

Triple negative breast cancer (TNBC) is an aggressive disease, but recent studies have identified heterogeneity in patient outcomes. However, the utility of histologic subtyping in TNBC has not yet been well-characterised. This study utilises data from the National Cancer Center Database (NCDB) to complete the largest series to date investigating the prognostic importance of histology within TNBC. A total of 729,920 patients (pts) with invasive ductal carcinoma (IDC), metaplastic breast carcinoma (MBC), medullary breast carcinoma (MedBC), adenoid cystic carcinoma (ACC), invasive lobular carcinoma (ILC) or apocrine breast carcinoma (ABC) treated between 2004 and 2012 were identified in the NCDB. Of these, 89,222 pts with TNBC that received surgery were analysed. Kaplan-Meier analysis, log-rank testing and multivariate Cox proportional hazards regression were utilised with overall survival (OS) as the primary outcome. MBC (74.1%), MedBC (60.6%), ACC (75.7%), ABC (50.1%) and ILC (1.8%) had significantly different proportions of triple negativity when compared to IDC (14.0%, p < 0.001). TNBC predicted an inferior OS in IDC (p < 0.001) and ILC (p < 0.001). Lumpectomy and radiation (RT) were more common in MedBC (51.7%) and ACC (51.5%) and less common in MBC (33.1%) and ILC (25.4%), when compared to IDC (42.5%, p < 0.001). TNBC patients with MBC (HR 1.39, p < 0.001), MedBC (HR 0.42, p < 0.001) and ACC (HR 0.32, p = 0.003) differed significantly in OS when compared to IDC. Our results indicate that histologic heterogeneity in TNBC significantly informs patient outcomes and thus, has the potential to aid in the development of optimum personalised treatments. Copyright © 2018 Elsevier Ltd. All rights reserved.

Development of a TES-Based Anti-Coincidence Detector for Future X-Ray Observations

NASA Technical Reports Server (NTRS)

Bailey, Catherine N.; Adams, J. S.; Bandler, S. R.; Eckart, M. E.; Ewin, A. J.; Finkbeiner, F. M.; Kelley, R. L.; Kilbourne, C. A.; Porter, F. S.; Sadleir, J. E.;

Development of a TES-Based Anti-Coincidence Detector for Future X-ray Observatories

NASA Technical Reports Server (NTRS)

Bailey, Catherine

2011-01-01

Microcalorimeters onboard future x-ray observatories require an anti-coincidence detector to remove environmental backgrounds. In order to most effectively integrate this anticoincidence detector with the main microcalorimeter array, both instruments should use similar read-out technology. The detectors used in the Cryogenic Dark Matter Search (CDMS) use a phonon measurement technique that is well suited for an anti-coincidence detector with a microcalorimeter array using SQUID readout. This technique works by using a transition-edge sensor (TES) connected to superconducting collection fins to measure the athermal phonon signal produced when an event occurs in the substrate crystal. Energy from the event propagates through the crystal to the superconducting collection fins, creating quasiparticles, which are then trapped as they enter the TES where they produce a signal. We are currently developing a prototype anti-coincidence detector for future x-ray missions and have recently fabricated test devices with Mo/Au TESs and Al collection fins. We will present results from the first tests of these devices which indicate a proof of concept that quasiparticle trapping is occurring in these materials.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Diaz-Cruz, J. Lorenzo

We propose a dark matter candidate within the class of models where electroweak symmetry breaking is triggered by a light composite Higgs boson. In these dual anti-de Sitter/conformal field theory models, the Higgs boson emerges as a holographic pseudo-Goldstone boson, while dark matter can be identified with a stable composite fermion X{sup 0}. The effective Lagrangian description of the Higgs and X{sup 0}-multiplets, including higher-dimensional operators, can be tested at future colliders (LHC, ILC) and through astrophysical signals (ultrahigh-energy cosmic rays). The expected mass of X{sup 0}, m{sub X{sup 0}} < or approx. 4{pi}f{approx_equal}O (TeV), satisfies the bounds extracted frommore » the cosmological relic density, while the experimental searches for dark matter further constrains the possible models.« less

High-Reflection Coatings for Gravitational-Wave Detectors: State of The Art and Future Developments

NASA Astrophysics Data System (ADS)

Amato, Alex; Cagnoli, Gianpietro; Canepa, Maurizio; Coillet, Elodie; Degallaix, Jerome; Dolique, Vincent; Forest, Daniele; Granata, Massimo; Martinez, Valérie; Michel, Christophe; Pinard, Laurent; Sassolas, Benoit; Teillon, Julien

2018-02-01

We report on the optical, mechanical and structural characterization of the sputtered coating materials of Advanced LIGO, Advanced Virgo and KAGRA gravitational- waves detectors. We present the latest results of our research program aiming at decreasing coating thermal noise through doping, optimization of deposition parameters and post- deposition annealing. Finally, we propose sputtered Si3N4 as a candidate material for the mirrors of future detectors.

Performance of today’s dual energy CT and future multi energy CT in virtual non-contrast imaging and in iodine quantification: A simulation study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Faby, Sebastian, E-mail: sebastian.faby@dkfz.de; Kuchenbecker, Stefan; Sawall, Stefan

2015-07-15

Purpose: To study the performance of different dual energy computed tomography (DECT) techniques, which are available today, and future multi energy CT (MECT) employing novel photon counting detectors in an image-based material decomposition task. Methods: The material decomposition performance of different energy-resolved CT acquisition techniques is assessed and compared in a simulation study of virtual non-contrast imaging and iodine quantification. The material-specific images are obtained via a statistically optimal image-based material decomposition. A projection-based maximum likelihood approach was used for comparison with the authors’ image-based method. The different dedicated dual energy CT techniques are simulated employing realistic noise models andmore » x-ray spectra. The authors compare dual source DECT with fast kV switching DECT and the dual layer sandwich detector DECT approach. Subsequent scanning and a subtraction method are studied as well. Further, the authors benchmark future MECT with novel photon counting detectors in a dedicated DECT application against the performance of today’s DECT using a realistic model. Additionally, possible dual source concepts employing photon counting detectors are studied. Results: The DECT comparison study shows that dual source DECT has the best performance, followed by the fast kV switching technique and the sandwich detector approach. Comparing DECT with future MECT, the authors found noticeable material image quality improvements for an ideal photon counting detector; however, a realistic detector model with multiple energy bins predicts a performance on the level of dual source DECT at 100 kV/Sn 140 kV. Employing photon counting detectors in dual source concepts can improve the performance again above the level of a single realistic photon counting detector and also above the level of dual source DECT. Conclusions: Substantial differences in the performance of today’s DECT approaches were found for the application of virtual non-contrast and iodine imaging. Future MECT with realistic photon counting detectors currently can only perform comparably to dual source DECT at 100 kV/Sn 140 kV. Dual source concepts with photon counting detectors could be a solution to this problem, promising a better performance.« less

Imaging detectors and electronics—a view of the future

NASA Astrophysics Data System (ADS)

Spieler, Helmuth

2004-09-01

Imaging sensors and readout electronics have made tremendous strides in the past two decades. The application of modern semiconductor fabrication techniques and the introduction of customized monolithic integrated circuits have made large-scale imaging systems routine in high-energy physics. This technology is now finding its way into other areas, such as space missions, synchrotron light sources, and medical imaging. I review current developments and discuss the promise and limits of new technologies. Several detector systems are described as examples of future trends. The discussion emphasizes semiconductor detector systems, but I also include recent developments for large-scale superconducting detector arrays.

NASA's Ultraviolet Astrophysics Branch: Present and future detector program

NASA Technical Reports Server (NTRS)

Welsh, Barry Y.

1992-01-01

The various concepts in ultraviolet detector technology currently being funded by NASA's Astrophysics Division to carry out observations in the 100 to 3000 A region are reviewed. In order to match the science objectives of future space missions with new observational techniques, critical detector technology needs in the ultraviolet regime have been identified. The attempt by NASA's Astrophysics Division Advanced Programs Branch to formulate an integrated detector technology plan as part of the ongoing 'Astrotech 21' program in order to provide the technology base for these astrophysics missions of the 21st century is described.

Damping Ring R&D at CESR-TA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rubin, David L.

2015-01-23

Accelerators that collide high energy beams of matter and anti-matter are essential tools for the investigation of the fundamental constituents of matter, and the search for new forms of matter and energy. A “Linear Collider” is a machine that would bring high energy and very compact bunches of electrons and positrons (anti-electrons) into head-on collision. Such a machine would produce (among many other things) the newly discovered Higgs particle, enabling a detailed study of its properties. Among the most critical and challenging components of a linear collider are the damping rings that produce the very compact and intense beams ofmore » electrons and positrons that are to be accelerated into collision. Hot dilute particle beams are injected into the damping rings, where they are compressed and cooled. The size of the positron beam must be reduced more than a thousand fold in the damping ring, and this compression must be accomplished in a fraction of a second. The cold compact beams are then extracted from the damping ring and accelerated into collision at high energy. The proposed International Linear Collider (ILC), would require damping rings that routinely produce such cold, compact and intense beams. The goal of the Cornell study was a credible design for the damping rings for the ILC. Among the technical challenges of the damping rings; the development of instrumentation that can measure the properties of the very small beams in a very narrow window of time, and mitigation of the forces that can destabilize the beams and prevent adequate cooling, or worse lead to beam loss. One of the most pernicious destabilizing forces is due to the formation of clouds of electrons in the beam pipe. The electron cloud effect is a phenomenon in particle accelerators in which a high density of low energy electrons, build up inside the vacuum chamber. At the outset of the study, it was anticipated that electron cloud effects would limit the intensity of the positron ring, and that an instability associated with residual gas in the beam pipe would limit the intensity of the electron ring. It was also not clear whether the required very small beam size could be achieved. The results of this study are important contributions to the design of both the electron and positron damping rings in which all of those challenges are addressed and overcome. Our findings are documented in the ILC Technical Design Report, a document that represents the work of an international collaboration of scientists. Our contributions include design of the beam magnetic optics for the 3 km circumference damping rings, the vacuum system and surface treatments for electron cloud mitigation, the design of the guide field magnets, design of the superconducting damping wigglers, and new detectors for precision measurement of beam properties. Our study informed the specification of the basic design parameters for the damping rings, including alignment tolerances, magnetic field errors, and instrumentation. We developed electron cloud modelling tools and simulations to aid in the interpretation of the measurements that we carried out in the Cornell Electron-positron Storage Ring (CESR). The simulations provide a means for systematic extrapolation of our measurements at CESR to the proposed ILC damping rings, and ultimately to specify how the beam pipes should be fabricated in order to minimize the effects of the electron cloud. With the conclusion of this study, the design of the essential components of the damping rings is complete, including the development and characterization (with computer simulations) of the beam optics, specification of techniques for minimizing beam size, design of damping ring instrumentation, R&D into electron cloud suppression methods, tests of long term durability of electron cloud coatings, and design of damping ring vacuum system components.« less

Macrophage and Innate Lymphoid Cell Interplay in the Genesis of Fibrosis

PubMed Central

Hams, Emily; Bermingham, Rachel; Fallon, Padraic G.

2015-01-01

Fibrosis is a characteristic pathological feature of an array of chronic diseases, where development of fibrosis in tissue can lead to marked alterations in the architecture of the affected organs. As a result of this process of sustained attrition to organs, many diseases that involve fibrosis are often progressive conditions and have a poor long-term prognosis. Inflammation is often a prelude to fibrosis, with innate and adaptive immunity involved in both the initiation and regulation of the fibrotic process. In this review, we will focus on the emerging roles of the newly described innate lymphoid cells (ILCs) in the generation of fibrotic disease with an examination of the potential interplay between ILC and macrophages and the adaptive immune system. PMID:26635811

Cooperative Security in Northeast Asia. A China-Japan-South Korea Coalition Approach

DTIC Science & Technology

1990-01-01

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Cavity BPM system tests for the ILC energy spectrometer

NASA Astrophysics Data System (ADS)

Slater, M.; Adolphsen, C.; Arnold, R.; Boogert, S.; Boorman, G.; Gournaris, F.; Hildreth, M.; Hlaing, C.; Jackson, F.; Khainovski, O.; Kolomensky, Yu. G.; Lyapin, A.; Maiheu, B.; McCormick, D.; Miller, D. J.; Orimoto, T. J.; Szalata, Z.; Thomson, M.; Ward, D.; Wing, M.; Woods, M.

2008-07-01

The main physics programme of the International Linear Collider (ILC) requires a measurement of the beam energy at the interaction point with an accuracy of 10-4 or better. To achieve this goal a magnetic spectrometer using high resolution beam position monitors (BPMs) has been proposed. This paper reports on the cavity BPM system that was deployed to test this proposal. We demonstrate sub-micron resolution and micron level stability over 20 h for a 1 m long BPM triplet. We find micron-level stability over 1 h for 3 BPM stations distributed over a 30 m long baseline. The understanding of the behaviour and response of the BPMs gained from this work has allowed full spectrometer tests to be carried out.

The Bright Future of Gravitational Wave Astronomy

NASA Astrophysics Data System (ADS)

Gonzalez, Gabriela

2008-04-01

These are exciting times in the search for gravitational waves. Gravitational waves are expected from many different astrophysical sources: brief transients from violent events like supernova explosions and collisions of neutron stars and black holes, coalescence of compact binary systems, continuous waves from rotating systems, and stochastic signals from cosmological origin or unresolved transients. The LIGO gravitational wave detectors have achieved unprecedented sensitivity to gravitational waves, and other detectors around the world are expected to reach similar sensitivities. The LIGO Scientific Collaboration (LSC) has recently completed their most sensitive observation run to date with LIGO and GEO detectors, including several months of joint observations with the European VIRGO detector. The LIGO Laboratory and the LSC, as well as the Virgo Collaboration, are actively preparing for operating enhanced detectors in the very near future. The next decade will see the construction and commissioning of Advanced LIGO and VIRGO, and quite possibly the launch of the space-based LISA mission, starting for sure then, if not earlier, a new era for gravitational wave astronomy. Plans for a world-wide network of ground based detectors involving more detectors in Europe, Japan and Australia are becoming more concrete. The future of gravitational wave astronomy is bright indeed! In this talk, will briefly describe the present status of the ground and space based detector projects and discuss the science we may expect to do with the detectors (and detections!) we will have in the upcoming era of gravitational wave astronomy.

R&D for the Future

NASA Astrophysics Data System (ADS)

Hübner, Kurt; Treille, Daniel; Schulte, Daniel

The following sections are included: * The LHC and Beyond * Accelerator Magnets with Ever-Higher Fields * Teasing Performance from Superconductors Old and New * RF Power for CLIC: Acceleration by Deceleration * The Next Energy Frontier e+e- Collider: Innovation in Detectors * Hadron Collider Detectors: A Bright and Energetic Future * References

Future Trends in MIcroelectronics: Up the Nano Creek

DTIC Science & Technology

2006-06-01

developed focal plane arrays (FPA)3𔃾 in addition to emphasizing future development in UV-to-far infrared multicolor FPA detectors 5𔄀 for next generation... detectors ", IEEE J. Quantum Electronics 35, 1685 (1999). 3. P. Bois, E. Costard, X. Marcadet, and E. Herniou, "Development of quantum well infrared ...photodetector array", Infrared Phys. Technol. 44, 369 (2003). 5. M. N. Abedin, T. F. Refaat, J. M. Zawodny, et al., "Multicolor focal plane array detector

LIGO: The instruments that launched gravitational-wave astronomy

NASA Astrophysics Data System (ADS)

Fritschel, Peter; LIGO Scientific Collaboration

2018-01-01

After decades of development, the advanced gravitational wave detectors are now in the business of making detections of the types of astrophysical sources they were designed for. And yet these detectors still have a ways to go to reach their designed sensitivity levels. This talk will cover the design and performance of these advanced detectors, with emphasis on Advanced LIGO. I will lay out the path to reaching design sensitivity, and then turn to plans for future improvements to the existing LIGO detectors’ sensitivity. Looking even further into the future, I will discuss concepts for a new generation of detectors that will be needed to probe much deeper into the cosmos.

Radiation damage caused by cold neutrons in boron doped CMOS active pixel sensors

NASA Astrophysics Data System (ADS)

Linnik, B.; Bus, T.; Deveaux, M.; Doering, D.; Kudejova, P.; Wagner, F. M.; Yazgili, A.; Stroth, J.

2017-05-01

CMOS Monolithic Active Pixel Sensors (MAPS) are considered as an emerging technology in the field of charged particle tracking. They will be used in the vertex detectors of experiments like STAR, CBM and ALICE and are considered for the ILC and the tracker of ATLAS. In those applications, the sensors are exposed to sizeable radiation doses. While the tolerance of MAPS to ionizing radiation and fast hadrons is well known, the damage caused by low energy neutrons was not studied so far. Those slow neutrons may initiate nuclear fission of 10B dopants found in the B-doped silicon active medium of MAPS. This effect was expected to create an unknown amount of radiation damage beyond the predictions of the NIEL (Non Ionizing Energy Loss) model for pure silicon. We estimate the impact of this effect by calculating the additional NIEL created by this fission. Moreover, we show first measured data for CMOS sensors which were irradiated with cold neutrons. The empirical results contradict the prediction of the updated NIEL model both, qualitatively and quantitatively: the sensors irradiated with slow neutrons show an unexpected and strong acceptor removal, which is not observed in sensors irradiated with MeV neutrons.

Latest Results of ILC High-Gradient R&D 9-cell Cavities at JLAB

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geng, Rongli

2008-02-11

It has been over a year since JLAB started processing and testing ILC 9-cell cavities in the frame work of ILC high-gradient cavity R&D, aiming at the goal of a 35 MV/m gradient at a Q of 1E10 with a yield of 90%. The necessary cavity processing steps include field flatness tuning, electropolishing (EP), hydrogen out-gassing under vacuum, high-pressure water rinsing, clean room assembly, and low temperature bake. These are followed by RF test at 2 Kelvin. Ultrasonic cleaning with Micro-90, an effective post-EP rinsing recipe discovered at JLAB, is routinely used. Seven industry manufactured 9-cell TESLAshape cavities are processedmore » and tested repeatedly. So far, 33 EP cycles are accumulated, corresponding to more than 65 hours of active EP time. An emphasis put on RF testing is to discern cavity quench characteristics, including its nature and its location. Often times, the cavity performance is limited by thermal-magnetic quench instead of field emission. The quench field in some cavities is lower than 20 MV/m and remains unchanged despite repeated EP, implying material and/or fabrication defects. The quench field in some other cavities is high but changes unpredictably after repeated EP, suggesting processing induced defects. Based on our experience and results, several areas are identified where improvement is needed to improve cavity performance as well as yield.« less

The Future of Single- to Multi-band Detector Technologies: Review

NASA Technical Reports Server (NTRS)

Abedin, M. Nurul; Bhat, Ishwara; Gunapala, Sarath D.; Bandara, Sumith V.; Refaat, Tamer F.; Sandford, Stephen P.; Singh, Upendra N.

2006-01-01

Using classical optical components such as filters, prisms and gratings to separate the desired wavelengths before they reach the detectors results in complex optical systems composed of heavy components. A simpler system will result by utilizing a single optical system and a detector that responds separately to each wavelength band. Therefore, a continuous endeavors to develop the capability to reliably fabricate detector arrays that respond to multiple wavelength regions. In this article, we will review the state-of-the-art single and multicolor detector technologies over a wide spectral-range, for use in space-based and airborne remote sensing applications. Discussions will be focused on current and the most recently developed focal plane arrays (FPA) in addition to emphasizing future development in UV-to-Far infrared multicolor FPA detectors for next generation space-based instruments to measure water vapor and greenhouse gases. This novel detector component will make instruments designed for these critical measurements more efficient while reducing complexity and associated electronics and weight. Finally, we will discuss the ongoing multicolor detector technology efforts at NASA Langley Research Center, Jet Propulsion Laboratory, Rensselaer Polytechnic Institute, and others.

Progress of ILC High Gradient SRF Cavity R&D at Jefferson Lab

DOE Office of Scientific and Technical Information (OSTI.GOV)

R.L. Geng, J. Dai, G.V. Eremeev, A.D. Palczewski

2011-09-01

Latest progress of ILC high gradient SRF cavity R&D at Jefferson Lab will be presented. 9 out of 10 real 9-cell cavities reached an accelerating gradient of more than 38 MV/m at a unloaded quality factor of more than 8 {center_dot} 109. New understandings of quench limitation in 9-cell cavities are obtained through instrumented studies of cavities at cryogenic temperatures. Our data have shown that present limit reached in 9-cell cavities is predominantly due to localized defects, suggesting that the fundamental material limit of niobium is not yet reached in 9-cell cavities and further gradient improvement is still possible. Somemore » examples of quench-causing defects will be given. Possible solutions to pushing toward the fundamental limit will be described.« less

Design of An 18 MW Beam Dump for 500 GeV Electron/Positron Beams at An ILC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amann, John; /SLAC; Arnold, Ray

This article presents a report on the progress made in designing 18 MW water based Beam Dumps for electrons or positrons for an International Linear Collider (ILC). Multi-dimensional technology issues have to be addressed for the successful design of the Beam Dump. They include calculations of power deposition by the high energy electron/positron beam bunch trains, computational fluid dynamic analysis of turbulent water flow, mechanical design, process flow analysis, hydrogen/oxygen recombiners, handling of radioactive 7Be and 3H, design of auxiliary equipment, provisions for accident scenarios, remote window exchanger, radiation shielding, etc. The progress made to date is summarized, the currentmore » status, and also the issues still to be addressed.« less

FPGA-based Klystron linearization implementations in scope of ILC

DOE PAGES

Omet, M.; Michizono, S.; Matsumoto, T.; ...

2015-01-23

We report the development and implementation of four FPGA-based predistortion-type klystron linearization algorithms. Klystron linearization is essential for the realization of ILC, since it is required to operate the klystrons 7% in power below their saturation. The work presented was performed in international collaborations at the Fermi National Accelerator Laboratory (FNAL), USA and the Deutsches Elektronen Synchrotron (DESY), Germany. With the newly developed algorithms, the generation of correction factors on the FPGA was improved compared to past algorithms, avoiding quantization and decreasing memory requirements. At FNAL, three algorithms were tested at the Advanced Superconducting Test Accelerator (ASTA), demonstrating a successfulmore » implementation for one algorithm and a proof of principle for two algorithms. Furthermore, the functionality of the algorithm implemented at DESY was demonstrated successfully in a simulation.« less

Cavity BPM System Tests for the ILC Spectrometer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Slater, M.

2007-12-21

The main physics program of the International Linear Collider (ILC) requires a measurement of the beam energy at the interaction point with an accuracy of 10{sup -4} or better. To achieve this goal a magnetic spectrometer using high resolution beam position monitors (BPMs) has been proposed. This paper reports on the cavity BPM system that was deployed to test this proposal. We demonstrate sub-micron resolution and micron level stability over 20 hours for a 1 m long BPM triplet. We find micron-level stability over 1 hour for 3 BPM stations distributed over a 30 m long baseline. The understanding ofmore » the behavior and response of the BPMs gained from this work has allowed full spectrometer tests to be carried out.« less

Development of an S-band cavity Beam Position Monitor for ATF2

NASA Astrophysics Data System (ADS)

Heo, A.; Kim, E.-S.; Kim, H.; Son, D.; Honda, Y.; Tauchi, T.

2013-04-01

We have developed an S-band cavity Beam Position Monitor (BPM) in order to measure the position of an electron beam in the final focus area at ATF2, which is the test facility for the final focus design for the International Linear Collider (ILC). The lattice of the ILC Beam Delivery System (BDS) has been modified, requiring a larger physical aperture of 40 mm in the final focus area. The beam orbit measurement in this area is now covered with high resolution S-Band cavity BPMs. In this paper we summarize the design of the cavity BPM and the first experimental results. The calibration slopes were measured as 0.87 counts/μm in the x-coordinate direction and 1.16 counts/μm in the y-coordinate direction.

Theoretical physics implications of gravitational wave observation with future detectors

NASA Astrophysics Data System (ADS)

Chamberlain, Katie; Yunes, Nicolás

2017-10-01

Gravitational waves encode invaluable information about the nature of the relatively unexplored extreme gravity regime, where the gravitational interaction is strong, nonlinear and highly dynamical. Recent gravitational wave observations by advanced LIGO have provided the first glimpses into this regime, allowing for the extraction of new inferences on different aspects of theoretical physics. For example, these detections provide constraints on the mass of the graviton, Lorentz violation in the gravitational sector, the existence of large extra dimensions, the temporal variability of Newton's gravitational constant, and modified dispersion relations of gravitational waves. Many of these constraints, however, are not yet competitive with constraints obtained, for example, through Solar System observations or binary pulsar observations. In this paper, we study the degree to which theoretical physics inferences drawn from gravitational wave observations will strengthen with detections from future detectors. We consider future ground-based detectors, such as the LIGO-class expansions A + , Voyager, Cosmic Explorer and the Einstein Telescope, as well as space-based detectors, such as various configurations of eLISA and the recently proposed LISA mission. We find that space-based detectors will place constraints on general relativity up to 12 orders of magnitude more stringently than current aLIGO bounds, but these space-based constraints are comparable to those obtained with the ground-based Cosmic Explorer or the Einstein Telescope (A + and Voyager only lead to modest improvements in constraints). We also generically find that improvements in the instrument sensitivity band at low frequencies lead to large improvements in certain classes of constraints, while sensitivity improvements at high frequencies lead to more modest gains. These results strengthen the case for the development of future detectors, while providing additional information that could be useful in future design decisions.

Optical-Microwave Interactions in Semiconductor Devices.

DTIC Science & Technology

1981-03-01

Interdigital Photoconductors ( IDPC ) ......... ..... 112 G. Conclusions.. ....... .. 120 6 CONCLUSIONS AND RECOMMENDATIONS FOR FUTURE WORK . 121...The detector developed at the Hughes Research Laboratories ( IDPC ) involves placing an interdigital metal electrode 53- 5 5 structure on top of a F...easier to perform with the IDPC detector. We believe the interdigital photoconductive detector has many advantages over existing detectors. First, the

ISS/IDS Detector Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cervera-Villanueva, A.

2008-02-21

This article summarises the results obtained by the detector working group of the 'International Scooping Study' (ISS) of a future neutrino oscillations facility. Special emphasis is put on far detectors, for which some of the main issues are identified. A detector R and D strategy in the context of the 'International Design Study' (IDS) for a neutrino factory is also presented.

Workshop on detectors for third-generation synchrotron sources: Proceedings

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1994-12-01

The aims of the workshop were (1) to acquaint APS users with current R and D being carried out on detectors, (2) to identify new detector systems possible during the next five years, (3) to identify new detectors theoretically possible in the future, (4) to stimulate interactions between user groups and detector developers, and (5) to obtain recommendations from expert panels on technical issues needing resolution. Development of detectors at ESRF, Spring-8, BNL, CERN and LBL are included.

Characterization and development of an event-driven hybrid CMOS x-ray detector

NASA Astrophysics Data System (ADS)

Griffith, Christopher

2015-06-01

Hybrid CMOS detectors (HCD) have provided great benefit to the infrared and optical fields of astronomy, and they are poised to do the same for X-ray astronomy. Infrared HCDs have already flown on the Hubble Space Telescope and the Wide-Field Infrared Survey Explorer (WISE) mission and are slated to fly on the James Webb Space Telescope (JWST). Hybrid CMOS X-ray detectors offer low susceptibility to radiation damage, low power consumption, and fast readout time to avoid pile-up. The fast readout time is necessary for future high throughput X-ray missions. The Speedster-EXD X-ray HCD presented in this dissertation offers new in-pixel features and reduces known noise sources seen on previous generation HCDs. The Speedster-EXD detector makes a great step forward in the development of these detectors for future space missions. This dissertation begins with an overview of future X-ray space mission concepts and their detector requirements. The background on the physics of semiconductor devices and an explanation of the detection of X-rays with these devices will be discussed followed by a discussion on CCDs and CMOS detectors. Next, hybrid CMOS X-ray detectors will be explained including their advantages and disadvantages. The Speedster-EXD detector and its new features will be outlined including its ability to only read out pixels which contain X-ray events. Test stand design and construction for the Speedster-EXD detector is outlined and the characterization of each parameter on two Speedster-EXD detectors is detailed including read noise, dark current, interpixel capacitance crosstalk (IPC), and energy resolution. Gain variation is also characterized, and a Monte Carlo simulation of its impact on energy resolution is described. This analysis shows that its effect can be successfully nullified with proper calibration, which would be important for a flight mission. Appendix B contains a study of the extreme tidal disruption event, Swift J1644+57, to search for periodicities in its X-ray light curve. iii.

A Test Stand to Characterize and Contribute to the Development of DEPFET X-ray Detectors

NASA Astrophysics Data System (ADS)

Falcone, Abe

The field of X-ray astronomy is currently looking forward to several new missions (e.g Athena, BeppiColumbo, and IXPE which is a new SMEX polarimeter), and there is the possibility of a flag-ship mission (e.g. the Lynx X-ray Surveyor) and/or other SMEX through probe class missions in the long-term future with many mission concepts being developed (e.g. ARCUS). The X-ray detec-tors for these future missions must be developed to suitable maturity to be proposed for flight, and expertise operating the newest versions of the detectors must be acquired by potential mis-sion designers and proposers. There are several silicon X-ray imaging active pixel sensor (APS) detectors being developed at this time (hybrid CMOS, monolithic CMOS, and DEPFETs), and each of these have their own advantages and levels of maturity, while they all provide enhanced radia-tion hardness, lower power operation, and versatile readout modes. Of the new APS X-ray detec-tors being developed, the DEPleted p-channel Field Effect Transistors (DEPFETs) have exhibited the best noise performance to-date. While they do require larger pixel structures than their com-petitors, the low noise performance of these detectors makes them an excellent choice for many mission applications (e.g. they will be launched on 2 ESA missions, Athena & BepiColumbo), and their further development could benefit other missions, particularly future missions that might be led by NASA and US scientists. Up until now, the development of these detectors has been lim-ited to only two groups located in Germany; one group is at Max Planck Institute and the other is PNSensors which is comprised of engineers and scientists that previously led the DEPFET design work at Max Planck. We propose to engage one of these groups in order to: (a) acquire newly de-signed test DEPFET detectors built by PNSensor, through a very-low-cost arrangement, (b) build a test stand that can operate these detectors and gain valuable experience running them in vari-ous modes with variations on the detector settings, (c) characterize the DEPFETs independently of the manufacturer and in modes that are relevant to our x-ray applications, and (d) use this new operation experience and characterization data to inform the next design iterations and the op-timization of DEPFET detectors for future X-ray missions.

Kitty for the kitty

NASA Astrophysics Data System (ADS)

2016-11-01

Officials at the International Linear Collider (ILC) - a proposed successor to the Large Hadron Collider at CERN - have turned to Hello Kitty to help promote the project, which is set to be built in Japan.

Imaging hadron calorimetry for future Lepton Colliders

NASA Astrophysics Data System (ADS)

Repond, José

2013-12-01

To fully exploit the physics potential of a future Lepton Collider requires detectors with unprecedented jet energy and dijet-mass resolution. To meet these challenges, detectors optimized for the application of Particle Flow Algorithms (PFAs) are being designed and developed. The application of PFAs, in turn, requires calorimeters with very fine segmentation of the readout, so-called imaging calorimeters. This talk reviews progress in imaging hadron calorimetry as it is being developed for implementation in a detector at a future Lepton Collider. Recent results from the large prototypes built by the CALICE Collaboration, such as the Scintillator Analog Hadron Calorimeter (AHCAL) and the Digital Hadron Calorimeters (DHCAL and SDHCAL) are being presented. In addition, various R&D efforts beyond the present prototypes are being discussed.

Localization of binary neutron star mergers with second and third generation gravitational-wave detectors

NASA Astrophysics Data System (ADS)

Mills, Cameron; Tiwari, Vaibhav; Fairhurst, Stephen

2018-05-01

The observation of gravitational wave signals from binary black hole and binary neutron star mergers has established the field of gravitational wave astronomy. It is expected that future networks of gravitational wave detectors will possess great potential in probing various aspects of astronomy. An important consideration for successive improvement of current detectors or establishment on new sites is knowledge of the minimum number of detectors required to perform precision astronomy. We attempt to answer this question by assessing the ability of future detector networks to detect and localize binary neutron stars mergers on the sky. Good localization ability is crucial for many of the scientific goals of gravitational wave astronomy, such as electromagnetic follow-up, measuring the properties of compact binaries throughout cosmic history, and cosmology. We find that although two detectors at improved sensitivity are sufficient to get a substantial increase in the number of observed signals, at least three detectors of comparable sensitivity are required to localize majority of the signals, typically to within around 10 deg2 —adequate for follow-up with most wide field of view optical telescopes.

2D Array of Far-infrared Thermal Detectors: Noise Measurements and Processing Issues

NASA Technical Reports Server (NTRS)

Lakew, B.; Aslam, S.; Stevenson, T.

2008-01-01

A magnesium diboride (MgB2) detector 2D array for use in future space-based spectrometers is being developed at GSFC. Expected pixel sensitivities and comparison to current state-of-the-art infrared (IR) detectors will be discussed.

Tobacco and the Movies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Glantz, Stanton

The principal aim of this roadmap is to place the US and Fermilab in the best position to host the International Linear Collider (ILC). The strategy must be resilient against the many vicissitudes that will attend the development of such a large project. Pier Oddone will explore the tension between the needed concentration of effort to move a project as large as the ILC forward and the need to maintain the breadth of our field. America's leading health organizations agree. Smoking on screen is the #1 recruiter of new adolescent smokers in the United States - 390,000 kids a year,more » of whom 120,000 will die from tobacco-caused diseases. That's more Americans than die from drunk driving, criminal violence, illicit drugs, and HIV/AIDS combined. Why does Hollywood still promote smoking? Is it corrupt? Or stupid?« less

The determination of ethyl glucuronide in hair: Experiences from nine consecutive interlaboratory comparison rounds.

PubMed

Becker, R; Lô, I; Sporkert, F; Baumgartner, M

2018-07-01

The increasing request for hair ethyl glucuronide (HEtG) in alcohol consumption monitoring according to cut-off levels set by the Society of Hair Testing (SoHT) has triggered a proficiency testing program based on interlaboratory comparisons (ILC). Here, the outcome of nine consecutive ILC rounds organised by the SoHT on the determination of HEtG between 2011 and 2017 is summarised regarding interlaboratory reproducibility and the influence of procedural variants. Test samples prepared from cut hair (1mm) with authentic (in-vivo incorporated) and soaked (in-vitro incorporated) HEtG concentrations up to 80pg/mg were provided for 27-35 participating laboratories. Laboratory results were evaluated according to ISO 5725-5 and provided robust averages and relative reproducibility standard deviations typically between 20 and 35% in reasonable accordance with the prediction of the Horwitz model. Evaluation of results regarding the analytical techniques revealed no significant differences between gas and liquid chromatographic methods In contrast, a detailed evaluation of different sample preparations revealed significantly higher average values in case when pulverised hair is tested compared to cut hair. This observation was reinforced over the different ILC rounds and can be attributed to the increased acceptance and routine of hair pulverisation among laboratories. Further, the reproducibility standard deviations among laboratories performing pulverisation were on average in very good agreement with the prediction of the Horwitz model. Use of sonication showed no effect on the HEtG extraction yield. Copyright © 2018 Elsevier B.V. All rights reserved.

AhR modulates the IL-22-producing cell proliferation/recruitment in imiquimod-induced psoriasis mouse model.

PubMed

Cochez, Perrine M; Michiels, Camille; Hendrickx, Emilie; Van Belle, Astrid B; Lemaire, Muriel M; Dauguet, Nicolas; Warnier, Guy; de Heusch, Magali; Togbe, Dieudonnée; Ryffel, Bernhard; Coulie, Pierre G; Renauld, Jean-Christophe; Dumoutier, Laure

2016-06-01

IL-22 has a detrimental role in skin inflammatory processes, for example in psoriasis. As transcription factor, AhR controls the IL-22 production by several cell types (i.e. Th17 cells). Here, we analyzed the role of Ahr in IL-22 production by immune cells in the inflamed skin, using an imiquimod-induced psoriasis mouse model. Our results indicate that IL-22 is expressed in the ear of imiquimod-treated Ahr(-/-) mice but less than in wild-type mice. We then studied the role of AhR on three cell populations known to produce IL-22 in the skin: γδ T cells, Th17 cells, and ILC3, and a novel IL-22-producing cell type identified in this setting: CD4(-) CD8(-) TCRβ(+) T cells. We showed that AhR is required for IL-22 production by Th17, but not by the three other cell types, in the imiquimod-treated ears. Moreover, AhR has a role in the recruitment of γδ T cells, ILC3, and CD4(-) CD8(-) TCRβ(+) T cells into the inflamed skin or in their local proliferation. Taken together, AhR has a direct role in IL-22 production by Th17 cells in the mouse ear skin, but not by γδ T cells, CD4(-) CD8(-) TCRβ(+) T cells and ILCs. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

IL-17 producing innate lymphoid cells 3 (ILC3) but not Th17 cells might be the potential danger factor for preeclampsia and other pregnancy associated diseases.

PubMed

Barnie, Prince A; Lin, Xin; Liu, Yueqin; Xu, Huaxi; Su, Zhaoliang

2015-01-01

In pregnancy, the immunologic system plays an important role that ensures normal pregnancy development and can as well promote the development of complications. Pregnancy success appears to rely on a discrete balance between the Th cytokines, which are involved in fetal growth and development. Preeclampsia and gestational diabetes are known complications associated with pregnancy. However, the source of the increased IL-17 cytokine in preeclampsia and other pregnancy associated diseases still remains unclear amidst numerous inconsistencies. The recent identification of innate lymphoid cells (ILC) has raised more doubts about the sources of most of the Th associated cytokines. We investigated the source of peripheral IL-17 levels in preeclamptic, gestational diabetics and chronic diabetics compared to healthy pregnancy subjects. To evaluate the source of the increased IL-17 cytokine among preeclampsia, chronic diabetic and gestational diabetic patients we investigated the proportion of Th17 cell populations in peripheral blood mononuclear cells using flow cytometry as well as analyzing levels of IFN-γ, IL-17, IL-1β and HMGB1. This study found that the Th17 cell populations in peripheral blood of preeclamptic, gestational nor chronic diabetes during pregnancy did not correlate with the increased IL-17. We report that the increased IL-17 levels observed in patients with preeclampsia, gestational diabetes and chronic diabetes are associated with innate lymphoid cells 3 (ILC3) and may pose threats to the fetus if disregulated.

Mapping of NKp46+ Cells in Healthy Human Lymphoid and Non-Lymphoid Tissues

PubMed Central

Tomasello, Elena; Yessaad, Nadia; Gregoire, Emilie; Hudspeth, Kelly; Luci, Carmelo; Mavilio, Domenico; Hardwigsen, Jean; Vivier, Eric

2012-01-01

Understanding Natural Killer (NK) cell anatomical distribution is key to dissect the role of these unconventional lymphocytes in physiological and disease conditions. In mouse, NK cells have been detected in various lymphoid and non-lymphoid organs, while in humans the current knowledge of NK cell distribution at steady state is mainly restricted to lymphoid tissues. The translation to humans of findings obtained in mice is facilitated by the identification of NK cell markers conserved between these two species. The Natural Cytotoxicity Receptor (NCR) NKp46 is a marker of the NK cell lineage evolutionary conserved in mammals. In mice, NKp46 is also present on rare T cell subsets and on a subset of gut Innate Lymphoid Cells (ILCs) expressing the retinoic acid receptor-related orphan receptor γt (RORγt) transcription factor. Here, we documented the distribution and the phenotype of human NKp46+ cells in lymphoid and non-lymphoid tissues isolated from healthy donors. Human NKp46+ cells were found in splenic red pulp, in lymph nodes, in lungs, and gut lamina propria, thus mirroring mouse NKp46+ cell distribution. We also identified a novel cell subset of CD56dimNKp46low cells that includes RORγt+ ILCs with a lineage−CD94−CD117brightCD127bright phenotype. The use of NKp46 thus contributes to establish the basis for analyzing quantitative and qualitative changes of NK cell and ILC subsets in human diseases. PMID:23181063

Modeling radiation loads in the ILC main linac and a novel approach to treat dark current

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mokhov, Nilolai V.; Rakhno, Igor L.; Tropin, Igor S.

Electromagnetic and hadron showers generated by electrons of dark current (DC) can represent a significant radiation threat to the ILC linac equipment and personnel. In this study, a commissioning scenario is analysed which is considered as the worst-case scenario for the main linac regarding the DC contribution to the radiation environment in the tunnel. A normal operation scenario is analysed as well. An emphasis is made on radiation load to sensitive electronic equipment—cryogenic thermometers inside the cryomodules. Prompt and residual dose rates in the ILC main linac tunnels were also calculated in these new high-statistics runs. A novel approach wasmore » developed—as a part of general purpose Monte Carlo code MARS15—to model generation, acceleration and transport of DC electrons in electromagnetic fields inside SRF cavities. Comparisons were made with a standard approach when a set of pre-calculated DC electron trajectories is used, with a proper normalization, as a source for Monte Carlo modelling. Results of MARS15 Monte Carlo calculations, performed for the current main linac tunnel design, reveal that the peak absorbed dose in the cryogenic thermometers in the main tunnel for 20 years of operation is about 0.8 MGy. The calculated contact residual dose on cryomodules and tunnel walls in the main tunnel for typical irradiation and cooling conditions is 0.1 and 0.01 mSv/hr, respectively.« less

Model-Free Primitive-Based Iterative Learning Control Approach to Trajectory Tracking of MIMO Systems With Experimental Validation.

PubMed

Radac, Mircea-Bogdan; Precup, Radu-Emil; Petriu, Emil M

2015-11-01

This paper proposes a novel model-free trajectory tracking of multiple-input multiple-output (MIMO) systems by the combination of iterative learning control (ILC) and primitives. The optimal trajectory tracking solution is obtained in terms of previously learned solutions to simple tasks called primitives. The library of primitives that are stored in memory consists of pairs of reference input/controlled output signals. The reference input primitives are optimized in a model-free ILC framework without using knowledge of the controlled process. The guaranteed convergence of the learning scheme is built upon a model-free virtual reference feedback tuning design of the feedback decoupling controller. Each new complex trajectory to be tracked is decomposed into the output primitives regarded as basis functions. The optimal reference input for the control system to track the desired trajectory is next recomposed from the reference input primitives. This is advantageous because the optimal reference input is computed straightforward without the need to learn from repeated executions of the tracking task. In addition, the optimization problem specific to trajectory tracking of square MIMO systems is decomposed in a set of optimization problems assigned to each separate single-input single-output control channel that ensures a convenient model-free decoupling. The new model-free primitive-based ILC approach is capable of planning, reasoning, and learning. A case study dealing with the model-free control tuning for a nonlinear aerodynamic system is included to validate the new approach. The experimental results are given.

The future of RICH detectors through the light of the LHCb RICH

NASA Astrophysics Data System (ADS)

D'Ambrosio, C.; LHCb RICH Collaboration

2017-12-01

The limitations in performance of the present RICH system in the LHCb experiment are given by the natural chromatic dispersion of the gaseous Cherenkov radiator, the aberrations of the optical system and the pixel size of the photon detectors. Moreover, the overall PID performance can be affected by high detector occupancy as the pattern recognition becomes more difficult with high particle multiplicities. This paper shows a way to improve performance by systematically addressing each of the previously mentioned limitations. These ideas are applied in the present and future upgrade phases of the LHCb experiment. Although applied to specific circumstances, they are used as a paradigm on what is achievable in the development and realisation of high precision RICH detectors.

Monte-Carlo background simulations of present and future detectors in x-ray astronomy

NASA Astrophysics Data System (ADS)

Tenzer, C.; Kendziorra, E.; Santangelo, A.

2008-07-01

Reaching a low-level and well understood internal instrumental background is crucial for the scientific performance of an X-ray detector and, therefore, a main objective of the instrument designers. Monte-Carlo simulations of the physics processes and interactions taking place in a space-based X-ray detector as a result of its orbital environment can be applied to explain the measured background of existing missions. They are thus an excellent tool to predict and optimize the background of future observatories. Weak points of a design and the main sources of the background can be identified and methods to reduce them can be implemented and studied within the simulations. Using the Geant4 Monte-Carlo toolkit, we have created a simulation environment for space-based detectors and we present results of such background simulations for XMM-Newton's EPIC pn-CCD camera. The environment is also currently used to estimate and optimize the background of the future instruments Simbol-X and eRosita.

Cosmic ray positron research and silicon track detector development

NASA Technical Reports Server (NTRS)

Jones, W. Vernon; Wefel, John P.

1991-01-01

The purpose was to conduct research on: (1) position sensing detector systems, particularly those based upon silicon detectors, for use in future balloon and satellite experiments; and (2) positrons, electrons, proton, anti-protons, and helium particles as measured by the NASA NMSU Balloon Magnet Facility.

Improved detectivity of pyroelectric detectors

NASA Technical Reports Server (NTRS)

Marshall, D. E.; Gelpey, J. C.; Marciniec, J. W.; Chiang, A. M.; Maciolek, R. B.

1978-01-01

High detectivity single-element SBN pyroelectric detectors were fabricated. The theory and technology developments related to improved detector performance were identified and formulated. Improved methods of material characterization, thinning, mounting, blackening and amplifier matching are discussed. Detectors with detectivities of 1.3 x 10 to the 9th power square root of Hz/watt at 1 Hz are reported. Factors limiting performance and recommendations for future work are discussed.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nazarewicz, W.

The new large detector systems are certain to shed new light on many aspects of nuclear structure. Some of these areas for future studies are discussed. In this contribution the author concentrates on several aspects of nuclear spectroscopy, that will be accessible by modern detector systems (e.g., {gamma}-ray crystal balls or new-generation particle detectors).

The ̅PANDA Detector at FAIR

NASA Astrophysics Data System (ADS)

Ikegami Andersson, W.; ̅PANDA Collaboration

2016-11-01

The future ̅PANDA detector at FAIR is a state-of-the-art internal target detector designed for strong interaction studies. By utilizing an antiproton beam, a rich and unique physics programme is planned. The ̅PANDA experiment, as well as feasibility studies for hyperon and charmonium physics, are discussed.

Semi-blind Bayesian inference of CMB map and power spectrum

NASA Astrophysics Data System (ADS)

Vansyngel, Flavien; Wandelt, Benjamin D.; Cardoso, Jean-François; Benabed, Karim

2016-04-01

We present a new blind formulation of the cosmic microwave background (CMB) inference problem. The approach relies on a phenomenological model of the multifrequency microwave sky without the need for physical models of the individual components. For all-sky and high resolution data, it unifies parts of the analysis that had previously been treated separately such as component separation and power spectrum inference. We describe an efficient sampling scheme that fully explores the component separation uncertainties on the inferred CMB products such as maps and/or power spectra. External information about individual components can be incorporated as a prior giving a flexible way to progressively and continuously introduce physical component separation from a maximally blind approach. We connect our Bayesian formalism to existing approaches such as Commander, spectral mismatch independent component analysis (SMICA), and internal linear combination (ILC), and discuss possible future extensions.

Design, Project Execution, and Commissioning of the 1.8 K Superfluid Helium Refrigeration System for SRF Cryomodule Testing

DOE PAGES

Treite, P.; Nuesslein, U.; Jia, Yi; ...

2015-07-15

The Fermilab Cryomodule Test Facility (CMTF) provides a test bed to measure the performance of superconducting radiofrequency (SRF) cryomodules (CM). These SRF components form the basic building blocks of future high intensity accelerators such as the International Linear Collider (ILC) and a Muon Collider. Linde Kryotechnik AG and Linde Cryogenics have designed, constructed and commissioned the superfluid helium refrigerator needed to support SRF component testing at the CMTF Facility. The hybrid refrigerator is designed to operate in a variety of modes and under a wide range of boundary conditions down to 1.8 Kelvin set by CM design. Special features ofmore » the refrigerator include the use of warm and cold compression and high efficiency turbo expanders.This paper gives an overview on the wide range of the challenging cooling requirements, the design, fabrication and the commissioning of the installed cryogenic system.« less

Working Group Report: Higgs Boson

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dawson, Sally; Gritsan, Andrei; Logan, Heather

2013-10-30

This report summarizes the work of the Energy Frontier Higgs Boson working group of the 2013 Community Summer Study (Snowmass). We identify the key elements of a precision Higgs physics program and document the physics potential of future experimental facilities as elucidated during the Snowmass study. We study Higgs couplings to gauge boson and fermion pairs, double Higgs production for the Higgs self-coupling, its quantum numbers and $CP$-mixing in Higgs couplings, the Higgs mass and total width, and prospects for direct searches for additional Higgs bosons in extensions of the Standard Model. Our report includes projections of measurement capabilities frommore » detailed studies of the Compact Linear Collider (CLIC), a Gamma-Gamma Collider, the International Linear Collider (ILC), the Large Hadron Collider High-Luminosity Upgrade (HL-LHC), Very Large Hadron Colliders up to 100 TeV (VLHC), a Muon Collider, and a Triple-Large Electron Positron Collider (TLEP).« less

Gravitational wave and collider implications of electroweak baryogenesis aided by non-standard cosmology

DOE PAGES

Artymowski, Michal; Lewicki, Marek; Wells, James D.

2017-03-13

Here, we consider various models realizing baryogenesis during the electroweak phase transition (EWBG). Our focus is their possible detection in future collider experiments and possible observation of gravitational waves emitted during the phase transition. We also discuss the possibility of a non-standard cosmological history which can facilitate EWBG. We show how acceptable parameter space can be extended due to such a modification and conclude that next generation precision experiments such as the ILC will be able to confirm or falsify many models realizing EWBG. We also show that, in general, collider searches are a more powerful probe than gravitational wavemore » searches. However, observation of a deviation from the SM without any hints of gravitational waves can point to models with modified cosmological history that generically enable EWBG with weaker phase transition and thus, smaller GW signals.« less

Analysis of Cadmium Based Neutron Detector Configurations

NASA Astrophysics Data System (ADS)

James, Brian; Rees, Lawrence; Czirr, J. Bart

2012-10-01

Due to national security concerns pertaining to the smuggling of special nuclear materials and a small supply of He-3 for use in neutron detectors, there is currently a need for a new kind of neutron detector. Using Monte Carlo techniques I have studied the neutron capture efficiency of an array of cadmium wedge detectors in the presence of a californium source. By using varying numbers of wedges and comparing their capture ratios we will be better able to design future detectors.

Gaseous Electron Multiplier (GEM) Detectors

NASA Astrophysics Data System (ADS)

Gnanvo, Kondo

2017-09-01

Gaseous detectors have played a pivotal role as tracking devices in the field of particle physics experiments for the last fifty years. Recent advances in photolithography and micro processing techniques have enabled the transition from Multi Wire Proportional Chambers (MWPCs) and Drift Chambers to a new family of gaseous detectors refer to as Micro Pattern Gaseous Detectors (MPGDs). MPGDs combine the basic gas amplification principle with micro-structure printed circuits to provide detectors with excellent spatial and time resolution, high rate capability, low material budget and high radiation tolerance. Gas Electron Multiplier (GEMs) is a well-established MPGD technology invented by F. Sauli at CERN in 1997 and deployed various high energy physics (HEP) and nuclear NP experiment for tracking systems of current and future NP experiments. GEM detector combines an exceptional high rate capability (1 MHz / mm2) and robustness against harsh radiation environment with excellent position and timing resolution performances. Recent breakthroughs over the past decade have allowed the possibility for large area GEMs, making them cost effective and high-performance detector candidates to play pivotal role in current and future particle physics experiments. After a brief introduction of the basic principle of GEM technology, I will give a brief overview of the GEM detectors used in particle physics experiments over the past decades and especially in the NP community at Thomas Jefferson National Laboratory (JLab) and Brookhaven National Laboratory (BNL). I will follow by a review of state of the art of the new GEM development for the next generation of colliders such as Electron Ion Collider (EIC) or High Luminosity LHC and future Nuclear Physics experiments. I will conclude with a presentation of the CERN-based RD51 collaboration established in 2008 and its major achievements regarding technological developments and applications of MPGDs.

Genomic features of lobular breast carcinoma

Cancer.gov

Investigators with The Cancer Genome Atlas (TCGA) Research Network have identified molecular characteristics of a type of breast cancer, invasive lobular carcinoma (ILC), that distinguishes it from invasive ductal carcinoma (IDC), the most common invasive breast cancer subtype.

Genomic features of lobular breast carcinoma - TCGA

Cancer.gov

Investigators with The Cancer Genome Atlas (TCGA) Research Network have identified molecular characteristics of a type of breast cancer, invasive lobular carcinoma (ILC), that distinguishes it from invasive ductal carcinoma (IDC), the most common invasive breast cancer subtype.

Distribution and Dynamic Properties of Xenon Dissolved in the Ionic Smectic Phase of [C16mim][NO3]: MD Simulation and Theoretical Model.

PubMed

Frezzato, Diego; Saielli, Giacomo

2016-03-10

We have investigated the structural and dynamic properties of Xe dissolved in the ionic liquid crystal (ILC) phase of 1-hexadecyl-3-methylimidazolium nitrate using classical molecular dynamics (MD) simulations. Xe is found to be preferentially dissolved within the hydrophobic environment of the alkyl chains rather than in the ionic layers of the smectic phase. The structural parameters and the estimated local diffusion coefficients concerning the short-time motion of Xe are used to parametrize a theoretical model based on the Smoluchowski equation for the macroscopic dynamics across the smectic layers, a feature which cannot be directly obtained from the relatively short MD simulations. This protocol represents an efficient combination of computational and theoretical tools to obtain information on slow processes concerning the permeability and diffusivity of the xenon in smectic ILCs.

New Baseline Design of the ILC RTML System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seletskiy, S.; Kapin, V. V.; Solyak, N.

2012-05-01

The new ILC baseline was proposed in 2009 (Strawman baseline - SB2009) to minimize cost of the machine and accommodate many changes made in the design of the accelerator systems. The biggest changes are made in the central area, where BDS, RTM L, DR, electron and positron sources are sharing the tunnels. A new layout of the compact DR and re-location of the electron and positron sources to the main tunnel requires a new lattice design for all beamlines in this area. The lattice design was coord inated between accelerator systems and Convention Facility and Siting (CFS) group to eliminatemore » conflicts between beamlines and satisfy construction requirements. In this paper we present a new design of the RTML electron and positron lattices in the centr al area and other modifications made in the RTML line to accommodate changes to the beamline layouts.« less

Isolation and Flow Cytometry Analysis of Innate Lymphoid Cells from the Intestinal Lamina Propria.

PubMed

Gronke, Konrad; Kofoed-Nielsen, Michael; Diefenbach, Andreas

2017-01-01

The intestinal mucosa constitutes the biggest surface area of the body. It is constantly challenged by bacteria, commensal and pathogenic, protozoa, and food-derived irritants. In order to maintain homeostasis, a complex network of signaling circuits has evolved that includes contributions of immune cells. In recent years a subset of lymphocytes, which belong to the innate immune system, has caught particular attention. These so-called innate lymphoid cells (ILC) reside within the lamina propria of the small and large intestines and rapidly respond to environmental challenges. They provide immunity to various types of infections but may also contribute to organ homeostasis as they produce factors acting on epithelial cells thereby enhancing barrier integrity. Here, we describe how these cells can be isolated from their environment and provide an in-depth protocol how to visualize the various ILC subsets by flow cytometry.

Orchestration of intestinal homeostasis and tolerance by group 3 innate lymphoid cells.

PubMed

Penny, Hugo A; Hodge, Suzanne H; Hepworth, Matthew R

2018-05-08

The gastrointestinal tract is the primary site of exposure to a multitude of microbial, environmental, and dietary challenges. As a result, immune responses in the intestine need to be tightly regulated in order to prevent inappropriate inflammatory responses to exogenous stimuli. Intestinal homeostasis and tolerance are mediated through a multitude of immune mechanisms that act to reinforce barrier integrity, maintain the segregation and balance of commensal microbes, and ensure tissue health and regeneration. Here, we discuss the role of group 3 innate lymphoid cells (ILC3) as key regulators of intestinal health and highlight how increasing evidence implicates dysregulation of this innate immune cell population in the onset or progression of a broad range of clinically relevant pathologies. Finally, we discuss how the next generation of immunotherapeutics may be utilized to target ILC3 in disease and restore gastrointestinal tolerance and tissue health.

Development of Gating Foils To Inhibit Ion Feedback Using FPC Production Techniques

NASA Astrophysics Data System (ADS)

Arai, D.; Ikematsu, K.; Sugiyama, A.; Iwamura, M.; Koto, A.; Katsuki, K.; Fujii, K.; Matsuda, T.

2018-02-01

Positive ion feedback from a gas amplification device to the drift region of the Time Projection Chamber for the ILC can deteriorate the position resolution. In order to inhibit the feedback ions, MPGD-based gating foils having good electron transmission have been developed to be used instead of the conventional wire gate. The gating foil needs to control the electric field locally in opening or closing the gate. The gating foil with a GEM (gas electron multiplier)-like structure has larger holes and smaller thickness than standard GEMs for gas amplification. It is known that the foil transmits over 80 % of electrons and blocks ions almost completely. We have developed the gating foils using flexible printed circuit (FPC) production techniques including an improved single-mask process. In this paper, we report on the production technique of 335 μm pitch, 12.5 μm thick gating foil with 80 % transmittance of electrons in ILC conditions.

A metrology system for a high resolution cavity beam position monitor system

NASA Astrophysics Data System (ADS)

Walston, Sean; Boogert, Stewart; Chung, Carl; Fitsos, Pete; Frisch, Joe; Gronberg, Jeff; Hayano, Hitoshi; Hinton, Shantell; Honda, Yosuke; Khainovski, Oleg; Kolomensky, Yury; Loscutoff, Peter; Lyapin, Alexey; Malton, Stephen; May, Justin; McCormick, Douglas; Meller, Robert; Miller, David; Orimoto, Toyoko; Ross, Marc; Slater, Mark; Smith, Steve; Smith, Tonee; Terunuma, Nobuhiro; Thomson, Mark; Urakawa, Junji; Vogel, Vladimir; Ward, David; White, Glen

2013-11-01

International Linear Collider (ILC) interaction region beam sizes and component position stability requirements will likely be as small as a few nanometers. It is important to the ILC design effort to demonstrate that these tolerances can be achieved-ideally using a beam-based stability measurement. We developed a high resolution RF cavity Beam Position Monitor (BPM) system. A triplet of these BPMs, installed in the extraction line of the KEK Accelerator Test Facility (ATF) and tested with its ultra-low emittance beam, achieved a position measurement resolution of 15 nm. A metrology system for the three BPMs was subsequently installed. This system employed optical encoders to measure each BPM's position and orientation relative to a zero-coefficient of thermal expansion carbon fiber frame. We have demonstrated that the three BPMs behave as a rigid-body at the level of less than 5 nm.

SuperCDMS Underground Detector Fabrication Facility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Platt, M.; Mahapatra, R.; Bunker, Raymond A.

The SuperCDMS SNOLAB dark matter experiment processes Ge and Si crystals into fully tested phonon and ionization detectors at surface fabrication and test facilities. If not mitigated, it is anticipated that trace-level production of radioisotopes in the crystals due to exposure to cosmic rays at (or above) sea level will result in the dominant source of background events in future dark matter searches using the current SuperCDMS detector technology. Fabrication and testing of detectors in underground facilities shielded from cosmic radiation is one way to directly reduce production of trace levels of radioisotopes, thereby improving experimental sensitivity for the discoverymore » of dark matter beyond the level of the current experiment. In this report, we investigate the cost and feasibility to establish a complete detector fabrication processing chain in an underground location to mitigate cosmogenic activation of the Ge and Si detector substrates. For a specific and concrete evaluation, we explore options for such a facility located at SNOLAB, an underground laboratory in Sudbury, Canada hosting the current and future experimental phases of SuperCDMS.« less

Neutron detectors for the ESS diffractometers

NASA Astrophysics Data System (ADS)

Stefanescu, I.; Christensen, M.; Fenske, J.; Hall-Wilton, R.; Henry, P. F.; Kirstein, O.; Müller, M.; Nowak, G.; Pooley, D.; Raspino, D.; Rhodes, N.; Šaroun, J.; Schefer, J.; Schooneveld, E.; Sykora, J.; Schweika, W.

2017-01-01

The ambitious instrument suite for the future European Spallation Source whose civil construction started recently in Lund, Sweden, demands a set of diverse and challenging requirements for the neutron detectors. For instance, the unprecedented high flux expected on the samples to be investigated in neutron diffraction or reflectometry experiments requires detectors that can handle high counting rates, while the investigation of sub-millimeter protein crystals will only be possible with large-area detectors that can achieve a position resolution as low as 200 μm. This has motivated an extensive research and development campaign to advance the state-of-the-art detector and to find new technologies that can reach maturity by the time the ESS will operate at full potential. This paper presents the key detector requirements for three of the Time-of-Flight (TOF) diffraction instrument concepts selected by the Scientific Advisory Committee to advance into the phase of preliminary engineering design. We discuss the detector technologies commonly employed at the existing similar instruments and their major challenges for ESS. The detector technologies selected by the instrument teams to collect the diffraction patterns are also presented. Analytical calculations, Monte-Carlo simulations, and real experimental data are used to develop a generic method to estimate the event rate in the diffraction detectors. We apply this method to make predictions for the future diffraction instruments, and thus provide additional information that can help the instrument teams with the optimisation of the detector designs.

Forging T-Lymphocyte Identity: Intersecting Networks of Transcriptional Control

PubMed Central

Rothenberg, Ellen V.; Ungerbäck, Jonas; Champhekar, Ameya

2016-01-01

T lymphocyte development branches off from other lymphoid developmental programs through its requirement for sustained environmental signals through the Notch pathway. In the thymus, Notch signaling induces a succession of T-lineage regulatory factors that collectively create the T-cell identity through distinct steps. This process involves both the staged activation of T-cell identity genes and the staged repression of progenitor-cell-inherited regulatory genes once their roles in self-renewal and population expansion are no longer needed. With the recent characterization of Innate Lymphoid Cells (ILCs) that share transcriptional regulation programs extensively with T cell subsets, T-cell identity can increasingly be seen as defined in modular terms, as the processes selecting and actuating effector function are potentially detachable from the processes generating and selecting clonally unique T-cell receptor structures. The developmental pathways of different classes of T cells and ILCs are distinguished by the numbers of prerequisites of gene rearrangement, selection, and antigen contact before the cells gain access to nearly-common regulatory mechanisms for choosing effector function. Here, the major classes of transcription factors that interact with Notch signals during T-lineage specification are discussed in terms of their roles in these programs, the evidence for their spectra of target genes at different stages, and their cross-regulatory and cooperative actions with each other. Specific topics include Notch modulation of PU.1 and GATA-3, PU.1-Notch competition, the relationship between PU.1 and GATA-3, and the roles of E proteins, Bcl11b, and GATA-3 in guiding acquisition of T-cell identity while avoiding redirection to an ILC fate. PMID:26791859

Psycho-education for substance use and antisocial personality disorder: a randomized trial.

PubMed

Thylstrup, Birgitte; Schrøder, Sidsel; Hesse, Morten

2015-11-14

Antisocial personality disorder often co-exists with drug and alcohol use disorders. This trial examined the effectiveness of offering psycho-education for antisocial personality disorder in community substance use disorder treatment centers in Denmark. A total of 176 patients were randomly allocated to treatment as usual (TAU, n = 80) or TAU plus a psycho-educative program, Impulsive Lifestyle Counselling (ILC, n = 96) delivered by site clinicians (n = 39). Using follow-up interviews 3 and 9 months after randomization, we examined changes in drug and alcohol use (Addiction Severity Index Composite Scores), percent days abstinent (PDA) within last month, and aggression as measured with the Buss-Perry Aggression Questionnaire-Short Form and the Self-Report of Aggression and Social Behavior Measure. Overall engagement in psychological interventions was modest: 71 (76 %) of participants randomized to psycho-education attended at least one counselling session, and 21 (23 %) attended all six sessions. The Median number of sessions was 2. All patients reduced drug and alcohol problems at 9 months with small within-group effect sizes. Intention-to-treat analyses indicated significant differences between ILC and TAU in mean drugs composite score (p = .018) and in PDA (p = .041) at 3 months. Aggression declined in both groups, but no differences between ILC and TAU were observed in terms of alcohol problems or aggression at any follow-up. Moderate short-term improvements in substance use were associated with randomization to Impulsive Lifestyle Counselling. The findings support the usefulness of providing psycho-education to outpatients with antisocial personality disorder. ISRCTN registry, ISRCTN67266318 , 17/7/2012.

Cherenkov water detector NEVOD

NASA Astrophysics Data System (ADS)

Petrukhin, A. A.

2015-05-01

A unique multipurpose Cherenkov water detector, the NEVOD facility, uses quasispherical measuring modules to explore all the basic components of cosmic rays on Earth's surface, including neutrinos. Currently, the experimental complex includes the Cherenkov water detector, a calibration telescope system, and a coordinate detector. This paper traces the basic development stages of NEVOD, examines research directions, presents the results obtained, including the search for the solution to the 'muon puzzle', and discusses possible future development prospects.

Belief Systems and Language Understanding

DTIC Science & Technology

1975-01-01

Sedlak (1074), Searle (1060), Gtrawson (196U), and Wittgenstein (1958). [4] (1973), Charniak (1072), ilcCarthy and Hayes (1969), HcDermott (107...in Speech Acts", Philosophical Review 73, ^39-460. Wittgenstein , Ludwig 1958 Philosophical Investigations ( New York: The Macmillan Co.) (Tr

CD11b+Gr-1dim Tolerogenic Dendritic Cell-Like Cells Are Expanded in Interstitial Lung Disease in SKG Mice.

PubMed

Sendo, Sho; Saegusa, Jun; Okano, Takaichi; Takahashi, Soshi; Akashi, Kengo; Morinobu, Akio

2017-12-01

SKG mice develop interstitial lung disease (ILD) resembling rheumatoid arthritis-associated ILD in humans. The aim of this study was to clarify the mechanism underlying the lung pathology by analyzing lung-infiltrating cells in SKG mice with ILD. We assessed the severity of zymosan A (ZyA)-induced ILD in SKG mice histologically, and we examined lung-infiltrating cells by flow cytometry. Total lung cells and isolated monocytic myeloid-derived suppressor cells (MDSCs) were cultured in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. The proliferation of 5,6-carboxyfluorescein diacetate N-succinimidyl ester-labeled naive T cells cocultured with isolated CD11b+Gr-1 dim cells and MDSCs was evaluated by flow cytometry. CD11b+Gr-1 dim cells were adoptively transferred to ZyA-treated SKG mice. MDSCs, Th17 cells, and group 1 and 3 innate lymphoid cells (ILC1s and ILC3s) were increased in the lungs; the proportion of these cells varied with ILD severity. In this process, we found that a unique cell population, CD11b+Gr-1 dim cells, was expanded in the severely inflamed lungs. Approximately half of the CD11b+Gr-1 dim cells expressed CD11c. CD11b+Gr-1 dim cells were induced from monocytic MDSCs with GM-CSF in vitro and were considered tolerogenic because they suppressed T cell proliferation. These CD11b+Gr-1 dim cells have never been described previously, and we termed them CD11b+Gr-1 dim tolerogenic dendritic cell (DC)-like cells. Th17 cells, ILC1s, and ILC3s in the inflamed lung produced GM-CSF, which may have expanded CD11b+Gr-1 dim tolerogenic DC-like cells in vivo. Furthermore, adoptive transfer of CD11b+Gr-1 dim tolerogenic DC-like cells significantly suppressed progression of ILD in SKG mice. We identified unique suppressive myeloid cells that were differentiated from monocytic MDSCs in SKG mice with ILD, and we termed them CD11b+Gr-1 dim tolerogenic DC-like cells. © 2017, American College of Rheumatology.

Radiation-Resistant Photon-Counting Detector Package Providing Sub-ps Stability for Laser Time Transfer in Space

NASA Technical Reports Server (NTRS)

Prochzaka, Ivan; Kodat, Jan; Blazej, Josef; Sun, Xiaoli (Editor)

2015-01-01

We are reporting on a design, construction and performance of photon-counting detector packages based on silicon avalanche photodiodes. These photon-counting devices have been optimized for extremely high stability of their detection delay. The detectors have been designed for future applications in fundamental metrology and optical time transfer in space. The detectors have been qualified for operation in space missions. The exceptional radiation tolerance of the detection chip itself and of all critical components of a detector package has been verified in a series of experiments.

Update on the Fabrication and Performance of 2-D Arrays of Superconducting Magnesium Diboride (MgB2) Thermal Detectors for Outer-Planets Exploration

NASA Technical Reports Server (NTRS)

Lakew, Brook; Aslam, S.

2011-01-01

Detectors with better performance than the current thermopile detectors that operate at room temperature will be needed at the focal plane of far-infrared instruments on future planetary exploration missions. We will present an update on recent results from the 2-D array of MgB2 thermal detectors being currently developed at NASA Goddard. Noise and sensitivity results will be presented and compared to thermal detectors currently in use on planetary missions.

Considerations on Energy Frontier Colliders after LHC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shiltsev, Vladimir

2016-11-15

Since 1960’s, particle colliders have been in the forefront of particle physics, 29 total have been built and operated, 7 are in operation now. At present the near term US, European and international strategies of the particle physics community are centered on full exploitation of the physics potential of the Large Hadron Collider (LHC) through its high-luminosity upgrade (HL-LHC). The future of the world-wide HEP community critically depends on the feasibility of possible post-LHC colliders. The concept of the feasibility is complex and includes at least three factors: feasibility of energy, feasibility of luminosity and feasibility of cost. Here wemore » overview all current options for post-LHC colliders from such perspective (ILC, CLIC, Muon Collider, plasma colliders, CEPC, FCC, HE-LHC) and discuss major challenges and accelerator R&D required to demonstrate feasibility of an energy frontier accelerator facility following the LHC. We conclude by taking a look into ultimate energy reach accelerators based on plasmas and crystals, and discussion on the perspectives for the far future of the accelerator-based particle physics. This paper largely follows previous study [1] and the presenta ion given at the ICHEP’2016 conference in Chicago [2].« less

Future prospects of mass-degenerate Higgs bosons in the C P -conserving two-Higgs-doublet model

NASA Astrophysics Data System (ADS)

Bian, Ligong; Chen, Ning; Su, Wei; Wu, Yongcheng; Zhang, Yu

2018-06-01

The scenario of two mass-degenerate Higgs bosons within the general two-Higgs-doublet model (2HDM) is revisited. We focus on the global picture when two C P -even Higgs bosons of h and H are nearly mass-degenerate. A global fit to the signal strength of the 125 GeV Higgs measured at the LHC is performed. Based on the best-fit result of the 2HDM mixing angles (α ,β ), theoretical constraints, charged and C P -odd Higgs boson direct search constraints and the electroweak precision constraints are imposed to the 2HDM parameter space. We present the signal predictions of the (4 b ,2 b 2 γ ) channels for the benchmark models at the LHC 14 TeV runs. We also study the direct Higgs boson pair productions at the LHC, and the Z-associated Higgs boson pair production search at the ILC 500 GeV runs, as well as the indirect probes at the CEPC 250 GeV run. We find that the mass-degenerate Higgs boson scenario in the Type-II 2HDM can be fully probed by these future experimental searches.

Initial performance studies of a general-purpose detector for multi-TeV physics at a 100 TeV pp collider

DOE PAGES

Chekanov, S. V.; Beydler, M.; Kotwal, A. V.; ...

2017-06-13

This paper describes simulations of detector response to multi-TeV physics at the Future Circular Collider (FCC-hh) or Super proton-proton Collider (SppC) which aim to collide proton beams with a centre-of-mass energy of 100 TeV. The unprecedented energy regime of these future experiments imposes new requirements on detector technologies which can be studied using the detailed geant4 simulations presented in this paper. The initial performance of a detector designed for physics studies at the FCC-hh or SppC experiments are described with an emphasis on measurements of single particles up to 33 TeV in transverse momentum. Furthermore, the granularity requirements for calorimetrymore » are investigated using the two-particle spatial resolution achieved for hadron showers.« less

Initial performance studies of a general-purpose detector for multi-TeV physics at a 100 TeV pp collider

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chekanov, S. V.; Beydler, M.; Kotwal, A. V.

This paper describes simulations of detector response to multi-TeV physics at the Future Circular Collider (FCC-hh) or Super proton-proton Collider (SppC) which aim to collide proton beams with a centre-of-mass energy of 100 TeV. The unprecedented energy regime of these future experiments imposes new requirements on detector technologies which can be studied using the detailed geant4 simulations presented in this paper. The initial performance of a detector designed for physics studies at the FCC-hh or SppC experiments are described with an emphasis on measurements of single particles up to 33 TeV in transverse momentum. Furthermore, the granularity requirements for calorimetrymore » are investigated using the two-particle spatial resolution achieved for hadron showers.« less

Learning from Higgs physics at future Higgs factories

NASA Astrophysics Data System (ADS)

Gu, Jiayin; Li, Honglei; Liu, Zhen; Su, Shufang; Su, Wei

2017-12-01

Future Higgs factories can reach impressive precision on Higgs property measurements. In this paper, instead of conventional focus of Higgs precision in certain interaction bases, we explore its sensitivity to new physics models at the electron-positron colliders. In particular, we study two categories of new physics models, Standard Model (SM) with a real scalar singlet extension, and Two Higgs Double Model (2HDM) as examples of weakly-interacting models, Minimal Composite Higgs Model (MCHM) and three typical patterns of the more general operator counting for strong interacting models as examples of strong dynamics. We perform a global fit to various Higgs search channels to obtain the 95% C.L. constraints on the model parameter space. In the SM with a singlet extension, we obtain the limits on the singlet-doublet mixing angle sin θ, as well as the more general Wilson coefficients of the induced higher dimensional operators. In the 2HDM, we analyze tree level effects in tan β vs. cos( β - α) plane, as well as the one-loop contributions from the heavy Higgs bosons in the alignment limit to obtain the constraints on heavy Higgs masses for different types of 2HDM. In strong dynamics models, we obtain lower limits on the strong dynamics scale. In addition, once deviations of Higgs couplings are observed, they can be used to distinguish different models. We also compare the sensitivity of various future Higgs factories, namely Circular Electron Positron Collider (CEPC), Future Circular Collider (FCC)-ee and International Linear Collider (ILC).

Quantum efficiency performances of the NIR European Large Format Array detectors tested at ESTEC

NASA Astrophysics Data System (ADS)

Crouzet, P.-E.; Duvet, L.; de Wit, F.; Beaufort, T.; Blommaert, S.; Butler, B.; Van Duinkerken, G.; ter Haar, J.; Heijnen, J.; van der Luijt, K.; Smit, H.

2015-10-01

Publisher's Note: This paper, originally published on 10/12/2015, was replaced with a corrected/revised version on 10/23/2015. If you downloaded the original PDF but are unable to access the revision, please contact SPIE Digital Library Customer Service for assistance. The Payload Technology Validation Section (SRE-FV) at ESTEC has the goal to validate new technology for future or on-going mission. In this framework, a test set up to characterize the quantum efficiency of near-infrared (NIR) detectors has been created. In the context of the NIR European Large Format Array ("LFA"), 3 deliverables detectors coming from SELEX-UK/ATC (UK) on one side, and CEA/LETI- CEA/IRFU-SOFRADIR (FR) on the other side were characterized. The quantum efficiency of an HAWAII-2RG detector from Teledyne was as well measured. The capability to compare on the same setup detectors from different manufacturers is a unique asset for the future mission preparation office. This publication will present the quantum efficiency results of a HAWAII-2RG detector from Teledyne with a 2.5um cut off compared to the LFA European detectors prototypes developed independently by SELEX-UK/ATC (UK) on one side, and CEA/LETI- CEA/IRFU-SOFRADIR (FR) on the other side.

Quantum efficiency test set up performances for NIR detector characterization at ESTEC

NASA Astrophysics Data System (ADS)

Crouzet, P.-E.; Duvet, L.; De Wit, F.; Beaufort, T.; Blommaert, S.; Butler, B.; Van Duinkerken, G.; ter Haar, J.; Heijnen, J.; van der Luijt, K.; Smit, H.; Viale, T.

2014-07-01

The Payload Technology Validation Section (Future mission preparation Office) at ESTEC is in charge of specific mission oriented validation activities, for science and robotic exploration missions, aiming at reducing development risks in the implementation phase. These activities take place during the early mission phases or during the implementation itself. In this framework, a test set up to characterize the quantum efficiency of near infrared detectors has been developed. The first detector to be tested will an HAWAII-2RG detector with a 2.5μm cut off, it will be used as commissioning device in preparation to the tests of prototypes European detectors developed under ESA funding. The capability to compare on the same setup detectors from different manufacturers will be a unique asset for the future mission preparation office. This publication presents the performances of the quantum efficiency test bench to prepare measurements on the HAWAII-2RG detector. A SOFRADIR Saturn detector has been used as a preliminary test vehicle for the bench. A test set up with a lamp, chopper, monochromator, pinhole and off axis mirrors allows to create a spot of 1mm diameter between 700nm and 2.5μm.The shape of the beam has been measured to match the rms voltage read by the Merlin Lock -in amplifier and the amplitude of the incoming signal. The reference detectors have been inter-calibrated with an uncertainty up to 3 %. For the measurement with HAWAII-2RG detector, the existing cryostat [1] has been modified to adapt cold black baffling, a cold filter wheel and a sapphire window. An statistic uncertainty of +/-2.6% on the quantum efficiency on the detector under test measurement is expected.

X-ray imaging detectors for synchrotron and XFEL sources

PubMed Central

Hatsui, Takaki; Graafsma, Heinz

2015-01-01

Current trends for X-ray imaging detectors based on hybrid and monolithic detector technologies are reviewed. Hybrid detectors with photon-counting pixels have proven to be very powerful tools at synchrotrons. Recent developments continue to improve their performance, especially for higher spatial resolution at higher count rates with higher frame rates. Recent developments for X-ray free-electron laser (XFEL) experiments provide high-frame-rate integrating detectors with both high sensitivity and high peak signal. Similar performance improvements are sought in monolithic detectors. The monolithic approach also offers a lower noise floor, which is required for the detection of soft X-ray photons. The link between technology development and detector performance is described briefly in the context of potential future capabilities for X-ray imaging detectors. PMID:25995846

Radiation Assessment Detector for Mars Science Laboratory

NASA Image and Video Library

2010-11-09

The Radiation Assessment Detector, shown prior to its September 2010 installation onto NASA Mars rover Curiosity, will aid future human missions to Mars by providing information about the radiation environment on Mars and on the way to Mars.

Modeling Thermal Noise From Crystalline Coatings For Gravitational-Wave Detectors

NASA Astrophysics Data System (ADS)

Demos, Nicholas; Lovelace, Geoffrey; LSC Collaboration

2017-01-01

In 2015, Advanced LIGO made the first direct detection of gravitational waves. The sensitivity of current and future ground-based gravitational-wave detectors is limited by thermal noise in each detector's test mass substrate and coating. This noise can be modeled using the fluctuation-dissipation theorem, which relates thermal noise to an auxiliary elastic problem. I will present results from a new code that numerically models thermal noise for different crystalline mirror coatings. The thermal noise in crystalline mirror coatings could be significantly lower but is challenging to model analytically. The code uses a finite element method with adaptive mesh refinement to model the auxiliary elastic problem which is then related to thermal noise. Specifically, I will show results for a crystal coating on an amorphous substrate of varying sizes and elastic properties. This and future work will help develop the next generation of ground-based gravitational-wave detectors.

INO as atmospheric and magic baseline detector

NASA Astrophysics Data System (ADS)

Indumathi, D.

2011-10-01

We present a status report on the proposed India-based Neutrino Observatory (INO). We focus on the physics studies possible with an iron calorimeter detector (ICAL) at INO. Such a detector would make precision measurements of neutrino oscillation parameters with atmospheric neutrinos in the first phase with the possibility of acting as a far-end detector of a future neutrino factory or beta beam. This talk was given at the 12th International Workshop on Neutrino Factories, Super beams and Beta Beams, 2010 (Nufact10), in Oct 2010.

Integrated infrared detector arrays for low-background applications

NASA Technical Reports Server (NTRS)

Mccreight, C. R.; Goebel, J. H.

1982-01-01

Advanced infrared detector and detector array technology is being developed and characterized for future NASA space astronomy applications. Si:Bi charge-injection-device arrays have been obtained, and low-background sensitivities comparable to that of good discrete detectors have been measured. Intrinsic arrays are being assessed, and laboratory and telescope data have been collected on a monolithic InSb CCD array. For wavelengths longer than 30 microns, improved Ge:Ga detectors have been produced, and steps have been taken to prove the feasibility of an integrated extrinsic germanium array. Other integrated arrays and cryogenic components are also under investigation.

A new method for detection of distant supernova neutrino bursts

NASA Astrophysics Data System (ADS)

Cline, D.; Fenyves, E.; Foshe, T.; Fuller, G.; Meyer, B.; Wilson, J.

1990-03-01

The feasibility of astrophysical neutrino detectors is studied, which is based on the detection of neutrons produced in neutrino-nucleus inelastic scattering events. Collective nuclear effects greatly enhancing the relevant interaction cross sections over those of single particle interactions are discussed. These effects can help to reduce the mass required for neutrino detectors. An example of a simple detector based on CaCO3 neutrino targets and BF3 neutron counters is presented. Neutron background limitations are discussed and the possibility of forming a coincidence between neutrino detectors and future gravity wave detectors is also considered.

LWIR detector requirements for low-background space applications

NASA Technical Reports Server (NTRS)

Deluccia, Frank J.

1990-01-01

Detection of cold bodies (200 to 300 K) against space backgrounds has many important applications, both military and non-military. The detector performance and design characteristics required to support low-background applications are discussed, with particular emphasis on those characteristics required for space surveillance. The status of existing detector technologies under active development for these applications is also discussed. In order to play a role in future systems, new, potentially competing detector technologies such as multiple quantum well detectors must not only meet system-derived requirements, but also offer distinct performance or other advantages over these incumbent technologies.

Evaluation of the effectiveness of ATM messages used during incidents : final report.

DOT National Transportation Integrated Search

2016-01-01

This project investigated the use of Intelligent Lane Control Signs based Active Traffic Management for : Incident Management on a heavily traveled urban freeway. The subject of the research was the ILCS : system on I-94 westbound in downtown Minneap...

Low Emittance Guns for the ILC Polarized Electron Beam

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clendenin, J. E.; Brachmann, A.; Ioakeimidi, K.

Polarized electron beams generated by DC guns are routinely available at several accelerators including JLAB, Mainz and SLAC. These guns operate with a cathode bias on the order of -100 kV. To minimize space charge effects, relatively long bunches are generated at the gun and then compressed longitudinally external to the gun just before and during initial acceleration. For linear colliders, this compression is accomplished using a combination of rf bunchers. For the basic design of the International Linear Collider (ILC), a 120 kV DC photocathode gun is used to produce a series of nanosecond bunches that are each compressedmore » by two sub-harmonic bunchers (SHBs) followed by an L-band buncher and capture section. The longitudinal bunching process results in a significantly higher emittance than produced by the gun alone. While high-energy experiments using polarized beams are not generally sensitive to the source emittance, there are several benefits to a lower source emittance including a simpler more efficient injector system and a lower radiation load during transport especially at bends as at the damping ring. For the ILC, the SHBs could be eliminated if the voltage of the gun is raised sufficiently. Simulations using the General Particle Tracer (GPT) package indicate that a cathode bias voltage of {>=}200 kV should allow both SHBs to be operated at 433 or even 650 MHz, while {>=}500 kV would be required to eliminate the SHBs altogether. Simulations can be used to determine the minimum emittance possible if the injector is designed for a given increased voltage. A possible alternative to the DC gun is an rf gun. Emittance compensation, routinely used with rf guns, is discussed for higher-voltage DC guns.« less

Low Emittance Guns for the ILC Polarized Electron Beam

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clendenin, J.E.; Brachmann, A.; Ioakeimidi, K.

Polarized electron beams generated by DC guns are routinely available at several accelerators including JLAB, Mainz and SLAC. These guns operate with a cathode bias on the order of -100 kV. To minimize space charge effects, relatively long bunches are generated at the gun and then compressed longitudinally external to the gun just before and during initial acceleration. For linear colliders, this compression is accomplished using a combination of rf bunchers. For the basic design of the International Linear Collider (ILC), a 120 kV DC photocathode gun is used to produce a series of nanosecond bunches that are each compressedmore » by two sub-harmonic bunchers (SHBs) followed by an L-band buncher and capture section. The longitudinal bunching process results in a significantly higher emittance than produced by the gun alone. While high-energy experiments using polarized beams are not generally sensitive to the source emittance, there are several benefits to a lower source emittance including a simpler more efficient injector system and a lower radiation load during transport especially at bends as at the damping ring. For the ILC, the SHBs could be eliminated if the voltage of the gun is raised sufficiently. Simulations using the General Particle Tracer (GPT) package indicate that a cathode bias voltage of {ge}200 kV should allow both SHBs to be operated at 433 or even 650 MHz, while {ge}500 kV would be required to eliminate the SHBs altogether. Simulations can be used to determine the minimum emittance possible if the injector is designed for a given increased voltage. A possible alternative to the DC gun is an rf gun. Emittance compensation, routinely used with rf guns, is discussed for higher-voltage DC guns.« less

Functional electrical stimulation mediated by iterative learning control and 3D robotics reduces motor impairment in chronic stroke

PubMed Central

2012-01-01

Background Novel stroke rehabilitation techniques that employ electrical stimulation (ES) and robotic technologies are effective in reducing upper limb impairments. ES is most effective when it is applied to support the patients’ voluntary effort; however, current systems fail to fully exploit this connection. This study builds on previous work using advanced ES controllers, and aims to investigate the feasibility of Stimulation Assistance through Iterative Learning (SAIL), a novel upper limb stroke rehabilitation system which utilises robotic support, ES, and voluntary effort. Methods Five hemiparetic, chronic stroke participants with impaired upper limb function attended 18, 1 hour intervention sessions. Participants completed virtual reality tracking tasks whereby they moved their impaired arm to follow a slowly moving sphere along a specified trajectory. To do this, the participants’ arm was supported by a robot. ES, mediated by advanced iterative learning control (ILC) algorithms, was applied to the triceps and anterior deltoid muscles. Each movement was repeated 6 times and ILC adjusted the amount of stimulation applied on each trial to improve accuracy and maximise voluntary effort. Participants completed clinical assessments (Fugl-Meyer, Action Research Arm Test) at baseline and post-intervention, as well as unassisted tracking tasks at the beginning and end of each intervention session. Data were analysed using t-tests and linear regression. Results From baseline to post-intervention, Fugl-Meyer scores improved, assisted and unassisted tracking performance improved, and the amount of ES required to assist tracking reduced. Conclusions The concept of minimising support from ES using ILC algorithms was demonstrated. The positive results are promising with respect to reducing upper limb impairments following stroke, however, a larger study is required to confirm this. PMID:22676920

Measurement of the Higgs boson mass and e + e - → Z H cross section using Z → μ + μ - and Z → e + e - at the ILC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yan, J.; Watanuki, S.; Fujii, K.

This paper presents a full simulation study of the measurement of the production cross section(ZH) of the Higgsstrahlung process e+e- ZH and the Higgs boson mass (MH) at the International Linear Collider (ILC), using events in which a Higgs boson recoils against a Z boson decaying into a pair of muons or electrons. The analysis is carried out for three center-of-mass energiesps =250, 350, and 500 GeV, and two beam polarizations e L e+ R and e Re+L , for which the polarizationsof e and e+ are Pe-; Pe+ =(-80%, +30%) and (+80%, -30%), respectively. Assuming an integrated luminosity ofmore » 250 fb1 for each beam polarization at ps = 250 GeV, where the best lepton momentum resolution is obtainable, ZH and MH can be determined with a precision of 2.5%and 37 MeV for e L e+R and 2.9% and 41 MeV for e-Re+L , respectively. Regarding a 20 year ILC physics program, the expected precisions for the HZZ coupling and MH are estimated to be 0.4% and 14MeV, respectively. The event selection is designed to optimize the precisions of ZH and MH while minimizing the bias on the measured ZH due to discrepancy in signal efficiencies among Higgs decay modes. For the first time, model independence has been demonstrated to a sub-percent level for the ZH measurement at each of the three center-of-mass energies. The results presented show the impact of center-of-mass energy and beam polarization on the evaluated precisons and serve as« less

Forging T-Lymphocyte Identity: Intersecting Networks of Transcriptional Control.

PubMed

Rothenberg, Ellen V; Ungerbäck, Jonas; Champhekar, Ameya

2016-01-01

T-lymphocyte development branches off from other lymphoid developmental programs through its requirement for sustained environmental signals through the Notch pathway. In the thymus, Notch signaling induces a succession of T-lineage regulatory factors that collectively create the T-cell identity through distinct steps. This process involves both the staged activation of T-cell identity genes and the staged repression of progenitor-cell-inherited regulatory genes once their roles in self-renewal and population expansion are no longer needed. With the recent characterization of innate lymphoid cells (ILCs) that share transcriptional regulation programs extensively with T-cell subsets, T-cell identity can increasingly be seen as defined in modular terms, as the processes selecting and actuating effector function are potentially detachable from the processes generating and selecting clonally unique T-cell receptor structures. The developmental pathways of different classes of T cells and ILCs are distinguished by the numbers of prerequisites of gene rearrangement, selection, and antigen contact before the cells gain access to nearly common regulatory mechanisms for choosing effector function. Here, the major classes of transcription factors that interact with Notch signals during T-lineage specification are discussed in terms of their roles in these programs, the evidence for their spectra of target genes at different stages, and their cross-regulatory and cooperative actions with each other. Specific topics include Notch modulation of PU.1 and GATA-3, PU.1-Notch competition, the relationship between PU.1 and GATA-3, and the roles of E proteins, Bcl11b, and GATA-3 in guiding acquisition of T-cell identity while avoiding redirection to an ILC fate. © 2016 Elsevier Inc. All rights reserved.

Intraoperative specimen radiography in patients with nonpalpable malignant breast lesions.

PubMed

Schmachtenberg, C; Engelken, F; Fischer, T; Bick, U; Poellinger, A; Fallenberg, E M

2012-07-01

Specimen mammography of nonpalpable wire-localized breast lesions is the standard in breast-conserving surgery. The aim of this study was to evaluate the reliability of intraoperative 2-view specimen mammography in different cancer types. After ethics approval, 3 readers retrospectively evaluated margins on 266 2-view specimen radiographs. They determined the closest margin and the orientation. The results were correlated with the histopathology (intra-class correlation coefficient [ICC] and contingency coefficient [CC]) and compared (Wilcoxon test). Invasive ductal carcinoma (IDC) with ductal carcinoma in situ (DCIS) was present in 115 (43 %), IDC in 75 (28 %), invasive lobular carcinoma (ILC) in 57 (22 %) and rare cancers (CA) in 19 specimens (7 %). The sensitivity/specificity and positive/negative predictive value (P/NPV) of specimen mammography were 0.50/0.86 and 0.86/0.50 for CA, 0.42/0.68 and 0.48/0.63 for IDC, 0.36/0.81 and 0.69/0.51 for ILC, and 0.22/0.78 and 0.68/0.32 for IDC+DCIS. Readers correctly identified the orientation of the closest margin in at least one view in an average of 149 specimens (56 %). CCs were between 0.680 (IDC) and 0.912 (CA), suggesting a moderate correlation between radiographic and histological orientation. The correlations were worse for the radiographic and histological distances, with ICC ranging from 0.238 (ILC) to 0.475 (CA). The Wilcoxon test revealed overestimation of the radiographic margins compared to the histological ones for DCIS. Our results suggest that specimen radiography has relatively good overall specificity and good PPV, while the sensitivity and NPV are low for DCIS. A negative result on specimen radiography does not rule out histologically involved margins. © Georg Thieme Verlag KG Stuttgart · New York.

Notch Signaling Contributes to Liver Inflammation by Regulation of Interleukin-22-Producing Cells in Hepatitis B Virus Infection

PubMed Central

Wei, Xin; Wang, Jiu-Ping; Hao, Chun-Qiu; Yang, Xiao-Fei; Wang, Lin-Xu; Huang, Chang-Xing; Bai, Xue-Fan; Lian, Jian-Qi; Zhang, Ye

2016-01-01

The mechanism of hepatitis B virus (HBV) induced liver inflammation is not fully elucidated. Notch signaling augmented interleukin (IL)-22 secretion in CD4+ T cells, and Notch-IL-22 axis fine-tuned inflammatory response. We previously demonstrated a proinflammatory role of IL-22 in HBV infection. Thus, in this study, we analyzed the role of Notch in development of IL-22-producing cells in HBV infection by inhibition of Notch signaling using γ-secretase inhibitor DAPT in both hydrodynamic induced HBV-infected mouse model and in peripheral blood cells isolated from patients with HBV infection. mRNA expressions of Notch1 and Notch2 were significantly increased in livers and CD4+ T cells upon HBV infection. Inhibition of Notch signaling in vivo leaded to the reduction in NKp46+ innate lymphoid cells 22 (ILC22) and lymphoid tissue inducer 4 (LTi4) cells in the liver. This process was accompanied by downregulating the expressions of IL-22 and related proinflammatory cytokines and chemokines in the liver, as well as blocking the recruitment of antigen-non-specific inflammatory cells into the liver and subsequent liver injury, but did not affect HBV antigens production and IL-22 secretion in the serum. Furthermore, IL-22 production in HBV non-specific cultured CD4+ T cells, but not HBV-specific CD4+ T cells, was reduced in response to in vitro inhibition of Notch signaling. In conclusion, Notch siganling appears to be an important mediator of the liver inflammation by modulating hepatic ILC22. The potential proinflammatory effect of Notch-mediated ILC22 may be significant for the development of new therapeutic approaches for treatment of hepatitis B. PMID:27800305

Functional electrical stimulation mediated by iterative learning control and 3D robotics reduces motor impairment in chronic stroke.

PubMed

Meadmore, Katie L; Hughes, Ann-Marie; Freeman, Chris T; Cai, Zhonglun; Tong, Daisy; Burridge, Jane H; Rogers, Eric

2012-06-07

Novel stroke rehabilitation techniques that employ electrical stimulation (ES) and robotic technologies are effective in reducing upper limb impairments. ES is most effective when it is applied to support the patients' voluntary effort; however, current systems fail to fully exploit this connection. This study builds on previous work using advanced ES controllers, and aims to investigate the feasibility of Stimulation Assistance through Iterative Learning (SAIL), a novel upper limb stroke rehabilitation system which utilises robotic support, ES, and voluntary effort. Five hemiparetic, chronic stroke participants with impaired upper limb function attended 18, 1 hour intervention sessions. Participants completed virtual reality tracking tasks whereby they moved their impaired arm to follow a slowly moving sphere along a specified trajectory. To do this, the participants' arm was supported by a robot. ES, mediated by advanced iterative learning control (ILC) algorithms, was applied to the triceps and anterior deltoid muscles. Each movement was repeated 6 times and ILC adjusted the amount of stimulation applied on each trial to improve accuracy and maximise voluntary effort. Participants completed clinical assessments (Fugl-Meyer, Action Research Arm Test) at baseline and post-intervention, as well as unassisted tracking tasks at the beginning and end of each intervention session. Data were analysed using t-tests and linear regression. From baseline to post-intervention, Fugl-Meyer scores improved, assisted and unassisted tracking performance improved, and the amount of ES required to assist tracking reduced. The concept of minimising support from ES using ILC algorithms was demonstrated. The positive results are promising with respect to reducing upper limb impairments following stroke, however, a larger study is required to confirm this.

IL233, A Novel IL-2 and IL-33 Hybrid Cytokine, Ameliorates Renal Injury.

PubMed

Stremska, Marta E; Jose, Sheethal; Sabapathy, Vikram; Huang, Liping; Bajwa, Amandeep; Kinsey, Gilbert R; Sharma, Poonam R; Mohammad, Saleh; Rosin, Diane L; Okusa, Mark D; Sharma, Rahul

2017-09-01

CD4 + Foxp3 + regulatory T cells (Tregs) protect the kidney during AKI. We previously found that IL-2, which is critical for Treg homeostasis, upregulates the IL-33 receptor (ST2) on CD4 + T cells, thus we hypothesized that IL-2 and IL-33 cooperate to enhance Treg function. We found that a major subset of Tregs in mice express ST2, and coinjection of IL-2 and IL-33 increased the number of Tregs in lymphoid organs and protected mice from ischemia-reperfusion injury (IRI) more efficiently than either cytokine alone. Accordingly, we generated a novel hybrid cytokine (IL233) bearing the activities of IL-2 and IL-33 for efficient targeting to Tregs. IL233 treatment increased the number of Tregs in blood and spleen and prevented IRI more efficiently than a mixture of IL-2 and IL-33. Injection of IL233 also increased the numbers of Tregs in renal compartments. Moreover, IL233-treated mice had fewer splenic Tregs and more Tregs in kidneys after IRI. In vitro , splenic Tregs from IL233-treated mice suppressed CD4 + T cell proliferation better than Tregs from saline-treated controls. IL233 treatment also improved the ability of isolated Tregs to inhibit IRI in adoptive transfer experiments and protected mice from cisplatin- and doxorubicin-induced nephrotoxic injury. Finally, treatment with IL233 increased the proportion of ST2-bearing innate lymphoid cells (ILC2) in blood and kidneys, and adoptive transfer of ILC2 also protected mice from IRI. Thus, the novel IL233 hybrid cytokine, which utilizes the cooperation of IL-2 and IL-33 to enhance Treg- and ILC2-mediated protection from AKI, bears strong therapeutic potential. Copyright © 2017 by the American Society of Nephrology.

Scenario analysis of energy-based low-carbon development in China.

PubMed

Zhou, Yun; Hao, Fanghua; Meng, Wei; Fu, Jiafeng

2014-08-01

China's increasing energy consumption and coal-dominant energy structure have contributed not only to severe environmental pollution, but also to global climate change. This article begins with a brief review of China's primary energy use and associated environmental problems and health risks. To analyze the potential of China's transition to low-carbon development, three scenarios are constructed to simulate energy demand and CO₂ emission trends in China up to 2050 by using the Long-range Energy Alternatives Planning System (LEAP) model. Simulation results show that with the assumption of an average annual Gross Domestic Product (GDP) growth rate of 6.45%, total primary energy demand is expected to increase by 63.4%, 48.8% and 12.2% under the Business as Usual (BaU), Carbon Reduction (CR) and Integrated Low Carbon Economy (ILCE) scenarios in 2050 from the 2009 levels. Total energy-related CO₂ emissions will increase from 6.7 billiontons in 2009 to 9.5, 11, 11.6 and 11.2 billiontons; 8.2, 9.2, 9.6 and 9 billiontons; 7.1, 7.4, 7.2 and 6.4 billiontons in 2020, 2030, 2040 and 2050 under the BaU, CR and ILCE scenarios, respectively. Total CO₂ emission will drop by 19.6% and 42.9% under the CR and ILCE scenarios in 2050, compared with the BaU scenario. To realize a substantial cut in energy consumption and carbon emissions, China needs to make a long-term low-carbon development strategy targeting further improvement of energy efficiency, optimization of energy structure, deployment of clean coal technology and use of market-based economic instruments like energy/carbon taxation. Copyright © 2014. Published by Elsevier B.V.

Anomalous optical surface absorption in nominally pure silicon samples at 1550 nm

NASA Astrophysics Data System (ADS)

Bell, Angus S.; Steinlechner, Jessica; Martin, Iain W.; Craig, Kieran; Cunningham, William; Rowan, Sheila; Hough, Jim; Schnabel, Roman; Khalaidovski, Alexander

2017-10-01

The announcement of the direct detection of gravitational waves (GW) by the LIGO and Virgo collaboration in February 2016 has removed any uncertainty around the possibility of GW astronomy. It has demonstrated that future detectors with sensitivities ten times greater than the Advanced LIGO detectors would see thousands of events per year. Many proposals for such future interferometric GW detectors assume the use of silicon test masses. Silicon has low mechanical loss at low temperatures, which leads to low displacement noise for a suspended interferometer mirror. In addition to the low mechanical loss, it is a requirement that the test masses have a low optical loss. Measurements at 1550 nm have indicated that material with a low enough bulk absorption is available; however there have been suggestions that this low absorption material has a surface absorption of  >100 ppm which could preclude its use in future cryogenic detectors. We show in this paper that this surface loss is not intrinsic but is likely to be a result of particular polishing techniques and can be removed or avoided by the correct polishing procedure. This is an important step towards high gravitational wave detection rates in silicon based instruments.

Scientific Benefit of Enlarging Gravitational Wave Detector Networks

NASA Astrophysics Data System (ADS)

Chu, Qi; Wen, Linqing; Blair, David

2012-06-01

Localising the sources of gravitational waves (GWs) in the sky is crucial to observing the electromagnetic counterparts of GW sources. The localisation capability is poor by a single GW detector yet can be improved by adding more detectors to the detector network. In this paper we review recent studies on scientific benefits of global detector networks and focus on their localisation capability. We employ Wen-Chen's formula to compare this merit of current and future detector networks for localising gravitational wave bursts. We find that the addition of a new detector located in Japan, or India, or Australia will increase angular resolution 3~5 fold with respect to current LIGO-Virgo network, and that the angular resolution improvement by adding a single detector in Australia is comparable to that achieved by adding detectors in both India and Japan. A six-site network achieves a 11-fold improvement in angular resolution compared with the existing three-site network.

Open-closed-loop iterative learning control for a class of nonlinear systems with random data dropouts

NASA Astrophysics Data System (ADS)

Cheng, X. Y.; Wang, H. B.; Jia, Y. L.; Dong, YH

2018-05-01

In this paper, an open-closed-loop iterative learning control (ILC) algorithm is constructed for a class of nonlinear systems subjecting to random data dropouts. The ILC algorithm is implemented by a networked control system (NCS), where only the off-line data is transmitted by network while the real-time data is delivered in the point-to-point way. Thus, there are two controllers rather than one in the control system, which makes better use of the saved and current information and thereby improves the performance achieved by open-loop control alone. During the transfer of off-line data between the nonlinear plant and the remote controller data dropout occurs randomly and the data dropout rate is modeled as a binary Bernoulli random variable. Both measurement and control data dropouts are taken into consideration simultaneously. The convergence criterion is derived based on rigorous analysis. Finally, the simulation results verify the effectiveness of the proposed method.

NASA Research Announcement Phase 1 Report and Phase 2 Proposal for the Development of a Power Assisted Space Suit Glove Assembly

NASA Technical Reports Server (NTRS)

Cadogan, Dave; Lingo, Bob

1996-01-01

In July of 1996, ILC Dover was awarded Phase 1 of a contract for NASA to develop a prototype Power Assisted Space Suit glove to enhance the performance of astronauts during Extra-Vehicular Activity (EVA). This report summarizes the work performed to date on Phase 1, and details the work to be conducted on Phase 2 of the program. Phase 1 of the program consisted of research and review of related technical sources, concept brainstorming, baseline design development, modeling and analysis, component mock-up testing, and test data analysis. ILC worked in conjunction with the University of Maryland's Space Systems Laboratory (SSL) to develop the power assisted glove. Phase 2 activities will focus on the design maturation and the manufacture of a working prototype system. The prototype will be tested and evaluated in conjunction with existing space suit glove technology to determine the performance enhancement anticipated with the implementation of the power assisted joint technology in space suit gloves.

Signals of leptophilic dark matter at the ILC

NASA Astrophysics Data System (ADS)

Dutta, Sukanta; Rawat, Bharti; Sachdeva, Divya

2017-09-01

Adopting a model independent approach, we constrain the various effective interactions of leptophilic DM particles with the visible world from the WMAP and Planck data. The thermally averaged indirect DM annihilation cross section and the DM-electron direct-detection cross section for such a DM candidate are observed to be consistent with the respective experimental data. We study the production of cosmologically allowed leptophilic DM in association with Z (Z→ f\\bar{f}), f≡ q, e^-, μ ^- at the ILC. We perform the χ ^2 analysis and compute the 99% C.L. acceptance contours in the m_χ and Λ plane from the two-dimensional differential distributions of various kinematic observables obtained after employing parton showering and hadronisation to the simulated data. We observe that the dominant hadronic channel provides the best kinematic reach of 2.62 TeV (m_χ = 25 GeV), which further improves to ˜ 3 TeV for polarised beams at √{s} = 1 TeV and an integrated luminosity of 1 ab^{-1}.

The Electromagnetic Calorimeter of the future PANDA Detector

DOE Office of Scientific and Technical Information (OSTI.GOV)

Novotny, Rainer

2006-10-27

Experiments with a cooled antiproton beam at the future accelerator facility FAIR at GSI, Darmstadt, will be performed with the 4{pi} detector PANDA comprising a high resolution, compact and fast homogeneous electromagnetic calorimeter to detect photons between 10MeV and 10GeV energy inside a superconducting solenoid (2T). The target calorimeter comprises more than 20,000 PbWO4 crystals of significantly enhanced quality read-out with large area avalanche photodiodes at an operating temperature of -25 degree sign C. The paper describes the quality of PWO-II and illustrates the future performance based on response measurements with high-energy photons.

A compact and modular x- and gamma-ray detector with a CsI scintillator and double-readout Silicon Drift Detectors

NASA Astrophysics Data System (ADS)

Campana, R.; Fuschino, F.; Labanti, C.; Marisaldi, M.; Amati, L.; Fiorini, M.; Uslenghi, M.; Baldazzi, G.; Bellutti, P.; Evangelista, Y.; Elmi, I.; Feroci, M.; Ficorella, F.; Frontera, F.; Picciotto, A.; Piemonte, C.; Rachevski, A.; Rashevskaya, I.; Rignanese, L. P.; Vacchi, A.; Zampa, G.; Zampa, N.; Zorzi, N.

2016-07-01

A future compact and modular X and gamma-ray spectrometer (XGS) has been designed and a series of proto- types have been developed and tested. The experiment envisages the use of CsI scintillator bars read out at both ends by single-cell 25 mm2 Silicon Drift Detectors. Digital algorithms are used to discriminate between events absorbed in the Silicon layer (lower energy X rays) and events absorbed in the scintillator crystal (higher energy X rays and -rays). The prototype characterization is shown and the modular design for future experiments with possible astrophysical applications (e.g. for the THESEUS mission proposed for the ESA M5 call) are discussed.

Status of a Deep Learning Based Measurement of the Inclusive Muon Neutrino Charged-current Cross Section in the NOvA Near Detector

DOE Office of Scientific and Technical Information (OSTI.GOV)

Behera, Biswaranjan

NOvA is a long-baseline neutrino oscillation experiment. It uses the NuMI beam from Fermilab and two sampling calorimeter detectors placed off-axis from the beam. The 293 ton Near Detector measures the unoscillated neutrino energy spectrum, which can be used to predict the neutrino energy spectrum observed at the 14 kton Far Detector. The Near Detector also provides an excellent opportunity to measure neutrino interaction cross sections with high statistics, which will benefit current and future long-baseline neutrino oscillation experiments. This analysis implements new algorithms to identifymore » $$\

Impact of infrasound atmospheric noise on gravity detectors used for astrophysical and geophysical applications

NASA Astrophysics Data System (ADS)

Fiorucci, Donatella; Harms, Jan; Barsuglia, Matteo; Fiori, Irene; Paoletti, Federico

2018-03-01

Density changes in the atmosphere produce a fluctuating gravity field that affects gravity strainmeters or gravity gradiometers used for the detection of gravitational waves and for geophysical applications. This work addresses the impact of the atmospheric local gravity noise on such detectors, extending previous analyses. In particular we present the effect introduced by the building housing the detectors, and we analyze local gravity-noise suppression by constructing the detector underground. We present also new sound spectra and correlation measurements. The results obtained are important for the design of future gravitational-wave detectors and gravity gradiometers used to detect prompt gravity perturbations from earthquakes.

Signal Conditioning for Satellite Borne Energetic-Charged-Particle Experiments

NASA Technical Reports Server (NTRS)

Ludwig, George H.

1961-01-01

Many of the spacecraft launched thus far have carried detectors for investigating cosmic rays, solar protons, solar plasmas, and the geomagnetically trapped radiation. These detectors, which will find continued application in the future, include ion chambers; proportional, Geiger-Muller, scintillation, Cerenkov, and solid state detectors; ion collectors; and nuclear emulsions. The instrumentation required to condition the signals from these detectors prior to telemetering is steadily growing more complex in order to permit more meaningful measurements. This report describes a number of instrumentation elements typical of the present state of the art, and a present-generation three-detector system which illustrates the integration of such basic elements into a complex system.

Second-generation detector work in Israel

NASA Astrophysics Data System (ADS)

Rosenfeld, David

2001-10-01

A tremendous developmental effort in the field of infrared detectors during the last decade in Israel has resulted in a variety of InSb and HgCdTe infrared detectors. Additional and significant R&D effort associated with other IR components, have also been done in Israel, in order to integrate the detectors into advanced Detector-Dewar-Cooler assemblies (DDCs). This R&D effort included notable activities in the field of materials, signal processors, dewars and cryocoolers. These activities are presented together with the status of infrared detector work in Israel. Several two-dimensional InSb staring detectors and DDCs are demonstrated. This includes two versions of the classical 256 X 256 detectors and DDCs, improved 640 X 480 InSb detectors and DDC, and a 2000- element detector with high TDI level. SADA II type HgCdTe detectors are also presented. Considerations regarding the course of future detector work are also described. The classical DDC requirement list which traditionally included demands for high D*, low NETD and high resolution is widened to include cost related issues such as higher reliability, lower maintenance, smaller volume, lower power consumption and higher operation temperature.

Semiconductor Radiation Detectors: Basic principles and some uses of a recent tool that has revolutionized nuclear physics are described.

PubMed

Goulding, F S; Stone, Y

1970-10-16

The past decade has seen the rapid development and exploitation of one of the most significant tools of nuclear physics, the semiconductor radiation detector. Applications of the device to the analysis of materials promises to be one of the major contributions of nuclear research to technology, and may even assist in some aspects of our environmental problems. In parallel with the development of these applications, further developments in detectors for nuclear research are taking place: the use of very thin detectors for heavyion identification, position-sensitive detectors for nuclear-reaction studies, and very pure germanium for making more satisfactory detectors for many applications suggest major future contributions to physics.

Neural network tracking and extension of positive tracking periods

NASA Technical Reports Server (NTRS)

Hanan, Jay C.; Chao, Tien-Hsin; Moreels, Pierre

2004-01-01

Feature detectors have been considered for the role of supplying additional information to a neural network tracker. The feature detector focuses on areas of the image with significant information. Basically, if a picture says a thousand words, the feature detectors are looking for the key phrases (keypoints). These keypoints are rotationally invariant and may be matched across frames. Application of these advanced feature detectors to the neural network tracking system at JPL has promising potential. As part of an ongoing program, an advanced feature detector was tested for augmentation of a neural network based tracker. The advance feature detector extended tracking periods in test sequences including aircraft tracking, rover tracking, and simulated Martian landing. Future directions of research are also discussed.

Neural network tracking and extension of positive tracking periods

NASA Astrophysics Data System (ADS)

Hanan, Jay C.; Chao, Tien-Hsin; Moreels, Pierre

2004-04-01

Feature detectors have been considered for the role of supplying additional information to a neural network tracker. The feature detector focuses on areas of the image with significant information. Basically, if a picture says a thousand words, the feature detectors are looking for the key phrases (keypoints). These keypoints are rotationally invariant and may be matched across frames. Application of these advanced feature detectors to the neural network tracking system at JPL has promising potential. As part of an ongoing program, an advanced feature detector was tested for augmentation of a neural network based tracker. The advance feature detector extended tracking periods in test sequences including aircraft tracking, rover tracking, and simulated Martian landing. Future directions of research are also discussed.

Small Pixel Hybrid CMOS X-ray Detectors

NASA Astrophysics Data System (ADS)

Hull, Samuel; Bray, Evan; Burrows, David N.; Chattopadhyay, Tanmoy; Falcone, Abraham; Kern, Matthew; McQuaide, Maria; Wages, Mitchell

2018-01-01

Concepts for future space-based X-ray observatories call for a large effective area and high angular resolution instrument to enable precision X-ray astronomy at high redshift and low luminosity. Hybrid CMOS detectors are well suited for such high throughput instruments, and the Penn State X-ray detector lab, in collaboration with Teledyne Imaging Sensors, has recently developed new small pixel hybrid CMOS X-ray detectors. These prototype 128x128 pixel devices have 12.5 micron pixel pitch, 200 micron fully depleted depth, and include crosstalk eliminating CTIA amplifiers and in-pixel correlated double sampling (CDS) capability. We report on characteristics of these new detectors, including the best read noise ever measured for an X-ray hybrid CMOS detector, 5.67 e- (RMS).

CARE activities on superconducting RF cavities at INFN Milano

NASA Astrophysics Data System (ADS)

Bosotti, A.; Pierini, P.; Michelato, P.; Pagani, C.; Paparella, R.; Panzeri, N.; Monaco, L.; Paulon, R.; Novati, M.

2005-09-01

The SC RF group at INFN Milano-LASA is involved both in the TESLA/TTF collaboration and in the research and design activity on superconducting cavities for proton accelerators. Among these activities, some are supported by the European community within the CARE project. In the framework of the JRASRF collaboration we are developing a coaxial blade tuner for ILC (International Linear Collider) cavities, integrated with piezoelectric actuators for the compensation of the Lorenz force detuning and microphonics perturbation. Another activity, regarding the improved component design on SC technology, based on the information retrieving about the status of art on ancillaries and experience of various laboratories involved in SCRF, has started in our laboratory. Finally, in the framework of the HIPPI collaboration, we are testing two low beta superconducting cavities, built for the Italian TRASCO project, to verify the possibility to use them for pulsed operation. All these activities will be described here, together with the main results and the future perspectives.

Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation.

PubMed

Molofsky, Ari B; Savage, Adam K; Locksley, Richard M

2015-06-16

Interleukin-33 (IL-33) is a nuclear-associated cytokine of the IL-1 family originally described as a potent inducer of allergic type 2 immunity. IL-33 signals via the receptor ST2, which is highly expressed on group 2 innate lymphoid cells (ILC2s) and T helper 2 (Th2) cells, thus underpinning its association with helminth infection and allergic pathology. Recent studies have revealed ST2 expression on subsets of regulatory T cells, and for a role for IL-33 in tissue homeostasis and repair that suggests previously unrecognized interactions within these cellular networks. IL-33 can participate in pathologic fibrotic reactions, or, in the setting of microbial invasion, can cooperate with inflammatory cytokines to promote responses by cytotoxic NK cells, Th1 cells, and CD8(+) T cells. Here, we highlight the regulation and function of IL-33 and ST2 and review their roles in homeostasis, damage, and inflammation, suggesting a conceptual framework for future studies. Copyright © 2015 Elsevier Inc. All rights reserved.

CsI-Silicon Particle detector for Heavy ions Orbiting in Storage rings (CsISiPHOS)

NASA Astrophysics Data System (ADS)

Najafi, M. A.; Dillmann, I.; Bosch, F.; Faestermann, T.; Gao, B.; Gernhäuser, R.; Kozhuharov, C.; Litvinov, S. A.; Litvinov, Yu. A.; Maier, L.; Nolden, F.; Popp, U.; Sanjari, M. S.; Spillmann, U.; Steck, M.; Stöhlker, T.; Weick, H.

2016-11-01

A heavy-ion detector was developed for decay studies in the Experimental Storage Ring (ESR) at the GSI Helmholtz Centre for Heavy Ion Research in Darmstadt, Germany. This detector serves as a prototype for the in-pocket particle detectors for future experiments with the Collector Ring (CR) at FAIR (Facility for Antiproton and Ion Research). The detector includes a stack of six silicon pad sensors, a double-sided silicon strip detector (DSSD), and a CsI(Tl) scintillation detector. It was used successfully in a recent experiment for the detection of the β+-decay of highly charged 142Pm60+ ions. Based on the ΔE / E technique for particle identification and an energy resolution of 0.9% for ΔE and 0.5% for E (Full Width at Half Maximum (FWHM)), the detector is well-suited to distinguish neighbouring isobars in the region of interest.

A kilo-pixel imaging system for future space based far-infrared observatories using microwave kinetic inductance detectors

NASA Astrophysics Data System (ADS)

Baselmans, J. J. A.; Bueno, J.; Yates, S. J. C.; Yurduseven, O.; Llombart, N.; Karatsu, K.; Baryshev, A. M.; Ferrari, L.; Endo, A.; Thoen, D. J.; de Visser, P. J.; Janssen, R. M. J.; Murugesan, V.; Driessen, E. F. C.; Coiffard, G.; Martin-Pintado, J.; Hargrave, P.; Griffin, M.

2017-05-01

Aims: Future astrophysics and cosmic microwave background space missions operating in the far-infrared to millimetre part of the spectrum will require very large arrays of ultra-sensitive detectors in combination with high multiplexing factors and efficient low-noise and low-power readout systems. We have developed a demonstrator system suitable for such applications. Methods: The system combines a 961 pixel imaging array based upon Microwave Kinetic Inductance Detectors (MKIDs) with a readout system capable of reading out all pixels simultaneously with only one readout cable pair and a single cryogenic amplifier. We evaluate, in a representative environment, the system performance in terms of sensitivity, dynamic range, optical efficiency, cosmic ray rejection, pixel-pixel crosstalk and overall yield at an observation centre frequency of 850 GHz and 20% fractional bandwidth. Results: The overall system has an excellent sensitivity, with an average detector sensitivity < NEPdet> =3×10-19 WHz measured using a thermal calibration source. At a loading power per pixel of 50 fW we demonstrate white, photon noise limited detector noise down to 300 mHz. The dynamic range would allow the detection of 1 Jy bright sources within the field of view without tuning the readout of the detectors. The expected dead time due to cosmic ray interactions, when operated in an L2 or a similar far-Earth orbit, is found to be <4%. Additionally, the achieved pixel yield is 83% and the crosstalk between the pixels is <-30 dB. Conclusions: This demonstrates that MKID technology can provide multiplexing ratios on the order of a 1000 with state-of-the-art single pixel performance, and that the technology is now mature enough to be considered for future space based observatories and experiments.

Learning from Higgs physics at future Higgs factories

DOE PAGES

Gu, Jiayin; Li, Honglei; Liu, Zhen; ...

2017-12-29

Future Higgs factories can reach impressive precision on Higgs property measurements. In this paper, instead of conventional focus of Higgs precision in certain interaction bases, we explored its sensitivity to new physics models at the electron-positron colliders. In particular, we studied two categories of new physics models, Standard Model (SM) with a real scalar singlet extension, and Two Higgs Double Model (2HDM) as examples of weakly-interacting models, Minimal Composite Higgs Model (MCHM) and three typical patterns of the more general operator counting for strong interacting models as examples of strong dynamics. We performed a global fit to various Higgs searchmore » channels to obtain the 95% C.L. constraints on the model parameter space. In the SM with a singlet extension, we obtained the limits on the singlet-doublet mixing angle sin(theta), as well as the more general Wilson coefficients of the induced higher dimensional operators. In the 2HDM, we analyzed tree level effects in tan(beta) vs. cos(beta-alpha) plane, as well as the one-loop contributions from the heavy Higgs bosons in the alignment limit to obtain the constraints on heavy Higgs masses for different types of 2HDM. In strong dynamics models, we obtained lower limits on the strong dynamics scale. In addition, once deviations of Higgs couplings are observed, they can be used to distinguish different models. Here, we also compared the sensitivity of various future Higgs factories, namely Circular Electron Positron Collider (CEPC), Future Circular Collider (FCC)-ee and International Linear Collider (ILC).« less

Learning from Higgs physics at future Higgs factories

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gu, Jiayin; Li, Honglei; Liu, Zhen

Future Higgs factories can reach impressive precision on Higgs property measurements. In this paper, instead of conventional focus of Higgs precision in certain interaction bases, we explored its sensitivity to new physics models at the electron-positron colliders. In particular, we studied two categories of new physics models, Standard Model (SM) with a real scalar singlet extension, and Two Higgs Double Model (2HDM) as examples of weakly-interacting models, Minimal Composite Higgs Model (MCHM) and three typical patterns of the more general operator counting for strong interacting models as examples of strong dynamics. We performed a global fit to various Higgs searchmore » channels to obtain the 95% C.L. constraints on the model parameter space. In the SM with a singlet extension, we obtained the limits on the singlet-doublet mixing angle sin(theta), as well as the more general Wilson coefficients of the induced higher dimensional operators. In the 2HDM, we analyzed tree level effects in tan(beta) vs. cos(beta-alpha) plane, as well as the one-loop contributions from the heavy Higgs bosons in the alignment limit to obtain the constraints on heavy Higgs masses for different types of 2HDM. In strong dynamics models, we obtained lower limits on the strong dynamics scale. In addition, once deviations of Higgs couplings are observed, they can be used to distinguish different models. Here, we also compared the sensitivity of various future Higgs factories, namely Circular Electron Positron Collider (CEPC), Future Circular Collider (FCC)-ee and International Linear Collider (ILC).« less

High Resolution PET with 250 micrometer LSO Detectors and Adaptive Zoom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cherry, Simon R.; Qi, Jinyi

2012-01-08

There have been impressive improvements in the performance of small-animal positron emission tomography (PET) systems since their first development in the mid 1990s, both in terms of spatial resolution and sensitivity, which have directly contributed to the increasing adoption of this technology for a wide range of biomedical applications. Nonetheless, current systems still are largely dominated by the size of the scintillator elements used in the detector. Our research predicts that developing scintillator arrays with an element size of 250 {micro}m or smaller will lead to an image resolution of 500 {micro}m when using 18F- or 64Cu-labeled radiotracers, giving amore » factor of 4-8 improvement in volumetric resolution over the highest resolution research systems currently in existence. This proposal had two main objectives: (i) To develop and evaluate much higher resolution and efficiency scintillator arrays that can be used in the future as the basis for detectors in a small-animal PET scanner where the spatial resolution is dominated by decay and interaction physics rather than detector size. (ii) To optimize one such high resolution, high sensitivity detector and adaptively integrate it into the existing microPET II small animal PET scanner as a 'zoom-in' detector that provides higher spatial resolution and sensitivity in a limited region close to the detector face. The knowledge gained from this project will provide valuable information for building future PET systems with a complete ring of very high-resolution detector arrays and also lay the foundations for utilizing high-resolution detectors in combination with existing PET systems for localized high-resolution imaging.« less

Modeling Thermal Noise from Crystaline Coatings for Gravitational-Wave Detectors

NASA Astrophysics Data System (ADS)

Demos, Nicholas; Lovelace, Geoffrey; LSC Collaboration

2016-03-01

The sensitivity of current and future ground-based gravitational-wave detectors are, in part, limited in sensitivity by Brownian and thermoelastic noise in each detector's mirror substrate and coating. Crystalline mirror coatings could potentially reduce thermal noise, but thermal noise is challenging to model analytically in the case of crystalline materials. Thermal noise can be modeled using the fluctuation-dissipation theorem, which relates thermal noise to an auxiliary elastic problem. In this poster, I will present results from a new code that numerically models thermal noise by numerically solving the auxiliary elastic problem for various types of crystalline mirror coatings. The code uses a finite element method with adaptive mesh refinement to model the auxiliary elastic problem which is then related to thermal noise. I will present preliminary results for a crystal coating on a fused silica substrate of varying sizes and elastic properties. This and future work will help develop the next generation of ground-based gravitational-wave detectors.

Initial performance studies of a general-purpose detector for multi-TeV physics at a 100 TeV pp collider

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chekanov, S. V.; Beydler, M.; Kotwal, A. V.

This paper describes simulations of detector response to multi-TeV physics at the Future Circular Collider (FCC-hh) or Super proton-proton Collider (SppC) which aim to collide proton beams with a centre-of-mass energy of 100 TeV. The unprecedented energy regime of these future experiments imposes new requirements on detector technologies which can be studied using the detailed GEANT4 simulations presented in this paper. The initial performance of a detector designed for physics studies at the FCC-hh or SppC experiments is described with an emphasis on measurements of single particles up to 33 TeV in transverse momentum. The reconstruction of hadronic jets hasmore » also been studied in the transverse momentum range from 50 GeV to 26 TeV. The granularity requirements for calorimetry are investigated using the two-particle spatial resolution achieved for hadron showers.« less

Development of a queue warning system utilizing ATM infrastructure system development and field-testing : final report.

DOT National Transportation Integrated Search

2017-06-13

MnDOT has already deployed an extensive infrastructure for Active Traffic Management (ATM) on I-35W and I-94 with plans to expand on other segments of the Twin Cities freeway network. The ATM system includes intelligent lane control signals (ILCS) sp...

Feasibility of near-unstable cavities for future gravitational wave detectors

NASA Astrophysics Data System (ADS)

Wang, Haoyu; Dovale-Álvarez, Miguel; Collins, Christopher; Brown, Daniel David; Wang, Mengyao; Mow-Lowry, Conor M.; Han, Sen; Freise, Andreas

2018-01-01

Near-unstable cavities have been proposed as an enabling technology for future gravitational wave detectors, as their compact structure and large beam spots can reduce the coating thermal noise of the interferometer. We present a tabletop experiment investigating the behavior of an optical cavity as it is parametrically pushed to geometrical instability. We report on the observed degeneracies of the cavity's eigenmodes as the cavity becomes unstable and the resonance conditions become hyper-sensitive to mirror surface imperfections. A simple model of the cavity and precise measurements of the resonant frequencies allow us to characterize the stability of the cavity and give an estimate of the mirror astigmatism. The significance of these results for gravitational wave detectors is discussed, and avenues for further research are suggested.

Operation and performance of new NIR detectors from SELEX

NASA Astrophysics Data System (ADS)

Atkinson, D.; Bezawada, N.; Hipwood, L. G.; Shorrocks, N.; Milne, H.

2012-07-01

The European Space Agency (ESA) has funded SELEX Galileo, Southampton, UK to develop large format near infrared (NIR) detectors for its future space and ground based programmes. The UKATC has worked in collaboration with SELEX Galileo to test and characterise the new detectors produced during phase-1 of the development. In order to demonstrate the detector material performance, the HgCdTe (MCT) detector diodes (grown on GaAs substrate through MOVPE process in small 320×256, 24μm pixel format) are hybridised to the existing SELEX Galileo SWALLOW CMOS readout chip. The substrate removed and MCT thinned detector arrays were then tested and evaluated at the UKATC following screening tests at SELEX. This paper briefly describes the test setup, the operational aspects of the readout multiplexer and presents the performance parameters of the detector arrays including: conversion gain, detector dark current, read noise, linearity, quantum efficiency and persistence for various detector temperatures between 80K and 140K.

Prospects for future experiments to search for nucleon decay

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ayres, D.S.; Heller, K.; LoSecco, J.

1982-01-01

We review the status of theoretical expectations and experimental searches for nucleon decay, and predict the sensitivities which could be reached by future experiments. For the immediate future, we concur with the conclusions of the 1982 Summer Workshop on Proton Decay Experiments: all detectors now in operation or construction will be relatively insensitive to some potentially important decay modes. Next-generation experiments must therefore be designed to search for these modes, and should be undertaken whether or not present experiments detect nucleon decay in other modes. These future experiments should be designed to push the lifetime limits on all decay modesmore » to the levels at which irreducible cosmic-ray neutrino-induced backgrounds become important. Since the technology for these next-generation experiments is available now, the timetable for starting work on them will be determined by funding constraints and not by the need for extensive development of detectors. Efforts to develop advanced detector techniques should also be pursued, in order to mount more sensitive searches than can be envisioned using current technology, or to provide the most precise measurements possible of the properties of the nucleon decay interaction if it should occur at a detectable rate.« less

The development of infrared detectors and mechanisms for use in future infrared space missions

NASA Technical Reports Server (NTRS)

Houck, James R.

1995-01-01

The environment above earth's atmosphere offers significant advantages in sensitivity and wavelength coverage in infrared astronomy over ground-based observatories. In support of future infrared space missions, technology development efforts were undertaken to develop detectors sensitive to radiation between 2.5 micron and 200 micron. Additionally, work was undertaken to develop mechanisms supporting the imaging and spectroscopy requirements of infrared space missions. Arsenic-doped-Silicon and Antimony-doped-Silicon Blocked Impurity Band detectors, responsive to radiation between 4 micron and 45 micron, were produced in 128x128 picture element arrays with the low noise, high sensitivity performance needed for space environments. Technology development continued on Gallium-doped-Germanium detectors (for use between 80 micron and 200 micron), but were hampered by contamination during manufacture. Antimony-doped-Indium detectors (for use between 2.5 micron and 5 micron) were developed in a 256x256 pixel format with high responsive quantum efficiency and low dark current. Work began on adapting an existing cryogenic mechanism design for space-based missions; then was redirected towards an all-fixed optical design to improve reliability and lower projected mission costs.

Life Finder Detectors: An Overview of Detector Technologies for Detecting Life on Other Worlds

NASA Astrophysics Data System (ADS)

Rauscher, Bernard J.; Domagal-Goldman, Shawn; Greenhouse, Matthew A.; Hsieh, Wen-Ting; McElwain, Michael W.; Moseley, Samuel H.; Noroozian, Omid; Norton, Tim; Kutyrev, Alexander; Rinehart, Stephen; stock, Joseph

2015-01-01

Future large space telescopes will seek evidence for life on other worlds by searching for spectroscopic biosignatures. Atmospheric biosignature gases include oxygen, ozone, water vapor, and methane. Non-biological gases, including carbon monoxide and carbon dioxide, are important for discriminating false positives. All of these gases imprint spectroscopic features in the UV through mid-IR that are potentially detectable using future space based coronagraphs or star shades for starlight suppression.Direct spectroscopic biosignature detection requires sensors capable of robustly measuring photon arrival rates on the order of 10 per resolution element per hour. Photon counting is required for some wavefront sensing and control approaches to achieve the requisite high contrast ratios. We review life finder detector technologies that either exist today, or are under development, that have the potential to meet these challenging requirements. We specifically highlight areas where more work or development is needed.Life finder detectors will be invaluable for a wide variety of other major science programs. Because of its cross cutting nature; UV, optical, and infrared (UVOIR) detector development features prominently in the 2010 National Research Council Decadal Survey, 'New Worlds, New Horizons in Astronomy and Astrophysics', and the NASA Cosmic Origins Program Technology Roadmap.

Performance studies of X3 silicon detectors for the future ELISSA array at ELI-NP

NASA Astrophysics Data System (ADS)

Chesnevskaya, S.; Balabanski, D. L.; Choudhury, D.; Constantin, P.; Filipescu, D. M.; Ghita, D. G.; Guardo, G. L.; Lattuada, D.; Matei, C.; Rotaru, A.; State, A.

2018-05-01

ELISSA is an array of silicon strip detectors under construction at the ELI-NP facility for measurements of photodissociation reactions using high-brilliance, quasi monoenergetic gamma beams. The detection system consists of 35 single-sided position-sensitive X3 detectors arranged in a cylindrical configuration and eight QQQ3 detectors as end-caps. A batch of forty X3 detectors have been tested at ELI-NP. The energy and position resolution, ballistic deficit, leakage currents, and depletion voltage were measured and analyzed. Measurements of the energy resolution were carried out using two read-out electronic chains, one based on multichannel preamplifiers and another based on multiplexers.