315 results on '"Kufer, P."'
Search Results
2. A systematic mapping of public health master’s and structured doctoral programs in Germany
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Hanna Saturska, Katrina Kufer, Sara Pedron, Gesa Meyer, Karl Emmert-Fees, Michael Laxy, and Anna-Janina Stephan
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Public health ,Education ,Curricula ,Doctoral program ,Master’s program ,MPH programs ,Special aspects of education ,LC8-6691 ,Medicine - Abstract
Abstract Background Well-trained public health professionals are key to addressing both global and local public health challenges of the twenty-first century. Though availability of programs has increased, the population health science (PHS) and public health (PH) higher education landscape in Germany remains scattered. To date, no comprehensive overview of programs exists. Objectives This study aimed to map PHS and PH master’s and structured doctoral programs in Germany, including selected program characteristics, curricula and target competencies. Methods We conducted a systematic mapping of PHS and PH programs in Germany following a prospectively registered protocol ( https://doi.org/10.17605/OSF.IO/KTCBA ). Relevant master’s and doctoral programs were identified by two study authors independently searching a comprehensive higher education database, which was, for doctoral programs, supplemented with a google search. For PHS programs, general characteristics were mapped and for the subset of PH programs, in-depth characteristics were extracted. Results Overall, 75 master’s and 18 structured doctoral PHS programs were included. Of these, 23 master’s and 8 doctoral programs focused specifically on PH. The majority of PHS master’s programs awarded a Master of Science degree (55 out of 75 programs). The PH master’s program curricula offered various courses, allowing for different specializations. Courses on topics like public health, epidemiology, health systems (research) and research methods were common for the majority of the master’s programs, while courses on physical activity, behavioral science, nutrition, and mental health were offered less frequently. Structured PH doctoral programs were mainly offered by medical faculties (6 out of 8 programs) and awarded a doctorate of philosophy (Ph.D.) (6 out of 8 programs). PH doctoral programs were very heterogeneous regarding curricula, entry, and publication requirements. There was a broad geographical distribution of programs across Germany, with educational clusters in Munich, Berlin, Bielefeld and Düsseldorf. Conclusion Germany offers a diverse landscape of PHS and PH master’s programs, but only few structured doctoral programs. The variety of mandatory courses and competencies in these programs reflect Germany’s higher education system’s answer to the evolving demands of the PH sector. This review may aid in advancing PH education both in Germany and globally.
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- 2024
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3. A systematic mapping of public health master’s and structured doctoral programs in Germany
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Saturska, Hanna, Kufer, Katrina, Pedron, Sara, Meyer, Gesa, Emmert-Fees, Karl, Laxy, Michael, and Stephan, Anna-Janina
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- 2024
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4. Temporal recalibration in response to delayed visual feedback of active versus passive actions: an fMRI study
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Kufer, Konstantin, Schmitter, Christina V., Kircher, Tilo, and Straube, Benjamin
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- 2024
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5. Temporal recalibration in response to delayed visual feedback of active versus passive actions: an fMRI study
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Konstantin Kufer, Christina V. Schmitter, Tilo Kircher, and Benjamin Straube
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Medicine ,Science - Abstract
Abstract The brain can adapt its expectations about the relative timing of actions and their sensory outcomes in a process known as temporal recalibration. This might occur as the recalibration of timing between the sensory (e.g. visual) outcome and (1) the motor act (sensorimotor) or (2) tactile/proprioceptive information (inter-sensory). This fMRI recalibration study investigated sensorimotor contributions to temporal recalibration by comparing active and passive conditions. Subjects were repeatedly exposed to delayed (150 ms) or undelayed visual stimuli, triggered by active or passive button presses. Recalibration effects were tested in delay detection tasks, including visual and auditory outcomes. We showed that both modalities were affected by visual recalibration. However, an active advantage was observed only in visual conditions. Recalibration was generally associated with the left cerebellum (lobules IV, V and vermis) while action related activation (active > passive) occurred in the right middle/superior frontal gyri during adaptation and test phases. Recalibration transfer from vision to audition was related to action specific activations in the cingulate cortex, the angular gyrus and left inferior frontal gyrus. Our data provide new insights in sensorimotor contributions to temporal recalibration via the middle/superior frontal gyri and inter-sensory contributions mediated by the cerebellum.
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- 2024
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6. White Paper on Leading-Edge technology And Feasibility-directed (LEAF) Program aimed at readiness demonstration for Energy Frontier Circular Colliders by the next decade
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Ambrosio, G., Apollinari, G., Baldini, M., Carcagno, R., Boffo, C., Claypool, B., Feher, S., Hays, S., Hoang, D., Kashikhin, V., Kashikhin, V. V., Krave, S., Kufer, M., Lee, J., Lombardo, V., Marinozzi, V., Nobrega, F., Peng, X., Piekarz, H., Shiltsev, V., Stoynev, S., Strauss, T., Tran, N., Velev, G., Xu, X., Zlobin, A., Amm, K., Anerella, M., Yahia, A. Ben, Gupta, R., Joshi, P., Parker, B., Schmalzle, J., Ferracin, P., Pong, I., Prestemon, S., Wang, X., Sabbi, G., Shen, T., Cooley, L., Rochester, J., and Sumption, M. D.
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Physics - Accelerator Physics - Abstract
In this White Paper for the Snowmass 2021 Process, we propose the establishment of a magnet Leading-Edge technology And Feasibility-directed Program (LEAF Program) to achieve readiness for a future collider decision on the timescale of the next decade. The LEAF Program would rely on, and be synergetic with, generic R&D efforts presently covered - in the US - by the Magnet Development Program (MDP), the Conductor Procurement and R&D (CPRD) Program and other activities in the Office of HEP supported by Early Career Awards (ECA) or Lab Directed R&D (LDRD) funds. Where possible, ties to synergetic efforts in other Offices of DOE or NSF are highlighted and suggested as wider Collaborative efforts on the National scale. International efforts are also mentioned as potential partners in the LEAF Program. We envision the LEAF Program to concentrate on demonstrating the feasibility of magnets for muon colliders as well as next generation high energy hadron colliders, pursuing, where necessary and warranted by the nature of the application, the transition from R&D models to long models/prototypes. The LEAF Program will naturally drive accelerator-quality and experiment-interface design considerations. LEAF will also concentrate, where necessary, on cost reduction and/or industrialization steps., Comment: Contribution to Snowmass 2021, 19 pages, 5 figures. Corresponding Author: G. Apollinari apollina@fnal.gov
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- 2022
7. Fast cycling HTS based superconducting accelerator magnets: Feasibility study and readiness demonstration program driven by neutrino physics and muon collider needs
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Piekarz, Henryk, Claypool, Bradley, Hays, Steven, Kufer, Matthew, Shiltsev, Vladimir, Zlobin, Alexander, and Rossi, Lucio
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Physics - Accelerator Physics - Abstract
Development of energy-efficient fast cycling accelerator magnets is critical for the next generation of proton rapid cycling synchrotrons (RCS) for neutrino research and booster accelerators of future muon colliders. We see a unique opportunity for having such magnets to be built on base of High Temperature Superconductors (HTS). Besides being superconducting at relatively high temperatures, rare-earth HTS tapes have shown very small AC losses compared to low-temperature NbTi superconductor cables. Recent tests of the HTS-based 0.5 m long two-bore superconducting accelerator magnet have shown record high dB/dt ramping rates of about 300 T/s at 10 Hz repetition rate and 0.5 T B-field span. No temperature rise in 6 K cooling He was observed within the 0.003 K error setting the upper limit on the cryogenic power loss in the magnet conductor coil to be less than 0.2 W/m. Based on this result we outline a possible upgrade of this test magnet design to 2 T B-field in the 10 mm beam gap with the dB/dt ramping rates up to 1000 T/s. The power test results of this short sample magnet will be used to project both cryogenic and electrical power losses as a function of the magnet B-field and the dB/dt ramping rates. Then these projections will be scaled to the range of expected accelerator magnet beam gaps and B-fields for the proton and muon RCS accelerators. We invite collaborators to join these studies and call for support of the R&D program aimed at comprehensive demonstration of this approach that includes design, construction, and power tests of a long prototype of the HTS-based fast-cycling accelerator magnet by 2028., Comment: Submitted to the Proceeding of Snowmass 2021 (Accelerator Frontier)
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- 2022
8. Record High Ramping Rates in HTS Based Super-conducting Accelerator Magnet
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Piekarz, Henryk, Hays, Steven, Claypool, Bradley, Kufer, Matthew, and Shiltsev, Vladimir
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Physics - Accelerator Physics - Abstract
We report results of the experimental test of the High Temperature Superconductor based fast cycling prototype accelerator magnet capable to operate up to about 300 Tesla per second field ramping rate with some 0.5 T field in the magnet gap. The measured upper limit for the cryogenic cooling power required to support magnet conductor operation at high ramping rates indicates great potential for such types of magnets in rapid cycling synchrotrons for neutrino research or muon acceleration. The test magnet design, construction, and supporting cryogenic and power systems are briefly described. The magnet power test results are discussed in terms of a possible upgrade of this magnet design to 2 T field, a maximum feasible with superferric magnet., Comment: 4 pages, 10 figures; presented at the 27th International Conference on Magnet Technology (MT27, Fukuoka, Japan, November 15-19, 2021)
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- 2021
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9. NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice
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Tran, L. S., Ying, L., D’Costa, K., Wray-McCann, G., Kerr, G., Le, L., Allison, C. C., Ferrand, J., Chaudhry, H., Emery, J., De Paoli, A., Colon, N., Creed, S., Kaparakis-Liaskos, M., Como, J., Dowling, J. K., Johanesen, P. A., Kufer, T. A., Pedersen, J. S., Mansell, A., Philpott, D. J., Elgass, K. D., Abud, H. E., Nachbur, U., Croker, B. A., Masters, S. L., and Ferrero, R. L.
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- 2023
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10. Mitochondrial damage activates the NLRP10 inflammasome
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Próchnicki, Tomasz, Vasconcelos, Matilde B., Robinson, Kim S., Mangan, Matthew S. J., De Graaf, Dennis, Shkarina, Kateryna, Lovotti, Marta, Standke, Lena, Kaiser, Romina, Stahl, Rainer, Duthie, Fraser G., Rothe, Maximilian, Antonova, Kateryna, Jenster, Lea-Marie, Lau, Zhi Heng, Rösing, Sarah, Mirza, Nora, Gottschild, Clarissa, Wachten, Dagmar, Günther, Claudia, Kufer, Thomas A., Schmidt, Florian I., Zhong, Franklin L., and Latz, Eicke
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- 2023
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11. NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice
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L. S. Tran, L. Ying, K. D’Costa, G. Wray-McCann, G. Kerr, L. Le, C. C. Allison, J. Ferrand, H. Chaudhry, J. Emery, A. De Paoli, N. Colon, S. Creed, M. Kaparakis-Liaskos, J. Como, J. K. Dowling, P. A. Johanesen, T. A. Kufer, J. S. Pedersen, A. Mansell, D. J. Philpott, K. D. Elgass, H. E. Abud, U. Nachbur, B. A. Croker, S. L. Masters, and R. L. Ferrero
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Science - Abstract
Abstract The interleukin-1 family members, IL-1β and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1β processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori. Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori-induced pathology.
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- 2023
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12. Technical advancement and practical considerations of LC-MS/MS-based methods for host cell protein identification and quantitation to support process development
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Jia Guo, Regina Kufer, Delia Li, Stefanie Wohlrab, Midori Greenwood-Goodwin, and Feng Yang
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Host cell protein (HCP) ,identification ,impurities ,liquid chromatography tandem mass spectrometry (LC-MS/MS) ,process development ,quantitation ,Therapeutics. Pharmacology ,RM1-950 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
ABSTRACTHost cell proteins (HCPs) are process-related impurities derived from the manufacturing of recombinant biotherapeutics. Residual HCP in drug products, ranging from 1 to 100 ppm (ng HCP/mg product) or even below sub-ppm level, may affect product quality, stability, efficacy, or safety. Therefore, removal of HCPs to appropriate levels is critical for the bioprocess development of biotherapeutics. Liquid chromatography-mass spectrometry (LC-MS) analysis has become an important tool to identify, quantify, and monitor the clearance of individual HCPs. This review covers the technical advancement of sample preparation strategies, new LC-MS-based techniques, and data analysis approaches to robustly and sensitively measure HCPs while overcoming the high dynamic range analytical challenges. We also discuss our strategy for LC-MS-based HCP workflows to enable fast support of process development throughout the product life cycle, and provide insights into developing specific analytical strategies leveraging LC-MS tools to control HCPs in process and mitigate their potential risks to drug quality, stability, and patient safety.
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- 2023
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13. Stronger influence of systemic than local hemodynamic-vascular factors on resting-state BOLD functional connectivity
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Sebastian C. Schneider, Stephan Kaczmarz, Jens Göttler, Jan Kufer, Benedikt Zott, Josef Priller, Michael Kallmayer, Claus Zimmer, Christian Sorg, and Christine Preibisch
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Resting state ,functional MRI ,BOLD functional connectivity ,hemodynamic-vascular MRI ,internal carotid artery stenosis ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Correlated fluctuations in the blood oxygenation level dependent (BOLD) signal of resting-state functional MRI (i.e., BOLD-functional connectivity, BOLD-FC) reflect a spectrum of neuronal and non-neuronal processes. In particular, there are multiple hemodynamic-vascular influences on BOLD-FC on both systemic (e.g., perfusion delay) and local levels (e.g., neurovascular coupling). While the influence of individual factors has been studied extensively, combined and comparative studies of systemic and local hemodynamic-vascular factors on BOLD-FC are scarce, notably in humans. We employed a multi-modal MRI approach to investigate and compare distinct hemodynamic-vascular processes and their impact on homotopic BOLD-FC in healthy controls and patients with unilateral asymptomatic internal carotid artery stenosis (ICAS). Asymptomatic ICAS is a cerebrovascular disorder, in which neuronal functioning is largely preserved but hemodynamic-vascular processes are impaired, mostly on the side of stenosis. Investigated indicators for local hemodynamic-vascular processes comprise capillary transit time heterogeneity (CTH) and cerebral blood volume (CBV) from dynamic susceptibility contrast (DSC) MRI, and cerebral blood flow (CBF) from pseudo-continuous arterial spin labeling (pCASL). Indicators for systemic processes are time-to-peak (TTP) from DSC MRI and BOLD lags from functional MRI. For each of these parameters, their influence on BOLD-FC was estimated by a comprehensive linear mixed model. Equally across groups, we found that individual mean BOLD-FC, local (CTH, CBV, and CBF) and systemic (TTP and BOLD lag) hemodynamic-vascular factors together explain 40.7% of BOLD-FC variance, with 20% of BOLD-FC variance explained by hemodynamic-vascular factors, with an about two-times larger contribution of systemic versus local factors. We conclude that regional differences in blood supply, i.e., systemic perfusion delays, exert a stronger influence on BOLD-FC than impairments in local neurovascular coupling.
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- 2023
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14. Characterization of the Inflammatory Response Evoked by Bacterial Membrane Vesicles in Intestinal Cells Reveals an RIPK2-Dependent Activation by Enterotoxigenic Escherichia coli Vesicles
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Himadri B. Thapa, Paul Kohl, Franz G. Zingl, Dominik Fleischhacker, Heimo Wolinski, Thomas A. Kufer, and Stefan Schild
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bacterial membrane vesicles ,outer membrane vesicles ,ETEC ,cytokine ,intestinal epithelial cell ,HT-29 ,Microbiology ,QR1-502 - Abstract
ABSTRACT Although the immunomodulatory potency of bacterial membrane vesicles (MVs) is widely acknowledged, their interactions with host cells and the underlying signaling pathways have not been well studied. Herein, we provide a comparative analysis of the proinflammatory cytokine profile secreted by human intestinal epithelial cells exposed to MVs derived from 32 gut bacteria. In general, outer membrane vesicles (OMVs) from Gram-negative bacteria induced a stronger proinflammatory response than MVs from Gram-positive bacteria. However, the quality and quantity of cytokine induction varied between MVs from different species, highlighting their unique immunomodulatory properties. OMVs from enterotoxigenic Escherichia coli (ETEC) were among those showing the strongest proinflammatory potency. In depth analyses revealed that the immunomodulatory activity of ETEC OMVs relies on a so far unprecedented two-step mechanism, including their internalization into host cells followed by intracellular recognition. First, OMVs are efficiently taken up by intestinal epithelial cells, which mainly depends on caveolin-mediated endocytosis as well as the presence of the outer membrane porins OmpA and OmpF on the MVs. Second, lipopolysaccharide (LPS) delivered by OMVs is intracellularly recognized by novel caspase- and RIPK2-dependent pathways. This recognition likely occurs via detection of the lipid A moiety as ETEC OMVs with underacylated LPS exhibited reduced proinflammatory potency but similar uptake dynamics compared to OMVs derived from wild-type (WT) ETEC. Intracellular recognition of ETEC OMVs in intestinal epithelial cells is pivotal for the proinflammatory response as inhibition of OMV uptake also abolished cytokine induction. The study signifies the importance of OMV internalization by host cells to exercise their immunomodulatory activities. IMPORTANCE The release of membrane vesicles from the bacterial cell surface is highly conserved among most bacterial species, including outer membrane vesicles (OMVs) from Gram-negative bacteria as well as vesicles liberated from the cytoplasmic membrane of Gram-positive bacteria. It is becoming increasingly evident that these multifactorial spheres, carrying membranous, periplasmic, and even cytosolic content, contribute to intra- and interspecies communication. In particular, gut microbiota and the host engage in a myriad of immunogenic and metabolic interactions. This study highlights the individual immunomodulatory activities of bacterial membrane vesicles from different enteric species and provides new mechanistic insights into the recognition of ETEC OMVs by human intestinal epithelial cells.
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- 2023
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15. Interactions of Autophagy and the Immune System in Health and Diseases
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Aarti Pant, Xiaomin Yao, Aude Lavedrine, Christophe Viret, Jacob Dockterman, Swati Chauhan, Chong-Shan Shi, Ravi Manjithaya, Ken Cadwell, Thomas A. Kufer, John H. Kehrl, Jörn Coers, L. David Sibley, Mathias Faure, Gregory A. Taylor, and Santosh Chauhan
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Cytology ,QH573-671 - Abstract
Autophagy is a highly conserved process that utilizes lysosomes to selectively degrade a variety of intracellular cargo, thus providing quality control over cellular components and maintaining cellular regulatory functions. Autophagy is triggered by multiple stimuli ranging from nutrient starvation to microbial infection. Autophagy extensively shapes and modulates the inflammatory response, the concerted action of immune cells, and secreted mediators aimed to eradicate a microbial infection or to heal sterile tissue damage. Here, we first review how autophagy affects innate immune signaling, cell-autonomous immune defense, and adaptive immunity. Then, we discuss the role of non-canonical autophagy in context of microbial infections and inflammation. Finally, we review how crosstalk between autophagy and inflammation influences infectious diseases as well as metabolic and autoimmune disorders.
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- 2022
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16. NLRC5 affects diet-induced adiposity in female mice and co-regulates peroxisome proliferator-activated receptor PPARγ target genes
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Sarah Bauer, Vanessa Aeissen, Alena M. Bubeck, Ioannis Kienes, Kornelia Ellwanger, Mona Scheurenbrand, Fjolla Rexhepi, Sheela Ramanathan, Philip Rosenstiel, W. Florian Fricke, and Thomas A. Kufer
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Diet ,Immunology ,Molecular mechanism of gene regulation ,Science - Abstract
Summary: Nucleotide-binding and oligomerization domain containing 5 (NLRC5) is the key transcriptional regulator of major histocompatibility (MHC) class I genes. Recent observations suggest a role for NLRC5 in metabolic traits and in transcriptional regulation beyond MHC class I genes. To understand the function of NLRC5 in metabolic disease, we subjected Nlrc5−/− mice to high-fat diet (HFD) feeding. Female Nlrc5−/− mice presented with higher weight gain and more adipose tissue (AT) compared to wild-type (WT) animals. Mechanistically, we demonstrate that NLRC5 enhanced the expression of peroxisome proliferator-activated receptor (PPAR) γ target genes in human cells. We identify Sin3A and negative elongation factor (NELF) B as two novel NLRC5 interaction partners and show that Sin3A partly modulates the synergistic transcriptional effect of NLRC5 on PPARγ. Collectively, we show that NLRC5 contributes to weight gain in mice, which involves transcriptional enhancement of PPARγ targets by NLRC5 that is co-regulated by Sin3A.
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- 2023
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17. The FNAL Booster 2nd Harmonic RF Cavity
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Madrak, R., Dey, J., Duel, K., Kufer, M., Kuharik, J., Makarov, A., Padilla, R., Pellico, W., Reid, J., Romanov, G., Slabaugh, M., Sun, D., Tan, C. Y., and Terechkine, I.
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Physics - Accelerator Physics - Abstract
A second harmonic RF cavity which uses perpendicularly biased garnet for frequency tuning is currently being constructed for use in the Fermilab Booster. The cavity will operate at twice the fundamental RF frequency, from ~76 - 106 MHz, and will be turned on only during injection, and transition or extraction. Its main purpose is to reduce beam loss as required by Fermilab's Proton Improvement Plan (PIP). After three years of optimization and study, the cavity design has been finalized and all constituent parts have been received. We discuss the design aspects of the cavity and its associated systems, component testing, and status of the cavity construction., Comment: 6 pp
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- 2018
18. High Burst Rate Charging System for the Lithium Lens Power Supply
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Pfeffer, H., Frolov, D., Jensen, C. C., Kufer, M. E., and Quinn Jr., K.
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Physics - Accelerator Physics - Abstract
Two pulsed power systems have been upgraded for the g-2 experiment at Fermilab. The Pbar Lithium Lens supply previously ran with a half sine pulsed current of 75 kA peak, 400 us duration and a repetition rate of 0.45 pps. For the g-2 experiment, the peak current was reduced to 25 kA, but the repetition rate was increased to an average of 12 pps. Furthermore, the pulses come in a burst of 8 with 10 ms between each of 8 pulses and then a delay until the next burst. The charging rate has gone up by a factor of 20 due to the burst speed. A major challenge for the upgrade was to charge the capacitor bank while keeping the power line loading and charging supply cost to a reasonable level. This paper will discuss how those issues were solved and results from the operational system., Comment: 3 pp. Accepted to IEEE Trans. Dielectrics Elec. Insulation
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- 2018
19. Editorial: Updates on RIG-I-like receptor-mediated innate immune responses
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Uday Kishore and Thomas A. Kufer
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innate immunity ,PAMP (pathogen-associated molecular pattern) ,immune escape ,RIG1 receptors ,signalling ,transcription factor ,Immunologic diseases. Allergy ,RC581-607 - Published
- 2023
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20. Hemodynamic MRI parameters to predict asymptomatic unilateral carotid artery stenosis with random forest machine learning
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Carina Gleißner, Stephan Kaczmarz, Jan Kufer, Lena Schmitzer, Michael Kallmayer, Claus Zimmer, Benedikt Wiestler, Christine Preibisch, and Jens Göttler
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asymptomatic carotid artery stenosis ,hemodynamics ,random forest–ensemble classifier ,machine learning ,individual watershed areas ,magnetic resonance imaging (MRI) ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
BackgroundInternal carotid artery stenosis (ICAS) can cause stroke and cognitive decline. Associated hemodynamic impairments, which are most pronounced within individual watershed areas (iWSA) between vascular territories, can be assessed with hemodynamic-oxygenation-sensitive MRI and may help to detect severely affected patients. We aimed to identify the most sensitive parameters and volumes of interest (VOI) to predict high-grade ICAS with random forest machine learning. We hypothesized an increased predictive ability considering iWSAs and a decreased cognitive performance in correctly classified patients.Materials and methodsTwenty-four patients with asymptomatic, unilateral, high-grade carotid artery stenosis and 24 age-matched healthy controls underwent MRI comprising pseudo-continuous arterial spin labeling (pCASL), breath-holding functional MRI (BH-fMRI), dynamic susceptibility contrast (DSC), T2 and T2* mapping, MPRAGE and FLAIR. Quantitative maps of eight perfusion, oxygenation and microvascular parameters were obtained. Mean values of respective parameters within and outside of iWSAs split into gray (GM) and white matter (WM) were calculated for both hemispheres and for interhemispheric differences resulting in 96 features. Random forest classifiers were trained on whole GM/WM VOIs, VOIs considering iWSAs and with additional feature selection, respectively.ResultsThe most sensitive features in decreasing order were time-to-peak (TTP), cerebral blood flow (CBF) and cerebral vascular reactivity (CVR), all of these inside of iWSAs. Applying iWSAs combined with feature selection yielded significantly higher receiver operating characteristics areas under the curve (AUC) than whole GM/WM VOIs (AUC: 0.84 vs. 0.90, p = 0.039). Correctly predicted patients presented with worse cognitive performances than frequently misclassified patients (Trail-making-test B: 152.5s vs. 94.4s, p = 0.034).ConclusionRandom forest classifiers trained on multiparametric MRI data allow identification of the most relevant parameters and VOIs to predict ICAS, which may improve personalized treatments.
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- 2023
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21. Bacterial subversion of NLR-mediated immune responses
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Ioannis Kienes, Ella L. Johnston, Natalie J. Bitto, Maria Kaparakis-Liaskos, and Thomas A. Kufer
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PAMP ,DAMP ,infection ,tolerance ,pathogens ,NLRs ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Members of the mammalian Nod-like receptor (NLR) protein family are important intracellular sensors for bacteria. Bacteria have evolved under the pressure of detection by host immune sensing systems, leading to adaptive subversion strategies to dampen immune responses for their benefits. These include modification of microbe-associated molecular patterns (MAMPs), interception of innate immune pathways by secreted effector proteins and sophisticated instruction of anti-inflammatory adaptive immune responses. Here, we summarise our current understanding of subversion strategies used by bacterial pathogens to manipulate NLR-mediated responses, focusing on the well-studied members NOD1/2, and the inflammasome forming NLRs NLRC4, and NLRP3. We discuss how bacterial pathogens and their products activate these NLRs to promote inflammation and disease and the range of mechanisms used by bacterial pathogens to evade detection by NLRs and to block or dampen NLR activation to ultimately interfere with the generation of host immunity. Moreover, we discuss how bacteria utilise NLRs to facilitate immunotolerance and persistence in the host and outline how various mechanisms used to attenuate innate immune responses towards bacterial pathogens can also aid the host by reducing immunopathologies. Finally, we describe the therapeutic potential of harnessing immune subversion strategies used by bacteria to treat chronic inflammatory conditions.
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- 2022
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22. Achieving ultrahigh carrier mobility and photo-responsivity in solution-processed perovskite/carbon nanotubes phototransistors
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Wang, Hong, Li, Feng, Kufer, Dominik, Yu, Weili, Alarousu, Erkki, Ma, Chun, Li, Yangyang, Liu, Zhixiong, Liu, Changxu, Wei, Nini, Chen, Yin, Wang, Fei, Chen, Lang, Mohammed, Omar F., Fratalocchi, Andrea, Konstantatos, Gerasimos, and Wu, Tom
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Condensed Matter - Materials Science - Abstract
Organolead trihalide perovskites have drawn substantial interest for applications in photovoltaic and optoelectronic devices due to their low processing cost and remarkable physical properties. However, perovskite thin films still suffer from low carrier mobility, limiting their device performance and application potential. Here we report that embedding single-walled carbon nanotubes into halide perovskite films can significantly enhance the hole and electron mobilities to record-high values of 595.3 and 108.7 cm2 V-1 s-1, respectively. In the ambipolar phototransistors with such hybrid channels, photo-carriers generated in the light-absorbing perovskite matrix are transported by the carbon nanotubes, leading to ultrahigh detectivity of 6 * 1014 Jones and responsivity of 1 * 104 A W-1. We find that the perovskite precursor in dimethylformamide solution serve as an excellent stabilizer for the dispersion of carbon nanotubes, which potentially extend the scope of applications of perovskites in solution-processed functional composites. The unprecedented high performances underscore the perovskite/carbon nanotubes hybrids as an emerging class of functional materials in optoelectronic and other applications., Comment: We have to withdraw the submission of our paper (Identifier: 1512.03893), because we found that we have not yet studied this work completely, and we certainly should pay much time to do new experiments and add the new data in the revised paper
- Published
- 2015
23. NOD-like Receptors—Emerging Links to Obesity and Associated Morbidities
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Sarah Bauer, Lucy Hezinger, Fjolla Rexhepi, Sheela Ramanathan, and Thomas A. Kufer
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NLRP3 ,IL-1β ,NOD1 ,NOD2 ,NLRP12 ,NLRC5 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Obesity and its associated metabolic morbidities have been and still are on the rise, posing a major challenge to health care systems worldwide. It has become evident over the last decades that a low-grade inflammatory response, primarily proceeding from the adipose tissue (AT), essentially contributes to adiposity-associated comorbidities, most prominently insulin resistance (IR), atherosclerosis and liver diseases. In mouse models, the release of pro-inflammatory cytokines such as TNF-alpha (TNF-α) and interleukin (IL)-1β and the imprinting of immune cells to a pro-inflammatory phenotype in AT play an important role. However, the underlying genetic and molecular determinants are not yet understood in detail. Recent evidence demonstrates that nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family proteins, a group of cytosolic pattern recognition receptors (PRR), contribute to the development and control of obesity and obesity-associated inflammatory responses. In this article, we review the current state of research on the role of NLR proteins in obesity and discuss the possible mechanisms leading to and the outcomes of NLR activation in the obesity-associated morbidities IR, type 2 diabetes mellitus (T2DM), atherosclerosis and non-alcoholic fatty liver disease (NAFLD) and discuss emerging ideas about possibilities for NLR-based therapeutic interventions of metabolic diseases.
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- 2023
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24. NLRC5-CIITA Fusion Protein as an Effective Inducer of MHC-I Expression and Antitumor Immunity
- Author
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Madanraj Appiya Santharam, Akhil Shukla, Dominique Levesque, Thomas A. Kufer, François-Michel Boisvert, Sheela Ramanathan, and Subburaj Ilangumaran
- Subjects
NLRC5 ,MHC-I ,tumor immunogenicity ,NLRC5-SA ,B16-F10 ,EL4 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Aggressive tumors evade cytotoxic T lymphocytes by suppressing MHC class-I (MHC-I) expression that also compromises tumor responsiveness to immunotherapy. MHC-I defects strongly correlate to defective expression of NLRC5, the transcriptional activator of MHC-I and antigen processing genes. In poorly immunogenic B16 melanoma cells, restoring NLRC5 expression induces MHC-I and elicits antitumor immunity, raising the possibility of using NLRC5 for tumor immunotherapy. As the clinical application of NLRC5 is constrained by its large size, we examined whether a smaller NLRC5-CIITA fusion protein, dubbed NLRC5-superactivator (NLRC5-SA) as it retains the ability to induce MHC-I, could be used for tumor growth control. We show that stable NLRC5-SA expression in mouse and human cancer cells upregulates MHC-I expression. B16 melanoma and EL4 lymphoma tumors expressing NLRC5-SA are controlled as efficiently as those expressing full-length NLRC5 (NLRC5-FL). Comparison of MHC-I-associated peptides (MAPs) eluted from EL4 cells expressing NLRC5-FL or NLRC5-SA and analyzed by mass spectrometry revealed that both NLRC5 constructs expanded the MAP repertoire, which showed considerable overlap but also included a substantial proportion of distinct peptides. Thus, we propose that NLRC5-SA, with its ability to increase tumor immunogenicity and promote tumor growth control, could overcome the limitations of NLRC5-FL for translational immunotherapy applications.
- Published
- 2023
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- View/download PDF
25. Design of a Marx-Topology Modulator for FNAL Linac
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Butler, T. A., Garcia, F. G., Kufer, M. R., Pfeffer, H., and Wolff, D.
- Subjects
Physics - Accelerator Physics - Abstract
The Fermilab Proton Improvement Plan (PIP) was formed in late 2011 to address important and necessary upgrades to the Proton Source machines (Injector line, Linac and Booster). The goal is to increase the proton flux by doubling the Booster beam cycle rate while maintaining the same intensity per cycle, the same uptime, and the same residual activation in the enclosure. For the Linac, the main focus within PIP is to address reliability. One of the main tasks is to replace the present hard-tube modulator used on the 200 MHz RF system. Plans to replace this high power system with a Marx-topology modulator, capable of providing the required waveform shaping to stabilize the accelerating gradient and compensate for beam loading, will be presented, along with development data from the prototype unit.
- Published
- 2015
26. NLRC5 Deficiency Deregulates Hepatic Inflammatory Response but Does Not Aggravate Carbon Tetrachloride-Induced Liver Fibrosis
- Author
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Akouavi Julite I. Quenum, Akhil Shukla, Fjolla Rexhepi, Maryse Cloutier, Amit Ghosh, Thomas A. Kufer, Sheela Ramanathan, and Subburaj Ilangumaran
- Subjects
NLRC5 ,NF-κB ,liver fibrosis ,carbon tetrachloride ,hepatic stellate cells ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The nucleotide-binding leucine-rich repeat-containing receptor (NLR) family protein-5 (NLRC5) controls NF-κB activation and production of inflammatory cytokines in certain cell types. NLRC5 is considered a potential regulator of hepatic fibrogenic response due to its ability to inhibit hepatic stellate activation in vitro. To test whether NLRC5 is critical to control liver fibrosis, we treated wildtype and NLRC5-deficient mice with carbon tetrachloride (CCl4) and assessed pathological changes in the liver. Serum alanine transaminase levels and histopathology examination of liver sections revealed that NLRC5 deficiency did not exacerbate CCl4-induced liver damage or inflammatory cell infiltration. Sirius red staining of collagen fibers and hydroxyproline content showed comparable levels of liver fibrosis in CCl4-treated NLRC5-deficient and control mice. Myofibroblast differentiation and induction of collagen genes were similarly increased in both groups. Strikingly, the fibrotic livers of NLRC5-deficient mice showed reduced expression of matrix metalloproteinase-3 (Mmp3) and tissue inhibitor of MMPs-1 (Timp1) but not Mmp2 or Timp2. Fibrotic livers of NLRC5-deficient mice had increased expression of TNF but similar induction of TGFβ compared to wildtype mice. CCl4-treated control and NLRC5-deficient mice displayed similar upregulation of Cx3cr1, a monocyte chemoattractant receptor gene, and the Cd68 macrophage marker. However, the fibrotic livers of NLRC5-deficient mice showed increased expression of F4/80 (Adgre1), a marker of tissue-resident macrophages. NLRC5-deficient livers showed increased phosphorylation of the NF-κB subunit p65 that remained elevated following fibrosis induction. Taken together, NLRC5 deficiency deregulates hepatic inflammatory response following chemical injury but does not significantly aggravate the fibrogenic response, showing that NLRC5 is not a critical regulator of liver fibrosis pathogenesis.
- Published
- 2021
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27. Cytosolic Gram-negative bacteria prevent apoptosis by inhibition of effector caspases through lipopolysaccharide
- Author
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Günther, Saskia D., Fritsch, Melanie, Seeger, Jens M., Schiffmann, Lars M., Snipas, Scott J., Coutelle, Maria, Kufer, Thomas A., Higgins, Paul G., Hornung, Veit, Bernardini, Maria L., Höning, Stefan, Krönke, Martin, Salvesen, Guy S., and Kashkar, Hamid
- Published
- 2020
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28. Design, Installation, and Initial Commissioning of the MTA Beamline
- Author
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Moore, Craig, Anderson, John, Garcia, Fernanda, Gerardi, Michael, Johnstone, Carol, Kobilarcik, Thomas, Kucera, Michael, Kufer, Mathew, Newhart, Duane, Rakhno, Igor, and Vogel, Gregory
- Subjects
Physics - Accelerator Physics - Abstract
A new experimental area designed to develop, test and verify muon ionization cooling apparatus using the 400-MeV Fermilab Linac proton beam has been fully installed and is presently being commissioned. Initially, this area was used for cryogenic tests of liquid-hydrogen absorbers for the MUCOOL R&D program and, now, for high-power beam tests of absorbers, high-gradient rf cavities in the presence of magnetic fields (including gas-filled cavities), and other prototype muon-cooling apparatus. The experimental scenarios being developed for muon facilities involve collection, capture, and cooling of large-emittance, high-intensity muon beams--~10**13 muons, so that conclusive tests of the apparatus require full Linac beam, which is 1.6 x 10**13 p/pulse. To support the muon cooling facility, this new primary beamline extracts and transports beam directly from the Linac to the test facility. The design concept for the MuCool facility is taken from an earlier proposal, but modifications were necessary to accommodate high-intensity beam, cryogenics, and the increased scale of the cooling experiments. Further, the different mode of operation to provide precision line incorporates a specialized section and utilizes a measurements of Linac beam parameters. This paper reports on the technical details of the MuCool beamline for both modes., Comment: 3 pp. 1st International Particle Accelerator Conference (IPAC'10). 23-28 May 2010. Kyoto, Japan
- Published
- 2012
29. DDX3X Links NLRP11 to the Regulation of Type I Interferon Responses and NLRP3 Inflammasome Activation
- Author
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Ioannis Kienes, Sarah Bauer, Clarissa Gottschild, Nora Mirza, Jens Pfannstiel, Martina Schröder, and Thomas A. Kufer
- Subjects
innate immunity ,nod-like receptors ,anti-viral ,DEAD-box helicase ,inflammasome ,IL-1 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Tight regulation of inflammatory cytokine and interferon (IFN) production in innate immunity is pivotal for optimal control of pathogens and avoidance of immunopathology. The human Nod-like receptor (NLR) NLRP11 has been shown to regulate type I IFN and pro-inflammatory cytokine responses. Here, we identified the ATP-dependent RNA helicase DDX3X as a novel binding partner of NLRP11, using co-immunoprecipitation and LC-MS/MS. DDX3X is known to enhance type I IFN responses and NLRP3 inflammasome activation. We demonstrate that NLRP11 can abolish IKKϵ-mediated phosphorylation of DDX3X, resulting in lower type I IFN induction upon viral infection. These effects were dependent on the LRR domain of NLRP11 that we mapped as the interaction domain for DDX3X. In addition, NLRP11 also suppressed NLRP3-mediated caspase-1 activation in an LRR domain-dependent manner, suggesting that NLRP11 might sequester DDX3X and prevent it from promoting NLRP3-induced inflammasome activation. Taken together, our data revealed DDX3X as a central target of NLRP11, which can mediate the effects of NLRP11 on type I IFN induction as well as NLRP3 inflammasome activation. This expands our knowledge of the molecular mechanisms underlying NLRP11 function in innate immunity and suggests that both NLRP11 and DDX3X might be promising targets for modulation of innate immune responses.
- Published
- 2021
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- View/download PDF
30. Tevatron Electron Lenses: Design and Operation
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Shiltsev, Vladimir, Bishofberger, Kip, Kamerdzhiev, Vsevolod, Kozub, Sergei, Kufer, Matthew, Kuznetsov, Gennady, Martinez, Alexander, Olson, Marvin, Pfeffer, Howard, Saewert, Greg, Scarpine, Vic, Seryi, Andrey, Solyak, Nikolai, Sytnik, Veniamin, Tiunov, Mikhail, Tkachenko, Leonid, Wildman, David, Wolff, Daniel, and Zhang, Xiao-Long
- Subjects
Physics - Accelerator Physics - Abstract
The beam-beam effects have been the dominating sources of beam loss and lifetime limitations in the Tevatron proton-antiproton collider [1]. Electron lenses were originally proposed for compensation of electromagnetic long-range and head-on beam-beam interactions of proton and antiproton beams [2]. Results of successful employment of two electron lenses built and installed in the Tevatron are reported in [3,4,5]. In this paper we present design features of the Tevatron electron lenses (TELs), discuss the generation of electron beams, describe different modes of operation and outline the technical parameters of various subsystems., Comment: submitted to Phys. Rev. ST-AB
- Published
- 2008
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31. Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens
- Author
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Sylvain Normand, Nadine Waldschmitt, Andreas Neerincx, Ruben Julio Martinez-Torres, Camille Chauvin, Aurélie Couturier-Maillard, Olivier Boulard, Laetitia Cobret, Fawaz Awad, Ludovic Huot, Andre Ribeiro-Ribeiro, Katja Lautz, Richard Ruez, Myriam Delacre, Clovis Bondu, Martin Guilliams, Charlotte Scott, Anthony Segal, Serge Amselem, David Hot, Sonia Karabina, Erwin Bohn, Bernhard Ryffel, Lionel F. Poulin, Thomas A. Kufer, and Mathias Chamaillard
- Subjects
Science - Abstract
Mutations in nucleotide-binding oligomerization domain protein 12 (NLRP12) are known to effect inflammatory processes. Here the authors show that NLRP12-mediated proteasomal degradation of NOD2 in monocytes promotes bacterial tolerance and colonisation in a model of enteric infection.
- Published
- 2018
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32. Subcellular antigen localization in commensal E. coli is critical for T cell activation and induction of specific tolerance
- Author
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Bennek, Eveline, Mandić, Ana D., Verdier, Julien, Roubrocks, Silvia, Pabst, Oliver, Van Best, Niels, Benz, Inga, Kufer, Thomas, Trautwein, Christian, and Sellge, Gernot
- Published
- 2019
- Full Text
- View/download PDF
33. Changes in clinical laboratory parameters and pharmacodynamic markers in response to blinatumomab treatment of patients with relapsed/refractory ALL
- Author
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Virginie Nägele, Andrea Kratzer, Gerhard Zugmaier, Chris Holland, Youssef Hijazi, Max S. Topp, Nicola Gökbuget, Patrick A. Baeuerle, Peter Kufer, Andreas Wolf, and Matthias Klinger
- Subjects
Acute lymphoblastic leukemia ,Blinatumomab ,Bispecific ,BiTE® ,CD19 ,Liver enzymes ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Blinatumomab has shown a remission rate of 69% in an exploratory single-arm, phase II dose-escalation study in adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We evaluated changes in laboratory parameters and immunopharmacodynamic markers in patients who received blinatumomab in the exploratory phase II study. Methods Data from 36 adults with relapsed/refractory ALL receiving blinatumomab as 4-week continuous IV infusions in various dose cohorts were analyzed for changes in liver enzymes, first-dose parameters, peripheral blood cell subpopulations, and cytokine/granzyme B release. Associations with clinical response were evaluated. Results Liver enzymes and inflammatory parameters transiently increased primarily during the first treatment week without clinical symptoms and reversed to baseline levels thereafter. B and T cells showed expected depletion and redistribution kinetics, respectively. Similarly, thrombocytes and T cells displayed an initial decline in cell counts, whereas neutrophils peaked during the first days after infusion start. T-cell redistribution coincided with upregulation of LFA-1 and CD69. Patients who responded to blinatumomab had more pronounced T-cell expansion, which was associated with proliferation of CD4+ and CD8+ T cells and memory subsets. Release of cytokines and granzyme B primarily occurred during the first week of cycle 1, except for IL-10, which was released in subsequent cycles. Blinatumomab step-dosing was associated with lower cytokine release and lower body temperature. Conclusions In this study of relapsed/refractory ALL, blinatumomab-induced changes in laboratory parameters were transient and reversible. The evaluated PD markers demonstrated blinatumomab activity, and the analysis of cytokines supported the rationale for stepwise dosing. (ClinicalTrials.gov Identifier NCT01209286.)
- Published
- 2017
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34. NOD1 modulates IL-10 signalling in human dendritic cells
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Theresa Neuper, Kornelia Ellwanger, Harald Schwarz, Thomas A. Kufer, Albert Duschl, and Jutta Horejs-Hoeck
- Subjects
Medicine ,Science - Abstract
Abstract NOD1 belongs to the family of NOD-like receptors, which is a group of well-characterised, cytosolic pattern-recognition receptors. The best-studied function of NOD-like receptors is their role in generating immediate pro-inflammatory and antimicrobial responses by detecting specific bacterial peptidoglycans or by responding to cellular stress and danger-associated molecules. The present study describes a regulatory, peptidoglycan-independent function of NOD1 in anti-inflammatory immune responses. We report that, in human dendritic cells, NOD1 balances IL-10-induced STAT1 and STAT3 activation by a SOCS2-dependent mechanism, thereby suppressing the tolerogenic dendritic cell phenotype. Based on these findings, we propose that NOD1 contributes to inflammation not only by promoting pro-inflammatory processes, but also by suppressing anti-inflammatory pathways.
- Published
- 2017
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- View/download PDF
35. Programmed necrotic cell death of macrophages: Focus on pyroptosis, necroptosis, and parthanatos
- Author
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Nirmal Robinson, Raja Ganesan, Csaba Hegedűs, Katalin Kovács, Thomas A. Kufer, and László Virág
- Subjects
Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Macrophages are highly plastic cells of the innate immune system. Macrophages play central roles in immunity against microbes and contribute to a wide array of pathologies. The processes of macrophage activation and their functions have attracted considerable attention from life scientists. Although macrophages are highly resistant to many toxic stimuli, including oxidative stress, macrophage death has been reported in certain diseases, such as viral infections, tuberculosis, atherosclerotic plaque development, inflammation, and sepsis. While most studies on macrophage death focused on apoptosis, a significant body of data indicates that programmed necrotic cell death forms may be equally important modes of macrophage death. Three such regulated necrotic cell death modalities in macrophages contribute to different pathologies, including necroptosis, pyroptosis, and parthanatos. Various reactive oxygen and nitrogen species, such as superoxide, hydrogen peroxide, and peroxynitrite have been shown to act as triggers, mediators, or modulators in regulated necrotic cell death pathways. Here we discuss recent advances in necroptosis, pyroptosis, and parthanatos, with a strong focus on the role of redox homeostasis in the regulation of these events. Keywords: Cell death, Macrophage, Regulated necrosis, Pyroptosis, Necroptosis, Parthanatos, Redox, Pathogens, Myeloid cells
- Published
- 2019
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36. Detection of Bacterial Membrane Vesicles by NOD-Like Receptors
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Ella L. Johnston, Begoña Heras, Thomas A. Kufer, and Maria Kaparakis-Liaskos
- Subjects
bacterial membrane vesicles (BMVs) ,outer membrane vesicles (OMVs) ,membrane vesicles (MVs) ,NOD-like receptors (NLRs) ,NODs ,NOD1 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Bacterial membrane vesicles (BMVs) are nanoparticles produced by both Gram-negative and Gram-positive bacteria that can function to modulate immunity in the host. Both outer membrane vesicles (OMVs) and membrane vesicles (MVs), which are released by Gram-negative and Gram-positive bacteria, respectively, contain cargo derived from their parent bacterium, including immune stimulating molecules such as proteins, lipids and nucleic acids. Of these, peptidoglycan (PG) and lipopolysaccharide (LPS) are able to activate host innate immune pattern recognition receptors (PRRs), known as NOD-like receptors (NLRs), such as nucleotide-binding oligomerisation domain-containing protein (NOD) 1, NOD2 and NLRP3. NLR activation is a key driver of inflammation in the host, and BMVs derived from both pathogenic and commensal bacteria have been shown to package PG and LPS in order to modulate the host immune response using NLR-dependent mechanisms. Here, we discuss the packaging of immunostimulatory cargo within OMVs and MVs, their detection by NLRs and the cytokines produced by host cells in response to their detection. Additionally, commensal derived BMVs are thought to shape immunity and contribute to homeostasis in the gut, therefore we also highlight the interactions of commensal derived BMVs with NLRs and their roles in limiting inflammatory diseases.
- Published
- 2021
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- View/download PDF
37. Role of NLRs in the Regulation of Type I Interferon Signaling, Host Defense and Tolerance to Inflammation
- Author
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Ioannis Kienes, Tanja Weidl, Nora Mirza, Mathias Chamaillard, and Thomas A. Kufer
- Subjects
NOD-like receptors ,Interferons ,innate immunity ,immune regulation ,type I interferon ,antiviral ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.
- Published
- 2021
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- View/download PDF
38. Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens
- Author
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Normand, Sylvain, Waldschmitt, Nadine, Neerincx, Andreas, Martinez-Torres, Ruben Julio, Chauvin, Camille, Couturier-Maillard, Aurélie, Boulard, Olivier, Cobret, Laetitia, Awad, Fawaz, Huot, Ludovic, Ribeiro-Ribeiro, Andre, Lautz, Katja, Ruez, Richard, Delacre, Myriam, Bondu, Clovis, Guilliams, Martin, Scott, Charlotte, Segal, Anthony, Amselem, Serge, Hot, David, Karabina, Sonia, Bohn, Erwin, Ryffel, Bernhard, Poulin, Lionel F., Kufer, Thomas A., and Chamaillard, Mathias
- Published
- 2018
- Full Text
- View/download PDF
39. Integrating an electrically active colloidal quantum dot photodiode with a graphene phototransistor
- Author
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Ivan Nikitskiy, Stijn Goossens, Dominik Kufer, Tania Lasanta, Gabriele Navickaite, Frank H. L. Koppens, and Gerasimos Konstantatos
- Subjects
Science - Abstract
The combination of fast photo-response and high gain plays a pivotal role in photodetector devices. Here the authors combine a colloidal quantum dot photodiode with a graphene phototransistor to overcome the speed, quantum efficiency and linear dynamic range limitations of available phototransistors.
- Published
- 2016
- Full Text
- View/download PDF
40. Long-term relapse-free survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia
- Author
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Nicola Gökbuget, Gerhard Zugmaier, Matthias Klinger, Peter Kufer, Matthias Stelljes, Andreas Viardot, Heinz A. Horst, Svenja Neumann, Monika Brüggemann, Oliver G. Ottmann, Thomas Burmeister, Dorothea Wessiepe, Max S. Topp, and Ralf Bargou
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2017
- Full Text
- View/download PDF
41. Dual energy can accurately differentiate uric acid-containing urinary calculi from calcium stones
- Author
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Spek, A., Strittmatter, F., Graser, A., Kufer, P., Stief, C., and Staehler, M.
- Published
- 2016
- Full Text
- View/download PDF
42. Using Summaries to Search and Visualize Distributed Resources Addressing Spatial and Multimedia Features
- Author
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Blank, Daniel, Henrich, Andreas, and Kufer, Stefan
- Published
- 2016
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43. Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism
- Author
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Krupka, C, Kufer, P, Kischel, R, Zugmaier, G, Lichtenegger, F S, Köhnke, T, Vick, B, Jeremias, I, Metzeler, K H, Altmann, T, Schneider, S, Fiegl, M, Spiekermann, K, Bauerle, P A, Hiddemann, W, Riethmüller, G, and Subklewe, M
- Published
- 2016
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44. NLR-protein functions in immunity
- Author
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Jorg Hermann eFritz and Thomas A. Kufer
- Subjects
innate immunity ,Microbes ,inflammatory responses ,NLR ,protein ,Immunologic diseases. Allergy ,RC581-607 - Published
- 2015
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45. Impact of Diverse Immune Evasion Mechanisms of Cancer Cells on T Cells Engaged by EpCAM/CD3-Bispecific Antibody Construct AMG 110.
- Author
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Wibke Deisting, Tobias Raum, Peter Kufer, Patrick A Baeuerle, and Markus Münz
- Subjects
Medicine ,Science - Abstract
Bispecific T cell engager (BiTE®) are single-chain bispecific antibody constructs with dual specificity for CD3 on T cells and a surface antigen on target cells. They can elicit a polyclonal cytotoxic T cell response that is not restricted by T cell receptor (TCR) specificity, and surface expression of MHC class I/peptide antigen complexes. Using human EpCAM/CD3-bispecific BiTE® antibody construct AMG 110, we here assessed to what extent surface expression of PD-L1, cytoplasmic expression of indoleamine-2,3-deoxygenase type 1, Bcl-2 and serpin PI-9, and the presence of transforming growth factor beta (TGF-β), interleukin-10 (IL-10) and adenosine in culture medium can impact redirected lysis by AMG 110-engaged T cells.The seven factors, which are all involved in inhibiting T cell functions by cancer cells, were tested with human EpCAM-expressing Chinese hamster ovary (CHO) target cells at levels that in most cases exceeded those observed in a number of human cancer cell lines. Co-culture experiments were used to determine the impact of the evasion mechanisms on EC50 values and amplitude of redirected lysis by AMG 110, and on BiTE®-induced proliferation of previously resting human peripheral T cells.An inhibitory effect on redirected lysis by AMG 110-engaged T cells was seen upon overexpression of serpin PI-9, Bcl-2, TGF-β and PD-L1. An inhibitory effect on induction of T cell proliferation was only seen with CHO cells overexpressing IDO. In no case, a single evasion mechanism rendered target cells completely resistant to BiTE®-induced lysis, and even various combinations could not.Our data suggest that diverse mechanisms employed by cancer cells to fend off T cells cannot inactivate AMG 110-engaged T cells, and that inhibitory effects observed in vitro may be overcome by increased concentrations of the BiTE® antibody construct.
- Published
- 2015
- Full Text
- View/download PDF
46. The cofilin phosphatase slingshot homolog 1 (SSH1) links NOD1 signaling to actin remodeling.
- Author
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Harald Bielig, Katja Lautz, Peter R Braun, Maureen Menning, Nikolaus Machuy, Christine Brügmann, Sandra Barisic, Stephan A Eisler, Maria Andree, Birte Zurek, Hamid Kashkar, Philippe J Sansonetti, Angelika Hausser, Thomas F Meyer, and Thomas A Kufer
- Subjects
Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
NOD1 is an intracellular pathogen recognition receptor that contributes to anti-bacterial innate immune responses, adaptive immunity and tissue homeostasis. NOD1-induced signaling relies on actin remodeling, however, the details of the connection of NOD1 and the actin cytoskeleton remained elusive. Here, we identified in a druggable-genome wide siRNA screen the cofilin phosphatase SSH1 as a specific and essential component of the NOD1 pathway. We show that depletion of SSH1 impaired pathogen induced NOD1 signaling evident from diminished NF-κB activation and cytokine release. Chemical inhibition of actin polymerization using cytochalasin D rescued the loss of SSH1. We further demonstrate that NOD1 directly interacted with SSH1 at F-actin rich sites. Finally, we show that enhanced cofilin activity is intimately linked to NOD1 signaling. Our data thus provide evidence that NOD1 requires the SSH1/cofilin network for signaling and to detect bacterial induced changes in actin dynamics leading to NF-κB activation and innate immune responses.
- Published
- 2014
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47. T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct
- Author
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Aigner, M, Feulner, J, Schaffer, S, Kischel, R, Kufer, P, Schneider, K, Henn, A, Rattel, B, Friedrich, M, Baeuerle, P A, Mackensen, A, and Krause, S W
- Published
- 2013
- Full Text
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48. NLRC5, AT THE HEART OF ANTIGEN PRESENTATION
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Andreas eNeerincx, Wilson eCastro, Greta eGuarda, and Thomas A. Kufer
- Subjects
Antigen Presentation ,Nuclear Proteins ,Transcription, Genetic ,MHC class I ,Disease Models, Animal ,NLR ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Nucleotide-binding domain and leucine-rich repeat containing receptors (NLRs) are intracellular proteins mainly involved in pathogen recognition, inflammatory responses, and cell death. Until recently, the function of the family member NLR caspase recruitment domain (CARD) containing 5 (NLRC5) has been a matter of debate. It is now clear that NLRC5 acts as a transcriptional regulator of the major-histocompatibility complex (MHC) class I. In this review we detail the development of our understanding of NLRC5 function, discussing both the accepted and the controversial aspects of NLRC5 activity. We give insight into the molecular mechanisms, and the potential implications, of NLRC5 function in health and disease.
- Published
- 2013
- Full Text
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49. Epitope distance to the target cell membrane and antigen size determine the potency of T cell-mediated lysis by BiTE antibodies specific for a large melanoma surface antigen
- Author
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Bluemel, Claudia, Hausmann, Susanne, Fluhr, Petra, Sriskandarajah, Mirnalini, Stallcup, William B., Baeuerle, Patrick A., and Kufer, Peter
- Published
- 2010
- Full Text
- View/download PDF
50. Therapeutic window of an EpCAM/CD3-specific BiTE antibody in mice is determined by a subpopulation of EpCAM-expressing lymphocytes that is absent in humans
- Author
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Amann, Maria, Friedrich, Matthias, Lutterbuese, Petra, Vieser, Eva, Lorenczewski, Grit, Petersen, Laetitia, Brischwein, Klaus, Kufer, Peter, Kischel, Roman, Baeuerle, Patrick A., and Schlereth, Bernd
- Published
- 2009
- Full Text
- View/download PDF
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