106 results on '"Endres, T."'
Search Results
2. PReS-FINAL-2331: Low-penetrance NLRP3 variants
- Author
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Endres, T, Hofer, F, Goldbach-Mansky, R, Hoffman, HM, Blank, N, Krause, K, Rietschel, C, Horneff, G, Lohse, P, and Kuemmerle-Deschner, J
- Published
- 2013
3. PW02-040 - Low-penetrance NLRP3 variants
- Author
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Endres, T, Hofer, F, Goldbach-Mansky, R, Hoffman, HM, Blank, N, Krause, K, Rietschel, C, Horneff, G, Lohse, P, and Kuemmerle-Deschner, J
- Published
- 2013
4. Low-temperature and low-pressure effective fluorescence lifetimes and spectra of gaseous anisole and toluene
- Author
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Beuting, M., Dreier, T., Schulz, C., and Endres, T.
- Published
- 2021
- Full Text
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5. Presynaptic Regulation of Tonic Inhibition by Neuromodulatory Transmitters in the Basal Amygdala
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Meis, S., Endres, T., Munsch, T., and Lessmann, V.
- Published
- 2018
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6. Formation of the Troodos Ophiolite at a triple junction: Evidence from trace elements in volcanic glass
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Regelous, M., Haase, K.M., Freund, S., Keith, M., Weinzierl, C.G., Beier, C., Brandl, P.A., Endres, T., and Schmidt, H.
- Published
- 2014
- Full Text
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7. Brief Report: Clinical and Molecular Phenotypes of Low‐Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges
- Author
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Kuemmerle‐Deschner, J. B., Verma, D., Endres, T., Broderick, L., de Jesus, A. A., Hofer, F., Blank, N., Krause, K., Rietschel, C., Horneff, G., Aksentijevich, I., Lohse, P., Goldbach‐Mansky, R., Hoffman, H. M., and Benseler, S. M.
- Published
- 2017
- Full Text
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8. 245 ATP12A as an anti-inflammatory in cystic fibrosis primary epithelial cells.
- Author
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Endres, T.
- Subjects
- *
CYSTIC fibrosis , *EPITHELIAL cells - Published
- 2024
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9. Postsynaptic BDNF signalling regulates long-term potentiation at thalamo-amygdala afferents
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Meis, S., Endres, T., and Lessmann, V.
- Published
- 2012
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10. Survivability of the thermographic phosphors YAG:Pr and SMP:Sn in a premixed flame.
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Kopf, A, Bardi, M, Kohler, E, Endres, T, Bruneaux, G, and Schulz, C
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MICROSCOPY ,FLAME stability ,WASTE gases ,LUMINESCENCE ,TEMPERATURE measurements ,THERMOGRAPHY ,X-ray diffraction ,FLAME - Abstract
The survivability of two thermographic phosphors, YAG:Pr
3+ and SMP:Sn2+ ((Sr,Mg)3 (PO4 )2 :Sn2+ ), in a combustion environment is studied in the post-flame regime of a premixed propane/air flame. While the laser-induced luminescence of YAG:Pr3+ can be exploited for in situ temperature measurements in the exhaust gas above the flame, there is no in situ detectable luminescence for SMP:Sn2+ for any reaction conditions within the stability limits of the flame. The phosphor particles are recaptured above the flame and ex situ analyzed for chemical or structural changes using microscopic analysis (SEM/EDX) and x-ray diffraction. The microscopic analysis of post-flame YAG:Pr3+ does not show any alteration, whereas morphology and chemical composition of SMP:Sn2+ have been modified upon passing through the reaction zone, which is responsible for the loss of its luminescence properties. [ABSTRACT FROM AUTHOR]- Published
- 2021
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11. The influence of hydrogen and methane on the growth of carbon particles during acetylene pyrolysis in a burnt-gas flow reactor.
- Author
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Peukert, S., Sallom, A., Emelianov, A., Endres, T., Fikri, M., Böhm, H., Jander, H., Eremin, A., and Schulz, C.
- Abstract
Abstract The growth of carbon particles was studied in heated flows of a burnt-gas flow reactor containing mixtures of N 2 /C 2 H 2 , and N 2 /C 2 H 2 with addition of H 2 or CH 4 surrounded by a rich C 2 H 4 /air flame. Soot particle sizes and volume fractions were measured by laser-induced incandescence (LII) between 50 and 130 mm above the nozzle exit. The measurements indicate a soot-inhibiting effect of adding H 2 to the C 2 H 2 /N 2 flow on both, particle sizes and soot volume fractions. The effect of CH 4 addition to the C 2 H 2 /N 2 flows was ambivalent, depending on the methane-to-acetylene ratio. At gas mixtures with N 2 :CH 4 :C 2 H 2 = 0.42:0.35:0.23 and 0.39:0.32:0.29 by volume at fixed total flow rates, the measured soot volume fractions were substantially increased in presence of CH 4 , while the mean diameters of the particles were slightly decreased. Gas temperatures were measured by a generalized line-reversal method with Abel transformation. Temperatures of the surrounding C 2 H 4 /air flame were around 1600 K, and temperatures of the inner flows, where soot formation was measured, were between 1550 and 1630 K. Plug-flow reactor calculations provided a qualitative understanding of the influence of CH 4 on the soot particle growth. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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12. The Relation Between Long-Term Synaptic Plasticity at Glutamatergic Synapses in the Amygdala and Fear Learning in Adult Heterozygous BDNF-Knockout Mice.
- Author
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Meis, S., Endres, T., Munsch, T., and Lessmann, V.
- Published
- 2018
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13. Clinical and Molecular Phenotypes of Low-Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges.
- Author
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Kuemmerle‐Deschner, J. B., Verma, D., Endres, T., Broderick, L., Jesus, A. A., Hofer, F., Blank, N., Krause, K., Rietschel, C., Horneff, G., Aksentijevich, I., Lohse, P., Goldbach‐Mansky, R., Hoffman, H. M., and Benseler, S. M.
- Subjects
ENZYME metabolism ,TREATMENT effectiveness ,CELL death ,EYE diseases ,FEVER ,GENETIC disorders ,HEARING disorders ,INFLAMMATION ,INTERLEUKINS ,KIDNEYS ,MEDICAL cooperation ,RESEARCH ,SKIN diseases ,PHENOTYPES ,DNA-binding proteins ,STATISTICAL significance ,DESCRIPTIVE statistics ,CHEMICAL inhibitors - Abstract
Objective Cryopyrin-associated periodic syndromes ( CAPS) result from gain-of-function mutations in the NLRP3 gene, which causes excessive release of interleukin-1β ( IL-1β) and systemic inflammation. While pathogenetic NLRP3 variant phenotypes are well-characterized, low-penetrance NLRP3 variants represent a significant clinical challenge. The aims of this study were to determine the clinical phenotype, the in vitro biologic phenotype, and the effect of anti- IL-1 treatment in patients with low-penetrance NLRP3 variants. Methods A multicenter study of consecutive symptomatic patients with low-penetrance NLRP3 variants recruited from 7 centers between May 2012 and May 2013 was performed. The observed findings were transferred into a study database, from which they were extracted for analysis. Controls were patients with a known pathogenetic NLRP3 variant. Clinical presentation and CAPS markers of inflammation were captured. Functional assays of inflammasome activation, including caspase 1 activity, NF-κB release, cell death, and IL-1β release, were performed. Treatment effects of IL-1 were determined. Comparisons between low-penetrance and pathogenetic NLRP3 variants were performed. Results The study included 45 patients, 21 of which were female (47%); 26 of the patients (58%) were children. NLRP3 low-penetrance variants identified in the patients were Q703K (n = 19), R488K (n = 6), and V198M (n = 20). In the controls, 28 had pathogenetic NLRP3 variants. Patients with low-penetrance NLRP3 variants had significantly more fever (76%) and gastrointestinal symptoms (73%); eye disease, hearing loss, and renal involvement were less common. Functional inflammasome testing identified an intermediate phenotype in low-penetrance NLRP3 variants as compared to wild-type and pathogenetic NLRP3 variants. All treated patients responded to IL-1 inhibition, with complete response documented in 50% of patients. Conclusion Patients with low-penetrance NLRP3 variants display a distinct clinical phenotype and an intermediate biologic phenotype, including IL-1β and non- IL-1β-mediated inflammatory pathway activation. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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14. RFID based patient registration in mass casualty incidents
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Nestler, S, Artinger, E, Coskun, T, Endres, T, and Klinker, G
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ddc: 610 ,lcsh:R858-859.7 ,lcsh:RC109-216 ,610 Medical sciences ,Medicine ,lcsh:Computer applications to medicine. Medical informatics ,lcsh:Infectious and parasitic diseases - Abstract
In MCIs (mass casualty incidents) the EMC (emergency medical chief) has to gain an overview on all patients at the scene. When using paper based patient tags the patient-related information remains at the patients themselves and the information relay is complex. We propose a mobile, RFID based solution, which makes the local patient-related information available to all relief workers at the scene. As a consequence all processes in an MCI are more transparent and the resulting medication and transport of the injured is more efficient. The introduction of RFID enhanced patient tags leads to various usability challenges which are discussed in this paper. Furthermore, three different implementations show, how these challenges can be solved in the future. These solutions have been evaluated in a disaster control exercise in order to get an impression of the practical suitability of the proposed solutions. The future introduction of RFID tags in rescue and emergency services can be based on this work., GMS Medizinische Informatik, Biometrie und Epidemiologie; 7(1):Doc02; ISSN 1860-9171
- Published
- 2011
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15. Results and functional outcome of femoral neck fractures in young adults
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Jones, C, Sietsema, D, Ringler, J, Endres, T, and Coulibaly, M
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Objective: The purpose of this study was to evaluate long-term functional outcome, results and complications after operative treatment of femoral neck fracture (FNF) in young adults. Methods: Over a five-year period, 2002–2007, 87 skeletally mature patients were retrospectively identified [for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie; 74. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 96. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie, 51. Tagung des Berufsverbandes der Fachärzte für Orthopädie
- Published
- 2010
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16. OSG-4-Schrauben-Arthrodese.
- Author
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Endres, T. and Zwipp, H.
- Published
- 2016
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17. Self-quenching in toluene LIF.
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Fuhrmann, D., Benzler, T., Fernando, S., Endres, T., Dreier, T., Kaiser, S.A., and Schulz, C.
- Abstract
Toluene is frequently used as laser-induced fluorescence (LIF) tracer for visualizing mixing processes, for example, in internal combustion engines. The signal evaluation relies on a linear dependence of the LIF signal on tracer concentration – which is not present in many practically relevant cases. This paper presents an investigation of the dependence of the LIF signal intensities on the toluene concentration, revealing a non-linear signal response already at concentrations approximately ten times below those given by the room-temperature vapor pressure. Toluene was vaporized in a mass-flow controlled evaporator and investigated in a free jet. Nitrogen was used as bath gas with a variable addition of oxygen. After excitation at 266 nm, an intensified CCD camera recorded the spectrally filtered fluorescence. In separate experiments, the effective fluorescence lifetime upon picosecond UV-laser excitation was determined. The results indicate that the fluorescence lifetime decreases with increasing tracer concentration due to self-quenching. Results from imaging and fluorescence lifetime measurements are consistent. The investigation reveals that the self-quenching of toluene is dominated by collisions with excited-state toluene molecules, which causes an additional dependence of the magnitude of self-quenching on the laser fluence. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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18. Building communities that promote successful aging
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Fried, L. P., Freedman, M., Endres, T. E., and Barbara A. Wasik
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Male ,Aging ,Life Expectancy ,Health Services for the Aged ,Humans ,Female ,Health Promotion ,Community Networks ,United States ,Research Article ,Aged - Abstract
Despite the fact that, in a few years, a fifth of the US population will be older than 65 years and people will be living a third of their lives after retirement, we have developed few avenues that would permit older adults to play meaningful roles as they age and few institutions to harness the experience that older adults could contribute to society. In fact, older adults constitute this country's only increasing natural resource--and the least used one. In this article we consider the rationale for developing institutions that harness the abilities and time of older adults, rather than focusing solely on their needs. Such an approach would decrease the structural lag between a social concept of retirement as unproductive leisure and an aging population that is larger, healthier, and with a need for more productive opportunities. Gerontologically designed opportunities for contribution on a large social scale could well provide a national approach to primary prevention to maintain health and function in older adults.
- Published
- 1997
19. 420 Microtubule dysfunction as a mechanism of cystic fibrosis inflammation.
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Endres, T., Duesler, L., and Kelley, T.
- Subjects
- *
CYSTIC fibrosis , *MICROTUBULES , *INFLAMMATION - Published
- 2022
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20. Reduction of switching losses in bidirectional DC/DC converters for automotive use.
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Endres, T., Schroder, J., and Fuchs, F. W.
- Published
- 2013
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21. RespectAbility in America: guiding principles for civic engagement among adults 55-plus.
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Endres T and Holmes CA
- Published
- 2006
22. Elemental carbon and hydrogen concentrations as the main factors in gas-phase graphene synthesis: Quantitative fourier-transform infrared spectroscopy study.
- Author
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Musikhin, S., Fortugno, P., Endres, T., Dreier, T., Daun, K.J., and Schulz, C.
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INFRARED spectroscopy , *GRAPHENE synthesis , *ATOMIC hydrogen , *CHEMICAL precursors , *CARBON , *CHEMICAL kinetics - Abstract
Gas-phase microwave plasma-assisted synthesis of freestanding graphene is a promising route to produce high-quality graphene flakes. However, a comprehensive understanding of the gas-phase kinetics that is required to advance production rates and yields is still lacking. Here, we use line-of-sight Fourier-transform infrared (FTIR) absorption spectroscopy as an in situ diagnostic to measure gaseous species formed during graphene synthesis, thereby elucidating the chemical kinetics mechanism. Different carbonaceous precursors that lead to the formation of either few-layer graphene flakes or soot-like particles are examined, and the results are compared with numerical simulations and mass spectrometry measurements. Quantitative FTIR measurements show a correlation between concentration of atomic carbon and hydrogen in the post-plasma region and particle morphology. Lower carbon and higher hydrogen concentrations lead to graphene formation, while higher carbon and lower hydrogen concentrations shift the reaction toward soot-like particles. We also investigate how the precursor chemical composition, precursor flowrate, and delivered microwave power affect the carbon concentration in the post-plasma region, thus enabling to control particle morphology. [Display omitted] [ABSTRACT FROM AUTHOR]
- Published
- 2023
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23. Robustness of Fractionally-Spaced Equalizer Length Using the Constant Modulus Criterion.
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Endres, T. J. and Anderson, B. D. O.
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- *
ALGORITHMS , *SIGNAL processing - Abstract
Provides information on a study which examined the robustness properties of fractionally spaced constant modulus algorithm (CMA) and constant modulus criterion. Description of the fractionally spaced CMA; Two algebraic analysis approaches; Conclusion.
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- 1999
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24. Simulated comparisons of blind equalization algorithms for cold start-up applications.
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Endres, T. J., Halford, S. D., Johnson, C. R., and Giannakis, G. B.
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- 1998
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25. Sodium-affected soil identification in south-central Illinois by electromagnetic induction
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Nettleton, W. D., Endres, T. J., Indorante, S. J., Bushue, L., and Doolittle, J. A.
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ELECTROMAGNETIC induction - Published
- 1994
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26. Children and residential experiences: a comprehensive strategy for implementing a research-informed program model for residential care.
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Holden MJ, Izzo C, Nunno M, Smith EG, Endres T, Holden JC, and Kuhn F
- Abstract
This paper describes an effort to bridge research and practice in residential care through implementing a program model titled Children and Residential Experiences (CARE). The strategy involves consulting at all levels of the organization to guide personnel to incorporate CARE evidence-based principles into daily practice, and fostering an organizational culture and climate that sustains the integration of CARE principles. CARE aims to promote residential care programs that serve the best interests of children. [ABSTRACT FROM AUTHOR]
- Published
- 2010
27. HLTF resolves G4s and promotes G4-induced replication fork slowing to maintain genome stability.
- Author
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Bai G, Endres T, Kühbacher U, Mengoli V, Greer BH, Peacock EM, Newton MD, Stanage T, Dello Stritto MR, Lungu R, Crossley MP, Sathirachinda A, Cortez D, Boulton SJ, Cejka P, Eichman BF, and Cimprich KA
- Subjects
- Humans, Telomere Homeostasis, DNA Damage, HEK293 Cells, Multifunctional Enzymes metabolism, Multifunctional Enzymes genetics, DNA-Directed DNA Polymerase, Genomic Instability, DNA Replication, G-Quadruplexes, Transcription Factors metabolism, Transcription Factors genetics, DNA-Binding Proteins metabolism, DNA-Binding Proteins genetics, MutS Homolog 2 Protein metabolism, MutS Homolog 2 Protein genetics, DNA Primase metabolism, DNA Primase genetics
- Abstract
G-quadruplexes (G4s) form throughout the genome and influence important cellular processes. Their deregulation can challenge DNA replication fork progression and threaten genome stability. Here, we demonstrate an unexpected role for the double-stranded DNA (dsDNA) translocase helicase-like transcription factor (HLTF) in responding to G4s. We show that HLTF, which is enriched at G4s in the human genome, can directly unfold G4s in vitro and uses this ATP-dependent translocase function to suppress G4 accumulation throughout the cell cycle. Additionally, MSH2 (a component of MutS heterodimers that bind G4s) and HLTF act synergistically to suppress G4 accumulation, restrict alternative lengthening of telomeres, and promote resistance to G4-stabilizing drugs. In a discrete but complementary role, HLTF restrains DNA synthesis when G4s are stabilized by suppressing primase-polymerase (PrimPol)-dependent repriming. Together, the distinct roles of HLTF in the G4 response prevent DNA damage and potentially mutagenic replication to safeguard genome stability., Competing Interests: Declaration of interests K.A.C. is a member of the scientific advisory board of IDEAYA Biosciences and RADD Pharmaceuticals and is on the oncology advisory board for GlaxoSmithKline. S.J.B. is a co-founder, VP Science Strategy and shareholder at Artios Pharma Ltd. K.A.C. and S.J.B. are also members of the advisory board at Molecular Cell., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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28. HLTF Prevents G4 Accumulation and Promotes G4-induced Fork Slowing to Maintain Genome Stability.
- Author
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Bai G, Endres T, Kühbacher U, Greer BH, Peacock EM, Crossley MP, Sathirachinda A, Cortez D, Eichman BF, and Cimprich KA
- Abstract
G-quadruplexes (G4s) form throughout the genome and influence important cellular processes, but their deregulation can challenge DNA replication fork progression and threaten genome stability. Here, we demonstrate an unexpected, dual role for the dsDNA translocase HLTF in G4 metabolism. First, we find that HLTF is enriched at G4s in the human genome and suppresses G4 accumulation throughout the cell cycle using its ATPase activity. This function of HLTF affects telomere maintenance by restricting alternative lengthening of telomeres, a process stimulated by G4s. We also show that HLTF and MSH2, a mismatch repair factor that binds G4s, act in independent pathways to suppress G4s and to promote resistance to G4 stabilization. In a second, distinct role, HLTF restrains DNA synthesis upon G4 stabilization by suppressing PrimPol-dependent repriming. Together, the dual functions of HLTF in the G4 response prevent DNA damage and potentially mutagenic replication to safeguard genome stability.
- Published
- 2023
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29. Can prior knowledge increase task complexity? - Cases in which higher prior knowledge leads to higher intrinsic cognitive load.
- Author
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Endres T, Lovell O, Morkunas D, Rieß W, and Renkl A
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- Humans, Students, Climate Change, Germany, Cognition, Problem Solving
- Abstract
Background & Aims: Cognitive load theory assumes that the higher the learner's prior knowledge (i.e., the more expert the learner), the lower the intrinsic cognitive load (complexity) experienced for a given problem. While this is the case in many scenarios, there can be cases in which the converse is also true, resulting in more expert learners reporting higher intrinsic cognitive load than novices for the same problem. This can occur in relation to problems involving complex systems (e.g., ecological systems), for which novices' problem representations may underestimate problem complexity and therefore report lower intrinsic load than experts. This finding is borne out in the current paper., Samples, Methods & Results: In Study 1 with 118 participants from the Black Forest area in Germany, participants with higher levels of forestry and ecological expertise evaluated a problem relating to the restructuring of the Black Forest to adapt to climate change as more complex than did novices. In Study 2 (within-subjects design, n = 66 primary-school students), we conceptually replicated this finding in a domain more typical of cognitive load theory studies, mathematics. We found that higher prior knowledge also reduced the underestimation of the complexity of 'tricky', but frequently used, mathematics word problems., Conclusion: Our findings suggest that cognitive load theory's assumptions about intrinsic load and prior knowledge should be refined, as there seems to exist a sub-set of problem-solving tasks for which the traditional relationship between prior knowledge and reported ICL is reversed., (© 2022 The Authors. British Journal of Educational Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)
- Published
- 2023
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30. Repurposing drugs against Alzheimer's disease: can the anti-multiple sclerosis drug fingolimod (FTY720) effectively tackle inflammation processes in AD?
- Author
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Leßmann V, Kartalou GI, Endres T, Pawlitzki M, and Gottmann K
- Subjects
- Mice, Animals, Humans, Aged, Fingolimod Hydrochloride pharmacology, Fingolimod Hydrochloride therapeutic use, Drug Repositioning, Sclerosis, Inflammation drug therapy, Inflammation metabolism, Alzheimer Disease drug therapy, Multiple Sclerosis drug therapy
- Abstract
Therapeutic approaches providing effective medication for Alzheimer's disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models and in humans suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals or in elderly humans before onset of disease symptoms. However, a pharmacological treatment that can reverse memory deficits in AD patients was thus far not identified. Importantly, AD disease-related dysfunctions have increasingly been associated with neuro-inflammatory mechanisms and searching for anti-inflammatory medication to treat AD seems promising. Like for other diseases, repurposing of FDA-approved drugs for treatment of AD is an ideally suited strategy to reduce the time to bring such medication into clinical practice. Of note, the sphingosine-1-phosphate analogue fingolimod (FTY720) was FDA-approved in 2010 for treatment of multiple sclerosis patients. It binds to the five different isoforms of Sphingosine-1-phosphate receptors (S1PRs) that are widely distributed across human organs. Interestingly, recent studies in five different mouse models of AD suggest that FTY720 treatment, even when starting after onset of AD symptoms, can reverse synaptic deficits and memory dysfunction in these AD mouse models. Furthermore, a very recent multi-omics study identified mutations in the sphingosine/ceramide pathway as a risk factor for sporadic AD, suggesting S1PRs as promising drug target in AD patients. Therefore, progressing with FDA-approved S1PR modulators into human clinical trials might pave the way for these potential disease modifying anti-AD drugs., (© 2023. The Author(s).)
- Published
- 2023
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31. In vivo impact of tubulin polymerization promoting protein (Tppp) knockout to the airway inflammatory response.
- Author
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Endres T, Duesler L, Corey DA, and Kelley TJ
- Subjects
- Animals, Mice, Microtubules metabolism, Polymerization, Cystic Fibrosis metabolism, Nerve Tissue Proteins metabolism, Tubulin metabolism
- Abstract
Microtubule dysfunction has been implicated as a mediator of inflammation in multiple diseases such as disorders of the cardiovascular and neurologic systems. Tubulin polymerization promoting protein (Tppp) facilitates microtubule elongation and regulates tubulin acetylation through inhibition of cytosolic deacetylase enzymes. Pathologic alterations in microtubule structure and dynamics have been described in cystic fibrosis (CF) and associated with inflammation, however the causality and mechanism remain unclear. Likewise, Tppp has been identified as a potential modifier of CF airway disease severity. Here we directly assess the impact of microtubule dysfunction on infection and inflammation by interrogating wild type and a Tppp knockout mouse model (Tppp - / -). Mice are challenged with a clinical isolate of Pseudomonas aeruginosa-laden agarose beads and assessed for bacterial clearance and inflammatory markers. Tppp - / - mouse model demonstrate impaired bacterial clearance and an elevated inflammatory response compared to control mice. These data are consistent with the hypothesis microtubule dysregulation is sufficient to lead to CF-like airway responses in mice., (© 2023. The Author(s).)
- Published
- 2023
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32. Water-film thickness imaging based on time-multiplexed near-infrared absorption with up to 500 Hz repetition rate.
- Author
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Lubnow M, Dreier T, Schulz C, and Endres T
- Abstract
We demonstrate high-repetition-rate imaging of the liquid-film thickness in the 50-1000 µm range resulting from impinging water droplets on a glass surface. The pixel-by-pixel ratio of line-of-sight absorption at two time-multiplexed near-infrared wavelengths at 1440 and 1353 nm was detected with a high-frame-rate InGaAs focal-plane array camera. Frame rates of 1 kHz and thus measurement rates of 500 Hz could be achieved, well suited to capture the fast dynamics of droplet impingement and film formation. The droplets were sprayed onto the glass surface using an atomizer. Suitable absorption wavelength bands for water droplet/film imaging were determined from Fourier-transform infrared (FTIR) spectra of pure water between 298 and 338 K. At 1440 nm, the water absorption is nearly temperature-independent, making the measurements robust against temperature fluctuations. Time-resolved imaging measurements capturing the dynamics of the water droplet impingement and evolution were successfully demonstrated.
- Published
- 2023
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33. Spatially resolved measurement of the distribution of solid and liquid Si nanoparticles in plasma synthesis through line-of-sight extinction spectroscopy.
- Author
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Liu G, Wollny P, Menser J, Dreier T, Endres T, Wlokas I, Daun KJ, and Schulz C
- Abstract
In many high-temperature gas-phase nanoparticle synthesis processes, freshly nucleated particles are liquid and solidify during growth and cooling. This study presents an approach to determine the location of the liquid-to-solid phase transition and the volume fraction and number density of particles of both phases within a gas phase reactor. Spectrally-resolved line-of-sight attenuation (LOSA) measurements are applied to a silicon nanoparticle aerosol generated from monosilane in a microwave plasma reactor. A phantom-based analysis using particle number density, particle size, and temperature distribution from direct numerical simulation (DNS) of the reacting flow indicates that the contributions from the two particle phases can be decoupled under practical conditions, even with noisy data. The approach was applied to analyze spatially and spectrally resolved LOSA measurements from the hot gas flow downstream of the plasma zone where both solid and liquid silicon particles coexist. Extinction spectra were recorded along a line perpendicular to the flow direction by a spectrometer with an electron-multiplying charge-coupled device (EMCCD) camera, and two-dimensional projections were deconvolved to obtain radial extinction coefficient distributions of solid and liquid particles across the cross-section of the flow. Particle number densities of both particle phases were retrieved simultaneously based on the size-dependent extinction cross-sections of the nanoparticles. The particle-size distribution was determined via thermophoretic sampling at the same location with subsequent transmission electron microscopy (TEM) analysis. The particle temperature distribution was determined from the particle's thermal radiation based on line-of-sight emission (LOSE) measurements. The approach for phase-selective data analysis can be transferred to other materials aerosol systems as long as significant differences exist in extinction spectra for the related different particle classes.
- Published
- 2023
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34. MYC multimers shield stalled replication forks from RNA polymerase.
- Author
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Solvie D, Baluapuri A, Uhl L, Fleischhauer D, Endres T, Papadopoulos D, Aziba A, Gaballa A, Mikicic I, Isaakova E, Giansanti C, Jansen J, Jungblut M, Klein T, Schülein-Völk C, Maric H, Doose S, Sauer M, Beli P, Rosenwald A, Dobbelstein M, Wolf E, and Eilers M
- Subjects
- Humans, Chromatin genetics, Promoter Regions, Genetic genetics, RNA Polymerase II metabolism, Transcription, Genetic, Tumor Suppressor Proteins metabolism, Ubiquitin-Protein Ligases metabolism, DNA Breaks, Double-Stranded, S Phase, Binding Sites, RNA, Messenger biosynthesis, DNA-Directed RNA Polymerases metabolism
- Abstract
Oncoproteins of the MYC family drive the development of numerous human tumours
1 . In unperturbed cells, MYC proteins bind to nearly all active promoters and control transcription by RNA polymerase II2,3 . MYC proteins can also coordinate transcription with DNA replication4,5 and promote the repair of transcription-associated DNA damage6 , but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from many of its binding sites in active promoters and forms multimeric, often sphere-like structures in response to perturbation of transcription elongation, mRNA splicing or inhibition of the proteasome. Multimerization is accompanied by a global change in the MYC interactome towards proteins involved in transcription termination and RNA processing. MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround FANCD2, ATR and BRCA1 proteins, which are located at stalled forks7,8 . MYC multimerization is triggered in a HUWE16 and ubiquitylation-dependent manner. At active promoters, MYC multimers block antisense transcription and stabilize FANCD2 association with chromatin. This limits DNA double strand break formation during S-phase, suggesting that the multimerization of MYC enables tumour cells to proliferate under stressful conditions., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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35. MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling.
- Author
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Zimmerli D, Brambillasca CS, Talens F, Bhin J, Linstra R, Romanens L, Bhattacharya A, Joosten SEP, Da Silva AM, Padrao N, Wellenstein MD, Kersten K, de Boo M, Roorda M, Henneman L, de Bruijn R, Annunziato S, van der Burg E, Drenth AP, Lutz C, Endres T, van de Ven M, Eilers M, Wessels L, de Visser KE, Zwart W, Fehrmann RSN, van Vugt MATM, and Jonkers J
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Interferons, Lymphocytes, Tumor-Infiltrating, Signal Transduction, Tumor Microenvironment genetics, Proto-Oncogene Proteins c-myc metabolism, Triple Negative Breast Neoplasms metabolism
- Abstract
The limited efficacy of immune checkpoint inhibitor treatment in triple-negative breast cancer (TNBC) patients is attributed to sparse or unresponsive tumor-infiltrating lymphocytes, but the mechanisms that lead to a therapy resistant tumor immune microenvironment are incompletely known. Here we show a strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of TNBC proficient or deficient of breast cancer type 1 susceptibility gene (BRCA1), MYC overexpression dramatically decreases lymphocyte infiltration in tumors, along with immune signature remodelling. MYC-mediated suppression of inflammatory signalling induced by BRCA1/2 inactivation is confirmed in human TNBC cell lines. Moreover, MYC overexpression prevents the recruitment and activation of lymphocytes in both human and mouse TNBC co-culture models. Chromatin-immunoprecipitation-sequencing reveals that MYC, together with its co-repressor MIZ1, directly binds promoters of multiple interferon-signalling genes, resulting in their downregulation. MYC overexpression thus counters tumor growth inhibition by a Stimulator of Interferon Genes (STING) agonist via suppressing induction of interferon signalling. Together, our data reveal that MYC suppresses innate immunity and facilitates tumor immune escape, explaining the poor immunogenicity of MYC-overexpressing TNBCs., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
36. Sustaining program implementation: A co-constructed technical assistance process to support continuous high-quality implementation of the Therapeutic Crisis Intervention program.
- Author
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McCabe LA, Ruberti MR, and Endres T
- Subjects
- Child, Health Services, Humans, Program Evaluation, Quality Improvement, Crisis Intervention, Implementation Science
- Abstract
Strategies for sustaining a program beyond initial implementation remain one of the most poorly understood aspects of high-quality program implementation. This paper describes the Quality Improvement and Fidelity Assessment Process (QIFAP), a program purveyor-agency partnership that uses a unique, multi-step method for supporting sustained implementation of the Therapeutic Crisis Intervention (TCI) system to manage crises in child serving organizations. It outlines the steps of the process and highlights how specific activities are linked to current knowledge and principles from implementation science. The QIFAP occurs over a period of about three months, during which time program developers and agency representatives conduct staff surveys, a two-day site visit, and fidelity assessments in order to gather information, discuss findings, and plan steps for improving the TCI system in the organization. The process is guided by principles that emphasize the importance of organization leadership, building relationships, co-learning, using an individualized approach, data informed decision making, acknowledging risk, and congruence. We describe ways in which the strategies and approaches within the QIFAP are rooted in implementation science literature. Thus, the model represents an illustration of how research-based knowledge can work in practice to support long-term, high-quality program implementation., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
37. ProBDNF Dependence of LTD and Fear Extinction Learning in the Amygdala of Adult Mice.
- Author
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Ma X, Vuyyuru H, Munsch T, Endres T, Lessmann V, and Meis S
- Subjects
- Amygdala metabolism, Animals, Learning physiology, Mice, Neuronal Plasticity, Extinction, Psychological physiology, Fear physiology
- Abstract
Neurotrophins are secreted proteins that control survival, differentiation, and synaptic plasticity. While mature neurotrophins regulate these functions via tyrosine kinase signaling (Trk), uncleaved pro-neurotrophins bind preferentially to the p75 neurotrophin receptor (p75NTR) and often exert opposite effects to those of mature neurotrophins. In the amygdala, brain-derived neurotrophic factor (BDNF) enables long-term potentiation as well as fear and fear extinction learning. In the present study, we focused on the impact of mature BDNF and proBDNF signaling on long-term depression (LTD) in the lateral amygdala (LA). Hence, we conducted extracellular field potential recordings in an in vitro slice preparation and recorded LTD in cortical and thalamic afferents to the LA. LTD was unchanged by acute block of BDNF/TrkB signaling. In contrast, LTD was inhibited by blocking p75NTR signaling, by disinhibition of the proteolytic cleavage of proBDNF into mature BDNF, and by preincubation with a function-blocking anti-proBDNF antibody. Since LTD-like processes in the amygdala are supposed to be related to fear extinction learning, we locally inhibited p75NTR signaling in the amygdala during or after fear extinction training, resulting in impaired fear extinction memory. Overall, these results suggest that in the amygdala proBDNF/p75NTR signaling plays a pivotal role in LTD and fear extinction learning., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
38. A Novel Aminomethacrylate-Based Copolymer for Solubility Enhancement-From Radical Polymer Synthesis to Manufacture and Characterization of Amorphous Solid Dispersions.
- Author
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Schmied FP, Bernhardt A, Moers C, Meier C, Endres T, and Klein S
- Abstract
The present study covers the synthesis, purification and evaluation of a novel aminomethacrylate-based copolymer in terms of its suitability for improving the solubility and in vitro release of poorly water-soluble drug compounds. The new copolymer was synthesized by solvent polymerization with radical initiation and by use of a chain transfer agent. Based on its composition, it can be considered as a modified type of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate "EUDRAGIT
® E PO" (ModE). ModE was specifically developed to provide a copolymer with processing and application properties that exceed those of commercially available (co-)polymers in solubility enhancement technologies where possible. By varying the concentration of the chain transfer agent in the radical polymerization process, the molecular weight of ModE was varied in a range of 173-305 kDa. To evaluate the solubility-enhancing properties of ModE, a series of drug-loaded extrudates were prepared by hot melt extrusion using the novel-as well as several commercially available-(co-)polymers. These extrudates were then subjected to comparative tests for amorphousness, solubility-enhancing properties, storage stability, and drug release. Celecoxib, efavirenz, and fenofibrate were used as model drugs in all experiments. Of all the (co-)polymers included in the study, ModE with a molecular weight of 173 kDa showed the best performance in terms of desired properties and was shown to be particularly suitable for preparing amorphous solid dispersions (ASDs) of the three model drugs, which in a first set of dissolution experiments showed better release behavior under pH conditions of the fasting stomach than higher molecular weight ModE types, as well as a variety of commercially available (co-)polymers. Therefore, the results demonstrate the successful synthesis of a new copolymer, which in future studies will be investigated in more detail for universal application in the field of solubility enhancement.- Published
- 2022
- Full Text
- View/download PDF
39. A Compact Fiber-Coupled NIR/MIR Laser Absorption Instrument for the Simultaneous Measurement of Gas-Phase Temperature and CO, CO 2 , and H 2 O Concentration.
- Author
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Shi L, Endres T, Jeffries JB, Dreier T, and Schulz C
- Abstract
A fiber-coupled, compact, remotely operated laser absorption instrument is developed for CO, CO
2 , and H2 O measurements in reactive flows at the elevated temperatures and pressures expected in gas turbine combustor test rigs with target pressures from 1-25 bar and temperatures of up to 2000 K. The optical engineering for solutions of the significant challenges from the ambient acoustic noise (~120 dB) and ambient test rig temperatures (60 °C) are discussed in detail. The sensor delivers wavelength-multiplexed light in a single optical fiber from a set of solid-state lasers ranging from diodes in the near-infrared (~1300 nm) to quantum cascade lasers in the mid-infrared (~4900 nm). Wavelength-multiplexing systems using a single optical fiber have not previously spanned such a wide range of laser wavelengths. Gas temperature is inferred from the ratio of two water vapor transitions. Here, the design of the sensor, the optical engineering required for simultaneous fiber delivery of a wide range of laser wavelengths on a single optical line-of-sight, the engineering required for sensor survival in the harsh ambient environment, and laboratory testing of sensor performance in the exhaust gas of a flat flame burner are presented.- Published
- 2022
- Full Text
- View/download PDF
40. MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts.
- Author
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Papadopoulos D, Solvie D, Baluapuri A, Endres T, Ha SA, Herold S, Kalb J, Giansanti C, Schülein-Völk C, Ade CP, Schneider C, Gaballa A, Vos S, Fischer U, Dobbelstein M, Wolf E, and Eilers M
- Subjects
- Animals, Ataxia Telangiectasia Mutated Proteins genetics, Ataxia Telangiectasia Mutated Proteins metabolism, BRCA1 Protein genetics, BRCA1 Protein metabolism, Cell Line, Tumor, Cell Nucleus genetics, DNA Breaks, Double-Stranded, Exoribonucleases genetics, Exoribonucleases metabolism, Exosomes genetics, Female, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Male, Mice, N-Myc Proto-Oncogene Protein genetics, NIH 3T3 Cells, Neuroblastoma genetics, Neuroblastoma pathology, Promoter Regions, Genetic, RNA Caps genetics, RNA Caps metabolism, RNA Polymerase II genetics, Transcription Termination, Genetic, Cell Nucleus enzymology, Cell Proliferation, DNA Replication, Exosomes enzymology, N-Myc Proto-Oncogene Protein metabolism, Neuroblastoma enzymology, RNA Polymerase II metabolism, Transcription, Genetic
- Abstract
The MYCN oncoprotein drives the development of numerous neuroendocrine and pediatric tumors. Here we show that MYCN interacts with the nuclear RNA exosome, a 3'-5' exoribonuclease complex, and recruits the exosome to its target genes. In the absence of the exosome, MYCN-directed elongation by RNA polymerase II (RNAPII) is slow and non-productive on a large group of cell-cycle-regulated genes. During the S phase of MYCN-driven tumor cells, the exosome is required to prevent the accumulation of stalled replication forks and of double-strand breaks close to the transcription start sites. Upon depletion of the exosome, activation of ATM causes recruitment of BRCA1, which stabilizes nuclear mRNA decapping complexes, leading to MYCN-dependent transcription termination. Disruption of mRNA decapping in turn activates ATR, indicating transcription-replication conflicts. We propose that exosome recruitment by MYCN maintains productive transcription elongation during S phase and prevents transcription-replication conflicts to maintain the rapid proliferation of neuroendocrine tumor cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2022
- Full Text
- View/download PDF
41. Simultaneous measurement of liquid-film thickness and solute concentration of aqueous solutions of two urea derivatives using NIR absorption.
- Author
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Lubnow M, Dreier T, Schulz C, and Endres T
- Abstract
We present a method to simultaneously measure the film thickness and individual concentrations of two urea derivates (urea C H
4 N2 O and dimethylurea C3 H8 N2 O ) mixed in an aqueous solution at constant temperature using near-infrared (NIR) absorption at multiple specific wavelengths. Fourier transform infrared (FTIR) spectra of aqueous mixtures of urea and dimethylurea solutions were recorded in the 1250-2500 nm wavelength range in thin-layer quartz cuvettes at room temperature. The spectra reveal suitable detection wavelengths, i.e., 1450, 1933, 2200, and 2270 nm, for which both the absorption coefficient and its variation with the species concentration are large enough to achieve satisfactory detection sensitivity and selectivity. For validation measurements, samples were prepared in thin-layer quartz transmission cells with known path lengths and mixture compositions in the range 100-1000 µm and 0-40 wt.%, respectively. Film thickness and mass fractions of both species were determined from measured absorbance ratios in the determined characteristic wavelength bands.- Published
- 2021
- Full Text
- View/download PDF
42. A new polymer-excipient for ethanol-resistant, sustained-release oral dosage forms.
- Author
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Endres T, Meier C, Schattka JH, Gronewold C, and Moers C
- Subjects
- Delayed-Action Preparations, Drug Compounding, Ethanol, Humans, Solubility, Excipients, Polymers
- Abstract
The use of alcoholic beverages can cause uncontrolled release of drugs from sustained-release solid oral dosage forms and pose severe risks to patient health. The aim of this work was to design a new polymeric excipient with ethanol resistance inherent to the polymer. Polymers were systematically designed, manufactured via emulsion polymerization, and fully characterized. Glass transition temperatures between 10 and 18 °C and minimum film forming temperatures between 10 and 25 °C were chosen because these parameters are ideal for aqueous film-coating processing. Three model drug formulations were made with the new polymer excipients and tested in the presence and absence of ethanol. The concept of an alcohol resistance factor based on Weibull regression analysis was introduced. In vitro results confirmed the hypothesized structure-function relationship between comonomer composition and ethanol resistance. That is, nonionic hydrophilic functional groups interacted more strongly with the ethanolic solvent, as compared with cationic hydrophilic comonomer that interacted more strongly with the surrounding water molecules. The alcohol resistance factor varied between - 44 ± 2% (slower drug release in presence of ethanol) and + 34 ± 0% (faster drug release in presence of ethanol) depending on the comonomer ratio. The main advantages of these new excipients compared with ethanol-resistant excipient blends include ease of use, plasticizers are not necessary, and shorter coating times., (© 2021. Controlled Release Society.)
- Published
- 2021
- Full Text
- View/download PDF
43. Phase-sensitive detection of gas-borne Si nanoparticles via line-of-sight UV/VIS attenuation.
- Author
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Asif M, Menser J, Endres T, Dreier T, Daun K, and Schulz C
- Abstract
The distinct optical properties of solid and liquid silicon nanoparticles are exploited to determine the distribution of gas-borne solid and liquid particles in situ using line-of-sight attenuation measurements carried out across a microwave plasma reactor operated at 100 mbar. The ratio between liquid and solid particles detected downstream of the plasma varied with measurement location, microwave power, and flow rate. Temperatures of the liquid particles were pyrometrically-inferred using a spectroscopic model based on Drude theory. The phase-sensitive measurement supports the understanding of nanoparticle formation and interaction and thus the overall gas-phase synthesis process.
- Published
- 2021
- Full Text
- View/download PDF
44. Characterization of tracers for two-color laser-induced fluorescence thermometry of liquid-phase temperature in ethanol, 2-ethylhexanoic-acid/ethanol mixtures, 1-butanol, and o-xylene.
- Author
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Prenting MM, Shilikhin M, Dreier T, Schulz C, and Endres T
- Abstract
The fluorescence spectra of dye solutions change their spectral signature with temperature. This effect is frequently used for temperature imaging in liquids and sprays based on two-color laser-induced fluorescence (2cLIF) measurements by simultaneously detecting the fluorescence intensity in two separate wavelength channels resulting in a temperature-sensitive ratio. In this work, we recorded temperature-dependent absorption and fluorescence spectra of solutions of five laser dyes (coumarin 152, coumarin 153, rhodamine B, pyrromethene 597, and DCM) dissolved in ethanol, a 35/65 vol.% mixture of ethanol/2-ethylhexanoic acid, ethanol/hexamethylsiloxane, o-xylene, and 1-butanol to investigate their potential as temperature tracers in evaporating and burning sprays. The dissolved tracers were excited at either 266, 355, and 532 nm (depending on the tracer) for temperatures between 296 and 393 K (depending on the solvent) and for concentrations ranging between 0.1 and 10 mg/l. Absorption and fluorescence spectra of the tracers were investigated for their temperature dependence, the magnitude of signal re-absorption, the impact of different solvents, and varying two-component solvent compositions. Based on the measured fluorescence spectra, the tracers were analyzed for their 2cLIF temperature sensitivity in the respective solvents. Coumarin 152 showed for single-component solvents the overall best spectroscopic properties for our specific measurement situation related to temperature imaging measurements in spray-flame synthesis of nanoparticles as demonstrated previously in ethanol spray flames [Exp. Fluids61, 77 (2020)10.1007/s00348-020-2909-9].
- Published
- 2021
- Full Text
- View/download PDF
45. BDNF haploinsufficiency induces behavioral endophenotypes of schizophrenia in male mice that are rescued by enriched environment.
- Author
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Harb M, Jagusch J, Durairaja A, Endres T, Leßmann V, and Fendt M
- Subjects
- Animals, Endophenotypes, Haploinsufficiency, Male, Mice, Mice, Inbred C57BL, Reflex, Startle, Brain-Derived Neurotrophic Factor genetics, Schizophrenia genetics
- Abstract
Brain-derived neurotrophic factor (BDNF) is implicated in a number of processes that are crucial for healthy functioning of the brain. Schizophrenia is associated with low BDNF levels in the brain and blood, however, not much is known about BDNF's role in the different symptoms of schizophrenia. Here, we used BDNF-haploinsufficient (BDNF
+/- ) mice to investigate the role of BDNF in different mouse behavioral endophenotypes of schizophrenia. Furthermore, we assessed if an enriched environment can prevent the observed changes. In this study, male mature adult wild-type and BDNF+/- mice were tested in mouse paradigms for cognitive flexibility (attentional set shifting), sensorimotor gating (prepulse inhibition), and associative emotional learning (safety and fear conditioning). Before these tests, half of the mice had a 2-month exposure to an enriched environment, including running wheels. After the tests, BDNF brain levels were quantified. BDNF+/- mice had general deficits in the attentional set-shifting task, increased startle magnitudes, and prepulse inhibition deficits. Contextual fear learning was not affected but safety learning was absent. Enriched environment housing completely prevented the observed behavioral deficits in BDNF+/- mice. Notably, the behavioral performance of the mice was negatively correlated with BDNF protein levels. These novel findings strongly suggest that decreased BDNF levels are associated with several behavioral endophenotypes of schizophrenia. Furthermore, an enriched environment increases BDNF protein to wild-type levels and is thereby able to rescue these behavioral endophenotypes.- Published
- 2021
- Full Text
- View/download PDF
46. Spatial distribution of gas-phase synthesized germanium nanoparticle volume-fraction and temperature using combined in situ line-of-sight emission and extinction spectroscopy.
- Author
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Liu G, Asif M, Menser J, Dreier T, Mohri K, Schulz C, and Endres T
- Abstract
In this study, emission and extinction spectroscopy were combined to in situ measure temperature and volume fraction distributions of liquid germanium nanoparticle gas-phase synthesized in an argon/hydrogen/germane flow through a microwave plasma. Emission of the hot particles and extinction against a continuous background were recorded by a spectrometer in the 380-703 nm and 230-556 nm ranges, respectively, selected based on the specific optical properties of the material. Absorption coefficients were deconvoluted from line-of-sight attenuation (LOSA) measurements by a least-square algorithm and then used to determine the local volume fraction distribution. The temperature field was derived from the line-of-sight emission (LOSE) spectra with the prior knowledge of absorption coefficients. A multi-wavelength reconstruction model was developed for the determination of the spatially-resolved distribution of the measured quantities assuming a stationary axisymmetric flow. Advantages of the method include experimental simplicity, low cost, and adaptability to up-scaled reactor sizes.
- Published
- 2021
- Full Text
- View/download PDF
47. Ubiquitylation of MYC couples transcription elongation with double-strand break repair at active promoters.
- Author
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Endres T, Solvie D, Heidelberger JB, Andrioletti V, Baluapuri A, Ade CP, Muhar M, Eilers U, Vos SM, Cramer P, Zuber J, Beli P, Popov N, Wolf E, Gallant P, and Eilers M
- Subjects
- ATPases Associated with Diverse Cellular Activities genetics, ATPases Associated with Diverse Cellular Activities metabolism, Cell Line, Tumor, Histones genetics, Histones metabolism, Humans, Proto-Oncogene Proteins c-myc genetics, RNA Polymerase II genetics, RNA Polymerase II metabolism, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Ubiquitination, DNA Breaks, Double-Stranded, DNA Repair, Promoter Regions, Genetic, Proto-Oncogene Proteins c-myc metabolism, Transcription Elongation, Genetic
- Abstract
The MYC oncoprotein globally affects the function of RNA polymerase II (RNAPII). The ability of MYC to promote transcription elongation depends on its ubiquitylation. Here, we show that MYC and PAF1c (polymerase II-associated factor 1 complex) interact directly and mutually enhance each other's association with active promoters. PAF1c is rapidly transferred from MYC onto RNAPII. This transfer is driven by the HUWE1 ubiquitin ligase and is required for MYC-dependent transcription elongation. MYC and HUWE1 promote histone H2B ubiquitylation, which alters chromatin structure both for transcription elongation and double-strand break repair. Consistently, MYC suppresses double-strand break accumulation in active genes in a strictly PAF1c-dependent manner. Depletion of PAF1c causes transcription-dependent accumulation of double-strand breaks, despite widespread repair-associated DNA synthesis. Our data show that the transfer of PAF1c from MYC onto RNAPII efficiently couples transcription elongation with double-strand break repair to maintain the genomic integrity of MYC-driven tumor cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
48. Threshold photoionization shows no sign of nitryl hydride in methane oxidation with nitric oxide.
- Author
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Hoener M, Bodi A, Hemberger P, Endres T, and Kasper T
- Abstract
Methane was doped with nitric oxide and oxidized in a high-pressure flow reactor. The nitrogen chemistry during partial oxidation was studied using photoelectron photoion coincidence spectroscopy with vacuum ultraviolet synchrotron radiation. The adiabatic ionization energy of nitrous acid, HONO, has been determined as 10.95 ± 0.03 eV. The HONO breakdown diagram was plotted based solely on the measured parent signal and the computed Franck-Condon envelope of trans-HONO, confirming the trans-HONO dissociative photoionization threshold to NO+ + ˙OH at 11.34 eV. The spectra show strong indication for the presence of cis-HONO. We expected the m/z 47 photoion mass selected threshold photoelectron signal to rebound near 12 eV, i.e., at the ionization energy of nitryl hydride, the third HNO2 isomer. Recent computational studies suggest nitryl hydride is formed at a rate similar to trans-HONO, is more thermally stable than nitrous acid, its cation is bound, and its photoelectron spectrum is predicted to exhibit a strong origin band near 12 eV. The absence of its mass selected threshold photoelectron signal shows that nitryl hydride is either not formed in measurable amounts or is consumed faster than nitrous acid, for instance by isomerization to trans-HONO.
- Published
- 2021
- Full Text
- View/download PDF
49. Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model.
- Author
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Kartalou GI, Salgueiro-Pereira AR, Endres T, Lesnikova A, Casarotto P, Pousinha P, Delanoe K, Edelmann E, Castrén E, Gottmann K, Marie H, and Lessmann V
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Peptides genetics, Animals, Anti-Inflammatory Agents pharmacology, Astrocytes metabolism, Astrocytes pathology, Disease Models, Animal, Fingolimod Hydrochloride pharmacology, Hippocampus drug effects, Hippocampus metabolism, Humans, Inflammation genetics, Inflammation metabolism, Inflammation pathology, Memory Disorders genetics, Memory Disorders metabolism, Memory Disorders pathology, Mice, Mice, Transgenic, Microglia drug effects, Microglia metabolism, Synapses genetics, Synapses pathology, Alzheimer Disease drug therapy, Amyloid beta-Protein Precursor genetics, Inflammation drug therapy, Memory Disorders drug therapy, Presenilin-1 genetics
- Abstract
Therapeutic approaches providing effective medication for Alzheimer's disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms, while a pharmacological treatment that can reverse synaptic and memory deficits in AD mice was thus far not identified. Repurposing food and drug administration (FDA)-approved drugs for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. The sphingosine-1 phosphate analog fingolimod (FTY720) was approved recently for treatment of multiple sclerosis patients. Here, we addressed whether fingolimod rescues AD-related synaptic deficits and memory dysfunction in an amyloid precursor protein/presenilin-1 (APP/PS1) AD mouse model when medication starts after onset of symptoms (at five months). Male mice received intraperitoneal injections of fingolimod for one to two months starting at five to six months. This treatment rescued spine density as well as long-term potentiation in hippocampal cornu ammonis-1 (CA1) pyramidal neurons, that were both impaired in untreated APP/PS1 animals at six to seven months of age. Immunohistochemical analysis with markers of microgliosis (ionized calcium-binding adapter molecule 1; Iba1) and astrogliosis (glial fibrillary acid protein; GFAP) revealed that our fingolimod treatment regime strongly down regulated neuroinflammation in the hippocampus and neocortex of this AD model. These effects were accompanied by a moderate reduction of Aβ accumulation in hippocampus and neocortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology that is believed to underlie memory deficits in AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes.
- Published
- 2020
- Full Text
- View/download PDF
50. Neurotrophin signalling in amygdala-dependent cued fear learning.
- Author
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Meis S, Endres T, and Lessmann V
- Subjects
- Amygdala, Animals, Humans, Signal Transduction, Brain-Derived Neurotrophic Factor genetics, Fear physiology, Learning physiology, Neurotrophin 3 physiology
- Abstract
The amygdala is a central hub for fear learning assessed by Pavlovian fear conditioning. Indeed, the prevailing hypothesis that learning and memory are mediated by changes in synaptic strength was shown most convincingly at thalamic and cortical afferents to the lateral amygdala. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to regulate synaptic plasticity and memory formation in many areas of the mammalian brain including the amygdala, where BDNF signalling via tropomyosin-related kinase B (TrkB) receptors is prominently involved in fear learning. This review updates the current understanding of BDNF/TrkB signalling in the amygdala related to fear learning and extinction. In addition, actions of proBDNF/p75NTR and NGF/TrkA as well as NT-3/TrkC signalling in the amygdala are introduced.
- Published
- 2020
- Full Text
- View/download PDF
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