46 results on '"Schütz, M"'
Search Results
2. High count rates using Timepix3 Detectors: Efficient Data Processing in spectroscopic CT
- Author
-
Schütz, M. K., primary, Useche, S. J., additional, Roque, G. A., additional, Jakubek, J., additional, Procz, S., additional, and Fiederle, M., additional
- Published
- 2023
- Full Text
- View/download PDF
3. Author Correction: Nutrients cause grassland biomass to outpace herbivory
- Author
-
Borer, E. T., Harpole, W. S., Adler, P. B., Arnillas, C. A., Bugalho, M. N., Cadotte, M. W., Caldeira, M. C., Campana, S., Dickman, C. R., Dickson, T. L., Donohue, I., Eskelinen, A., Firn, J. L., Graff, P., Gruner, D. S., Heckman, R. W., Koltz, A. M., Komatsu, K. J., Lannes, L. S., MacDougall, A. S., Martina, J. P., Moore, J. L., Mortensen, B., Ochoa-Hueso, R., Venterink, H. Olde, Power, S. A., Price, J. N., Risch, A. C., Sankaran, M., Schütz, M., Sitters, J., Stevens, C. J., Virtanen, R., Wilfahrt, P. A., and Seabloom, E. W.
- Published
- 2021
- Full Text
- View/download PDF
4. Drivers of the microbial metabolic quotient across global grasslands
- Author
-
Risch, A. C., primary, Zimmermann, S., additional, Schütz, M., additional, Borer, E. T., additional, Broadbent, A. A. D., additional, Caldeira, M. C., additional, Davies, K. F., additional, Eisenhauer, N., additional, Eskelinen, A., additional, Fay, P. A., additional, Hagedorn, F., additional, Knops, J. M. H., additional, Lembrechts, J. J., additional, MacDougall, A. S., additional, McCulley, R. L., additional, Melbourne, B. A., additional, Moore, J. L., additional, Power, S. A., additional, Seabloom, E. W., additional, Silviera, M. L., additional, Virtanen, R., additional, Yahdjian, L., additional, and Ochoa‐Hueso, R., additional
- Published
- 2023
- Full Text
- View/download PDF
5. The extracellular juncture domains of Type 5 autotransporters
- Author
-
Weikum, J., primary, Kulakova, A., additional, Tesei, G., additional, Yoshimoto, S., additional, Vejby Jægerum, L., additional, Schütz, M., additional, Hori, K., additional, Skepö, M., additional, Harris, P., additional, Leo, J.C., additional, and Morth, J.P., additional
- Published
- 2022
- Full Text
- View/download PDF
6. Nitrogen increases early-stage and slows late-stage decomposition across diverse grasslands
- Author
-
Gill, AL, Adler, PB, Borer, ET, Buyarski, CR, Cleland, EE, D'Antonio, CM, Davies, KF, Gruner, DS, Harpole, WS, Hofmockel, KS, MacDougall, AS, McCulley, RL, Melbourne, BA, Moore, JL, Morgan, John, Risch, AC, Schütz, M, Seabloom, EW, Wright, JP, Yang, LH, Hobbie, SE, and Wiley-Blackwell Publishing Ltd.
- Subjects
nitrogen deposition ,50399 Soil Sciences not elsewhere classified ,FOS: Agriculture, forestry and fisheries ,grasslands ,Nutrient Network (NutNet) ,Life Sciences ,litter decomposition ,phosphorus ,nitrogen - Abstract
To evaluate how increased anthropogenic nutrient inputs alter carbon cycling in grasslands, we conducted a litter decomposition study across 20 temperate grasslands on three continents within the Nutrient Network, a globally distributed nutrient enrichment experiment We determined the effects of addition of experimental nitrogen (N), phosphorus (P) and potassium plus micronutrient (Kμ) on decomposition of a common tree leaf litter in a long-term study (maximum of 7 years; exact deployment period varied across sites). The use of higher order decomposition models allowed us to distinguish between the effects of nutrients on early- versus late-stage decomposition. Across continents, the addition of N (but not other nutrients) accelerated early-stage decomposition and slowed late-stage decomposition, increasing the slowly decomposing fraction by 28% and the overall litter mean residence time by 58%. Synthesis. Using a novel, long-term cross-site experiment, we found widespread evidence that N enhances the early stages of above-ground plant litter decomposition across diverse and widespread temperate grassland sites but slows late-stage decomposition. These findings were corroborated by fitting the data to multiple decomposition models and have implications for N effects on soil organic matter formation. For example, following N enrichment, increased microbial processing of litter substrates early in decomposition could promote the production and transfer of low molecular weight compounds to soils and potentially enhance the stabilization of mineral-associated organic matter. By contrast, by slowing late-stage decomposition, N enrichment could promote particulate organic matter (POM) accumulation. Such hypotheses deserve further testing.
- Published
- 2022
- Full Text
- View/download PDF
7. Spaceborne GNSS-Receiver Evolution – From Classical HiRel to NewSpace Constellation
- Author
-
Schütz, M., Zehetmayer, S., Zajac, K., Laabs, M., Borany, J., Zangl, R., and Sust, M.
- Abstract
Spaceborne Global Navigation Satellite System (GNSS) receivers have become indispensable components of satellites, in particular for real-time navigation as part of the attitude and orbit control system and for precise orbit determination in support of highly accurate earth observation instruments. In cooperation with the project partners TU Dresden and the Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Beyond Gravity (formerly RUAG Space) has developed a flexible GNSS receiver platform targeting NewSpace applications but leveraging the performance of the current gold standards with respect to spaceborne GNSS-receiver technology. A novel radiation test environment was introduced, and selected components were radiation tested to ensure a consistent reliability.
- Published
- 2022
8. Nitrogen but not phosphorus addition affects symbiotic N₂ fixation by legumes in natural and semi-natural grasslands located on four continents
- Author
-
Vázquez, E. (Eduardo), Schleuss, P.-M. (Per-Marten), Borer, E. T. (Elizabeth T.), Bugalho, M. N. (Miguel N.), Caldeira, M. C. (Maria C.), Eisenhauer, N. (Nico), Eskelinen, A. (Anu), Fay, P. A. (Philip A.), Haider, S. (Sylvia), Jentsch, A. (Anke), Kirkman, K. P. (Kevin P.), McCulley, R. L. (Rebecca L.), Peri, P. L. (Pablo L.), Price, J. (Jodi), Richards, A. E. (Anna E.), Risch, A. C. (Anita C.), Roscher, C. (Christiane), Schütz, M. (Martin), Seabloom, E. W. (Eric W.), Standish, R. J. (Rachel J.), Stevens, C. J. (Carly J.), Tedder, M. J. (Michelle J.), Virtanen, R. (Risto), and Spohn, M. (Marie)
- Subjects
Nitrogen addition ,Grasslands ,Nutrient Network (NutNet) ,Phosphorus addition ,N-15 natural abundance method ,Legumes - Abstract
Background and aims: The amount of nitrogen (N) derived from symbiotic N₂ fixation by legumes in grasslands might be affected by anthropogenic N and phosphorus (P) inputs, but the underlying mechanisms are not known. Methods: We evaluated symbiotic N₂ fixation in 17 natural and semi-natural grasslands on four continents that are subjected to the same full-factorial N and P addition experiment, using the ¹⁵N natural abundance method. Results: N as well as combined N and P (NP) addition reduced aboveground legume biomass by 65% and 45%, respectively, compared to the control, whereas P addition had no significant impact. Addition of N and/or P had no significant effect on the symbiotic N₂ fixation per unit legume biomass. In consequence, the amount of N fixed annually per grassland area was less than half in the N addition treatments compared to control and P addition, irrespective of whether the dominant legumes were annuals or perennials. Conclusion: Our results reveal that N addition mainly impacts symbiotic N₂ fixation via reduced biomass of legumes rather than changes in N₂ fixation per unit legume biomass. The results show that soil N enrichment by anthropogenic activities significantly reduces N₂ fixation in grasslands, and these effects cannot be reversed by additional P amendment.
- Published
- 2022
9. P227 The impact of de novo Class II donor specific antibody on combined liver/heart or liver/kidney transplant: Can the liver protect the second allograft?
- Author
-
Johnson, K.P., Schuetz, M., Helmick, D., Lomago, J., Hunter, B., Ellison, M.A., Xu, Q., and Zeevi, A.
- Published
- 2023
- Full Text
- View/download PDF
10. Das neue winkelstabile LIS-System zur Versorgung von periprothetischen Frakturen. 1-Jahres-Ergebnisse von 14 Fällen
- Author
-
Schütz, M, Kääb, M, Stefansky, J, Müller, M, and Haas, NP
- Published
- 2024
- Full Text
- View/download PDF
11. Understanding the Cytomegalovirus Cyclin-Dependent Kinase Ortholog pUL97 as a Multifaceted Regulator and an Antiviral Drug Target.
- Author
-
Marschall M, Schütz M, Wild M, Socher E, Wangen C, Dhotre K, Rawlinson WD, and Sticht H
- Subjects
- Humans, Virus Replication drug effects, Cytomegalovirus Infections drug therapy, Cytomegalovirus Infections virology, Animals, Cyclins metabolism, Phosphotransferases (Alcohol Group Acceptor), Antiviral Agents pharmacology, Cytomegalovirus drug effects, Cytomegalovirus physiology, Viral Proteins metabolism, Viral Proteins chemistry, Cyclin-Dependent Kinases metabolism, Cyclin-Dependent Kinases antagonists & inhibitors
- Abstract
Herpesviral protein kinases, such as the therapy-relevant pUL97 of human cytomegalovirus (HCMV), are important for viral replication efficiency as well as pathogenesis, and represent key antiviral drug targets. HCMV pUL97 is a viral cyclin-dependent kinase (CDK) ortholog, as it shares functional and structural properties with human CDKs. Recently, the formation of vCDK/pUL97-cyclin complexes and the phosphorylation of a variety of viral and cellular substrate proteins has been demonstrated. Genetic mapping and structural modeling approaches helped to define two pUL97 interfaces, IF1 and IF2, responsible for cyclin binding. In particular, the regulatory importance of interactions between vCDK/pUL97 and host cyclins as well as CDKs has been highlighted, both as determinants of virus replication and as a novel drug-targeting option. This aspect was substantiated by the finding that virus replication was impaired upon cyclin type H knock-down, and that such host-directed interference also affected viruses resistant to existing therapies. Beyond the formation of binary interactive complexes, a ternary pUL97-cyclin H-CDK7 complex has also been described, and in light of this, an experimental trans-stimulation of CDK7 activity by pUL97 appeared crucial for virus-host coregulation. In accordance with this understanding, several novel antiviral targeting options have emerged. These include kinase inhibitors directed to pUL97, to host CDKs, and to the pUL97-cyclin H interactive complexes. Importantly, a statistically significant drug synergy has recently been reported for antiviral treatment schemes using combinations of pharmacologically relevant CDK7 and vCDK/pUL97 inhibitors, including maribavir. Combined, such findings provide increased options for anti-HCMV control. This review focuses on regulatory interactions of vCDK/pUL97 with the host cyclin-CDK apparatus, and it addresses the functional relevance of these key effector complexes for viral replication and pathogenesis. On this basis, novel strategies of antiviral drug targeting are defined.
- Published
- 2024
- Full Text
- View/download PDF
12. Multicenter Real-World Analysis of Combined MET and EGFR Inhibition in Patients With Non-Small Cell Lung Cancer and Acquired MET Amplification or Polysomy After EGFR Inhibition.
- Author
-
Acker F, Klein A, Rasokat A, Eisert A, Kron A, Christopoulos P, Stenzinger A, Kulhavy J, Hummel HD, Waller CF, Hummel A, Rittmeyer A, Kropf-Sanchen C, Zimmermann H, Lörsch A, Kauffmann-Guerrero D, Schütz M, Herster F, Thielert F, Demes M, Althoff FC, Aguinarte L, Heinzen S, Rost M, Schulte H, Stratmann J, Rohde G, Büttner R, Wolf J, Sebastian M, and Michels S
- Abstract
Purpose: MET amplification is a common resistance mechanism to EGFR inhibition in EGFR-mutant non-small cell lung cancer (NSCLC). Several trials showed encouraging results with combined EGFR and MET inhibition (EGFRi/METi). However, MET amplification has been inconsistently defined and frequently included both polysomy and true amplification., Methods: This is a multicenter, real-world analysis in patients with disease progression on EGFR inhibition and MET copy number gain (CNG), defined as either true amplification (MET to centromere of chromosome 7 ratio [MET-CEP7] ≥ 2) or polysomy (gene copy number ≥ 5, MET-CEP7 < 2)., Results: A total of 43 patients with MET CNG were included, 42 of whom were detected by FISH. Twenty-three, 7, and 14 received EGFRi/METi, METi, and SoC, respectively. Patients in the EGFRi/METi cohort exhibited a superior real-world clinical benefit rate, defined as stable disease or better, of 82% (95% confidence interval [CI], 60-95) compared to METi (29%, 4-71) and SoC (50%, 23-77). Median real-world progression-free survival was longer with EGFRi/METi with 9.8 vs. 4.3 months with METi (hazard ratio [HR], 0.19, 95% CI, 0.06-0.57) and 3.7 months with SoC (0.41, 0.18-0.91), respectively. Overall survival was numerically improved. Interaction analysis with treatment and type of CNG (amplification vs. polysomy) suggests that differences were exclusively driven by MET-amplified patients receiving EGFRi/METi (HR for OS, 0.09, 0.01-0.54)., Conclusion: In this real-world study, EGFRi/METi showed clinical benefit over METi and SoC. Future studies should focus on the differential impact of the type of MET CNG with a focus on true MET amplification as predictor of response., Competing Interests: Disclosure F. A. received support for attending meetings and speaker's honoraria from AstraZeneca, and consultant fees from IQVIA. P. C. received research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Merck, Novartis, Roche, and Takeda, speaker's honoraria from AstraZeneca, Gilead, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, and Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Janssen, Gilead, Novartis, Pfizer, Takeda, and personal fees for participating to advisory boards from AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche, all outside the submitted work. H.-D. H. received personal fees for participating to advisory boards from Amgen, speaker's honoraria from Amgen, Boehringer Ingelheim, and Bristol-Myers Squibb. C. F. W. received personal fees for participating to advisory boards from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Lilly, Merck, MSD, Novartis, Pfizer, Roche, and Takeda, consultancy fees from Mylan/Viatris, Alvotech, Roche, support for attending meetings from Amgen, Bristol-Myers Squibb, Janssen, Lilly. A. Ri. received speaker's honoraria and consulting fees from Abbvie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Lilly, GSK, MSD, Novartis, Pfizer, Roche/Genentech. H. Z. received support for attending meetings from Janssen, speaker's honoraria from Pierre Fabre, and Roche. A. L. received support for attending meetings from Abbvie. D. K.-G. received consultant fees from AstraZeneca, Boehringer Ingelheim, Roche, MSD, Pfizer, Bristol-Myers Squibb, GSK, Novartis, Takeda, Sanofi, and Janssen, support for attending meetings from Takeda, Boehringer-Ingelheim, Janssen. R. B. received honoraries for lectures and advisory boards for AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Illumina, Janssen, Lilly, Merck-Serono, MSD, Novartis, Qiagen, Pfizer, Roche, Targos MP Inc. R.B. is a Co-Founder and Co-Owner of Targos Inc / Kassel (previous); Gnothis Inc / Stockholm (current); Timer Therapeutics Inc / Fulda & Freiburg (current). M. D. received personal fees for participating in advisory boards from AstraZeneca, Bayer, Diaceutics, Biocartis, Sophia Genetics, and ThermoFisher. F. C. A. has received research grants from Novartis, support for attending meetings and/or travel from Amgen, and consultant fees from IQVIA. S. H. has received research grants from Novartis and travel support from BeiGene. J. A. S. received personal fees from Boehringer Ingelheim, AstraZeneca, Roche, Bristol-Myers Squibb, Amgen, LEO pharma, Novartis, and Takeda. J. W. received speaker's honoraria and personal fees for participating in advisory boards from Amgen, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, Merck, Mirati, MSD, Novartis, Nuvalent, Pfizer, Roche, Seattle Genetics, Takeda, and Turning Point and received institutional research grants from Bristol-Myers Squibb, Janssen, Novartis, Pfizer, and AstraZeneca. M. S. received research grants from AstraZeneca, consulting fees from AstraZeneca, Bristol-Myers Squibb, MSD, Novartis, Lilly, Roche, Boehringer Ingelheim, Amgen, Takeda, Johnson, Merck-Serono, and GSK, and speaker's honoraria from AstraZeneca, Bristol-Myers Squibb, MSD, Novartis, Lilly, Roche, Boehringer Ingelheim, Amgen, Takeda, Johnson, CureVac, BioNTech, Merck-Serono, GSK, Daiichi, and Pfizer. S. M. has received research grants from Novartis and Pfizer, personal fees from Eli Lilly, Janssen, and Astra Zeneca as well as support for attending meetings and/or travel from Eli Lilly, and Janssen. A. S. has received speaker's honoraria from Agilent, Aignostics, Amgen, Astellas, Astra Zeneca, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Qlucore, Roche, Seagen, Servier, Takeda, and Thermo Fisher, and institutional research grants from Bayer, BMS, Chugai, and Incyte. All other authors declared no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
13. Human Cytomegalovirus Dysregulates Cellular Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases and Sonic Hedgehog Pathway Proteins in Neural Astrocyte and Placental Models.
- Author
-
Egilmezer E, Hamilton ST, Lauw G, Follett J, Sonntag E, Schütz M, Marschall M, and Rawlinson WD
- Subjects
- Humans, Pregnancy, Female, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases genetics, Phosphorylation, Trophoblasts virology, Trophoblasts metabolism, Dyrk Kinases, Cell Line, Cells, Cultured, Hedgehog Proteins metabolism, Hedgehog Proteins genetics, Cytomegalovirus physiology, Placenta virology, Placenta metabolism, Astrocytes virology, Astrocytes metabolism, Protein-Tyrosine Kinases metabolism, Protein-Tyrosine Kinases genetics, Cytomegalovirus Infections virology, Cytomegalovirus Infections metabolism, Signal Transduction
- Abstract
Human cytomegalovirus (CMV) infection is the leading non-genetic cause of congenital malformation in developed countries, causing significant fetal injury, and in some cases fetal death. The pathogenetic mechanisms through which this host-specific virus infects then damages both the placenta and the fetal brain are currently ill-defined. We investigated the CMV modulation of key signaling pathway proteins for these organs including dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) and Sonic Hedgehog (SHH) pathway proteins using human first trimester placental trophoblast (TEV-1) cells, primary human astrocyte (NHA) brain cells, and CMV-infected human placental tissue. Immunofluorescence demonstrated the accumulation and re-localization of SHH proteins in CMV-infected TEV-1 cells with Gli2, Ulk3, and Shh re-localizing to the CMV cytoplasmic virion assembly complex (VAC). In CMV-infected NHA cells, DYRK1A re-localized to the VAC and DYRK1B re-localized to the CMV nuclear replication compartments, and the SHH proteins re-localized with a similar pattern as was observed in TEV-1 cells. Western blot analysis in CMV-infected TEV-1 cells showed the upregulated expression of Rb, Ulk3, and Shh, but not Gli2. In CMV-infected NHA cells, there was an upregulation of DYRK1A, DYRK1B, Gli2, Rb, Ulk3, and Shh. These in vitro monoculture findings are consistent with patterns of protein upregulation and re-localization observed in naturally infected placental tissue and CMV-infected ex vivo placental explant histocultures. This study reveals CMV-induced changes in proteins critical for fetal development, and identifies new potential targets for CMV therapeutic development.
- Published
- 2024
- Full Text
- View/download PDF
14. Multiparametric Characterization of the DSL-6A/C1 Pancreatic Cancer Model in Rats.
- Author
-
Schmidt P, Lindemeyer J, Raut P, Schütz M, Saniternik S, Jönsson J, Endepols H, Fischer T, Quaas A, Schlößer HA, Thelen M, and Grüll H
- Abstract
The DSL-6A/C1 murine pancreatic ductal adenocarcinoma (PDAC) tumor model was established in Lewis rats and characterized through a comprehensive multiparametric analysis to compare it to other preclinical tumor models and explore potential diagnostic and therapeutical targets. DSL-6A/C1 tumors were histologically analyzed to elucidate PDAC features. The tumor microenvironment was studied for immune cell prevalence. Multiparametric MRI and PET imaging were utilized to characterize tumors, and
68 Ga-FAPI-46-targeting cancer-associated fibroblasts (CAFs), were used to validate the histological findings. The histology confirmed typical PDAC characteristics, such as malformed pancreatic ductal malignant cells and CAFs. Distinct immune landscapes were identified, revealing an increased presence of CD8+ T cells and a decreased CD4+ T cell fraction within the tumor microenvironment. PET imaging with68 Ga-FAPI tracers exhibited strong tracer uptake in tumor tissues. The MRI parameters indicated increasing intralesional necrosis over time and elevated contrast media uptake in vital tumor areas. We have demonstrated that the DSL-6A/C1 tumor model, particularly due to its high tumorigenicity, tumor size, and68 Ga-FAPI-46 sensitivity, is a suitable alternative to established small animal models for many forms of preclinical analyses and therapeutic studies of PDAC.- Published
- 2024
- Full Text
- View/download PDF
15. Mobocertinib in Patients with EGFR Exon 20 Insertion-Positive Non-Small Cell Lung Cancer (MOON): An International Real-World Safety and Efficacy Analysis.
- Author
-
Illini O, Saalfeld FC, Christopoulos P, Duruisseaux M, Vikström A, Peled N, Demedts I, Dudnik E, Eisert A, Hashemi SMS, Janzic U, Kian W, Mohorcic K, Mohammed S, Silvoniemi M, Rothschild SI, Schulz C, Wesseler C, Addeo A, Armster K, Itchins M, Ivanović M, Kauffmann-Guerrero D, Koivunen J, Kuon J, Pavlakis N, Piet B, Sebastian M, Velthaus-Rusik JL, Wannesson L, Wiesweg M, Wurm R, Albers-Leischner C, Aust DE, Janning M, Fabikan H, Herold S, Klimova A, Loges S, Sharapova Y, Schütz M, Weinlinger C, Valipour A, Overbeck TR, Griesinger F, Jakopovic M, Hochmair MJ, and Wermke M
- Subjects
- Male, Humans, Female, Aged, ErbB Receptors genetics, Exons, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Aniline Compounds, Indoles, Pyrimidines
- Abstract
EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.
- Published
- 2024
- Full Text
- View/download PDF
16. Strategic Ambiguity: The Pragmatic Utopianism of Daniel Callahan's "Bioethics as a Discipline".
- Author
-
Schütz M
- Subjects
- Humans, Bioethics
- Abstract
This article highlights the continuing relevance of a classic bioethical text, "Bioethics as a Discipline," published by the Hastings Center's cofounder Daniel Callahan in 1973. Connecting the text's programmatic recommendations with later reflections and interventions Callahan wrote about the development of bioethics illuminates how the vision Callahan established and the reality this vision helped create were interrelated-just not in the way Callahan had hoped for. Although this portrait relies on an individual perception of the development of bioethics, it might nevertheless, through its unique linkage of different bioethical temporalities, contribute to a broader reassessment of what bioethics became and why.
- Published
- 2024
- Full Text
- View/download PDF
17. Fast 19 F spectroscopic imaging with pseudo-spiral k-space sampling.
- Author
-
Yildirim M, Kovalyk X, Scholtz P, Schütz M, Lindemeyer J, Lamerichs R, Grüll H, and Isik EO
- Subjects
- Mice, Animals, Fluorine, Magnetic Resonance Imaging methods, Imaging, Three-Dimensional methods, Fluorocarbons, Hydrocarbons, Brominated
- Abstract
Fluorine MRI is finding wider acceptance in theranostics applications where imaging of
19 F hotspots of fluorinated contrast material is central. The essence of such applications is to capture ghosting-artifact-free images of the inherently low MR response under clinically viable conditions. To serve this purpose, this work introduces the balanced spiral spectroscopic imaging (BaSSI) sequence, which is implemented on a 3.0 T clinical scanner and is capable of generating19 F hotspot images in an efficient manner. The sequence utilizes an all-phase-encoded pseudo-spiral k-space trajectory, enabling the acquisition of broadband (80 ppm) fluorine spectra free from chemical shift ghosting. BaSSI can acquire a 64 × 64 image with 1 mm × 1 mm voxels in just 14 s, significantly outperforming typical MRSI sequences used in1 H or31 P imaging. The study employed in silico characterization to verify essential design choices such as the excitation pulse, as well as to identify the boundaries of the parameter space explored for optimization. BaSSI's performance was further benchmarked against the 3D ultrashort-echo-time balanced steady-state free precession (3D UTE BSSFP) sequence, a well established method used in19 F MRI, in vitro. Both sequences underwent extensive optimization through exploration of a wide parameter space on a small phantom containing 10 μL of non-diluted bulk perfluorooctylbromide (PFOB) prior to comparative experiments. Subsequent to optimization, BaSSI and 3D UTE BSSFP were employed to capture images of small non-diluted bulk PFOB samples (0.10 and 0.05 μL), with variations in the number of signal averages, and thus the total scan time, in order to assess the detection sensitivities of the sequences. In these experiments, the detection sensitivity was evaluated using the Rose criterion (Rc ), which provides a quantitative metric for assessing object visibility. The study further demonstrated BaSSI's utility as a (pre)clinical tool through postmortem imaging of polymer microspheres filled with PFOB in a BALB/c mouse. Anatomic localization of19 F hotspots was achieved by denoising raw data obtained with BaSSI using a filter based on the Rose criterion. These data were then successfully registered to1 H anatomical images. BaSSI demonstrated superior detection sensitivity in the benchmarking analysis, achieving Rc values approximately twice as high as those obtained with the 3D UTE BSSFP method. The technique successfully facilitated imaging and precise localization of19 F hotspots in postmortem experiments. However, it is important to highlight that imaging 10 mM PFOB in small mice postmortem, utilizing a 48 × 48 × 48 3D scan, demanded a substantial scan time of 1 h and 45 min. Further studies will explore accelerated imaging techniques, such as compressed sensing, to enhance BaSSI's clinical utility., (© 2023 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)- Published
- 2024
- Full Text
- View/download PDF
18. Iron from Tutankhamun's Tomb
- Author
-
Broschat, Katja, Ströbele, Florian, Koeberl, Christian, Eckmann, Christian, Mertah, Eid, Schutz, Manon, Translated by, Broschat, Katja, Ströbele, Florian, Koeberl, Christian, Eckmann, Christian, Mertah, Eid, and Schutz, Manon
- Published
- 2022
- Full Text
- View/download PDF
19. All-Hydrocarbon-Ligated Superatomic Gold/Aluminum Clusters.
- Author
-
Antsiburov I, Schütz M, Bühler R, Muhr M, Stephan J, Gemel C, Klein W, Kahlal S, Saillard JY, and Fischer RA
- Abstract
Key strategies in cluster synthesis include the use of modulating agents (e.g., coordinating additives). We studied the influence of various phosphines exhibiting different steric and electronic properties on the reduction of the Au(I) precursor to Au(0) clusters. We report a synthesis of the bimetallic clusters [Au
6 (AlCp*)6 ] = [Au6 Al6 ](Cp*)6 ( 1 ) and [HAu7 (AlCp*)6 ] = [HAu7 Al6 ](Cp*)6 ( 2 ) (Cp* = pentamethylcyclopentadiene) using Au(I) precursors and AlCp*. The cluster [Au2 (AlCp*)5 ] = [Au2 Al5 ](Cp*)5 ( 3 ) was isolated and identified as an intermediate species in the reactions to 1 and 2 . The processes of cluster growth and degradation were investigated by in situ1 H NMR and LIFDI-MS techniques. The structures of 1 and 2 were established by DFT geometry optimization. These octahedral clusters can both be described as closed-shell 18-electron superatoms.- Published
- 2024
- Full Text
- View/download PDF
20. Assignment of individual structures from intermetalloid nickel gallium cluster ensembles.
- Author
-
Muhr M, Stephan J, Staiger L, Hemmer K, Schütz M, Heiß P, Jandl C, Cokoja M, Kratky T, Günther S, Huber D, Kahlal S, Saillard JY, Cador O, Da Silva ACH, Da Silva JLF, Mink J, Gemel C, and Fischer RA
- Abstract
Poorly selective mixed-metal cluster synthesis and separation yield reaction solutions of inseparable intermetalloid cluster mixtures, which are often discarded. High-resolution mass spectrometry, however, can provide precise compositional data of such product mixtures. Structure assignments can be achieved by advanced computational screening and consideration of the complete structural space. Here, we experimentally verify structure and composition of a whole cluster ensemble by combining a set of spectroscopic techniques. Our study case are the very similar nickel/gallium clusters of M
12 , M13 and M14 core composition Ni6+x Ga6+y (x + y ≤ 2). The rationalization of structure, bonding and reactivity is built upon the organometallic superatom cluster [Ni6 Ga6 ](Cp*)6 = [Ga6 ](NiCp*)6 (1; Cp* = C5 Me5 ). The structural conclusions are validated by reactivity tests using carbon monoxide, which selectively binds to Ni sites, whereas (triisopropylsilyl)acetylene selectively binds to Ga sites., (© 2024. The Author(s).)- Published
- 2024
- Full Text
- View/download PDF
21. An Antiherpesviral Host-Directed Strategy Based on CDK7 Covalently Binding Drugs: Target-Selective, Picomolar-Dose, Cross-Virus Reactivity.
- Author
-
Yu D, Wagner S, Schütz M, Jeon Y, Seo M, Kim J, Brückner N, Kicuntod J, Tillmanns J, Wangen C, Hahn F, Kaufer BB, Neipel F, Eickhoff J, Klebl B, Nam K, and Marschall M
- Abstract
The repertoire of currently available antiviral drugs spans therapeutic applications against a number of important human pathogens distributed worldwide. These include cases of the pandemic severe acute respiratory coronavirus type 2 (SARS-CoV-2 or COVID-19), human immunodeficiency virus type 1 (HIV-1 or AIDS), and the pregnancy- and posttransplant-relevant human cytomegalovirus (HCMV). In almost all cases, approved therapies are based on direct-acting antivirals (DAAs), but their benefit, particularly in long-term applications, is often limited by the induction of viral drug resistance or side effects. These issues might be addressed by the additional use of host-directed antivirals (HDAs). As a strong input from long-term experiences with cancer therapies, host protein kinases may serve as HDA targets of mechanistically new antiviral drugs. The study demonstrates such a novel antiviral strategy by targeting the major virus-supportive host kinase CDK7. Importantly, this strategy focuses on highly selective, 3D structure-derived CDK7 inhibitors carrying a warhead moiety that mediates covalent target binding. In summary, the main experimental findings of this study are as follows: (1) the in vitro verification of CDK7 inhibition and selectivity that confirms the warhead covalent-binding principle (by CDK-specific kinase assays), (2) the highly pronounced antiviral efficacies of the hit compounds (in cultured cell-based infection models) with half-maximal effective concentrations that reach down to picomolar levels, (3) a particularly strong potency of compounds against strains and reporter-expressing recombinants of HCMV (using infection assays in primary human fibroblasts), (4) additional activity against further herpesviruses such as animal CMVs and VZV, (5) unique mechanistic properties that include an immediate block of HCMV replication directed early (determined by Western blot detection of viral marker proteins), (6) a substantial drug synergism in combination with MBV (measured by a Loewe additivity fixed-dose assay), and (7) a strong sensitivity of clinically relevant HCMV mutants carrying MBV or ganciclovir resistance markers. Combined, the data highlight the huge developmental potential of this host-directed antiviral targeting concept utilizing covalently binding CDK7 inhibitors.
- Published
- 2024
- Full Text
- View/download PDF
22. The Interactive Complex between Cytomegalovirus Kinase vCDK/pUL97 and Host Factors CDK7-Cyclin H Determines Individual Patterns of Transcription in Infected Cells.
- Author
-
Schütz M, Cordsmeier A, Wangen C, Horn AHC, Wyler E, Ensser A, Sticht H, and Marschall M
- Subjects
- Humans, Cytomegalovirus genetics, Cyclin H metabolism, Cyclin-Dependent Kinases genetics, Cyclin-Dependent Kinases metabolism, Phosphorylation, Cyclins metabolism, Herpesviridae Infections
- Abstract
The infection of human cytomegalovirus (HCMV) is strongly determined by the host-cell interaction in a way that the efficiency of HCMV lytic replication is dependent on the regulatory interplay between viral and cellular proteins. In particular, the activities of protein kinases, such as cyclin-dependent kinases (CDKs) and the viral CDK ortholog (vCDK/pUL97), play an important role in both viral reproduction and virus-host interaction. Very recently, we reported on the complexes formed between vCDK/pUL97, human cyclin H, and CDK7. Major hallmarks of this interplay are the interaction between cyclin H and vCDK/pUL97, which is consistently detectable across various conditions and host cell types of infection, the decrease or increase in pUL97 kinase activity resulting from cyclin H knock-down or elevated levels, respectively, and significant trans-stimulation of human CDK7 activity by pUL97 in vitro. Due to the fact that even a ternary complex of vCDK/pUL97-cyclin H-CDK7 can be detected by coimmunoprecipitation and visualized by bioinformatic structural modeling, we postulated a putative impact of the respective kinase activities on the patterns of transcription in HCMV-infected cells. Here, we undertook a first vCDK/pUL97-specific transcriptomic analysis, which combined conditions of fully lytic HCMV replication with those under specific vCDK/pUL97 or CDK7 drug-mediated inhibition or transient cyclin H knockout. The novel results were further strengthened using bioinformatic modeling of the involved multi-protein complexes. Our data underline the importance of these kinase activities for the C-terminal domain (CTD) phosphorylation-driven activation of host RNA polymerase in HCMV-infected cells. The impact of the individual experimental conditions on differentially expressed gene profiles is described in detail and discussed.
- Published
- 2023
- Full Text
- View/download PDF
23. Evaluation of viscosities of typical drainage fluids to promote more evidence-based catheter size selection.
- Author
-
Celik E, Goertz L, Henze J, Schütz M, Mink B, Brinkmann S, Laasch HU, Schmidt AM, Grüll H, Maintz D, Kloeckner R, Lorenz F, Pinto Dos Santos D, and Chon SH
- Subjects
- Humans, Viscosity, Catheters, Water, Drainage methods, Abscess therapy
- Abstract
Percutaneous drainage is a first-line therapy for abscesses and other fluid collections. However, experimental data on the viscosity of body fluids are scarce. This study analyses the apparent viscosity of serous, purulent and biliary fluids to provide reference data for the evaluation of drainage catheters. Serous, purulent and biliary fluid samples were collected during routine drainage procedures. In a first setup, the apparent kinematic viscosity of 50 fluid samples was measured using an Ubbelohde viscometer. In a second setup, the apparent dynamic viscosity of 20 fluid samples obtained during CT-guided percutaneous drainage was measured using an in-house designed capillary extrusion experiment. The median apparent kinematic viscosity was 0.96 mm
2 /s (IQR 0.90-1.15 mm2 /s) for serous samples, 0.98 mm2 /s (IQR 0.97-0.99 mm2 /s) for purulent samples and 2.77 mm2 /s (IQR 1.75-3.70 mm2 /s) for biliary samples. The median apparent dynamic viscosity was 1.63 mPa*s (IQR 1.27-2.09 mPa*s) for serous samples, 2.45 mPa*s (IQR 1.69-3.22 mPa*s) for purulent samples and 3.50 mPa*s (IQR 2.81-3.90 mPa*s) for biliary samples (all differences p < 0.01). Relative to water, dynamic viscosities were increased by a factor of 1.36 for serous fluids, 2.26 for purulent fluids, and 4.03 for biliary fluids. Serous fluids have apparent viscosities similar to water, but biliary and purulent fluids are more viscous. These data can be used as a reference when selecting the drainage catheter size, with 8F catheters being appropriate for most percutaneous drainage cases., (© 2023. The Author(s).)- Published
- 2023
- Full Text
- View/download PDF
24. Cytomegalovirus cyclin-dependent kinase ortholog vCDK/pUL97 undergoes regulatory interaction with human cyclin H and CDK7 to codetermine viral replication efficiency.
- Author
-
Schütz M, Wangen C, Sommerer M, Kögler M, Eickhoff J, Degenhart C, Klebl B, Naing Z, Egilmezer E, Hamilton ST, Rawlinson WD, Sticht H, and Marschall M
- Subjects
- Humans, Antiviral Agents, Cyclin H, Phosphorylation, Cyclin-Dependent Kinases genetics, Cytomegalovirus genetics
- Abstract
Human cytomegalovirus (HCMV) infection is shaped by a tightly regulated interplay between viral and cellular proteins. Distinct kinase activities, such as the viral cyclin-dependent kinase ortholog (vCDK) pUL97 and cellular CDK7 are both crucial for efficient viral replication. Previously, we reported that both kinases, vCDK/pUL97 and CDK7, interact with cyclin H, thereby achieving an enhanced level of kinase activity and overall functionality in viral replication. Here we provide a variety of novel results, as generated on a methodologically extended basis, and present a concept for the codetermination of viral replication efficiency through these kinase activities: (i) cyclin H expression, in various human cell types, is substantially upregulated by strains of HCMV including the clinically relevant HCMV Merlin; (ii) vCDK/pUL97 interacts with human cyclin H in both HCMV-infected and plasmid-transfected cell systems; (iii) a doxycycline-inducible shRNA-dependent knock-down (KD) of cyclin H significantly reduces pUL97 activity (qSox in vitro kinase assay); (iv) accordingly, pUL97 in vitro kinase activity is seen significantly increased upon addition of recombinant cyclin H; (v) as a point of specific importance, human CDK7 activity shows an increase by vCDK/pUL97-mediated trans-stimulation (whereas pUL97 is not stimulated by CDK7); (vi) phosphosite-specific antibodies indicate an upregulated CDK7 phosphorylation upon HCMV infection, as mediated through a pUL97-specific modulatory effect (i.e. shown by pUL97 inhibitor treatment or pUL97-deficient viral mutant); (vii) finally, an efficient KD of cyclin H in primary fibroblasts generally results in an impaired HCMV replication efficiency as measured on protein and genomic levels. These results show evidence for the codetermination of viral replication by vCDK/pUL97, cyclin H and CDK7, thus supporting the specific importance of cyclin H as a central regulatory factor, and suggesting novel targeting options for antiviral drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)
- Published
- 2023
- Full Text
- View/download PDF
25. Photochemically generated reactive sites at ruthenium/gallium complexes: catalysis vs . cluster growth.
- Author
-
Bühler R, Muhr M, Stephan J, Wolf RA, Schütz M, Gemel C, and Fischer RA
- Abstract
Irradiation of [Ru(GaCp*)
3 (SiEt3 )H3 ] (1) at 350 nm induces reductive elimination of dihydrogen and triethylsilane and generates unsaturated Ru/Ga species. This photochemically induced cascading reductive elimination processes generate the reactive intermediate [Ru(GaCp*)3 ], which can be trapped by diphosphine coordination to yield the stable complex [(dppe)Ru(GaCp*)3 ] (4). The photochemically generated RuGa3 species is catalytically active in the hydrogenation of alkynes, which is further investigated by1 H NMR and mass spectrometry. Formation of intermetallic Ru/Ga clusters is observed as a competing and for the catalytic activity of the species limiting side reaction.- Published
- 2023
- Full Text
- View/download PDF
26. Metal-Metal Bonding in Late Transition-Metal [M 2 L 5 ] Complexes: Exploring the Limits of the Isolobal Analogy between the CO and AlCp* Ligands.
- Author
-
Hornung J, Muhr M, Schütz M, Heiß P, Stephan J, Jandl C, Gemel C, Kahlal S, Saillard JY, and Fischer RA
- Abstract
Late dinuclear transition-metal (especially group 10 and 11) homoleptic carbonyl complexes are elusive species and have so far not been isolated. A typical example is the 30-electron species [Ni
2 (CO)5 ], the structure and bonding of which is still debated. We show that, by using the AlCp* ligand (isolobal to CO), it is possible to isolate and fully characterize [Ni2 (AlCp*)5 ] ( 1 ), which inspired us to revisit by DFT calculations, the bonding situation within [Ni2 L5 ] (L = CO, AlCp*) and other isoelectronic species. The short Ni-Ni X-ray distance in 1 (2.270 Å) should not be attributed to the existence of a typical localized triple-bond between the metals, but rather to a strong through-bond interaction involving the three bridging ligands via their donating lone pairs and accepting π* orbitals. In contrast, in the isostructural 32-electron [Au2 (AlCp*)5 ] ( 2 ) cluster an orbital with M-M antibonding and Al...Al bonding character is occupied, which is in accordance with the particularly long Au-Au distance (3.856 Å) and rather short Al...Al contacts between the bridging ligands (2.843 Å). This work shows that, unlike late transition-metal [M2 (CO)x ] species, stable [M2 (AlCp*)x ] complexes can be isolated, owing to the subtle differences between CO and AlCp*. We propose a similar approach for rationalizing the bonding in the emblematic 34 electron species [Fe2 (CO)9 ].- Published
- 2023
- Full Text
- View/download PDF
27. Ethicizing history. Bioethical representations of Nazi medicine.
- Author
-
Schütz M and Braswell H
- Subjects
- Humans, History, 20th Century, Human Experimentation, Bioethical Issues, Germany, National Socialism, Bioethics
- Abstract
The article presents and analyzes different approaches of U.S. bioethicists in comprehending the Nazi medical crimes after 1945. The account is divided into two sections: one dealing with discussions on research ethics and the Nuremberg Code up until the 1970s and the other ranging from the 1970s to the present and highlighting bioethics' engagement with Nazi analogies. The portrayal of different bioethical scholars, institutions, and documents-most notably Henry K. Beecher, Jay Katz, the Belmont Report, the Hastings Center, Arthur L. Caplan, and Robert M. Veatch-provides a nuanced interpretation of the motives that bioethicists held and the strategies that they applied to establish an understanding of the Nazi medical crimes and their relation to contemporary bioethical issues. In this, the different approaches shared a common goal: To integrate the Nazi medical crimes into an ethical framework by means of selective acknowledgments and representation of their history., (© 2023 The Authors. Bioethics published by John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
28. Von Gierke Disease (Glycogen Storage Disease Type I) and Life-Threatening Abdominal Aortic Aneurysm: A Case Report of an Extremely Rare Condition.
- Author
-
Pitoulias AG, Bakr NA, Kazemtash M, Dahi F, Schütz M, and Donas KP
- Abstract
Von Gierke disease, also known as glycogen storage disease type I, co-existent with an abdominal aortic aneurysm (AAA), is an extremely rare combination of diseases that requires challenging therapeutic measures. We present, for the first time in literature, the case of a 62-year-old female with von Gierke disease who required open surgical repair of an AAA with challenging neck anatomy outside of instructions for use of endovascular repair. Even though the surgical risks for life-threatening complications, such as pancreatitis, metabolic acidosis, and kidney failure, were high, the 6-month postoperative course was uneventful. Despite the invasiveness of the treatment, surgery to treat the AAA was safe and effective. Further data is needed to draw robust conclusions about the treatment of choice for those patients with diseases in co-existence with AAAs.
- Published
- 2023
- Full Text
- View/download PDF
29. Reward processing in adolescents with social phobia and depression.
- Author
-
Luckhardt C, Mühlherr AM, Schütz M, Jarczok TA, Jungmann SM, Howland V, Veit L, Althen H, and Freitag CM
- Subjects
- Humans, Adolescent, Electroencephalography, Depression, Evoked Potentials physiology, Reward, Depressive Disorder, Major, Phobia, Social
- Abstract
Objective: Impaired reward processing has been found in individuals with anxiety, but also major depressive disorder (MDD). Here, we studied neural correlates of reward anticipation and processing in a sample of youth with severe social phobia and comorbid depression (SP/MDD) and investigated the specific contribution of SP and MDD symptoms., Methods: 15 affected, unmedicated and 25 typically developing (TD) youth completed a monetary gambling task, which included a positive, negative and ambiguous reward condition. Event-related potentials representing cue processing (cue P300), reward anticipation (stimulus preceding negativity, SPN), reward sensitivity (feedback related negativity, FRN) and reward processing (reward P300) were analysed., Results: Reduced amplitudes of the right hemispheric (r)SPN and reward P300 were observed in SP/MDD compared to TD. Within the SP/MDD group SP symptoms correlated with larger rSPN, and FRN amplitudes. MDD symptoms correlated with smaller rSPN and smaller FRN positive-negative difference wave., Conclusions: Reward anticipation and feedback processing are reduced in SP/MDD. Higher SP symptoms are associated with stronger neural activation during reward anticipation and reward sensitivity. Depressive symptoms are associated with decreased reward anticipation and sensitivity. Findings are in line with the theory of heightened vigilance in anxiety and blunted reward processing due to anhedonia in MDD., Significance: The study results can inform behavioural interventions for SP and MDD., Competing Interests: Conflict of interest There are no conflicts of interest for any of the authors., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
30. Intention Attribution in Children and Adolescents with Autism Spectrum Disorder: An EEG Study.
- Author
-
Schütz M, Boxhoorn S, Mühlherr AM, Mössinger H, Freitag CM, and Luckhardt C
- Subjects
- Humans, Child, Adolescent, Intention, Social Perception, Electroencephalography methods, Autism Spectrum Disorder
- Abstract
The ability to infer intentions from observed behavior and predict actions based on this inference, known as intention attribution (IA), has been hypothesized to be impaired in individuals with autism spectrum disorder (ASD). The underlying neural processes, however, have not been conclusively determined. The aim of this study was to examine the neural signature of IA in children and adolescents with ASD, and to elucidate potential links to contextual updating processes using electroencephalography. Results did not indicate that IA or early contextual updating was impaired in ASD. However, there was evidence of aberrant processing of expectation violations in ASD, particularly if the expectation was based on IA. Results are discussed within the context of impaired predictive coding in ASD., (© 2021. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
31. YgfB increases β-lactam resistance in Pseudomonas aeruginosa by counteracting AlpA-mediated ampDh3 expression.
- Author
-
Eggers O, Renschler FA, Michalek LA, Wackler N, Walter E, Smollich F, Klein K, Sonnabend MS, Egle V, Angelov A, Engesser C, Borisova M, Mayer C, Schütz M, and Bohn E
- Subjects
- Ciprofloxacin pharmacology, beta-Lactams pharmacology, Pseudomonas aeruginosa genetics, beta-Lactam Resistance genetics
- Abstract
YgfB-mediated β-lactam resistance was recently identified in multi drug resistant Pseudomonas aeruginosa. We show that YgfB upregulates expression of the β-lactamase AmpC by repressing the function of the regulator of the programmed cell death pathway AlpA. In response to DNA damage, the antiterminator AlpA induces expression of the alpBCDE autolysis genes and of the peptidoglycan amidase AmpDh3. YgfB interacts with AlpA and represses the ampDh3 expression. Thus, YgfB indirectly prevents AmpDh3 from reducing the levels of cell wall-derived 1,6-anhydro-N-acetylmuramyl-peptides, required to induce the transcriptional activator AmpR in promoting the ampC expression and β-lactam resistance. Ciprofloxacin-mediated DNA damage induces AlpA-dependent production of AmpDh3 as previously shown, which should reduce β-lactam resistance. YgfB, however, counteracts the β-lactam enhancing activity of ciprofloxacin by repressing ampDh3 expression and lowering the benefits of this drug combination. Altogether, YgfB represents an additional player in the complex regulatory network of AmpC regulation., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
32. The effect of perceptual expectation on processing gain, attention and the perceptual decision bias in children and adolescents with Autism Spectrum Disorder (ASD).
- Author
-
Boxhoorn S, Schütz M, Mühlherr AM, Mössinger H, Luckhardt C, and Freitag CM
- Subjects
- Humans, Adolescent, Child, Orientation physiology, Attention physiology, Reaction Time physiology, Motivation, Autism Spectrum Disorder
- Abstract
Perceptual expectations influence perception, attention and the perceptual decision bias during visuospatial orienting, which is impaired in individuals with Autism Spectrum Disorder (ASD). In this study, we investigated whether during visuospatial orienting, perceptual expectations in ASD differentially influence perception, attention and the perceptual decision bias relative to neurotypical controls (NT). Twenty-three children and adolescents with ASD and 23 NT completed a visuospatial orienting task, which compared the effect of a valid relative to an invalid perceptual expectation on target detection (cue validity effect). Group differences were calculated regarding the cue validity effect on neural correlates of processing gain (N1a amplitude) and attention (N1pc amplitude), the perceptual decision bias and mean reaction time (RT). In ASD relative to NT, findings showed a reduced processing gain for validly relative to invalidly cued targets and increased attentional response following invalidly relative to validly cued targets. Increased attention correlated with faster performance across groups. Increased processing correlated with a higher perceptual decision bias and faster mean RT in NT, but not in ASD. Results suggest that during visuospatial orienting, perceptual expectations in ASD may drive changes in sensory processing and stimulus-driven attention, which may differentially guide behavioural responses., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
33. 'Shared-Hook' and 'Changed-Hook' Binding Activities of Herpesviral Core Nuclear Egress Complexes Identified by Random Mutagenesis.
- Author
-
Lösing J, Häge S, Schütz M, Wagner S, Wardin J, Sticht H, and Marschall M
- Subjects
- Humans, Herpesvirus 4, Human, Cytomegalovirus, Cell Nucleus metabolism, Simplexvirus, Mutagenesis, Epstein-Barr Virus Infections
- Abstract
Herpesviruses replicate their genomes and assemble their capsids in the host cell nucleus. To progress towards morphogenesis in the cytoplasm, herpesviruses evolved the strategy of nuclear egress as a highly regulated process of nucleo-cytoplasmic capsid transition. The process is conserved among α-, β- and γ-herpesviruses and involves the formation of a core and multicomponent nuclear egress complex (NEC). Core NEC is assembled by the interaction between the nucleoplasmic hook protein, i.e., pUL53 (human cytomegalovirus, HCMV), and the integral membrane-associated groove protein, i.e., pUL50. Our study aimed at the question of whether a panherpesviral NEC scaffold may enable hook-into-groove interaction across herpesviral subfamilies. For this purpose, NEC constructs were generated for members of all three subfamilies and analyzed for multi-ligand interaction using a yeast two-hybrid (Y2H) approach with randomized pUL53 mutagenesis libraries. The screening identified ten library clones displaying cross-viral shared hook-into-groove interaction. Interestingly, a slightly modified Y2H screening strategy provided thirteen further changed-hook pUL53 clones having lost parental pUL50 interaction but gained homolog interaction. In addition, we designed a sequence-predicted hybrid construct based on HCMV and Epstein-Barr virus (EBV) core NEC proteins and identified a cross-viral interaction phenotype. Confirmation was provided by applying protein-protein interaction analyses in human cells, such as coimmunoprecipitation settings, confocal nuclear rim colocalization assays, and HCMV ΔUL53 infection experiments with pUL53-complementing cells. Combined, the study provided the first examples of cross-viral NEC interaction patterns and revealed a higher yield of human cell-confirmed binding clones using a library exchange rate of 3.4 than 2.7. Thus, the study provides improved insights into herpesviral NEC protein binding specificities of core NEC formation. This novel information might be exploited to gain a potential target scaffold for the development of broadly acting NEC-directed inhibitory small molecules.
- Published
- 2022
- Full Text
- View/download PDF
34. An Unprecedented Tolerance to Deletion of the Periplasmic Chaperones SurA, Skp, and DegP in the Nosocomial Pathogen Acinetobacter baumannii.
- Author
-
Birkle K, Renschler F, Angelov A, Wilharm G, Franz-Wachtel M, Maček B, Bohn E, Weber E, Müller J, Friedrich L, and Schütz M
- Subjects
- Humans, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents metabolism, Cross Infection microbiology, DNA-Binding Proteins metabolism, Escherichia coli genetics, Escherichia coli metabolism, Hospitals, Molecular Chaperones genetics, Molecular Chaperones metabolism, Periplasm metabolism, Protein Folding, SEC Translocation Channels metabolism, Virulence Factors metabolism, Yersinia enterocolitica, Pseudomonas aeruginosa, Drug Resistance, Multiple, Bacterial, Acinetobacter baumannii genetics, Acinetobacter baumannii metabolism, Bacterial Outer Membrane Proteins genetics, Bacterial Outer Membrane Proteins metabolism, Disinfectants
- Abstract
The outer membrane (OM) of Gram-negative bacteria efficiently protects from harmful environmental stresses such as antibiotics, disinfectants, or dryness. The main constituents of the OM are integral OM β-barrel proteins (OMPs). In Gram-negative bacteria such as Escherichia coli, Yersinia enterocolitica, and Pseudomonas aeruginosa, the insertion of OMPs depends on a sophisticated biogenesis pathway. This comprises the SecYEG translocon, which enables inner membrane (IM) passage; the chaperones SurA, Skp, and DegP, which facilitate the passage of β-barrel OMPs through the periplasm; and the β-barrel assembly machinery (BAM), which facilitates insertion into the OM. In E. coli, Y. enterocolitica, and P. aeruginosa, the deletion of SurA is particularly detrimental and leads to a loss of OM integrity, sensitization to antibiotic treatment, and reduced virulence. In search of targets that could be exploited to develop compounds that interfere with OM integrity in Acinetobacter baumannii, we employed the multidrug-resistant strain AB5075 to generate single gene knockout strains lacking individual periplasmic chaperones. In contrast to E. coli, Y. enterocolitica, and P. aeruginosa, AB5075 tolerates the lack of SurA, Skp, or DegP with only weak mutant phenotypes. While the double knockout strains Δ surA Δ skp and Δ surA Δ degP are conditionally lethal in E. coli, all double deletions were well tolerated by AB5075. Strikingly, even a triple-knockout strain of AB5075, lacking surA , skp , and degP , was viable. IMPORTANCE Acinetobacter baumannii is a major threat to human health due to its ability to persist in the hospital environment, resistance to antibiotic treatment, and ability to deploy multiple and redundant virulence factors. In a rising number of cases, infections with multidrug-resistant A. baumannii end up fatally, because all antibiotic treatment options fail. Thus, novel targets have to be identified and alternative therapeutics have to be developed. The knockout of periplasmic chaperones has previously proven to significantly reduce virulence and even break antibiotic resistance in other Gram-negative pathogens. Our study in A. baumannii demonstrates how variable the importance of the periplasmic chaperones SurA, Skp, and DegP can be and suggests the existence of mechanisms allowing A. baumannii to cope with the lack of the three periplasmic chaperones.
- Published
- 2022
- Full Text
- View/download PDF
35. Recombinant Human Cytomegalovirus Expressing an Analog-Sensitive Kinase pUL97 as Novel Tool for Functional Analyses.
- Author
-
Krämer N, Schütz M, Mato UG, Herhaus L, Marschall M, and Zimmermann C
- Subjects
- Humans, Phosphotransferases (Alcohol Group Acceptor) genetics, Phosphotransferases (Alcohol Group Acceptor) metabolism, Virus Replication, Adenosine Triphosphate metabolism, Phosphorylation, Cytomegalovirus physiology, DNA, Viral metabolism
- Abstract
The human cytomegalovirus (HCMV) is a member of the beta-herpesvirus family and inflicts life-long latent infections in its hosts. HCMV has been shown to manipulate and dysregulate many cellular processes. One major interactor with the cellular host is the viral kinase pUL97. The UL97 gene is essential for viral replication, and kinase-deficient mutants of pUL97 display a severe replication defect. Recently, another group established an analog-sensitive version of the pUL97 protein. This mutant kinase can be treated with a non-hydrolysable ATP analog, thereby inhibiting its kinase function. This process is reversible by removing the ATP analog by media change. We introduced this mutant version of the pUL97 protein into the laboratory strain Ad169 of HCMV, BADwt, creating a BAD-UL97-as1 viral mutant. This mutant virus replicated normally in infected cells in the absence of the ATP analog and maintained its ability to phosphorylate its cellular substrates. However, when treated with the ATP analog, BAD-UL97-as1 displayed a defect in the production of intra- and extracellular viral DNA and in the production of viral progeny. Furthermore, in the presence of 3MB-PP1, a well-established substrate of pUL97 was no longer hyperphosphorylated. This effect was detectable as early as 4 h post treatment, which allows for studies on pUL97 without the complication of low viral titers. Nevertheless, we observed off-target effects of 3MB-PP1 on several cellular processes, which should be considered with this approach.
- Published
- 2022
- Full Text
- View/download PDF
36. Highly Conserved Interaction Profiles between Clinically Relevant Mutants of the Cytomegalovirus CDK-like Kinase pUL97 and Human Cyclins: Functional Significance of Cyclin H.
- Author
-
Schütz M, Müller R, Socher E, Wangen C, Full F, Wyler E, Wong D, Scherer M, Stamminger T, Chou S, Rawlinson WD, Hamilton ST, Sticht H, and Marschall M
- Subjects
- Amino Acids metabolism, Cyclin T genetics, Cyclin T metabolism, Cyclin-Dependent Kinases genetics, Cyclin-Dependent Kinases metabolism, Genetic Markers, Humans, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor) metabolism, Virus Replication genetics, Cyclin H genetics, Cyclin H metabolism, Cytomegalovirus physiology, Viral Proteins genetics
- Abstract
The complex host interaction network of human cytomegalovirus (HCMV) involves the regulatory protein kinase pUL97, which represents a viral cyclin-dependent kinase (CDK) ortholog. pUL97 interacts with the three human cyclin types T1, H, and B1, whereby the binding region of cyclin T1 and the pUL97 oligomerization region were both assigned to amino acids 231-280. We further addressed the question of whether HCMVs harboring mutations in ORF-UL97, i.e., short deletions or resistance-conferring point mutations, are affected in the interaction with human cyclins and viral replication. To this end, clinically relevant UL97 drug-resistance-conferring mutants were analyzed by whole-genome sequencing and used for genetic marker transfer experiments. The recombinant HCMVs indicated conservation of pUL97-cyclin interaction, since all viral UL97 point mutants continued to interact with the analyzed cyclin types and exerted wild-type-like replication fitness. In comparison, recombinant HCMVs UL97 Δ231-280 and also the smaller deletion Δ236-275, but not Δ241-270, lost interaction with cyclins T1 and H, showed impaired replication efficiency, and also exhibited reduced kinase activity. Moreover, a cellular knock-out of cyclins B1 or T1 did not alter HCMV replication phenotypes or pUL97 kinase activity, possibly indicating alternative, compensatory pUL97-cyclin interactions. In contrast, however, cyclin H knock-out, similar to virus deletion mutants in the pUL97-cyclin H binding region, exhibited strong defective phenotypes of HCMV replication, as supported by reduced pUL97 kinase activity in a cyclin H-dependent coexpression setting. Thus, cyclin H proved to be a very relevant determinant of pUL97 kinase activity and viral replication efficiency. As a conclusion, the results provide evidence for the functional importance of pUL97-cyclin interaction. High selective pressure on the formation of pUL97-cyclin complexes was identified by the use of clinically relevant mutants.
- Published
- 2022
- Full Text
- View/download PDF
37. Evolutionary history of grazing and resources determine herbivore exclusion effects on plant diversity.
- Author
-
Price JN, Sitters J, Ohlert T, Tognetti PM, Brown CS, Seabloom EW, Borer ET, Prober SM, Bakker ES, MacDougall AS, Yahdjian L, Gruner DS, Olde Venterink H, Barrio IC, Graff P, Bagchi S, Arnillas CA, Bakker JD, Blumenthal DM, Boughton EH, Brudvig LA, Bugalho MN, Cadotte MW, Caldeira MC, Dickman CR, Donohue I, Grégory S, Hautier Y, Jónsdóttir IS, Lannes LS, McCulley RL, Moore JL, Power SA, Risch AC, Schütz M, Standish R, Stevens CJ, Veen GF, Virtanen R, and Wardle GM
- Subjects
- Animals, Mammals, Plants, Soil, Biodiversity, Herbivory
- Abstract
Ecological models predict that the effects of mammalian herbivore exclusion on plant diversity depend on resource availability and plant exposure to ungulate grazing over evolutionary time. Using an experiment replicated in 57 grasslands on six continents, with contrasting evolutionary history of grazing, we tested how resources (mean annual precipitation and soil nutrients) determine herbivore exclusion effects on plant diversity, richness and evenness. Here we show that at sites with a long history of ungulate grazing, herbivore exclusion reduced plant diversity by reducing both richness and evenness and the responses of richness and diversity to herbivore exclusion decreased with mean annual precipitation. At sites with a short history of grazing, the effects of herbivore exclusion were not related to precipitation but differed for native and exotic plant richness. Thus, plant species' evolutionary history of grazing continues to shape the response of the world's grasslands to changing mammalian herbivory., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
- Full Text
- View/download PDF
38. Cation-π Interactions between a Noble Metal and a Polyfunctional Aromatic Ligand: Ag + (benzylamine).
- Author
-
Corinti D, Maccelli A, Chiavarino B, Schütz M, Bouchet A, Dopfer O, Crestoni ME, and Fornarini S
- Subjects
- Cations chemistry, Ligands, Spectrophotometry, Infrared methods, Benzylamines, Silver chemistry
- Abstract
The structure of an isolated Ag
+ (benzylamine) complex is investigated by infrared multiple photon dissociation (IRMPD) spectroscopy complemented with quantum chemical calculations of candidate geometries and their vibrational spectra, aiming to ascertain the role of competing cation-N and cation-π interactions potentially offered by the polyfunctional ligand. The IRMPD spectrum has been recorded in the 800-1800 cm-1 fingerprint range using the IR free electron laser beamline coupled with an FT-ICR mass spectrometer at the Centre Laser Infrarouge d'Orsay (CLIO). The resulting IRMPD pattern points toward a chelate coordination (N-Ag+ -π) involving both the amino nitrogen atom and the aromatic π-system of the phenyl ring. The gas-phase reactivity of Ag+ (benzylamine) with a neutral molecular ligand (L) possessing either an amino/aza functionality or an aryl group confirms N- and π-binding affinity and suggests an augmented silver coordination in the product adduct ion Ag + ( benzylamine ) ( L ) ., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)- Published
- 2022
- Full Text
- View/download PDF
39. Nutrients and herbivores impact grassland stability across spatial scales through different pathways.
- Author
-
Chen Q, Wang S, Seabloom EW, MacDougall AS, Borer ET, Bakker JD, Donohue I, Knops JMH, Morgan JW, Carroll O, Crawley M, Bugalho MN, Power SA, Eskelinen A, Virtanen R, Risch AC, Schütz M, Stevens C, Caldeira MC, Bagchi S, Alberti J, and Hautier Y
- Subjects
- Biodiversity, Ecosystem, Nutrients, Grassland, Herbivory
- Abstract
Nutrients and herbivores are well-known drivers of grassland diversity and stability in local communities. However, whether they interact to impact the stability of aboveground biomass and whether these effects depend on spatial scales remain unknown. It is also unclear whether nutrients and herbivores impact stability via different facets of plant diversity including species richness, evenness, and changes in community composition through time and space. We used a replicated experiment adding nutrients and excluding herbivores for 5 years in 34 global grasslands to explore these questions. We found that both nutrient addition and herbivore exclusion alone reduced stability at the larger spatial scale (aggregated local communities; gamma stability), but through different pathways. Nutrient addition reduced gamma stability primarily by increasing changes in local community composition over time, which was mainly driven by species replacement. Herbivore exclusion reduced gamma stability primarily by decreasing asynchronous dynamics among local communities (spatial asynchrony). Their interaction weakly increased gamma stability by increasing spatial asynchrony. Our findings indicate that disentangling the processes operating at different spatial scales may improve conservation and management aiming at maintaining the ability of ecosystems to reliably provide functions and services for humanity., (© 2022 John Wiley & Sons Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
40. Global Grassland Diazotrophic Communities Are Structured by Combined Abiotic, Biotic, and Spatial Distance Factors but Resilient to Fertilization.
- Author
-
Nepel M, Angel R, Borer ET, Frey B, MacDougall AS, McCulley RL, Risch AC, Schütz M, Seabloom EW, and Woebken D
- Abstract
Grassland ecosystems cover around 37% of the ice-free land surface on Earth and have critical socioeconomic importance globally. As in many terrestrial ecosystems, biological dinitrogen (N
2 ) fixation represents an essential natural source of nitrogen (N). The ability to fix atmospheric N2 is limited to diazotrophs, a diverse guild of bacteria and archaea. To elucidate the abiotic (climatic, edaphic), biotic (vegetation), and spatial factors that govern diazotrophic community composition in global grassland soils, amplicon sequencing of the dinitrogenase reductase gene- nifH -was performed on samples from a replicated standardized nutrient [N, phosphorus (P)] addition experiment in 23 grassland sites spanning four continents. Sites harbored distinct and diverse diazotrophic communities, with most of reads assigned to diazotrophic taxa within the Alphaproteobacteria (e.g., Rhizobiales ), Cyanobacteria (e.g., Nostocales ), and Deltaproteobacteria (e.g., Desulforomonadales ) groups. Likely because of the wide range of climatic and edaphic conditions and spatial distance among sampling sites, only a few of the taxa were present at all sites. The best model describing the variation among soil diazotrophic communities at the OTU level combined climate seasonality (temperature in the wettest quarter and precipitation in the warmest quarter) with edaphic (C:N ratio, soil texture) and vegetation factors (various perennial plant covers). Additionally, spatial variables (geographic distance) correlated with diazotrophic community variation, suggesting an interplay of environmental variables and spatial distance. The diazotrophic communities appeared to be resilient to elevated nutrient levels, as 2-4 years of chronic N and P additions had little effect on the community composition. However, it remains to be seen, whether changes in the community composition occur after exposure to long-term, chronic fertilization regimes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nepel, Angel, Borer, Frey, MacDougall, McCulley, Risch, Schütz, Seabloom and Woebken.)- Published
- 2022
- Full Text
- View/download PDF
41. Cyclin-Dependent Kinases (CDKs) and the Human Cytomegalovirus-Encoded CDK Ortholog pUL97 Represent Highly Attractive Targets for Synergistic Drug Combinations.
- Author
-
Wild M, Hahn F, Brückner N, Schütz M, Wangen C, Wagner S, Sommerer M, Strobl S, and Marschall M
- Subjects
- Drug Combinations, Drug Resistance, Viral, Humans, Viral Proteins metabolism, Virus Replication, Cyclin-Dependent Kinases metabolism, Cytomegalovirus genetics
- Abstract
Human cytomegalovirus (HCMV) is a pathogenic human herpesvirus associated with serious, potentially life-threatening symptoms in the immunocompromised or immunonaïve host. The limitations encountered by antiviral therapy options currently available include a narrow panel of accessible targets, the induction of viral drug resistance as well as severe drug dosage-mediated side-effects. Improved drug-targeting strategies to resolve these issues are the focus of our investigations. In particular, pharmaceutical kinase inhibitors (PKIs), either directed to host kinases or directed to the viral protein kinase pUL97, have been considered to overcome these restrictions. Recently, we reported the identification of a synergistic combination of two PKIs directed to host cyclin-dependent kinase 7 (CDK7) and viral CDK ortholog pUL97. Here, we substantiate these findings with the following results: (i) true drug synergy was exhibited by various chemical classes of PKI pairs directed to pUL97 and CDK7; (ii) no putative amplification of cytotoxicity by these drug combinations was observed; (iii) a reduction in drug dosage levels for synergistic combinations was defined on a quantitative basis and compared to monotreatments; (iv) the quantities of target proteins CDK7 and pUL97 expressed in HCMV-infected cells were assessed by confocal imaging, indicating a strong down-modulation of CDK7 levels as a result of synergistic drug treatment; (v) the functional importance of these target kinases, both binding to cyclin H, was illustrated by assessing HCMV replication under the viral genomic deletion of ORF-UL97 or cellular cyclin knock-out; (vi) new combinations of HCMV-specific drug synergy were demonstrated for solely host-directed treatments using PKIs against CDK2, CDK7, CDK8 and/or CDK9 and (vii) a triple PKI combination provided further support for the synergy approach. With these combined findings, this study highlights the potential of therapeutic drug combinations of approved, developmental and preclinical PKIs for expanding future options for anti-HCMV therapy.
- Published
- 2022
- Full Text
- View/download PDF
42. The Trimeric Autotransporter Adhesin YadA of Yersinia enterocolitica Serotype O:9 Binds Glycan Moieties.
- Author
-
Meuskens I, Leva-Bueno J, Millner P, Schütz M, Peyman SA, and Linke D
- Abstract
Yersinia adhesin A (YadA) is a key virulence factor of Yersinia enterocolitica and Yersinia pseudotuberculosis . YadA is a trimeric autotransporter adhesin, a class of adhesins that have been shown to enable many Gram-negative pathogens to adhere to/interact with the host extracellular matrix proteins such as collagen, vitronectin, and fibronectin. Here, we show for the first time that YadA of Yersinia enterocolitica serotype O:9 not only interacts with proteinaceous surface molecules but can also attach directly to glycan moieties. We show that YadA from Y. enterocolitica serotype O:9 does not interact with the vitronectin protein itself but exclusively with its N-linked glycans. We also show that YadA can target other glycan moieties as found in heparin, for example. So far, little is known about specific interactions between bacterial autotransporter adhesins and glycans. This could potentially lead to new antimicrobial treatment strategies, as well as diagnostic applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Meuskens, Leva-Bueno, Millner, Schütz, Peyman and Linke.)
- Published
- 2022
- Full Text
- View/download PDF
43. [Case report: phlegmasia cerulea dolens of the upper extremities in severe COVID-19 infection].
- Author
-
Kazemtash M, Abu Bakr N, Bechtold C, Kriegsmann P, Schütz M, and Donas K
- Published
- 2022
- Full Text
- View/download PDF
44. Antiviral Strategies Using Natural Source-Derived Sulfated Polysaccharides in the Light of the COVID-19 Pandemic and Major Human Pathogenic Viruses.
- Author
-
Ray B, Ali I, Jana S, Mukherjee S, Pal S, Ray S, Schütz M, and Marschall M
- Subjects
- Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Biological Products chemical synthesis, Biological Products chemistry, Heparin chemical synthesis, Heparin chemistry, Heparin pharmacology, Humans, Polysaccharides chemistry, SARS-CoV-2 drug effects, Structure-Activity Relationship, Sulfates chemistry, Sulfates pharmacology, Virus Diseases drug therapy, Virus Internalization drug effects, Viruses pathogenicity, COVID-19 Drug Treatment, Antiviral Agents pharmacology, Biological Products pharmacology, COVID-19 epidemiology, Polysaccharides pharmacology, Viruses drug effects
- Abstract
Only a mere fraction of the huge variety of human pathogenic viruses can be targeted by the currently available spectrum of antiviral drugs. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has highlighted the urgent need for molecules that can be deployed quickly to treat novel, developing or re-emerging viral infections. Sulfated polysaccharides are found on the surfaces of both the susceptible host cells and the majority of human viruses, and thus can play an important role during viral infection. Such polysaccharides widely occurring in natural sources, specifically those converted into sulfated varieties, have already proved to possess a high level and sometimes also broad-spectrum antiviral activity. This antiviral potency can be determined through multifold molecular pathways, which in many cases have low profiles of cytotoxicity. Consequently, several new polysaccharide-derived drugs are currently being investigated in clinical settings. We reviewed the present status of research on sulfated polysaccharide-based antiviral agents, their structural characteristics, structure-activity relationships, and the potential of clinical application. Furthermore, the molecular mechanisms of sulfated polysaccharides involved in viral infection or in antiviral activity, respectively, are discussed, together with a focus on the emerging methodology contributing to polysaccharide-based drug development.
- Published
- 2021
- Full Text
- View/download PDF
45. Soil properties as key predictors of global grassland production: Have we overlooked micronutrients?
- Author
-
Radujković D, Verbruggen E, Seabloom EW, Bahn M, Biederman LA, Borer ET, Boughton EH, Catford JA, Campioli M, Donohue I, Ebeling A, Eskelinen A, Fay PA, Hansart A, Knops JMH, MacDougall AS, Ohlert T, Olde Venterink H, Raynaud X, Risch AC, Roscher C, Schütz M, Silveira ML, Stevens CJ, Van Sundert K, Virtanen R, Wardle GM, Wragg PD, and Vicca S
- Subjects
- Biomass, Carbon, Ecosystem, Micronutrients, Nitrogen analysis, Grassland, Soil
- Abstract
Fertilisation experiments have demonstrated that nutrient availability is a key determinant of biomass production and carbon sequestration in grasslands. However, the influence of nutrients in explaining spatial variation in grassland biomass production has rarely been assessed. Using a global dataset comprising 72 sites on six continents, we investigated which of 16 soil factors that shape nutrient availability associate most strongly with variation in grassland aboveground biomass. Climate and N deposition were also considered. Based on theory-driven structural equation modelling, we found that soil micronutrients (particularly Zn and Fe) were important predictors of biomass and, together with soil physicochemical properties and C:N, they explained more unique variation (32%) than climate and N deposition (24%). However, the association between micronutrients and biomass was absent in grasslands limited by NP. These results highlight soil properties as key predictors of global grassland biomass production and point to serial co-limitation by NP and micronutrients., (© 2021 John Wiley & Sons Ltd.)
- Published
- 2021
- Full Text
- View/download PDF
46. Species loss due to nutrient addition increases with spatial scale in global grasslands.
- Author
-
Seabloom EW, Batzer E, Chase JM, Stanley Harpole W, Adler PB, Bagchi S, Bakker JD, Barrio IC, Biederman L, Boughton EH, Bugalho MN, Caldeira MC, Catford JA, Daleo P, Eisenhauer N, Eskelinen A, Haider S, Hallett LM, Svala Jónsdóttir I, Kimmel K, Kuhlman M, MacDougall A, Molina CD, Moore JL, Morgan JW, Muthukrishnan R, Ohlert T, Risch AC, Roscher C, Schütz M, Sonnier G, Tognetti PM, Virtanen R, Wilfahrt PA, and Borer ET
- Subjects
- Ecosystem, Herbivory, Nutrients, Biodiversity, Grassland
- Abstract
The effects of altered nutrient supplies and herbivore density on species diversity vary with spatial scale, because coexistence mechanisms are scale dependent. This scale dependence may alter the shape of the species-area relationship (SAR), which can be described by changes in species richness (S) as a power function of the sample area (A): S = cA
z , where c and z are constants. We analysed the effects of experimental manipulations of nutrient supply and herbivore density on species richness across a range of scales (0.01-75 m2 ) at 30 grasslands in 10 countries. We found that nutrient addition reduced the number of species that could co-occur locally, indicated by the SAR intercepts (log c), but did not affect the SAR slopes (z). As a result, proportional species loss due to nutrient enrichment was largely unchanged across sampling scales, whereas total species loss increased over threefold across our range of sampling scales., (© 2021 John Wiley & Sons Ltd.)- Published
- 2021
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.