19 research outputs found
Two novel, complementary next generation sequencing approaches to reveal the dorso-ventral gene regulatory network of Tribolium castaneum
No full textSynthetic optimization of cystobactamids as broad-spectrum antibiotics
No full textBacterial resistance is omnipresent and expected to be a future problem as warned by the World Health Organization (WHO) reports and guidelines since 2014,[1-3] Centers for Disease Control and Prevention (CDC)[4] and European Centre of Disease Prevention and Control (ECDC)[5]. Novel scaffolds for broad-spectrum antibiotics that can displace β-lactams and quinolones are rare and their development is slow,[6] although a variety of compounds with antibacterial properties is known from nature.[7] With the cystobactamids, a highly promising antibiotic compound class was found and comprehensively expanded towards an applicable medication.[8-11] In this Thesis, the currently known library of cystobactamids was synthetically extended and the in vitro efficacy of the novel analogues was determined against various bacteria, including the highly relevant ESKAPE pathogens. Based on the current cystobactamid CN-CC 861 as lead-scaffold,[11] several new CDE-fragments were synthesized. Various highly
substituted aromatic systems were synthetically accessed and implemented as ring D derivatives. These methods embrace metal-mediated aromatic functionalization, and heterocyclization among others. The cystobactamid assembly protocols were improved and simplified and applied to several new derivatives. An updated general SAR of ring D was derived by evaluating the activity test results of all new compounds. Thereby, both replacement of the hydroxy group and a rigidification between ring D and E proved difficult. Analysis of the activity against ESKAPE pathogens led to new insights into the
effects of these modifications, based on which future cystobactamid analogues were targeted. A reversed amide bond between ring C and D proved to be highly advantageous here in terms of broad-spectrum activity. Novel CDE-fragments were combined with Western-fragments of the lead compound, as well as of current front-running cystobactamids. The latter included benzimidazoles, bicyclo[1.1.1]pentane and pyridin as substructures, resp. isosteres for benzene.
The two most active compounds in this Thesis were part of a preclinical in vivo ADME study and will be included in follow-up trials. Besides, serine as central amino acid was found to be well tolerated and represents a more polar alternative for the central alkyl amino acid which probably has a positive effect on solubility.
[1] Antimicrobial resistance: global report on surveillance, World Health Organization, 2014
[2] No time to wait: securing the future from drug-resistant infections, World Health Organization, 2019
[3] Global priority list of antibioticresistant bacteria to guide research, discovery, and development of new antibiotics, World Health Organization, 2017
[4] Antibiotic resistance threats in the United States, 2013, Centers for Disease Control and Prevention, Office of Infectious Disease., 2013
[5] Antimicrobial resistance surveillance in Europe; 2023 - 2021 data, European Centre for Disease Prevention and Control (ECDC) and World Health Organization (WHO), 2023
[6] H. W. Boucher, G. H. Talbot, J. S. Bradley, J. E. Edwards, D. Gilbert, L. B. Rice, M. Scheld, B. Spellberg, J. Bartlett, Clin. Infect. Dis. 2009, 48, 1-12.
[7] M. Miethke, M. Pieroni, T. Weber, M. Brönstrup, P. Hammann, L. Halby, P. B. Arimondo, P. Glaser, B. Aigle, H. B. Bode, R. Moreira, Y. Li, A. Luzhetskyy, M. H. Medema, J.-L. Pernodet, M. Stadler, J. R. Tormo, O. Genilloud, A. W. Truman, K. J. Weissman, E. Takano, S. Sabatini, E. Stegmann, H. Brötz-Oesterhelt, W. Wohlleben, M. Seemann, M. Empting, A. K. H. Hirsch, B. Loretz, C.-M. Lehr, A. Titz, J. Herrmann, T. Jaeger, S. Alt, T. Hesterkamp, M. Winterhalter, A. Schiefer, K. Pfarr, A. Hoerauf, H. Graz, M. Graz, M. Lindvall, S. Ramurthy, A. Karlén, M. van Dongen, H. Petkovic, A. Keller, F. Peyrane, S. Donadio, L. Fraisse, L. J. V. Piddock, I. H. Gilbert, H. E. Moser, R. Müller, Nat. Rev. Chem. 2021, 5, 726-749.
[8] S. Baumann, J. Herrmann, R. Raju, H. Steinmetz, K. I. Mohr, S. Hüttel, K. Harmrolfs, M. Stadler, R. Müller, Angew. Chem., Int. Ed. 2014, 53, 14605-14609.
[9] G. Testolin, K. Cirnski, K. Rox, H. Prochnow, V. Fetz, C. Grandclaudon, T. Mollner, A. Baiyoumy, A. Ritter, C. Leitner, J. Krull, J. van den Heuvel, A. Vassort, S. Sordello, M. M. Hamed, W. A. M. Elgaher, J. Herrmann, R. W. Hartmann, R. Müller, M. Brönstrup, Chem. Sci. 2020, 11, 1316-1334.
[10] T. Seedorf, Doctoral thesis, LUH 2023.
[11] D. Kohnhäuser, Doctoral thesis, LUH 2021
Patterning the dorsal–ventral axis of the wasp Nasonia vitripennis
No full textAbstractRegulatory networks composed of interacting genes are responsible for pattern formation and cell type specification in a wide variety of developmental contexts. Evolution must act on these regulatory networks in order to change the proportions, distribution, and characteristics of specified cells. Thus, understanding how these networks operate in homologous systems across multiple levels of phylogenetic divergence is critical for understanding the evolution of developmental systems. Among the most thoroughly characterized regulatory networks is the dorsal–ventral patterning system of the fly Drosophila melanogaster. Due to the thorough understanding of this system, it is an ideal starting point for comparative analyses. Here we report an analysis of the DV patterning system of the wasp, Nasonia vitripennis. This wasp undergoes a mode of long germ embryogenesis that is superficially nearly identical to that of Drosophila, but one that was likely independently derived. We have found that while the expression of genes just prior to the onset of gastrulation is almost identical in Nasonia and Drosophila, both the upstream network responsible for generating this pattern, and the downstream morphogenetic movements that it sets in motion, are significantly diverged. From this we conclude that many network structures are available to evolution to achieve particular developmental ends
The Aurora space launcher concept
No full textThis paper gives an overview about the Aurora reusable space launcher concept study that was initiated in late-2015/early-
2016. Within the Aurora study, several spaceplane-like vehicle configurations with different geometries, propulsion systems
and mission profiles will be designed, investigated and evaluated with respect to their technical and economic feasibility.
The first part of this paper will discuss the study logic and the current status of the Aurora studies and introduces the first
vehicle configurations and their system design status. As the identification of highly efficient structural designs is of particular
interest for Aurora, the structural design and analysis approach will be discussed in higher level of detail. A special
design feature of the Aurora vehicle configurations is the utilization of the novel thin-ply composite material technology for
structural mass reductions. Therefore, the second part of this paper will briefly discuss this technology and investigate the
application and potential mass savings on vehicle level within simplified structural analysis studies. The results indicate that
significant mass savings could be possible. Finally, an outlook on the next steps is provided
Reciprocal Regulation between Bifunctional miR-9/9∗ and its Transcriptional Modulator Notch in Human Neural Stem Cell Self-Renewal and Differentiation
No full textSummaryTight regulation of the balance between self-renewal and differentiation of neural stem cells is crucial to assure proper neural development. In this context, Notch signaling is a well-known promoter of stemness. In contrast, the bifunctional brain-enriched microRNA miR-9/9∗ has been implicated in promoting neuronal differentiation. Therefore, we set out to explore the role of both regulators in human neural stem cells. We found that miR-9/9∗ decreases Notch activity by targeting NOTCH2 and HES1, resulting in an enhanced differentiation. Vice versa, expression levels of miR-9/9∗ depend on the activation status of Notch signaling. While Notch inhibits differentiation of neural stem cells, it also induces miR-9/9∗ via recruitment of the Notch intracellular domain (NICD)/RBPj transcriptional complex to the miR-9/9∗_2 genomic locus. Thus, our data reveal a mutual interaction between bifunctional miR-9/9∗ and the Notch signaling cascade, calibrating the delicate balance between self-renewal and differentiation of human neural stem cells
DataSheet1_Evolution of a New Testis-Specific Functional Promoter Within the Highly Conserved Map2k7 Gene of the Mouse.xlsx
No full textMap2k7 (synonym Mkk7) is a conserved regulatory kinase gene and a central component of the JNK signaling cascade with key functions during cellular differentiation. It shows complex transcription patterns, and different transcript isoforms are known in the mouse (Mus musculus). We have previously identified a newly evolved testis-specific transcript for the Map2k7 gene in the subspecies M. m. domesticus. Here, we identify the new promoter that drives this transcript and find that it codes for an open reading frame (ORF) of 50 amino acids. The new promoter was gained in the stem lineage of closely related mouse species but was secondarily lost in the subspecies M. m. musculus and M. m. castaneus. A single mutation can be correlated with its transcriptional activity in M. m. domesticus, and cell culture assays demonstrate the capability of this mutation to drive expression. A mouse knockout line in which the promoter region of the new transcript is deleted reveals a functional contribution of the newly evolved promoter to sperm motility and the spermatid transcriptome. Our data show that a new functional transcript (and possibly protein) can evolve within an otherwise highly conserved gene, supporting the notion of regulatory changes contributing to the emergence of evolutionary novelties.</p
DataSheet2_Evolution of a New Testis-Specific Functional Promoter Within the Highly Conserved Map2k7 Gene of the Mouse.docx
No full textMap2k7 (synonym Mkk7) is a conserved regulatory kinase gene and a central component of the JNK signaling cascade with key functions during cellular differentiation. It shows complex transcription patterns, and different transcript isoforms are known in the mouse (Mus musculus). We have previously identified a newly evolved testis-specific transcript for the Map2k7 gene in the subspecies M. m. domesticus. Here, we identify the new promoter that drives this transcript and find that it codes for an open reading frame (ORF) of 50 amino acids. The new promoter was gained in the stem lineage of closely related mouse species but was secondarily lost in the subspecies M. m. musculus and M. m. castaneus. A single mutation can be correlated with its transcriptional activity in M. m. domesticus, and cell culture assays demonstrate the capability of this mutation to drive expression. A mouse knockout line in which the promoter region of the new transcript is deleted reveals a functional contribution of the newly evolved promoter to sperm motility and the spermatid transcriptome. Our data show that a new functional transcript (and possibly protein) can evolve within an otherwise highly conserved gene, supporting the notion of regulatory changes contributing to the emergence of evolutionary novelties.</p
