Project description:In screening for novel antibiotics, an attractive element of novelty can be represented by screening previously underexplored groups of microorganisms. We report the results of screening 200 strains belonging to the actinobacterial genus Actinoallomurus for their production of antibacterial compounds. When grown under just one condition, about half of the strains produced an extract that was able to inhibit growth of Staphylococcus aureus. We report here on the metabolites produced by 37 strains. In addition to previously reported aminocoumarins, lantibiotics and aromatic polyketides, we described two novel and structurally unrelated polyethers, designated α-770 and α-823. While we identified only one producer strain of the former polyether, 10 independent Actinoallomurus isolates were found to produce α-823, with the same molecule as main congener. Remarkably, production of α-823 was associated with a common lineage within Actinoallomurus, which includes A.fulvus and A.amamiensis. All polyether producers were isolated from soil samples collected in tropical parts of the world.
Project description:Background: Ependymomas encompass multiple, clinically relevant tumor types based on localization and molecular profiles. Although tumors of the methylation class “spinal ependymoma” (SP-EPN) represent the most common intramedullary neoplasms in children and adults, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical meaning have been described in a large, epigenetically defined series. Methods: We mapped SP-EPN transcriptomes (n=76) to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. In addition, transcriptomic, epigenetic (n=234), genetic (n=140), and clinical analyses (n=115) were integrated for a detailed overview on this entity. Results: Integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord identified mature adult ependymal cells to display highest similarities to SP-EPN. Unsupervised hierarchical clustering of tumor data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype 1 predominantly contained NF2 wild type sequences with regular NF2 expression but revealed more extensive copy number alterations. Subtype 2 harbored previously known germline or sporadic NF2 mutations and was NF2-deficient in most cases, more often showed multilocular disease, and demonstrated a significantly reduced progression-free survival. Conclusion: Based on integrated molecular profiling of a large tumor series we identify two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.
Project description:Background: Ependymomas encompass multiple, clinically relevant tumor types based on localization and molecular profiles. Although tumors of the methylation class “spinal ependymoma” (SP-EPN) represent the most common intramedullary neoplasms in children and adults, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical meaning have been described in a large, epigenetically defined series. Methods: We mapped SP-EPN transcriptomes (n=76) to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. In addition, transcriptomic, epigenetic (n=234), genetic (n=140), and clinical analyses (n=115) were integrated for a detailed overview on this entity. Results: Integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord identified mature adult ependymal cells to display highest similarities to SP-EPN. Unsupervised hierarchical clustering of tumor data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype 1 predominantly contained NF2 wild type sequences with regular NF2 expression but revealed more extensive copy number alterations. Subtype 2 harbored previously known germline or sporadic NF2 mutations and was NF2-deficient in most cases, more often showed multilocular disease, and demonstrated a significantly reduced progression-free survival. Conclusion: Based on integrated molecular profiling of a large tumor series we identify two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.
Project description:Background: Ependymomas encompass multiple, clinically relevant tumor types based on localization and molecular profiles. Although tumors of the methylation class “spinal ependymoma” (SP-EPN) represent the most common intramedullary neoplasms in children and adults, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical meaning have been described in a large, epigenetically defined series. Methods: We mapped SP-EPN transcriptomes (n=76) to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. In addition, transcriptomic, epigenetic (n=234), genetic (n=140), and clinical analyses (n=115) were integrated for a detailed overview on this entity. Results: Integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord identified mature adult ependymal cells to display highest similarities to SP-EPN. Unsupervised hierarchical clustering of tumor data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype 1 predominantly contained NF2 wild type sequences with regular NF2 expression but revealed more extensive copy number alterations. Subtype 2 harbored previously known germline or sporadic NF2 mutations and was NF2-deficient in most cases, more often showed multilocular disease, and demonstrated a significantly reduced progression-free survival. Conclusion: Based on integrated molecular profiling of a large tumor series we identify two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.
Project description:In the search for structurally novel metabolites with antibacterial activity, innovative approaches must be implemented to increase the probability of discovering novel chemistry from microbial sources. Here we report on the application of metabolomic tools to the genus Actinoallomurus, a poorly explored member of the Actinobacteria. From examining extracts derived from 88 isolates belonging to this genus, we identified a family of cyclodepsipeptides acylated with a C20 polyketide chain, which we named allopeptimicins. These molecules possess unusual structural features, including several double bonds in the amino-polyketide chain and four non-proteinogenic amino acids in the octapeptide. Remarkably, allopeptimicins are produced as a complex of active and inactive congeners, the latter carrying a sulfate group on the polyketide amine. This modification is also a mechanism of self-protection in the producer strain. The structural uniqueness of allopeptimicins is reflected in a biosynthetic gene cluster showing a mosaic structure, with dedicated gene cassettes devoted to formation of specialized precursors and modular assembly lines related to those from different pathways.
Project description:BACKGROUND: Human SP-A1 and SP-A2, encoded by SFTPA1 and SFTPA2 and their genetic variants differentially impact alveolar macrophage (AM) functions and regulation, including the miRNome. We investigated whether miRNome differences previously observed between AM from SP-A2 and SP-A1/SP-A2 mice are due to continued qualitative differences or a delayed response of mice carrying a single gene. METHODS: Human transgenic (hTG) mice, carrying SP-A2 or both SP-A genes and SP-A-KO mice were exposed to filtered air (FA) or O3. AM miRNA levels, target gene expression and pathways determined 18 h after O3 exposure. RESULTS: We found: (a) Differences in miRNome due to sex, SP-A genotype, and exposure; (b) miRNome of both sexes was largely downregulated by O3 ; co-ex had fewer changed (≥2X) miRNAs than either group. (c) the number and direction of expression of genes with significant changes in males and females in co-ex is almost the opposite of those in SP-A2; (iv) The same pathways were found in the studied groups; (e) O3 exposure attenuated sex differences; a higher number of genotype-dependent and genotype-independent miRNAs was common in both sexes after O3 exposure. CONCLUSION: Qualitative differences between SP-A2 and co-ex persist 18 h post-O3, and O3 attenuates sex differences.