| 1. |
- Boekel, Jorrit, et al.
(författare)
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Comparative tissue transcriptomics reveal prompt inter-organ communication in response to local bacterial kidney infection
- 2011
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 12, s. 123-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mucosal infections elicit inflammatory responses via regulated signaling pathways. Infection outcome depends strongly on early events occurring immediately when bacteria start interacting with cells in the mucosal membrane. Hitherto reported transcription profiles on host-pathogen interactions are strongly biased towards in vitro studies. To detail the local in vivo genetic response to infection, we here profiled host gene expression in a recent experimental model that assures high spatial and temporal control of uropathogenic Escherichia coli (UPEC) infection within the kidney of a live rat. Results: Transcriptional profiling of tissue biopsies from UPEC-infected kidney tissue revealed 59 differentially expressed genes 8 h post-infection. Their relevance for the infection process was supported by a Gene Ontology (GO) analysis. Early differential expression at 3 h and 5 h post-infection was of low statistical significance, which correlated to the low degree of infection. Comparative transcriptomics analysis of the 8 h data set and online available studies of early local infection and inflammation defined a core of 80 genes constituting a "General tissue response to early local bacterial infections". Among these, 25% were annotated as interferon-gamma (IFN-gamma) regulated. Subsequent experimental analyses confirmed a systemic increase of IFN-gamma in rats with an ongoing local kidney infection, correlating to splenic, rather than renal Ifng induction and suggested this inter-organ communication to be mediated by interleukin (IL)-23. The use of comparative transcriptomics allowed expansion of the statistical data handling, whereby relevant data could also be extracted from the 5 h data set. Out of the 31 differentially expressed core genes, some represented specific 5 h responses, illustrating the value of comparative transcriptomics when studying the dynamic nature of gene regulation in response to infections. Conclusion: Our hypothesis-free approach identified components of infection-associated multi-cellular tissue responses and demonstrated how a comparative analysis allows retrieval of relevant information from lower-quality data sets. The data further define marked representation of IFN-gamma responsive genes and a prompt inter-organ communication as a hallmark of an early local tissue response to infection.
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| 2. |
- Boekel, Jorrit, et al.
(författare)
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Multi-omic data analysis using Galaxy
- 2015
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Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 33:2, s. 137-9
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Boekel, Jorrit
(författare)
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Tissue responses and host transcriptomics in bacterial infections
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bacterial infections can damage host tissue and are as such a potential threat to their hosts. To protect themselves from pathogens, hosts therefore can employ diverse immune reactions. When bacteria are recognized by their hosts, complex signaling cascades are triggered that lead to an influx of specialized immune cells into the infected tissue and a change in tissue integrity. The inflammation that is mounted may eliminate the pathogens, but will also cause substantial tissue damage. The foundation for the inflammatory process is laid early, in the first 12 hours of infection. This thesis aims to reveal host responses within this early time frame. While in vitro studies can yield highly detailed data on subjects as protein-protein and cell-bacterial interactions, they cannot reproduce all aspects that occur in a live animal, such as immune infiltration, nerve, and hormone effects. We have developed a kidney infection model of bacterial infection to study early whole-host responses to bacteria. Using micropuncture techniques, we delivered bacteria to a known nephron, from where the infection progressed. Within hours, we observed numerous physiological changes of the tissue volume bordering the infection. Infection kinetics could be visualized and showed markedly faster host responses to haemolysin (Hlγ)-carrying bacteria compared to Hlγ-knockouts. Tissue oxygen levels decreased in response to infection, possibly caused both by blood ow restriction combined with epithelial oxygen consumption. Blood ow shutdown at the infected nephron was due to activation of the coagulation cascade. Coagulation also protected against sepsis, as animals died due to bacteremia when this cascade was inhibited. Some of these phenomena could be found in the host transcriptome. We also found that a core of common gene expression exists in live host innate immune responses by applying bioinformatic methods on the gene expression measurements. This core had a strong IFN-γ signature, a cytokine which we consequently found increased in the blood stream, and expressed by cells in the spleen. We go on to show that IFN-γ downregulates transcription of several neutrophil-attracting chemokines, and that this does not occur through canonical effectors of either IFN-γ or inflammatory signaling pathways. The data I present here show that using a live host infection model can reveal host processes that cannot be found using in vitro models. By combining this model with analysis methods that yield detailed data, early responses could be studied. The data show the importance of live models for discovering unknown contributors and functions in inflammation, which may lead to possible future medicine development.
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| 4. |
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| 5. |
- Grüning, Björn, et al.
(författare)
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Bioconda: A sustainable and comprehensive software distribution for the life sciences
- 2017
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We present Bioconda (https://bioconda.github.io), a distribution of bioinformatics software for the lightweight, multi-platform and language-agnostic package manager Conda. Currently, Bioconda offers a collection of over 3000 software packages, which is continuously maintained, updated, and extended by a growing global community of more than 200 contributors. Bioconda improves analysis reproducibility by allowing users to define isolated environments with defined software versions, all of which are easily installed and managed without administrative privileges.
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| 6. |
- Hessa, Tara, et al.
(författare)
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Recognition of transmembrane helices by the endoplasmic reticulum translocon
- 2005
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 433:7024, s. 377-381
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Tidskriftsartikel (refereegranskat)abstract
- Membrane proteins depend on complex translocation machineries for insertion into target membranes. Although it has long been known that an abundance of nonpolar residues in transmembrane helices is the principal criterion for membrane insertion, the specific sequence-coding for transmembrane helices has not been identified. By challenging the endoplasmic reticulum Sec61 translocon with an extensive set of designed polypeptide segments, we have determined the basic features of this code, including a 'biological' hydrophobicity scale. We find that membrane insertion depends strongly on the position of polar residues within transmembrane segments, adding a new dimension to the problem of predicting transmembrane helices from amino acid sequences. Our results indicate that direct protein - lipid interactions are critical during translocon-mediated membrane insertion.
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| 7. |
- Johansson, Henrik J., et al.
(författare)
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Breast cancer quantitative proteome and proteogenomic landscape
- 2019
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.
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| 8. |
- Pernemalm, Maria, et al.
(författare)
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In-depth human plasma proteome analysis captures tissue proteins and transfer of protein variants across the placenta
- 2019
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Ingår i: eLIFE. - : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Here, we present a method for in-depth human plasma proteome analysis based on high-resolution isoelectric focusing HiRIEF LC-MS/MS, demonstrating high proteome coverage, reproducibility and the potential for liquid biopsy protein profiling. By integrating genomic sequence information to the MS-based plasma proteome analysis, we enable detection of single amino acid variants and for the first time demonstrate transfer of multiple protein variants between mother and fetus across the placenta. We further show that our method has the ability to detect both low abundance tissue-annotated proteins and phosphorylated proteins in plasma, as well as quantitate differences in plasma proteomes between the mother and the newborn as well as changes related to pregnancy.
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| 9. |
- Zhu, Yafeng, et al.
(författare)
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Discovery of coding regions in the human genome by integrated proteogenomics analysis workflow
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Proteogenomics enable the discovery of novel peptides (from unannotated genomic protein-coding loci) and single amino acid variant peptides (derived from single-nucleotide polymorphisms and mutations). Increasing the reliability of these identifications is crucial to ensure their usefulness for genome annotation and potential application as neoantigens in cancer immunotherapy. We here present integrated proteogenomics analysis workflow (IPAW), which combines peptide discovery, curation, and validation. IPAW includes the SpectrumAI tool for automated inspection of MS/MS spectra, eliminating false identifications of single-residue substitution peptides. We employ IPAW to analyze two proteomics data sets acquired from A431 cells and five normal human tissues using extended (pH range, 3-10) high-resolution isoelectric focusing (HiRIEF) pre-fractionation and TMT-based peptide quantitation. The IPAW results provide evidence for the translation of pseudogenes, lncRNAs, short ORFs, alternative ORFs, N-terminal extensions, and intronic sequences. Moreover, our quantitative analysis indicates that protein production from certain pseudogenes and lncRNAs is tissue specific.
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