| 1. |
- Montanuy, Helena, et al.
(författare)
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High content drug screening for Fanconi anemia therapeutics
- 2020
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fanconi anemia is a rare disease clinically characterized by malformations, bone marrow failure and an increased risk of solid tumors and hematologic malignancies. The only therapies available are hematopoietic stem cell transplantation for bone marrow failure or leukemia, and surgical resection for solid tumors. Therefore, there is still an urgent need for new therapeutic options. With this aim, we developed a novel high-content cell-based screening assay to identify drugs with therapeutic potential in FA.Results: A TALEN-mediated FANCA-deficient U2OS cell line was stably transfected with YFP-FANCD2 fusion protein. These cells were unable to form fluorescent foci or to monoubiquitinate endogenous or exogenous FANCD2 upon DNA damage and were more sensitive to mitomycin C when compared to the parental wild type counterpart. FANCA correction by retroviral infection restored the cell line's ability to form FANCD2 foci and ubiquitinate FANCD2. The feasibility of this cell-based system was interrogated in a high content screening of 3802 compounds, including a Prestwick library of 1200 FDA-approved drugs. The potential hits identified were then individually tested for their ability to rescue FANCD2 foci and monoubiquitination, and chromosomal stability in the absence ofFANCA.Conclusions: While, unfortunately, none of the compounds tested were able to restore cellular FANCA-deficiency, our study shows the potential capacity to screen large compound libraries in the context of Fanconi anemia therapeutics in an optimized and cost-effective platform.
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| 2. |
- Guillén, Yolanda, et al.
(författare)
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Genomics of ecological adaptation in cactophilic Drosophila.
- 2014
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Ingår i: Genome Biology and Evolution. - : Oxford University Press (OUP). - 1759-6653. ; 7:1, s. 349-66
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Tidskriftsartikel (refereegranskat)abstract
- Cactophilic Drosophila species provide a valuable model to study gene-environment interactions and ecological adaptation. Drosophila buzzatii and Drosophila mojavensis are two cactophilic species that belong to the repleta group, but have very different geographical distributions and primary host plants. To investigate the genomic basis of ecological adaptation, we sequenced the genome and developmental transcriptome of D. buzzatii and compared its gene content with that of D. mojavensis and two other noncactophilic Drosophila species in the same subgenus. The newly sequenced D. buzzatii genome (161.5 Mb) comprises 826 scaffolds (>3 kb) and contains 13,657 annotated protein-coding genes. Using RNA sequencing data of five life-stages we found expression of 15,026 genes, 80% protein-coding genes, and 20% noncoding RNA genes. In total, we detected 1,294 genes putatively under positive selection. Interestingly, among genes under positive selection in the D. mojavensis lineage, there is an excess of genes involved in metabolism of heterocyclic compounds that are abundant in Stenocereus cacti and toxic to nonresident Drosophila species. We found 117 orphan genes in the shared D. buzzatii-D. mojavensis lineage. In addition, gene duplication analysis identified lineage-specific expanded families with functional annotations associated with proteolysis, zinc ion binding, chitin binding, sensory perception, ethanol tolerance, immunity, physiology, and reproduction. In summary, we identified genetic signatures of adaptation in the shared D. buzzatii-D. mojavensis lineage, and in the two separate D. buzzatii and D. mojavensis lineages. Many of the novel lineage-specific genomic features are promising candidates for explaining the adaptation of these species to their distinct ecological niches.
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| 3. |
- Laurie, Steven, et al.
(författare)
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The RD-Connect Genome-Phenome Analysis Platform : Accelerating diagnosis, research, and gene discovery for rare diseases
- 2022
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Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 43:6, s. 717-733
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Tidskriftsartikel (refereegranskat)abstract
- Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes.
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| 4. |
- Gaedcke, Jochen, et al.
(författare)
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The Rectal Cancer microRNAome - microRNA Expression in Rectal Cancer and Matched Normal Mucosa.
- 2012
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 18:18, s. 4919-4930
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: miRNAs play a prominent role in a variety of physiologic and pathologic biologic processes, including cancer. For rectal cancers, only limited data are available on miRNA expression profiles, whereas the underlying genomic and transcriptomic aberrations have been firmly established. We therefore, aimed to comprehensively map the miRNA expression patterns of this disease. EXPERIMENTAL DESIGN: Tumor biopsies and corresponding matched mucosa samples were prospectively collected from 57 patients with locally advanced rectal cancers. Total RNA was extracted, and tumor and mucosa miRNA expression profiles were subsequently established for all patients. The expression of selected miRNAs was validated using semi-quantitative real-time PCR. RESULTS: Forty-nine miRNAs were significantly differentially expressed (log(2)-fold difference >0.5 and P < 0.001) between rectal cancer and normal rectal mucosa. The predicted targets for these miRNAs were enriched for the following pathways: Wnt, TGF-beta, mTOR, insulin, mitogen-activated protein kinase, and ErbB signaling. Thirteen of these 49 miRNAs seem to be rectal cancer-specific, and have not been previously reported for colon cancers: miR-492, miR-542-5p, miR-584, miR-483-5p, miR-144, miR-2110, miR-652, miR-375, miR-147b, miR-148a, miR-190, miR-26a/b, and miR-338-3p. Of clinical impact, miR-135b expression correlated significantly with disease-free and cancer-specific survival in an independent multicenter cohort of 116 patients. CONCLUSION: This comprehensive analysis of the rectal cancer miRNAome uncovered novel miRNAs and pathways associated with rectal cancer. This information contributes to a detailed view of this disease. Moreover, the identification and validation of miR-135b may help to identify novel molecular targets and pathways for therapeutic exploitation. Clin Cancer Res; 1-12. ©2012 AACR.
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| 5. |
- Khaliq, Muhammad Waqas, et al.
(författare)
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GHz sample excitation at the ALBA-PEEM
- 2023
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Ingår i: Ultramicroscopy. - 0304-3991. ; 250
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Tidskriftsartikel (refereegranskat)abstract
- We describe a setup that is used for high-frequency electrical sample excitation in a cathode lens electron microscope with the sample stage at high voltage as used in many synchrotron light sources. Electrical signals are transmitted by dedicated high-frequency components to the printed circuit board supporting the sample. Sub-miniature push-on connectors (SMP) are used to realize the connection in the ultra-high vacuum chamber, bypassing the standard feedthrough. A bandwidth up to 4 GHz with -6 dB attenuation was measured at the sample position, which allows to apply sub-nanosecond pulses. We describe different electronic sample excitation schemes and demonstrate a spatial resolution of 56 nm employing the new setup.
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| 6. |
- Mendoza, Charmae Franchesca, et al.
(författare)
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Benchmarking the Cooperative Awareness Service at Application Layer with IEEE 802.11p and LTE-PC5 Mode-4
- 2021
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Ingår i: 2021 IEEE International Mediterranean Conference on Communications and Networking, MeditCom 2021. - : Institute of Electrical and Electronics Engineers (IEEE). ; , s. 389-394
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Konferensbidrag (refereegranskat)abstract
- Vehicular communications hold the promise of disrupting mobility services and supporting the mass adoption of future autonomous vehicles. Regulators have set aside specific spectrum at the 5.9 GHz band to support Intelligent Transport Systems (ITS) safety applications, for which a world-wide adoption of a standardized radio technology is a key factor to deliver on this promise. Two technologies are currently positioned to begin its commercial path, IEEE 802.11p and LTE-PC5 Mode-4. The main differences between these technologies lie on the design of their channel access mechanisms. This paper provides an analysis of the impact that the Medium Access Control (MAC) mechanisms included in 802.11p and LTE-PC5 Mode-4 will have on the performance of the applications using the Cooperative Awareness Service, applying two new application-level metrics used by safety applications: Neighborhood Awareness Ratio and Position Error. We have found that, even with an equivalent physical layer performance, the MAC layer of LTE-PC5 Mode-4 will mostly outperform the MAC layer of IEEE 802.11p (or its not yet ready enhanced version 802.11bd). However, IEEE 802.11p/bd results in slightly better vehicle positioning accuracy at lower distances.
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