lnu.sePublications
Change search
Refine search result
1 - 24 of 24
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Alneberg, Johannes
    et al.
    KTH Royal Institute of Technology.
    Sundh, John
    Stockholm University.
    Bennke, Christin
    Leibniz Inst Balt Sea Res Warnemunde, Germany.
    Beier, Sara
    Leibniz Inst Balt Sea Res Warnemunde, Germany.
    Lundin, Daniel
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Hugerth, Luisa W.
    KTH Royal Institute of Technology.
    Pinhassi, Jarone
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Kisand, Veljo
    Univ Tartu, Estonia. .
    Riemann, Lasse
    Univ Copenhagen, Denmark.
    Juergens, Klaus
    Leibniz Inst Balt Sea Res Warnemunde, Germany.
    Labrenz, Matthias
    Leibniz Inst Balt Sea Res Warnemunde, Germany.
    Andersson, Anders F.
    KTH Royal Institute of Technology.
    BARM and BalticMicrobeDB, a reference metagenome and interface to meta-omic data for the Baltic Sea2018In: Scientific Data, E-ISSN 2052-4463, Vol. 5, article id 180146Article in journal (Refereed)
    Abstract [en]

    The Baltic Sea is one of the world's largest brackish water bodies and is characterised by pronounced physicochemical gradients where microbes are the main biogeochemical catalysts. Meta-omic methods provide rich information on the composition of, and activities within, microbial ecosystems, but are computationally heavy to perform. We here present the Baltic Sea Reference Metagenome (BARM), complete with annotated genes to facilitate further studies with much less computational effort. The assembly is constructed using 2.6 billion metagenomic reads from 81 water samples, spanning both spatial and temporal dimensions, and contains 6.8 million genes that have been annotated for function and taxonomy. The assembly is useful as a reference, facilitating taxonomic and functional annotation of additional samples by simply mapping their reads against the assembly. This capability is demonstrated by the successful mapping and annotation of 24 external samples. In addition, we present a public web interface, BalticMicrobeDB, for interactive exploratory analysis of the dataset. [GRAPHICS] .

  • 2.
    Amnebrink, Dennis
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Transcriptomic profiling of marine bacteria between development and senescence phases of a phytoplankton bloom2018Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Bacterioplankton provide important ecosystem functions by carrying out biogeochemical cycling of organic matter. Playing an important role in the microbial loop they help remineralize carbon and nutrients. Bacteria also interact with phytoplankton during phytoplankton blooms. However, fundamental understanding on the underlying molecular mechanisms involved in the degradation of phytoplankton-derived organic matter is still in its infancy. Therefore, we analysed data from a mesocosm experiment following a natural phytoplankton-bloom from an upwelling system in the North- East Atlantic Ocean. The purpose was to contribute a mechanistic understanding based on functional gene expression analysis of natural microbial assemblages. Our results show the difference in functional gene expression within a bacterial metacommunity and how this functional response drastically switches between bloom build up and senescence. Transcripts showed a broad change in gene expression involving major SEED categories, with the bloom senescence phase exhibiting a higher relative abundance in major categories such as Carbohydrates, Protein Metabolism and Amino Acids and Derivatives. Within these categories genes connected to carbon utilization and transport systems (Ton and Tol) as well as chemotaxis showed a higher abundance during bloom senescence. The change in functionality based on transcripts showed a different bacterial community composition appearing over a very short time. We thus conclude that the bacterial functional gene expression response between build-up and degradation bloom phases is remarkably different and associated with a change in the identity of bacteria with active expression. Our findings highlight the importance of bacterial substrate specialists with different functional roles during different time points of phytoplankton blooms.

    Download full text (pdf)
    Master_arbete_DA
  • 3.
    Baichoo, Shakuntala
    et al.
    University of Mauritius, Mauritius.
    Botha, Gerrit
    University of Cape Town, South Africa.
    Jaufeerally-Fakim, Yasmina
    University of Mauritius, Mauritius.
    Mungloo-Dilmohamud, Zahra
    University of Mauritius, Mauritius.
    Lundin, Daniel
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. Stockholm University.
    Mulder, Nicola
    University of Cape Town, South Africa.
    Promponas, Vasilis J.
    University of Cyprus, Cyprus.
    Ouzounis, Christos A.
    Centre for Research & Technology (CERTH), Greece.
    H3ABioNet computational metagenomics workshop in Mauritius: training to analyse microbial diversity for Africa2015In: Standards in Genomic Sciences, ISSN 1944-3277, E-ISSN 1944-3277, Vol. 10, article id 115Article in journal (Refereed)
    Abstract [en]

    In the context of recent international initiatives to bolster genomics research for Africa, and more specifically to develop bioinformatics expertise and networks across the continent, a workshop on computational metagenomics was organized during the end of 2014 at the University of Mauritius. The workshop offered background on various aspects of computational biology, including databases and algorithms, sequence analysis fundamentals, metagenomics concepts and tools, practical exercises, journal club activities and research seminars. We have discovered a strong interest in metagenomics research across Africa, to advance practical applications both for human health and the environment. We have also realized the great potential to develop genomics and bioinformatics through collaborative efforts across the continent, and the need for further reinforcing the untapped human potential and exploring the natural resources for stronger engagement of local scientific communities, with a view to contributing towards the improvement of human health and well-being for the citizens of Africa.

    Download full text (pdf)
    fulltext
  • 4.
    Buetti-Dinh, Antoine
    USI, Switzerland .
    Gene Regulation by Numbers: Steady-State and Equilibrium Binding Applied to Gene Regulation Systems.2012Doctoral thesis, monograph (Other academic)
  • 5.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Dethlefsen, Olga
    Stockholm University.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Dopson, Mark
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Transcriptomic analysis reveals how a lack of potassium ions increases Sulfolobus acidocaldarius sensitivity to pH changes2016In: Microbiology, ISSN 1350-0872, E-ISSN 1465-2080, Vol. 162, no 8, p. 1422-1434Article in journal (Refereed)
    Abstract [en]

    Extremely acidophilic microorganisms (optimum growth pH of ≤3) maintain a near neutral cytoplasmic pH via several homeostatic mechanisms, including an inside positive membrane potential created by potassium ions. Transcriptomic responses to pH stress in the thermoacidophilic archaeon, Sulfolobus acidocaldarius were investigated by growing cells without added sodium and/or potassium ions at both optimal and sub-optimal pH. Culturing the cells in the absence of added sodium or potassium ions resulted in a reduced growth rate compared to full-salt conditions as well as 43 and 75 significantly different RNA transcript ratios, respectively. Differentially expressed RNA transcripts during growth in the absence of added sodium ions included genes coding for permeases, a sodium/proline transporter and electron transport proteins. In contrast, culturing without added potassium ions resulted in higher RNA transcripts for similar genes as a lack of sodium ions plus genes related to spermidine that has a general role in response to stress and a decarboxylase that potentially consumes protons. The greatest RNA transcript response occurred when S. acidocaldarius cells were grown in the absence of potassium and/or sodium at a sub-optimal pH. These adaptations included those listed above plus osmoregulated glucans and mechanosensitive channels that have previously been shown to respond to osmotic stress. In addition, data analyses revealed two co-expressed IclR family transcriptional regulator genes with a previously unknown role in the S. acidocaldarius pH stress response. Our study provides additional evidence towards the importance of potassium in acidophile growth at acidic pH.

  • 6.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Università della Svizzera Italiana, Italy;Swiss Institute of Bioinformatics, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Computer simulations of the signalling network in FLT3+-acute myeloid leukaemia: indications for an optimal dosage of inhibitors against FLT3 and CDK62018In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 19, p. 1-13, article id 155Article in journal (Refereed)
    Abstract [en]

    Background

    Mutations in the FMS-like tyrosine kinase 3 (FLT3) are associated with uncontrolled cellular functions that contribute to the development of acute myeloid leukaemia (AML). We performed computer simulations of the FLT3-dependent signalling network in order to study the pathways that are involved in AML development and resistance to targeted therapies.

    Results

    Analysis of the simulations revealed the presence of alternative pathways through phosphoinositide 3 kinase (PI3K) and SH2-containing sequence proteins (SHC), that could overcome inhibition of FLT3. Inhibition of cyclin dependent kinase 6 (CDK6), a related molecular target, was also tested in the simulation but was not found to yield sufficient benefits alone.

    Conclusions

    The PI3K pathway provided a basis for resistance to treatments. Alternative signalling pathways could not, however, restore cancer growth signals (proliferation and loss of apoptosis) to the same levels as prior to treatment, which may explain why FLT3 resistance mutations are the most common resistance mechanism. Finally, sensitivity analysis suggested the existence of optimal doses of FLT3 and CDK6 inhibitors in terms of efficacy and toxicity.

  • 7.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Università della Svizzera italiana, Switzerland;Swiss Institute of Bioinformatics, Switzerland.
    Herold, Malte
    University of Luxembourg, Luxembourg.
    Christel, Stephan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    El Hajjami, Mohamed
    QNLM, China.
    Delogu, Francesco
    Norwegian University of Life Sciences, Norway.
    Ilie, Olga
    Università della Svizzera italiana, Switzerland;Swiss Institute of Bioinformatics, Switzerland.
    Bellenberg, Sören
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Wilmes, Paul
    University of Luxembourg, Luxembourg.
    Poetsch, Ansgar
    Ruhr University Bochum, Germany;QNLM, China;Ocean University of China, China.
    Sand, Wolfgang
    University Duisburg-Essen, Germany;Donghua University, China;3Mining Academy and Technical University Freiberg, Germany.
    Vera, Mario
    Pontificia Universidad Católica de Chile, Chile.
    Pivkin, Igor V.
    Università della Svizzera italiana, Switzerland;Swiss Institute of Bioinformatics, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Dopson, Mark
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Reverse engineering directed gene regulatory networks from transcriptomics and proteomics data of biomining bacterial communities with approximate Bayesian computation and steady-state signalling simulations2020In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 21, no 1, p. 1-15, article id 23Article in journal (Refereed)
    Abstract [en]

    Background: Network inference is an important aim of systems biology. It enables the transformation of OMICs datasets into biological knowledge. It consists of reverse engineering gene regulatory networks from OMICs data, such as RNAseq or mass spectrometry-based proteomics data, through computational methods. This approach allows to identify signalling pathways involved in specific biological functions. The ability to infer causality in gene regulatory networks, in addition to correlation, is crucial for several modelling approaches and allows targeted control in biotechnology applications. Methods: We performed simulations according to the approximate Bayesian computation method, where the core model consisted of a steady-state simulation algorithm used to study gene regulatory networks in systems for which a limited level of details is available. The simulations outcome was compared to experimentally measured transcriptomics and proteomics data through approximate Bayesian computation. Results: The structure of small gene regulatory networks responsible for the regulation of biological functions involved in biomining were inferred from multi OMICs data of mixed bacterial cultures. Several causal inter- and intraspecies interactions were inferred between genes coding for proteins involved in the biomining process, such as heavy metal transport, DNA damage, replication and repair, and membrane biogenesis. The method also provided indications for the role of several uncharacterized proteins by the inferred connection in their network context. Conclusions: The combination of fast algorithms with high-performance computing allowed the simulation of a multitude of gene regulatory networks and their comparison to experimentally measured OMICs data through approximate Bayesian computation, enabling the probabilistic inference of causality in gene regulatory networks of a multispecies bacterial system involved in biomining without need of single-cell or multiple perturbation experiments. This information can be used to influence biological functions and control specific processes in biotechnology applications.

  • 8.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Svizzera Italiana, Switzerland;Swiss Inst Bioinformat, Switzerland.
    Jensen, Rebecca
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Svizzera Italiana, Switzerland;Swiss Inst Bioinformat, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    A computational study of hedgehog signalling involved in basal cell carcinoma reveals the potential and limitation of combination therapy2018In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 18, no 1, p. 1-8, article id 569Article in journal (Refereed)
    Abstract [en]

    Background: The smoothened (SMO) receptor is an essential component of the Sonic hedgehog (SHH) signalling, which is associated with the development of skin basal cell carcinoma (BCC). SMO inhibitors are indicated for BCC patients when surgical treatment or radiation therapy are not possible. Unfortunately, SMO inhibitors are not always well tolerated due to severe side effects, and their therapeutical success is limited by resistance mutations. Methods: We investigated how common are resistance-causing mutations in two genomic databases which are not linked to BCC or other cancers, namely 1000 Genomes and ExAC. To examine the potential for combination therapy or other treatments, we further performed knowledge-based simulations of SHH signalling, in the presence or absence of SMO and PI3K/Akt inhibitors. Results: The database analysis revealed that of 18 known mutations associated with Vismodegib-resistance, three were identified in the databases. Treatment of individuals carrying such mutations is thus liable to fail a priori. Analysis of the simulations suggested that a combined inhibition of SMO and the PI3K/Akt signalling pathway may provide an effective reduction in tumour proliferation. However, the inhibition dosage of SMO and PI3K/Akt depended on the activity of phosphodiesterases (PDEs). Under high PDEs activities, SMO became the most important control node of the network. By applying PDEs inhibition, the control potential of SMO decreased and P13K appeared as a significant factor in controlling tumour proliferation. Conclusions: Our systems biology approach employs knowledge-based computer simulations to help interpret the large amount of data available in public databases, and provides application-oriented solutions for improved cancer resistance treatments.

  • 9.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Svizzera Italiana, Switzerland;Swiss Inst Bioinformat, Switzerland.
    O'Hare, Thomas
    Univ Utah, USA;Huntsman Canc Inst, USA.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, article id e0163011Article in journal (Refereed)
    Abstract [en]

    A large subset of anaplastic large cell lymphoma (ALCL) patients harbour a somatic aberration in which anaplastic lymphoma kinase (ALK) is fused to nucleophosmin (NPM) resulting in a constitutively active signalling fusion protein, NPM-ALK. We computationally simulated the signalling network which mediates pathological cell survival and proliferation through NPM-ALK to identify therapeutically targetable nodes through which it may be possible to regain control of the tumourigenic process. The simulations reveal the predominant role of the VAV1-CDC42 (cell division control protein 42) pathway in NPM-ALK-driven cellular proliferation and of the Ras / mitogen-activated ERK kinase (MEK) / extracellular signal-regulated kinase (ERK) cascade in controlling cell survival. Our results also highlight the importance of a group of interleukins together with the Janus kinase 3 (JAK3) / signal transducer and activator of transcription 3 (STAT3) signalling in the development of NPM-ALK derived ALCL. Depending on the activity of JAK3 and STAT3, the system may also be sensitive to activation of protein tyrosine phosphatase-1 (SHP1), which has an inhibitory effect on cell survival and proliferation. The identification of signalling pathways active in tumourigenic processes is of fundamental importance for effective therapies. The prediction of alternative pathways that circumvent classical therapeutic targets opens the way to preventive approaches for countering the emergence of cancer resistance.

  • 10.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Svizzera Italiana, Switzerland.
    Pivkin, Igor
    Univ Svizzera Italiana, Switzerland ;Swiss Inst Bioinformat, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    S100A4 and its role in metastasis – computational integration of data on biological networks2015In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 11, p. 2238-2246Article in journal (Refereed)
    Abstract [en]

    Characterising signal transduction networks is fundamental to our understanding of biology. However, redundancy and different types of feedback mechanisms make it difficult to understand how variations of the network components contribute to a biological process. In silico modelling of signalling interactions therefore becomes increasingly useful for the development of successful therapeutic approaches. Unfortunately, quantitative information cannot be obtained for all of the proteins or complexes that comprise the network, which limits the usability of computational models. We developed a flexible computational framework for the analysis of biological signalling networks. We demonstrate our approach by studying the mechanism of metastasis promotion by the S100A4 protein, and suggest therapeutic strategies. The advantage of the proposed method is that only limited information (interaction type between species) is required to set up a steady-state network model. This permits a straightforward integration of experimental information where the lack of details are compensated by efficient sampling of the parameter space. We investigated regulatory properties of the S100A4 network and the role of different key components. The results show that S100A4 enhances the activity of matrix metalloproteinases (MMPs), causing higher cell dissociation. Moreover, it leads to an increased stability of the pathological state. Thus, avoiding metastasis in S100A4-expressing tumours requires multiple target inhibition. Moreover, the analysis could explain the previous failure of MMP inhibitors in clinical trials. Finally, our method is applicable to a wide range of biological questions that can be represented as directional networks.

    Download full text (pdf)
    fulltext
    Download (pdf)
    Supplementary material
  • 11.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Svizzera Italiana, Switzerland.
    Pivkin, Igor V.
    Univ Svizzera Italiana, Switzerland ; Swiss Inst Bioinformat, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    S100A4 and its role in metastasis: simulations of knockout and amplification of epithelial growth factor receptor and matrix metalloproteinases2015In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 11, no 8, p. 2247-2254Article in journal (Refereed)
    Abstract [en]

    The calcium-binding signalling protein S100A4 enhances metastasis in a variety of cancers. Despite a wealth of data available, the molecular mechanism by which S100A4 drives metastasis is unknown. Integration of the current knowledge defies straightforward intuitive interpretation and requires computer-aided approaches to represent the complexity emerging from cross-regulating species. Here we carried out a systematic sensitivity analysis of the S100A4 signalling network in order to identify key control parameters for efficient therapeutic intervention. Our approach only requires limited details of the molecular interactions and permits a straightforward integration of the available experimental information. By integrating the available knowledge, we investigated the effects of combined inhibition of signalling pathways. Through selective knockout or inhibition of the network components, we show that the interaction between epidermal growth factor receptor (EGFR) and S100A4 modulates the sensitivity of angiogenesis development to matrix metalloproteinases (MMPs) activity. We also show that, in cells that express high EGFR, MMP inhibitors are not expected to be useful in tumours if high activity of S100A4 is present.

    Download full text (pdf)
    fulltext
    Download (pdf)
    Supplementary material
  • 12.
    Buetti-Dinh, Antoine
    et al.
    University of Zurich, Switzerland.
    Ungricht, Rosemarie
    University of Zurich, Switzerland.
    Kelemen, János Z.
    University of Zurich, Switzerland.
    Shetty, Chetak
    University of Zurich, Switzerland.
    Ratna, Prasuna
    University of Zurich, Switzerland.
    Becskei, Attila
    University of Zurich, Switzerland.
    Control and signal processing by transcriptional interference2009In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 5, p. Article ID: 300-Article in journal (Refereed)
    Abstract [en]

    A transcriptional activator can suppress gene expression by interfering with transcription initiated by another activator. Transcriptional interference has been increasingly recognized as a regulatory mechanism of gene expression. The signals received by the two antagonistically acting activators are combined by the polymerase trafficking along the DNA. We have designed a dual-control genetic system in yeast to explore this antagonism systematically. Antagonism by an upstream activator bears the hallmarks of competitive inhibition, whereas a downstream activator inhibits gene expression non-competitively. When gene expression is induced weakly, the antagonistic activator can have a positive effect and can even trigger paradoxical activation. Equilibrium and non-equilibrium models of transcription shed light on the mechanism by which interference converts signals, and reveals that self-antagonism of activators imitates the behavior of feed-forward loops. Indeed, a synthetic circuit generates a bell-shaped response, so that the induction of expression is limited to a narrow range of the input signal. The identification of conserved regulatory principles of interference will help to predict the transcriptional response of genes in their genomic context.

  • 13.
    Chavan, Swapnil
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Towards new computational tools for predicting toxicity2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The toxicological screening of the numerous chemicals that we are exposed to requires significant cost and the use of animals. Accordingly, more efficient methods for the evaluation of toxicity are required to reduce cost and the number of animals used. Computational strategies have the potential to reduce both the cost and the use of animal testing in toxicity screening. The ultimate goal of this thesis is to develop computational models for the prediction of toxicological endpoints that can serve as an alternative to animal testing. In Paper I, an attempt was made to construct a global quantitative structure-activity relationship (QSAR)model for the acute toxicity endpoint (LD50 values) using the Munro database that represents a broad chemical landscape. Such a model could be used for acute toxicity screening of chemicals of diverse structures. Paper II focuses on the use of acute toxicity data to support the prediction of chronic toxicity. The results of this study suggest that for related chemicals having acute toxicities within a similar range, their lowest observed effect levels (LOELs) can be used in read-across strategies to fill gaps in chronic toxicity data. In Paper III a k-nearest neighbor (k-NN) classification model was developed to predict human ether-a-go-go related gene (hERG)-derived toxicity. The results suggest that the model has potential for use in identifying compounds with hERG-liabilities, e.g. in drug development.

    Download full text (pdf)
    Swapnil Chavan, Doctoral Thesis (Kappa)
    Download (jpg)
    Front page
  • 14.
    Chieh, Hsu
    et al.
    University of Basel, Switzerland.
    Scherrer, S
    University of Basel, Switzerland.
    Buetti-Dinh, Antoine
    University of Basel, Switzerland.
    Ratna, P
    University of Basel, Switzerland.
    Pizzolato, J
    University of Basel, Switzerland.
    Jaquet, V
    University of Basel, Switzerland.
    Becskei, A
    University of Basel, Switzerland.
    Stochastic signalling rewires the interaction map of a multiple feedback network during yeast evolution.2012In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 3, p. Article ID: 682-Article in journal (Refereed)
    Abstract [en]

    During evolution, genetic networks are rewired through strengthening or weakening their interactions to develop new regulatory schemes. In the galactose network, the GAL1/GAL3paralogues and the GAL2 gene enhance their own expression mediated by the Gal4p transcriptional activator. The wiring strength in these feedback loops is set by the number of Gal4p binding sites. Here we show using synthetic circuits that multiplying the binding sites increases the expression of a gene under the direct control of an activator, but this enhancement is not fed back in the circuit. The feedback loops are rather activated by genes that have frequent stochastic bursts and fast RNA decay rates. In this way, rapid adaptation to galactose can be triggered even by weakly expressed genes. Our results indicate that nonlinear stochastic transcriptional responses enable feedback loops to function autonomously, or contrary to what is dictated by the strength of interactions enclosing the circuit.

  • 15.
    Friedman, Ran
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Boye, Kjetil
    Flatmark, Kjersti
    Molecular modelling and simulations in cancer research2013In: Biochimica et Biophysica Acta. CR. Reviews on Cancer, ISSN 0304-419X, E-ISSN 1879-2561, Vol. 1836, no 1, p. 1-14Article, review/survey (Refereed)
    Abstract [en]

    The complexity of cancer and the vast amount of experimental data available have made computer-aided approaches necessary. Biomolecular modelling techniques are becoming increasingly easier to use, whereas hardware and software are becoming better and cheaper. Cross-talk between theoretical and experimental scientists dealing with cancer-research from a molecular approach, however, is still uncommon. This is in contrast to other fields, such as amyloid-related diseases, where molecular modelling studies are widely acknowledged. The aim of this review paper is therefore to expose some of the more common approaches in molecular modelling to cancer scientists in simple terms, illustrating success stories while also revealing the limitations of computational studies at the molecular level.

    Download full text (pdf)
    fulltext
  • 16.
    Jusufi, Ilir
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Computer Science, Physics and Mathematics.
    Kerren, Andreas
    Linnaeus University, Faculty of Science and Engineering, School of Computer Science, Physics and Mathematics.
    Aleksakhin, Vladyslav
    Linnaeus University, Faculty of Science and Engineering, School of Computer Science, Physics and Mathematics.
    Schreiber, Falk
    Martin-Luther University.
    Visualization of Mappings between the Gene Ontology and Cluster Trees2012In: Proceedings of the SPIE 2012 Conference on Visualization and Data Analysis (VDA '12) / [ed] Pak Chung Wong, David L. Kao, Ming C. Hao, Chaomei Chen, Robert Kosara, Mark A. Livingston, Jinah Park, and Ian Roberts, SPIE - International Society for Optical Engineering, 2012Conference paper (Refereed)
    Abstract [en]

    Ontologies and hierarchical clustering are both important tools in biology and medicine to study high-throughput data such as transcriptomics and metabolomics data. Enrichment of ontology terms in the data is used to identify statistically overrepresented ontology terms, giving insight into relevant biological processes or functional modules. Hierarchical clustering is a standard method to analyze and visualize data to find relatively homogeneous clusters of experimental data points. Both methods support the analysis of the same data set, but are usually considered independently. However, often a combined view is desired: visualizing a large data set in the context of an ontology under consideration of a clustering of the data. This paper proposes a new visualization method for this task.

  • 17.
    Kerren, Andreas
    et al.
    Linnaeus University, Faculty of Technology, Department of Computer Science.
    Schreiber, Falk
    Martin Luther University .
    Network Visualization for Integrative Bioinformatics2014In: Approaches in Integrative Bioinformatics: Towards the Virtual Cell / [ed] Ming Chen and Ralf Hofestädt, Berlin Heidelberg: Springer, 2014, p. 173-202Chapter in book (Refereed)
    Abstract [en]

    Approaches to investigate biological processes have been of strong interest in the past few years and are the focus of several research areas like systems biology. Biological networks as representations of such processes are crucial for an extensive understanding of living beings. Due to their size and complexity, their growth and continuous change, as well as their compilation from databases on demand, researchers very often request novel network visualization, interaction and exploration techniques. In this chapter, we first provide background information that is needed for the interactive visual analysis of various biological networks. Fields such as (information) visualization, visual analytics and automatic layout of networks are highlighted and illustrated by a number of examples. Then, the state of the art in network visualization for the life sciences is presented together with a discussion of standards for the graphical representation of cellular networks and biological processes.

  • 18.
    Kerren, Andreas
    et al.
    Linnaeus University, Faculty of Technology, Department of Computer Science.
    Schreiber, Falk
    Monash Univ, Australia.
    Why Integrate InfoVis and SciVis?: An Example from Systems Biology2014In: IEEE Computer Graphics and Applications, ISSN 0272-1716, E-ISSN 1558-1756, Vol. 34, no 6, p. 69-73Article in journal (Other academic)
    Abstract [en]

    The more-or-less artificial barrier between information visualization and scientific visualization hinders knowledge discovery. Having an integrated view of many aspects of the target data, including a seamlessly interwoven visual display of structural abstract data and 3D spatial information, could lead to new discoveries, insights, and scientific questions. Such a view also could reduce the user’s cognitive load—that is, reduce the effort the user expends when comparing views.

  • 19.
    Lindström, Jonathan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    de Wijn, Astrid S.
    Norwegian University of Science and Technology, Norway.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Stochastic modelling of tyrosine kinase inhibitor rotation therapy in chronic myeloid leukaemia2019In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, p. 1-13, article id 508Article in journal (Refereed)
    Abstract [en]

    BackgroundResistance towards targeted cancer treatments caused by single nucleotide variations is a major issue in many malignancies. Currently, there are a number of available drugs for chronic myeloid leukaemia (CML), which are overcome by different sets of mutations. The main aim of this study was to explore if it can be possible to exploit this and create a treatment protocol that outperforms each drug on its own.MethodsWe present a computer program to test different treatment protocols against CML, based on available resistance mutation growth data. The evolution of a relatively stable pool of cancer stem cells is modelled as a stochastic process, with the growth of cells expressing a tumourigenic protein (here, Abl1) and any emerging mutants determined principally by the drugs used in the therapy.ResultsThere can be some benefit to Bosutinib-Ponatinib rotation therapy even if the mutation status is unknown, whereas Imatinib-Nilotinib rotation is unlikely to improve the outcomes. Furthermore, an interplay between growth inhibition and selection effects generates a non-linear relationship between drug doses and the risk of developing resistance.ConclusionsDrug rotation therapy might be able to delay the onset of resistance in CML patients without costly ongoing observation of mutation status. Moreover, the simulations give credence to the suggestion that lower drug concentrations may achieve better results following major molecular response in CML.

  • 20.
    Lindström, Jonathan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    The effects of combination treatments on drug resistance in chronic myeloid leukaemia: an evaluation of the tyrosine kinase inhibitors axitinib and asciminib2020In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 20, article id 397Article in journal (Refereed)
  • 21.
    Orozovic, Goran
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Resistance to neuraminidase inhibitors in influenza A virus isolated from mallards2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Influenza A virus belongs to the Orothomyxoviridae family of viruses and is one of the most common pathogens that cause infections of the respiratory tract. The aim of this thesis was to investigate if neuraminidase inhibitor (NAI) Tamiflu® (oseltamivir, OC) and Relenza® (zanamivir, ZA) - related resistance mutations exist in the neuraminidase (NA) gene of viruses collected from wild birds.

    A new set of degenerate primers was designed for the sequencing procedure, which resulted in a protocol that reduced time and costs of NA sequencing. This protocol was employed for subtyping of 120 NA genes (i.e. influenza viruses). Altogether, 230 NA sequences from avian influenza viruses originating from wild mallards (Ottenby, Sweden) were scanned for NAI-related mutations together with 5,490 avian, 379 swine and 122 environmental NA sequences from the NCBI dataset. The screening showed a distinction between the numbers of mutants found in avian virus sequences derived from NCBI (2.4%) as compared to virus sequences form mallards (6.5%). This is the first report of NAI resistance mutations in viruses isolated from wild birds.

    The mutants carrying NAI resistance-related and resistance-unrelated mutations were screened using NA inhibition assay (NAIA) with ZA and OC inhibitors. The majority of mutations assayed showed IC50 values indicating an inhibitor sensitive phenotype. One H12N3 mutant showed a cross-resistant phenotype, i.e. insensitive to both ZA and OC treatment. Protein structure homology-modeling indicated that this cross-resistance might be associated to a D151K mutation, possibly supported by changes in NA residue 149, 150, 152 and 153. In addition, an OC resistance-related emergence of H274Y mutants was revealed in an experimental set up where mallard ducks, subjected to different concentrations of OC ( 0.28, 3.5 and 280 nM)  in their water pool, were infected with avian H1N1 virus.

    In conclusion, this thesis provides new insights into the field of NAI resistance in avian influenza virus as well as indicating the evolutionary forces modern drug design has to confront. This thesis also emphasizes the importance of a continuous search for new means of protecting the human population from this potentially devastating pathogen. 

  • 22.
    Palma, Daniela
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Analysis of metatranscriptomes from an acidophilic electricity generating community treating acidic mining wastewaters2018Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Human ́s constant need for metals requires unsustainable mining and refining of metalore. As a result, highly contaminated wastewaters are discharged in the environmentcompromising the nearby habitat together with all its life forms. Microbial fuel cells arebioelectrochemical systems (BES’s) that use microorganisms to convert organic andinorganic matter, producing electricity as the final product. This technology has shownto have great potential for application for bioremediation of wastewaters. This thesisdescribes the gene expression and the taxonomical abundance of an acidophilic,electricity generating community that was used to treat mining wastewaters in amicrobial fuel cell. A complete metatranscriptomics analysis has been performed onduplicate MFC anode acidophilic microbial community generating electricity frominorganic sulfur compounds (ISC) oxidation at extremely low pH. The analysis showsthat the most expressed genus is Ferroplasma-like, the genus Acidithiobacillus-like isfollowing along with Sulfobacillus-like and Thermoplasma-like. Some of the generaexpressed show behaviours never described before suggesting that potentially, newspecies have been selected. The reactions of the sulfur pathway are regulated mostly bytwo genera: Acidithiobacillus-like during the disproportionation of tetrathionate, andFerroplasma-like by expressing the hdr gene that catalyses the reaction from elementalsulfur to sulfite, the sulfite is then converted to sulfate. The hdr gene has not previouslybeen found in F. acidarmanus-like suggesting that the specie might have been selectedfor this trait. Acidithiobacillus-like genus has a bigger role for the energy conservationand the electron transport in the sample, however the data are not sufficient to point outwhich gene has the major role in the process. The CO2 fixation in the chamber wasconsiderably low as a result from a significant carboxysomes production, bacterialcompartiments involved in the carbon dioxide fixation. The transcripts abundanceregarding the metal resistance genes have shown low expression suggesting that thecells were not under stress. This result is indicated by the synthesis of a transcriptionalrepressor protein that had prevented a significant production of metal resistanceenzymes. Likewise, the pH homeostasis plot does not show vast transcripts abundances,indicating that the cells were thriving under conditions not far from the optimum.

    Download full text (pdf)
    fulltext
  • 23.
    Sachpazidou, Varvara
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Microbial community and activity during re-oxygenation of Baltic Sea “dead zone” sediments2017Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
  • 24.
    Salgado, Marco G.
    et al.
    Stockholm University.
    van Velzen, Robin
    Wageningen Univ, Netherlands.
    Nguyen, Thanh Van
    Stockholm University.
    Battenberg, Kai
    Univ Calif Davis, USA.
    Berry, Alison M.
    Univ Calif Davis, USA.
    Lundin, Daniel
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. Stockholm University.
    Pawlowski, Katharina
    Stockholm University.
    Comparative Analysis of the Nodule Transcriptomes of Ceanothus thyrsiflorus (Rhamnaceae, Rosales) and Datisca glomerate (Datiscaceae, Cucurbitales)2018In: Frontiers in Plant Science, ISSN 1664-462X, E-ISSN 1664-462X, Vol. 9, article id 1629Article in journal (Refereed)
    Abstract [en]

    Two types of nitrogen-fixing root nodule symbioses are known, rhizobial and actinorhizal symbioses. The latter involve plants of three orders, Fagales, Rosales, and Cucurbitales. To understand the diversity of plant symbiotic adaptation, we compared the nodule transcriptomes of Datisca glomerate (Datiscaceae, Cucurbitales) and Ceanothus thyrsiflorus (Rhamnaceae, Rosales); both species are nodulated by members of the uncultured Frankia Glade, cluster II. The analysis focused on various features. In both species, the expression of orthologs of legume Nod factor receptor genes was elevated in nodules compared to roots. Since arginine has been postulated as export form of fixed nitrogen from symbiotic Frankia in nodules of D. glomerate, the question was whether the nitrogen metabolism was similar in nodules of C. thyrsiflorus. Analysis of the expression levels of key genes encoding enzymes involved in arginine metabolism revealed up-regulation of arginine catabolism, but no up-regulation of arginine biosynthesis, in nodules compared to roots of D. glomerate, while arginine degradation was not upregulated in nodules of C. thyrsiflorus. This new information corroborated an arginine-based metabolic exchange between host and microsymbiont for D. glomerate, but not for C. thyrsiflorus. Oxygen protection systems for nitrogenase differ dramatically between both species. Analysis of the antioxidant system suggested that the system in the nodules of D. glomerate leads to greater oxidative stress than the one in the nodules of C. thyrsiflorus, while no differences were found for the defense against nitrosative stress. However, induction of nitrite reductase in nodules of C. thyrsiflorus indicated that here, nitrite produced from nitric oxide had to be detoxified. Additional shared features were identified: genes encoding enzymes involved in thiamine biosynthesis were found to be upregulated in the nodules of both species. Orthologous nodule-specific subtilisin-like proteases that have been linked to the infection process in actinorhizal Fagales, were also upregulated in the nodules of D. glomerate and C. thyrsiflorus. Nodule-specific defensin genes known from actinorhizal Fagales and Cucurbitales, were also found in C. thyrsiflorus. In summary, the results underline the variability of nodule metabolism in different groups of symbiotic plants while pointing at conserved features involved in the infection process.

1 - 24 of 24
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf