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  • 1.
    Alexandre, Campos
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Apraiz, Itzaso
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    da Fonseca, Rute R
    The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Shotgun analysis of the marine mussel Mytilus edulis hemolymph proteome and mapping the innate immunity elements.2015In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 15, no 23-24, p. 4021-4029Article in journal (Refereed)
    Abstract [en]

    The marine mussel innate immunity provides protection to pathogen invasion and inflammation.In this regard, the mussel hemolymph takes a main role in the animal innate response.Despite the importance of this body fluid in determining the physiological condition of theanimal, little is known about the molecular mechanisms underlying the cellular and humoralresponses. In this work, we have applied aMS (nano-LC-MS/MS) strategy integrating genomicand transcriptomic data with the aim to: (i) identify the main protein functional groups thatcharacterize hemolymph and (ii) to map the elements of innate immunity in the marine musselMytilus edulis hemolymph proteome. After sample analysis and first protein identificationbased onMS/MS data comparison, proteins with unknown functions were annotated with blastusing public database (nrNCBI) information. Overall 595 hemolymph proteins were identifiedwith high confidence and annotated. These proteins encompass primary cellular metabolicprocesses: energy production and metabolism of biomolecules, as well as processes related tooxidative stress defence, xenobiotic detoxification, drug metabolism, and immune response.A group of proteins was identified with putative immune effector, receptor, and signalingfunctions in M. edulis. Data are available via ProteomeXchange with identifier PXD001951(http://proteomecentral.proteomexchange.org/dataset/PXD001951).

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  • 2.
    Almeida, A. M.
    et al.
    CVZ Centre Vet and Zootecnia, Portugal; CIISA Centre Interdisciplinar Invest Sanidade Anim, Portugal; UNL, Portugal; IBET Institute Biol Expt and Tecnol, Portugal.
    Bassols, A.
    University of Autonoma Barcelona, Spain.
    Bendixen, E.
    Aarhus University, Denmark.
    Bhide, M.
    University of Vet Medical and Pharm, Slovakia.
    Ceciliani, F.
    University of Milan, Italy.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. University of Basque Country, Spain.
    Eckersall, P. D.
    University of Glasgow, Scotland.
    Hollung, K.
    Nofima AS, Norway.
    Lisacek, F.
    Swiss Institute Bioinformat, Switzerland.
    Mazzucchelli, G.
    University of Liege, Belgium.
    McLaughlin, M.
    University of Glasgow, Scotland.
    Miller, I.
    University of Vet Med, Austria.
    Nally, J. E.
    ARS, IA 50010 USA.
    Plowman, J.
    AgResearch, New Zealand.
    Renaut, J.
    Centre Rech Public Gabriel Lippmann, Luxembourg.
    Rodrigues, P.
    University of Algarve, Portugal.
    Roncada, P.
    University of Milan, Italy.
    Staric, J.
    University of Ljubljana, Slovenia.
    Turk, R.
    University of Zagreb, Croatia.
    Animal board invited review: advances in proteomics for animal and food sciences2015In: Animal, ISSN 1751-7311, E-ISSN 1751-732X, Vol. 9, no 1Article, review/survey (Refereed)
    Abstract [en]

    Animal production and health (APH) is an important sector in the world economy, representing a large proportion of the budget of all member states in the European Union and in other continents. APH is a highly competitive sector with a strong emphasis on innovation and, albeit with country to country variations, on scientific research. Proteomics (the study of all proteins present in a given tissue or fluid - i.e. the proteome) has an enormous potential when applied to APH. Nevertheless, for a variety of reasons and in contrast to disciplines such as plant sciences or human biomedicine, such potential is only now being tapped. To counter such limited usage, 6 years ago we created a consortium dedicated to the applications of Proteomics to APH, specifically in the form of a Cooperation in Science and Technology (COST) Action, termed FA1002 - Proteomics in Farm Animals: www.cost-faproteomics.org. In 4 years, the consortium quickly enlarged to a total of 31 countries in Europe, as well as Israel, Argentina, Australia and New Zealand. This article has a triple purpose. First, we aim to provide clear examples on the applications and benefits of the use of proteomics in all aspects related to APH. Second, we provide insights and possibilities on the new trends and objectives for APH proteomics applications and technologies for the years to come. Finally, we provide an overview and balance of the major activities and accomplishments of the COST Action on Farm Animal Proteomics. These include activities such as the organization of seminars, workshops and major scientific conferences, organization of summer schools, financing Short-Term Scientific Missions (STSMs) and the generation of scientific literature. Overall, the Action has attained all of the proposed objectives and has made considerable difference by putting proteomics on the global map for animal and veterinary researchers in general and by contributing significantly to reduce the East-West and North-South gaps existing in the European farm animal research. Future activities of significance in the field of scientific research, involving members of the action, as well as others, will likely be established in the future.

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  • 3.
    Amelina, Hanna
    et al.
    Stockholm University.
    Sjodin, Marcus O. D.
    Uppsala University.
    Bergquist, Jonas
    Uppsala University.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Quantitative subproteomic analysis of age-related changes in mouse liver peroxisomes by iTRAQ LC-MS/MS2011In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 879, no 30, p. 3393-3400Article in journal (Refereed)
    Abstract [en]

    Aging is a complex multifactorial phenomenon, which is believed to result from the accumulation of cellular damage to biological macromolecules. Peroxisomes recently emerged as another important source of reactive oxygen species (ROS) production in addition to mitochondria. However, the role of these organelles in the process of aging is still not clear. The aim of this study was to characterize the changes in protein expression profiles of young (10 weeks old) versus old (18 months old) mouse liver peroxisome-enriched fractions. We have applied shotgun proteomic approach based on liquid chromatography and tandem mass spectrometry (LC-MS/MS) combined with iTRAQ (isobaric tags for relative and absolute quantitation) labeling that allows comparative quantitative multiplex analysis. Our analysis led to identification and quantification of 150 proteins, 8 out of which were differentially expressed between two age groups at a statistically significant level (p less than 0.05), with folds ranging from 1.2 to 4.1. These proteins involved in peroxisornal beta-oxidation, detoxification of xenobiotics and production of ROS. Noteworthy, differences in liver proteome have been observed between as well as within different age groups. In conclusion, our subproteomic quantitative study suggests that mouse liver proteome is sufficiently maintained until certain age.

  • 4.
    Bayat, N.
    et al.
    Stockholm University, Sweden.
    Lopes, Viviana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Sanchez-Dominguez, M.
    Centre Invest Mat Avanzados CIMAV SC, Mexico.
    Lakshmanan, R.
    Royal Institute Technology KTH, Sweden.
    Rajarao, G. K.
    Royal Institute Technology KTH, Sweden.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Basque Country Medical Sch, Spain.
    Assessment of functionalized iron oxide nanoparticles in vitro: introduction to integrated nanoimpact index2015In: ENVIRONMENTAL SCIENCE-NANO, ISSN 2051-8153, Vol. 2, no 4, p. 380-394Article in journal (Refereed)
    Abstract [en]

    Functionalization of super paramagnetic iron oxide NPs (SPIONs) with different coatings renders them with unique physicochemical properties that allow them to be used in a broad range of applications such as drug targeting and water purification. However, it is required to fill the gap between the promises of any new functionalized SPIONs and the effects of these coatings on the NPs safety. Nanotoxicology is offering diverse strategies to assess the effect of exposure to SPIONs in a case-by-case manner but an integrated nanoimpact scale has not been developed yet. We have implemented the classical integrated biological response (IBR) into an integrated nanoimpact index (INI) as an early warning scale of nano-impact based on a combination of toxicological end points such as cell proliferation, oxidative stress, apoptosis and genotoxicity. Here, the effect of SPIONs functionalized with tri-sodium citrate (TSC), polyethylenimine (PEI), aminopropyl-triethoxysilane (APTES) and Chitosan (chitosan) were assessed on human keratinocytes and endothelial cells. Our results show that endothelial cells were more sensitive to exposure than keratinocytes and the initial cell culture density modulated the toxicity. PEI-SPIONs had the strongest effects in both cell types while TSC-SPIONS were the most biocompatible. This study emphasizes not only the importance of surface coatings but also the cell type and the initial cell density on the selection of toxicity assays. The INI developed here could offer an initial rationale to choose either modifying SPIONs properties to reduce its nanoimpact or performing a complete risk assessment to define the risk boundaries.

  • 5.
    Bayat, Narges
    et al.
    Stockholm University, Sweden.
    Lopes, Viviana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Schoelermann, Julia
    University of Bergen, Norway.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Stockholm University, Sweden; University of Basque Country, Spain.
    Vascular toxicity of ultra-small TiO2 nanoparticles and single walled carbon nanotubes in vitro and in vivo2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 63Article in journal (Refereed)
    Abstract [en]

    Ultra-small nanoparticles (USNPs) at 1-3 nm are a subset of nanoparticles (NPs) that exhibit intermediate physicochemical properties between molecular dispersions and larger NPs. Despite interest in their utilization in applications such as theranostics, limited data about their toxicity exist. Here the effect of TiO2-USNPs on endothelial cells in vitro, and zebrafish embryos in vivo, was studied and compared to larger TiO2-NPs (30 nm) and to single walled carbon nanotubes (SWCNTs). In vitro exposure showed that TiO2-USNPs were neither cytotoxic, nor had oxidative ability, nevertheless were genotoxic. In vivo experiment in early developing zebrafish embryos in water at high concentrations of TiO2-USNPs caused mortality possibly by acidifying the water and caused malformations in the form of pericardial edema when injected. Myo1C involved in glomerular development of zebrafish embryos was upregulated in embryos exposed to TiO2-USNPs. They also exhibited anti-angiogenic effects both in vitro and in vivo plus decreased nitric oxide concentration. The larger TiO2-NPs were genotoxic but not cytotoxic. SWCNTs were cytotoxic in vitro and had the highest oxidative ability. Neither of these NPs had significant effects in vivo. To our knowledge this is the first study evaluating the effects of TiO2-USNPs on vascular toxicity in vitro and in vivo and this strategy could unravel USNPs potential applications. (C) 2015 Elsevier Ltd. All rights reserved.

  • 6.
    Bayat, Narges
    et al.
    Stockholm University, Sweden .
    Rajapakse, Katarina
    University of Ljubljana, Slovenia .
    Marinsek-Logar, Romana
    University of Ljubljana, Slovenia .
    Drobne, Damjana
    University of Ljubljana, Slovenia Centre Excellence Adv Mat and Technology Future CONAMASTE, Slovenia Centre Excellence Nanosci and Nanotechnol CO Nanoctr, Slovenia .
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    The effects of engineered nanoparticles on the cellular structure and growth of Saccharomyces cerevisiae2014In: Nanotoxicology, ISSN 1743-5390, E-ISSN 1743-5404, Vol. 8, no 4, p. 363-373Article in journal (Refereed)
    Abstract [en]

    In order to study the effects of nanoparticles (NPs) with different physicochemical properties on cellular viability and structure, Saccharomyces cerevisiae were exposed to different concentrations of TiO2-NPs (1-3 nm), ZnO-NPs (less than100 nm), CuO-NPs (less than50 nm), their bulk forms, Ag-NPs (10 nm) and single-walled carbon nanotubes (SWCNTs). The GreenScreen assay was used to measure cyto- and genotoxicity, and transmission electron microscopy (TEM) used to assess ultrastructure. Cu-ONPs were highly cytotoxic, reducing the cell density by 80% at 9 cm(2)/ml, and inducing lipid droplet formation. Cells exposed to Ag-NPs (19 cm(2)/ml) and TiO2-NPs (147 cm(2)/ml) contained dark deposits in intracellular vacuoles, the cell wall and vesicles, and reduced cell density (40 and 30%, respectively). ZnO-NPs (8 cm(2)/ml) caused an increase in the size of intracellular vacuoles, despite not being cytotoxic. SWCNTs did not cause cytotoxicity or significant alterations in ultrastructure, despite high oxidative potential. Two genotoxicity assays, GreenScreen and the comet assay, produced different results and the authors discuss the reasons for this discrepancy. Classical assays of toxicity may not be the most suitable for studying the effects of NPs in cellular systems, and the simultaneous assessment of other measures of the state of cells, such as TEM are highly recommended.

  • 7.
    Bendz, Maria
    et al.
    Stockholm University, Sweden .
    Skwark, Marcin
    Stockholm University, Sweden .
    Nilsson, Daniel
    Stockholm University, Sweden .
    Granholm, Viktor
    Stockholm University, Sweden .
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Kall, Lukas
    Royal Institute Technology KTH, Sweden .
    Elofsson, Arne
    Stockholm University, Sweden .
    Membrane protein shaving with thermolysin can be used to evaluate topology predictors2013In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 13, no 9, p. 1467-1480Article in journal (Refereed)
    Abstract [en]

    Topology analysis of membrane proteins can be obtained by enzymatic shaving in combination with MS identification of peptides. Ideally, such analysis could provide quite detailed information about the membrane spanning regions. Here, we examine the ability of some shaving enzymes to provide large-scale analysis of membrane proteome topologies. To compare different shaving enzymes, we first analyzed the detected peptides from two over-expressed proteins. Second, we analyzed the peptides from non-over-expressed Escherichia coli membrane proteins with known structure to evaluate the shaving methods. Finally, the identified peptides were used to test the accuracy of a number of topology predictors. At the end we suggest that the usage of thermolysin, an enzyme working at the natural pH of the cell for membrane shaving, is superior because: (i) we detect a similar number of peptides and proteins using thermolysin and trypsin; (ii) thermolysin shaving can be run at a natural pH and (iii) the incubation time is quite short. (iv) Fewer detected peptides from thermolysin shaving originate from the transmembrane regions. Using thermolysin shaving we can also provide a clear separation between the best and the less accurate topology predictors, indicating that using data from shaving can provide valuable information when developing new topology predictors.

  • 8.
    Benede, Sara
    et al.
    UAM, Spain.
    Lozano-Ojalvo, Daniel
    Icahn Sch Med Mt Sinai, NY 10029 USA.
    Cristobal, Susana
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Basque Country UPV EHU, Spain.
    Costa, Joana
    Univ Porto, Portugal.
    DAuria, Enza
    Univ Studi Milano, Italy.
    Velickovic, Tanja Cirkovic
    Univ Belgrade, Serbia; Ghent Univ Global Campus, South Korea; Univ Ghent, Belgium; Serbian Acad Arts & Sci, Serbia.
    Garrido-Arandia, Maria
    Univ Politecn Madrid, Spain.
    Karakaya, Sibel
    Ege Univ, Turkey.
    Mafra, Isabel
    Univ Porto, Portugal.
    Mazzucchelli, Gabriel
    Univ Liege, Belgium.
    Picariello, Gianluca
    Inst Food Sci, Italy.
    Romero-Sahagun, Alejandro
    Univ Politecn Madrid, Spain.
    Villa, Caterina
    Univ Porto, Portugal.
    Roncada, Paola
    Magna Graecia Univ Catanzaro, Italy.
    Molina, Elena
    UAM, Spain.
    New applications of advanced instrumental techniques for the characterization of food allergenic proteins2022In: Critical reviews in food science and nutrition, ISSN 1040-8398, E-ISSN 1549-7852, Vol. 62, no 31, p. 8686-8702Article, review/survey (Refereed)
    Abstract [en]

    Current approaches based on electrophoretic, chromatographic or immunochemical principles have allowed characterizing multiple allergens, mapping their epitopes, studying their mechanisms of action, developing detection and diagnostic methods and therapeutic strategies for the food and pharmaceutical industry. However, some of the common structural features related to the allergenic potential of food proteins remain unknown, or the pathological mechanism of food allergy is not yet fully understood. In addition, it is also necessary to evaluate new allergens from novel protein sources that may pose a new risk for consumers. Technological development has allowed the expansion of advanced technologies for which their whole potential has not been entirely exploited and could provide novel contributions to still unexplored molecular traits underlying both the structure of food allergens and the mechanisms through which they sensitize or elicit adverse responses in human subjects, as well as improving analytical techniques for their detection. This review presents cutting-edge instrumental techniques recently applied when studying structural and functional aspects of proteins, mechanism of action and interaction between biomolecules. We also exemplify their role in the food allergy research and discuss their new possible applications in several areas of the food allergy field.

  • 9.
    Berlin, Emmanuel
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lizano Fallas, Veronica
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Carrasco Del Amor, Ana Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Fresnedo, Olatz
    Univ Basque Country UPV EHU, Spain.
    Cristobal, Susana
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Basque Country UPV EHU, Spain.
    Nonionic Surfactants can Modify the Thermal Stability of Globular and Membrane Proteins Interfering with the Thermal Proteome Profiling Principles to Identify Protein Targets2023In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 95, no 8, p. 4033-4042Article in journal (Refereed)
    Abstract [en]

    The membrane proteins are essential targets for understanding cellular function. The unbiased identification of membrane protein targets is still the bottleneck for a system-level understanding of cellular response to stimuli or perturbations. It has been suggested to enrich the soluble proteome with membrane proteins by introducing nonionic surfactants in the solubilization solution. This strategy aimed to simultaneously identify the globular and membrane protein targets by thermal proteome profiling principles. However, the thermal shift assay would surpass the cloud point temperature from the nonionic surfactants frequently utilized for membrane protein solubilization. It is expected that around the cloud point temperature, the surfactant micelles would suffer structural modifications altering protein solubility. Here, we show that the presence of nonionic surfactants can alter protein thermal stability from a mixed, globular, and membrane proteome. In the presence of surfactant micelles, the changes in protein solubility analyzed after the thermal shift assay was affected by the thermally dependent modification of the micellar size and its interaction with proteins. We demonstrate that the introduction of nonionic surfactants for the solubilization of membrane proteins is not compatible with the principles of target identification by thermal proteome profiling methodologies. Our results lead to exploring thermally independent strategies for membrane protein solubilization to assure confident membrane protein target identification. The proteome-wide thermal shift methods have already shown their capability to elucidate mechanisms of action from pharma, biomedicine, analytical chemistry, or toxicology, and finding strategies, free from surfactants, to identify membrane protein targets would be the next challenge.

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  • 10.
    Bertile, Fabrice
    et al.
    Univ Strasbourg, France.
    Matallana-Surget, Sabine
    Univ Stirling, Scotland.
    Tholey, Andreas
    Christian Albrechts Univ Kiel, Germany.
    Cristobal, Susana
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Basque Country UPV EHU, Spain.
    Armengaud, Jean
    Univ Paris Saclay, France.
    Diversifying the concept of model organisms in the age of -omics2023In: Communications Biology, E-ISSN 2399-3642, Vol. 6, no 1, article id 1062Article in journal (Refereed)
    Abstract [en]

    In today's post-genomic era, it is crucial to rethink the concept of model organisms. While a few historically well-established organisms, e.g. laboratory rodents, have enabled significant scientific breakthroughs, there is now a pressing need for broader inclusion. Indeed, new organisms and models, from complex microbial communities to holobionts, are essential to fully grasp the complexity of biological principles across the breadth of biodiversity. By fostering collaboration between biology, advanced molecular science and omics communities, we can collectively adopt new models, unraveling their molecular functioning, and uncovering fundamental mechanisms. This concerted effort will undoubtedly enhance human health, environmental quality, and biodiversity conservation. The concept of model organisms in biological studies needs to be re-evaluated to reflect novel technological advances and help further scientific discovery.

  • 11.
    Campos, Alexandre
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Danielsson, Gabriela
    Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Stockholm, Sweden.
    Farinha, Ana Paula
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kuruvilla, Jacob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Warholm, Per
    Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Stockholm, Sweden.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Shotgun proteomics to unravel marine mussel (Mytilus edulis) response to long-term exposure to low salinity and propranolol in a Baltic Sea microcosm2016In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 137, p. 97-106Article in journal (Refereed)
    Abstract [en]

    Pharmaceuticals, among them the β-adrenoreceptor blocker propranolol, are an important group of environmental contaminants reported in European waters. Laboratory exposure to pharmaceuticals on marine species has been performed without considering the input of the ecosystem flow. To unravel the ecosystem response to long-term exposure to propranolol we have performed long-term exposure to propranolol and low salinity in microcosms. We applied shotgun proteomic analysis to gills of Mytilus edulis from those Baltic Sea microcosms and identified 2071 proteins with a proteogenomic strategy. The proteome profiling patterns from the 587 highly reproductive proteins among groups define salinity as a key factor in the mussel´s response to propranolol. Exposure at low salinity drives molecular mechanisms of adaptation based on a decrease in the abundance of several cytoskeletal proteins, signalling and intracellular membrane trafficking pathway combined with a response towards the maintenance of transcription and translation. The exposure to propranolol combined with low salinity modulates the expression of structural proteins including cilia functions and decrease the expression membrane protein transporters. This study reinforces the environment concerns of the impact of low salinity in combination with anthropogenic pollutants and anticipate critical physiological conditions for the survival of the blue mussel in the northern areas.

  • 12.
    Campos, Alexandre
    et al.
    University of Porto, Portugal .
    Tedesco, Sara
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Vasconcelos, Vitor
    University of Porto, Portugal University of Porto, Portugal .
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Proteomic research in bivalves Towards the identification of molecular markers of aquatic pollution2012In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 75, no 14, p. 4346-4359Article, review/survey (Refereed)
    Abstract [en]

    Biomonitoring of aquatic environment and assessment of ecosystem health play essential roles in the development of effective strategies for the protection of the environment, human health and sustainable development. Biomarkers of pollution exposure have been extensively utilized in the last few decades to monitor the health of organisms and hence assess environmental status. However, the use of single biomarkers against biotic or abiotic stressors may be limited by the lack of sensitivity and specificity. Therefore, more recently, the search for novel biomarkers has been focused on the application of OMICS methodologies. Environmental proteomics focuses on the analysis of an organisms proteome and the detection of changes in the level of individual proteins/peptides in response to environmental stressors. Proteomics can provide a more robust approach for the assessment of environmental stress and therefore exposure to pollutants. This review aims to summarize the proteomic research in bivalves, a group of sessile and filter feeding organisms that play an important function as "sentinels" of the aquatic environment. A description of the main proteomic methodologies is provided. The current knowledge in bivalves toxicology, achieved with proteomics, is reported describing the main biochemical markers identified. A brief discussion regarding future challenges in this area of research emphasizing the development of more descriptive gene/protein databases that could support the OMICs approaches is presented. less thanbrgreater than less thanbrgreater thanThis article is part of a Special Issue entitled: Farm animal proteomics.

  • 13.
    Carrasco Del Amor, Ana Maria
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bautista, Rene Hernandez
    Helmholtz Ctr Munich, Germany.
    Ussar, Siegfried
    Helmholtz Ctr Munich, Germany.
    Cristobal, Susana
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Basque Country UPV EHU, Spain.
    Urbatzka, Ralph
    Univ Porto, Portugal.
    Insights into the mechanism of action of the chlorophyll derivative<i> 13-2-hydroxypheophytine</i> a on reducing neutral lipid reserves in zebrafish larvae and mice adipocytes2023In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 960, article id 176158Article in journal (Refereed)
    Abstract [en]

    Obesity is a worldwide epidemic and natural products may hold promise in its treatment. The chlorophyll derivative 13-2-hydroxypheophytine (hpa) was isolated in a screen with zebrafish larvae to identify lipid reducing molecules from cyanobacteria. However, the mechanisms underlying the lipid-reducing effects of hpa in zebrafish larvae remain poorly understood. Thus, investigating the mechanism of action of hpa and validation in other model organisms such as mice represents important initial steps.In this study, we identified 14 protein targets of hpa in zebrafish larvae by thermal proteome profiling, and selected two targets (malate dehydrogenase and pyruvate kinase) involved in cellular metabolism for further validation by enzymatic measurements. Our findings revealed a dose-dependent inhibition of pyruvate kinase by hpa exposure using protein extracts of zebrafish larvae in vitro, and in exposure experiments from 3 to 5 days post fertilization in vivo. Analysis of untargeted metabolomics of zebrafish larvae detected 940 mass peaks (66 increased, 129 decreased) and revealed that hpa induced the formation of various phospholipid species (phosphoinositol, phosphoethanolamine, phosphatidic acid). Inter-species validation showed that brown adipocytes exposed to hpa significantly reduced the size of lipid droplets, increased maximal mitochondrial respiratory capacity, and the expression of PPARy during adipocyte differentiation.In line with our data, previous work described that reduced pyruvate kinase activity lowered hepatic lipid content via reduced pyruvate and citrate, and improved mitochondrial function via phospholipids. Thus, our data provide new insights into the molecular mechanism underlying the lipid reducing activities of hpa in zebrafish larvae, and species overlapping functions in reduction of lipids.

  • 14.
    Carrasco Del Amor, Ana Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Freitas, Sara
    Interdisciplinary Ctr Marine and Environm Res, Portugal.
    Urbatzka, Ralph
    Interdisciplinary Ctr Marine and Environm Res, Portugal.
    Fresnedo, Olatz
    Univ Basque Country, Spain.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Basque Country, Spain.
    Application of Bioactive Thermal Proteome Profiling to Decipher the Mechanism of Action of the Lipid Lowering 13(2)-Hydroxy-pheophytin Isolated from a Marine Cyanobacteria2019In: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 17, no 6Article in journal (Refereed)
    Abstract [en]

    The acceleration of the process of understanding the pharmacological application of new marine bioactive compounds requires identifying the compound protein targets leading the molecular mechanisms in a living cell. The thermal proteome profiling (TPP) methodology does not fulfill the requirements for its application to any bioactive compound lacking chemical and functional characterization. Here, we present a modified method that we called bTPP for bioactive thermal proteome profiling that guarantees target specificity from a soluble subproteome. We showed that the precipitation of the microsomal fraction before the thermal shift assay is crucial to accurately calculate the melting points of the protein targets. As a probe of concept, the protein targets of 13(2)-hydroxy-pheophytin, a compound previously isolated from a marine cyanobacteria for its lipid reducing activity, were analyzed on the hepatic cell line HepG2. Our improved method identified 9 protein targets out of 2500 proteins, including 3 targets (isocitrate dehydrogenase, aldehyde dehydrogenase, phosphoserine aminotransferase) that could be related to obesity and diabetes, as they are involved in the regulation of insulin sensitivity and energy metabolism. This study demonstrated that the bTPP method can accelerate the field of biodiscovery, revealing protein targets involved in mechanisms of action (MOA) connected with future applications of bioactive compounds.

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  • 15.
    Cristobal, Susana
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Amelina, H
    Stockholm University.
    Apraiz, I
    Stockholm University.
    Bayat, N
    Stockholm University.
    Danielsson, G
    Stockholm University.
    Environmental proteomics in pollution assessment in INTEGRATIVE AND COMPARATIVE BIOLOGY, vol 52, issue , pp E38-E382012In: INTEGRATIVE AND COMPARATIVE BIOLOGY, Oxford University Press (OUP): Policy B , 2012, Vol. 52, p. E38-E38Conference paper (Refereed)
    Abstract [en]

    n/a

  • 16.
    Cristobal, Susana
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Tedesco, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Bayat, Narges
    Stockholm University.
    Danielsson, Gabriela
    Stockholm University.
    Buque, Xavier
    Basque country University, Spain.
    Aspichueta, Patricia
    Basque Country University, Spain.
    Fresnedo, Olatz
    Basque Country University, Spain.
    Proteomic and lipidomic analysis of primary mouse hepatocytes exposed to metal and metal oxide nanoparticles2015In: Journal of Integrated OMICS, ISSN 2182-0287, Vol. 5, no 1, p. 44-57Article in journal (Refereed)
    Abstract [en]

    The global analysis of the cellular lipid and protein content upon exposure to metal and metal oxide nanoparticles (NPs) can provide an overviewof the possible impact of exposure. Proteomic analysis has been applied to understand the nanoimpact however the relevance of the alterationon the lipidic proOle has been underestimated. In our study, primary mouse hepatocytes were treated with ultra-small (US) TiO2-USNPsas well as ZnO-NPs, CuO-NPs and Ag-NPs. e protein extracts were analysed by 2D-DIGE and quantiOed by imaging soPware and the selecteddi9erentially expressed proteins were identiOed by nLC-ESI-MS/MS. In parallel, lipidomic analysis of the samples was performed usingthin layer chromatography (TLC) and analyzed by imaging soPware. Our Ondings show an overall ranking of the nanoimpact at the cellularand molecular level: TiO2-USNPs<ZnO-NPs<Ag-NPs<CuO-NPs. CuO-NPs and Ag-NPs were cytotoxic while ZnO-NPs and CuO-NPs hadoxidative capacity. TiO2-USNPs did not have oxidative capacity and were not cytotoxic. e most common cellular impact of the exposurewas the down-regulation of proteins. e proteins identiOed were involved in urea cycle, lipid metabolism, electron transport chain, metabolismsignaling, cellular structure and we could also identify nuclear proteins. CuO-NPs exposure decreased phosphatidylethanolamine andphosphatidylinositol and caused down-regulation of electron transferring protein subunit beta. Ag-NPs exposure caused increased of totallipids and triacylglycerol and decrease of sphingomyelin. TiO2-USNPs also caused decrease of sphingomyelin as well as up-regulation of ATPsynthase and electron transferring protein alfa. ZnO-NPs a9ected the proteome in a concentration-independent manner with down-regulationof RNA helicase. ZnO-NPs exposure did not a9ect the cellular lipids. To our knowledge this work represents the Orst integrated proteomic andlipidomic approach to study the e9ect of NPs exposure to primary mouse hepatocytes in vitro.

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  • 17.
    Fleenor, Courtney J.
    et al.
    Natl Jewish Hlth, CO 80206 USA; Univ Colorado, CO 80045 USA; Globeimmune Inc, CO USA.
    Arends, Tessa
    Univ Colorado, CO 80045 USA.
    Lei, Hong
    Natl Jewish Hlth, CO 80206 USA; Univ Colorado, CO 80045 USA.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Okuyama, Kazuki
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kuruvilla, Jacob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rabe, Jennifer L.
    Univ Colorado, CO 80045 USA.
    Pandey, Ahwan
    Univ Colorado, CO USA; Univ Colorado, CO USA.
    Danhorn, Thomas
    Natl Jewish Hlth, CO USA.
    Straign, Desiree
    Natl Jewish Hlth, CO 80206 USA.
    Espinosa, Joaquin M.
    Univ Colorado, CO USA; Univ Colorado, CO USA.
    Warming, Soren
    Genentech Inc, CA 94080 USA.
    Pietras, Eric M.
    Univ Colorado, CO USA.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hagman, James R.
    Natl Jewish Hlth, CO 80206 USA; Univ Colorado, CO 80045 USA; Univ Colorado, CO 80045 USA.
    Zinc Finger Protein 521 Regulates Early Hematopoiesis through Cell-Extrinsic Mechanisms in the Bone Marrow Microenvironment2018In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 38, no 17, article id UNSP e00603-17Article in journal (Refereed)
    Abstract [en]

    Zinc finger protein 521 (ZFP521), a DNA-binding protein containing 30 Kruppel-like zinc fingers, has been implicated in the differentiation of multiple cell types, including hematopoietic stem and progenitor cells (HSPC) and B lymphocytes. Here, we report a novel role for ZFP521 in regulating the earliest stages of hematopoiesis and lymphoid cell development via a cell-extrinsic mechanism. Mice with inactivated Zfp521 genes (Zfp521(-/-)) possess reduced frequencies and numbers of hematopoietic stem and progenitor cells, common lymphoid progenitors, and B and T cell precursors. Notably, ZFP521 deficiency changes bone marrow microenvironment cytokine levels and gene expression within resident HSPC, consistent with a skewing of hematopoiesis away from lymphopoiesis. These results advance our understanding of ZFP521s role in normal hematopoiesis, justifying further research to assess its potential as a target for cancer therapies.

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  • 18.
    Garcia-Sanchez, Susana
    et al.
    University of Basque Country UPV EHU, Spain.
    Bernales, Irantzu
    University of Basque Country UPV EHU, Spain.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. University of Basque Country UPV EHU, Spain.
    Early response to nanoparticles in the Arabidopsis transcriptome compromises plant defence and root-hair development through salicylic acid signalling2015In: BMC Genomics, E-ISSN 1471-2164, Vol. 16, no 341Article in journal (Refereed)
    Abstract [en]

    Background: The impact of nano-scaled materials on photosynthetic organisms needs to be evaluated. Plants represent the largest interface between the environment and biosphere, so understanding how nanoparticles affect them is especially relevant for environmental assessments. Nanotoxicology studies in plants allude to quantum size effects and other properties specific of the nano-stage to explain increased toxicity respect to bulk compounds. However, gene expression profiles after exposure to nanoparticles and other sources of environmental stress have not been compared and the impact on plant defence has not been analysed. Results: Arabidopsis plants were exposed to TiO2-nanoparticles, Ag-nanoparticles, and multi-walled carbon nanotubes as well as different sources of biotic (microbial pathogens) or abiotic (saline, drought, or wounding) stresses. Changes in gene expression profiles and plant phenotypic responses were evaluated. Transcriptome analysis shows similarity of expression patterns for all plants exposed to nanoparticles and a low impact on gene expression compared to other stress inducers. Nanoparticle exposure repressed transcriptional responses to microbial pathogens, resulting in increased bacterial colonization during an experimental infection. Inhibition of root hair development and transcriptional patterns characteristic of phosphate starvation response were also observed. The exogenous addition of salicylic acid prevented some nano-specific transcriptional and phenotypic effects, including the reduction in root hair formation and the colonization of distal leaves by bacteria. Conclusions: This study integrates the effect of nanoparticles on gene expression with plant responses to major sources of environmental stress and paves the way to remediate the impact of these potentially damaging compounds through hormonal priming.

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  • 19.
    Ge, Yue
    et al.
    National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency.
    Wang, Da-Zhi
    State Key Laboratory of Marine Environmental Science, College of the Environment and Ecology, Xiamen University, China .
    Chiu, Jen-Fu
    University of Hong Kong and Shantou University College of Medicine, China.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Sheehan, David
    Department of Biochemistry, University College Cork, Ireland.
    Silvestre, Frédéric
    Research Unit in Environmental and Evolutionary Biology, University of Namur, Belgium.
    Peng, Xianxuan
    Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Sun Yat-Sen University, China.
    Li, Hui
    Center for Proteomics, State Key Laboratory of Bio-Control, School of Life Sciences, Sun Yat-Sen University, China.
    Gong, Zhiyuan
    Department of Biological Sciences, National University of Singapore, Singapore.
    Lam, Siew Hong
    Department of Biological Sciences, National University of Singapore, Singapore.
    Wentao, Hu
    Department of Biochemistry, University College Cork, Ireland.
    Iwahashi, Hitoshi
    Department of Applied Biological Sciences, Gifu University, Japan.
    Liu, Jianjun
    Shenzhen Center for Disease Control and Prevention, China.
    Mei, Nan
    National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
    Shi, Leming
    National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
    Bruno, Maribel
    National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency.
    Foth, Heidi
    Institute for Environmental Toxicology, Martin Luther University, Halle/Saale, Germany.
    Teichman, Kevin
    Office of Research and Development, U.S. Environmental Protection Agency, Washington D.C., USA.
    Environmental OMICS: Current Status and Future Directions2013In: JOURNAL OF INTEGRATED OMICS, ISSN 2182-0287, Vol. 3, no 2, p. 75-87Article in journal (Refereed)
    Abstract [en]

    Applications of OMICS to high throughput studies of changes of genes, RNAs, proteins, metabolites, and their associated functionsin cells or organisms exposed to environmental chemicals has led to the emergence of a very active research field: environmental OMICS.This developing field holds an important key for improving the scientific basis for understanding the potential impacts of environmentalchemicals on both health and the environment. Here we describe the state of environmental OMICS with an emphasis on its recent accomplishmentsand its problems and potential solutions to facilitate the incorporation of OMICS into mainstream environmental and healthresearch.Data sources: We reviewed relevant and recently published studies on the applicability and usefulness of OMICS technologies to the identificationof toxicity pathways, mechanisms, and biomarkers of environmental chemicals for environmental and health risk monitoring andassessment, including recent presentations and discussions on these issues at The First International Conference on Environmental OMICS(ICEO), held in Guangzhou, China during November 8-12, 2011. This paper summarizes our review.Synthesis: Environmental OMICS aims to take advantage of powerful genomics, transcriptomics, proteomics, and metabolomics tools toidentify novel toxicity pathways/signatures/biomarkers so as to better understand toxicity mechanisms/modes of action, to identify/categorize/prioritize/screen environmental chemicals, and to monitor and predict the risks associated with exposure to environmental chemicalson human health and the environment. To improve the field, some lessons learned from previous studies need to be summarized, aresearch agenda and guidelines for future studies need to be established, and a focus for the field needs to be developed.Conclusions: OMICS technologies for identification of RNA, protein, and metabolic profiles and endpoints have already significantly improvedour understanding of how environmental chemicals affect our ecosystem and human health. OMICS breakthroughs are empoweringthe fields of environmental toxicology, chemical toxicity characterization, and health risk assessment. However, environmental OMICS is stillin the data generation and collection stage. Important data gaps in linking and/or integrating toxicity data with OMICS endpoints/profilesneed to be filled to enable understanding of the potential impacts of chemicals on human health and the environment. It is expected thatfuture environmental OMICS will focus more on real environmental issues and challenges such as the characterization of chemical mixturetoxicity, the identification of environmental and health biomarkers, and the development of innovative environmental OMICS approachesand assays. These innovative approaches and assays will inform chemical toxicity testing and prediction, ecological and health risk monitoringand assessment, and natural resource utilization in ways that maintain human health and protects the environment in a sustainable manner.

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  • 20.
    Gouveia, Duarte
    et al.
    Laboratoire Innovations technologiques pour la Détection et le Diagnostic (Li2D), Service de Pharmacologie et Immunoanalyse (SPI), CEA, INRA, F-30207 Bagnols-sur-Cèze, France.
    Almunia, Christine
    Laboratoire Innovations technologiques pour la Détection et le Diagnostic (Li2D), Service de Pharmacologie et Immunoanalyse (SPI), CEA, INRA, F-30207 Bagnols-sur-Cèze, France.
    Cogne, Yannick
    Laboratoire Innovations technologiques pour la Détection et le Diagnostic (Li2D), Service de Pharmacologie et Immunoanalyse (SPI), CEA, INRA, F-30207 Bagnols-sur-Cèze, France.
    Pible, Olivier
    Laboratoire Innovations technologiques pour la Détection et le Diagnostic (Li2D), Service de Pharmacologie et Immunoanalyse (SPI), CEA, INRA, F-30207 Bagnols-sur-Cèze, France.
    Degli-Esposti, Davide
    Irstea, UR Riverly Laboratoire d'écotoxicologie, Centre de Lyon-Villeurbanne, F-69625 Villeurbanne, France.
    Salvador, Arnaud
    Université Claude Bernard Lyon 1, CNRS, ENS de Lyon, Institut des Sciences Analytiques, UMR 5280, 5 rue de la Doua, F-69100 Villeurbanne, France.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Department of Physiology, Ikerbasque, Faculty of Medicine and Dentistry, University of the Basque Country, Spain.
    Sheehan, David
    College of Arts and Sciences, Khalifa University of Science and Technology, PO Box 127788, Abu Dhabi, United Arab Emirates.
    Chaumot, Arnaud
    Irstea, UR Riverly Laboratoire d'écotoxicologie, Centre de Lyon-Villeurbanne, F-69625 Villeurbanne, France.
    Geffard, Olivier
    Irstea, UR Riverly Laboratoire d'écotoxicologie, Centre de Lyon-Villeurbanne, F-69625 Villeurbanne, France.
    Armengaud, Jean
    Laboratoire Innovations technologiques pour la Détection et le Diagnostic (Li2D), Service de Pharmacologie et Immunoanalyse (SPI), CEA, INRA, F-30207 Bagnols-sur-Cèze, France.
    Ecotoxicoproteomics: A decade of progress in our understanding of anthropogenic impact on the environment2019In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 198, p. 66-77, article id S1874-3919(18)30423-8Article in journal (Refereed)
    Abstract [en]

    Anthropogenic pollutants are found worldwide. Their fate and effects on human and ecosystem health must be appropriately monitored. Today, ecotoxicology is focused on the development of new methods to assess the impact of pollutant toxicity on living organisms and ecosystems. In situ biomonitoring often uses sentinel animals for which, ideally, molecular biomarkers have been defined thanks to which environmental quality can be assessed. In this context, high-throughput proteomics methods offer an attractive approach to study the early molecular responses of organisms to environmental stressors. This approach can be used to identify toxicity pathways, to quantify more precisely novel biomarkers, and to draw the possible adverse outcome pathways. In this review, we discuss the major advances in ecotoxicoproteomics made over the last decade and present the current state of knowledge, emphasizing the technological and conceptual advancements that allowed major breakthroughs in this field, which aims to “make our planet great again”.

    Significance

    Ecotoxicoproteomics is a protein-centric methodology that is useful for ecotoxicology and could have future applications as part of chemical risk assessment and environmental monitoring. Ecotoxicology employing non-model sentinel organisms with highly divergent phylogenetic backgrounds aims to preserve the functioning of ecosystems and the overall range of biological species supporting them. The classical proteomics workflow involves protein identification, functional annotation, and extrapolation of toxicity across species. Thus, it is essential to develop multi-omics approaches in order to unravel molecular information and construct the most suitable databases for protein identification and pathway analysis in non-model species. Current instrumentation and available software allow relevant combined transcriptomic/proteomic studies to be performed for almost any species. This review summarizes these approaches and illustrates how they can be implemented in ecotoxicology for routine biomonitoring.

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  • 21.
    Helander, Sara
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Montecchio, Meri
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Pilstål, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Su, Yulong
    Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
    Kuruvilla, Jacob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Sweden.
    Johansson, Malin
    Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Sweden.
    Mohammed, Javed
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Lundström, Patrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Sears, Rosalie
    Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
    Wallner, Björn
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Department of Social and Welfare Studies, Learning, Aesthetics, Natural science. Linköping University, Faculty of Educational Sciences. Linköping University, Faculty of Science & Engineering.
    Sunnerhagen, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity2015In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 23, no 12, p. 2267-2279Article in journal (Refereed)
    Abstract [en]

    Hierarchic phosphorylation and concomitant Pin1-mediated proline isomerization of the oncoprotein c-Myc controls its cellular stability and activity. However, the molecular basis for Pin1 recognition and catalysis of c-Myc and other multisite, disordered substrates in cell regulation and disease is unclear. By nuclear magnetic resonance, surface plasmon resonance, and molecular modeling, we show that Pin1 subdomains jointly pre-anchor unphosphorylated c-Myc1–88 in the Pin1 interdomain cleft in a disordered, or “fuzzy”, complex at the herein named Myc Box 0 (MB0) conserved region N-terminal to the highly conserved Myc Box I (MBI). Ser62 phosphorylation in MBI intensifies previously transient MBI-Pin1 interactions in c-Myc1–88 binding, and increasingly engages Pin1PPIase and its catalytic region with maintained MB0 interactions. In cellular assays, MB0 mutated c-Myc shows decreased Pin1 interaction, increased protein half-life, but lowered rates of Myc-driven transcription and cell proliferation. We propose that dynamic Pin1 recognition of MB0 contributes to the regulation of c-Myc activity in cells

  • 22.
    Kuruvilla, Jacob
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology.
    Bayat, Narges
    Stockholm Univ, Sweden.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Basque Country, Spain.
    Proteomic Analysis of Endothelial Cells Exposed to Ultrasmall Nanoparticles Reveals Disruption in Paracellular and Transcellular Transport2019In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 19, no 5, article id 1800228Article in journal (Refereed)
    Abstract [en]

    The large interactive surfaces of nanoparticles (NPs) increase the opportunities to develop NPs for vascular targeting. Proteomic analysis of endothelial cells exposed to NPs reveals the cellular response and turns the focus into the impairment of the endothelial permeability. Here, quantitative proteomics and transcriptome sequencing are combined to evaluate the effects of exposure to sub-lethal concentrations of TiO2-USNPs and TiO2-NPs on human dermal microvascular endothelial cells. Endothelial cells react to preserve the semi-permeable properties that are essential for vascular tissue fluid homeostasis, vascular development, and angiogenesis. The main impact of the exposure was alteration of functional complexes involved in cell adhesion, vesicular transport, and cytoskeletal structure. Those are the core cellular structures that are linked to the permeability and the integrity of the endothelial tissue. Moreover, the extracellular proteins uptake along wih the NPs into the endothelial cells escape the lysosomal degradation pathway. These findings improve the understanding of the interaction of NPs with endothelial cell. The effects of the studied NPs modulating cell-cell adhesion and vesicular transport can help to evaluate the distribution of NPs via intravenous administration.

  • 23.
    Kuruvilla, Jacob
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Farinha, Ana Paula
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bayat, Narges
    Department of Biochemistry and Biophysics, Arrhenius laboratories, Stockholm University, Stockholm, Sweden.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. IKERBASQUE, Basque Foundation for Science, Department of Physiology, Faculty of Medicine and Dentristy, University of the Basque Country, Leioa, Spain.
    Surface proteomics on nanoparticles, a step to simplify the rapid prototyping of nanoparticles2017In: Nanoscale Horizons, ISSN 2055-6764, E-ISSN 2055-6756, no 1, p. 55-64Article in journal (Refereed)
    Abstract [en]

    Engineered nanoparticles for biomedical applications requireincreasing effectiveness in targeting specific cells while preservingnon-target cell’s safety. We developed a surface proteomicsmethod for a rapid and systematic analysis of the interphasebetween the nanoparticle protein corona and the targeting cellsthat could implement the rapid prototyping of nanomedicines.Native nanoparticles entering in a protein-rich liquid mediaquickly form a macromolecular structure called protein corona.This protein structure defines the physical interaction betweennanoparticles and target cells. The surface proteins compose thefirst line of interaction between this macromolecular structureand the cell surface of a target cell. We demonstrated that SUSTU(SUrface proteomics, Safety, Targeting, Uptake) provides aqualitative and quantitative analysis from the protein coronasurface. With SUSTU, the spatial dynamics of the protein coronasurface can be studied. Data from SUSTU would ascertain thenanoparticle functionalized groups exposed at destiny that couldcircumvent preliminary in vitro experiments. Therefore thismethod could implement the analysis of nanoparticle targetingand uptake capability and could be integrated into a rapidprototyping strategy which is a major challenge in nanomaterialscience. Data are available via ProteomeXchange with identifierPXD004636.

  • 24.
    Legler, Juliette
    et al.
    Univ Utrecht, Netherlands.
    Zalko, Daniel
    Univ Toulouse, France.
    Jourdan, Fabien
    Univ Toulouse, France.
    Jacobs, Miriam
    Publ Hlth England, England.
    Fromenty, Bernard
    Univ Rennes, France.
    Balaguer, Patrick
    Univ Montpellier, France.
    Bourguet, William
    Univ Montpellier, France.
    Kos, Vesna Munic
    Karolinska Inst, Sweden.
    Nadal, Angel
    Univ Miguel Hernandez, Spain; Univ Miguel Hernandez, Spain.
    Beausoleil, Claire
    Agence Natl Secur Sanit Alimentat Environm & Trav, France.
    Cristobal, Susana
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Remy, Sylvie
    VITO, Belgium.
    Ermler, Sibylle
    Brunel Univ London, England.
    Margiotta-Casaluci, Luigi
    Brunel Univ London, England.
    Griffin, Julian L.
    Imperial Coll London, England.
    Blumberg, Bruce
    Univ Calif Irvine, CA 92697 USA.
    Chesne, Christophe
    Biopred Int, France.
    Hoffmann, Sebastian
    Seh Consulting Serv, Germany.
    Andersson, Patrik L.
    Umea Univ, Sweden.
    Kamstra, Jorke H.
    Univ Utrecht, Netherlands.
    The GOLIATH Project: Towards an Internationally Harmonised Approach for Testing Metabolism Disrupting Compounds2020In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 21, no 10, article id 3480Article in journal (Refereed)
    Abstract [en]

    The purpose of this project report is to introduce the European "GOLIATH" project, a new research project which addresses one of the most urgent regulatory needs in the testing of endocrine-disrupting chemicals (EDCs), namely the lack of methods for testing EDCs that disrupt metabolism and metabolic functions. These chemicals collectively referred to as "metabolism disrupting compounds" (MDCs) are natural and anthropogenic chemicals that can promote metabolic changes that can ultimately result in obesity, diabetes, and/or fatty liver in humans. This project report introduces the main approaches of the project and provides a focused review of the evidence of metabolic disruption for selected EDCs. GOLIATH will generate the worlds first integrated approach to testing and assessment (IATA) specifically tailored to MDCs. GOLIATH will focus on the main cellular targets of metabolic disruption-hepatocytes, pancreatic endocrine cells, myocytes and adipocytes-and using an adverse outcome pathway (AOP) framework will provide key information on MDC-related mode of action by incorporating multi-omic analyses and translating results from in silico, in vitro, and in vivo models and assays to adverse metabolic health outcomes in humans at real-life exposures. Given the importance of international acceptance of the developed test methods for regulatory use, GOLIATH will link with ongoing initiatives of the Organisation for Economic Development (OECD) for test method (pre-)validation, IATA, and AOP development.

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  • 25.
    Lizano Fallas, Veronica
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Carrasco Del Amor, Ana Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Cristobal, Susana
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Basque Country UPV EHU, Spain.
    Prediction of Molecular Initiating Events for Adverse Outcome Pathways Using High-Throughput Identification of Chemical Targets2023In: Toxics, E-ISSN 2305-6304, Vol. 11, no 2, article id 189Article in journal (Refereed)
    Abstract [en]

    The impact of exposure to multiple chemicals raises concerns for human and environmental health. The adverse outcome pathway method offers a framework to support mechanism-based assessment in environmental health starting by describing which mechanisms are triggered upon interaction with different stressors. The identification of the molecular initiating event and the molecular interaction between a chemical and a protein target is still a challenge for the development of adverse outcome pathways. The cellular response to chemical exposure studied with omics could not directly identify the protein targets. However, recent mass spectrometry-based methods are offering a proteome-wide identification of protein targets interacting with s but unrevealing a molecular initiating event from a set of targets is still dependent on available knowledge. Here, we directly coupled the target identification findings from the proteome integral solubility alteration assay with an analytical hierarchy process for the prediction of a prioritized molecular initiating event. We demonstrate the applicability of this combination of methodologies with a test compound (TCDD), and it could be further studied and integrated into AOPs. From the eight protein targets identified by the proteome integral solubility alteration assay after analyzing 2824 human hepatic proteins, the analytical hierarchy process can select the most suitable protein for an AOP. Our combined method solves the missing links between high-throughput target identification and prediction of the molecular initiating event. We anticipate its utility to decipher new molecular initiating events and support more sustainable methodologies to gain time and resources in chemical assessment.

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  • 26.
    Lizano-Fallas, Veronica
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Carrasco Del Amor, Ana Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Cristobal, Susana
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Basque Country, Spain.
    Systematic analysis of chemical-protein interactions from zebrafish embryo by proteome-wide thermal shift assay, bridging the gap between molecular interactions and toxicity pathways2021In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 249, article id 104382Article in journal (Refereed)
    Abstract [en]

    The molecular interaction between chemicals and proteins often promotes alteration of cellular function. One of the challenges of the toxicology is to predict the impact of exposure to chemicals. Assessing the impact of exposure implies to understand their mechanism of actions starting from identification of specific protein targets of the interaction. Current methods can mainly predict effects of characterized chemicals with knowledge of its targets, and mechanism of actions. Here, we show that proteome-wide thermal shift methods can identify chemical-protein interactions and the protein targets from bioactive chemicals. We analyzed the identified targets from a soluble proteome extracted from zebrafish embryo, that is a model system for toxicology. To evaluate the utility to predict mechanism of actions, we discussed the applicability in four cases: single chemicals, chemical mixtures, novel chemicals, and novel drugs. Our results showed that this methodology could identify the protein targets, discriminate between protein increasing and decreasing in solubility, and offering additional data to complement the map of intertwined mechanism of actions. We anticipate that the proteome integral solubility alteration (PISA) assay, as it is defined here for the unbiased identification of protein targets of chemicals could bridge the gap between molecular interactions and toxicity pathways. Significance: One of the challenges of the environmental toxicology is to predict the impact of exposure to chemicals on environment and human health. Our phenotype should be explained by our genotype and the environmental exposure. Genomic methodologies can offer a deep analysis of human genome that alone cannot explain our risks of disease. We are starting to understand the key role of exposure to chemicals on our health and risks of disease. Here, we present a proteomic-based method for the identification of soluble proteins interacting with chemicals in zebrafish embryo and discuss the opportunities to complement the map of toxicity pathway perturbations. We anticipate that this PISA assay could bridge the gap between molecular interactions and toxicity pathways.

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  • 27.
    Lopes, Viviana R
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Loitto, Vesa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Audinot, Jean‑Nicolas
    Luxembourg Institute of Science and Technology, Luxembourg.
    Bayat, Narges
    Stockholm University, Sweden.
    Gutleb, Arno C.
    Luxembourg Institute of Science and Technology, Luxembourg.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Dose‑dependent autophagic effectof titanium dioxide nanoparticles in humanHaCaT cells at non‑cytotoxic levels2016In: Journal of Nanobiotechnology, E-ISSN 1477-3155, Vol. 14, no 22, p. 1-13Article in journal (Refereed)
    Abstract [en]

    Background: Interactions between nanoparticles and cells are now the focus of a fast-growing area of research.Though many nanoparticles interact with cells without any acute toxic responses, metal oxide nanoparticles includingthose composed of titanium dioxide (TiO2-NPs) may disrupt the intracellular process of macroautophagy.Autophagy plays a key role in human health and disease, particularly in cancer and neurodegenerative diseases. Weherein investigated the in vitro biological effects of TiO2-NPs (18 nm) on autophagy in human keratinocytes (HaCaT)cells at non-cytotoxic levels.Results: TiO2-NPs were characterized by transmission electron microscopy (TEM) and dynamic light scatteringtechniques. Cellular uptake, as evaluated by TEM and NanoSIMS revealed that NPs internalization led to the formationof autophagosomes. TiO2-NPs treatment did not reduce cell viability of HaCaT cells nor increased oxidative stress. Cellularautophagy was additionally evaluated by confocal microscopy using eGFP-LC3 keratinocytes, western blottingof autophagy marker LC3I/II, immunodetection of p62 and NBR1 proteins, and gene expression of LC3II, p62, NBR1,beclin1 and ATG5 by RT-qPCR. We also confirmed the formation and accumulation of autophagosomes in NPs treatedcells with LC3-II upregulation. Based on the lack of degradation of p62 and NBR1 proteins, autophagosomes accumulationat a high dose (25.0 μg/ml) is due to blockage while a low dose (0.16 μg/ml) promoted autophagy. Cellularviability was not affected in either case.Conclusions: The uptake of TiO2-NPs led to a dose-dependent increase in autophagic effect under non-cytotoxicconditions. Our results suggest dose-dependent autophagic effect over time as a cellular response to TiO2-NPs. Mostimportantly, these findings suggest that simple toxicity data are not enough to understand the full impact of TiO2-NPsand their effects on cellular pathways or function.

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  • 28.
    Marco-Ramell, Anna
    et al.
    Universitat Autònoma de Barcelona, Spain; Univ Barcelona, Spain.
    de Almeida, Andree M
    Instituto de Biologia Experimental e Tecnologica, Oeiras, Portugal; Univ Lisbon, Fac, Lisbon, Portugal; Ross Univ, Sch Vet Med, Basseterre, St Kitts & Nevi.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Basque Country, Leioa, Spain.
    Rodrigues, Pedro
    University of Algarve, Portugal.
    Roncada, Paola
    Istituto Sperimentale Italiano L. Spallanzani, Milano, Italy.
    Bassols, Anna
    Universitat Autònoma de Barcelona, Spain.
    Proteomics and the search for welfare and stress biomarkers in animal production in the one health context2016In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 12, no 7, p. 2024-2035Article, review/survey (Refereed)
    Abstract [en]

    Stress and welfare are important factors to animal production in a context of growing production optimization and scrutiny by the general public. In a context in which animal and human health are intertwined aspects of the one-health concept it is of utmost importance to define markers for stress and welfare. These are important tools for producers, retailers, regulatory agents and ultimately consumers to effectively monitor and assess the welfare state of production animals. Proteomics is the science that studies the proteins existing in a given tissue or fluid. In this review we address this topic by showing clear examples where proteomics has been used to study stress-induced changes at various levels. We adopt a multi-species (cattle, swine, small ruminants, poultry, fish and shellfish) approach under the effect of varied stress inducers (handling, transport, management, nutritional, thermal and exposure to pollutants) clearly demonstrating how Proteomics and Systems Biology are key elements to the study of stress and welfare on farm animals and a powerful tool to animal welfare, health and productivity.

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  • 29.
    Okuyama, Kazuki
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden.
    Kuruvilla, Jacob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden.
    Somasundaram, Rajesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Smith, Emma
    Lund Univ, Sweden.
    Prasad, Mahadesh
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Fioretos, Thoas
    Lund Univ, Sweden.
    Lilljebjorn, Henrik
    Lund Univ, Sweden.
    Soneji, Shamit
    Lund Univ, Sweden.
    Lang, Stefan
    Lund Univ, Sweden.
    Ungerback, Jonas
    Lund Univ, Sweden.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden.
    PAX5 is part of a functional transcription factor network targeted in lymphoid leukemia2019In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 15, no 8, article id e1008280Article in journal (Refereed)
    Abstract [en]

    One of the most frequently mutated proteins in human B-lineage leukemia is the transcription factor PAX5. These mutations often result in partial rather than complete loss of function of the transcription factor. While the functional dose of PAX5 has a clear connection to human malignancy, there is limited evidence for that heterozygote loss of PAX5 have a dramatic effect on the development and function of B-cell progenitors. One possible explanation comes from the finding that PAX5 mutated B-ALL often display complex karyotypes and additional mutations. Thus, PAX5 might be one component of a larger transcription factor network targeted in B-ALL. To investigate the functional network associated with PAX5 we used BioID technology to isolate proteins associated with this transcription factor in the living cell. This identified 239 proteins out of which several could be found mutated in human B-ALL. Most prominently we identified the commonly mutated IKZF1 and RUNX1, involved in the formation of ETV6-AML1 fusion protein, among the interaction partners. ChIP- as well as PLAC-seq analysis supported the idea that these factors share a multitude of target genes in human B-ALL cells. Gene expression analysis of mouse models and primary human leukemia suggested that reduced function of PAX5 increased the ability of an oncogenic form of IKZF1 or ETV6-AML to modulate gene expression. Our data reveals that PAX5 belong to a regulatory network frequently targeted by multiple mutations in B-ALL shedding light on the molecular interplay in leukemia cells. Author summary The use of modern high throughput DNA-sequencing has dramatically increased our ability to identify genetic alterations associated with cancer. However, while the mutations per se are rather easily identified, our understanding of how these mutations impact cellular functions and drive malignant transformation is more limited. We have explored the function of the transcription factor PAX5, commonly mutated in human B-lymphocyte leukemia, to identify a regulatory network of transcription factors often targeted in human disease. Hence, we propose that malignant conversion of B-lymphocyte progenitors involves multiple targeting of a central transcription factor network aggravating the impact of the individual mutations. These data increase our understanding for how individual mutations collaborate to drive the formation of B-lineage leukemia.

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  • 30.
    Rajapakse, K.
    et al.
    University of Ljubljana, Ljubljana, Slovenia.
    Drobne, D.
    University of Ljubljana, Ljubljana, Slovenia.
    Kastelec, D.
    University of Ljubljana, Ljubljana, Slovenia.
    Kogej, K.
    University of Ljubljana, Ljubljana, Slovenia.
    Makovec, D.
    Jožef Stefan Institute, Ljubljana, Slovenia.
    Gallampois, Christine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Amelina, H.
    Stockholm University, Stockholm, Sweden.
    Danielsson, G.
    Stockholm University, Stockholm, Sweden.
    Fanedl, L.
    University of Ljubljana, Ljubljana, Slovenia.
    Marinsek-Logar, R.
    University of Ljubljana, Ljubljana, Slovenia.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. IKERBASQUE, Basque Foundation for Science, University of the Basque Country, Leioa, Spain.
    Proteomic analyses of early response of unicellular eukaryotic microorganism Tetrahymena thermophila exposed to TiO2 particles.2016In: Nanotoxicology, ISSN 1743-5390, E-ISSN 1743-5404, Vol. 10, no 5, p. 542-556Article in journal (Refereed)
    Abstract [en]

    Key biological functions involved in cell survival have been studied to understand the difference between the impact of exposure to TiO2 nanoparticles (TiO2-NPs) and their bulk counterparts (bulk-TiO2). By selecting a unicellular eukaryotic model organism and applying proteomic analysis an overview of the possible impact of exposure could be obtained. In this study, we investigated the early response of unicellular eukaryotic protozoan Tetrahymena thermophila exposed to TiO2-NPs or bulk-TiO2 particles at subtoxic concentrations for this organism. The proteomic analysis based on 2DE + nLC-ESI-MS/MS revealed 930 distinct protein spots, among which 77 were differentially expressed and 18 were unambiguously identified. We identified alterations in metabolic pathways, including lipid and fatty acid metabolism, purine metabolism and energetic metabolism, as well as salt stress and protein degradation. This proteomic study is consistent with our previous findings, where the early response of T. thermophila to subtoxic concentrations of TiO2 particles included alterations in lipid and fatty acid metabolism and ion regulation. The response to the lowest TiO2-NPs concentration differed significantly from the response to higher TiO2-NPs concentration and both bulk-TiO2concentrations. Alterations on the physiological landscape were significant after exposure to both nano- and bulk-TiO2; however, no toxic effects were evidenced even at very high exposure concentrations. This study confirms the relevance of the alteration of the lipid profile and lipid metabolism in understanding the early impact of TiO2-NPs in eukaryotic cells, for example, phagocytosing cells like macrophages and ciliated cells in the respiratory epithelium.

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  • 31.
    Rodrigues, Pedro M.
    et al.
    University of Algarve, Faro, Portugal.
    Campos, Alexandre
    University of Porto, Porto, Portugal.
    Kuruvilla, Jacob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Schrama, Denise
    University of Porto, Porto, Portugal.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of the Basque Country, Leioa, Spain.
    Chapter 17 - Proteomics in Aquaculture: Quality and Safety2017In: Proteomics in Food Science / [ed] Colgrave, Michelle L., Elsevier, 2017, p. 279-295Chapter in book (Other academic)
    Abstract [en]

    Aquaculture is a growing sector of the food industry that actively tries to integrate scientific knowledge into its management strategies. Aquaculture faces several key challenges including the provision of high-quality nutritional sources that serve to address both quality and safety, thus transforming production and management strategies to integrate sustainable principles. Proteomics has been established as a powerful and unbiased instrument in environmental monitoring and risk assessment. Proteomics in aquaculture has been applied to address welfare, nutrition, health, environmental quality, and safety. In this review, we will focus on the proteomics-based method developed and implemented for its application to elucidate the key challenges that face the fish and seafood industries: quality and safety. The latest methodological developments in high-throughput proteomics and metaproteomics are seeing rapid integration into aquaculture research contributing to the common goal of offering high quality food production processes and environmental sustainability.

  • 32.
    Strid, Tobias
    et al.
    Region Östergötland, Center for Diagnostics, Clinical pathology. Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Division of Molecular Hematology, Lund University, Lund, Sweden.
    Okuyama, Kazuki
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Tingvall-Gustafsson, Johanna
    Lund Univ, Sweden.
    Kuruvilla, Jacob
    Lund Univ, Sweden.
    Jensen, Christina T.
    Lund Univ, Sweden.
    Lang, Stefan
    Lund Univ, Sweden.
    Prasad, Mahadesh
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Somasundaram, Rajesh
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Åhsberg, Josefine
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Cristobal, Susana
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Soneji, Shamit
    Lund Univ, Sweden.
    Ungerback, Jonas
    Lund Univ, Sweden.
    Sigvardsson, Mikael
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden.
    B Lymphocyte Specification Is Preceded by Extensive Epigenetic Priming in Multipotent Progenitors2021In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 206, no 11, p. 2700-2713Article in journal (Refereed)
    Abstract [en]

    B lymphocyte development is dependent on the interplay between the chromatin landscape and lineage-specific transcription factors. It has been suggested that B lineage commitment is associated with major changes in the nuclear chromatin environment, proposing a critical role for lineage-specific transcription factors in the formation of the epigenetic landscape. In this report, we have used chromosome conformation capture in combination with assay for transposase-accessible chromatin sequencing analysis to enable highly efficient annotation of both proximal and distal transcriptional control elements to genes activated in B lineage specification in mice. A large majority of these genes were annotated to at least one regulatory element with an accessible chromatin configuration in multipotent progenitors. Furthermore, the majority of binding sites for the key regulators of B lineage specification, EBF1 and PAX5, occurred in already accessible regions. EBF1 did, however, cause a dynamic change in assay for transposase-accessible chromatin accessibility and was critical for an increase in distal promoter-enhancer interactions. Our data unravel an extensive epigenetic priming at regulatory elements annotated to lineage-restricted genes and provide insight into the interplay between the epigenetic landscape and transcription factors in cell specification.

  • 33.
    Tedesco, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mullen, William
    University of Glasgow, Scotland .
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Univ Basque Country, Spain .
    High-Throughput Proteomics: A New Tool for Quality and Safety in Fishery Products2014In: Current protein and peptide science, ISSN 1389-2037, E-ISSN 1875-5550, Vol. 15, no 2, p. 118-133Article, review/survey (Refereed)
    Abstract [en]

    In order to cope with the increasing demand for fishery products, sensitive technological tools are required to ensure high quality and wholesomeness and to monitor their production process in a sustainable manner while complying with the strict standards imposed by regulatory authorities. Proteomics may assist the industry as it allows an unbiased approach in the discovery of biomarkers that could be used to increase our understanding of different biological, physiological and ecological aspects that may be advantageous in optimizing quality and safety in aquatic species. The aim of this review is to highlight the potential of cost-effective high-throughput technologies, such as those offered by proteomics using "on-line" mass spectrometry to improve the efficiency of the industry in identifying biomarkers relevant for safe high quality products.

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  • 34.
    Virkki, Minttu T.
    et al.
    Stockholm University, Solna, Sweden.
    Agrawal, Nitin
    Åbo Akademi, Turku, Finland.
    Edsbacker, Elin
    Stockholm University, Solna, Sweden.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. University of the Basque Country, Leioa, Spain.
    Elofsson, Arne
    Stockholm University, Solna, Sweden.
    Kauko, Anni
    Åbo Akademi, Turku, Finland.
    Folding of Aquaporin 1: multiple evidence that helix 3 can shift out of the membrane core2014In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 23, no 7, p. 981-992Article in journal (Refereed)
    Abstract [en]

    The folding of most integral membrane proteins follows a two-step process: initially, individual transmembrane helices are inserted into the membrane by the Sec translocon. Thereafter, these helices fold to shape the final conformation of the protein. However, for some proteins, including Aquaporin 1 (AQP1), the folding appears to follow a more complicated path. AQP1 has been reported to first insert as a four-helical intermediate, where helix 2 and 4 are not inserted into the membrane. In a second step, this intermediate is folded into a six-helical topology. During this process, the orientation of the third helix is inverted. Here, we propose a mechanism for how this reorientation could be initiated: first, helix 3 slides out from the membrane core resulting in that the preceding loop enters the membrane. The final conformation could then be formed as helix 2, 3, and 4 are inserted into the membrane and the reentrant regions come together. We find support for the first step in this process by showing that the loop preceding helix 3 can insert into the membrane. Further, hydrophobicity curves, experimentally measured insertion efficiencies and MD-simulations suggest that the barrier between these two hydrophobic regions is relatively low, supporting the idea that helix 3 can slide out of the membrane core, initiating the rearrangement process.

  • 35.
    Virkki, Minttu T.
    et al.
    Stockholm University, Sweden .
    Peters, Christoph
    Stockholm University, Sweden; Swedish e-Science Research Center (SeRC), Stockholm, Sweden.
    Nilsson, Daniel
    Stockholm University, Sweden .
    Sörensen, Therese
    Stockholm University, Sweden .
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. University of the Basque Country, Leioa, Spain.
    Wallner, Björn
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Elofsson, Arne
    Stockholm University, Sweden; Swedish E Science Research Centre SeRC, Stockholm, Sweden .
    The Positive Inside Rule Is Stronger When Followed by a Transmembrane Helix2014In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 426, no 16, p. 2982-2991Article in journal (Refereed)
    Abstract [en]

    The translocon recognizes transmembrane helices with sufficient level of hydrophobicity and inserts them into the membrane. However, sometimes less hydrophobic helices are also recognized. Positive inside rule, orientational preferences of and specific interactions with neighboring helices have been shown to aid in the recognition of these helices, at least in artificial systems. To better understand how the translocon inserts marginally hydrophobic helices, we studied three naturally occurring marginally hydrophobic helices, which were previously shown to require the subsequent helix for efficient translocon recognition. We find no evidence for specific interactions when we scan all residues in the subsequent helices. Instead, we identify arginines located at the N-terminal part of the subsequent helices that are crucial for the recognition of the marginally hydrophobic transmembrane helices, indicating that the positive inside rule is important. However, in two of the constructs, these arginines do not aid in the recognition without the rest of the subsequent helix; that is, the positive inside rule alone is not sufficient. Instead, the improved recognition of marginally hydrophobic helices can here be explained as follows: the positive inside rule provides an orientational preference of the subsequent helix, which in turn allows the marginally hydrophobic helix to be inserted; that is, the effect of the positive inside rule is stronger if positively charged residues are followed by a transmembrane helix. Such a mechanism obviously cannot aid C-terminal helices, and consequently, we find that the terminal helices in multi-spanning membrane proteins are more hydrophobic than internal helices.

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