| 1. |
- Smith, Bradley P., et al.
(författare)
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Taxonomic status of the Australian dingo : the case for Canis dingo Meyer, 1793
- 2019
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Ingår i: Zootaxa. - : MAGNOLIA PRESS. - 1175-5326 .- 1175-5334. ; 4564:1, s. 173-197
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Tidskriftsartikel (refereegranskat)abstract
- The taxonomic status and systematic nomenclature of the Australian dingo remain contentious, resulting in decades of inconsistent applications in the scientific literature and in policy. Prompted by a recent publication calling for dingoes to be considered taxonomically as domestic dogs (Jackson et al. 2017, Zootaxa 4317, 201-224), we review the issues of the taxonomy applied to canids, and summarise the main differences between dingoes and other canids. We conclude that (1) the Australian dingo is a geographically isolated (allopatric) species from all other Canis, and is genetically, phenotypically, ecologically, and behaviourally distinct; and (2) the dingo appears largely devoid of many of the signs of domestication, including surviving largely as a wild animal in Australia for millennia. The case of defining dingo taxonomy provides a quintessential example of the disagreements between species concepts (e.g., biological, phylogenetic, ecological, morphological). Applying the biological species concept sensu stricto to the dingo as suggested by Jackson et al. (2017) and consistently across the Canidae would lead to an aggregation of all Canis populations, implying for example that dogs and wolves are the same species. Such an aggregation would have substantial implications for taxonomic clarity, biological research, and wildlife conservation. Any changes to the current nomen of the dingo (currently Canis dingo Meyer, 1793), must therefore offer a strong, evidence-based argument in favour of it being recognised as a subspecies of Canis lupus Linnaeus, 1758, or as Canis familiaris Linnaeus, 1758, and a successful application to the International Commission for Zoological Nomenclature - neither of which can be adequately supported. Although there are many species concepts, the sum of the evidence presented in this paper affirms the classification of the dingo as a distinct taxon, namely Canis dingo.
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| 2. |
- Brorsson, Ann-Christin, et al.
(författare)
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Intrinsic determinants of neurotoxic aggregate formation by the amyloid beta peptide
- 2010
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Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 98:8, s. 1677-84
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which proteins aggregate into distinct structures ranging from prefibrillar oligomers to amyloid fibrils is key to the pathogenesis of many age-related degenerative diseases. We describe here for the Alzheimer's disease-related amyloid beta peptide (Abeta) an investigation of the sequence-based determinants of the balance between the formation of prefibrillar aggregates and amyloid fibrils. We show that by introducing single-point mutations, it is possible to convert the normally harmless Abeta40 peptide into a pathogenic species by increasing its relative propensity to form prefibrillar but not fibrillar aggregates, and, conversely, to abolish the pathogenicity of the highly neurotoxic E22G Abeta42 peptide by reducing its relative propensity to form prefibrillar species rather than mature fibrillar ones. This observation can be rationalized by the demonstration that whereas regions of the sequence of high aggregation propensity dominate the overall tendency to aggregate, regions with low intrinsic aggregation propensities exert significant control over the balance of the prefibrillar and fibrillar species formed, and therefore play a major role in determining the neurotoxicity of the Abeta peptide.
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| 3. |
- Brorsson, Ann-Christin, et al.
(författare)
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Methods and models in neurodegenerative and systemic protein aggregation diseases
- 2010
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Ingår i: Frontiers in bioscience : a journal and virtual library. - : Frontiers in Bioscience Publications. - 1093-4715. ; 15, s. 373-396
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Forskningsöversikt (refereegranskat)abstract
- Protein misfolding and aggregation are implicated in a wide range of increasingly prevalent human diseases ranging from dementia to diabetes. In this review we discuss the current experimental strategies that are being employed in the investigation of the pathogenesis of three important protein misfolding disorders. The first, Alzheimers disease (AD), is the most prevalent neurodegenerative disease and is thought to be initiated by the aggregation of a natively unstructured peptide called amyloid beta (Abeta). We discuss methods for the characterization of the aggregation properties of Abeta in vitro and how the results of such experiments can be correlated with data from animal models of disease. We then consider another form of amyloidosis, where a systemic distribution of amyloid deposit is caused by aggregation and deposition of mutational variants of lysozyme. We describe how experiments in vitro, and more recently in vivo, have provided insights into the origins of this disease. Finally we outline the varied paradigms that have been employed in the study of the serpinopathies, and in particular, a dementia caused by neuroserpin polymerization.
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| 4. |
- Fabre, Kristin M., et al.
(författare)
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Utilizing microphysiological systems and induced pluripotent stem cells for disease modeling : a case study for blood brain barrier research in a pharmaceutical setting
- 2019
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Ingår i: Advanced Drug Delivery Reviews. - : Elsevier. - 0169-409X .- 1872-8294. ; 140, s. 129-135
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Tidskriftsartikel (refereegranskat)abstract
- Microphysiological systems (MPS) may be able to provide the pharmaceutical industry models that can reflect human physiological responses to improve drug discovery and translational outcomes. With lack of efficacy being the primary cause for drug attrition, developing MPS disease models would help researchers identify novel targets, study mechanisms in more physiologically-relevant depth, screen for novel biomarkers and test/optimize various therapeutics (small molecules, nanoparticles and biologics). Furthermore, with advances in inducible pluripotent stem cell technology (iPSC), pharmaceutical companies can access cells from patients to help recreate specific disease phenotypes in MPS platforms. Combining iPSC and MPS technologies will contribute to our understanding of the complexities of neurodegenerative diseases and of the blood brain barrier (BBB) leading to development of enhanced therapeutics. © 2018
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| 5. |
- Kumita, Janet R, et al.
(författare)
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Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster
- 2012
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Ingår i: The FASEB Journal. - : Federation of American Society of Experimental Biology (FASEB). - 0892-6638 .- 1530-6860. ; 26:1, s. 192-202
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Tidskriftsartikel (refereegranskat)abstract
- We have created a Drosophila model of lysozyme amyloidosis to investigate the in vivo behavior of disease-associated variants. To achieve this objective, wild-type (WT) protein and the amyloidogenic variants F57I and D67H were expressed in Drosophila melanogaster using the UAS-gal4 system and both the ubiquitous and retinal expression drivers Act5C-gal4 and gmr-gal4. The nontransgenic w(1118) Drosophila line was used as a control throughout. We utilized ELISA experiments to probe lysozyme protein levels, scanning electron microscopy for eye phenotype classification, and immunohistochemistry to detect the unfolded protein response (UPR) activation. We observed that expressing the destabilized F57I and D67H lysozymes triggers UPR activation, resulting in degradation of these variants, whereas the WT lysozyme is secreted into the fly hemolymph. Indeed, the level of WT was up to 17 times more abundant than the variant proteins. In addition, the F57I variant gave rise to a significant disruption of the eye development, and this correlated to pronounced UPR activation. These results support the concept that the onset of familial amyloid disease is linked to an inability of the UPR to degrade completely the amyloidogenic lysozymes prior to secretion, resulting in secretion of these destabilized variants, thereby leading to deposition and associated organ damage.-Kumita, J. R., Helmfors, L., Williams, J., Luheshi, L. M., Menzer, L., Dumoulin, M., Lomas, D. A., Crowther, D. C., Dobson, C. M., Brorsson, A.-C. Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster.
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| 6. |
- Luheshi, Leila M., et al.
(författare)
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Sequestration of the A beta Peptide Prevents Toxicity and Promotes Degradation In Vivo
- 2010
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 8:3, s. e1000334-
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Tidskriftsartikel (refereegranskat)abstract
- Protein aggregation, arising from the failure of the cell to regulate the synthesis or degradation of aggregation-prone proteins, underlies many neurodegenerative disorders. However, the balance between the synthesis, clearance, and assembly of misfolded proteins into neurotoxic aggregates remains poorly understood. Here we study the effects of modulating this balance for the amyloid-beta (A beta) peptide by using a small engineered binding protein (Z(A beta 3)) that binds with nanomolar affinity to A beta, completely sequestering the aggregation-prone regions of the peptide and preventing its aggregation. Co-expression of Z(A beta 3) in the brains of Drosophila melanogaster expressing either A beta(42) or the aggressive familial Alzheimer's disease (AD) associated E22G variant of A beta(42) abolishes their neurotoxic effects. Biochemical analysis indicates that monomer A beta binding results in degradation of the peptide in vivo. Complementary biophysical studies emphasize the dynamic nature of A beta aggregation and reveal that Z(A beta 3) not only inhibits the initial association of A beta monomers into oligomers or fibrils, but also dissociates pre-formed oligomeric aggregates and, although very slowly, amyloid fibrils. Toxic effects of peptide aggregation in vivo can therefore be eliminated by sequestration of hydrophobic regions in monomeric peptides, even when these are extremely aggregation prone. Our studies also underline how a combination of in vivo and in vitro experiments provide mechanistic insight with regard to the relationship between protein aggregation and clearance and show that engineered binding proteins may provide powerful tools with which to address the physiological and pathological consequences of protein aggregation.
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| 7. |
- Luheshi, Leila M, et al.
(författare)
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Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.
- 2007
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1545-7885. ; 5:11, s. e290-
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Tidskriftsartikel (refereegranskat)abstract
- Protein aggregation into amyloid fibrils and protofibrillar aggregates is associated with a number of the most common neurodegenerative diseases. We have established, using a computational approach, that knowledge of the primary sequences of proteins is sufficient to predict their in vitro aggregation propensities. Here we demonstrate, using rational mutagenesis of the Abeta42 peptide based on such computational predictions of aggregation propensity, the existence of a strong correlation between the propensity of Abeta42 to form protofibrils and its effect on neuronal dysfunction and degeneration in a Drosophila model of Alzheimer disease. Our findings provide a quantitative description of the molecular basis for the pathogenicity of Abeta and link directly and systematically the intrinsic properties of biomolecules, predicted in silico and confirmed in vitro, to pathogenic events taking place in a living organism.
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| 8. |
- Stephens, Lucas, et al.
(författare)
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Archaeological assessment reveals Earth’s early transformation through land use
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 365:6456, s. 897-902
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Tidskriftsartikel (refereegranskat)abstract
- Humans began to leave lasting impacts on Earth’s surface starting 10,000 to 8000 years ago. Through a synthetic collaboration with archaeologists around the globe, Stephens et al. compiled a comprehensive picture of the trajectory of human land use worldwide during the Holocene (see the Perspective by Roberts). Hunter-gatherers, farmers, and pastoralists transformed the face of Earth earlier and to a greater extent than has been widely appreciated, a transformation that was essentially global by 3000 years before the present.Science, this issue p. 897; see also p. 865Environmentally transformative human use of land accelerated with the emergence of agriculture, but the extent, trajectory, and implications of these early changes are not well understood. An empirical global assessment of land use from 10,000 years before the present (yr B.P.) to 1850 CE reveals a planet largely transformed by hunter-gatherers, farmers, and pastoralists by 3000 years ago, considerably earlier than the dates in the land-use reconstructions commonly used by Earth scientists. Synthesis of knowledge contributed by more than 250 archaeologists highlighted gaps in archaeological expertise and data quality, which peaked for 2000 yr B.P. and in traditionally studied and wealthier regions. Archaeological reconstruction of global land-use history illuminates the deep roots of Earth’s transformation and challenges the emerging Anthropocene paradigm that large-scale anthropogenic global environmental change is mostly a recent phenomenon.
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