| 1. |
- Bernhard, Sara, et al.
(author)
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The outer membrane protein OlpA contributes to Moraxella catarrhalis serum resistance via interaction with factor H and the alternative pathway.
- 2014
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In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 210:8, s. 1306-1310
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Journal article (peer-reviewed)abstract
- Factor H is an important complement regulator of the alternative pathway commonly recruited by pathogens for increased survival in the human host. The respiratory pathogen Moraxella catarrhalis that resides in the mucosa is highly serum resistant and causes otitis media in children and respiratory tract infections in individuals with underlying diseases. In this study, we show that M. catarrhalis binds factor H via the outer membrane protein OlpA. M. catarrhalis serum resistance was dramatically decreased in the absence of either OlpA or factor H, demonstrating that this inhibition of the alternative pathway significantly contributes to the virulence of M. catarrhalis.
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| 2. |
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| 3. |
- Bonagas, Nadilly, et al.
(author)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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In: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Journal article (peer-reviewed)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 4. |
- Carlsson, Julia, et al.
(author)
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Att planera för hela skogslandskapet : utmaningar och möjligheter
- 2016
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Reports (pop. science, debate, etc.)abstract
- Skogens många värden behöver samplaneras och sättas i sitt sammanhang utifrån ett landskapsperspektiv. Vi intervjuade skogsägare och skogliga intressenter om hur de ser på skogens värden, äganderätten och skogspolitiska förutsättningar, samt synen på att samarbeta och ta hänsyn till varandras intressen. Vi utgår från behov identifierade i planeringsprocesser som inkluderar många deltagare och intressen, när det gäller att förbättrakommunikation, information och mötesplatser. Vi ser tre möjliga verktyg för att skapa förutsättningar för ett landskapsperspektiv i planeringen av skogens värden: en landskapslots, en samverkansarena, samt utformningen och användandet av skogsbruksplanen.
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| 5. |
- Carlsson, Julia, et al.
(author)
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Opportunites for Integrated Landscape Planning : the Broker, the Arena, the Tool
- 2017
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In: Landscape Online. - 1865-1542. ; 55, s. 1-20
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Journal article (peer-reviewed)abstract
- As an integrated social and ecological system, the forest landscape includes multiple values. The need for a landscape approach in land use planning is being increasingly advocated in research, policy and practice. This paper explores how institutional conditions in the forest policy and management sector can be developed to meet demands for a multifunctional landscape perspective. Departing from obstacles recognised in collaborative planning literature, we build an analytical framework which is operationalised in a Swedish context at municipal level. Our case illustrating this is Vilhelmina Model Forest, where actual barriers and opportunities for a multiple-value landscape approach are identified through 32 semi-structured interviews displaying stakeholders’ views on forest values, ownership rights and willingness to consider multiple values, forest policy and management premises, and collaboration. As an opportunity to overcome the barriers, we suggest and discuss three key components by which an integrated landscape planning approach could be realized in forest management planning: the need for a landscape coordinator (broker), the need for a collaborative forum (arena), and the development of the existing forest management plan into an advanced multifunctional landscape plan (tool).
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| 6. |
- Conti, David, V, et al.
(author)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Journal article (peer-reviewed)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 7. |
- Deknuydt, Florence, et al.
(author)
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Diversion of the host humoral response: a novel virulence mechanism of Haemophilus influenzae mediated via outer membrane vesicles.
- 2014
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In: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 95:6, s. 983-991
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Journal article (peer-reviewed)abstract
- The respiratory tract pathogen Haemophilus influenzae frequently causes infections in humans. In parallel with all Gram-negative bacteria, H. influenzae has the capacity to release OMV. The production of these nanoparticles is an intriguing and partly unexplored phenomenon in pathogenesis. Here, we investigated how purified human peripheral blood B lymphocytes respond to OMV derived from unencapsulated, i.e., NTHi and the nonpathogenic Haemophilus parainfluenzae. We found that H. influenzae OMV directly interacted with the IgD BCR, as revealed by anti-IgD pAb and flow cytometry. Importantly, H. influenzae OMV-induced cellular activation via IgD BCR cross-linking and TLR9 resulted in a significant proliferative response. OMV isolated from the related species H. parainfluenzae did not, however, interact with B cells excluding that the effect by H. influenzae OMV was linked to common membrane components, such as the LOS. We also observed an up-regulation of the cell surface molecules CD69 and CD86, and an increased IgM and IgG secretion by B cells incubated with H. influenzae OMV. The Igs produced did not recognize H. influenzae, suggesting a polyclonal B cell activation. Interestingly, the density of the cell surface receptor TACI was increased in the presence of OMV that sensitized further the B cells to BAFF, resulting in an enhanced IgG class-switch. In conclusion, the ability of NTHi OMV to activate B cells in a T cell-independent manner may divert the adaptive humoral immune response that consequently promotes bacterial survival within the human host.
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| 8. |
- Fagerqvist, Therese, et al.
(author)
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Monoclonal antibodies selective for α-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α-synuclein transgenic mice with the disease-causing A30P mutation
- 2013
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In: Journal of Neurochemistry. - : Wiley-Blackwell. - 0022-3042 .- 1471-4159. ; 126:1, s. 131-144
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Journal article (peer-reviewed)abstract
- Inclusions of intraneuronal alpha-synuclein (-synuclein) can be detected in brains of patients with Parkinson's disease and dementia with Lewy bodies. The aggregation of -synuclein is a central feature of the disease pathogenesis. Among the different -synuclein species, large oligomers/protofibrils have particular neurotoxic properties and should therefore be suitable as both therapeutic and diagnostic targets. Two monoclonal antibodies, mAb38F and mAb38E2, with high affinity and strong selectivity for large -synuclein oligomers were generated. These antibodies, which do not bind amyloid-beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in -synuclein transgenic mice than linear epitope antibodies. An oligomer-selective sandwich ELISA, based on mAb38F, was set up to analyze brain extracts of the transgenic mice. The overall levels of -synuclein oligomers/protofibrils were found to increase with age in these mice, although the levels displayed a large interindividual variation. Upon subcellular fractionation, higher levels of -synuclein oligomers/protofibrils could be detected in the endoplasmic reticulum around the age when behavioral disturbances develop. In summary, our novel oligomer-selective -synuclein antibodies recognize relevant pathology and should be important tools to further explore the pathogenic mechanisms in Lewy body disorders. Moreover, they could be potential candidates both for immunotherapy and as reagents in an assay to assess a potential disease biomarker.
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| 9. |
- Hallström, Teresia, et al.
(author)
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Immune Evasion of Moraxella catarrhalis Involves Ubiquitous Surface Protein A-Dependent C3d Binding.
- 2011
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In: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 186, s. 3120-3129
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Journal article (peer-reviewed)abstract
- The complement system plays an important role in eliminating invading pathogens. Activation of complement results in C3b deposition (opsonization), phagocytosis, anaphylatoxin (C3a, C5a) release, and consequently cell lysis. Moraxella catarrhalis is a human respiratory pathogen commonly found in children with otitis media and in adults with chronic obstructive pulmonary disease. The species has evolved multiple complement evasion strategies, which among others involves the ubiquitous surface protein (Usp) family consisting of UspA1, A2, and A2 hybrid. In the present study, we found that the ability of M. catarrhalis to bind C3 correlated with UspA expression and that C3 binding contributed to serum resistance in a large number of clinical isolates. Recombinantly expressed UspA1 and A2 inhibit both the alternative and classical pathways, C3b deposition, and C3a generation when bound to the C3 molecule. We also revealed that the M. catarrhalis UspA-binding domain on C3b was located to C3d and that the major bacterial C3d-binding domains were within UspA1(299-452) and UspA2(165-318). The interaction with C3 was not species specific since UspA-expressing M. catarrhalis also bound mouse C3 that resulted in inhibition of the alternative pathway of mouse complement. Taken together, the binding of C3 to UspAs is an efficient strategy of Moraxella to block the activation of complement and to inhibit C3a-mediated inflammation.
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| 10. |
- Lindström, Veronica, et al.
(author)
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Immunotherapy targeting α-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] α-synuclein mice
- 2014
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In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 69, s. 134-143
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Journal article (peer-reviewed)abstract
- Several lines of evidence suggest that accumulation of aggregated alpha-synuclein (α-synuclein) in the central nervous system (CNS) is an early pathogenic event and therefore a suitable therapeutic target in Parkinson’s disease and other Lewy body disorders. In recent years, animal studies have indicated immunotherapy with antibodies directed against α-synuclein as a promising novel treatment strategy. Since large α-synuclein oligomers, or protofibrils, have been demonstrated to possess pronounced cytotoxic properties, such species should be particularly attractive as therapeutic targets. An α-synuclein protofibril-selective monoclonal antibody, mAb47, was evaluated in the (Thy-1)-h[A30P] α-synuclein transgenic mouse model, featuring an age- and motor dysfunction-associated increase of α-synuclein protofibrils in the CNS. As measured by ELISA, mAb47-treated mice displayed significantly lower levels of both soluble and membrane-associated protofibrils in the spinal cord. In addition, a trend for increased survival as a result of reduced motor symptoms was observed with antibody treatment. Taken together, this study demonstrates reduced levels of pathogenic α-synuclein and indicates a reduction of motor dysfunction in transgenic mice upon peripheral administration of an α-synuclein protofibril-selective antibody. Thus, immunotherapy with antibodies targeting toxic α-synuclein species holds promise as a future disease-modifying treatment in Parkinson’s disease and related disorders.
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